Sep 2018

PNN July-September 2018

PNN Pharmacotherapy Line
July 2, 2018 * Vol. 25, No. 127
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
June 30 issue of Lancet (2018; 391).
MEDI0382 in Obese/Overweight & T2D: A balanced glucagon-like peptide-1 and glucagon receptor dual agonist designed to yield glycemic control and weight loss, MEDI0382 provided positive results in a multiple-ascending dose (MAD) and phase 2a trial in Germany (pp. 2807–18). Intention-to-treat (ITT) findings were as follows for 61 and 51 patients randomly assigned to the MAD and phase 2a trials, respectively: “In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0–4 h post [mixed-meal tolerance test] decreased significantly with MEDI0382 versus placebo (least squares [LS] mean −32.78% [90% CI −36.98 to −28.57] vs −10.16% [–14.10 to −6.21], and the mean difference was −22.62% [–28.40 to −16.85]; p <0.0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean −3.84 kg [90% CI −4.55 to −3.12] vs −1.70 kg [–2.40 to −1.01] and mean difference of 2.14 kg [–3.13 to −1.31]; p = 0.0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group).” (P. Ambery, amberyp@medImmune.com)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 361).
MRSA, C. diff & Penicillin Allergy: Patients with documented penicillin allergies has higher risks of methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile in a population-based matched cohort study (k2400). Attributing the results to greater need for alternative beta-lactam antibiotics, the investigators found these risks of MRSA or C. difficile among patients seen in U.K. general practices during the 1995–2015 period: “Among 64,141 adults with penicillin allergy and 237,258 matched comparators, 1,365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1,688 developed C difficile (442 participants with penicillin allergy and 1,246 comparators) during a mean 6.0 years of follow-up. Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26 (1.12 to 1.40). The adjusted incidence rate ratios for antibiotic use among patients with penicillin allergy were 4.15 (95% confidence interval 4.12 to 4.17) for macrolides, 3.89 (3.66 to 4.12) for clindamycin, and 2.10 (2.08 to 2.13) for fluoroquinolones. Increased use of beta-lactam alternative antibiotics accounted for 55% of the increased risk of MRSA and 35% of the increased risk of C difficile.” (K. G. Blumenthal, kblumenthal1@partners.org)
>>>PNN NewsWatch
* LL’s Magnetic Clay is recalling certain lots of the dietary supplement Prescript-Assist because of possible undeclared allergens, including almonds, crustaceans, dairy, casein, eggs, and peanuts.
*
PNN will not be published on Tues. and Wed., July 3–4, Independence Day.
>>>PNN JournalWatch
* Prophylaxis Against Upper Gastrointestinal Bleeding in Hospitalized Patients, in New England Journal of Medicine, 2018; 378: 2506–16. (D. Cook, debcook@mcmaster.ca)
*
Belimumab in Kidney Transplantation: An Experimental Medicine, Randomised, Placebo-Controlled Phase 2 Trial, in Lancet, 2018; 391: 2619–30. (M. R. Clatworthy, mrc38@cam.ac.uk)
*
Metformin Exposure in First Trimester of Pregnancy and Risk of All or Specific Congenital Anomalies: Exploratory Case-Control Study, in BMJ, 2018; 361: k2477. (J. E. Given, je.given@ulster.ac.uk)
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Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels, in American Journal of Psychiatry, 2018; 175: 598–604. (B. M. Cohen)
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Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia, in American Journal of Psychiatry, 2018; 175: 674–82. (K. Kauppi)

PNN Pharmacotherapy Line
July 5, 2018 * Vol. 25, No. 128
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
July 3 issue of JAMA (2018; 320).
Insulin & ED Visits: Improvements in emergency department (ED) visits for hypoglycemia were not observed in a retrospective study of those on long-acting insulin analogs versus human NPH insulin, researchers report (pp. 53–62). Kaiser Permanente data from northern California show these hypoglycemia-related ED visits and hospital admissions in 2006 to 2015 among patients with type 2 diabetes: “There were 25,489 patients with type 2 diabetes who initiated basal insulin therapy (mean age, 60.2 [SD, 11.8] years; 51.9% white; 46.8% female). During a mean follow-up of 1.7 years, there were 39 hypoglycemia-related ED visits or hospital admissions among 1,928 patients who initiated insulin analogs (11.9 events [95% CI, 8.1 to 15.6] per 1000 person–years) compared with 354 hypoglycemia-related ED visits or hospital admissions among 23,561 patients who initiated NPH insulin (8.8 events [95% CI, 7.9 to 9.8] per 1,000 person–years) (between-group difference, 3.1 events [95% CI, −1.5 to 7.7] per 1,000 person–years; P = .07). Among 4,428 patients matched by propensity score, the adjusted hazard ratio was 1.16 (95% CI, 0.71 to 1.78) for hypoglycemia-related ED visits or hospital admissions associated with insulin analog use. Within 1 year of insulin initiation, hemoglobin A1c level decreased from 9.4% (95% CI, 9.3% to 9.5%) to 8.2% (95% CI, 8.1% to 8.2%) after initiation of insulin analogs and from 9.4% (95% CI, 9.3% to 9.5%) to 7.9% (95% CI, 7.9% to 8.0%) after initiation of NPH insulin (adjusted difference-in-differences for glycemic control, −0.22% [95% CI, −0.09% to −0.37%]).” (K. J. Lipska, kasia.lipska@yale.edu)
The “path forward” might best be a “step back” to NPH insulin, editorialists write (
pp. 38–9). Noting that the price of basal insulin analogs is more than 10 times that of NPH products, the group concludes: “In this era of high costs of diabetes care, questions of value in insulin prescribing are unlikely to be resolved anytime soon. Newer, even higher-priced basal insulin analogs are now being promoted despite their minor absolute benefits vs current widely used analog options, so questions about value will remain pressing into the foreseeable future.” (M. L. Maciejewski, matthew.maciejewski@va.gov)
>>>Internal Medicine Report
Source:
Early-release article and July 3 issue of Annals of Internal Medicine (2018; 169).
Marijuana Use & Lung Function: Cough, sputum production, and wheezing are all adverse effects associated with smoking of marijuana, a systematic review and meta-analysis shows (10.7326/M18-0522). Links between this practice and obstructive lung disease or decreased pulmonary function are less certain, the authors conclude based on these data from 22 studies: “A pooled analysis of 2 prospective studies showed that marijuana use was associated with an increased risk for cough (risk ratio [RR], 2.04 [95% CI, 1.02 to 4.06]) and sputum production (RR, 3.84 [CI, 1.62 to 9.07]). Pooled analysis of cross-sectional studies (1 low and 3 moderate risk of bias) showed that marijuana use was associated with cough (RR, 4.37 [CI, 1.71 to 11.19]), sputum production (RR, 3.40 [CI, 1.99 to 5.79]), wheezing (RR, 2.83 [CI, 1.89 to 4.23]), and dyspnea (RR, 1.56 [CI, 1.33 to 1.83]). Data on pulmonary function and obstructive lung disease were insufficient.” (M. Ghasemiesfe, mehrnaz.ghasemiesfe@va.gov)
>>>NEJM Report
Source:
July 5 issue of the New England Journal of Medicine (2018; 379).
Treating Opioid-Use Disorder: Perspective authors discuss appropriate use of buprenorphine in management of opioid-use disorder (pp. 1–4, 4–6) and ways methadone therapy could be improved and access expanded (pp. 7–8).
>>>PNN NewsWatch
* “As of the end of May 2018, a total of 199 cases of salmonellosis in 41 states have been linked to kratom consumption; 38 percent of those illnesses led to hospitalizations,” FDA officials report in a statement. “Kratom is not legally marketed in the United States as a drug or dietary supplement. Kratom is an opioid, is addictive, and has been linked to severe health consequences and deaths among users. Despite these risks, we know that kratom has grown in popularity in recent years due to unsubstantiated claims about its purported benefits.”

PNN Pharmacotherapy Line
July 6, 2018 * Vol. 25, No. 129
Providing news and information about medications and their proper use

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>>>Psychiatry Report
Source:
July issue of the American Journal of Psychiatry (2018; 175).
Intranasal Esketamine in Depression and Suicidality: Compared with standard-of-care treatment, intranasal esketamine produced “significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide,” researchers report (pp. 620–30). In a proof-of-concept study, 68 participants had these responses to esketamine 84 mg or placebo twice weekly for 4 weeks: “A significantly greater improvement in [Montgomery-Åsberg Depression Rating Scale (MADRS)] score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference = −5.3, SE=2.10; effect size = 0.61) and at ~24 hours (least-square mean difference = −7.2, SE = 2.85; effect size = 0.65), but not at day 25 (least-square mean difference = −4.5, SE = 3.14; effect size = 0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size = 0.67), but not at 24 hours (effect size = 0.35) or at day 25 (effect size = 0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.” (C. M. Canuso)
Editorialists explore the potential of abuse of ketamine, asking whether a framework can be established for safe use of the drug in these at-risk patients (
pp. 587–9): “Ketamine drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision.… The protection of the public’s health is part of our responsibility as well, and as physicians, we are responsible for preventing new drug epidemics.” (R. Freedman)
Medication-Assisted Treatment for Alcohol Dependence: In adults with serious mental illness, medication-assisted treatment (MAT) for moderate-to-severe comorbid alcohol dependence is underused yet could provide “reduce both crisis service utilization and criminal recidivism” according to a study of 5,743 participants (pp. 665–73). Diagnoses included schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder, and participants had been incarcerated for at least 1 night during 2002–09. Compared with other outpatient substance abuse treatments, evidence-based MAT had these effects on inpatient mental health and substance abuse hospitalizations, emergency department visits, criminal convictions, and incarcerations: “MAT was associated with significant improvements in clinical outcomes in the 12 months following initiation compared with non-MAT comparison treatment, including greater reductions in mental health hospitalization and emergency department visits and greater improvements in psychotropic medication adherence. No benefits of MAT were found for most criminal justice outcomes, except for significant reductions in felony convictions among adults with bipolar disorder.” (A. G. Robertson)
>>>Pediatrics Highlights
Source:
July issue of Pediatrics (2018; 142).
DTaP Safety: Commenting on a Vaccine Adverse Event Reporting System (VAERS) analysis showing vaccination errors with diphtheria-tetanus-acellular pertussis (DTaP) vaccines in the U.S. (10.1542/peds.2017-4171; P. L. Moro, pmoro@cdc.gov), an editorialist writes (10.1542/peds.2018-1036): “There is an imperative need to develop more immunogenic pertussis vaccines that are also safe. Fortunately, active research is ongoing for the development of novel vaccines, including live attenuated vaccines, whole-cell vaccines with reduced endotoxin content to be less reactogenic, outer membrane vesicles–based vaccines, and acellular vaccine formulations prepared with new adjuvants or additional and novel antigens.… Much work is needed to learn more about this fascinating pathogen and its interactions with humans, to improve our understanding of how immunity and long lasting protection can be achieved, to engineer and produce novel vaccines, and to design and perform the clinical studies that will eventually lead to the control of pertussis disease and its global impact. …” (F. M. Munoz, florm@bcm.edu)

PNN Pharmacotherapy Line
July 9, 2018 * Vol. 25, No. 130
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
July 7 issue of Lancet (2018; 392).
Sodium Bicarbonate for Severe Metabolic Acidemia: In critically ill patients with severe metabolic acidemia, sodium bicarbonate therapy decreased risks of all-cause death and organ failure only in a subgroup of patients with acute kidney injury, researchers report (pp. 31–40). A phase 3 trial conducted in 26 intensive-care units in France included 389 patients admitted within the prior 48 hours with severe acidemia. Randomization was stratified by age, sepsis status, and Acute Kidney Injury Network (AKIN) score. Based on a primary outcome of composite of death from any cause by day 28 and the presence of at least one organ failure at day 7, results were as follows: “The primary outcome occurred in 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate −5.5%, 95% CI −15.2 to 4.2; p = 0.24). The Kaplan–Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group was not significant (46% [95% CI 40–54] vs 55% [49–63]; p = 0.09. In the prespecified AKIN stratum of patients with a score of 2 or 3, the Kaplan–Meier method estimate of survival by day 28 between the control group and bicarbonate group was significant (63% [95% CI 52–72] vs 46% [35–55]; p = 0.0283). Metabolic alkalosis, hypernatraemia, and hypocalcaemia were observed more frequently in the bicarbonate group than in the control group, with no life-threatening complications reported.” (S. Jaber, s-jaber@chu-montpellier.fr)
Management of Multimorbidity Using Patient-Centered Care: A “3D approach” to patient-centered care — based on the dimensions of health, depression, and drugs — did not improve patients’ quality of life, according to a cluster-randomized study of general practices in England and Scotland (pp. 41–50). Adults with three or more chronic conditions received either patient-centered or usual care, with these results based on a primary outcome of quality of life as assessed using the EQ-5D-5L instrument (a generic instrument with five questions about mobility, self-care, usual activities, pain and discomfort, and anxiety and depression): “Between May 20, 2015, and Dec. 31, 2015, we recruited 1,546 patients from 33 practices and randomly assigned them to receive the intervention (n = 797) or usual care (n = 749). In our intention-to-treat analysis, there was no difference between trial groups in the primary outcome of quality of life (adjusted difference in mean EQ-5D-5L 0.00, 95% CI −0.02 to 0.02; p = 0.93). 78 patients died, and the deaths were not considered as related to the intervention.” (C. Salisbury, c.salisbury@bristol.ac.uk)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 362).
Type 1 Diabetes Glycemic Control & Major Birth Defects: Risks of major cardiac defects among infants born to mothers with type 1 diabetes increased in parallel with worsening glycemic control in the 3 months before and 3 months after conception, according to a population-based historical cohort study conducted in Sweden (k2638). National registers from the years 2003 to 2015 led investigators to this conclusion: “Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.” (J. F. Ludvigsson, jonasludvigsson@yahoo.com)
>>>PNN JournalWatch
* Paracetamol/Acetaminophen During Pregnancy Induces Prenatal Ductus Arteriosus Closure, in Pediatrics, 2018; 142: 10.1542/peds.2017-4021. (O. Becquet)
*
Are We Ready to Bell The Cat? A Call for Cardiologists to Embrace Glucose-Lowering Therapies Proven to Improve Cardiovascular Outcomes, in Circulation, 2018; 138: 4–6. (M. Kosiborod, mkosiborod@saint-lukes.org)
*
Fatal or Irreversible Bleeding and Ischemic Events With Rivaroxaban in Acute Coronary Syndrome, in Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.04.055. (C. M. Gibson)
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Sleep in Women Across the Life Span, in Chest, 2018; 154: 196–206. (G. Bourjeily, ghada_bourjeily@brown.edu)

PNN Pharmacotherapy Line
July 10, 2018 * Vol. 25, No. 131
Providing news and information about medications and their proper use

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>>> Internal Medicine Report
Source:
Early-online articles from and July issue of JAMA Internal Medicine (2018; 178).
EHR-Based Medication Support & Nurse-Led MTM: Worsened blood pressures among patients receiving interventions in a cluster-randomized trial lead investigators to observe, “This study highlights the importance of testing system-level changes for unintended effects and suggests that improving some aspects of medication self-management alone is not sufficient to improve hypertension control.” (10.1001/jamainternmed.2018.2372). At Chicago-area community health centers, participants received either electronic health record (EHR)–based medication management tools (medication review sheets at visit check-in, lay medication information sheets printed after visits; EHR-alone group), EHR-based tools plus nurse-led medication therapy management support (EHR plus education group), or usual care, leading to this conclusion: “The study found that EHR tools in isolation improved medication reconciliation but worsened blood pressure. Combining these tools with nurse-led support suggested improved understanding of medication instructions and dosing but did not lower blood pressure compared with usual care.” (S. D. Persell, spersell@nm.org)
Aldosterone Antagonist Therapy in STEMI Without HF: Already demonstrated to provide an advantage in patients with ST-segment elevation myocardial infarction (STEMI) and left ventricular ejection fraction (LVEF) less than 40%, aldosterone antagonists decreased mortality in a study of patients with STEMI whose LVEF is greater than 40% and those who do not have heart failure, researchers report in a systematic review and meta-analysis (pp. 913–20): “In all, 10 randomized clinical trials with a total of 4,147 unique patients were included in the meta-analysis. In patients who presented with STEMI without heart failure, treatment with aldosterone antagonists compared with control was associated with lower risk of mortality (2.4% vs 3.9%; odds ratio [OR], 0.62; 95% CI, 0.42–0.91; P = .01) and similar risks of myocardial infarction (1.6% vs 1.5%; OR, 1.03; 95% CI, 0.57–1.86; P = .91), new congestive heart failure (4.3% vs 5.4%; OR, 0.82; 95% CI, 0.56–1.20; P = .31), and ventricular arrhythmia (4.1% vs 5.1%; OR, 0.76; 95% CI, 0.45–1.31; P = .33). Similarly, treatment with aldosterone antagonists compared with control was associated with a small yet significant increase in LVEF (mean difference, 1.58%; 95% CI, 0.18%–2.97%; P = .03), a small increase in serum potassium level (mean difference, 0.07 mEq/L; 95% CI, 0.01–0.13 mEq/L; P = .02), and no change in serum creatinine level (standardized mean difference, 1.4; 95% CI, −0.43 to 3.24; P = .13).” (K. Modi, kmodi@lsuhsc.edu)
“Although [these investigators] are to be commended for focusing our attention on the possibility that treatment with [mineralocorticoid receptor antagonists (MRAs)] could further reduce mortality among patients with STEMI but without heart failure or severe left ventricular dysfunction, we should await the results of further adequately powered prospective, randomized studies of treatment with MRAs among patients with STEMI, such as Colchicine and Spironolactone in Patients With STEMI/SYNERGY Stent Registry (CLEAR-SYNERGY) (NCT03048825),” editorialists write (
pp. 920–1). “It will also be important to develop additional experience with the newer nonsteroidal MRAs and potassium-lowering agents before routine adoption of this strategy in clinical practice. If we are to change clinical practice among patients with STEMI but without heart failure or severe left ventricular dysfunction, we will need a strategy that is not only safe and effective but also able to be widely adopted, well tolerated, and cost-effective.” (B. Pitt, bpitt@med.umich.edu)
>>>PNN NewsWatch
* “The FDA remains focused on striking the right balance between reducing the rate of new addiction by decreasing exposure to opioids and rationalizing prescribing, while still enabling appropriate access to those patients who have legitimate medical need for these medicines,” Commissioner Gottlieb said yesterday in conjunction with a public meeting on patient-focused drug development for chronic pain. During the meeting, adult and pediatric patients presented their perspectives on living with chronic pain.

PNN Pharmacotherapy Line
July 11, 2018 * Vol. 25, No. 132
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
July 10 issue of JAMA (2018; 320).
Alteplase v. Aspirin in Acute Ischemic Stroke With Minor Deficits: Lack of significant benefit with alteplase compared with aspirin resulted in early termination of a phase 3b trial of patients with acute ischemic stroke with minor nondisabling neurologic deficits (pp. 156–66). The Potential of rtPA for Ischemic Strokes With Mild Symptoms (PRISMS) study compared effects of aspirin versus alteplase using a primary outcome of difference in favorable functional outcome (modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test) and was to have enrolled 948 patients. Results showed: “Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1–3]; median time to treatment, 2.7 hours [IQR, 2.1–2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had [symptomatic intracranial hemorrhage] (risk difference, 3.3%; 95% CI, 0.8%–7.4%).” Because of the early study termination, definitive conclusions cannot be reached, the authors note, and additional research may be warranted. (P. Khatri, pooja.khatri@uc.edu)
“The findings from the report by Khatri et al provide more certain, but not definitive, evidence suggesting that intravenous alteplase appears unlikely to meaningfully improve functional outcome in patients with mild ischemic stroke with initial [National Institutes of Health Stroke Scale (NIHSS)] scores of 5 or lower and with nondisabling deficits, and that for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action, an editorialist writes (
pp. 141–3). “Current [American Heart Association/American Stroke Association] guidelines recommend mechanical thrombectomy performed within 6 hours of symptom onset with a stent retriever for patients with causative occlusion of the internal carotid artery or proximal middle cerebral artery and NIHSS scores of 6 or higher who meet additional criteria, but the guidelines note that the benefit for patients with NIHSS scores lower than 6 is uncertain.” (W. J. Powers, powersw@neurology.unc.edu)
Acupuncture for Aromatase Inhibitor Joint Pain: Postmenopausal women who developed arthralgias while being treated with aromatase inhibitors for early-stage breast cancer had statistically significant improvements in joint pain with true acupuncture, compared with sham acupuncture or with waitlist control, researchers report (pp. 167–76). While significant, the improvements may not be of clinical relevance, the authors concluded based on these 6-week results on the Brief Pain Inventory Worst Pain (BPI-WP) item: “Among 226 randomized patients (mean [SD] age, 60.7 [8.6] years; 88% white; mean [SD] baseline BPI-WP score, 6.6 [1.5]), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20–1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24–1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01).” (D. L. Hershman, dlh23@columbia.edu)
Ending Addiction: The research plan developed at the NIH National Rx Drug Abuse and Heroin Summit in April 2018 is summarized in a Viewpoint article (pp. 129–30; F. S. Collins, collinsf@mail.nih.gov).
>>>PNN NewsWatch
* FDA yesterday said it is requiring safety labeling changes for fluoroquinolones to strengthen the warnings about the risks of mental health adverse effects and serious blood sugar disturbances, and make these warnings more consistent across the labeling for all fluoroquinolones taken by mouth or given by injection. The new label changes will add that hypoglycemia can lead to coma and make the mental health side effects more prominent and more consistent across the systemic fluoroquinolone drug class.

PNN Pharmacotherapy Line
July 12, 2018 * Vol. 25, No. 133
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
July 12 issue of the New England Journal of Medicine (2018; 379).
Gene Expression Assay–Guided Breast Cancer Therapy: In a prospective trial of 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer with midrange results on a 21-gene breast cancer assay, adjuvant endocrine therapy alone produced similar outcomes compared with chemoendocrine therapy (pp. 111–21; editorial, pp. 191–2). A high score on the gene-expression assay (risk of recurrence is high) predicts chemotherapy benefit and a low risk of recurrence in absence of chemotherapy when the score is low. In this study, participants had midrange scores. They were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone, with these results: “Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P = 0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P = 0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.” (J. A. Sparano, jsparano@montefiore.org)
Endocrine Therapy in Premenopausal Breast Cancer: Disease-free and overall survival rates at 8 years were significantly higher among premenopausal women with breast cancer when ovarian-suppression therapy was added to tamoxifen treatment, and rates were even higher with exemestane plus ovarian suppression, researchers report (pp. 122–37; editorial, pp. 193–4). The following results extend to 8 years the 5-year findings of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT): “In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P = 0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P = 0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen–ovarian suppression group, and 32.3% of the exemestane–ovarian suppression group.” (P. A. Francis, prue.francis@petermac.org)
>>>PNN NewsWatch
* “Gene therapy represents one of the most promising opportunities for developing highly effective and even curative treatments for many vexing disorders,” FDA Commissioner Scott Gottlieb, MD, said in a statement released yesterday announcing the release of guidances on human gene therapy for hemophilia, retinal disorders, and rare disorders, and on manufacturing gene therapies. “In the past 12 months, we’ve seen three separate gene therapy products approved by the FDA. This reflects the rapid advancements in this field. An inflection point was reached with the development of vectors that could reliably deliver gene cassettes in vivo, into cells and human tissue. In the future, we expect this field to continue to expand, with the potential approval of new treatments for many debilitating diseases. These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field.”

PNN Pharmacotherapy Line
July 13, 2018 * Vol. 25, No. 134
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Cardiology Report
Source:
July 17 issue of the Journal of the American College of Cardiology (2018; 72).
Future Lipid Management With PCSK9 Inhibitors: Clinical studies increasingly support use of PCSK9 inhibitors for lipid management in high-risk patients, conclude authors of a state-of-the-art review (10.1016/j.jacc.2018.04.054): “Clinical trials with PCSK9 inhibitors have demonstrated reductions in atherosclerotic cardiovascular disease events, particularly in patients with recent acute coronary syndrome, multivessel coronary artery disease, or peripheral arterial disease. Commonly observed profound reductions in LDL-C to levels <25 mg/dl have been accompanied by even lower rates of atherosclerotic cardiovascular disease events, thus supporting the concept that there may be no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been accompanied by a safety profile that has been very favorable. On the basis of clinical trial evidence, LDL lowering with PCSK9 inhibitors is recommended for high-risk patients with LDL-C levels ≥70 mg/dl on maximally tolerated oral therapies including statins and/or ezetimibe.” (R. S. Rosenson)
Adjunctive Dyslipidemia in Hypertriglyceridemia: Reviewing adjunctive lipid therapies that go beyond high-intensity statins, authors of a review article write, “Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non–high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies” (10.1016/j.jacc.2018.04.061). “Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were ‘optimally controlled’ with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.” (O. P. Ganda)
>>>Circulation Highlights
Source:
July 10 issue of Circulation (2018; 138).
Residual Inflammatory Risk With PCSK9 Inhibitors/Statins: In a post-hoc analysis of the SPIRE trials, inflammatory risk persisted among 9,738 patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition (10.1161/CIRCULATIONAHA.118.034645). On-treatment levels of high sensitivity C-reactive protein (hsCRPOT) and on-treatment levels of LDL cholesterol (LDL-COT) were as follows: “At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was −60.5% (95% confidence interval [CI], −61.2 to −59.8; P <0.001; median change, −65.4%) as compared to 6.6% (95% CI, −1.0 to 14.1; P = 0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person–years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81–1.66), and 1.62 (95% CI, 1.14–2.30) (P-trend = 0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30–50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend = 0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction = 0.87).” (A. D. Pradhan, apradhan@bwh.harvard.edu)
>>>PNN NewsWatch
* FDA yesterday announced formation of a new Drug Shortages Task Force. “The shortages task force [will] delve more deeply into the reasons why some shortages remain a persistent challenge,” FDA Commissioner Gottlieb said in a statement. “The charge to this new task force is to look for holistic solutions to addressing the underlying causes for these shortages.”

PNN Pharmacotherapy Line
July 16, 2018 * Vol. 25, No. 135
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 362).
Guideline Impact on Hypertension Treatment: In the U.S. and China, adoption of the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guidelines will result in large proportions of middle-aged and older people being “labeled as having hypertension and treated with drugs,” an analysis shows (k2357). Applying the guidelines to national data from the two countries produces these figures: “Adoption of the … guidelines in the US would label 70.1 (95% confidence interval 64.9 to 75.3) million people in the 45–75 year age group as having hypertension, representing 63% (60.6% to 65.4%) of the population in this age group. Their adoption in China would lead to labeling of 266.9 (252.9 to 280.8) million people or 55% (53.4% to 56.7%) of the same age group as having hypertension. This would represent an increase in prevalence of 26.8% (23.2% to 30.9%) in the US and 45.1% (41.3% to 48.9%) in China. Furthermore, on the basis of treatment patterns and current guidelines, 8.1 (6.5 to 9.7) million Americans with hypertension are untreated, which would be expected to increase to 15.6 (13.6 to 17.7) million after the implementation of the ACC/AHA guidelines. In China, on the basis of current treatment patterns, 74.5 (64.1 to 84.8) million patients with hypertension are untreated, estimated to increase to 129.8 (118.7 to 140.9 million.… Among people receiving treatment, the proportion that are candidates for intensification of treatment is estimated to increase by 13.9 (12.2 to 15.6) million (from 24.0% to 54.4% of treated patients) in the US, and 30 (24.3 to 35.7) million (41.4% to 76.2% of treated patients) in China, if the ACC/AHA treatment targets are adopted.” (H. M. Krumholz, harlan.krumholz@yale.edu)
>>>Lancet Highlights
Source:
July 14 issue of Lancet (2018; 392).
Pembrolizumab in Advanced Gastric Cancer: In 395 patients with advanced gastric or gastroesophageal junction cancer that had progressed on chemotherapy, pembrolizumab failed to improve overall survival in a phase 3 comparison with paclitaxel, researchers report (pp. 123–33). Based on a primary endpoint of overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher, results showed: “As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9.1 months (95% CI 6.2–10.7) with pembrolizumab and 8.3 months (7.6–9.0) with paclitaxel (hazard ratio [HR] 0.82, 95% CI 0.66–1.03; one-sided p = 0.0421). Median progression-free survival was 1.5 months (95% CI 1.4–2.0) with pembrolizumab and 4.1 months (3.1–4.2) with paclitaxel (HR 1.27, 95% CI 1.03–1.57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.” (K. Shitara, kshitara@east.ncc.go.jp)
>>>PNN NewsWatch
* Certain valsartan products are being recalled voluntarily because of presence of an impurity, N-nitrosodimethylamine (NDMA), FDA said on Friday. The presence of NDMA was unexpected and is thought to be related to changes in the way the active substance was manufactured. Affected products are marketed by Major Pharmaceuticals, Solco Healthcare, and Teva Pharmaceuticals. NDMA is classified as a probable human carcinogen based on results from laboratory tests.
*
Tecovirimat (Tpoxx, SIGA Technologies) on Friday became the first drug approved for treatment of smallpox, FDA said.
>>>PNN JournalWatch
* A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis, in Clinical Infectious Diseases, 2018; 67: 303–9. (K. L. LaPlante, kerrylaplante@uri.edu)
*
Next-Generation Drugs Targeting the Cereblon Ubiquitin Ligase, in Journal of Clinical Oncology, 2018; 36: 2101–4. (P. L. McCarthy, philip.mccarthy@roswellpark.org)
*
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update, in Journal of Clinical Oncology, 2018; 36: 2105–22. (A. C. Wolff, guidelines@asco.org)

PNN Pharmacotherapy Line
July 17, 2018 * Vol. 25, No. 136
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Early-release article from and July 17 issue of Annals of Internal Medicine (2018; 169).
Safety Data Lacking in Microbiota-Modification Studies: Reports of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics often lack sufficient safety data, according to a systematic review (10.7326/M18-0343). Without such data, reaching conclusions about the safety of these interventions is impossible, the authors note, adding these details about their review: “Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators.” (A. Bafeta, aida.bafeta@aphp.fr)
Cancer Prevention With Antiretroviral Therapy: Patients who achieve long-term viral suppression through antiretroviral therapy have lower risk of developing cancer, particularly of AIDS-defining cancer (ADC), a study shows (pp. 87–96). Prospective cohort analysis of 42,441 HIV-positive veterans and matched controls showed these outcomes in 1999 to 2015: “Cancer incidence for HIV-positive versus uninfected persons was highest for unsuppressed persons (RR, 2.35 [95% CI, 2.19 to 2.51]), lower among persons with early suppression (RR, 1.99 [CI, 1.87 to 2.12]), and lowest among persons with long-term suppression (RR, 1.52 [CI, 1.44 to 1.61]). This trend was strongest for ADC (unsuppressed: RR, 22.73 [CI, 19.01 to 27.19]; early suppression: RR, 9.48 [CI, 7.78 to 11.55]; long-term suppression: RR, 2.22 [CI, 1.69 to 2.93]), much weaker for [non–AIDS-defining cancer (NADC)] caused by viruses (unsuppressed: RR, 3.82 [CI, 3.24 to 4.49]; early suppression: RR, 3.42 [CI, 2.95 to 3.97]; long-term suppression: RR, 3.17 [CI, 2.78 to 3.62]), and absent for NADC not caused by viruses.” (L. S. Park, lesley.park@stanford.edu)
Physician Certification Status & Performance on HEDIS Process Measure: Maintenance of physicians’ certification status is associated with higher performance on Healthcare Effectiveness Data and Information Set (HEDIS) process measures, researchers report (pp. 97–105). Assessment of quality of care provided to Medicare beneficiaries by 1,260 general internists who were initially certified in 1991 was as follows based on certification maintenance: “Among the 1,260 physicians, 786 maintained their certification from 1991 to 2012 and 474 did not. The mean annual percentage of HEDIS-eligible diabetic patients who completed semiannual hemoglobin A1c testing was 58.4% among physicians who maintained certification and 54.4% among those who did not (regression-adjusted difference, 4.2 percentage points [95% CI, 2.0 to 6.5 percentage points]; P < 0.001). Diabetic patients of physicians who maintained certification more frequently met the annual standard for low-density lipoprotein (LDL) cholesterol measurement (83.1% vs. 80.5%; regression-adjusted difference, 2.3 percentage points [CI, 0.6 to 4.1 percentage points]; P = 0.008) and all 3 diabetic standards (46.0% vs. 41.6%; regression-adjusted difference, 3.1 percentage points [CI, 0.5 to 5.7 percentage points]; P = 0.019). The regression-adjusted difference in biennial eye examinations was statistically insignificant (P = 0.112). Measures for LDL cholesterol testing in patients with coronary heart disease and biennial mammography were also met more frequently among physicians who maintained certification (79.4% vs. 77.4% and 72.0% vs. 67.8%, respectively), with regression-adjusted differences of 1.7 percentage points (CI, 0.2 to 3.3 percentage points; P = 0.032) and 4.6 percentage points (CI, 2.9 to 6.3 percentage points; P < 0.001), respectively.” (B. Gray, bgray@abim.org)

PNN Pharmacotherapy Line
July 18, 2018 * Vol. 25, No. 137
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
July 17 issue of JAMA (2018; 320).
Nontraditional Risk Factors in CVD Assessment: Evidence is insufficient for adding several nontraditional risk factors to assessments of cardiovascular disease, concludes the U.S. Preventive Services Task Force (USPSTF) in an update to its 2009 recommendation statement (pp. 272–80). In combination with the Framingham Risk Score or Pooled Cohort Equations, the nontraditional risk factors — ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) level, and coronary artery calcium (CAC) score — have produced these outcomes in studies: “The USPSTF found adequate evidence that adding the ABI, hsCRP level, and CAC score to existing CVD risk assessment models results in small improvements in discrimination and risk reclassification; however, the clinical meaning of these changes is largely unknown. Evidence on adding the ABI, hsCRP level, and CAC score to the Pooled Cohort Equations is limited. The USPSTF found inadequate evidence to assess whether treatment decisions guided by the ABI, hsCRP level, or CAC score, in addition to risk factors in existing CVD risk assessment models, leads to reduced incidence of CVD events or mortality. The USPSTF found adequate evidence to conceptually bound the harms of early detection and interventions as small. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the ABI, hsCRP level, or CAC score in risk assessment for CVD in asymptomatic adults to prevent CVD events.” (S. J. Curry, chair@uspstf.net)
Commenting on this update and a related evidence assessment (
pp. 281–97; J. S. Lin, jennifer.s.lin@kpchr.org), editorialists write (pp. 242–4): “The current literature demonstrates that CAC measurement, when used in intermediate-risk patients, helps refine risk assessment in important ways that can help identify patients far more correctly for use (or avoidance) of efficacious risk-reducing statin medications. These USPSTF recommendations should spur ascertainment of the data needed to turn I statements into more definitive recommendations, specifically regarding the use of CAC measurement. If CAC measurement succeeds in an end points–driven clinical trial, it will be unnecessary to fund research developing weaker biomarkers. If CAC measurement were to fail as a useful biomarker for CVD risk in an adequately powered trial, it certainly would not be necessary to develop weaker biomarkers, but rather, the current approach to primary prevention of CVD would need to be fundamentally reconsidered. Clearly, identification of the right patients for the right therapy requires identification of the right patients for the right risk-assessment tests.” (D. M. Lloyd-Jones, dlj@northwestern.edu)
QI Intervention & Stroke Performance Measures: In a large, cluster-randomized trial of 40 public hospitals in China, a multifaceted quality improvement intervention (clinical pathway, care protocols, quality coordinator oversight, and performance measure monitoring and feedback) produced significant but small improvements in hospital personnel adherence to evidence-based performance measures in patients with acute ischemic stroke, according to results of the GOLDEN BRIDGE—AIS trial (pp. 245–54; Y. Wang, yongjunwang1962@gmail.com).
>>>PNN NewsWatch
* FDA is proposing creation of pathway allowing consumers to obtain prescription drugs on a nonprescription basis. In a statement released yesterday, Commissioner Scott Gottlieb, MD, made these points about the agency proposal: “This draft guidance outlines two innovative approaches for demonstrating safety and effectiveness that may be useful to consider in cases where the [drug facts labeling (DFL)] alone is not sufficient to ensure that the drug product can be used safely and effectively in a nonprescription setting. The first is the development of labeling in addition to the DFL. The second approach is the implementation of additional conditions so that consumers appropriately self-select and use the product. Either of these approaches could involve the use of technology, such as mobile apps or other tools. The appropriateness and specific details of either of these approaches will depend on the circumstances that apply to a particular drug product.”

PNN Pharmacotherapy Line
July 19, 2018 * Vol. 25, No. 138
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
July 19 New England Journal of Medicine (2018; 379).
Clopidogrel/Aspirin in Acute Ischemic Stroke and High-Risk TIA: Seeking to replicate results from China in an international population, POINT investigators confirmed that the combination of clopidogrel plus aspirin is more effective for preventing major ischemic events in patients with minor ischemic stroke or high-risk transient ischemic attacks (TIAs) than aspirin alone, but at a greater risk of major hemorrhage (pp. 215–25). Participants were randomized to clopidogrel 600 mg on day 1 followed by 75 mg/d plus aspirin 50–325 mg/d, or to aspirin alone, with these effects on a primary outcome of risk of a composite of major ischemic events (ischemic stroke, myocardial infarction, or death from an ischemic vascular event) at 90 days: “A total of 4,881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2,432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2,449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02).” (S. C. Johnston, clay.johnston@utexas.edu)
“The evidence from the SAMMPRIS, CHANCE, and POINT trials is that the combination of aspirin plus clopidogrel reduces the chance of recurrent ischemic stroke during the high-risk period in the first few weeks after a TIA or noncardioembolic ischemic stroke,” an editorialist advises clinicians (
pp. 291–2). “However, to conform to the results of the POINT trial, if dual therapy is used, it should be confined to the first 3 weeks after a TIA or minor stroke and then transitioned to monotherapy. If patient follow-up and adherence to therapy are not reliable, then dual therapy perhaps should not be considered. Dual therapy may also not be advisable in patients with an uncertain diagnosis of TIA, who either would have been excluded from the trial or did not benefit. Finally, patients who are at increased risk for bleeding, such as those with cerebral microbleeding or a history of brain or systemic bleeding, were excluded from this trial and may not be appropriate candidates for such dual therapy.” (J. C. Grotta)
l-Glutamine in Sickle Cell Disease: Commenting on a study showing benefits of pharmaceutical-grade l-glutamine in patients with sickle cell anemia (pp. 226–35; C. Stark, cstark@emmausmedical.com), an editorialist writes (pp. 292–4): “Caution may be warranted in prescribing l-glutamine to patients with sickle cell disease who have clinically significant renal and hepatic dysfunction. Of note, in the two randomized trials of l-glutamine involving patients with sickle cell disease, three deaths occurred in the l-glutamine groups, as compared with none in the placebo groups; the deaths were not considered to be related to the study drug. In the absence of specific guidelines, I believe that l-glutamine may be prescribed to persons older than 5 years of age who have any sickle genotype and continue to have episodes of acute disease exacerbations despite appropriate use of hydroxyurea or to those who cannot or do not use hydroxyurea.” (C. P. Minniti)
>>>PNN NewsWatch
* Ribociclib (Kisqali, Novartis) has been approved by FDA for combination use with an aromatase inhibitor in treatment of premenopausal, perimenopausal, or postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy. Ribociclib is also approved in combination with fulvestrant for treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.
*
FDA yesterday released a Biosimilar Action Plan aimed at promoting competition and affordability.

PNN Pharmacotherapy Line
July 20, 2018 * Vol. 25, No. 139
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Aug. 1 issue of Clinical Infectious Diseases (2018; 67).
Statins & Influenza Vaccine in Older Adults: “Statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults,” conclude investigators who conducted a retrospective cohort study of 2.8 million Medicare beneficiaries vaccinated at pharmacies in the 2010–11 through 2014–15 seasons (pp. 378–87). Contrary to other studies showing a possible interaction, those receiving statins and standard-dose (SD) or high-dose (HD) influenza vaccines were not at higher risk for influenza: “For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025–1.150) for influenza-related visits and 1.096 (95% CI, 1.013–1.185) for influenza-related hospitalizations. The risk difference ranged from –0.02 to 0.23 for influenza-related visits and from –0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users.” (H. S. Izurieta, Hector.izurieta@fda.hhs.gov)
Poor Immunogenicity v. Egg Adaptation in 2012–13 Influenza Vaccine: The low vaccine effectiveness (VE) observed in the 2012–13 influenza season was the result of low vaccine immunogenicity and not egg adaptation of the vaccine strain, researchers report (pp. 327–33). In contrast to ferret studies that implicated egg adaptation, the current study found these patterns in serologic responses of vaccinated and unvaccinated people to the actual vaccine strain (IVR-165) and both the intended vaccine strain (A/Victoria/361/2011) and the predominant circulating strains (clades 3C.2 and 3C.3): “We found no significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. Vaccination increased titers to A/Victoria/361/2011 and 3C.2 and 3C.3 representative strains as much as to IVR-165. These results are consistent with the hypothesis that vaccination boosted cross-reactive immune responses instead of specific responses against unique vaccine epitopes. Only approximately one-third of the cohort achieved a ≥4-fold increase in titer.” (Y. H. Grad, ygrad@hsph.harvard.edu)
Pandemic Assessment Using Clinical Research Networks: The clinical severity of pandemic influenza can be rapidly and accurately determined using data from clinical research networks with a global presence and using standardized protocols, a retrospective investigation shows (pp. 341–9). For the 2009 influenza A H1N1 pandemic (pH1N1) virus in 2009–11 (pandemic) and 2012–15 (post-pandemic) periods, the case fatality ratio (CFR) was as follows for medically attended influenza (CFRMA) and all infected persons (CFRAR): “During the pandemic period, 5.0% (3.1%–6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%–12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%–0.6%) in the pandemic period 2009–2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012–2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA.” (L. Simonsen, lsimonsen2@gmail.com)
Timing of Influenza Vaccination in Pregnancy: In a study from southern Nepal, women who presented late in pregnancy had similar vaccine efficacy as those who were received influenza vaccination earlier (pp. 334–40). “Infant influenza [incidence risk ratios] were 0.73 (95% CI: 0.51, 1.05) for those whose mothers were vaccinated earlier in gestation, and 0.63 (95% CI: 0.37, 1.08) for those later,” the authors report. (J. Katz, jkatz1@jhu.edu)
>>>PNN NewsWatch
* FDA said yesterday severe illnesses and deaths are resulting from the use of synthetic cannabinoid products that have been contaminated with brodifacoum, a very long-acting anticoagulant commonly used in rat poison. These unapproved products are being sold in convenience stores and gas stations as substitutes for marijuana under names such as “K2” and “Spice.” These illegal products pose significant public health concerns for both individuals who may use them and those receiving donated blood, as blood products donated by users could contain these substances.

PNN Pharmacotherapy Line
July 23, 2018 * Vol. 25, No. 140
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
July 21 issue of Lancet (2018; 392).
Baricitinib for Oral Treatment of SLE: An oral selective Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib 4 mg dose significantly improved signs and symptoms of active systemic lupus erythematosus in patients inadequately controlled on standard-of-care therapy, researchers report (pp. 222–31). In a 24-week, phase 2 trial, adult patients with systemic lupus erythematosus and involved skin or joints had these responses to one of two doses of barcitinib or placebo: “Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n = 105), baricitinib 2 mg (n = 105), or baricitinib 4 mg (n = 104). At week 24, resolution of [Systemic Lupus Erythematosus Disease Activity Index-2000] arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1.8, 95% CI 1.0–3.3; p = 0.0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1.3, 0.7–2.3; p = 0.39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo.” (D. J. Wallace, danielwallac@gmail.com)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 362).
Sulfonylureas as Second-Line Drugs in Type 2 Diabetes: An observational study using data from the U.K. Clinical Practice Research Datalink shows higher risks of serious adverse outcomes associated with use of sulfonylureas as second-line add-on or replacement drugs in patients with type 2 diabetes (k2693). Patients would be better left on metformin monotherapy, the authors conclude, than being placed on sulfonylureas: “Among 77,138 metformin initiators, 25,699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1,000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia.” (S. Suissa, samy.suissa@mcgill.ca)
>>>PNN NewsWatch
* FDA on Friday approved marketing of first-in-class ivosidenib (Tibsovo, Agios Pharmaceuticals) tablets for treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. Ivosidenib is the first approved isocitrate dehydrogenase-1 inhibitor; it is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.
*
King Bio is voluntarily recalling four lots of Aquaflora Candida HP9, Lymph Detox, and Baby Teething liquids because of potential microbial contamination.
* Steps taken by FDA to broaden access to generic versions of
abuse-deterrent opioid formulations are summarized in a statement issued on Friday by Commissioner Scott Gottlieb, MD, including a “new batch of 43 product-specific guidances” and a final guidance of a proposal from last fall.
>>>PNN JournalWatch
* Biological Therapies for Eosinophilic Gastrointestinal Diseases, in Journal of Allergy and Clinical Immunology, 2018; 142: 24–31.e2. (J. B. Wechsler, JWechsler@luriechildrens.org)
*
Temporomandibular Joint Disorders in Older Adults, in Journal of the American Geriatrics Society, 2018; 66: 1213–7. (S. Yadav, syadav@uchc.edu)

PNN Pharmacotherapy Line
July 24, 2018 * Vol. 25, No. 141
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>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2018; 169).
Integration of Care at the OUD/ID Intersection: Epidemics of infectious diseases are associated with widespread use and abuse of opioids, leading to increases in hospitalizations for bacteremia, endocarditis, skin and soft tissue infections, and osteomyelitis, according to authors of a call for action (10.7326/M18-1203). Writing after a workshop convened in March by the National Academies of Sciences, Engineering, and Medicine, the authors called for these action steps (S. A. Springer, sandra.springer@yale.edu):
* Implement screening for opioid use disorder (OUD) in all relevant health care settings.
* For patients with positive screening results, immediately prescribe effective medication for OUD and/or opioid withdrawal symptoms.
* Develop hospital-based protocols that facilitate OUD treatment initiation and linkage to community-based treatment upon discharge.
* Hospitals, medical schools, physician assistant schools, nursing schools, and residency programs should increase training to identify and treat OUD.
* Increase access to addiction care and funding to states to provide effective medications to treat OUD.
Evidence-Challenged Views on Marijuana Benefits/Risks: Americans’ ability to believe what they choose regardless of evidence is apparently not limited to vaccines and news reporting. In a large probability-based, online survey, their “view of marijuana use is more favorable than existing evidence supports,” researchers report (10.7326/M18-0810). Conducted in 2017, the survey of 16,280 American adults showed these views on the risks and benefits of marijuana: “The response rate was 55.3% (n = 9,003). Approximately 14.6% of U.S. adults reported using marijuana in the past year. About 81% of U.S. adults believe marijuana has at least 1 benefit, whereas 17% believe it has no benefit. The most common benefit cited was pain management (66%), followed by treatment of diseases, such as epilepsy and multiple sclerosis (48%), and relief from anxiety, stress, and depression (47%). About 91% of U.S. adults believe marijuana has at least 1 risk, whereas 9% believe it has no risks. The most common risk identified by the public was legal problems (51.8%), followed by addiction (50%) and impaired memory (42%). Among U.S. adults, 29.2% agree that smoking marijuana prevents health problems. About 18% believe exposure to secondhand marijuana smoke is somewhat or completely safe for adults, whereas 7.6% indicated that it is somewhat or completely safe for children. Of the respondents, 7.3% agree that marijuana use is somewhat or completely safe during pregnancy. About 22.4% of U.S. adults believe that marijuana is not at all addictive.” (S. Keyhani, Salomeh.Keyhani@ucsf.edu)
Marijuana Use & Pulmonary Function: While low-strength evidence “suggests that smoking marijuana is associated with cough, sputum production, and wheezing,” the connection between marijuana use and obstructive lung disease or pulmonary function lacks evidence, according to a systematic review and meta-analysis of observational and interventional studies (10.7326/M18-0522): “Twenty-two studies were included. A pooled analysis of 2 prospective studies showed that marijuana use was associated with an increased risk for cough (risk ratio [RR], 2.04 [95% CI, 1.02 to 4.06]) and sputum production (RR, 3.84 [CI, 1.62 to 9.07]). Pooled analysis of cross-sectional studies (1 low and 3 moderate risk of bias) showed that marijuana use was associated with cough (RR, 4.37 [CI, 1.71 to 11.19]), sputum production (RR, 3.40 [CI, 1.99 to 5.79]), wheezing (RR, 2.83 [CI, 1.89 to 4.23]), and dyspnea (RR, 1.56 [CI, 1.33 to 1.83]). Data on pulmonary function and obstructive lung disease were insufficient.” (M. Ghasemiesfe, mehrnaz.ghasemiesfe@va.gov)
>>>PNN NewsWatch
* Responding to a citizens’ petition and taking other compounding-related actions, FDA yesterday moved cesium chloride to category 2 under the agency’s interim policy on compounding with bulk drug substances under section 503A. FDA also announced research collaborations with Johns Hopkins U. and U. Maryland regarding its list of bulk substances that can be compounded under section 503B and announced interim policies on bulk substances under 503A and 503B while bulk lists are being developed.

PNN Pharmacotherapy Line
July 25, 2018 * Vol. 25, No. 142
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
July 24/31 issue of JAMA (2018; 320).
2018 ART Recommendations: Immediate initiation of antiretroviral therapy (ART), universal testing, and preexposure prophylaxis in at-risk individuals are among the recommendations included in the 2018 guidelines of the International Antiviral Society–USA Panel (pp. 379–96). In an update to its 2016 recommendations, the panel writes: “ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV.” (M. S. Saag, msaag@uabmc.edu)
“It is now clear that to effectively address the HIV epidemic, a multipronged approach is needed that includes new HIV prevention strategies (HIV preexposure prophylaxis, education regarding condom use), expanded HIV testing, rapid and immediate linkage to care when possible, viral suppression for persons who are HIV infected, and strategies to enhance adherence to therapy and retention in care,” an editorialist writes in reflecting on how clinicians can build on the “decades of progress” in HIV therapy (
pp. 347–9). “Since the initial IAS-USA guidelines for HIV treatment were published in 1996, much has changed in the way the medical community provides care for persons infected with HIV. Over time, patients have ultimately benefited from single-tablet regimens that are highly potent, have a high genetic barrier to resistance, and are associated with fewer adverse effects than drugs first developed in the late 1980s. It also is now recognized that starting treatment as early as possible is beneficial for individual patients and for the broader community at large to prevent HIV transmission.” (J. Riddell IV, jriddell@umich.edu)
Mortality & Completion of 1-Hour Pediatric Sepsis Bundle: Risk of in-hospital mortality was 41% lower when pediatric patients with sepsis and septic shock received a 1-hour bundle of interventions, researchers report (pp. 358–67): “Among 1,179 pediatric patients with sepsis at 54 adult and pediatric specialty hospitals in New York State, the completion of a 1-hour sepsis bundle that included blood cultures, broad spectrum antibiotics, and a 20-mL/kg fluid bolus was significantly associated with lower risk-adjusted in-hospital mortality compared with not completing the bundle within 1 hour (odds ratio, 0.59).” (C. W. Seymour, seymourcw@upmc.edu)
Escitalopram & Long-Term Cardiac Outcomes in ACS: During a median of 8.1 years of follow-up, patients receiving a 24-week course of escitalopram for depression following recent acute coronary syndrome had a significantly lower risk of major adverse cardiac events (MACE), according to a study from South Korea (pp. 350–8). The 300 participants received flexible doses of escitalopram or placebo and had these outcomes based on a MACE composite of all-cause mortality, myocardial infarction (MI), and percutaneous coronary intervention (PCI): “MACE occurred in 61 patients (40.9%) receiving escitalopram and in 81 (53.6%) receiving placebo (hazard ratio [HR], 0.69; 95% CI, 0.49–0.96; P = .03). Comparing individual MACE outcomes between the escitalopram and placebo groups, respectively, incidences for all-cause mortality were 20.8% vs 24.5% (HR, 0.82; 95% CI, 0.51–1.33; P = .43), for cardiac death, 10.7% vs 13.2% (HR, 0.79; 95% CI, 0.41–1.52; P = .48); for MI, 8.7% vs 15.2% (HR, 0.54; 95% CI, 0.27–0.96; P = .04), and for PCI, 12.8% vs 19.9% (HR, 0.58; 95% CI, 0.33–1.04; P = .07).” (J-M Kim, jmkim@chonnam.ac.kr)

PNN Pharmacotherapy Line
July 26, 2018 * Vol. 25, No. 143
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
July 26 issue of the New England Journal of Medicine (2018; 379).
PD-1 Blockade in Cutaneous Squamous-Cell Carcinoma: In phase 1 and phase 2 studies of a programmed death 1 (PD-1) inhibitor, cemiplimab induced a response in approximately half the patients with advanced cutaneous squamous-cell carcinoma, while producing adverse events typical for immune checkpoint inhibitors (pp. 341–51). The phase 1 study included patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, and a pivotal phase 2 study assessed participants with metastatic disease (metastatic-disease cohort). Results showed: “In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.” (M. R. Migden, mrmigden@mdanderson.org)
Oral Plasma Kallikrein Inhibitor for Hereditary Angioedema Prophylaxis: Compared with placebo, the small-molecule plasma kallikrein inhibitor BCX7353 produced a significantly lower rate of attacks in 75 patients with type I or II hereditary angioedema, researchers report (pp. 352–62). Participants in the dose-ranging trial were having at least two angioedema attacks per month at baseline. Based on efficacy and safety end points during a 28-day period, once-daily oral doses of BCX7353 produced these outcomes: “The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P <0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P <0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.” (E. Aygören-Pürsün, aygoeren@em.uni-frankfurt.de)
Prehospital Plasma in Trauma for Hemorrhagic Shock: The standard but unproven practice of administering plasma to patients at risk of hemorrhagic shock during transport was beneficial in a 501-patient study (pp. 315–26; J. L. Sperry, sperryjl@upmc.edu).
Keratinocyte Carcinomas: While “the majority of keratinocyte carcinomas are readily diagnosed and effectively treated with minimal morbidity,” authors of a review write that “improvements in preventive, diagnostic, prognostic, and therapeutic approaches are needed to address public health concerns about the increasing incidence of these skin cancers” (pp. 363–74). “Public awareness of the carcinogenic effect of [ultraviolet] radiation from natural sunlight and indoor tanning beds is paramount in efforts to curtail the rising number of skin cancers. Noninvasive imaging techniques are being investigated to improve real-time diagnosis and reduce unnecessary biopsies and associated costs. There is great interest in the ability of artificial intelligence, including convolutional neural networks, to aid in the diagnosis of skin cancers. Research interest in cutaneous squamous-cell carcinoma has historically been limited, in part because of the false assumption that the associated mortality is very low. Studies of prospective, worldwide cohorts are needed to establish accurate mortality rates and address the inadequacy of risk stratification with the use of current staging systems. Combination therapy for unresectable or metastatic basal-cell carcinoma, focused on additional downstream targets in the hedgehog pathway and topical delivery of such agents, is being investigated to improve the efficacy and safety of currently available drugs. Finally, additional clinical trials are evaluating immune checkpoint inhibitors for the treatment of locally advanced or metastatic basal-cell and cutaneous squamous-cell carcinomas, and the results of these trials are pending.” (K. S. Nehal)

PNN Pharmacotherapy Line
July 27, 2018 * Vol. 25, No. 144
Providing news and information about medications and their proper use

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>>>Vaccine Highlights
Source:
Aug. 9 issue of Vaccine (2018; 36).
Cost-effectiveness of Adjuvanted Recombinant Zoster Vaccine: In American patients 60 years of age or older, the new herpes zoster (HZ) vaccine is cost-effective in comparison to no vaccine and zoster vaccine live (ZVL), a study shows (pp. 5037–45). The new adjuvanted recombinant zoster vaccine (RZV) was compared in 1 million individuals using a multi-cohort Markov model and assuming a 69% second-dose vaccination rate, with these results: “The model estimated that, compared to No Vaccine against HZ, RZV would prevent 103,603 HZ cases, 11,197 postherpetic neuralgia (PHN) cases, and 14,455 other complications, at an incremental cost of $11,863 per quality-adjusted life-year saved from a societal perspective. Compared to ZVL, the model estimated that, RZV would prevent 71,638 additional HZ cases, 6,403 PHN cases, and over 10,582 other complications, resulting in net total societal cost savings of over $96 million. The results were robust to a wide range of sensitivity analyses.” (D. Curran, desmond.x.curran@gsk.com)
Moderate Influenza Vaccine Effectiveness in Beijing in 2015–16: Unlike in other locations in 2015–16, vaccination effectiveness (VE) was moderate against circulating strains of influenza A(H3N2) strains in Beijing, China, researchers report (pp. 4993–5001). The study used a test-negative design to estimate VE for the trivalent inactivated vaccine against laboratory-confirmed cases, with these results: “Of 11,000 eligible patients included in the study, 2,969 (27.0%) were influenza positive. Vaccination coverage was 4.2% in both cases and controls. Adjusted VE against all influenza was 8% (95% CI: −16% to 27%): 18% (95% CI: −38% to 52%) for influenza A(H1N1)pdm09, 54% (95% CI: 16% to 74%) for influenza A(H3N2), and −8% (95% CI: −40% to 18%) for influenza B/Victoria. The overall VE for receipt of 2015–2016 vaccination only, 2014–2015 vaccination only, and vaccinations in both seasons was −15% (95% CI: −63% to 19%), −25% (95% CI: −78% to 13%), and 18% (95% CI: −11% to 40%), respectively.” (P. Yang, yangpengcdc@163.com)
>>>Allergy/Immunology Report
Source:
July Journal of Allergy and Clinical Immunology (2018; 142).
Dupilumab in Perennial Allergic Rhinitis, Comorbid Asthma: The anti-interleukin-4-alpha inhibitor dupilumab every 2 weeks improved symptoms of allergic rhinitis (AR) in patients with uncontrolled persistent asthma and comorbid perennial allergic rhinitis (PAR), as shown in these phase 2b trial results (pp. 171–177.e1): “Overall, 241 (61%) patients had PAR. In asthma patients with PAR, dupilumab 300 mg q2w versus placebo significantly improved SNOT-22 total score (least squares mean difference, −5.98; 95% CI, −10.45 to −1.51; P = .009) and all 4 AR-associated symptoms evaluated (nasal blockage, −0.60; 95% CI, −0.96 to −0.25; runny nose, −0.67; 95% CI, −1.04 to −0.31; sneezing, −0.55; 95% CI, −0.89 to −0.21; postnasal discharge, −0.49; 95% CI, −0.83 to −0.16; all P < .01). Dupilumab 200 mg q2w demonstrated numerical, but not statistically significant, decreases in SNOT-22 total score (−1.82; 95% CI, −6.46 to 2.83; P = .443 vs placebo) and in each AR-associated symptom. In patients without PAR, no differences were observed for these measures versus placebo.” (S. F. Weinstein, sfw@ocallergy.com)
>>>PNN NewsWatch
* The influenza season in the southern hemisphere has been unusually mild this winter, the World Health Organization reports. Activity is increasing in some areas and may have peaked in others, but the level of activity in Australia and New Zealand is below the seasonal threshold — it’s more like the hotter months than the colder ones.
* Details on
mumps outbreaks at four Indiana universities are included in this week’s Morbidity and Mortality Weekly Report. “Mumps is an acute viral illness characterized by parotid gland swelling that can result in more serious complications such as orchitis and encephalitis,” the authors write. “A substantial increase in the number of mumps outbreaks and outbreak-associated cases has occurred in the United States since late 2014. Four large university mumps outbreaks with considerable community spread occurred in Indiana in 2016, contributing to the 6,366 mumps cases reported nationwide in 2016, the highest number of cases in a decade.”

PNN Pharmacotherapy Line
July 30, 2018 * Vol. 25, No. 145
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Early-release article from/July 28 issue of Lancet (2018; 392).
Esomeprazole/Aspirin in Barrett’s Esophagus: In 2,557 patients with Barrett’s esophagus of 1 cm or more, high-dose PPI therapy and aspirin chemoprevention therapy over 8 or more years improved outcomes, particularly when given in combination (10.1016/S0140-6736(18)31388-6). In the Aspirin and Esomeprazole Chemoprevention in Barrett’s metaplasia Trial, participants received esomeprazole 20 mg once daily or 40 mg twice daily with or without aspirin 300–325 mg/d. Results showed: “Median follow-up and treatment duration was 8.9 years (IQR 8.2–9.8), and we collected 20,095 follow-up years and 99.9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1,270 patients) was superior to low-dose PPI (174 events in 1,265 patients; time ratio [TR] 1.27, 95% CI 1.01–1.58, p = 0.038). Aspirin (127 events in 1,138 patients) was not significantly better than no aspirin (154 events in 1,142 patients; TR 1.24, 0.98–1.57, p = 0.068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1.29, 1.01–1.66, p = 0.043; n = 2,236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1.59, 1.14–2.23, p = 0.0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.” (J. A. Z. Jankowski, jjankowski@rcsi.ie)
Police Killings & Mental Health of Black Americans: Police killings of unarmed black Americans — but not armed blacks or unarmed whites — are associated with declines in mental health of black Americans living in the same state, according to 2013–15 Behavioral Risk Factor Surveillance System (BRFSS) data (10.1016/S0140-6736(18)31130-9): “Each additional police killing of an unarmed black American was associated with 0.14 additional poor mental health days (95% CI 0.07–0.22; p = 0.00047) among black American respondents. The largest effects on mental health occurred in the 1–2 months after exposure.&hellipWinking.” (A. S. Venkataramani, atheenv@pennmedicine.upenn.edu)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 362).
Outpatient Antibiotic Use & Prescribing: Guidelines and antibiotic stewardship were not likely the driving factors in changes in use observed in 2011–15 among Medicare beneficiaries, researchers report (k3155). Overall antibiotic and potentially inappropriate use remained steady or declined slightly, the analysis of Medicare data shows, but individual agents had divergent usage trends: “The number of antibiotic claims fell from 1364.7 to 1309.3 claims per 1,000 beneficiaries per year in 2011–14 (adjusted reduction of 2.1% (95% confidence interval 2.0% to 2.2%)), but then rose to 1364.3 claims per 1,000 beneficiaries per year in 2015 (adjusted reduction of 0.20% over 2011–15 (0.09% to 0.30%)). Potentially inappropriate antibiotic claims fell from 552.7 to 522.1 per 1,000 beneficiaries over 2011–14, an adjusted reduction of 3.9% (3.7% to 4.1%). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.5% (18.2% to 18.8%) while levofloxacin claims increased by 27.7% (27.2% to 28.3%). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses decreased, while levofloxacin use associated with each of those diagnoses increased.” (Y. H. Grad, ygrad@hsph.harvard.edu)
>>>PNN NewsWatch
* Ranier’s Rx Laboratory is voluntarily recalling all sterile compounded drug products within expiry to the hospital or consumer level. FDA said the recall results from inspection-related concerns about sterile-compounding practices at the pharmacy.
>>>PNN JournalWatch
* SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management, in Diabetes Care, 2018; 41: 1543–56. (M. J.B. van Baar, m.vanbaar@vumc.nl)
*
Value-Based Insurance Design Improves Medication Adherence Without An Increase In Total Health Care Spending, in Health Affairs, 2018; 37: 1057–64. (R. Agarwal, ragarwal@health-reform.org)
*
Growing Number Of Unsubsidized Part D Beneficiaries With Catastrophic Spending Suggests Need For An Out-Of-Pocket Cap, in Health Affairs, 2018; 37: 1048–56. (E. Trish, etrish@healthpolicy.usc.edu)

PNN Pharmacotherapy Line
July 31, 2018 * Vol. 25, No. 146
Providing news and information about medications and their proper use

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>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2018; 41).
Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: Interventions can help adults with type 1 diabetes who have impaired awareness of hypoglycemia, a study shows (pp. 1600–7). At five U.K. tertiary referral diabetes centers, 96 adults participated in a 2X2 factorial randomized controlled trial (HypoCOMPaSS) that compared pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education and attention to all groups. Results showed: “Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9; P <0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person–year over the 12 months prestudy to 0.4 ± 0.8 over 24 months (P <0.0001). HbA1c improved (baseline 8.2 ± 3.2% [66 ± 12 mmol/mol] vs. 24 months 7.7 ± 3.1% [61 ± 10 mmol/mol]; P = 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months.” (J. A. M. Shaw, jim.shaw@ncl.ac.uk)
This study brings “hypoglycemia to the forefront of a larger conversation,” editorialists write (
pp. 1557–9). “Hyperglycemia is, after all, only part of the puzzle in diabetes management. Long-term complications are decreasing across the population with improved interventions and their implementation. To this end, it is essential to shift our historical obsession with hyperglycemia and its long-term complications to equally emphasize the disabling, distressing, and potentially fatal near-term complication of our treatments, namely severe hypoglycemia. The American Diabetes Association (ADA) should assemble and expand current recommendations in the Standards of Medical Care in Diabetes with a dedicated chapter on both low-cost and technologically driven assessments for hypoglycemia unawareness and the prevention of severe hypoglycemia. The focus of such a chapter should be on implementation with an emphasis on individualization, patient autonomy, and overall well-being. The health care providers’ first dictum is primum non nocere—above all, do no harm. ADA must refocus our attention on severe hypoglycemia as an iatrogenic and preventable complication of our interventions.” (J. B. Buse, jbuse@med.unc.edu)
SGLT2 Inhibitors in Combination Therapy: In a Perspectives in Care review article, authors write, “The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained” (pp. 1543–56). “With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration–approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium–glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy–to–adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied.” (M. J. B. van Baar, m.vanbaar@vumc.nl)
>>>PNN NewsWatch
* FDA yesterday approved iobenguane I 131 (Azedra, Progenics Pharmaceuticals) injection for intravenous use for the treatment of adults and adolescents age 12 and older with pheochromocytoma or paraganglioma that is unresectable and metastatic, and requires systemic anticancer therapy. This is the first FDA-approved drug for this use.

PNN Pharmacotherapy Line
Aug. 1, 2018 * Vol. 25, No. 147
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
Early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Community Pharmacists & Medication Reviews for Older Adults: Better studies are needed to “assess the effect of community pharmacists’ contributions to reviewing medications and improving the health of older adults,” conclude authors of a systematic review (10.1111/jgs.15416). “Sixteen articles were found that described 12 medication review interventions, of which 6 were compliance and concordance reviews, 4 were clinical medication reviews, and 2 were prescription reviews according to a previously developed typology. Community pharmacists’ contributions to reviewing medications varied from sending the dispensing history to other healthcare providers to comprehensive involvement in medication management. The most commonly assessed outcomes of the interventions were medication changes leading to reduction in actual or potential drug-related problems (n = 12) and improved adherence (n = 5).” The writers conclude, “Regardless of community pharmacists’ contributions to interventions, medication review interventions seem to reduce drug-related problems and increase medication adherence. More well-designed, rigorous studies with more sensitive and specific outcomes measures need to be conducted to assess the effect of community pharmacists’ contributions to reviewing medications and improving the health of older adults.” (S. Kallio, sonja.kallio@helsinki.fi)
Medication-Related Harm in Older Adults After Hospital Discharge: A second review article demonstrates how common medication-related harm (MRH) is among community-dwelling older adults after hospital discharge and identifies risk factors for postdischarge adverse drug reactions (ADRs) or adverse drug events (ADEs) (10.1111/jgs.15419): “From 584 potentially relevant articles, 8 studies met our inclusion criteria: 5 North American and 3 European. Most of the included studies were of moderate quality. There was a wide range in MRH incidence, from 0.4% to 51.2% of participants, and 35% to 59% of MRH was preventable. MRH incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals). There is substantial methodological heterogeneity across multiple domains of the studies, including ADR and ADE definitions, characteristics of recruited populations, follow-up duration after discharge, and data collection.” (C. Rajkumar, c.rajkumar@bsms.ac.uk)
>>>Nephrology Highlights
Source:
Aug. issue of the American Journal of Kidney Diseases (2018; 72).
SGLT2 Inhibition in Diabetic Kidney Disease: A review article “summarizes the current understanding of mechanisms by which SGLT2 inhibitors block glucose reabsorption in the proximal tubule and improve systemic glucose homeostasis, the hypothesized mechanisms for kidney-protective effects of SGLT2 inhibition, and current recommendations for use of this class of antihyperglycemic agents in diabetic patients with low estimated glomerular filtration rates” (pp. 267–77). “Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and the world alike, and there is a great unmet need for treatments to reduce DKD development and progression. Inhibition of sodium/glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment, leading to regulatory approval of several first-generation SGLT2 inhibitors for the treatment of type 2 diabetes. In follow-on clinical trials for the cardiovascular safety of the SGLT2 inhibitors, secondary effects to prevent or reduce albuminuria and decline in estimated glomerular filtration rate spurred further investigation into their potential application in DKD.” (R. Z. Alicic, radica.alicic@providence.org)
>>>PNN NewsWatch
* The ASHP Guidelines on Managing Drug Product Shortages have been released on the AJHP website. Scheduled for print in the journal’s Nov. 1 issue, the guidelines provide a framework that can be used by health care teams in patient care settings to develop policies and procedures to minimize the impact of drug shortages on quality of care.

PNN Pharmacotherapy Line
Aug. 2, 2018 * Vol. 25, No. 148
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Aug. 2 issue of the New England Journal of Medicine (2018; 379).
Sunitinib in Metastatic Renal-Cell Carcinoma: Compared with nephrectomy plus sunitinib in patients with metastatic renal cell carcinoma, sunitinib alone was noninferior for those with intermediate risk or poor risk, researchers report (pp. 417–27). The phase 3 trial used a primary end point of overall survival and drug doses of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. Results showed: “A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy–sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy–sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group.” (B. Escudier, escudier@gustaveroussy.fr)
“The selection of patients plays a critical role in day-to-day patient care as well as in clinical trial design,” editorialists write (
pp. 481–2). “We think that nephrectomy in properly chosen patients with metastatic renal-cell carcinoma remains an essential component of care. Often, for patients with limited or slow-growing metastatic disease after nephrectomy, prolonged surveillance-only periods are used until the progression of distant metastases occurs and then systemic therapy is initiated. The CARMENA trial was heavily weighted toward poor-risk patients, and it is not surprising that the noninferiority end point was achieved. For practicing surgeons and medical oncologists, these data should not lead to the abandonment of nephrectomy but instead emphasize the importance of careful selection of patients undergoing nephrectomy, on the basis of published risk models. The main focus is on pretreatment risk features, resectability of the primary tumor, status of health, and presence of other medical conditions in determining who is most likely to benefit.” (R. J. Motzer)
Management of Tuberculosis: Articles address the management of latent tuberculosis in adults and children. The adult study found that 4 months of rifampin was not inferior to 9 months of isoniazid and was associated with higher rates of treatment completion and better safety (pp. 440–53). The differences in rates of confirmed active or clinically diagnosed active tuberculosis were less than 0.01 cases per 100 person–years, treatment completion rates were 15.1 percentage points higher with the shorter regimen, and rate differences of serious and hepatotoxic events were within about 1 percentage point for the two groups. (D. Menzies, dick.menzies@mcgill.ca)
In a similar comparison in children, the 4-month regimen of rifampin produced similar efficacy and safety measures, but with higher adherence rates than the 9-month isoniazid regimen (
pp. 454–63; D. Menzies, dick.menzies@mcgill.ca).
>>>PNN NewsWatch
* AuroMedics Pharma LLC is voluntarily recalling two lots of Piperacillin and Tazobactam for injection, USP 3.375 g (Piperacillin Sodium equivalent to 3 g of Piperacillin USP and Tazobactam Sodium equivalent to 0.375 g of Tazobactam USP) to the hospital level because of possible presence of particulate matter and silicone materials.
* On Friday,
FDA will host a public advisory committee meeting to review data from the most recent assessment of the Risk Evaluation and Mitigation Strategy (REMS) with Elements to Assure Safe Use (ETASU) for transmucosal immediate-release fentanyl products. “Combatting the crisis of opioid addiction facing our nation is a priority for me and the entire agency,” Commissioner Scott Gottlieb, MD, wrote in a statement released yesterday. “As we work to mitigate the risks of misuse, abuse, addiction, overdose, and complications due to medication errors associated with these opioid analgesic drugs; we’re also committed to ensuring that patients suffering from significant pain have access to appropriate medication and are not unduly burdened in getting the treatment they need.”
PNN Pharmacotherapy Line
Aug. 3, 2018 * Vol. 25, No. 149
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (2018; 142).
Outpatient Opioid Prescriptions for Children: Nearly three-quarters of opioid-related adverse events in Tennessee children covered by Medicaid occurred during therapeutic use of the agents, according to a retrospective cohort study from 1999 to 2014 (10.1542/peds.2017-2156). Children and adolescents ages 2 to 17 were included in the analysis, which showed the following usage rates and adverse events leading to an opioid-related emergency department visit, hospitalization, or death: “There were 1,362,503 outpatient opioid prescriptions; the annual mean prevalence of opioid prescriptions was 15.0%. The most common opioid indications were dental procedures (31.1% prescriptions), outpatient procedure and/or surgery (25.1%), trauma (18.1%), and infections (16.5%). There were 437 cases of opioid-related adverse events confirmed by medical record review; 88.6% were related to the child’s prescription and 71.2% had no recorded evidence of deviation from the prescribed regimen. The cumulative incidence of opioid-related adverse events was 38.3 of 100,000 prescriptions. Adverse events increased with age (incidence rate ratio = 2.22; 95% confidence interval, 1.67–2.96; 12–17 vs 2–5 years of age) and higher opioid doses (incidence rate ratio = 1.86 [1.45–2.39]; upper versus lower dose tertiles).” (C. P. Chung)
“Pediatric practitioners must use their best judgment when using opioids with solid indications and should always make good use of nonopioid alternatives,” editorialists write (
10.1542/peds.2018-1623). “But providing appropriate opioid prescriptions for moderately to severely painful conditions should not be curtailed on the basis of the data reported by Chung et al. Too often, consideration of the need to prevent and treat pain can be lost in the national discussion.” (E. J. Krane, ekrane@stanford.edu)
>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2018; 175).
Stimulant Use, Misuse Among American Adults: In the 2015 and 2016 National Surveys on Drug Use and Health, the most commonly reported reason for misusing prescription stimulants was cognitive enhancement, researchers report (pp. 741–55). The nationally representative study of 102,000 adults showed these measures of prescription stimulant use, misuse, and use disorders: “Among U.S. adults, 6.6% (annual average) used prescription stimulants overall; 4.5% used without misuse, 1.9% misused without use disorders, and 0.2% had use disorders. Adults with past-year prescription stimulant use disorders did not differ from those with misuse without use disorders in any of the examined sociodemographic characteristics and in many of the examined substance use problems. The most commonly reported motivations for misuse were to help be alert or concentrate (56.3%). The most likely source of misused prescription stimulants was by obtaining them free from friends or relatives (56.9%). More frequent prescription stimulant misuse and use disorder were associated with an increased likelihood of obtaining medications from physicians or from drug dealers or strangers and less likelihood of obtaining them from friends or relatives.” (W. M. Compton)
“Compton et al. observed striking associations between prescription stimulant use (with or without misuse) and experiencing major depressive episodes and suicidal ideation, as well as having asthma and utilizing emergency department services,” according to authors of an accompanying editorial (
pp. 707–8). “These findings amplify the need to comprehensively assess and address comorbid psychiatric disorders and other health conditions when prescribing stimulant medications. When managing the care of individuals who have comorbid substance use disorder and ADHD, recent guidelines published by the International Collaboration on ADHD and Substance Abuse consensus group recommend a combination of pharmacotherapy and psychotherapy.…
“The take-home messages for prescribing controlled substances generally and stimulants in particular are 1) to caution explicitly against diversion; 2) to assess substance use patterns routinely among patients; 3) to advise patients to use the medication only as prescribed and not in association with other substances, including alcohol; and 4) to closely monitor medication use and comorbid psychiatric symptoms and health problems.” (A. M. Arria)

PNN Pharmacotherapy Line
Aug. 6, 2018 * Vol. 25, No. 150
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Aug. 4 issue of Lancet (2018; 392).
Aspirin Doses, Patient Size & Cardiovascular, Cancer Outcomes: “A one-dose-fits-all approach to aspirin is unlikely to be optimal” for preventing cardiovascular disease or cancers, authors conclude based on analysis of individual patient data from 10 randomized controlled trials (pp. 387–99). The study looked for interactions between weight (in 10-kg bands) or height (in 10-cm bands) and low aspirin doses (≤100 mg/d) or high aspirin doses (300–325 or ≥500 mg/d), leading to this conclusion: “Low doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more.” (P. M. Rothwell, peter.rothwell@clneuro.ox.ac.uk)
>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 362).
Trends in U.S. Opioid Use: During 2007–16, opioid use among commercially insured and Medicare Advantage beneficiaries was higher for disabled individuals than aged 65 years or older, a study shows (k2833). Analysis of claims for 48 million Americans showed these patterns for any opioid prescription per quarter, average daily dose in milligram morphine equivalents (MME), and proportion of opioid use episodes that represented long term use: “Across all years of the study, annual opioid use prevalence was 14% for commercial beneficiaries, 26% for aged Medicare beneficiaries, and 52% for disabled Medicare beneficiaries. In the commercial beneficiary group, quarterly prevalence of opioid use changed little, starting and ending the study period at 6%; the average daily dose of 17 MME remained unchanged since 2011. For aged Medicare beneficiaries, quarterly use prevalence was also relatively stable, ranging from 11% at the beginning of the study period to 14% at the end. Disabled Medicare beneficiaries had the highest rates of opioid use, the highest rate of long term use, and the largest average daily doses. In this group, both quarterly use rates (39%) and average daily dose (56 MME) were higher at the end of 2016 than the low points observed in 2007 for each endpoint (26% prevalence and 53 MME).” (M. M. Jeffery, jeffery.molly@mayo.edu)
Alcohol Consumption & Risk of Dementia: Among 9,087 participants who were aged 35–55 years at study inception in 1985–88, the risk of dementia was highest among those abstaining from alcohol in midlife or consuming 14 or more units/wk (k2927). In addition to supporting other studies showing a U-shaped risk curve, this research has implications for countries where higher alcohol thresholds are used in recommendations: “In several countries, guidelines define thresholds for harmful alcohol consumption much higher than 14 units/week. The present findings encourage the downward revision of such guidelines to promote cognitive health at older ages.” (S. Sabia, severine.sabia@inserm.fr)
>>>PNN NewsWatch
* Health care professionals should not prescribe long-term azithromycin for prophylaxis of bronchiolitis obliterans syndrome in patients who undergo donor stem cell transplants because of the increased potential for cancer relapse and death, FDA said on Friday. Results of a clinical trial found an increased rate of relapse in cancers affecting the blood and lymph nodes, including death, in these patients. FDA is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.
>>>PNN JournalWatch
* Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective–2018 Update, in Circulation, 2018; 138: 527–36. (D. J. Angiolillo, dominick.angiolillo@jax.ufl.edu)
*
Clinical Genetic Testing for Familial Hypercholesterolemia, in Journal of the American College of Cardiology, 2018; 72: 662 ff. (JACC Scientific Expert Panel)
*
Neuroscience of Addiction: Relevance to Prevention and Treatment, in American Journal of Psychiatry, 2018; 175: 729–40. (N. D. Volkow)
*
Epigenetic Aging in Major Depressive Disorder, in American Journal of Psychiatry, 2018; 175: 774–82. (L. K. M. Han)
*
Transitioning From “Sick Kid” to Community Health Worker: Building Better Bridges to Adult Care, in Pediatrics, 2018; 142: 10.1542/peds.2018-0962. (K. Wu)

PNN Pharmacotherapy Line
Aug. 7, 2018 * Vol. 25, No. 151
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Aug. 7 issue of and early-release articles from the Annals of Internal Medicine (2018; 169).
Information on Storing & Disposing of Opioid Analgesics: Consistent information on storing and disposing of opioid analgesics should be required in product labeling so that providers that better counsel patients, conclude authors of a study of package inserts for hydrocodone, hydromorphone, tramadol, fentanyl, morphine, and oxycodone (pp. 198–9). Review of the online DailyMed resource showed the following: “Among the 98 reviewed package inserts, we identified 1 message on safe storage and 3 on safe disposal. The message on safe storage stated that medications should be securely stored to prevent theft. Approximately two thirds of the 35 package inserts with this message were for oxycodone (n = 16) or morphine (n = 8) products. Messages on safe disposal stated that unused medications should be discarded (n = 31) or flushed down the toilet (n = 34) or that providers should instruct patients to dispose of unused opioids (n = 28). Most (70% to 80%) inserts with messages on safe disposal were for oxycodone and morphine products. None of the inserts for tramadol products had messages on either storage or disposal; 1 of 33 inserts for hydrocodone products had a message on storage or disposal.” (M. L. Doucette, mdoucet3@jhmi.edu)
Value v. Cost-Effectiveness in Health Care: The emergence of value-based health care (VBHC) calls into question the similarities and differences between that approach and the well-established cost-effectiveness analysis (CEA), authors write, offering this perspective (10.7326/M18-0342): “Value-based health care focuses on maximizing outcomes achieved per dollar spent, [while CEA] provides a framework for comparing the relative value of different diagnostic or treatment interventions. Both approaches address ‘bang for the health care buck,’ but although they overlap in many ways, VBHC and CEA differ with regard to their main applications, their perspective, and the types of costs and outcomes they consider. For example, CEA generally considers costs and benefits from the societal or health care sector perspectives, whereas VBHC is intended to adopt the patient perspective. As such, CEA is intended to inform coverage decisions at a group or population level and VBHC is intended to be implemented at the level of clinician–patient interactions. Meanwhile, value-based payment has emerged as a visible component of VBHC and is gaining a foothold in the United States in various forms, particularly bundled payments, and accountable care organizations in an effort to reward high-value care and disincentivize low-value care. Differences aside, as the worlds of VBHC and CEA begin to intersect, each discipline can learn from the other.” (J. Tsevat, tsevat@uthscsa.edu)
Microvascular Complications & Bariatric Surgery: Compared with usual care in four integrated systems, bariatric surgery was associated with lower incidence of microvascular complications of type 2 diabetes mellitus (T2DM), researchers report (10.7326/M17-2383). During a median of 4.3 years of follow-up of 4,024 patients who had bariatric surgery and 11,059 nonsurgical participants, the risk of microvascular disease was 59% lower with surgery than usual care. (D. Arterburn, arterburn.d@ghc.org)
Editorialists advocate use of surgical interventions earlier in the clinical course of T2DM (
10.7326/M18-2114). “Bariatric surgery is safe and is, at present, our most evidence-based treatment to put hyperglycemia from T2DM into remission. We are on the verge of having the data to tell our patients with T2DM in the clinic that we can offer them a treatment that significantly reduces the feared complications of this dreadful disease. Surgery should not be a last resort but instead should be used earlier, because prevention is definitely better than cure.” (P. R. Schauer, schauep@ccf.org)
>>>PNN NewsWatch
* FDA yesterday issued new scientific recommendations aimed at encouraging more widespread innovation and development of novel medication-assisted treatment (MAT) drugs for the treatment of opioid use disorder (OUD). The draft guidance outlines new ways for drug developers to consider measuring and demonstrating the effectiveness and benefits of new or existing MAT products. MAT, coupled with relevant social, medical, and psychological services, is a highly effective treatment for OUD.

PNN Pharmacotherapy Line
Aug. 8, 2018 * Vol. 25, No. 152
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Aug. 7 issue of JAMA (2018; 320).
Opioid Overdose After Surgical Discharge: While rare, opioid overdoses were more frequent in surgical patients during the first month after discharge, a study shows (pp. 502–4). Analysis of data on 13.5 million beneficiaries from a nationwide commercial insurer show these risks among 1.3 million patients who had one of 22 prespecified surgical procedures: “Of the total patient sample, 134 were found to have an opioid overdose within 30 days of surgical discharge (0.01%). The frequency of overdose decreased over time after the operation with 10.3 overdoses (95% CI, 8.7–12.2) per 100,000 surgeries within 30 days after surgical discharge and 3.2 overdoses (95% CI, 2.3–4.3) per 100,000 surgeries within 61 to 90 days after surgical discharge (P < .001). The frequency of overdoses increased with increasing amounts of preoperative opioid use with 2.8 overdoses (95% CI, 1.9–4.1) per 100,000 surgeries for opioid-naive patients within 30 days of discharge and 142.5 overdoses (95% CI, 100.4–202.2) per 100,000 surgeries for patients taking more than 100 mg of daily morphine equivalents (P < .001). Overdose rates varied by surgical procedure, with the highest rates observed in patients undergoing lower extremity amputation and spinal fusion.” (K. Ladha, karim.ladha@uhn.ca)
Opioid Use After Wisdom Tooth Extraction: Following wisdom tooth extraction, opioid-naive patients who filled a perioperative opioid prescription had higher odds of persistent opioid use than those not obtaining the drugs (pp. 504–6). Deidentified insurance claims from the national MarketScan database were used to analyze outcomes for 70,942 patients who underwent wisdom tooth extraction: “56,686 patients filled and 14,256 patients did not fill a perioperative opioid prescription. Hydrocodone was the most common (70.3%), followed by oxycodone (24.3%). Compared with patients who did not fill an opioid prescription, patients who filled an opioid prescription were more often younger and female with higher rates of chronic pain, depression, anxiety, preoperative prescription use, and tooth impaction.
“Persistent opioid use occurred at an adjusted rate of 13 (95% CI, 9–19) per 1,000 patients with a filled opioid prescription compared with 5 (95% CI, 3–7) per 1,000 patients without a filled perioperative prescription. Controlling for patient characteristics, a filled perioperative opioid prescription was independently associated with persistent opioid use (adjusted odds ratio [OR], 2.69; 95% CI, 2.10–3.44).…” (C. M. Brummett,
cbrummet@umich.edu)
Probiotics & C. diff During Antibiotic Therapy: “Moderate-quality evidence suggests that probiotics are associated with a lower risk of Clostridium difficile infection and very low-quality evidence suggests that probiotics are associated with fewer adverse events vs placebo or no treatment,” conclude authors of a JAMA Clinical Evidence Synopsis (pp. 499–500). Based on 39 randomized controlled trials, 31 of which provided data on C. difficile infections (CDI), the authors report: “Probiotics were associated with a lower risk of CDI, adverse events, and antibiotic-associated diarrhea. In a post hoc analysis, a statistically significant association between probiotic use and the risk of CDI was found among trials with a high baseline CDI risk (>5%). However, the subgroup with a CDI risk of 3% to 5% was likely underpowered. Typical US hospitals have a CDI risk below 5%.” (B. C. Johnston, bjohnston@dal.ca)
Broad-Based Genomic Sequencing in NSCLC: In the community setting, broad-based testing for EGFR/ALK alterations in patients with advanced non–small cell lung cancer is of limited value, researchers report (pp. 469–77), concluding that it “directly informed treatment in a minority of patients and was not independently associated with better survival.” (C. J. Presley, carolyn.presley@osumc.edu)
This is “precisely the time for precision” in use of molecular tests, editorialists write (
pp. 445–6): “[This study] provides important insights into how broad-based genomic sequencing is used in the community oncology setting, where the majority of patients with advanced NSCLC in the United States receive care. However, the limitations of this investigation suggest that the authors’ conclusion that broad testing is not warranted should be tempered to ensure that patients receive the right therapy for the right alteration at the right time.” (P. A. Bunn Jr, paul.bunn@ucdenver.edu)

PNN Pharmacotherapy Line
Aug. 9, 2018 * Vol. 25, No. 153
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Aug. 9 issue of the New England Journal of Medicine (2018; 379).
Infant Growth & Vitamin D Supplements During Pregnancy/Lactation: Fetal or infant growth was unchanged when mothers in impoverished areas received vitamin D supplements from mid-pregnancy through 6 months after birth, a study shows (pp. 535–46). Conducted in Bangladesh, the trial tested weekly vitamin D supplements in amounts of 4,200 IU, 16,800 IU, and 28,000 IU, with these results: “Among 1,164 infants assessed at 1 year of age (89.5% of 1,300 pregnancies), there were no significant differences across groups in the mean (± SD) length-for-age z scores. Scores were as follows: placebo, −0.93 ± 1.05; prenatal 4,200, −1.11 ± 1.12; prenatal 16,800, −0.97 ± 0.97; prenatal 28,000, −1.06 ± 1.07; and prenatal and postpartum 28,000, −0.94 ± 1.00 (P = 0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose.” (D. E. Roth, daniel.roth@sickkids.ca)
Closed-Loop Insulin Delivery in Noncritical Care: In 136 adults with type 2 diabetes hospitalized for noncritical care, a closed-loop delivery system (artificial pancreas) produced significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia, researchers report (pp. 547–56). At two hospitals in the U.K. and Switzerland, therapy with the closed-loop insulin-delivery system produced these results based on a primary end point of percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge: “The mean (± SD) percentage of time that the sensor glucose measurement was in the target range was 65.8 ± 16.8% in the closed-loop group and 41.5 ± 16.9% in the control group, a difference of 24.3 ± 2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P <0.001); values above the target range were found in 23.6 ± 16.6% and 49.5 ± 22.8% of the patients, respectively, a difference of 25.9 ± 3.4 percentage points (95% CI, 19.2 to 32.7; P <0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P <0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P = 0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P = 0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group.” (R. Hovorka, rh347@cam.ac.uk)
>>>PNN NewsWatch
* FDA has approved mogamulizumab-kpkc (Poteligeo, Kyowa Kirin) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. The agent is a humanized monoclonal antibody directed against CC chemokine receptor 4. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.
* Acting through a new pathway designed to increase competition for single-source products,
FDA yesterday approved several strengths of potassium chloride oral solutions from Apotex as the first generic drugs to receive a Competitive Generic Therapy (CGT) designation. A drug can be designated as a CGT if there is inadequate generic competition for that drug, meaning there is not more than one approved drug in the active section of the Orange Book.
*
Product Quest voluntarily recalling lot 173089J of CVS Health 12 Hour Sinus Relief Nasal Mist to the consumer level because of contamination with Pseudomonas aeruginosa.

PNN Pharmacotherapy Line
Aug. 10, 2018 * Vol. 25, No. 154
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
Aug. issue of Chest (2018; 154).
Managing Low-Risk Pulmonary Embolism Without Hospitalization: Low-risk patients with acute pulmonary embolism (PE) can be safely and acceptably managed without hospitalization, researchers report (pp. 249–56). A total of 200 consecutive adults seen in five emergency departments had objectively confirmed acute PE and low risk as indicated by Pulmonary Embolism Severity Index (PESI) scores of less than 86, echocardiography, and whole-leg compression ultrasound (CUS). Participants were observed in emergency departments or hospitals (on observation status) and then treated with FDA-approved therapeutic anticoagulation. Based on a primary outcome of a 90-day composite rate of all-cause mortality, recurrent symptomatic venous thromboembolism (VTE), and major bleeding, results showed: “The composite outcome occurred in one of 200 patients (90-day composite rate = 0.5%; 95% CI, 0.02%–2.36%). No patient suffered recurrent VTE or died during the 90-day follow-up period. A major bleed occurred in one patient. Patients indicated a high level of satisfaction with their care.” (J. R. Bledsoe, Joseph.bledsoe@imail.org)
Reacting to these findings, an editorialist writes, “Intermountain Healthcare has once again demonstrated that innovation, collaboration, and dedication are a powerful mix that can transform usual practice to potentially best practice” (
pp. 233–4). “These investigators have streamlined the workup of PE risk stratification and have devised and tested a protocol that accurately identifies a low-risk population that can be treated safely without hospitalization. We owe them our congratulations and admiration.” (S. Z. Goldhaber, sgoldhaber@partners.org)
>>>Circulation Report
Source:
Aug. 7 issue of Circulation (2018; 138).
Sacubitril/Valsartan as an Antiarrhythmic Drug: Authors explore the possibility that sacubitril/valsartan, the first in the angiotensin receptor neprilysin inhibitor class, has antiarrhythmic properties (pp. 551–3): “No randomized [implantable cardioverter defibrillator (ICD)] trials have been performed yet in patients receiving sacubitril/valsartan, but it is reasonable to assume that, as new therapies improve overall survival and reduce sudden death, the additional survival benefit provided by an ICD will become narrower. In this new era of [heart failure (HF)] management, we may need to reassess the role of ICDs in primary prevention for patients with HF in the context of angiotensin receptor neprilysin inhibitor therapy added to beta-blockers and mineralocorticoid receptor antagonists, especially if evidence continues to suggest antiarrhythmic effects of sacubitril/valsartan.” (A. Bayes-Genis, abayesgenis@gmail.com)
NOACs & Catheter Ablation: Authors of a review look at management of patients with atrial fibrillation (AF) undergoing catheter ablation while on non-vitamin K antagonist oral anticoagulants (NOACs) (pp. 627–33): “Whereas observational studies and randomized controlled trials support the safety and efficacy of uninterrupted NOAC strategy for AF catheter ablation, recent experiences have questioned this point, showing a greater unfractionated heparin requirement in NOAC-treated patients compared with vitamin K antagonists–treated patients to achieve the target activated clotting time.… A thorough appreciation of the physiology of anticoagulation during AF catheter ablation and the relevant differences between vitamin K antagonists and NOACs is required, while also understanding the limitations of activated clotting time measurement with regard to accurate intraprocedural anticogulation monitoring. This review aims to provide a critical look at this relatively ignored aspect of AF catheter ablation, especially pitfalls in NOAC monitoring, and to identify gaps in knowledge that need to be addressed in the near future.” (A-C Martin, ac.martin75@gmail.com)
>>>PNN NewsWatch
* The national prevalence of opioid use disorder among women at the time of delivery increased 333% between 1999 and 2014, according to this week’s Morbidity and Mortality Weekly Report (pp. 845–9). Another article shows that the rate of naloxone administration events by emergency medical technicians increased 75.1% in 2012–16 (pp. 850–3).

PNN Pharmacotherapy Line
Aug. 13, 2018 * Vol. 25, No. 155
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Aug. 11 issue of Lancet (2018; 392).
Excess Mortality in T1D: Patients who develop type 1 diabetes at earlier ages are have 5 times the risk of mortality and cardiovascular outcomes, a study shows, particularly women (pp. 477–86). A greater emphasis on cardioprotection is needed for these patients based on data from a national study in Sweden for 1998 through 2012: “Patients who developed type 1 diabetes at 0–10 years of age had hazard ratios of 4.11 (95% CI 3.24–5.22) for all-cause mortality, 7.38 (3.65–14.94) for cardiovascular mortality, 3.96 (3.06–5.11) for non-cardiovascular mortality, 11.44 (7.95–16.44) for cardiovascular disease, 30.50 (19.98–46.57) for coronary heart disease, 30.95 (17.59–54.45) for acute myocardial infarction, 6.45 (4.04–10.31) for stroke, 12.90 (7.39–22.51) for heart failure, and 1.17 (0.62–2.20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26–30 years were 2.83 (95% CI 2.38–3.37) for all-cause mortality, 3.64 (2.34–5.66) for cardiovascular mortality, 2.78 (2.29–3.38) for non-cardiovascular mortality, 3.85 (3.05–4.87) for cardiovascular disease, 6.08 (4.71–7.84) for coronary heart disease, 5.77 (4.08–8.16) for acute myocardial infarction, 3.22 (2.35–4.42) for stroke, 5.07 (3.55–7.22) for heart failure, and 1.18 (0.79–1.77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1.9 (95% CI 1.71–2.11) per 100,000 person–years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17.7 life–years (95% CI 14.5–20.4) for women and 14.2 life–years (12.1–18.2) for men.” (A. Rawshani, araz.rawshani@gu.se)
Sodium, BP & CVD: The Prospective Urban Rural Epidemiology study, still ongoing in 21 countries, shows interesting associations between community-level sodium and potassium intake and cardiovascular disease and mortality (pp. 496–506). “Sodium intake was associated with cardiovascular disease and strokes only in communities where mean intake was greater than 5 g/day,” the authors conclude. “A strategy of sodium reduction in these communities and countries but not in others might be appropriate.” The study shows a nonlinear relationship between sodium intake and adverse outcomes. Those in the lowest tertile of intake (mean, 4.4 g/day) had fewer negative outcomes, while those in the middle (4.43–5.08 g/day) had no significant changes in risk and those in the highest tertile (>5.08 g/day) had a positive but nonsignificant association with cardiovascular risk and mortality. (A. Mente, andrew.mente@phri.ca)
>>>PNN NewsWatch
* FDA on Friday approved these new prescription drugs: patisiran (Onpattro, Alnylam Pharmaceuticals) infusion for treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis in adult patients and migalastat (Galafold, Amicus Therapeutics U.S.), the first oral medication for the treatment of adults with Fabry disease. Both agents were designated orphan drugs and reviewed on expedited bases, and patisiran is the first in a new class of small interfering ribonucleic acid drugs.
* Two new approaches to contraception were approved by FDA on Friday. Annovera is a vaginal ring containing
segesterone acetate and ethinyl estradiol; indicated for women of reproductive age to prevent pregnancy, it is the first vaginal ring contraceptive that can be used for an entire year. It is worn for 3 weeks and removed for 1 week, providing a hormone-free period in which the menstrual period can occur. FDA also permitted marketing of the first mobile medical application, Natural Cycles, for contraception through a “fertility awareness” app that predicts fertility based on daily body temperature readings and menstrual cycle timing. It is intended for use in premenopausal women aged 18 and older.
>>>PNN JournalWatch
* Is Parotitis One More Complication of Influenza? The Ongoing Challenge of Determining Causal Associations, in Clinical Infectious Diseases, 2018; 67: 502–3. (A. T. Pavia, andy.pavia@hsc.utah.edu)
*
Prophylactic Antimicrobial Therapy for Acute Aspiration Pneumonitis, in Clinical Infectious Diseases, 2018; 67: 513–8. (J. A. Leis, jerome.leis@sunnybrook.ca)
*
Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update, in Journal of Clinical Oncology, 2018; 36: 2433–43. (N. Denduluri)

PNN Pharmacotherapy Line
Aug. 14, 2018 * Vol. 25, No. 156
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Early-online articles from and Aug. issue of JAMA Internal Medicine (2018; 178).
SGLT-2 Inhibitors & Lower Extremity Amputation: Compared with use of some antidiabetic medications in patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT-2) inhibitor therapy may be associated with increased risk of lower-extremity amputation, researchers report (10.1001/jamainternmed.2018.3034). The CANVAS clinical trial previously linked use of the SGLT-2 inhibitor canagliflozin with increased risk of this adverse outcome. In the current study, retrospective cohort analysis of Truven Health MarketScan Commercial Claims and Encounters data for 2012–15 showed these associations between five outcomes and use of older oral medications, dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single group, or SGLT-2 inhibitors: “Among 2.0 million potentially eligible individuals, a total of 953,906 (516,046 women and 437,860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39,869 new users of SGLT-2 inhibitors (4.2%), 105,023 new users of DPP-4 inhibitors (11.0%), and 39,120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10,000 person–years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10,000 person–years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85–2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64–3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19–3.77). These results persisted in sensitivity analyses.” (G. C. Alexander, galexand@jhsph.edu)
This study “helps to contextualize the risk in a relatively low-risk patient population, but does not settle the debate,” editorialists write (
10.1001/jamainternmed.2018.3025). “It remains unclear if the risk of amputation is a class effect for all SGLT-2 inhibitors and how the risk observed in CANVAS will translate to older and sicker patients not included in the [current] study.… Until more data are available, the results of CANVAS provide the greatest evidence that canagliflozin is associated with an increased risk of amputation and should influence our prescribing accordingly.” (M. A. Fischer, mfischer@bwh.harvard.edu)
Tamsulosin & Ureteral Stone Passage: In a placebo-controlled trial of 512 emergency department patients, the alpha-blocker tamsulosin failed to increase the rate of passage of kidney stones smaller than 9 mm in diameter (pp. 1051–7). Using a primary outcome of stone passage based on visualization or capture by the study participant by day 28, the investigators found: “Stone passage rates were 50% in the tamsulosin group and 47% in the placebo group (relative risk, 1.05; 95.8% CI, 0.87–1.27; P = .60), a nonsignificant difference. None of the secondary outcomes were significantly different.” (A. C. Meltzer, ameltzer@mfa.gwu.edu)
Medical expulsive therapy continues to be an attractive option when patients present to the emergency department with renal colic, editorialists write (
pp. 1058–9). Stones of less than 5 mm in diameter often pass spontaneously, and data emerging from a large Chinese trial indicate that use of tamsulosin can benefit those with larger stones, the authors write. (J. M. Hollingsworth, kinks@med.umich.edu)
>>>PNN NewsWatch
* FDA has announced recall of all unexpired lots of Westminster Pharmaceuticals Levothyroxine and Liothyronine (Thyroid Tablets, USP) 15 mg, 30 mg, 60 mg, 90 mg, and 120 mg to the wholesale level because of possible adulteration, and lot 112710 of World Organix Blissful Remedies Red Maeng Da 100% Mitragyna Speciosa capsules, Blissful Remedies Red Maeng Da Liquid Kratom Mitragyna Speciosa, Blissful Remedies 4 Hour Chill Slow Motion Blend to the consumer level because of microbial contamination.

PNN Pharmacotherapy Line
Aug. 15, 2018 * Vol. 25, No. 157
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Aug. 14 issue of JAMA (2018; 320).
Polypill Treatment of Blood Pressure: In a study conducted in Sri Lanka of patients with hypertension, those receiving a single pill containing low doses of 3 antihypertensive medications had significantly lower blood pressures (BPs) than those receiving usual care (pp. 566–79). The open-label trial enrolled patients at 11 urban hospital clinics who had hypertension requiring treatment initiation (untreated patients) or escalation (patients receiving monotherapy). The once-daily polypill contained telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg. Results were as follows: “Among 700 randomized patients (mean age, 56 years; 58% women; 29% had diabetes; mean baseline systolic/diastolic BP, 154/90 mm Hg), 675 (96%) completed the trial. The triple combination pill increased the proportion achieving target BP vs usual care at 6 months (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Mean systolic/diastolic BP at 6 months was 125/76 mm Hg for the triple combination pill vs 134/81 mm Hg for usual care (adjusted difference in postrandomization BP over the entire follow-up: systolic BP, −9.8 [95% CI, −7.9 to −11.6] mm Hg; diastolic BP, −5.0 [95% CI, −3.9 to −6.1] mm Hg; P < .001 for both comparisons). Overall, 419 adverse events were reported in 255 patients (38.1% for triple combination pill vs 34.8% for usual care) with the most common being musculoskeletal pain (6.0% and 8.0%, respectively) and dizziness, presyncope, or syncope (5.2% and 2.8%). There were no significant between-group differences in the proportion of patient withdrawal from BP-lowering therapy due to adverse events (6.6% for triple combination pill vs 6.8% for usual care).” (R. Webster, rwebster@georgeinstitute.org.au)
“Efficiency gains from fixed-dose combination therapy will likely be greater in settings in which barriers are more prevalent than in the United States, and these barriers include complex drug supply chain, limited access to medications, and shortage of health care workers to titrate medications.,” editorialists write (
pp. 552–4). “The global scale of elevated BP suggests that an intervention like a fixed-dose combination … is more likely to be sustained than more complex, labor-intensive approaches.” (M. D. Huffman, m-huffman@northwestern.edu)
Preventing Cardiovascular Events in Patients at High Risk: The difficulty of choosing the best regimen for lowering risk of mortality and cardiovascular events in patients at high risk for or with cardiovascular disease is explored in a JAMA Clinical Evidence Synopsis article (pp. 593–4): Results were as follows: “The combination of aspirin and clopidogrel was associated with a lower risk of cardiovascular events compared with aspirin alone among patients at high risk for cardiovascular events and among patients with established cardiovascular disease but without coronary stents. However, the combination of aspirin and clopidogrel was not associated with lower mortality but was associated with an increased risk of bleeding. These results do not allow identification of a subset of patients who may benefit most from the combination of clopidogrel and aspirin.” (A. Squizzato, alessandro.squizzato@uninsubria.it)
Effects of Perinatal Marijuana Use: “The medical community should advise pregnant women to avoid perinatal [delta-9-tetrahydrocannabinol (THC)] exposure and intervene for women needing treatment, for children at risk for neurobiological and developmental problems, or for dyads at risk for negative outcomes associated with an untreated substance use disorder,” Viewpoint authors write (pp. 545–6). “Advice from medical professionals should be consistent: pregnant and lactating women should be advised to avoid cannabis use, and women (and men) caring for developing children also should be advised to maintain abstinence. Treatment programs for women with [cannabis use disorder] should be available and accessible, and gender and culturally specific, particularly during pregnancy and postpartum periods. Converging, systematic research is necessary at both the preclinical and clinical levels to address insufficient evidence regarding maternal cannabis use and to fully understand the short- and long-term effects of perinatal THC exposure, the effects of maternal cannabis use on fetal outcomes, and the consequences of polysubstance use in treatment and intervention efforts.” (L. M. Jansson, ljansson@jhmi.edu)

PNN Pharmacotherapy Line
Aug. 16, 2018 * Vol. 25, No. 158
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Aug. 16 New England Journal of Medicine (2018; 379).
Ibalizumab for Multidrug-Resistant HIV-1: A phase 3 study of 40 patients with multidrug-resistant HIV-1 infection shows benefits of treatment with the monoclonal antibody ibalizumab (pp. 645–54). The biologic agent is a humanized IgG4 monoclonal antibody that blocks entry of HIV-1 by noncompetitive binding to CD4. Study participants had failed multiple regimens of antiviral drugs and had viral loads of more than 1,000 copies of HIV-RNA per mL. Every-other-week doses of ibalizumab 800 mg produced these results when administered in combination with patients’ usual regimens: “A total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P <0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy.” (S. Lewis, slewis@taimedbio.com)
Smoking, Weight & Diabetes/CVD Outcomes: Two studies and an editorial examine the interplay among smoking, weight, and other common disease risk factors.
Weight gain following smoking cessation was detrimental in three cohort studies conducted in the U.S., particularly with respect to a short-term increase in type 2 diabetes (
pp. 623–32). Still, those risks “did not mitigate the benefits of quitting smoking on reducing cardiovascular and all-cause mortality,” the investigators write. “The risk of type 2 diabetes was higher among recent quitters (2 to 6 years since smoking cessation) than among current smokers (hazard ratio, 1.22; 95% confidence interval [CI], 1.12 to 1.32). The risk peaked 5 to 7 years after quitting and then gradually decreased. The temporary increase in the risk of type 2 diabetes was directly proportional to weight gain, and the risk was not increased among quitters without weight gain (P <0.001 for interaction). In contrast, quitters did not have a temporary increase in mortality, regardless of weight change after quitting.” (Q. Sun, qisun@hsph.harvard.edu)
Analysis of the Swedish National Diabetes Register shows that patients with type 2 diabetes who controlled five risk factors had “little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population” (
pp. 633–44). The factors were elevated glycated hemoglobin level, elevated LDL cholesterol level, albuminuria, smoking, and elevated blood pressure. “In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death,” the author report. (A. Rawshani, aidin.rawshani@gu.se)
“Given the high prevalence of obesity and the related increase in type 2 diabetes, prevention of cardiovascular complications is essential,” an editorialist writes in reaction to these studies (
pp. 684–5). “These two articles provide support for control of cardiovascular risk factors in patients with diabetes, as well as reassurance that the benefits of smoking cessation outweigh the risks of obesity-associated diabetes. A cautionary note is that pathways to target levels of risk-factor variables are not always straightforward and often involve issues of lifestyle, adherence to medication, and other behaviors that are hard to modify, despite best attempts. For vulnerable populations, risk-factor control may be especially challenging, as shown by the widening health gap between social classes.” (S. A. Schroeder)

PNN Pharmacotherapy Line
Aug. 17, 2018 * Vol. 25, No. 159
Providing news and information about medications and their proper use

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>>>Vaccine Highlights
Source:
Aug. 23 issue of Vaccine (2018; 36).
Polysaccharides, Beta-Glucans as Vaccine Adjuvants: In the first of two reviews on vaccine adjuvants, authors describe research that is increasing the effects of polysaccharides on immunogenicity (pp. 5226–34): “Polysaccharide adjuvants have attracted much attention in the preparation of nano vaccines and nano drugs because natural polysaccharides have the characteristics of intrinsic immunomodulating, biocompatibility, biodegradability, low toxicity and safety. Moreover, it has been proved that a variety of natural polysaccharides possess better immune promoting effects, and they can enhance the effects of humoral, cellular and mucosal immunities. In the present study, we systematically reviewed the recent studies on polysaccharides with vaccine adjuvant activities, including chitosan-based nanoparticles, glucan, mannose, inulin polysaccharide and Chinese medicinal herb polysaccharide. The application and future perspectives of polysaccharides as adjuvants were also discussed. These findings lay a foundation for the further development of polysaccharide adjuvants. Collectively, more and more polysaccharide adjuvants will be developed and widely used in clinical practice with more in-depth investigations of polysaccharide adjuvants.” (K. Zhao, zhaokai@hlju.edu.cn)
The second review focuses specifically on “application of beta-glucans as immune adjuvants, the receptors of beta-glucans, as well as their structure and activity relationship which will benefit future research” (
pp. 5235–44): “Beta-glucans [are] a group of polysaccharides [that] exist in many organism species such as mushrooms, yeasts, oats, barley, seaweed, but not mammalians, [and] have a variety of biological activities and applications in drugs and other healthcare products. In recent years, beta-glucans have been studied as adjuvants in anti-infection vaccines as well as immunomodulators in anti-cancer immunotherapy. Beta-glucans can regulate immune responses when administered alone and can connect innate and adaptive immunity to improve immunogenicity of vaccines. When beta-glucans act as immunostimulants or adjuvants, a set of receptors have been revealed to recognize beta-glucans, including dectin-1, complement receptor 3, CD5, lactosylceramide, and so on.” (F. Wang, fswang@sdu.edu.cn)
>>>Infectious Diseases Report
Source:
Sept. 1 issue of Clinical Infectious Diseases (2018; 67).
Serious Infections With Ibrutinib: Used for treating patients with lymphoid cancer, ibrutinib is associated with a high risk of serious infections, including invasive fungal infections (IFIs), a study shows (pp. 687–92). Patients (n = 378) treated at Memorial Sloan Kettering Cancer Ctr. had these outcomes following receipt of the Bruton tyrosine kinase inhibitor in 2012–16: “The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and IFIs in 16 (37.2%).The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%).” (G. Redelman-Sidi, redelmag@mskcc.org)
Oseltamivir Initiated on Hospital Admission: Delays between symptom onset and time of hospitalization, combined with a failure to enroll the projected sample size, limit interpretations of a study showing no effect of starting oseltamivir on hospital admission for influenza-associated lower respiratory tract infections (pp. 736–42; J. Ramirez, j.ramirez@louisville.edu).
>>>PNN NewsWatch
* FDA yesterday approved the first generic epinephrine auto-injector (Teva) for emergency treatment of life-threatening allergic reactions in adults and pediatric patients who weigh more than 15 kg (33 pounds). Approved in 0.3 mg and 0.15 mg strengths, the products are equivalent to EpiPen and EpiPen Jr.
* FDA is convening a
workshop cohosted with NIH on Sept. 17 that will discuss microbiome-based products and how manipulation of the microbiome may potentially be used to prevent or treat a variety of diseases.

PNN Pharmacotherapy Line
Aug. 20, 2018 * Vol. 25, No. 160
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Aug. 18 issue of Lancet (2018; 392).
Oral Steroids in Otitis Media With Effusion: Oral steroids were statistically equivalent to placebo for preventing further hearing loss in children with otitis media with effusion for at least 3 months, OSTRICH trial investigators write (pp. 557–68). Study participants were 2 to 8 years of age when they were seen at 20 outpatient practices in England and Wales. Based on a primary outcome of audiometry-confirmed acceptable hearing at 5 weeks, the study showed these effects of oral prednisolone or placebo: “Between March 20, 2014, and April 5, 2016, 1,018 children were screened, of whom 389 were randomised. 200 were assigned to receive oral steroids and 189 to receive placebo. Hearing at 5 weeks was assessed in 183 children in the oral steroid group and in 180 in the placebo group. Acceptable hearing was observed in 73 (40%) children in the oral steroid group and in 59 (33%) in the placebo group (absolute difference 7% [95% CI −3 to 17], number needed to treat 14; adjusted odds ratio 1·36 [95% CI 0·88–2·11]; p = 0·16). There was no evidence of any significant differences in adverse events or quality-of-life measures between the groups.” (N. A. Francis, francisna@cardiff.ac.uk)
>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 362).
Length of Life in U.S., Other Developed Nations: Declines in life expectancy in high-income countries, coupled with increases in mortality among middle-aged adults in the U.S., are reported in two analyses of vital statistics.
While decreases in life expectancy during 2014–15 in several high-income countries were reversed in 2015–16, the U.S. and the U.K. experienced continued declines, a study shows (
k2562). In 18 member countries of the Organization for Economic Cooperation and Development, vital statistics show these patterns: “The majority of high income countries in the study experienced declines in life expectancy during 2014–15; of the 18 countries, 12 experienced declines in life expectancy among women and 11 experienced declines in life expectancy among men. The average decline was 0.21 years for women and 0.18 years for men. In most countries experiencing declines in life expectancy, these declines were predominantly driven by trends in older age (≥65 years) mortality and in deaths related to respiratory disease, cardiovascular disease, nervous system disease, and mental disorders. In the United States, declines in life expectancy were more concentrated at younger ages (0–65 years), and drug overdose and other external causes of death played important roles in driving these declines. (J. Y. Ho, jessicyh@usc.edu)
U.S. data for 1999–2016 show that “mortality in midlife in the U.S. has increased across racial-ethnic populations for a variety of conditions, especially in recent years, offsetting years of progress in lowering mortality rates” (
k3096). “This reversal carries added consequences for racial groups with high baseline mortality rates, such as for [non-Hispanic (NH)] blacks and NH American Indians and Alaskan Natives,” the authors write. “That death rates are increasing throughout the U.S. population for dozens of conditions signals a systemic cause and warrants prompt action by policy makers to tackle the factors responsible for declining health in the U.S.” (S. H. Woolf, steven.woolf@vcuhealth.org)
>>>PNN NewsWatch
* Torrent Pharmaceuticals is voluntarily recalling 14 lots of Valsartan/Amlodipine/HCTZ tablets to the consumer level because of they contain trace amounts of N-nitrosodimethylamine, a probable carcinogen, in an active pharmaceutical ingredient manufactured by Zhejiang Huahai Pharmaceuticals.
>>>PNN JournalWatch
* Review: Unmet Needs and the Path Forward in Joint Disease Associated With Calcium Pyrophosphate Crystal Deposition, in Arthritis & Rheumatology, 2018; 70: 1182–91. (R. Terkeltaub, rterkeltaub@ucsd.edu)
*
Allergic Fungal Rhinosinusitis, in Journal of Allergy and Clinical Immunology, 2018; 142: 341–51. (M. S. Dykewicz, Mark.dykewicz@health.slu.edu)
*
Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2018; 36: 2545–56. (D. P. S. Sohal)
*
Interim Futility Monitoring Assessing Immune Therapies With a Potentially Delayed Treatment Effect, in Journal of Clinical Oncology, 2018; 36: 10.1200/JCO.2018.77.7144. (E. L. Korn, korne@ctep.nci.nih.gov)

PNN Pharmacotherapy Line
Aug. 21, 2018 * Vol. 25, No. 161
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>>>Internal Medicine Report
Source:
Early-online articles from the Annals of Internal Medicine (2018; 169).
Life-Threatening Pregabalin–Opioid Interaction: In a population-based, nested case–control study of Ontario residents, investigators “found compelling evidence for a potentially life-threatening drug–drug interaction involving pregabalin and opioids similar to that previously observed with gabapentin and opioids” (10.7326/M18-1136). The study included people who were eligible for public drug coverage who received opioids in 1997–2016. Among 1,417 case patients who also received pregabalin and 5,097 matched controls, these risks were determined: “After multivariable adjustment, concomitant exposure to pregabalin in the preceding 120 days was associated with significantly increased odds of opioid-related death compared with exposure to opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 to 2.36]). We observed consistent results in sensitivity analyses evaluating pregabalin use overlapping the index date (aOR, 1.81 [CI, 1.26 to 2.60]) and after matching on prior use of CNS depressants (aOR, 2.00 [CI, 1.39 to 2.88]). In the dose–response analysis, a high dose of pregabalin was associated with markedly increased odds of opioid-related death relative to no pregabalin exposure (aOR, 2.51 [CI, 1.24 to 5.06]), whereas a low or moderate dose of pregabalin was associated with lower but still significant odds of opioid-related death (aOR, 1.52 [CI, 1.04 to 2.22]). As expected, we found no association between coprescription of nonsteroidal anti-inflammatory drugs with opioids and risk for opioid-related mortality (aOR, 1.04 [CI, 0.90 to 1.19]).” (T. Gomes)
U.S. HIV Suppression Trends Over Time: Between 1997 and 2015, HIV viral suppression rates improved significantly among people living with HIV (PLWH) in the U.S., a study shows, but inequities are evident among younger and black people (10.7326/M17-2242). Researchers used data from 8 HIV clinics to conduct a longitudinal observational cohort study aimed at measuring viral suppression (≤400 copies/mL) and link those types with antiretroviral therapy being used. Results showed: “Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31,930 PLWH. In adjusted analyses, being older (odds ratio [OR], 0.76 per decade [95% CI, 0.74 to 0.78]) and using an [integrase strand transfer inhibitor]-based regimen (OR, 0.54 [CI, 0.51 to 0.57]) were associated with lower odds of having a detectable [viral load (VL)], and black race was associated with higher odds (OR, 1.68 [CI, 1.57 to 1.80]) (P <0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression.” (H. M. Crane, hcrane@uw.edu)
“As we strive to end the HIV epidemic in the United States, targeted treatment interventions for populations with low levels of viral suppression, paired with tailored prevention packages, will be essential,” editorialists write (
10.7326/M18-1944). “Further studies, such as [the above one], will be critical in identifying the disparities that must be addressed to close these implementation gaps.” (A. S. Fauci, afauci@niaid.nih.gov)
Adverse Effects of Marijuana Use in Pregnancy: “Guidelines from the American College of Obstetricians and Gynecologists strongly recommend that clinicians screen for and advise against marijuana use during pregnancy, but pregnant women themselves perceive a lack of evidence about the harms of prenatal marijuana use, expressing dissatisfaction with the quality of evidence available and a desire for better information,” editorialists write (10.7326/M18-1141). “Investment in rigorous studies that characterize and quantify the health risks associated with prenatal marijuana use and include data on mode of marijuana administration, dosage, and trimester of use may provide findings with immediate clinical implications that could be actively disseminated to clinicians and patients. If adverse effects are substantiated, such evidence-based information might help change the perception that marijuana use during pregnancy carries little risk. This is important because evidence exists that women who quit using marijuana during pregnancy are more likely than those who do not to believe that prenatal marijuana may be harmful. Likewise, it is imperative that any evidence of risks not be exaggerated.” (K. C. Young-Wolff, kelly.c.young-wolff@kp.org)

PNN Pharmacotherapy Line
Aug. 22, 2018 * Vol. 25, No. 162
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>>>JAMA Report
Source:
Aug. 21 issue of JAMA (2018; 320).
Medicare Spending on Brand-name Combo Meds: During 2016, the Medicare Part D program spent almost $1 billion more for 29 brand-name combination prescription drug products than generic single-ingredient products would have cost, a study shows (pp. 650–6). The authors add, “Promoting generic substitution and therapeutic interchange through prescriber education and more rational substitution policies may offer important opportunities to achieve substantial savings” for Part D. Specific findings were as follows: “Among the 1,500 medications evaluated, 29 brand-name combination medications were separated into 3 mutually exclusive categories: constituents available as generic medications at identical doses (n = 20), generic constituents at different doses (n = 3), and therapeutically equivalent generic substitutes (n = 6). For the constituents available as generic medications at identical doses category, total spending by Medicare in 2016 on the brand-name combination products was $303 million and the estimated spending for the generic constituents would have been $68 million, which is an estimated difference of $235 million. For the generic constituents at different doses category, total spending by Medicare in 2016 on the brand-name combination products was $232 million and the estimated spending for the generic constituents would have been $13 million, which is an estimated difference of $219 million. For the therapeutically equivalent generic substitutes category, total spending by Medicare in 2016 on the brand-name combination products was $491 million and the estimated spending for the generic constituents would have been $20 million, which is an estimated difference of $471 million. In 2016, the estimated spending for the generic constituents for these 29 drugs would have been $925 million less than the estimated spending for the brand-name combinations. For the 10 most costly combination products available during the entire study period, the listed Medicare spending could have been an estimated $2.7 billion lower between 2011 and 2016 if the generic constituents had been prescribed.” (C. A. Sacks, csacks@partners.org)
CVD Health & Cognitive Decline, Incident Dementia: Among older adults, better cardiovascular health was associated with a lower dementia score and lower rates of cognitive decline, a study shows (pp. 657–64). Investigators used the American Heart Association’s Life’s Simple 7 metrics and a global cardiovascular health score and a composite score of global cognition to find the following: “Among 6,626 participants (mean age, 73.7 years; 4,200 women [63.4%]), 2,412 (36.5%), 3,781 (57.1%), and 433 (6.5%) had 0 to 2, 3 to 4, and 5 to 7 health metrics at optimal levels, respectively, at baseline. Over a mean follow-up duration of 8.5 (range, 0.6–16.6) years, 745 participants had incident adjudicated dementia. Compared with the incidence rate of dementia of 1.76 (95% CI, 1.38–2.15) per 100 person–years among those with 0 or 1 health metrics at optimal levels, the absolute differences in incident dementia rates for 2, 3, 4, 5, and 6 to 7 metrics were, respectively, −0.26 (95% CI, −0.48 to −0.04), −0.59 (95% CI, −0.80 to −0.38), −0.43 (95% CI, −0.65 to −0.21), −0.93 (95% CI, −1.18 to −0.68), and −0.96 (95% CI, −1.37 to −0.56) per 100 person–years. In multivariable models, the hazard ratios for dementia were 0.90 (95% CI, 0.84–0.97) per additional optimal metric and 0.92 (95% CI, 0.89–0.96) per additional point on the global score. Furthermore, the gain in global cognition associated with each additional optimal metric at baseline was 0.031 (95% CI, 0.009–0.053) standard units at inclusion, 0.068 (95% CI, 0.045–0.092) units at year 6, and 0.072 (95% CI, 0.042–0.102) units at year 12.” (C. Samieri, cecilia.samieri@u-bordeaux.fr)
This and another study (
pp. 665–73; P. Leeson, paul.leeson@cardiov.ox.ac.uk) “convey an immediately actionable message to clinicians, policy makers, and patients,” editorialists write (pp. 645–7). “Available evidence indicates that to achieve a lifetime of robust brain health free of dementia, it is never too early or too late to strive for attainment of ideal cardiovascular health. Avoid smoking, eat a healthy diet, be physically active, maintain normal weight, and keep blood pressure, cholesterol levels, and glucose-insulin levels low. Given the aging population, this positive health message is important to communicate to all members of society.” (J. L. Saver)

PNN Pharmacotherapy Line
Aug. 23, 2018 * Vol. 25, No. 163
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>>>NEJM Report
Source:
Aug. 23 issue of the New England Journal of Medicine (2018; 379).
Immunotherapy for Melanoma Metastatic to the Brain: Consistent with results outside the cranium, immunotherapy with nivolumab plus ipilimumab is effective in treatment of brain metastases in patients with melanoma, researchers report (pp. 722–33). In a phase 2 trial, patients with metastatic melanoma and at least one measurable brain metastasis had these responses to the drugs: “Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.” (H. A. Tawbi, htawbi@mdanderson.org)
“Unquestionably, [these data] show that checkpoint inhibitors can be as efficacious for CNS metastases as they are for extracranial metastases from melanoma,” editorialists write (
pp. 789–90). “Therefore, we would recommend additional, larger trials involving patients with CNS metastases not just from melanoma but also from kidney, lung, and other cancers in which checkpoint inhibitors are active. Such patients should no longer generally be excluded from clinical trials.” (S. Turajlic)
Talazoparib in Advanced Breast Cancer: A phase 3 trial of 431 patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2) shows that single-agent talazoparib produces significantly longer progression-free survival than standard chemotherapy (pp. 753–63). “Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P <0.001),” investigators write. “The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P = 0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P <0.001).” (J. K. Litton, jlitton@mdanderson.org)
Tranexamic Acid for Prevention of Postpartum Blood Loss: Reacting to nonsignificant differences in the Tranexamic Acid for Preventing Postpartum Hemorrhage Following a Vaginal Delivery (TRAAP) trial (pp. 731–42; L. Sentilhes, loicsentilhes@hotmail.com), editorialists reach this conclusion (pp. 790–2): “The TRAAP trial did not show a significantly lower incidence of postpartum hemorrhage with the active drug than with placebo, and at this point we would not recommend its use to prevent postpartum hemorrhage; larger trials involving women at high risk for postpartum hemorrhage will be useful in determining its value in prevention. The WOMAN-2 trial (ClinicalTrials.gov number, NCT03475342), which we are investigators for, is planned to quantify the effect of tranexamic acid therapy on postpartum hemorrhage and other maternal outcomes in 10,000 women with moderate or severe anemia.” (H. Shakur-Still)
>>>PNN NewsWatch
* FDA yesterday made its first drug approval for treatment of the rare degenerative disease neurotrophic keratitis. Cenegermin (Oxervate, Dompé farmaceutici SpA) is recombinant human nerve growth factor; it was approved after a priority review and designated an orphan drug.
* “
FDA has awarded a contract to the National Academies of Sciences, Engineering, and Medicine to help advance the development of evidence-based guidelines for appropriate opioid analgesic prescribing for acute pain resulting from specific conditions or procedures,” Commissioner Gottlieb said in a statement released yesterday. “The primary scope of this work is to understand what evidence is needed to ensure that all current and future clinical practice guidelines for opioid analgesic prescribing are sufficient, and what research is needed to generate that evidence in a practical and feasible manner.”

PNN Pharmacotherapy Line
Aug. 24, 2018 * Vol. 25, No. 164
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
Early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Caregiver-Based Medication Safety Interventions: In a systematic, evidence-based review of 8 studies, investigators find that caregiver-focused interventions to support medication safety in older adults with chronic disease yielded some improvements in caregiver medication knowledge and self-efficacy (10.1111/jgs.15556). Clinical outcomes and health care utilization were poorly studied, the authors add, based on these findings: “The strategies used in randomized trials were a home-based medication review and adherence assessment by a clinical pharmacist (2 home visits 6–8 weeks apart, with pharmacist and physician meeting independently) that found no difference in nonelective hospital admissions (p = .8) but fewer medications (p = .03); a 19-minute educational DVD and an hour-long medication education and training that improved caregiver satisfaction (p <.04); a medication education and adherence intervention (2–3 home visits per care recipient and caregiver dyad over 8 weeks) that found no difference in knowledge, administration, or accessibility of medications (p = .29); and a collaborative case management program (16-month program of assessment, meeting, and monthly follow-up telephone calls) that reduced perceived caregiver burden (p = .03). Quasi-experimental trials included collaborative care transitional coaches, an outpatient collaborative care model, and education and training programs. Of these, educational interventions showed improvements in self-efficacy, confidence, and preparedness. The collaborative care intervention reduced rehospitalizations (p = .04) and improved quality-of-care outcomes.” (K. C. Wagle, kwagle@iu.edu)
Antipsychotic Use in Older Adults After Cardiac Surgery: A retrospective cohort study of 465 hospitals shows highly variable off-label antipsychotic medication (APM) use in older adults undergoing cardiac surgery and raises concerns about inappropriate use (10.1111/jgs.15418). National administrative data show these APM patterns in 293,212 older adults who had cardiac surgery and no known indication for APMs: “The rate of APM use declined from 8.8% in 2004 to 6.2% in 2014 (p <.001). Use of haloperidol (parenteral 7.0% to 4.5%, p <.001; oral: 1.9% to 0.5%, p <.001), and risperidone (1.1% to 0.3%, p <.001) declined, whereas quetiapine use tripled (0.6% to 1.9%, p = .03). Hospital APM prescribing intensity varied widely, from 0.3% to 35.6%, across 465 hospitals. Treated individuals at higher-prescribing hospitals were more likely to receive APMs on the day of discharge (highest vs lowest quintile: 15.1% vs 9.6%; p <.001) and for a longer duration (4.8 vs 3.7 days; p <.001) than those at lower-prescribing hospitals. Delirium was the strongest risk factor for APM exposure (odds ratio = 9.73, 95% confidence interval = 9.02–10.5), whereas none of the hospital characteristics were significantly associated. The rate of potentially excessive dosing declined (60.7% to 44.9%, p <.001), and risk factors for potentially excessive dosing were similar to those for any APM exposure.” (D. H. Kim, dkim12@bwh.harvard.edu)
Pain Among Hospitalized Older Adults: One-fifth of older adults admitted to the medicine service of a tertiary-care hospital had moderate-to-severe pain on admission, researchers report (10.1111/jgs.15459). Based on their treatment during hospitalization with opioids (80%) and acetaminophen (74%) but rarely NSAIDs (9%), the authors call for more research into how pain — especially chronic pain — is best managed. (C. Ritchie, christine.ritchie@ucsf.edu)
>>>PNN NewsWatch
* The number of adolescents who are up to date on HPV vaccination increased five percentage points from 2016 to 2017, according to results from a national survey in this week’s MMWR (2018;67:918–24). In 2017, nearly 66% of adolescents aged 13–17 years received the first dose to start the vaccine series, and nearly 49% of adolescents received all the recommended doses to complete the series.
*
King Bio is voluntarily recalling a number of pediatric OTC products to the consumer level because of possible microbial contamination.
*
FDA said yesterday that all 17 manufacturers, distributors, and retailers warned in May have stopped selling the nicotine-containing e-liquids used in e-cigarettes with labeling or advertising resembling kid-friendly food products.

PNN Pharmacotherapy Line
Aug. 27, 2018 * Vol. 25, No. 165
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Aug. 25 issue of Lancet (2018; 392).
Semaglutide for Weight Loss: Tested in patients with obesity, once-daily subcutaneous doses of the glucagon-like peptide-1 analogue semaglutide produced clinically relevant weight loss and was safe in a comparison with liraglutide and placebo, researchers report (pp. 637–49). The phase 2 trial, conducted in 8 countries, produced these intention-to-treat results based on a primary outcome of percentage of weight loss at week 52: “Mean baseline characteristics included age 47 years, body weight 111.5 kg, and BMI 39.3 kg/m2. Body weight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was −2.3% for the placebo group versus −6.0% (0.05 mg), −8.6% (0.1 mg), −11.6% (0.2 mg), −11.2% (0.3 mg), and −13.8% (0.4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p ≤0.0010), and remained significant after adjustment for multiple testing (p ≤0.0055). Mean body weight reductions for 0.2 mg or more of semaglutide versus liraglutide were all significant (−13.8% to −11.2% vs −7.8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37–65% receiving 0.1 mg or more of semaglutide (p <0.0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists.” (J. P. H. Wilding, j.p.h.wilding@liverpool.ac.uk)
Risankizumab in Moderate-to-Severe Plaque Psoriasis: The monoclonal IgG1 antibody risankizumab, an inhibitor of interleukin-23, had superior efficacy and similar adverse effects in a comparison with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis (pp. 650–61). Results from the replicate phase 3 UltIMMa-1 and UltIMMa-2 trials showed these results from 139 sites around the world: “At week 16 of UltIMMa-1, [Psoriasis Area Severity Index (PASI 90)] was achieved by 229 (75.3%) patients receiving risankizumab versus five (4.9%) receiving placebo (placebo-adjusted difference 70.3% [95% CI 64.0–76.7]) and 42 (42.0%) receiving ustekinumab (ustekinumab-adjusted difference 33.5% [22.7–44.3]; p <0.0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74.8%) patients receiving risankizumab versus two (2.0%) receiving placebo (placebo-adjusted difference 72.5% [95% CI 66.8–78.2]) and 47 (47.5%) receiving ustekinumab (ustekinumab-adjusted difference 27.6% [16.7–38.5]; p <0.0001 vs placebo and ustekinumab). In UltIMMa-1, [static Physician’s Global Assessment (sPGA) score of] 0 or 1 at week 16 was achieved by 267 (87.8%) patients receiving risankizumab versus eight (7.8%) receiving placebo (placebo-adjusted difference 79.9% [95% CI 73.5–86.3]) and 63 (63.0%) receiving ustekinumab (ustekinumab-adjusted difference 25.1% [15.2–35.0]; p <0.0001 vs placebo and ustekinumab). In UltIMMa-2, 246 (83.7%) patients receiving risankizumab versus five (5.1%) receiving placebo (placebo-adjusted difference 78.5% [95% CI 72.4–84.5]) and 61 (61.6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab-adjusted difference 22.3% [12.0–32.5]; p <0.0001 vs placebo and ustekinumab).…” (K. B. Gordon, kegordon@mcw.edu)
>>>PNN NewsWatch
* Torrent Pharmaceuticals has expanded its previously announced recall of Valsartan/Amlodipine/HCTZ tablets to include all lots of the product within expiry to the consumer level (see PNN, Aug. 20).
>>>PNN JournalWatch
* Intravenous Remifentanil Patient-Controlled Analgesia Versus Intramuscular Pethidine for Pain Relief in Labour (RESPITE): An Open-Label, Multicentre, Randomised Controlled Trial, in Lancet, 2018; 392: 662–72. (M. J. A. Wilson, m.j.wilson@sheffield.ac.uk)
*
Prescription Medications Account For One In Four Dollars Spent By A Commercial Health Plan [blog], in Health Affairs, 2018; 37: 10.1377/hblog20180821.820628. (M. Sherman)
*
Atypical Presentation of Pregnancy-Related Hemolytic Uremic Syndrome, in American Journal of Kidney Diseases, 2018; 72: 451–6. (J. A. Schaub, jschaub@pennstatehealth.psu.edu)
*
Patient-Important Adverse Events of Beta-blockers in Frail Older Adults after Acute Myocardial Infarction, in Journals of Gerontology: Series A, gly191. (A R. Zullo, andrew_zullo@brown.edu)

PNN Pharmacotherapy Line
Aug. 28, 2018 * Vol. 25, No. 166
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Rheumatology Report
Source:
Aug. issue of Arthritis & Rheumatology (2018; 70).
Allopurinol Dose Escalation & Mortality in Gout: The current practice of using limited allopurinol dose increases “is unlikely to improve the survival of patients with gout,” according to results of a 10-year, observational, active-comparator study of U.S. veterans (pp. 1298–307). Previous studies had associated gout and hyperuricemia with increased mortality, while allopurinol use was linked with reduced mortality. Two-year results for those whose doses were as follows: “Among the 6,428 dose escalators and 6,428 matched non-escalators, there were 2,867 deaths during the observation period (40.4 deaths per 1,000 person–years). Dose escalators experienced an increase in all-cause mortality (hazard ratio [HR] 1.08, 95% confidence interval [95% CI] 1.01–1.17), with the effect sizes being similar for incidence of cardiovascular-related deaths (HR 1.08, 95% CI 0.97–1.21) and cancer-related deaths (HR 1.06, 95% CI 0.88–1.27), although neither reached statistical significance. Dose escalation to achieve the goal of lowering the serum urate (SU) level to <6.0 mg/dl was infrequent. At 2 years, 10% of dose escalators were receiving a final daily dose of >300 mg and 31% had achieved the SU goal. In a sensitivity analysis limited to dose escalators achieving the SU goal, there was a nonsignificant reduction of 7% in the hazard of cardiovascular-related mortality (HR 0.93, 95% CI 0.76–1.14).” (T. R. Mikuls, tmikuls@unmc.edu)
Genetic Variation & IL-1 Antagonism in JIA: Taking “an important first step toward the personalized treatment of systemic [juvenile idiopathic arthritis (JIA)],” investigators link interleukin-1 receptor genetic variants with poor disease response to anakinra (pp. 1319–30). Single-nucleotide polymorphisms (SNPs) in 11 systemic JIA risk loci had these associations with disease markers and response to therapy: “We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10–4). Systemic JIA–associated SNPs correlated with IL1RN expression in [lymphoblastoid cell lines], with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2–255.8]).” (M. J. Ombrello, Michael.Ombrello@nih.gov)
>>>Health Affairs Highlights
Source:
Aug. issue of Health Affairs, a theme issue on Medicaid, Markets & More (2018; 37).
Medicaid Expansion & Treatment for Substance Use Disorders: While more low-income individuals were insured following expansion of state Medicaid programs under the Affordable Care Act, the coverage did not translate into increased treatment of substance use disorders, a study shows (pp. 1208–15). Data from 2008 to 2015 from the National Survey on Drug Use and Health showed the following: “The percentage of low-income expansion state residents with substance use disorders who were uninsured decreased from 34.4 percent in 2012–13 to 20.4 percent in 2014–15, while the corresponding decrease among residents of nonexpansion states was from 45.2 percent to 38.6 percent. However, there was no corresponding increase in overall substance use disorder treatment in either expansion or nonexpansion states. The differential increase in insurance coverage suggests that Medicaid expansion contributed to insurance gains, but corresponding treatment gains were not observed. Increasing treatment may require the integration of substance use disorder treatment with other medical services and clinical interventions to motivate people to engage in treatment.” (M. Olfson, mo49@cumc.columbia.edu)
Simplifying The Medicare Plan Finder Tool: Helping people make better use of CMS’s online Medicare Part D decision support tool is the goal of a study of hypothetical Part D choices (pp. 1290–7): “Reducing the amount of financial information displayed results in the selection of lower-cost plans, with no accompanying decrease in average plan quality or pharmacy network size but an increase in the take-up of convenience options such as a mail-order pharmacy,” the authors report. (B. E. McGarry, mcgarry@hcp.med.harvard.edu)

PNN Pharmacotherapy Line
Aug. 29, 2018 * Vol. 25, No. 167
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Aug. 28 issue of JAMA (2018; 320).
Pharmacotherapy of Alcohol Use Disorder: Better screening and diagnosis of alcohol use disorder (AUD) are needed, and those with the condition should be treated with FDA-approved medications, according to authors of a review article (pp. 815–24). Only about 8% of patients with AUD are treated in an alcohol treatment facility, the group notes, even though this “problematic pattern of alcohol use accompanied by clinically significant impairment or distress is present in up to 14% of US adults during a 1-year period.… Four medications are approved by the US Food and Drug Administration to treat AUD: disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate. However, patients with AUD most commonly receive counseling. Medications are prescribed to less than 9% of patients who are likely to benefit from them, given evidence that they exert clinically meaningful effects and their inclusion in clinical practice guidelines as first-line treatments for moderate to severe AUD. Naltrexone, which can be given once daily, reduces the likelihood of a return to any drinking by 5% and binge-drinking risk by 10%. Randomized clinical trials also show that some medications approved for other indications, including seizure disorder (eg, topiramate), are efficacious in treating AUD. Currently, there is not sufficient evidence to support the use of pharmacogenetics to personalize AUD treatments.” (H. R. Kranzler, kranzler@pennmedicine.upenn.edu)
A Rational Clinical Examination article explores how to predict whether hospitalized patients will develop severe alcohol withdrawal syndrome (SAWS) during admissions (
pp. 825–33). Published literature presents a variety of assessment tools for evaluating the risk of SAWS, as summarized in the article: “Of 530 identified studies, 14 high-quality studies that included 71,295 patients and 1,355 relevant cases of SAWS (1,051 cases), seizure (53 cases), or delirium tremens (251 cases) were analyzed. A history of delirium tremens ([likelihood ratios (LRs)], 2.9 [95% CI 1.7–5.2]) and baseline systolic blood pressure 140 mm Hg or higher (LR, 1.7 [95% CI, 1.3–2.3) were associated with an increased likelihood of SAWS. No single symptom or sign was associated with exclusion of SAWS. Six high-quality studies evaluated combinations of clinical findings and were useful for identifying patients in acute care facilities at high risk of developing SAWS. Of these combinations, the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) was most useful, with an LR of 174 (95% CI, 43–696; specificity, 0.93) when patients had 4 or more individual findings and an LR of 0.07 (95% CI, 0.02–0.26; sensitivity, 0.99) when there were 3 or fewer findings.” (E. Wood, bccsu-ew@bccsu.ubc.ca)
“Any efficacious treatment is better than no treatment for what can be a fatal chronic disease,” writes an editorialist (
pp. 766–8). “While awaiting better research and more effective treatments to be discovered, clinicians must focus on getting known effective medications into practice. Primary care is the logical place to treat this prevalent chronic illness, and trials find that treatment is effective there. Implementation research should now attend to better dissemination of screening for all adults with validated tools and treatment of all with alcohol use disorder, because it is not happening widely in practice.” (R. Saitz, Richard.Saitz@jamanetwork.org)
>>>PNN NewsWatch
* Reinforcing a previously announced voluntary recall of King Bio homeopathic drug and pet products, FDA yesterday warned of “a safety risk to people (especially infants, children, pregnant women and those with compromised immune systems), as well as pets due to high levels of microbial contamination identified at the [company’s] manufacturing site.”
*
Accord Healthcare is voluntarily recalling lot PW05264–46632 of Hydrochlorothiazide Tablets USP, 12.5 mg, to the consumer level because of a labeling mix-up.
*
Pfizer Consumer Healthcare is voluntarily recalling one lot of Children’s Advil Suspension Bubble Gum Flavored 4 fl oz bottle because of customer complaints that the dosage cup provided is marked in teaspoonfuls and the instructions on the label are described in milliliters.
*
FDA has added four online networks to the warnings it issued about the marketing of unapproved opioid medications.

PNN Pharmacotherapy Line
Aug. 30, 2018 * Vol. 25, No. 168
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Aug. 30 issue of the New England Journal of Medicine (2018; 379).
Bacterial Factors Predicting TB Relapse: For managing patients with tuberculosis, clinicians need to look beyond antibiotic breakpoints for Mycobacterium tuberculosis isolates, a study shows (pp. 823–33). Among participants in clinical trials, pretreatment isolates that were below the isoniazid or rifampin breakpoints but had higher minimum inhibitory concentrations (MICs) were associated with greater risk of relapse than isolates with lower MICs. (D. Alland, allandda@njms.rutgers.edu)
The MIC “values can be thought of more as probabilities of successful therapy than as absolute thresholds, a change in attitude that may dispel a false sense of security about the choice of regimen in the treatment of patients with tuberculosis,” writes an editorialist (
pp. 882–3). “If in vitro testing is not completely reliable, perhaps now is an opportunity to focus on the genetic determinants of treatment success. For example, much research effort is now being focused on the correlation between genomic sequencing of mycobacteria and in vitro antibiotic susceptibility testing, an approach that could be simpler and more rapid than current practice.” (E. J. Rubin)
Emicizumab Prophylaxis in Hemophilia A Without Factor VIII Inhibitors: Used as prophylaxis in people with hemophilia A without factor VIII inhibitors, the bispecific monoclonal antibody emicizumab was significantly more effective for preventing bleeding than no prophylaxis, researchers report (pp. 811–22). The agent “bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis,” the authors write, reaching this conclusion based on a trial of 152 participants: “Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis.” (J. Mahlangu, johnny.mahlangu@nhls.ac.za)
“Until more is known [about this agent], it will be important for discussions between providers and patients to focus on risk, benefit, cost, and participation in observational studies and clinical trials,” an editorialist writes (
pp. 880–2). “How might emicizumab therapy be implemented in the management of hemophilia? Will emicizumab be effective in treating acute bleeding? What is the role of age, severity, or degree of joint damage in the decision to switch to emicizumab therapy? What cost will society accept for a drug that reduces disease burden? Although emicizumab therapy is cost-effective in patients with a hemophilia inhibitor, is emicizumab prophylaxis cost-effective in a patient without an inhibitor who has a better response to treatment, higher quality of life, and fewer hospitalizations?” (M. V. Ragni)
Elements in the Poliovirus End Game: Responding to a study of vaccine-derived poliovirus (VDPV) outbreaks after the global withdrawal of trivalent oral vaccine (OPV) (pp. 834–45; I. M. Blake, isobel.blake@imperial.ac.uk), an editorialist discusses “a difficult move in the polio endgame” (pp. 801–3): “We still need to maintain a stockpile of polio vaccine for outbreak response. The existence of immunodeficient people who chronically excrete VDPV virus also necessitates an effective means of detection and intervention. Many of these issues will require additional research and development, including a better vaccine that produces mucosal immunity without the risk of VDPV, antivirals to treat chronic infections, and better surveillance tools for a world that will quickly forget about polio after eradication is achieved.” (M. A. Pallansch)
>>>PNN NewsWatch
* FDA is warning that cases of rare but serious necrotizing fasciitis of the perineum (Fournier’s gangrene) have been reported with use of SGLT2 inhibitors. Classwide information is being added to product labeling and Medication Guides.
* Possible
microbial contamination is the reason for recalls of Neuroveen, Respitrol, Thyroveev, and Compulsin (HelloLife) to the retail and consumer level, and one lot of CVS Health 12 Hour Sinus Relief Nasal Mist (Product Quest) to the retail level.

PNN Pharmacotherapy Line
Aug. 31, 2018 * Vol. 25, No. 169
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
Sept. issue of Diabetes Care (2018; 41).
Mini-Dose Glucagon for Exercise-Induced Hypoglycemia: Very low doses of glucagon provided a preferable option for preventing exercise-induced hypoglycemia in a study of participants with type 1 diabetes being treated with continuous subcutaneous insulin infusion, researchers report (pp. 1909–16). Mini-dose glucagon (MDG) 150 mcg subcutaneously was compared with no treatment, 50% reduction in basal insulin, and oral glucose 40 g in a crossover trial of 15 adults who exercised while fasting in the morning, with these results: “During exercise and early recovery from exercise, plasma glucose increased slightly with MDG compared with a decrease with control and insulin reduction and a greater increase with glucose tablets (P <0.001). Insulin levels were not different among sessions, whereas glucagon increased with MDG administration (P <0.001). Hypoglycemia (plasma glucose <70 mg/dL) was experienced by six subjects during control, five subjects during insulin reduction, and none with glucose tablets or MDG; five subjects experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one with MDG.” (S. N. DuBose, t1dstats@jaeb.org)
“Mini-dose glucagon was clearly a success in this study, both preventing hypoglycemia and minimizing the risk of hyperglycemia during the exercise period,” writes an editorialist (
pp. 1842–3). “Nausea was uncommon but did occur in two participants after eating. Another potential barrier to adoption of mini-dose glucagon is cost and the question of insurance coverage. One can clearly make a case that mini-dose glucagon could reduce the risk of unwanted weight gain that could otherwise occur with frequent rescue carbohydrate treatments. The use of mini-dose glucagon to avoid hypoglycemia may also reduce the risk of hypoglycemia unawareness that may occur with repeated episodes of hypoglycemia. Longer-term studies are needed to address these issues and also to evaluate the efficacy and safety of long-term glucagon therapy in the outpatient setting.” (J. R. Castle, castleje@ohsu.edu)
Sex, BMI & Antidiabetic Medications: Benefits and risks of thiazolidinedione and sulfonylurea therapy differ based on sex and body mass index (BMI) of patients being treated for type 2 diabetes, according to analysis of data from the U.K. Clinical Practice Research Datalink (CPRD) and two clinical trials (pp. 1844–53): “In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups.” (B. M. Shields, b.shields@exeter.ac.uk)
>>>PNN NewsWatch
* The spate of recalls of valsartan-containing products this summer is connected to a change in manufacturing of the valsartan active pharmaceutical ingredient (API) by Zhejiang Huahai Pharmaceutical Co., FDA officials write in a statement released yesterday. Seeking to determine how the carcinogenic impurity N-nitrosodimethylamine (NDMA) began showing up in the valsartan API, FDA writes: “A combination of conditions, which include certain chemicals, processing conditions and production steps, could lead to formation of the NDMA impurity. We believe that these risks are introduced through a specific sequence of steps in the manufacturing process, where certain chemical reactions are needed to form the active ingredient. Before we undertook this analysis, neither regulators nor industry fully understood how NDMA could form during this process. We are still not 100% sure that this is the root cause of the problem. Full understanding will require correlation of multiple test results from valsartan APIs made by different processes with the various process steps used by different manufacturers or at different times. We need to determine how NDMA can be formed and why it is not separated from the API during purification.”
*
PNN will not be published on Mon., Sept. 3, Labor Day.

PNN Pharmacotherapy Line
Sept. 4, 2018 * Vol. 25, No. 170
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-release article from and Sept. 4 issue of Annals of Internal Medicine (2018; 169).
TNF Inhibitors & Cancer Recurrence: In Swedish patients with rheumatoid arthritis and histories of cancer, use of tumor necrosis factor inhibitors (TNFi) was not statistically related to increased risk of cancer recurrence, researchers report, adding that “meaningful risk increases could not be ruled out completely” (pp. 291–9). The population-based cohort study relied on linked nationwide registers, producing these results: “Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2,164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2.” The authors note that one limitation of the study is that patients with better index cancer prognosis could have been more likely to receive TNFi therapy. (P. Raaschou, pauline.raaschou@sll.se)
Treatment Intensification in Type 2 Diabetes: The World Health Organization recommends the following regarding selection of medicines for treatment intensification in type 2 diabetes and use of insulin (human or analogue) in type 1 and 2 diabetes in low-resource settings (10.7326/M18-1149; G. Roglic, roglicg@who.int):
* Give a sulfonylurea to patients with type 2 diabetes who do not achieve glycemic control with metformin alone or who have contraindications to metformin (strong recommendation, moderate-quality evidence).
* Introduce human insulin treatment to patients with type 2 diabetes who do not achieve glycemic control with metformin and/or a sulfonylurea (strong recommendation, very-low-quality evidence).
* If insulin is unsuitable, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a sodium–glucose cotransporter-2 (SGLT-2) inhibitor, or a thiazolidinedione (TZD) may be added (weak recommendation, very-low-quality evidence).
* Use human insulin to manage blood glucose in adults with type 1 diabetes and in adults with type 2 diabetes for whom insulin is indicated (strong recommendation, low-quality evidence).
* Consider long-acting insulin analogues to manage blood glucose in adults with type 1 or type 2 diabetes who have frequent severe hypoglycemia with human insulin (weak recommendation, moderate-quality evidence for severe hypoglycemia).
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 362).
Opioid-Related Deaths in Ontario: Prescribed, diverted, and illicit opioids contributed to 2,833 opioid-related deaths in Ontario in 2013–16, a population-based cohort study shows (k3207). Postmortem toxicology results from the Drug and Drug/Alcohol Related Death database led investigators to this conclusion: “Although more than half of all opioid related deaths still involved prescription drugs (either dispensed or diverted) in 2016, the increased rate of deaths involving fentanyl between 2015 and 2016 is concerning and suggests the need for a multifactorial approach to this problem that considers both the prescribed and illicit opioid environments.” (T. Gomes, GomesT@smh.ca)
>>>PNN NewsWatch
* Camber Pharmaceuticals is recalling one lot of montelukast sodium tablets 10 mg, lot number MON17384, expiration 12/31/2019, because some bottles were found to contain 90 tablets of losartan potassium tablets 50 mg, FDA said.
>>>PNN JournalWatch
* A Scalable, Integrated Intervention to Engage People Who Inject Drugs in HIV Care and Medication-Assisted Treatment (HPTN 074): A Randomised, Controlled Phase 3 Feasibility and Efficacy Study, in Lancet, 2018; 392: 747–59. (W. C. Miller, miller.8332@osu.edu)
*
Diagnosis, Evaluation, and Management of High Blood Pressure in Children and Adolescents, in Pediatrics, 2018; 142: 10.1542/peds.2018-2096. (C. M. Baker-Smith et al., Subcommittee on Screening and Management of High BP in Children)
*
Marijuana Use During Pregnancy and Breastfeeding: Implications for Neonatal and Childhood Outcomes, in Pediatrics, 2018; 142: 10.1542/peds.2018-1889. (S. A. Ryan, et al., Subcommittee on Substance Use and Prevention, Section on Breastfeeding)

PNN Pharmacotherapy Line
Sept. 5, 2018 * Vol. 25, No. 171
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Sept. 4 issue of JAMA (2018; 320).
Biosimilar Filgrastim Uptake in Medicare Part B: Substantial uptake of the biosimilar alternative filgrastim-sndz occurred during 2014–16, according to an analysis of Medicare Part B billings (pp. 929–31). Use of the stand-alone alternative biologic tbo-filgrastim, which has a single indication, also increased during this period, as shown in these results: “Monthly administrations of any filgrastim product decreased by 13%, from 28,520 in January 2014 to 24,898 in December 2016. Monthly administrations of filgrastim-sndz increased to 32% of all filgrastim use and tbo-filgrastim increased to 16%, while the originator filgrastim product declined from 97% to 52%. Initial uptake of filgrastim-sndz was rapid, with monthly use surpassing tbo-filgrastim in March 2016.
“Beneficiaries who received filgrastim-sndz were on average slightly older. Product choice also differed by geographic region and original Medicare enrollment status. Among beneficiaries who received filgrastim-sndz, 22% had previously received the originator filgrastim and 73% were new users.” (S. Kozlowski,
steven.kozlowski@fda.hhs.gov)
Infliximab/Biosimilar Patient Costs Under Medicare Part D: Because manufacturer discounts for biologics and brand-name drugs during the Medicare Part D coverage gap do not apply to biosimilars, patients with rheumatoid arthritis have higher out-of-pocket costs for infliximab-dyyb than for the originator biologic product, researchers report (pp. 931–3). Data for all Part D plans from the June 2017 Medicare Prescription Drug Plan Formulary, Pharmacy Network, and Pricing Information Files were used to calculate mean total cost and out-of-pocket cost requirements for infliximab-dyyb and infliximab based on a standard 8-week dosing regimen that required 6.5 prescriptions per year, with these results: “Infliximab-dyyb had modestly lower mean total cost per 8-week prescription ($2,185 vs $2,667) and annually ($14,202 vs $17,335). However, plans universally required coinsurance cost-sharing for infliximab-dyyb, and set coinsurance rates similar to infliximab (26.6% vs 28.4% of drug cost, respectively). Without gap discounts, projected annual out-of-pocket costs were higher for infliximab-dyyb than infliximab ($5,118 vs $3,432).” The authors note that the recently passed Bipartisan Budget Act requires gap discounts for biosimilars beginning in 2019, but depending on drug pricing and plan cost-sharing requirements, that may not eliminate the difference in costs to the patient. (J. Yazdany, jinoos.yazdany@ucsf.edu)
Immediate v. Gradual Reduction in Cigarette Nicotine: In a group of smokers with no intention to quit within 30 days, immediate reduction in nicotine content of cigarettes was a better strategy than gradual reduction, a study shows (pp. 880–91). Used to measure smoke exposure were these toxicants: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons). Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes produced these results: “Among 1,250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, −4.06 parts per million [ppm] [95% CI, −4.89 to −3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, −3.38 [95% CI, −4.40 to −2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, −0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52).” (D. K. Hatsukami, hatsu001@umn.edu)

PNN Pharmacotherapy Line
Sept. 6, 2018 * Vol. 25, No. 172
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Sept. 6 issue of the New England Journal of Medicine (2018; 379).
Baloxavir Marboxil for Uncomplicated Influenza: An investigational selective inhibitor of influenza cap-dependent endonuclease, baloxavir marboxil performed well in two randomized, double-blind, controlled trials of otherwise healthy outpatients with acute uncomplicated influenza, but with signs of resistance (pp. 913–23). In a dose-ranging study and an active- and placebo-controlled comparative trial, “Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza,” the authors conclude based on these findings: “In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P <0.05). In the phase 3 trial, the intention-to-treat infected population included 1,064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P <0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.” (F. G. Hayden, fgh@virginia.edu)
“The significant reduction in influenza viral replication with baloxavir treatment suggests the potential for reducing influenza virus spread to close contacts and should be studied through randomized, controlled trials in households and during institutional influenza outbreaks such as in long-term care facilities,” writes an editorialist (
pp. 975–7). “If a single dose is successful in reducing influenza virus transmission, baloxavir could be a useful tool for seasonal and pandemic influenza preparedness and response. Further clinical, virologic, and transmission studies, and global surveillance for influenza viruses with reduced drug susceptibility, will inform the usefulness of baloxavir for clinical use and public health benefit.” (T. M. Uyeki)
Rituximab + Lenalidomide in Advanced Untreated Follicular Lymphoma: In the RELEVANCE trial of patients with previously untreated follicular lymphoma, rituximab plus lenalidomide was similarly effective as rituximab plus chemotherapy, with fewer adverse effects in some categories and more in others (pp. 934–47). The phase 3 trial compared the two regimens followed by maintenance rituximab therapy, with these results at 120 weeks and for progression-free survival: “A total of 1,030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab–lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab–chemotherapy group (P = 0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab–chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab–lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%).” (F. Morschhauser, franck.morschhauser@chru-lille.fr)
Quality of Care After Removal of Financial Incentives: In 2,819 primary care practices in England, removal of financial incentives was associated with an immediate decline in performance on quality measures, researchers report (pp. 948–57). While some evidence indicated that the decline was partially the result of decreased documentation in electronic medical records, orders for laboratory tests also dropped, which could reflect a change in care delivered. (B. Guthrie, b.guthrie@dundee.ac.uk)

PNN Pharmacotherapy Line
Sept. 7, 2018 * Vol. 25, No. 173
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Pediatrics Highlights
Source:
Sept. issue of Pediatrics (2018; 142).
Marijuana Use in Breastfeeding Mothers: The psychoactive ingredient in marijuana was detectable in breast milk for several days after maternal use, researchers report (10.1542/peds.2018-1076). In 50 breastfeeding women tested in 2014–17, concentrations of Δ-9-tetrahydrocannabinol (∆9-THC) and other components were as follows: “∆9-THC was detectable in 34 (63%) of the 54 samples up to ~6 days after last reported use; the median concentration of ∆9-THC was 9.47 ng/mL (range: 1.01–323.00). Five samples had detectable levels of 11-hydroxy-Δ-9-tetrahydrocannabinol (range: 1.33–12.80 ng/mL) or cannabidiol (range: 1.32–8.56 ng/mL). The sample with the highest concentration of cannabidiol (8.56 ng/mL) did not have measurable ∆9-THC. Cannabinol was not detected in any samples. The number of hours since last use was a significant predictor of log ∆9-THC concentrations (−0.03; 95% confidence interval [CI] −0.04 to −0.01; P = .005). Adjusted for time since last use, the number of daily uses and time from sample collection to analysis were also significant predictors of log ∆9-THC concentrations (0.51; 95% CI 0.03 to 0.99; P = .039; 0.08; 95% CI 0.00 to 0.15; P = .038, respectively).” (K. A. Bertrand)
Vaccine Studies: In three separate reports, investigators find that implementation of human papillomavirus (HPV) vaccine legislation has no impact on sexual behaviors of U.S. adolescents (10.1542/peds.2018-0458; E. E. Cook); prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination is not associated with autism spectrum disorder risk in offspring (10.1542/peds.2018-0120; T. A. Becerra-Culqui); and risk of primary ovarian insufficiency is not significantly increased after vaccination with HPV vaccine; tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed; inactivated influenza vaccine; or meningococcal conjugate vaccine (10.1542/peds.2018-0943; A. L. Naleway).
Rx Med Use Among American Children, Adolescents: In 2013–14, nearly 20% of American pediatric patients used at least 1 prescription medication, and 8.2% of concurrent medication users were at risk for serious drug–drug interactions, a study shows (10.1542/peds.2018-1042). “The vast majority of interacting regimens involved antidepressants and were more common among adolescent girls than boys (18.1% vs 6.6%; P < .05), driven largely by greater rates of use of acute medications,” the group writes. (D. M. Qato)
>>>Psychiatry Report
Source:
Sept. issue of American Journal of Psychiatry (2018; 175).
Pharmacogenetic Decision Support Tools for Antidepressant Drugs: After reviewing “the evidence base for several combinatorial pharmacogenetic decision support tools whose potential utility has been evaluated in clinical settings,” authors conclude that “at present, there are insufficient data to support the widespread use of combinatorial pharmacogenetic testing in clinical practice, although there are clinical situations in which the technology may be informative, particularly in predicting side effects” (pp. 873–86). “The accrual and analysis of genomic sequencing data have identified specific genetic variants that are associated with major depressive disorder,” the authors write. “Moreover, substantial investigations have been devoted to identifying gene–drug interactions that affect the response to antidepressant medications by modulating their pharmacokinetic or pharmacodynamic properties. Despite these advances, individual responses to antidepressants, as well as the unpredictability of adverse side effects, leave clinicians with an imprecise prescribing strategy that often relies on trial and error. These limitations have spawned several combinatorial pharmacogenetic testing products that are marketed to physicians. Typically, combinatorial pharmacogenetic decision support tools use algorithms to integrate multiple genetic variants and assemble the results into an easily interpretable report to guide prescribing of antidepressants and other psychotropic medications.” (Z. Zeier)
>>>PNN NewsWatch
* Beaumont Bio Med is voluntarily recalling its entire aqueous/alcohol-based homeopathic product line for human use, within expiry, to the consumer level. All products manufactured by the contract manufacturer, King Bio, have been recalled because of possible microbial contamination.

PNN Pharmacotherapy Line
Sept. 10, 2018 * Vol. 25, No. 174
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 362).
Primary CVD Prevention in Old and Very Old Adults: Among adults older than 74 years of age in Catalan, statins had diminishing benefits for primary prevention of cardiovascular disease (CVD) in those without diabetes but reduced atherosclerotic CVD and mortality in patients with diabetes to age 85, researchers report (k3359). Data in the Catalan primary care system for 2006–15 showed: “The cohort included 46,864 participants (mean age 77 years; 63% women; median follow-up 5.6 years). In participants without diabetes, the hazard ratios for statin use in 75–84 year olds were 0.94 (95% confidence interval 0.86 to 1.04) for atherosclerotic CVD and 0.98 (0.91 to 1.05) for all cause mortality, and in those aged 85 and older were 0.93 (0.82 to 1.06) and 0.97 (0.90 to 1.05), respectively. In participants with diabetes, the hazard ratio of statin use in 75–84 year olds was 0.76 (0.65 to 0.89) for atherosclerotic CVD and 0.84 (0.75 to 0.94) for all cause mortality, and in those aged 85 and older were 0.82 (0.53 to 1.26) and 1.05 (0.86 to 1.28), respectively. Similarly, effect analysis of age in a continuous scale, using splines, corroborated the lack of beneficial statins effect for atherosclerotic CVD and all cause mortality in participants without diabetes older than 74 years. In participants with diabetes, statins showed a protective effect against atherosclerotic CVD and all cause mortality; this effect was substantially reduced beyond the age of 85 years and disappeared in nonagenarians.” (R. Ramos, rramos.girona.ics@gencat.cat)
Diclofenac Use & Cardiovascular Risks: Based on 252 Danish cohort studies, diclofenac use elevated cardiovascular risk compared with nonuse, use of acetaminophen (paracetamol), or use of other NSAIDs (k3426): “The adverse event rate among diclofenac initiators increased by 50% compared with non-initiators (incidence rate ratio 1.5, 95% confidence interval 1.4 to 1.7), 20% compared with paracetamol or ibuprofen initiators (both 1.2, 1.1 to 1.3), and 30% compared with naproxen initiators (1.3, 1.1 to 1.5). The event rate for diclofenac initiators increased for each component of the combined endpoint (1.2 (1.1 to 1.4) for atrial fibrillation/flutter, 1.6 (1.3 to 2.0) for ischaemic stroke, 1.7 (1.4 to 2.0) for heart failure, 1.9 (1.6 to 2.2) for myocardial infarction, and 1.7 (1.4 to 2.1) for cardiac death) as well as for low doses of diclofenac, compared with non-initiators.… Diclofenac initiation also increased the risk of upper gastrointestinal bleeding at 30 days, by approximately 4.5-fold compared with no initiation, 2.5-fold compared with initiation of ibuprofen or paracetamol, and to a similar extent as naproxen initiation.” (M. Schmidt, morten.schmidt@clin.au.dk)
>>>PNN NewsWatch
* FDA on Friday approved buprenorphine and naloxone sublingual film (Cassipa, Teva) for the maintenance treatment of opioid dependence. This action provides a new dosage strength (16 mg/4 mg) of buprenorphine and naloxone sublingual film, which is also approved in both brand-name and generic versions and in various strengths.
* “Unfortunately, we continue to encounter compounders whose operations present serious public health risks,”
FDA Commissioner Scott Gottlieb, MD, wrote in a Friday statement announcing a revised draft memorandum of understanding with states concerning regulation of compounded drugs. “Sometimes, these involve situations where the compounders have already been warned to correct violations of law. We take our obligations in this area seriously. We’re committed to pursuing measures that promote greater safety. This field is in need of vigilant oversight. In such cases, it’s crucial that the FDA, in collaboration with the Department of Justice, act quickly to protect patients. So, we’re working to streamline our operations to expedite enforcement actions against compounders that threaten public health.”
>>>PNN JournalWatch
* Marijuana and Lung Disease, in Chest, 2018; 154: 653–63. (D. P. Tashkin, dtashkin@mednet.ucla.edu)
*
Heparin-Induced Thrombocytopenia in the Critically Ill Patient, in Chest, 2018; 154: 678–90. (J. T. Granton, john.granton@uhn.ca)
*
Orthostatic Hypotension: JACC State-of-the-Art Review, in Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.05.079. (R. Freeman)
*
Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure, in Circulation, 2018; 138: 1039–53. (S. J. Greene, stephen.greene@duke.edu)

PNN Pharmacotherapy Line
Sept. 11, 2018 * Vol. 25, No. 175
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-online articles from and Sept. issue of JAMA Internal Medicine (2018; 178).
Transitional Care Management in Medicare Fee-for-Service Patients: While usage is low, transitional care management (TCM) payment codes are associated with improved outcomes among Medicare Parts A, B, and D beneficiaries who are being discharged to the community from a hospital, an inpatient psychiatric facility, a long-term care hospital, a skilled nursing facility, an inpatient rehabilitation facility, or an outpatient facility for an observational stay, researchers report (pp. 1165–71). The codes, implemented in 2013 to cover a 30-day service that includes follow-up communication and a clinician visit, were evaluated based on fee-for-service claims involving 19 million eligible beneficiaries in 2013–15, with these results: “Of 18,756,707 eligible Medicare beneficiaries during the study period, 43.9% were male and had a mean (SD) age of 72.5 (13.8) years. Transitional care management services were billed following eligible discharges in 3.1% of cases in 2013, 5.5% in 2014, and 7.0% in 2015. The adjusted total Medicare costs ($3358; 95% CI, $3324–$3392 vs $3033; 95% CI, $3001–$3065; P < .001) and mortality (1.6%; 95% CI, 1.6%–1.6% vs 1.0%; 95% CI, 1.0%–1.1%; P < .001) were higher among those beneficiaries who did not receive TCM services compared with those who did receive TCM services in the 31 to 60 days following an eligible discharge.” (A. B. Bindman, andrew.bindman@ucsf.edu)
“The findings of Bindman and Cox support the conclusion that involvement of outpatient physicians in the management of transitional care for patients from medical facility back to the community can reduce readmission rates, lower mortality, and decrease health care costs,” editorialists write (
pp. 1171–3). “Like any improvement on the standard of care, diffusion of TCM will require workflow changes, investments in health care information technology, and a potential expansion of clinician capacity or staffing. The TCM services policy may need to be refined to more effectively align financial incentives with these goals.” (P. Huckfeldt, huckfeld@umn.edu)
Multicomponent Approach to Enhance Medication Taking: Among patients receiving medications for hyperlipidemia, hypertension, or diabetes, adherence was improved but outcomes unchanged by a remotely delivered, multicomponent, behaviorally tailored intervention, a study shows (pp. 1182–9). The intervention involved telephone-delivered behavioral interviewing by trained clinical pharmacists, text messaging, pillboxes, and mailed progress reports. Among adults aged 18 to 85 years who had suboptimal control of the target condition, these results were recorded based on a primary outcome of medication adherence as indicated by pharmacy refill records: “Fourteen practice sites with 4,078 participants had a mean (SD) age of 59.8 (11.6) years; 45.1% were female. Seven sites were each randomized to intervention or usual care. The intervention resulted in a 4.7% (95% CI, 3.0%–6.4%) improvement in adherence vs usual care but no difference in the odds of achieving good disease control for at least 1 (odds ratio [OR], 1.10; 95% CI, 0.94–1.28) or all eligible conditions (OR, 1.05; 95% CI, 0.91–1.22), hospitalization (OR, 1.02; 95% CI, 0.78–1.34), or having a physician office visit (OR, 1.11; 95% CI, 0.91–1.36). However, intervention participants were significantly less likely to have an emergency department visit (OR, 0.62; 95% CI, 0.45–0.85). In as-treated analyses, the intervention was associated with a 10.4% (95% CI, 8.2%–12.5%) increase in adherence, a significant increase in patients achieving disease control for at least 1 eligible condition (OR, 1.24; 95% CI, 1.03–1.50), and nonsignificantly improved disease control for all eligible conditions (OR, 1.18; 95% CI, 0.99–1.41).” (N. K. Choudhry, nkchoudhry@bwh.harvard.edu)
>>>PNN NewsWatch
* Pharm D Solutions, LLC is voluntarily recalling all sterile compounded drug products within expiry to the clinic, physician, or consumer level, according to an announcement posted on the FDA website. These drug products are being voluntarily recalled due to concerns that practices at the pharmacy have the potential to pose a risk of contamination to products that are intended to be sterile.

PNN Pharmacotherapy Line
Sept. 12, 2018 * Vol. 25, No. 176
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Sept. 11 issue of JAMA (2018; 320).
Piperacillin-Tazobactam in Gram-Negative Septicemia: In a study testing piperacillin-tazobactam as a meropenem-sparing treatment of septicemia caused by ceftriaxone-nonsusceptible Escherichia coli and Klebsiella pneumoniae, the combination failed to reach noninferiority, leading investigators to conclude, “These findings do not support use of piperacillin-tazobactam in this setting” (pp. 984–94). At 26 sites in 9 countries 2014–17, adult patients with at least 1 positive blood culture with E. coli or Klebsiella spp. testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam had these results based on a primary outcome of 30-day, all-cause mortality: “Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.” (D. L. Paterson, d.paterson1@uq.edu.au)
“The results of [this] MERINO trial make clear that piperacillin-tazobactam should no longer be considered an alternative to meropenem for definitive treatment of bloodstream infection due to ceftriaxone-resistant
E. coli or K. pneumoniae,” editorialists conclude (pp. 979–81). “How, then, can the use of carbapenems be decreased? First, as noted by the authors, the study results should not be extrapolated to newer beta-lactam/beta-lactamase inhibitors, which require specific investigation of efficacy in randomized clinical trials. Second, studies of short-duration antibiotic treatment and noncarbapenem options for empirical and step-down therapy are needed to identify safe and effective regimens that limit carbapenem exposure. New tools may soon be available, such as electronic decision support for antibiotic selection that calculates the estimated likelihood of antibiotic-resistant bacterial infection for each patient at the time of hospital admission. Third, prevention of infection should be emphasized so as to reduce the need for antibiotic treatment altogether.” (M. Hayden, mary_hayden@rush.edu)
Levofloxacin Prophylaxis Against Bacteremia in Children: Levofloxacin prophylaxis reduced the risk of bacteremia among children with acute leukemia who were receiving intensive chemotherapy but not in children undergoing hematopoietic stem cell transplantation (HSCT), researchers report (pp. 995–1004). Compared with no prophylaxis, levofloxacin prophylaxis had these effects during 2 chemotherapy cycles in those with acute leukemia or those with 1 transplant procedure: “A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6–15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3–14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%–34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%–13.0%; P = .06).…” (S. Alexander, sarah.alexander@sickkids.ca)
>>>PNN NewsWatch
* “Despite our warnings and previous regulatory and enforcement actions, we continue to find marketers actively selling kratom with unsubstantiated claims,” writes the Commissioner of Food and Drugs, Scott Gottlieb, MD, in a statement announcing new warning letters to companies marketing the product. “Fraudulent health claims can pose serious health risks. They may keep some patients from seeking appropriate, FDA-approved therapies. Reliance on products with unsubstantiated claims may delay those who suffer from opioid use disorder from entering recovery and may put them at greater risk of overdose and death.”

PNN Pharmacotherapy Line
Sept. 13, 2018 * Vol. 25, No. 177
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Sept. 13 New England Journal of Medicine (2018; 379).
Tafamidis for Transthyretin Amyloid Cardiomyopathy: In patients with transthyretin amyloid cardiomyopathy, a new drug that binds to transthyretin produced favorable changes in several outcomes in a phase 3 trial, researchers report (pp. 1007–16). A total of 441 participants received one of two doses of tafamidis or placebo in the 30-month trial, with these results: “In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P <0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P <0.001) and a lower rate of decline in [Kansas City Cardiomyopathy Questionnaire–Overall Summary] score (P <0.001). The incidence and types of adverse events were similar in the two groups.” (M. S. Maurer, msm10@cumc.columbia.edu)
“The results of the ATTR-ACT trial raise questions about the mechanism of action of tafamidis, the time course of benefit, and the timing of treatment in the course of a patient’s disease,” editorialists write (
pp. 1083–4). “Reductions in cardiovascular-related hospitalizations were seen only after 9 months, and all-cause mortality after 18 months, which may reflect the time necessary to influence the underlying pathology. Moreover, a subgroup analysis showing greater benefit in patients with less severe heart failure suggests that treatment might best be initiated at an early stage of disease, when the underlying pathology may be more easily reversed as compared with later stages. It is possible that by slowing or halting amyloid deposition, tafamidis may allow the activation of local recovery processes that progressively result in a remodeling of the amyloid deposits, a reduction in the strain on the cardiac walls, and ultimately in a clinical benefit. Once amyloid has caused irreversible organ damage, disease-modifying treatments may be less likely to be effective.” (C. C. Quarta)
Fingolimod in Pediatric Multiple Sclerosis: Better efficacy but worse adverse events were associated with use of fingolimod in a phase 3 comparison with interferon beta-1a in patients aged 10–17 years with multiple sclerosis (pp. 1017–27): “Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P <0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P <0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient).” (T. Chitnis, tchitnis@rics.bwh.harvard.edu)
“It will be a challenge to obtain long-term data related to the safety of immune modulation and to obtain clinical measures of neurologic disability, including cognition, brain volume, and myelin integrity, in patients treated from an early age with fingolimod or other agents,” writes an editorialist (
pp. 1085–6). “One hopes that subsequent trials in the pediatric population with multiple sclerosis will be designed to answer these basic and clinical questions.” (J. Antel)
>>>PNN NewsWatch
* FDA has taken aggressive actions to contain use of e-cigarettes and issued a statement on its support of innovation in digital health.

PNN Pharmacotherapy Line
Sept. 14, 2018 * Vol. 25, No. 178
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Sept. 15 issue of and advance articles from Clinical Infectious Diseases (2018; 67).
Waning of Influenza Vaccine Effectiveness: Substantial waning of influenza vaccine effectiveness — 16% every 28 days — calls into question the optimal timing of administration of seasonal influenza vaccine, investigators conclude (ciy770). Persons who received the inactivated vaccine in 2010–17 and were later tested for influenza and respiratory syncytial virus (RSV) showed waning based on a primary outcome of test-confirmed influenza and days since vaccination: “Compared with persons vaccinated 14 to 41 days prior to being tested, persons vaccinated 42 to 69 days prior to being tested had 1.32 (95% Confidence Interval (CI): 1.11 to 1.55) times the odds of testing positive for any influenza. The odds ratio (OR) increased in linear fashion by approximately 16% for each additional 28 days since vaccination; the OR was 2.06 (95% CI: 1.69 to 2.51) for persons vaccinated 154 or more days prior to being tested. No evidence of waning was found for RSV.” (G. T. Ray, tom.ray@kp.org)
Multidrug-Resistant Organisms in Short-Stay NF Residents: Nursing facility (NF) residents with short lengths of stay have a high prevalence of multidrug-resistant organisms (MDROs) near the time of admission and at discharge, researchers report, indicating they may serve as a reservoir for spread within the facility and to other healthcare settings (pp. 837–44). A prospective, longitudinal cohort study of newly admitted patients in 6 NFs in southeast Michigan showed these microbial surveillance results at multiple anatomical sites at enrollment, on days 14 and 30, and monthly for 6 months: “We enrolled 651 patients and collected 7,526 samples over 1,629 visits, with an average of 29 days of follow-up per participant. Nearly all participants were admitted for post–acute care (95%). More than half (56.8%) were colonized with MDROs at enrollment: methicillin-resistant Staphylococcus aureus (MRSA), 16.1%; vancomycin-resistant enterococci (VRE), 33.2%; and resistant gram-negative bacilli (R-GNB), 32.0%. Risk factors for colonization at enrollment included prolonged hospitalization (>14 days), functional disability, antibiotic use, or device use. Rates per 1,000 patient–days of acquiring a new MDRO were MRSA, 3.4; VRE, 8.2; and R-GNB, 13.6. MDRO colonization at discharge was similar to that at enrollment (56.4%): MRSA, 18.4%; VRE, 30.3%; and R-GNB, 33.6%.” (L. Mody, lonamody@umich.edu)
HCV Outbreak Associated With Drug Diversion by Health Care Technician: At a New Hampshire hospital, an epidemiologic investigation connected a large outbreak of drug-diversion–associated hepatitis C virus (HCV) infection with presence of a specific health care technician in the hospital cardiac catheterization laboratory (CCL) on the days when transmission occurred (pp. 845–53). While investigating an initial report of newly diagnosed HCV in the CCL technician and 3 patients, another 32 patients were identified who were infected with the outbreak strain. “The epidemiologic investigation revealed evidence of drug diversion by the HCV-infected technician, evidenced by gaps in controlled medication control, higher fentanyl use during procedures for confirmed cases, and building card key access records documenting the presence of the technician during days when transmission occurred,” the authors report. “The employee’s status as a traveling technician led to a multistate investigation, which identified additional cases at prior employment sites.” (E. R. Daly, elizabeth.daly@dhhs.nh.gov)
>>>PNN NewsWatch
* FDA yesterday approved moxetumomab pasudotox-tdfk (Lumoxiti) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. The agent is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.
*
FDA’s latest testing of products containing the active pharmaceutical ingredient (API) valsartan shows an additional unexpected impurity in three lots of Torrent Pharmaceuticals’ recalled valsartan drug products. This second impurity, N-nitrosodiethylamine (NDEA), is a known animal and suspected human carcinogen. These Torrent products were included in the company’s recall on August 23.

PNN Pharmacotherapy Line
Sept. 17, 2018 * Vol. 25, No. 179
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 362).
NDMA-Contaminated Valsartan Products & Cancer Risk: In a study relevant to recent warnings of N-nitrosodimethylamine (NDMA) contaminants in valsartan products (see PNN, Aug. 31 and Sept. 14), Danish investigators find no increased risk of cancer in exposed users in that country’s health registries (k3851). From the beginning of 2012 through mid-2017, valsartan users had these risks in a nationwide cohort study: “The final cohort comprised 5,150 people followed for a median of 4.6 years. In total, 3,625 cohort participants contributed 7,344 person years classified as unexposed to NDMA, and 3,450 participants contributed 11,920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P = 0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null.” (A. Pottegård, apottegaard@health.sdu.dk)
Potentially Harmful Hypertension Overtreatment at Hospital Discharge: A study of VA hospitals shows that 1 in 7 older adults admitted for noncardiac conditions were discharged on intensified antihypertensive regimens, but more than half of the patients were well controlled before admission (k3503). Concluding that “more attention is needed to reduce potentially harmful overtreatment of blood pressure as older adults transition from hospital to home,” the authors report these results for 14,915 older adults in 2011–13: “After adjustment for potential confounders, elevated inpatient blood pressure was strongly associated with being discharged on intensified antihypertensive regimens. Among patients with previously well controlled outpatient blood pressure, 8% (95% confidence interval 7% to 9%) of patients without elevated inpatient blood pressure, 24% (21% to 26%) of patients with moderately elevated inpatient blood pressure, and 40% (34% to 46%) of patients with severely elevated inpatient blood pressure were discharged with intensified antihypertensive regimens. No differences were seen in rates of intensification among patients least likely to benefit from tight blood pressure control (limited life expectancy, dementia, or metastatic malignancy), nor in those most likely to benefit (history of myocardial infarction, cerebrovascular disease, or renal disease).” (T. S. Anderson, timothy.anderson@ucsf.edu)
>>>Lancet Highlights
Source:
Sept. 15 issue of Lancet (2018; 392).
Ticagrelor After Drug-Eluting Stent Implantation: Among patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes, ticagrelor with aspirin for 1 month and alone for 23 months was not superior to standard dual-antiplatelet therapy, researchers report (pp. 940–9). Based on a primary endpoint at 2 years of a composite of all-cause mortality or nonfatal new Q-wave myocardial infarction, ticagrelor produced these results in 15,968 patients: “At 2 years, 304 (3.81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4.37%) participants in the control group (rate ratio 0.87 [95% CI 0.75–1.01]; p = 0.073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p = 0.93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2.04% vs 2.12%; rate ratio 0.97 [95% CI 0.78–1.20]; p = 0.77).” (P. W. Serruys, patrick.w.j.c.serruys@gmail.com)
>>>PNN JournalWatch
* Asthma Across the Lifespan: Time for a Paradigm Shift, in Journal of Allergy and Clinical Immunology, 2018; 142: 773–80. (S. J. Szefler, Stanley.Szefler@childrenscolorado.org)
*
Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: ASCO Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2018; 36: 2736–40. (S. H. Giordano)

PNN Pharmacotherapy Line
Sept. 18, 2018 * Vol. 25, No. 180
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Early-online articles from and Sept. 18 issue of Annals of Internal Medicine (2018; 169).
Drug Shortages & Drug-Price Increases: For 917 drugs with active shortages in 2015–16, monthly wholesale acquisition costs (WACs) increased disproportionately to other products, researchers report, particularly when shortages involved products with 3 or fewer manufacturers (10.7326/M18-1137). WACs before, during, and after shortages showed these patterns: “Prices of all drugs increased by 7.3% and 16.0% in the 11 months before and after the shortage began, respectively.… Prices of drugs supplied by 3 or fewer manufacturers increased by 12.1% and 27.4% in the 11 months before and after the shortage began, respectively. For drugs supplied by more than 3 manufacturers, prices increased by 2.5% and 4.8%, respectively. Mixed models showed that the shortage had a greater effect on prices of drugs supplied by 3 or fewer manufacturers (P = 0.002).
“In the 11 months after the shortage began, the expected price increase for all drugs was 20% compared with 9% in the absence of a shortage. Expected price increases under shortages were also 13 percentage points higher than those in the absence of a shortage for drugs supplied by 3 or fewer manufacturers (an increase from 17% to 30%) and 8 percentage points higher for drugs supplied by more than 3 manufacturers (an increase from 1% to 9%).” (I. Hernandez,
inh3@pitt.edu)
Effects of CDC 2016 Opioid Guideline on Prescribing: CDC release of the Guideline for Prescribing Opioids for Chronic Pain in March 2016 appears to be associated with a greater decline in prescribing of opioids, a study shows (pp. 367–75). Opioid prescribing was falling before the guideline’s release, but the decline accelerated thereafter, as shown in these data from community pharmacies: “The rate of high-dosage prescriptions (≥90 morphine equivalent milligrams per day) was 683 per 100,000 persons in January 2012 and declined by 3.56 (95% CI, −3.79 to −3.32) per month before March 2016 and by 8.00 (CI, −8.69 to −7.31) afterward. Likewise, the percentage of patients with overlapping opioid and benzodiazepine prescriptions was 21.04% in January 2012 and declined by 0.02% (CI, −0.04% to −0.01%) per month before the CDC guideline release and by 0.08% (CI, −0.08% to −0.07%) per month afterward. The overall opioid prescribing rate was 6,577 per 100,000 persons in January 2012 and declined by 23.48 (CI, −26.18 to −20.78) each month before the guideline release and by 56.74 (CI, −65.96 to −47.53) per month afterward.” (G. P. Guy Jr., gguy@cdc.gov)
Treating Skin Basal Cell Carcinoma: In a systematic review and network meta-analysis, authors describe the lack of comparative effectiveness studies of various surgical and medical options for treatment of basal cell carcinoma (BCC) of the skin (10.7326/M18-0678): “Estimated recurrence rates were similar for excision (3.8% [95% CI, 1.5% to 9.5%]), Mohs surgery (3.8% [CI, 0.7% to 18.2%]), curettage and diathermy (6.9% [CI, 0.9% to 36.6%]), and external-beam radiation (3.5% [CI, 0.7% to 16.8%]). Recurrence rates were higher for cryotherapy (22.3% [CI, 10.2% to 42.0%]), curettage and cryotherapy (19.9% [CI, 4.6% to 56.1%]), 5-fluorouracil (18.8% [CI, 10.1% to 32.5%]), imiquimod (14.1% [CI, 5.4% to 32.4%]), and photodynamic therapy using methyl-aminolevulinic acid (18.8% [CI, 10.1% to 32.5%]) or aminolevulinic acid (16.6% [CI, 7.5% to 32.8%]). The proportion of patients reporting good or better cosmetic outcomes was better for photodynamic therapy using methyl-aminolevulinic acid (93.8% [CI, 79.2% to 98.3%]) or aminolevulinic acid (95.8% [CI, 84.2% to 99.0%]) than for excision (77.8% [CI, 44.8% to 93.8%]) or cryotherapy (51.1% [CI, 15.8% to 85.4%]). Data on quality of life and mortality were too sparse for quantitative synthesis.” (A. M. Drucker, Aaron.Drucker@wchospital.ca)
Publication Characteristics & Treatment Effect Estimates: A “large meta-epidemiologic study shows larger treatment effects in published than unpublished trials, which underlines the importance of searching for unpublished data” when conducting systematic reviews and meta-analyses, authors write (pp. 385–93). “Treatment effects were significantly larger in trials published in a language other than English, which may be related to the lower methodological quality of these trials.” (A. Dechartres, agnes.dechartres@aphp.fr)

PNN Pharmacotherapy Line
Sept. 19, 2018 * Vol. 25, No. 181
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Sept. 18 issue of JAMA (2018; 320).
Behavioral and Pharmacotherapy Weight Loss Interventions: Compared with weight-loss medications used with the goal of preventing obesity-related morbidity and mortality in adults, behavioral interventions are more effective and safer, according to updated evidence from the U.S. Preventive Services Task Force (pp. 1172–91). “Behavior-based weight loss interventions with or without weight loss medications were associated with more weight loss and a lower risk of developing diabetes than control conditions,” conclude authors of a systematic review that support a USPSTF recommendation statement (pp. 1163–71; S. J. Curry, chair@uspstf.net). “Weight loss medications, but not behavior-based interventions, were associated with higher rates of harms. Long-term weight and health outcomes data, as well as data on important subgroups, were limited.” (E. S. LeBlanc, Erin.S.LeBlanc@kpchr.org)
“Greater alignment [is needed] between [the USPSTF] recommendations and the structure required for implementation in many primary care settings,” write authors of a
JAMA Internal Medicine editorial (10.1001/jamainternmed.2018.5259). “Recognition of the significant role multidisciplinary and lay interventionists play in delivery of behavioral weight loss interventions compels us to broaden reimbursement to those who can implement evidence-based treatment. Importantly, the development of obesity over the life course, and propensity for weight regain after successful weight loss, also requires us to advance multisector partnerships and broad public health approaches to treat obesity, prevent weight gain, and sustain healthy weight beyond primary care.” (D. Haire-Joshu, djoshu@wustl.edu)
“Although this USPSTF recommendation focuses on weight management interventions in patients with established obesity, research to develop effective prevention strategies throughout the life course, including infancy and early childhood, could ultimately decrease the number of adults who must confront the difficult challenge of losing excess weight,” adds the author of a
JAMA editorial (pp. 1111–3; S. Z. Yanovski, sy29f@nih.gov)
Incorporation of “Deep Learning” Into Health Care: “Artificial intelligence and deep learning are entering the mainstream of clinical medicine,” an editorialist (pp. 1107–8) writes in commenting on two Viewpoint articles (pp. 1099–100, C. D. Naylor, david.naylor@utoronto.ca; pp. 1101–2, G. Hinton, geoffrey.hinton@gmail.com) on applications of deep learning in health care based on large datasets and artificial intelligence. “This technology can augment human intelligence to improve decision making and operational processes. Physicians need to actively engage to adapt their practice and to shape the technology.” (W. W. Stead, bill.stead@vumc.org)
>>>PNN NewsWatch
* FDA yesterday approved the final version of its new Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). The agency said the new REMS includes several measures to help better communicate the serious risks about the use of opioid pain medications to patients and health care professionals. This expanded REMS now, for the first time, applies to immediate-release opioid analgesics intended for use in an outpatient setting. The new REMS also applies to the extended-release and long-acting opioid analgesics, which have been subject to a REMS since 2012.
*
FDA has launched “The Real Cost” Youth E-Cigarette Prevention Campaign, a new, comprehensive effort aimed at educating kids about the dangers of e-cigarettes. The campaign targets nearly 10.7 million youth, aged 12–17, who have used e-cigarettes or are open to trying them, and features hard-hitting advertising on digital and social media sites popular among teens, as well as placing posters with e-cigarette prevention messages in high schools across the nation. In a related statement, FDA Commissioner Scott Gottlieb, MD, said, “Research shows that, when done right, public health education campaigns are effective at reaching youth and educating about the dangers of tobacco. The new e-cig prevention effort builds off the FDA’s first youth tobacco prevention campaign, ‘The Real Cost,’ which launched in 2014 to reduce teen cigarette smoking.”

PNN Pharmacotherapy Line
Sept. 20, 2018 * Vol. 25, No. 182
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Sept. 20 issue of the New England Journal of Medicine (2018; 379).
Cardiovascular Safety of Lorcaserin in Weight Reduction: Among 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors, use of lorcaserin reduced weight without increasing the rate of major cardiovascular events, compared with placebo (pp. 1107–17). A primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) showed these risks with lorcaserin 10 mg twice daily: “At 1 year, weight loss of at least 5% had occurred in 1,986 of 5,135 patients (38.7%) in the lorcaserin group and in 883 of 5,083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P <0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P <0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P = 0.04).” (E.A. Bohula, ebohula11@bwh.harvard.edu)
“Will lorcaserin prove to be helpful over the long haul?” editorialists ask (
pp. 1174–5). “For now, the drug may be best used on a cautious basis according to the needs of individual patients. As in other reports on its use, the side effects of headache, fatigue, dizziness, diarrhea, and nausea led to twice the number of discontinuations in the lorcaserin group as in the placebo group, although the total rates of discontinuation were similar in the two groups. With respect to efficacy, liraglutide would provide a similar degree of weight loss but a lower risk of diabetes. Thus, whether this trial will lead to enhanced utilization of lorcaserin by providers is uncertain, as is the ultimate role of this drug in the treatment of patients who are overweight or obese.” (J. R. Ingelfinger)
Rivaroxaban for Posthospital Thromboprophylaxis: Extended thromboprophylaxis following hospitalization for medical illnesses had no impact on symptomatic venous thromboembolism and death due to venous thromboembolism than placebo, researchers report (pp. 1118–27). Once-daily rivaroxaban 10 mg or placebo for 45 days produced these outcomes in medically ill patients at increased risk for venous thromboembolism: “Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6,007 patients (0.83%) who were given rivaroxaban and in 66 of 6,012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P = 0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5,982 patients (0.28%) in the rivaroxaban group and in 9 of 5,980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23).” (A. C. Spyropoulos, aspyropoul@northwell.edu)
Spending in the Medicare Shared Savings Program: Physician groups participating in shared-savings contracts produced cost reductions for Medicare that grew over a 3-year study period, while hospital-integrated accountable care organizations (ACOs) did not, a study shows (pp. 1139–49). Before and after entry into the Medicare Shared Savings Program, costs were as follows: “By 2015, the mean differential change in per-patient Medicare spending was −$474 (−4.9% of the pre-entry mean, P <0.001) for physician-group ACOs that entered in 2012, −$342 (−3.5% of the pre-entry mean, P <0.001) for those that entered in 2013, and −$156 (−1.6% of the pre-entry mean, P = 0.009) for those that entered in 2014.…” (J. M. McWilliams, mcwilliams@hcp.med.harvard.edu)

PNN Pharmacotherapy Line
Sept. 21, 2018 * Vol. 25, No. 183
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>>>Vaccine Highlights
Source:
Oct. 1 issue of Vaccine (2018; 36).
Statins & Influenza in Older Adults: Among older patients in Taiwan who received seasonal influenza vaccine in the 2007–08 through 2012–13 seasons, exposure to statins was associated with a higher risk of medically attended acute respiratory illness (MAARI), a study shows (pp. 6133–7). Retrospective cohort analysis of data from the country’s National Health Insurance Research Database for adults aged 66 years or older yielded these results: “A total of 440,180 elderly were included in this study. In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02–1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02–1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (OR, simvastatin: 1.14, 95% CI: 1.10–1.18; OR, lovastatin: 1.18, 95% CI: 1.12–1.25).” (H-T Chiu, r04451001@ntu.edu.tw)
Influenza Vaccine Effectiveness & Medically Attended Infections: Assessed across influenza seasons with varying circulating viral subtypes and among patients in differing age groups, investigators found that the vaccine effectiveness (VE) was moderate in Hong Kong in 2014–17 (pp. 6117–23). “Influenza vaccination [had an impact] in reducing disease burden,” the authors concluded. “The reduced VE for influenza A(H3N2) is a continuing concern.” The test-negative study was conducted at 20 outpatient clinics in Hong Kong. Patients at least 6 months of age presented with at least two symptoms of acute respiratory illness (ARI) and were tested for influenza within 72 hours of onset. Correlating clinical experiences with self-reported vaccination status, the results showed: “We enrolled 2,566 patients, of whom 1,118 (43.6%) tested positive for influenza A or B virus by PCR. Test-positive subjects were generally older, more likely to present with one of the symptoms of ARI, and less likely to receive vaccination against influenza. VE estimates for influenza A(H1N1), A(H3N2), B/Yamagata and B/Victoria were 61.6% (95% confidence interval, CI: 21.8%, 81.1%), 26.4% (95% CI: −1.3%, 46.6%), 67.0% (95% CI: 25.9%, 85.3%), 60.4% (95% CI: 0.3%, 84.3%), respectively. Estimates of VE by age group were generally higher in adults aged 50–64 and lower among children and older adults.” (B. J. Cowling, bcowling@hku.hk)
High-Dose Influenza Vaccine in Hemodialysis: Among patients with end-stage renal disease (ESRD), influenza vaccination rates increased in 2010–13 in the U.S., but use of high-dose formulations remained low, researchers report (pp. 6087–94). Data from the U.S. Renal Data System produced these findings in a cohort study of 412,482 patients on hemodialsis: “The proportion of patients with ESRD who were vaccinated with any influenza vaccine increased from 68.3% in 2010 to 72.4% in 2013. High-dose vaccines were administered to 0.9% of patients during the study period, and 16.7% of high-dose vaccines were administered to patients <65 years of age. Among patients aged ≥65 years, older patients (>79 vs. 65–69 years: OR, 1.29; 95% CI, 1.19–1.41) and patients at hospital-based versus free-standing dialysis facilities (OR, 2.31; 95% CI, 2.13–2.45) were more likely to receive high-dose vaccine, while blacks (vs. whites [OR, 0.66; 95% CI, 0.61–0.71]) and patients with longer duration of ESRD (>9 vs. 0 years: OR, 0.66; 95% CI, 0.55–0.78) were less likely to receive the high-dose vaccine.” (A. M. Butler, anne.butler@wustl.edu)
>>>PNN NewsWatch
* The growing impact on Americans of drug overdoses, suicides, and chronic liver disease is evident in the annual health of the nation report recently yesterday by the Secretary of Health and Human Services. Health, United States, 2017 shows that life expectancy at birth decreased for the first time since 1993 by 0.2 year between 2014 and 2015, and then decreased another 0.1 year between 2015 and 2016. Between 2000 and 2016, death rates for five of the 12 leading causes of death increased: unintentional injuries, Alzheimer’s disease, suicide, chronic liver disease, and septicemia. Age-adjusted rates of drug overdose deaths and suicide deaths increased by 72% and 23%, respectively. Death rates for chronic liver disease and cirrhosis in young people aged 25–34 years increased annually by 7.9% in men and 11.4% in women.

PNN Pharmacotherapy Line
Sept. 24, 2018 * Vol. 25, No. 184
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>>>Lancet Highlights
Source:
Sept. 22 issue of Lancet (2018; 392).
Aspirin in Primary Prevention of Cardiovascular Events: In a population of patients deemed to be at moderate risk of a first cardiovascular event based on their numbers of risk factors, daily low-dose aspirin failed to reduce the event rate compared with placebo (pp. 1036–46). Because of the low rate of events, the authors concluded that the population was likely more representative of a low-risk group, perhaps based on the effectiveness of “contemporary risk management strategies.” The ARRIVE study included 12,546 participants from seven countries aged 55 years (men) or 60 years (women) and older with “an average cardiovascular risk”; those with high risk of gastrointestinal bleeding or diabetes were excluded. Randomization to placebo or enteric-coated aspirin 100 mg yielded these results over a median follow-up of 60 months based on a composite primary efficacy endpoint of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack: “In the intention-to-treat analysis, the primary endpoint occurred in 269 (4.29%) patients in the aspirin group versus 281 (4.48%) patients in the placebo group (hazard ratio [HR] 0.96; 95% CI 0.81–1.13; p = 0.6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0.97%) patients in the aspirin group versus 29 (0.46%) in the placebo group (HR 2.11; 95% CI 1.36–3.28; p = 0.0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n = 1,266 [20.19%] in the aspirin group vs n = 1,311 [20.89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n = 5,142 [82.01%] vs n = 5,129 [81.72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n = 1050 [16.75%] vs n = 850 [13.54%] in the placebo group; p <0.0001). There were 321 documented deaths in the intention-to-treat population (n = 160 [2.55%] vs n = 161 [2.57%] of 6,276 patients in the placebo group).” (J. M. Gaziano, jmgaziano@partners.org)
Brexanolone in Postpartum Depression: An investigational GABA-A modulator under FDA review, brexanolone injection produced significant and clinically meaningful improvements in women with postpartum depression, two phase 3 trials show, compared with placebo (pp. 1058–70). Among 375 women included in the two studies, two doses of brexanolone provided a “rapid onset of action and durable treatment response during the study period,” the investigators conclude, adding, “Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder.” (S. Meltzer-Brody, samantha_meltzer-brody@med.unc.edu)
Global Alcohol Use & Burden: Data from 195 countries show that “alcohol use is a leading risk factor for global disease burden and causes substantial health loss,” according to the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (pp. 1015–35). “We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero,” the authors write. “These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.” (GBD 2016 Alcohol Collaborators)
>>>PNN JournalWatch
* Association Between Maternal Gluten Intake and Type 1 Diabetes in Offspring: National Prospective Cohort Study in Denmark, in BMJ, 2018; 362: k3547. (K. Josefsen, knud@eln.dk)
*
Half A Decade In, Medicare Accountable Care Organizations Are Generating Net Savings: Part 1, in Health Affairs, 2018; 10.1377/hblog20180918.957502. (W. Bleser)
*
Half A Decade In, Medicare Accountable Care Organizations Are Generating Net Savings: Part 2, in Health Affairs, 2018; 10.1377/hblog20180920.604462. (W. Bleser)
*
Biological Age, Not Chronological Age, Is Associated with Late-Life Depression, in Journals of Gerontology, Series A, 2018; 73: 1370–6. (P. J. Brown, pb2410@cumc.columbia.edu)
*
Antidepressant Use and Cognitive Outcomes in Very Old Women, in Journals of Gerontology, Series A, 2018; 73: 1390–5. (K. Yaffe, kristine.yaffe@ucsf.edu)
*
Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study, in Journal of the American Geriatrics Society, 2018; 10.1111/jgs.15508. (D. M. Boudreau, boudreau.d@ghc.org)

PNN Pharmacotherapy Line
Sept. 25, 2018 * Vol. 25, No. 185
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Rheumatology Report
Source:
Sept. issue of Arthritis & Rheumatism (2018; 70).
Transitioning From Originator Etanercept to Biosimilar SB4: A nonmandatory switch from originator etanercept (ETN) to the SB4 biosimilar resulted in a significant decline in persistence and smaller decreases in disease activity, a study shows, but investigators conclude that “these differences were not considered clinically relevant” (pp. 1408–18). A structured communication strategy was used to convey information to patients about the change and an opt-out option. Comparing those transitioned to SB4 with a historical cohort from 2014 with respect to demographic and clinical variable, including 6-month change in C-reactive protein (CRP) level and Disease Activity Score in 28 joints using CRP level (DAS28-CRP), results showed the following: “Of the 642 ETN-treated patients, 635 (99%) agreed to transition from originator ETN to biosimilar SB4, of whom 625 patients (433 with rheumatoid arthritis, 128 with psoriatic arthritis, and 64 with ankylosing spondylitis) were included in the transition cohort, and 600 ETN-treated patients from 2014 were included in the historical cohort. The crude treatment persistence rate for biosimilar SB4 over 6 months was 90% (95% confidence interval [95% CI] 88–93%), compared to a 6-month treatment persistence rate of 92% (95% CI 90–94%) for originator ETN. Patients in the transition cohort, compared to the historical cohort, had a statistically significantly higher relative risk of treatment discontinuation (adjusted hazard ratio 1.57, 95% CI 1.05–2.36) and showed smaller decreases in the CRP level (adjusted difference 1.8, 95% CI 0.3–3.2) and DAS28-CRP (adjusted difference 0.15, 95% CI 0.05–0.25) over 6 months.” (L. Tweehuysen, l.tweehuysen@maartenskliniek.nl)
Pregnancy Outcomes After Exposure to Certolizumab Pegol: Maternal and fetal outcomes were not affected by use of the TNF modulator certolizumab pegol (CZP) during pregnancy, researchers report based on data from the UCB Pharma safety database (pp. 1399–407). “Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death,” the authors conclude. “The data are reassuring for women of childbearing age considering treatment with CZP.” (M. E. B. Clowse, megan.clowse@duke.edu)
>>>Nephrology Highlights
Source:
Oct. issue of the American Journal of Kidney Diseases (2018; 72).
Pharmacogenomics in Kidney Disease: Improved pharmacotherapy is an important advantage to increased use of genetic testing in clinical settings, authors write in a review article (pp. 569–81): “Genetic testing is used for screening, diagnosis, and prognosis of diseases consistent with a genetic cause and to guide drug therapy to improve drug efficacy and avoid adverse effects (pharmacogenomics). This In Practice review aims to inform about DNA-related genetic test availability, interpretation, and recommended clinical actions based on results using evidence from clinical guidelines, when available. We discuss challenges that limit the widespread use of genetic information in the clinical care setting, including a small number of actionable genetic variants with strong evidence of clinical validity and utility, and the need for improving the health literacy of health care providers and the public, including for direct-to-consumer tests. Ethical, legal, and social issues and incidental findings also need to be addressed. Because our understanding of genetic factors associated with disease and drug response is rapidly increasing and new genetic tests are being developed that could be adopted by clinicians in the short term, we also provide extensive resources for information and education on genetic testing.” (N. Franceschini, noraf@unc.edu)
iRhoms for Targeting of Lupus Nephritis: Inactive members of the rhomboid protease family, iRhom1 and iRhom2, could lead to development of a novel therapeutic strategy in patients with lupus nephritis, according to a summary of a recent study (pp. 617–9; A. Herrlich, aherrlich@wustl.edu).
>>>PNN NewsWatch
* Twelve new clinical trial research grants totaling more than $18 million over the next 4 years will enhance the development of medical products for patients with rare diseases by academic and industry investigators, FDA said yesterday.

PNN Pharmacotherapy Line
Sept. 26, 2018 * Vol. 25, No. 186
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Sept. 25 issue of JAMA (2018; 320).
Algorithm-Based Therapy in Staphylococcal Bacteremia: Compared with usual care of patients with staphylococcal bacteremia, an algorithm approach yielded a noninferior rate of clinical success, researchers report (pp. 1249–58). Using coprimary outcomes of clinical success and serious adverse event rates, the study demonstrated these results at 16 academic medical centers in the U.S. and Spain: “Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, −6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, −3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, −1.8 days [95% CI, −3.1 to −0.6]).” (V. G. Fowler Jr., fowle003@mc.duke.edu)
“The algorithm-defined antibiotic duration targets should be considered for inclusion in antimicrobial stewardship programs and guidelines,” editorialists write (
pp. 1243–4). “However, algorithms cannot simply be applied in a vacuum without ongoing monitoring and adjustment based on an individual patient’s clinical course. Moreover, algorithms can only be as good as the clinical evidence supporting their recommendations. The limited quality of evidence used in this algorithm, through no fault of the investigators, is an important reminder that future investment in clinical trials targeting optimal antibiotic selection and duration are essential to continued progress. Successful response to the antimicrobial resistance crisis demands better evidence and dedicated resources to support future investigations.” (P. N. Malani, pmalani@umich.edu)
Antibiotic Therapy for Acute Appendicitis: Five-year follow-up of patients managed with antibiotics for uncomplicated acute appendicitis shows a 39.1% recurrence rate and a significantly lower complication rate in comparison with appendectomy (6.5% versus 24.4%) (pp. 1259–65; P. Salminen, paulina.salminen@tyks.fi).
“Once medical treatments become universally accepted in clinical practice, they are very difficult to change, even if proven wrong or harmful,” a
JAMA editor writes in reaction to these long-term findings (pp. 1245–6). “Evidence from high-quality clinical trials has definitively shown that uncomplicated appendicitis can be treated with antibiotics, or in some cases, by observation alone. In this new era of appendicitis treatment in which the diagnosis can be made nearly error free with CT imaging, most cases of uncomplicated appendicitis can be successfully treated with antibiotics. Patients presenting with acute, noncomplicated, CT-proven appendicitis should be given an opportunity for shared decision making, understanding that there is a high probability that they can be successfully treated with antibiotics or undergo appendectomy if they do not want to worry about the chance for recurrence.” (E. H. Livingston, edward.livingston@jamanetwork.org)
>>>PNN NewsWatch
* Dead bugs, dog beds, exposed skin, rust, and use of coffee filters and toaster ovens in product preparation — those were some of the insanitary conditions noted in compounding facilities by FDA staffer Anna Abram at yesterday’s 2018 Intergovernmental Meeting on Drug Compounding. “I am heartened that since issuing the draft guidance on insanitary conditions in 2016, FDA has observed that many compounders have corrected insanitary conditions that prior FDA inspections of their facilities revealed,” Abram said. “However, while we are encouraged by such voluntary compliance, the agency has also taken regulatory action, such as issuing warning letters or working with the Department of Justice on injunctions, when compounding facilities have neglected to take appropriate action to correct the violations.” In conjunction with the meeting, FDA released a revised draft guidance on insanitary conditions of compounding facilities and final guidances on radiopharmaceuticals in pharmacies/federal facilities and in outsourcing facilities.

PNN Pharmacotherapy Line
Sept. 27, 2018 * Vol. 25, No. 187
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Early-release articles from and Sept. 27 issue of New England Journal of Medicine (2018; 379).
Synthetic Cannabinoid–Associated Coagulopathy: An Illinois outbreak of coagulopathy and bleeding diathesis earlier this year was associated with adulteration of synthetic cannabinoids with the anticoagulant brodifacoum, researchers report (pp. 1216–23). At a Peoria hospital, adult patients meeting the diagnostic criteria for synthetic cannabinoid–associated coagulopathy showed the following: “A total of 34 patients were identified as having synthetic cannabinoid–associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K1 (phytonadione) was administered orally in all 34 patients and was also administered intravenously in 23 (68%). Red-cell transfusion was performed in 5 patients (15%), and fresh-frozen plasma infusion in 19 (56%). Four-factor prothrombin complex concentrate was used in 1 patient. One patient died from complications of spontaneous intracranial hemorrhage.” (A. H. Kelkar, amar.kelkar@medicine.ufl.edu)
Discussing the obstacles to care in these patients, an editorialist notes lack of adherence (leaving the hospital against medical advice), reuse of the contaminated cannabinoid, and as noted in this passage, the cost of oral therapy for outpatient care (
pp. 1275–7): “These patients required thousands of dollars of oral vitamin K1. The out-of-pocket cost for three 5-mg tablets of the brand-name phytonadione product is $167.93 at retail pharmacies; the corresponding cost of the newly available generic version (released on May 15, 2018) is $80.99 (CVS Pharmacy, August 18, 2018). The authors and their colleagues solved the problem of access to vitamin K1 by working directly with pharmacies, insurance companies, and federal programs to ensure an adequate supply for their patients.” (J. M. Connors)
DNA Sequencing for Predicting TB Drug Susceptibility: Whole-genome analysis of isolates of Mycobacterium tuberculosis is useful in predicting phenotypic sensitivity to first-line antitubercular drugs, a study shows (10.1056/NEJMoa1800474). Susceptibility to isoniazid, rifampin, ethambutol, and pyrazinamide was tested in 16 countries on six continents. Among 10,209 isolates, the investigators found: “The largest proportion of phenotypes was predicted for rifampin (9,660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8,794 [89.8%] of 9,794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7,516 isolates with complete phenotypic drug-susceptibility profiles, 5,865 (78.0%) had complete genotypic predictions, among which 5,250 profiles (89.5%) were correctly predicted. Among the 4,037 phenotypic profiles that were predicted to be pansusceptible, 3,952 (97.9%) were correctly predicted.” (T. Walker, timothy.walker@ndm.ox.ac.uk)
“Although there are potential benefits associated with the availability of individualized therapy based on whole-genome predictions of susceptibility for all patients with tuberculosis, including those with drug-resistant tuberculosis, bringing such therapy to patients in high-burden, resource-limited settings will be challenging, to say the least,” editorialists write (
10.1056/NEJMe1811861). “Globally, only 22% of the 6.3 million people with newly diagnosed tuberculosis in 2016 had access to rifampin drug-susceptibility testing. However, previous programmatic failures, while underscoring the challenges, should not preclude us from aiming to provide the same standard of care for all patients with tuberculosis regardless of where they reside.… There is hope that renewed political will for mobilizing the resources needed to capitalize on advances such as [this] will be brought to bear on this formidable global health challenge.” (H. Cox)

PNN Pharmacotherapy Line
Sept. 28, 2018 * Vol. 25, No. 188
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
Oct. issue of Diabetes Care (2018; 41).
Once-Weekly Exenatide + Dapagliflozin in Type 2 Diabetes: In a phase 3 trial of patients with type 2 diabetes not controlled by metformin, the combination of exenatide once weekly (QW) plus dapagliflozin produced beneficial changes in glycemia, weight, and systolic blood pressure (SBP) over 52 weeks, with no unexpected safety findings, investigators conclude (pp. 2136–46): “Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change −1.75% [−19.1 mmol/mol]) versus exenatide QW (−1.38% [−15.1 mmol/mol]; P = 0.006) or dapagliflozin (−1.23% [−13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (−3.31 kg and −4.5 mmHg) versus exenatide QW (−1.51 kg and −0.7 mm Hg; both P < 0.001) but similar to those with dapagliflozin (−2.28 kg and −2.7 mm Hg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site–related adverse events. No major hypoglycemia occurred.” (S. A. Jabbour, serge.jabbour@jefferson.edu)
Glycemic Control & Infections Risk in Diabetes: In middle-aged and older adults with diabetes mellitus (DM), poor glycemic control was “powerfully associated with serious infections and should be a high priority,” researchers conclude (pp. 2127–35). Patient data for 85,312 patients with DM aged 40 to 89 years in 2008–09 was analyzed and associated with infection rates for 2010–15. Outcomes for primary care, linked hospital, and mortality records across 18 infection categories were as follows: “Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6–7% [42–53 mmol/mol], IRR 1.41 [95% CI 1.36–1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24–5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86–12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43–3.00]) after adjustment for duration and other confounders. [Attributable fractions] of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%).” (J. A. Critchley, jcritchl@sgul.ac.uk)
>>>PNN NewsWatch
* Kicking off the annual push for Americans to get vaccinated against seasonal influenza, presenters at a Thursday news conference in the nation’s capital emphasized several new reasons that everyone age 6 months or older needs to be immunized. First, the 2017–18 season was worse than any on record, with 900,000 hospitalizations, 80,000 deaths overall, and 180 pediatric deaths (80% of them in unvaccinated children). The H3N2 strain dominated, and it is particularly virulent among the older population where most deaths occur. Second, research increasingly shows a postinfluenza rise in risk of myocardial infarction and other serious conditions and in a drop in functional status in older adults, which can lead to decline, frailty, and death. Third, those who are vaccinated have less severe cases of influenza and spread the virus to others less often. “A seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family, and your community from the flu and serious flu-related complications, which can result in hospitalizations,” FDA Commissioner Scott Gottlieb, MD, wrote in a statement. “It’s especially important for people in high-risk groups, such as seniors, pregnant women, and young children, as well as people who are in close contact with those at high risk to get an influenza vaccine every year.” Gottlieb received his flu shot with U.S. Surgeon General Jerome M. Adams, MD, during the National Foundation for Infectious Diseases news conference.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533. Copyright © 2018, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, BSPharm, MA, Editor and Publisher. E-mail 
PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.