Mar 2017

PNN January–March 2017

PNN Pharmacotherapy Line
Jan. 3, 2017 * Vol. 24, No. 1
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Jan. 3 issue of the Annals of Internal Medicine (2017; 166).
Oral Treatment of Type 2 Diabetes: In an update to a 2012 clinical practice guideline, the American College of Physicians recommends first-line use of metformin for oral pharmacologic treatment of type 2 diabetes in adults (10.7326/M16-1860). The guideline, endorsed by the American Academy of Family Physicians, cites the safety advantages of metformin over other oral agents, particularly its weight loss effect. Based on a systematic review and meta-analysis of monotherapy and metformin-based combination therapy (2016;164:740–51; N. M. Maruthur, maruthur@jhmi.edu), ACP makes these recommendations (A. Qaseem, aqaseem@acponline.org):
* ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)
* ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.
Evidence Supporting Increased Metformin Use: Describing evidence that supports recent changes in recent FDA-approved labeling of metformin-containing products, authors of a systematic review conclude that “metformin use in patients with moderate [chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD)] with hepatic impairment is associated with improvements in key clinical outcomes” (10.7326/M16-1901). Studies selected for inclusion in the review assessed metformin’s effects in adults with type 2 diabetes and CKD, defined as estimated glomerular filtration rate less than 60 mL/min/1.73 sq m, and reported all-cause mortality, major adverse cardiovascular events, and other outcomes. The data showed: “On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.” (M. J. Crowley, matthew.crowley@dm.duke.edu)
Treatment of Gout: One of several articles in this issue on treatment of gout (pp. 26–36, S. J. Newberry, sydnen@rand.org; pp. 37–51, P. G. Shekelle, shekelle@rand.org; pp. 73–4, R. M. McLean, robert.mclean@ynhh.org; pp. 1–16, A. Qaseem), an editorial concludes that “although some approaches have not yet been formally tested in trials, a clear understanding of the pathophysiology of gout provides a strong foundation for rational recommendations while we await clarity on these important clinical issues” (pp. 71–2): “We acknowledge that the existing literature only indirectly addresses what the optimal serum urate target is. However, it is a disservice to our patients and primary care colleagues to suggest that treating to avoid symptoms is acceptable with [urate-lowering therapy (ULT)] in the absence of evidence. At the very least, based on the biochemistry of urate, a treatment target below the physiologic threshold of urate crystallization (<6.8 mg/dL) would be appropriate, even if a lower target is not yet supported by randomized trials. A target of less than 6.8 mg/dL (or <357 µmol/L [<6 mg/dL] with assay variation taken into account) seems reasonable, based on the authors’ own admission that serum urate levels exceeding this threshold are the cause of gout.” (T. Neogi)

>>>PNN JournalWatch
* 2017 Standards of Medical Care in Diabetes, in
Diabetes Care, 2017; 40 (suppl 1). (American Diabetes Association) 
* Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA, in
American Journal of Psychiatry, 2017; 174: 18–25. (W. V. McCall) 
* Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A Quality Improvement Project, in
Pediatrics, 2017; 139: 10.1542/peds.2016-0258. (R. Thienprayoon) 
* Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-0955. (D. Harrison) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 4, 2017 * Vol. 24, No. 2
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 3 issue of JAMA (2017; 317).
Trastuzumab Biosimilar in Metastatic Breast Cancer: In a randomized comparison, a proposed trastuzumab biosimilar performed similarly to the originator product in women with ERBB2 (HER2)–positive metastatic breast cancer, researchers report (pp. 37–47). The phase 3 trial included 500 women treated with a taxane plus either the biosimilar or trastuzumab, with these results: “Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The [overall response rate (ORR)] was 69.6% (95% CI, 63.62%–75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%–70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974–1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).” (H. S. Rugo, hope.rugo@ucsf.edu)
In addition to exploring the impact of a biosimilar on treatment in developing countries, editorialists delve into the effect on prices in the U.S. (
pp. 30–2): “The trastuzumab biosimilar will probably reduce prices, although this will not take full effect until the patent on trastuzumab expires in 2019. Under the prevailing ‘buy and bill’ system of Medicare Part B, oncology practices are reimbursed for chemotherapy based on a drug’s average sales price plus a 6% margin intended to cover overhead and inventory management. To mitigate the financial disincentive to prescribe inexpensive alternatives, the Centers for Medicare & Medicaid Services has wisely pegged reimbursement for biosimilar products to the average sales price of the biosimilar plus 6% of the branded version, that is, the 6% is based on the cost of the more expensive drug.” (D. Schrag, deb_schrag@dfci.harvard.edu)
JAMA editors explain their decision to publish this article in light of trial sponsorship by the biosimilar developers, including Mylan, which has been under scrutiny for its pricing of EpiPen (pp. 33–4): “Ultimately, the decision to publish this article was based on the determination that the scientific merit and potential to contribute meaningful clinical information for care of patients with breast cancer outweighed other considerations. The controversy over the pricing of drugs in the United States and around the world is an ongoing debate, and not unique to 1 company or 1 product. The authors have provided assurance to the editors that the study was conducted ethically and appropriately. The lead academic author indicates that she had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The data from this study will also be subject to additional scrutiny by regulatory agencies in making determinations about approval of the proposed trastuzumab biosimilar product.” (H. Bauchner, howard.bauchner@jamanetwork.org)
Longer Dosing Interval for Zoledronic Acid: Administration of zoledronic acid in patients with cancer every 12 weeks was noninferior to every-4-week dosing in a randomized open-label trial (pp. 48–58): “Among 1,822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of −0.3% [1-sided 95% CI, −4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma.…” (A. L. Himelstein, ahimelstein@cbg.org)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 5, 2017 * Vol. 24, No. 3
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 5 issue of the New England Journal of Medicine (2017; 376).
Inclisiran for PCSK9–Mediated Cholesterol Lowering: A long-acting RNA interference therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), inclisiran significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months without serious adverse events, researchers report (pp. 41–51). Tested in ascending and multiple doses in a phase 1 trial, inclisiran produced these results in small numbers of healthy volunteers: “The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the gamma-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).” (K. Fitzgerald, kfitzgerald@alnylam.com)
Entry of inclisiran into clinical testing brings attention to the new field of oligonucleotide therapeutics, according to the author of a Perspective article (
pp. 4–7): “The [small interfering RNAs (siRNAs)] consist of two strands, guide and passenger. The guide strand carries the sequence information necessary for target-gene recognition, while the passenger strand serves as a prodrug that supports the geometry required for loading into the RNA-induced silencing complex (RISC). When siRNAs are introduced into the cells, the guide strand enters the RISC and reprograms the powerful natural mechanism RNA interference (RNAi), silencing genes on demand. The loaded RISC has a long half-life, and as few as 100 to 200 loaded RISC complexes per cell are sufficient to eliminate expression of the targeted gene. The importance of this fundamental mechanism is well recognized — indeed, the two scientists who discovered it, Craig Mello and Andrew Fire, were awarded the Nobel Prize in 2006.” (A. Khvorova)
Oligonucleotide technology is also being tested with antisense agents, writes the author of a Clinical Implications of Basic Research article (
pp. 86–8). “The advantages of the targeted delivery strategy are … demonstrated by comparing the results of a pair of phase 2 studies in which the activity of two antisense oligonucleotides against apolipoprotein(a), which is expressed in the liver, were compared,” the author explains. “One of the antisense oligonucleotides was nontargeted, and the second was targeted to hepatocytes with the use of triantennary [N-acetylgalactosamine]. On the basis of the reductions in the mean change in circulating levels of apolipoprotein(a) according to dose, targeted delivery was determined to result in a median effective dose that was one thirtieth of that associated with nontargeted delivery, which clearly underscored the potential advantage of the approach.” (A. A. Levin)
Ticagrelor in Symptomatic Peripheral Artery Disease: In 13,885 patients with symptomatic peripheral artery disease, ticagrelor was not superior to clopidogrel for reduction of cardiovascular events, and major bleeding rates were similar (pp. 32–40). A primary efficacy composite end point of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke occurred in 751 of 6,930 patients (10.8%) receiving ticagrelor and in 740 of 6,955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P = 0.65), the investigators report. (M. R. Patel, manesh.patel@duke.edu)

>>>PNN NewsWatch
*
FDA, now classifying an October recall as Class I, yesterday issued an alert about a potential link between us of Nurse Assist I.V. Flush Syringes with Burkholderia cepacia bloodstream infections.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 6, 2017 * Vol. 24, No. 4
Providing news and information about medications and their proper use

>>>Diabetes Report
Source: Jan. issue and annual standards supplement of Diabetes Care (2017; 40).
2017 Standards of Medical Care in Diabetes: Psychosocial issues have been added to the ADA’s Standards of Care for 2017, including self-management, mental health, communication, complications, comorbidities, and life-stage considerations (supplement 1). Several tweaks were made to the pharmacotherapy recommendations, including the following (Am. Diabetes Assoc.):
* Patients on long-term metformin therapy should have periodic B12 measurements and supplementation as needed.
* A new section describes newly available biosimilar insulins.
* Empagliflozin or liraglutide are recommended in patients with established cardiovascular disease to reduce the risk of mortality.
* A figure illustrating antihyperglycemic therapy in type 2 diabetes is updated to acknowledge the high cost of insulin.
* An algorithm for the use of combination injectable therapy in patients with type 2 diabetes is changed to reflect studies demonstrating the noninferiority of basal insulin plus glucagon-like peptide 1 receptor agonist versus basal insulin plus rapid-acting insulin versus two daily injections of premixed insulin, as well as studies demonstrating the noninferiority of multiple-dose premixed insulin regimens versus basal-bolus therapy.
* New tables show the median costs of noninsulin agents.
Metformin & Gut Microbiome: Clinical data support an emerging hypothesis that use of metformin “shifts gut microbiota composition through the enrichment of mucin-degrading Akkermansia muciniphila as well as several [short-chain fatty acid (SCFA)]–producing microbiota,” researchers report (pp. 54–62). Among 28 patients with type 2 diabetes, half of whom were taking metformin, and 84 participants without diabetes, these results were found in clinical tests and gene sequencing of fecal samples: “We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus.” (J. S. Escobar, jsescobar@serviciosnutresa.com)
Saxagliptin & Renal Outcomes: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, saxagliptin significantly improved albumin/creatinine ratios (ACRs) among patients with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, an effect that could not be explained by the drug’s glycemic actions (pp. 69–76). “Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively),” the authors wrote of the 16,492 study participants. “At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was −19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA.…” (I. Raz, ntv502@netvision.net.il)

>>>PNN NewsWatch
* After a very quiet beginning of the
2016–17 influenza season, the bug produced its annual holiday bump in surveillance data during the week before Christmas as Americans shared a viral gift with other travelers and loved ones. Nationally, 10.4% of respiratory specimens tested positive for influenza that week, and 9 of the 10 regions in the U.S. had elevated activity. Remind patients that it’s not too late to get vaccinated and that peak activity last season was in March.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 9, 2017 * Vol. 24, No. 5
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 7 issue of Lancet (2017; 389).
Regorafenib in Hepatocellular Carcinoma: In a phase 3 trial of 567 patients with sorafenib-resistant hepatocellular carcinoma (HCC), regorafenib significantly improved overall and median survival, researchers report (pp. 56–66). “Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment,” the group concludes based on these study results: “Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50–0.79; one-sided p <0.0001); median survival was 10.6 months (95% CI 9.1–12.1) for regorafenib versus 7.8 months (6.3–8.8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand–foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.” (J. Bruix, jbruix@clinic.ub.es)
Atezolizumab in Urothelial Carcinoma: Results of a single-arm, phase 2 trial of the anti-programmed death-ligand 1 (PD-L1) atezolizumab show improved durable response rates, survival, and tolerability in 119 previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible (pp. 67–76): “At 17.2 months’ median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n = 11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.” (A. V. Balar, arjun.balar@nyumc.org)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
“Screen & Treat” in Type 2 Diabetes Prevention: Identification of prediabetes using the two available screening tests is often inaccurate, a systematic review and meta-analysis shows, indicating “‘screen and treat’ policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes” (i6538). Results indicated that “fasting glucose is specific but not sensitive and HbA1c is neither sensitive nor specific,” the authors conclude based on these findings: “The final analysis included 49 studies of screening tests (five of which were prevalence studies) and 50 intervention trials. HbA1c had a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of 0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic abnormality identified different subpopulations (for example, 47%of people with abnormal HbA1c had no other glycaemic abnormality). Lifestyle interventions were associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the trials.” (E. Barry, Eleanor.barry@phc.ox.ac.uk)

>>>PNN JournalWatch
* Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack, in
Circulation, 2017; 135: 21–33. (Y. Wang, yilong528@gmail.com
* Treatment of ARDS With Prone Positioning, in
Chest, 2017; 151: 215–24. (E. L. Scholten) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 10, 2017 * Vol. 24, No. 6
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. issue of JAMA Internal Medicine (2017; 177).
Treating Delirium in Palliative Care: In 247 patients at 11 Australian inpatient hospice or hospital palliative care units in 2008–14, individualized management and supportive strategies were significantly better than antipsychotic agents for reducing delirium symptoms, a study shows (pp. 34–42). Participants, all of whom had life-limiting illness, received oral risperidone, haloperidol, or placebo solution every 12 hours for 72 hours, based on symptoms of delirium as measured using the sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items, with these results: “In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09–0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06–0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09–1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17–1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20–2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91–1.84; P = .14).” (M. R. Agar)
Experiences with use of antipsychotic agents in patients with dementia may be instructive for use of the agents in delirium, editorialists write, noting a history of harms with use of antipsychotic agents for medicating distress (
pp. 42–3): “The advertisement for Thorazine with the white-haired gentleman wielding a cane illustrates that, since their development, antipsychotic drugs have been seen as useful to treat the distressing behavioral and psychological symptoms of dementia (BPSD). However, as manufacturers sought approval to use the newer atypical antipsychotic drugs specifically for distressing BPSD, it became clear that their use caused an increased risk of death relative to placebo. In 2005, the US Food and Drug Administration issued a black box warning regarding the increased risk of mortality associated with the use atypical antipsychotic drugs to treat BPSD.” (D. T. Maust)
Antihypertensive Medications & Fracture Risk: Compared with other antihypertensive medications, a thiazide diuretic lowered the risk of hip or pelvic fracture among 16,622 participants swith mild to moderate hypertension in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (pp. 67–76). Intention-to-treat analysis of data from 1994 through 2006 show these results: “During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63–0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58–0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63–1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74–1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up.” (J. I. Barzilay, joshua.barzilay@kp.org)
These results provide an excellent opportunity for “dodging complexity,” editorialists write (
pp. 77–8). “The large sample size and randomized, masked nature of ALLHAT greatly mitigate … concerns because … confounders are likely to be balanced between the groups,” the authors explain. “This is good news for those of us wanting to avoid complexity because thiazides are also a preferred class for first-line treatment of hypertension based on lower rates of cardiovascular events observed in ALLHAT and other trials, as described in American Heart Association/American College of Cardiology and Joint National Committee 8 guidelines.” (C. S. Colón-Emeric)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 11, 2017 * Vol. 24, No. 7
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 10 issue of JAMA (2017; 317).
Etelcalcetide in Secondary Hyperparathyroidism: The intravenous calcimimetic etelcalcetide was more effective for reducing serum parathyroid hormone (PTH) concentrations than placebo or orally administered cinacalcet in two trials of patients on hemodialysis (pp. 146–55, pp. 156–64, G M. Chertow, gchertow@stanford.edu). Commenting on the trials, editorialists write of “second chances” for improving outcomes in those with end-stage renal disease (ESRD) (pp. 139–41): “Can nephrologists soon expect a randomized trial of etelcalcetide with hard clinical end points? Demonstration of the efficacy of etelcalcetide for improving biochemical end points like PTH and serum phosphate is the low bar that must be overcome to secure regulatory approval for new treatments of disordered mineral metabolism in ESRD. This low-cost regulatory pathway enables more rapid introduction of new agents into ESRD practice but also serves as a powerful disincentive to conduct costly outcomes trials that are rightfully required in other therapeutic areas and thereby perpetuates the outcomes trial–deprived culture that permeates and stifles nephrology. Regulatory authorities should reconsider their approval processes to incentivize hard end-point trials in ESRD, and the manufacturer of etelcalcetide should conduct a rigorous second-generation trial to evaluate the effects of this promising second-generation calcimimetic for reducing mortality and major cardiovascular events and improving quality of life for patients with ESRD.” (M. Wolf, myles.wolf@duke.edu)
Folic Acid for PreventingNeural Tube Defects: Given the mandatory fortification of foods with folic acid, do women of child-bearing age still need folic acid supplements? Yes, says the U.S. Preventive Services Task Force (USPSTF) in a recommendation statement that updates its 2009 conclusion that benefits far outweigh risks (pp. 183–9): “The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation.” (K. Bibbins-Domingo, chair@uspstf.net)
Studies conducted before the 1998 initiation of food fortification demonstrate the effectiveness of the practice, according to authors of USPSTF’s evidence report (pp. 190–203). “Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.” (M. Viswanathan, viswanathan@rti.org)
“While identification of the causal link between folic acid and neural tube defects and the subsequent reduction in the prevalence of these conditions via folic acid fortification are remarkable public health successes, the current USPSTF recommendation provides an important reminder that we have yet to achieve the full benefit of these successes,” a
JAMA Pediatrics writer notes (10.1001/jamapediatrics.2016.4983). “The current recommendation statement should serve as a catalyst for renewed efforts to develop and deliver folic acid messages that will translate into further reductions in the population prevalence of neural tube defects.” (L. E. Mitchell, Laura.E.Mitchell@uth.tmc.edu)
A
JAMA editorialist agrees (pp. 144–5): “The USPSTF recommendation that all women of childbearing age take folic acid supplements is a prudent one. Ideally, it will educate all women who are planning or capable of pregnancy to follow this recommendation and thereby reduce the risk of these severe birth defects in their infants.” (J. L. Mills, jamesmills@nih.gov)
Marijuana Risks in Pregnancy: “Pregnant women and those considering becoming pregnant should be advised to avoid using marijuana or other cannabinoids either recreationally or to treat their nausea,” according to Viewpoint authors who note that 29 states and the District of Columbia now allow some form of legal cannabis. (pp. 129–30). “Physicians and other health care providers in a position to recommend medical marijuana must be mindful of the possible risks and err on the side of caution by not recommending this drug for patients who are pregnant.” (E. M. Wargo, wargoem@nida.nih.gov)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 13, 2017 * Vol. 24, No. 9
Providing news and information about medications and their proper use

>>>Cardiology Report
Source: Jan. 17 Journal of the Am. College of Cardiology (2017; 69).
Dual Antiplatelet Therapy After CABG: In patients with diabetes after coronary artery bypass grafting (CABG), routine dual antiplatelet therapy (DAPT) may not be needed, according to a post-hoc analysis of data from the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial (pp. 119–27). Comparing patients on aspirin plus thienopyridine or aspirin monotherapy after CABG, results show: “At 30 days post-CABG, 544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no significant difference in the 5-year primary composite outcome between DAPT- and aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.54 to 1.27; p = 0.39). The 5-year primary composite outcomes were similar for patients receiving DAPT versus aspirin monotherapy respectively, in subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p = 0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p = 0.42).… No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00; 95% CI: 0.50 to 1.99; p = 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to 2.34; p = 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI: 0.34 to 2.17; p = 0.74) were observed between aspirin- and DAPT-treated patients, respectively.” (S. van Diepen, sv9@ualberta.ca)
“Addition, intensification, or prolongation of antiplatelet therapy, although decreasing ischemic events, increases bleeding complications,” editorialists write (
pp. 128–30). “It is thus not surprising that many surgeons are not prescribing such therapy. Whether findings from this current study lead to modifications of future guideline recommendations or impact practice patterns remains to be determined.” (G. N. Levine, glevine@bcm.tmc.edu)
Cangrelor in PCI: For reducing ischemic complications after percutaneous coronary interventions (PCI), cangrelor is effective with or without concomitant glycoprotein IIb/IIIa inhibitors, CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) investigators report (pp. 176–85). Patient-level analysis of 24,902 participants showed the following based on a primary composite endpoint of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization: “Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%).… Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
“Further investigation is needed to better contextualize the role of cangrelor in the setting of other medications used during PCI,” writes an editorialist (
pp. 186–8). “Whether there is added benefit to using cangrelor with newer antiplatelet agents, such as ticagrelor and prasugrel, remains unknown. Also, decision making at the point of care may be challenging without a better accounting of the prognostic significance of the endpoints of interest.” (S. S. Brar, sbrar@cvri.org)

>>>PNN NewsWatch
* The
Biosimilars Forum is critical of an FDA decision to use nonsensical suffixes to differentiate biosimilars from innovator biologics. In a statement issued yesterday, the Forum wrote, “Nonmeaningful suffixes will certainly be more difficult for physicians and patients to recall than meaningful suffixes. Additionally, they will likely lessen the ability to carefully track the identity of the biologic drug administered to patients, thereby contrary to the stated purpose of having a suffix to enhance pharmacovigilance.”
*
PNN will not be published on Mon., Jan. 16, King Day.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 17, 2017 * Vol. 24, No. 10
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 17 issue of and early-online articles from the Annals of Internal Medicine (2017; 166).
Medication Adherence in Medical Homes: Adherence to medications for common, high-cost, chronic diseases is higher among patients receiving care in a patient-centered medical home than in other primary-care settings, a case–control study shows (pp. 81–8). Retrospective analysis of Aetna claims show these patterns of prescription refills for patients initiating therapy in 2011–13 for diabetes, hypertension, or hyperlipidemia: “Of 313,765 patients meeting study criteria, 18,611 (5.9%) received care in patient-centered medical homes. Mean rates of adherence were 64% among medical home patients and 59% among control patients. Among 4,660 matched control and medical home practices, medication adherence was significantly higher in medical homes (2.2% [95% CI, 1.5% to 2.9%]). The association between medical homes and better adherence did not differ significantly by disease state (diabetes, 3.0% [CI, 1.5% to 4.6%]; hypertension, 3.2% [CI, 2.2% to 4.2%]; hyperlipidemia, 1.5% [CI, 0.6% to 2.5%]).” (N. K. Choudhry, nkchoudhry@bwh.harvard.edu)
Figuring out what about medical homes helps people take their long-term medications is the next step in the research process, an editorialist writes (
pp. 146–7): “Success in 4 domains will likely be essential for overall success: 1) fostering sustained, trusting, and collaborative relationships between providers and patients; 2) systems to systematically monitor patients’ levels of adherence to medications from all prescribers and to identify barriers to adherence and appropriate strategies to address them; 3) proactive identification of patients who require higher levels of adherence support; and 4) provision of necessary support between face-to-face visits.” (M. Heisler)
Managing Osteoarthritis in Primary Care: Among 537 outpatients with symptomatic hip or knee osteoarthritis, a combined patient/provider intervention at a VA medical center did not result in statistically significant improvement in disease markers, compared with usual care, researchers report (10.7326/M16-1245). The patient intervention, which used telephone communications to focus on weight management, physical activity, and cognitive behavioral pain management, was combined with electronic delivery of patient-specific recommendations to providers. Results showed: “No difference was observed in [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)] score changes from baseline to 12 months in the patient (−1.5 [95% CI, −5.1 to 2.0]; P = 0.40), provider (2.5 [CI, −0.9 to 5.9]; P = 0.152), or patient–provider (−0.7 [CI, −4.2 to 2.8]; P = 0.69) intervention groups compared with usual care. All groups had improvements in WOMAC scores at 12 months (range, −3.7 to −7.7). In addition, no differences were seen in objective physical function or depressive symptoms at 12 months in any of the intervention groups compared with usual care.” (K. D. Allen, kdallen@email.unc.edu)

>>>Lancet Highlights
Source: Jan. 14 issue of Lancet (2017; 389).
Inhaled Corticosteroids in Mild Asthma: Results of the 3-year inhaled Steroid Treatment As Regular Therapy (START) study show benefits of once-daily, low-dose budesonide in patients with mild recent-onset asthma, countering assumptions that corticosteroids should be restricted to those with symptoms on more than 2 days per week (pp. 157–66). Findings for the 7,138 pediatric and adult study participants suggest that “treatment recommendations for mild asthma should consider both risk reduction and symptoms,” the authors conclude. (H. K. Reddel, helen.reddel@sydney.edu.au)

>>>PNN JournalWatch
* An Evidence-Based Medicine Approach to Antihyperglycemic Therapy in Diabetes Mellitus to Overcome Overtreatment, in
Circulation, 2017; 135: 180–95. (A. N. Makam, anil.makam@utsouthwestern.edu
* Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians, in
Annals of Internal Medicine, 2017; 166: 10.7326/M16-1785. (A. Qaseem, aqaseem@acponline.org)
* Migraine and Risk of Perioperative Ischemic Stroke and Hospital Readmission: Hospital Based Registry Study, in
BMJ, 2017; 356: i6635. (M. Eikermann, meikermann@partners.org

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 18, 2017 * Vol. 24, No. 11
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 17 issue of JAMA (2017; 317).
Fungal Infections After Empiric Antifungals in Critical Care: Among critically ill patients, use of antifungal agents before a definitive diagnosis of invasive fungal infection (IFI) is associated with lower rates of IFIs but no significant changes in mortality, according to a JAMA Clinical Evidence Synopsis (pp. 311–2). Noting the low quality of the evidence in a Cochrane review, the authors conclude: “Clinical practice guidelines from Infectious Diseases Society of America and European Society of Clinical Microbiology and Infectious Diseases support the use of antifungal treatment in critically ill patients administered before definitive diagnosis of IFI in certain circumstances (eg, patients at risk of IFI). Evidence from this Cochrane review is only partly consistent with these guidelines because although no association with reduced mortality was found, there was an association with lower incidence of [IFIs].” (A. Cortegiani, andrea.cortegiani@unipa.it)
Revisiting Asthma Diagnoses in Adults: In a study of adults diagnosed with asthma within the prior 5 years, one-third of participants had no symptoms after medications were stopped (pp. 269–79). In Canada in 2012–16, a cohort study found these results after daily asthma medications were weaned and stopped over 4 study visits: “Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%–36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%–33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%–21.5%).” (S. D. Aaron, saaron@ohri.ca)
Urban Diabetes in China: Over a 7-year period, a prospective nationwide study of 512,869 adults in China found a higher prevalence of diabetes in urban areas but a greater excess mortality rate from the disease in rural sections (pp. 280–9). With recruitment into the study in 2004–08 and follow-up through Jan. 2014, authors gathered these results for 30,380 adults with diabetes (4.1% of those in rural areas, 8.1% in urban areas): “During 3.64 million person–years of follow-up, there were 24,909 deaths, including 3,384 among individuals with diabetes. Compared with adults without diabetes, individuals with diabetes had a significantly increased risk of all-cause mortality (1,373 vs 646 deaths per 100,000; adjusted RR, 2.00 [95% CI, 1.93–2.08]), which was higher in rural areas than in urban areas (rural RR, 2.17 [95% CI, 2.07–2.29]; urban RR, 1.83 [95% CI, 1.73–1.94]). Presence of diabetes was associated with increased mortality from ischemic heart disease (3,287 deaths; RR, 2.40 [95% CI, 2.19–2.63]), stroke (4,444 deaths; RR, 1.98 [95% CI, 1.81–2.17]), chronic liver disease (481 deaths; RR, 2.32 [95% CI, 1.76–3.06]), infections (425 deaths; RR, 2.29 [95% CI, 1.76–2.99]), and cancer of the liver (1,325 deaths; RR, 1.54 [95% CI, 1.28–1.86]), pancreas (357 deaths; RR, 1.84 [95% CI, 1.35–2.51]), female breast (217 deaths; RR, 1.84 [95% CI, 1.24–2.74]), and female reproductive system (210 deaths; RR, 1.81 [95% CI, 1.20–2.74]). For chronic kidney disease (365 deaths), the RR was higher in rural areas (18.69 [95% CI, 14.22–24.57]) than in urban areas (6.83 [95% CI, 4.73–9.88]). Among those with diabetes, 10% of all deaths (16% rural; 4% urban) were due to definite or probable diabetic ketoacidosis or coma (408 deaths).” (Z. Chen, lmlee@vip.163.com)
“In public health, what gets measured gets done,” writes the WHO director-general (
pp. 264–6). “The quality of [these] precise measurement[s] … provides confidence that Chinese authorities will continue to move the country’s health reforms in the right direction, with results that also improve the prevention and control of diabetes. The World Health Organization has identified a number of best-buy interventions for diabetes and other noncommunicable diseases to help countries do so.” (M. Chan, chanm@who.int)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 19, 2017 * Vol. 24, No. 12
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 19 New England Journal of Medicine (2017; 376).
B-Cell Depletion in Relapsing Multiple Sclerosis: Articles report and discuss results of phase 3 trials of ocrelizumab, which selectively depletes CD20-expressing B cells.
Among 732 patients with primary progressive multiple sclerosis, ocrelizumab produced lower rates of clinical and MRI progression than placebo (
pp. 209–20). The phase 3 trial compared I.V. ocrelizumab 600 mg and placebo given every 24 weeks for at least 120 weeks or until progression of disability. Rates of progression were 32.9% and 39.3% in the two respective groups. Adverse effects were more common with active therapy, including neoplasms in 2.3% and 0.8% of those receiving ocrelizumab and placebo, respectively. (X. Montalban, xavier.montalban@cem-cat.org)
The second article finds lower rates of disease activity and progression with ocrelizumab in two identical, 96-week, phase 3, head-to-head comparisons with interferon beta-1a (
pp. 221–34): “The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P <0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P <0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P <0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P = 0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P <0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P <0.001). The change in the Multiple Sclerosis Functional Composite score … significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P = 0.004) but not in trial 1 (0.21 vs. 0.17, P = 0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.” (S. L. Hauser, stephen.hauser@ucsf.edu)
While “patients with primary progressive multiple sclerosis … are desperately in need of a therapy, side effects must also be considered,” an editorialist writes (
pp. 280–2). “Although the dreaded complication of other drugs for multiple sclerosis, infection with JC virus causing progressive multifocal leukoencephalopathy, has not been seen with B-cell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal risk of herpes reactivation and of neoplasms, especially breast cancer.” (P. A. Calabresi)
Extensively Drug-Resistant Tuberculosis in South Africa: In a tuberculosis-plagued region of South Africa, extensively drug-resistant (XDR) organisms are spreading through transmission rather than acquisition secondary to failed treatment, researchers report (pp. 243–53). This reinforces the importance of efforts to control the epidemic of drug-resistant tuberculosis through “an increased focus on interrupting transmission,” the authors conclude. Differentiating between acquired multidrug-resistant (MDR) tuberculosis strains and the transmitted XDR ones, the investigators report these results of data gathered in 2011–14 from interviews, medical records, and genetic analysis of XDR Mycobacterium tuberculosis isolates: “Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).” (N. R. Gandhi, neel.r.gandhi@emory.edu)

>>>PNN NewsWatch
*
FDA has released draft guidances on drug/device manufacturers’ communications with formulary committees and payers.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 20, 2017 * Vol. 24, No. 13
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Feb. 1 issue of Clinical Infectious Diseases (2017; 64).
Vancomycin Taper v. Fecal Transplantation in CDI: In a phase 2/3, open-label trial, 30 patients with single acute episodes of recurrent Clostridium difficile infection (CDI), fecal transplantation (FT) was not significantly different from oral vancomycin taper, researchers report (pp. 265–71). In Ontario, 14 days of oral vancomycin therapy followed by either FT or a 6-week taper of vancomycin produced these results: “The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon.” (S. S. Hota, susy.hota@uhn.ca)
While more evidence is needed to determine whether a “fecal fixation” is justified in those who see the intervention as “the holy grail for treatment of recurrent CDI,” this study adds to the evidence supporting vancomycin taper for this condition, editorialists write (
pp. 272–4): “Refinement of [fecal microbiota transplantation (FMT)] to make it a more acceptable, safe, and more defined product is an area of active research, with at least 2 products in phase 2/3 clinical trials.… As we go forward, it is clear that well- designed [randomized controlled trials] of FMT and related products with appropriate comparator groups conducted in patients with recently identified episodes of multiply recurrent CDI are required to assess the efficacy of this potentially highly effective strategy for prevention of CDI recurrence. In the meantime, we have additional evidence of the efficacy of vancomycin taper/pulse administration as an effective treatment.” (S. Johnson, stuart.johnson2@va.gov)

>>>Oncology Highlights
Source: Jan. issue of the Journal of Clinical Oncology (2017; 35).
Basket Trials in Oncology: Testing of targeted therapies that may be present in tumors of different subtypes or sites — “basket trials” — have “scientific goals [that] are typically more complex and frequently not specified with the precision conventionally used for clinical trials,” authors write in a Comments and Controversies article (pp. 271–3): “Most investigators view a basket trial as a series of independent phase II clinical trials. In fact, the simplest type of basket trial, the evaluation of a single drug targeting a single mutation in multiple disease sites, presents a much more complex framework than a conventional evaluation of a single drug in a single disease. We believe that creative investigation into design options offers the potential to meet the study goals faster, with fewer patients. Such investigation must recognize the fact that most basket trials typically aim to answer multiple questions simultaneously. Most importantly, in this period of transition to precision medicine, our clinical research tools must maintain the scientific rigor embedded in the traditional clinical trials paradigm, in which hypotheses are specified precisely and the clinical trial is designed to address these hypotheses.” (A. Iasonos, iasonosa@mskcc.org)

>>>PNN NewsWatch
*
Plecanatide (Trulance, Synergy Pharmaceuticals) was approved yesterday for treatment of chronic idiopathic constipation in adult patients. This is the first drug designed to replicate the function of uroguanylin, a naturally occurring and endogenous human gastrointestinal peptide that is thought to stimulate fluid secretion, the company said in a news release. The result of treatment is a stool consistency associated with more regular bowel function.
* Just in time for Inauguration Day,
FDA Commissioner Robert Califf, MD, has announced formation of the Oncology Center of Excellence, with Richard Pazdur, MD, as director. Creation of the center makes oncology the first disease area with a coordinated clinical review of drugs, biologics, and devices across the agency’s three medical product centers. Talk of a Trump appointment to head the FDA has centered around nontraditional picks from Silicon Valley. The president-elect has hinted at relaxed FDA standards for drug approval but has also attacked the pharmaceutical industry regarding pricing of drug products.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 23, 2017 * Vol. 24, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 21 issue of Lancet (2017; 389).
Atezolizumab in Previously Treated Non-Small-Cell Lung Cancer: In the first randomized phase 3 study to report results of a programmed death-1 (PD-1)–targeted therapy, atezolizumab treatment was significantly more effective than docetaxel for improving overall survival in previously treated patients with squamous or nonsquamous non-small-cell lung cancer (pp. 255–65). OAK investigators in 31 countries randomized patients with squamous or nonsquamous non-small-cell lung cancer to atezolizumab or docetaxel every 3 weeks, with these intention-to-treat (ITT) results in the first 850 of 1,225 enrolled patients: “Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13.8 months [95% CI 11.8–15.7] vs 9.6 months [8.6–11.2]; hazard ratio [HR] 0.73 [95% CI 0.62–0.87], p = 0.0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n = 241) compared with docetaxel (n = 222; median overall survival was 15.7 months [95% CI 12.6–18.0] with atezolizumab vs 10.3 months [8.8–12.0] with docetaxel; HR 0.74 [95% CI 0.58–0.93]; p = 0.0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12.6 months vs 8.9 months; HR 0.75 [95% CI 0.59–0.96]). Overall survival improvement was similar in patients with squamous (HR 0.73 [95% CI 0.54–0.98]; n = 112 in the atezolizumab group and n = 110 in the docetaxel group) or non-squamous (0.73 [0.60–0.89]; n = 313 and n = 315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.” (D. R. Gandara, drgandara@ucdavis.edu)
Filgotinib in Crohn Disease: In a phase 2 trial of 174 adults with moderate-to-active Crohn disease, the Janus kinase 1 (JAK1)-selective inhibitor filgotinib induced remission significantly more often than placebo, researchers report (pp. 266–75). The safety profile of the new drug was acceptable as well, the study shows, with these results based on primary endpoint was clinical remission, defined as Crohn’s Disease Activity Index (CDAI) less than 150 at week 10: “In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9–39], p = 0.0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.” (S. Vermeire, severine.vermeire@uzleuven.be)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
RAS Inhibitors in Stable Coronary Artery Disease: For treating patients with stable coronary artery disease without heart failure, available evidence does not support a “preferred status” for agents that inhibit the renin–angiotensin system (RASi), authors of a meta-analysis of 24 trials of 198,275 patients conclude (j4): “RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher control event rates but not in those with lower control event rates.” (S. Bangalore, sripalbangalore@gmail.com)

>>>PNN JournalWatch
* Early Oral Immunotherapy in Peanut-Allergic Preschool Children Is Safe and Highly Effective, in
Journal of Allergy and Clinical Immunology, 2017; 139: 173–81.e8. (A. W. Burks, wesley.burks@unc.edu
* Increased Antiviral Treatment Among Hospitalized Children and Adults With Laboratory-Confirmed Influenza, 2010–2015, in
Clinical Infectious Diseases, 2017; 64: 364–7. (A. P. Campbell, app4@cdc.gov
* Hormone-Related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization, in
Pharmacotherapy, 2017; 37: 120–8. (L. J. Cohen, lawrence.cohen@unthsc.edu

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 24, 2017 * Vol. 24, No. 15
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Jan. issue of the Journal of the American Geriatrics Society (2017; 65).
Hospitalizations & Pharmacists’ Medication Management: In Hawaii, provision of medication management services by specially trained community and hospital pharmacists reduced rehospitalizations of high-risk older adults by 38%, yielding a 2.6:1 return on investment, a study shows (pp. 212–9). Working with high-risk individuals from hospitalization through transition to home and for up to 1 year after discharge, Pharm2Pharm pharmacists produced these results at six study and five control Hawaiian hospitals with more than 50 beds: “The predicted, case mix–adjusted medication-related hospitalization rate of individuals aged 65 and older was 36.5% lower in the Pharm2Pharm hospitals after implementation than in the nonintervention hospitals (P = .01). The estimated annualized cost of avoided admissions was $6.6 million. The annual cost of the pharmacist services for all Pharm2Pharm participants was $1.8 million.” (K. L. Pellegrin, karen3@hawaii.edu)
Expected Benefit of Warfarin in Atrial Fibrillation: Over time, “competing death events” diminish the expected benefits of warfarin among patients with atrial fibrillation (AF), according to community-based cohort results from the Anticoagulation and Risk Factors in Atrial Fibrillation Study (pp. 35–41). Adults diagnosed with nonvalvular AF in 1996–2003—four-fifths of them aged 65 years or older—had these outcomes based on longitudinal warfarin exposure and rates of thromboembolism and all-cause deaths: “The rate of death was much higher in the group not taking warfarin (8.1 deaths/100 person–years (PY)) than in the group taking warfarin (5.5 deaths/100 PY). The cause-specific HR indicated a large reduction in thromboembolism with warfarin use (adjusted HR = 0.57, 95% confidence interval (CI) = 0.50–0.65), although this association was substantially attenuated after accounting for competing death events (adjusted HR = 0.87, 95% CI = 0.77–0.99). In analyses limited to 1 year of follow-up, with fewer competing death events, the results for models that did and did not account for competing risks were similar.” (J. M. Ashburner, jashburner@mgh.harvard.edu)
“These results reinforce the growing understanding that, when treating older adults, providers can no longer consider any disease or condition in isolation from the individual’s complete profile of health concerns,” editorialists write (
pp. 25–6): “There is general consensus that use of warfarin is effective in preventing stroke among older adults with AF. At the same time, there is research suggesting that, even in individuals at high risk of stroke, oral anticoagulants are widely underused. A plausible explanation for such underuse appears to be that long-term practitioners prioritize concern about the risk of bleeding over stroke prevention in some older adults with AF. There is also agreement that use of anticoagulants such as warfarin is most effective in individuals with high risk of stroke, whereas treatment with aspirin appears to suffice for persons at lower risk. The marked attenuation of the protective effect of warfarin reported here provides a new perspective on the decision-making process that providers and older adults must navigate. In addition to the older adult’s individual likelihood of stroke, the decision to prescribe anticoagulants must also consider chronic conditions and the overall risk of death from nonstroke causes.” (T. E. Murphy)
Medication Use After Dementia Diagnosis: In patients with type 2 diabetes, “use of cardiometabolic medications fell after a diagnosis of dementia, as recommended in national guidelines,” researchers report (pp. 77–82). The case–control study population included Kaiser patients in northern California, who had these outcomes following a new diagnosis of dementia: “After adjustment, the number of chronic medications and the subset of cardiovascular medications declined after a dementia diagnosis in the overall cohort and in age-, sex-, and time-matched reference individuals, but the decline was significantly greater in the group with dementia (0.71 medications fewer than the reference group, P = .02). The number of diabetes mellitus medications declined in both groups, but the declines were not statistically different (0.18 medications fewer than the reference group, P = .008).” (U. Sarkar, urmimala.sarkar@ucsf.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 25, 2017 * Vol. 24, No. 16
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 24/31 issue of JAMA (2017; 317).
Continuous Glucose Monitoring in Type 1 Diabetes: Two articles and an editorial examine utility of continuous glucose monitoring (CGM) in adults with type 1 diabetes.
In the DIAMOND randomized clinical trial, adults using multiple daily insulin injections had significantly better outcomes when they used continuous glucose monitoring (CGM), compared with usual care (
pp. 371–8). Investigators established a primary endpoint of decreased glycated hemoglobin levels for the 24-week trial, as noted in these results: “Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10–31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was –0.6% (95% CI, –0.8% to –0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27–69) in the CGM group vs 80 min/d (IQR, 36–111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group.” (R. W. Beck, rbeck@jaeb.org)
Similar results come from the GOLD randomized clinical trial, a 26-week comparison of CGM with usual care (
pp. 379–87): “Among 161 randomized participants, mean age was 43.7 years, 45.3% were women, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, −0.43% [95% CI, −0.57% to −0.29%] or −4.7 [−6.3 to −3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia.” (M. Lind, lind.marcus@telia.com)
These trials show benefits from CGM and that adult patients with type 1 diabetes like this approach, editorialists write (
pp. 363–4): “CGM limits hyperglycemia and hypoglycemia, improves diabetes control, and reduces glucose variability. These studies also show that selected patients favored this method of monitoring. Additional clinical trials are needed to determine the long-term effect of CGM and whether this approach translates to improved health outcomes and to determine the potential utility of real-time CGM for patients with type 1 diabetes encountered in usual clinical practice and in patients with type 2 diabetes who require insulin injections.” (M. B. Davidson, mayerdavidson@cdrewu.edu)
Gut Bacteria, Obesity & Diabetes: “It is plausible that the human microbiome may affect the risk of obesity and type 2 diabetes and other diseases such as atherosclerosis, and that manipulations of the microbiome might reduce that risk,” writes authors of a Commentary article (pp. 355–6): “However, biomedical science is a long way from proving either proposition. Dissecting the possible role of the microbiome in these and other diseases will be a great challenge, because (1) human genes influence the composition of the gut microbiota, (2) microbial genes influence the expression of human genes, (3) the metabolism of some gut microbes influences the metabolism of other gut microbes, and (4) diet influences both the microbiota and (possibly) the expression of human genes. In short, human genes, microbial genes, and diet share a complicated set of interdependencies.” (A. L. Komaroff, anthony_komaroff@hms.harvard.edu)

>>>PNN NewsWatch
* Hospira is voluntarily recalling one lot of
Vancomycin Hydrochloride for Injection, USP (Lot 591053A, Exp. 11/1/17), to the hospital/retail level due to confirmed presence of particulate matter, FDA said.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 26, 2017 * Vol. 24, No. 17
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 26 issue of the New England Journal of Medicine (2017; 376).
Bezlotoxumab for Recurrent Clostridium difficile Infection: In the phase 3 MODIFY I and MODIFY II trials, the antitoxin monoclonal antibody bezlotoxumab was associated with a substantially lower rate of recurrent Clostridium difficile infection than placebo without producing additional adverse effects, researchers report (pp. 305–17). Addition of a second monoclonal, actoxumab, had no added effect, as shown in these results: “In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P <0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P <0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P <0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P <0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.” (M. H. Wilcox, mark.wilcox@nhs.net)
“Bezlotoxumab is a new, now-FDA-approved anti–
C. difficile agent that has proved effective in reducing the rate of first post-treatment relapses of C. difficile infection,” writes an editorialist (pp. 381–2). “However, uptake by clinicians will vary on the basis of cost and assessments of relapse risk in association with this drug as compared with the alternative options.” (J. G. Bartlett)
Recombinant Vesicular Stomatitis Virus Ebola Vaccine: Phase 1 trials of an Ebola vaccine candidate support further evaluation “for preexposure prophylaxis and suggest that a second dose may boost antibody responses,” rVSV∆G-ZEBOV-GP investigators conclude (pp. 330–41). The attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)–based vaccine candidate was tested in 39 adults at each of two sites received one of three doses of the vaccine; volunteers at one site received a second dose at day 28. Results showed: “The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months.” (J. A. Regules, jason.a.regules.mil@mail.mil)
Treating Metastatic Renal-Cell Carcinoma: Additional progress against metastatic renal cell carcinoma will require “new drugs with new targets and mechanisms of action,” review authors conclude (pp. 354–66). “Although more than 14,000 patients die from kidney cancer each year, we have seen considerable progress in the systemic treatment of metastatic renal-cell carcinoma in the past 20 years. Researchers have achieved a better understanding of the pathogenesis of the most common type of renal-cell carcinoma, clear-cell renal-cell carcinoma. This understanding has led to new agents, expanded treatment options, and increased rates of survival.” (T. K. Choueiri, toni_choueiri@dfci.harvard.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 27, 2017 * Vol. 24, No. 18
Providing news and information about medications and their proper use

>>>Diabetes Care Report
Source: Feb. issue of Diabetes Care (2017; 40).
Adverse Pancreatic Reactions to Gliptins: Two studies and a commentary examine the link between gliptin use and adverse pancreatic outcomes.
In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), rates of pancreatitis and pancreatic cancer were statistically similar between sitagliptin and placebo groups, researchers report (
pp. 164–70). Prospective data on 14,671 participants followed for 3 years showed these patterns: “Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96–3.88], P = 0.065; 0.107 vs. 0.056/100 patient–years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28–1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient–years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13–2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28–1.04], P = 0.07).” (J. B. Buse, jbuse@med.unc.edu)
Combining TECOS data with those from the SAVOR-TIMI 53 (saxagliptin) and EXAMINE (alogliptin) trials, a significant risk of pancreatitis is evident, a second study shows (
pp. 284–6). A random-effects model meta-analysis of data on 18,238 gliptin-treated and 18,157 placebo-treated patients showed these results: “The incidence of acute pancreatitis was significantly increased in the gliptin-treated patients when compared with the control groups (odds ratio 1.79 [95% CI 1.13–2.82], P = 0.013). The difference in the absolute risk was small (0.13%).” (I. Tkác, ivan.tkac@upjs.sk)
“DPP-4 inhibitors are well-established agents, and their benefits clearly outweigh the risks,” Commentary authors conclude (
pp. 161–3). “Acute pancreatitis is real, but its frequency is very low to impede the generalized use of DPP-4 inhibitors unless more efficacious agents are preferred. Can we identify people at increased risk for developing DPP-4 inhibitor–related pancreatitis? For those with a history of pancreatitis, avoiding these drugs is a sensible recommendation. However, avoiding its use in subjects with risk factors for pancreatitis may sound justified but solid data supporting such a strategy is lacking. Amylase and lipase levels can be mildly elevated with incretin-based therapies, but the levels fluctuate to a large extent and therefore the positive predictive value of an increased level seems so low that this cannot be used to identify people at risk. Thus, we can conclude that pancreatitis is an established but rare side effect of DPP-4 inhibitors that occurs at a very low frequency. We should inform patients on this potential side effect, and in people on DPP-4 inhibitors having even mild gastrointestinal symptoms suggestive of pancreatitis, it would be justified to measure pancreatic enzymes and appropriate to perform an abdominal ultrasound to exclude gallstones. On the basis of the evidence so far, perhaps in some patients when gallstones are present (even if asymptomatic) and/or when lipase levels are >3 times normal (even if fluctuating), there may be enough basis to consider replacing an incretin-based agent used and consider an alternative therapy.” (J. H. DeVries, j.h.devries@amc.uva.nl)
Oral Diabetic Medications & HIV Infections: While a longitudinal cohort study shows that effectiveness of oral antidiabetic medications is similar in patients with and without HIV infection, data indicate a poorer response among the black and Hispanic patients who make up a large portion of those with the virus (pp. 218–25). The study included 2,454 HIV-infected and 8,892 HIV-uninfected veterans who initiated oral diabetes medications (metformin in half of patients, sulfonylurea in 49%, thiazolidinediones in 1%) between 1999 and 2010. Results showed: “Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA1c level of 0.16% (95% CI 0.08, 0.24) [1.7 mmol/mol (0.9, 2.6)] (P <0.001) and 0.25% (0.11, 0.39) [2.7 mmol/mol (1.2, 4.3)] (P = 0.001), respectively.” (J. H. Han, jennifer.han@uphs.upenn.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 30, 2017 * Vol. 24, No. 19
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 28 issue of Lancet (2017; 389).
Bionic Pancreas in Type 1 Diabetes: Compared with conventional and sensor-augmented insulin pump therapy in 43 patients, a bihormonal bionic pancreas provided superior glycemic regulation using only the person’s weight, a study shows (pp. 369–80). At four U.S. sites, adult volunteers with type 1 diabetes were randomized to the bionic device or pump therapy for 11 days and then crossed over to the alternative therapy. Participants continued all normal activities, and the bionic pancreas provided both insulin and glucagon. Results for 39 participants completing the study showed the following: “The mean [continuous glucose monitoring (CGM)] glucose concentration was 7.8 mmol/L (SD 0.6) in the bionic pancreas period versus 9.0 mmol/L (1.6) in the comparator period (difference 1.1 mmol/L, 95% CI 0.7–1.6; p <0.0001), and the mean time with CGM glucose concentration less than 3.3 mmol/L was 0.6% (0.6) in the bionic pancreas period versus 1.9% (1.7) in the comparator period (difference 1.3%, 95% CI 0.8–1.8; p <0.0001). The mean nausea score on the Visual Analogue Scale (score 0–10) was greater during the bionic pancreas period (0.52 [SD 0.83]) than in the comparator period (0.05 [0.17]; difference 0.47, 95% CI 0.21–0.73; p = 0.0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study.” (S. J. Russell, sjrussell@mgh.harvard.edu)

>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 354).
Thyroid in Subclinical Hypothyroidism of Pregnancy: Among 5,405 pregnant women with subclinical hypothyroidism whose experiences were recorded in a large U.S. administrative database, thyroid hormone treatment reduced the risk of pregnancy loss, a study shows, particularly in those with pretreatment levels of thyroid stimulating hormone (TSH) in the 4.1–10 mIU/L range (i6865). However, the authors add, other pregnancy-related adverse outcomes were more common among those receiving treatment, including preterm delivery, gestational diabetes, and pre-eclampsia. (R. G. McCoy, mccoy.rozalina@mayo.edu)
Atosiban v. Fenoterol as Uterine Relaxant: In 830 pregnant women undergoing external cephalic version (ECV) for breech presentation, the beta-mimetic fenoterol was more effective 30 minutes after the procedure than the oxytocin receptor antagonist atosiban, but neither agent yielded significant improvements at delivery, researchers report (i6773): “Cephalic position 30 minutes after ECV occurred significantly less in the atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95% confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n = 139) of the atosiban group and 40% (n = 166) of the fenoterol group (0.86, 0.72 to 1.03), and caesarean delivery was performed in 60% (n = 240) of women in the atosiban group and 55% (n = 218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were found in neonatal outcomes or drug related adverse events.” (J. Velzel, j.velzel@amc.nl)

>>>PNN NewsWatch
*
Homeopathic teething tablets contain inconsistent and sometimes much-higher-than-labeled amounts of belladonna, FDA said on Friday. The manufacturer of Hyland’s homeopathic teething products, Standard Homeopathic Company, has not agreed to conduct a recall, but FDA said it recommends that consumers stop using the products. “The body’s response to belladonna in children under 2 years of age is unpredictable and puts them at unnecessary risk,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research. ”We recommend that parents and caregivers not give these homeopathic teething tablets to children and seek advice from their health care professional for safe alternatives.” The announcement expands on a Sept. FDA alert and a Nov. recall by another manufacturer.

>>>PNN JournalWatch
* Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis, in
Arthritis & Rheumatology, 2017; 69: 257–67. (J. H. W. Distler, joerg.distler@uk-erlangen.de
* Gout and Risk of Fracture in Women: A Prospective Cohort Study, in
Arthritis & Rheumatology, 2017; 69: 422–8. (J. Paik, jmpaik@partners.org

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 31, 2017 * Vol. 24, No. 20
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source: Jan. issue of Health Affairs, a theme issue on Coverage Expansion, Accountable Care, and More, and online blogs (2017; 36).
ACA Replacement Bill: An Affordable Care Act (ACA) repeal-and-replace bill introduced recently by Republican Senators is built around maintaining popular ACA features, shifting decisions to the states, and pushing use of Roth HSAs as a subsidy mechanism (Jan. 24 blog). The Patient Freedom Act of 2017 (PFA) would selectively repeal most of the ACA that dealt with insurance reform and affordability but would give states the options of maintaining the ACA in their states, adopt a different approach based on subsidized Roth HSAs, or reject reform altogether. Noting that PFA is even more complex than ACA, the blog author concludes: “It has become increasingly clear in recent days that Republicans are trying to find a way to couple ACA repeal with ACA replacement. The PFA is an attempt to build a replacement plan on Republican principles of devolution of responsibility to the states and deregulation, but in a way that might appeal to some Democrats. The bill, however, appears to have been rushed into legislative language without adequate consideration of how it would actually work and what it would cost. It may form a basis for discussion, but it is not ready for enactment.” (T. Jost)
People Newly Insured In 2014: More than one-half of those gaining health insurance in 2014 were long-term uninsured individuals who had been without coverage for 3 years or more, researchers report (pp. 16–20). Examining the effects of the Affordable Care Act as reflected in data for 2013–14 from the National Health Interview Survey (NHIS), the investigators found “that 18.0 percent of nonelderly adults were uninsured in 2013, with over half of them (9.4 percent) uninsured for more than three years. The uninsurance rate fell 4.2 percentage points (from 18.0 percent to 13.9 percent) between 2013 and 2014. The percentage of adults uninsured for more than three years fell 2.2 percentage points (from 9.4 percent to 7.1 percent), compared to declines of 0.7 percentage point and 1.1 percentage points among the short- and medium-term uninsured, respectively.” The authors conclude, “Since those who have been uninsured for a long time might not be in the habit of using health care, it will be important to examine the impacts of premium and cost-sharing subsidies on those eligible for subsidized coverage under the ACA, and the extent to which members of this population are able to access appropriate health care providers.” (S. L. Decker, Sandra.decker@ahrq.hhs.gov)
Opioid Withdrawal Without Help: “The medical system is organized in a way that makes it quite difficult for physicians to live up to their withdrawal care responsibility,” writes an author who went through a difficult withdrawal after using opioid analgesics during the aftermath of a major motorcycle accident (pp. 182–5). “The plastic surgeon who had been managing my prescriptions eventually apologized and admitted that he simply had not known how to deal with opioid dependence. I hope that he committed to learning more after this experience.
“My goal is not, however, to change one doctor’s view about what he owes his patients. Instead, I want to start a broader conversation about physician responsibility for opioid-related harms, as well as the systemic forces that make it easier or harder for physicians to recognize and discharge their responsibilities. Opioid withdrawal isn’t minor. It’s not ‘just temporary’ or ‘the price to be paid’ for pain relief. It’s not morally innocuous. The moments that I was in withdrawal—all of the thousands of moments of genuine suffering—were the worst of my life. That kind of suffering matters, and its seriousness needs to be reflected in the way we deal with prescription opioids.” (T. N. Rieder,
trieder@jhu.edu)
ACA Repeal & the Opioid Epidemic: “As our country grapples with an ‘unprecedented opioid epidemic,’ Congress is taking steps to take away an important tool to fight it — the Affordable Care Act (ACA),” blog authors write (Jan. 30 blog). “Millions of people will lose health coverage, including comprehensive behavioral health and [substance use disorder (SUD)] benefits through Medicaid. People remaining covered in the individual and small group markets will lose benefits for SUD related services such as behavioral health services, preventive screenings, and prescription drugs.” (L. Clemans-Cope)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 1, 2017 * Vol. 24, No. 21
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Online-first articles from JAMA Internal Medicine (2017; 177).
Language Barriers & Antidiabetic Medication Adherence: Among Latinos with limited–English proficiency (LEP), control of diabetes improved when they changed to language-concordant primary care providers (PCPs), researchers report (10.1001/jamainternmed.2016.8648). The Kaiser study tracked 1,605 LEP Latino patients who preferred language Spanish and compared outcomes among those who changed PCPs in 2007–13: “There was a significant net improvement in glycemic and LDL control among patients who switched from language-discordant PCPs to concordant PCPs relative to those who switched from one discordant PCP to another discordant PCP. After adjustment and accounting for secular trends, the prevalence of glycemic control increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control decreased by 4% (95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95% CI, 1% to 17%; P = .03). No significant changes were observed in [systolic blood pressure] control. Prevalence of LDL control increased 15% (95% CI, 7% to 24%; P <.001) among LEP Latinos who switched from concordant to discordant PCPs. Risk factor control did not worsen following a PCP switch in any group.” (A. J. Karter, andy.j.karter@kp.org)
A second study shows that factors beyond language concordance are reducing adherence among Latino patients with diabetes (
10.1001/jamainternmed.2016.8653). Observational data from 2006 to 2012 in a large integrated health care delivery system led investigators to this conclusion: “Nonadherence to newly prescribed diabetes medications is substantially greater among Latino than white patients, even among English-speaking Latino patients. Limited English proficiency Latino patients are more likely to be nonadherent than English-speaking Latino patients independent of the Spanish-language fluency of their physicians. Interventions beyond access to interpreters or patient–physician language concordance will be required to improve medication adherence among Latino patients with diabetes.” (A. Fernández, alicia.fernandez@ucsf.edu)
“As the US health care system evolves to more accountable care organizations with integrated health systems, care of the most vulnerable must be prioritized,” editorialists write (
10.1001/jamainternmed.2016.8661). “Latinos with LEP who have diabetes represent such a population, as evidenced not only by their language status but by their socioeconomic disadvantage. There is a need to integrate greater granularity on social determinants into the medical record to provide more precision patient–clinician interactions. Metrics for our health care system need to include an equity outcome that sets a high bar for the most vulnerable patients. Healthcare outcomes of LEP Latinos with diabetes would be an excellent system measure of health equity.” (E. J. Pérez-Stable, eliseo.perez-stable@nih.gov)
High Drug Prices Despite Generic Competition: The case of Duexis — an ibuprofen–famotidine combination whose monthly wholesale price increased from $158 to $2061 in 2012–16 — provides lessons learned about high prices despite generic competition (10.1001/jamainternmed.2016.8423): “First, the states and the federal government should consider banning specialty pharmacies or other third parties from preparing or submitting prior authorization forms or other medical necessity paperwork; this is the responsibility of the physician who prescribes the medication. This practice undermines the intent of utilization controls and raises concerns about patient privacy. Second, states should consider markedly restricting the use of copay assistance programs, particularly since the majority of drug coupons are for brand-name medications for which lower-cost therapeutics are available. Third, better federal regulation and oversight of charity organizations that provide financial assistance to patients is needed. For example, contributions to such organizations from manufacturers should not be allowed for diseases treated by a single drug, because manufacturers can effectively ensure that donations will be spent only on copay assistance for their products. To preserve the long-term financial stability of the health care system, the use of medications that provide high value to patients should be the priority, not high-priced drugs with generic alternatives.” (J. S. Ross, joseph.ross@yale.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 2, 2017 * Vol. 24, No. 22
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 2 New England Journal of Medicine (2017; 376).
Radiation & Antiandrogen Therapy in Recurrent Prostate Cancer: Patients with prostate cancer lived longer and had fewer metastases when antiandrogen therapy was provided for 24 months following salvage radiation therapy, a study shows (pp. 417–28). Among 760 men with T2- or T3-stage tumors in 1998–2003, radiation plus bicalutamide 150 mg daily or placebo for 24 months yielded these results following prostatectomy with lymphadenectomy: “The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P = 0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P <0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P = 0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P <0.001).” (W. U. Shipley, wshipley@partners.org)
“This remarkable contribution by the National Clinical Trials Network of the National Cancer Institute shows the importance of randomized clinical trials with very long follow-up,” writes an editorialist (
pp. 484–5). “Studies that incorporate interventions without proprietary intellectual property (e.g., surgery or radiation therapy) or pharmaceutical agents whose patents often expire before the study is completed can be achieved only with the use of this invaluable national resource.” (I. M. Thompson, Jr.)
Crizanlizumab in Sickle Cell Disease: Pain episodes and adverse events occurred less frequently in patients with sickle cell disease who received crizanlizumab, compared with placebo, researchers report (pp. 429–39). The drug, an antibody against the adhesion molecule P-selectin, was given in low and high doses in a phase 2 trial of 198 patients. Results of 14 intravenous infusions over a 52-week period were as follows: “The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.” (K. I. Ataga, kataga@med.unc.edu)
An editorialist supports use of crizanlizumab along with hydroxyurea in management of sickle cell disease (
pp. 485–7): “Lacking a magical ‘silver bullet’ that would increase fetal hemoglobin in each sickle erythrocyte sufficiently to stop the polymerization of sickle hemoglobin or one that would completely normalize blood flow and prevent sickle vaso-occlusion, a polypharmaceutical approach that is focused on different aspects of the pathophysiology of sickle cell disease seems to be the most practical near-term approach. Most experts agree that hydroxyurea should be given to nearly all patients, starting very early in life. Added to this treatment might be an antiadhesive therapy that also should be taken for life and ideally started in childhood.” (M. H. Steinberg)

>>>PNN NewsWatch
* Does the pharmaceutical industry want a
deregulated FDA as Pres. Trump seems to be proposing? Not necessarily, according to an article on the STAT News website. “In a world where the FDA approved medications on scant data, pharma’s wealthiest giants could litter the market with dubious new drugs — and flood the airwaves with ads touting them,” reporter Mike Reddy writes. “That would crowd out upstart competitors and kill a whole industry’s incentive to try new things.”

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 3, 2017 * Vol. 24, No. 23
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source: Feb. issue of Pediatrics (2017; 139).
Protection From Single-Dose Meningococcal Vaccine: Effectiveness of the meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) wanes 3 to <8 years following a single dose, according to a study that led the Advisory Committee on Immunization Practices to recommend a booster dose (10.1542/peds.2016-2193). In a case–control study conducted in 2006–13, these patterns of vaccine effectiveness (VE) and duration of protection were identified: “Serogroup C accounted for 88 (49%), serogroup Y 80 (44%), and serogroup W 13 (7%) of enrolled cases. Thirty-six (20%) cases and 87 (44%) controls received MenACWY-D. The overall VE estimate 0 to 8 years postvaccination was 69% (51% to 80%); VE was 79% (49% to 91%) at <1 year, 69% (44% to 83%) at 1 to <3 years, and 61% (25% to 79%) at 3 to <8 years. VE was 77% (57% to 88%) against serogroup C and 51% (1% to 76%) against serogroup Y.” (A. C. Cohn)
E-cigarette Use by Adolescents: In the first of two studies of electronic cigarettes and other electronic vapor products (EVPs), researchers report other risky behaviors by adolescents who use EVP alone or with cigarette smoking (10.1542/peds.2016-2450). Among 15,624 students in the 2015 national Youth Risk Behavior Survey, health risk behaviors based on nonuse, cigarette smoking only, EVP use only, and dual use were as follows: “In 2015, 73.5% of high school students did not smoke cigarettes or use EVPs, 3.2% smoked cigarettes only, 15.8% used EVPs only, and 7.5% were dual users. Frequency of cigarette smoking and EVP use was greater among dual users than cigarette-only smokers and EVP-only users. Cigarette-only smokers, EVP-only users, and dual users were more likely than nonusers to engage in several injury, violence, and substance use behaviors; have ≥4 lifetime sexual partners; be currently sexually active; and drink soda ≥3 times/day. Only dual users were more likely than nonusers not to use a condom at last sexual intercourse.” (Z. Demissie)
Adolescents using e-cigarettes would not likely have smoked regular cigarettes, an analysis of the 2004–2014 National Youth Tobacco Surveys shows (
10.1542/peds.2016-2193): “Youth cigarette smoking decreased linearly between 2004 and 2014 (P = .009 for ever smoking and P = .05 for current smoking), with no significant change in this trend after 2009 (P = .57 and .23). Based on the psychosocial model of smoking, including demographic characteristics, willingness to wear clothing with a tobacco logo, living with a smoker, likelihood of smoking in the next year, likelihood of smoking cigarettes from a friend, and use of tobacco products other than cigarettes or e-cigarettes, the model categorized <25% of current e-cigarette–only users (between 11.0% in 2012 and 23.1% in 2013) as current smokers.” (L. M. Dutra)
Dietary Supplements & Young Teens: Creatine and testosterone products are being pushed to boy high school athletes by health food store employees, a study shows (10.1542/peds.2016-1257). Contacted by telephone by research personnel posing as 15-year-olds, staff at 244 U.S. health food stores made these recommendations when asked about supplements: “A total of 67.2% (164/244) of sales attendants recommended creatine: 38.5% (94/244) recommended creatine without prompting, and an additional 28.7% (70/244) recommended creatine after being asked specifically about it. A total of 9.8% (24/244) of sales attendants recommended a testosterone booster. Regarding availability for sale, 74.2% (181/244) of sales attendants stated a 15-year-old was allowed to purchase creatine, whereas 41.4% (101/244) stated one could purchase a testosterone booster.” The authors conclude, “In response to these findings, pediatricians should inform their teenage patients, especially athletes, about safe, healthy methods to improve athletic performance and discourage them from using creatine or testosterone boosters. Retailers and state legislatures should also consider banning the sale of these products to minors.” (R. Milanaik, rmilanai@northwell.edu)

>>>PNN NewsWatch
* FDA yesterday warned consumers about two dietary supplements containing undeclared drugs:
Lean Extreme Max, which contains sibutramine (pulled from the market in 2010 for safety reasons), and Goldreallas XXX, a sexual enhancement product containing sildenafil.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 6, 2017 * Vol. 24, No. 24
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 4 issue of Lancet (2017; 389).
Treatment of Newly Diagnosed Myeloma Without Intent for Stem-Cell Transplant: Addition of bortezomib to lenalidomide and dexamethasone significantly improved progression-free and overall survival of patients with newly diagnosed myeloma and no intent for immediate autologous stem-cell transplant, researchers report (pp. 519–27). In the phase 3 SWOG S0777 trial, open-label bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group) produced these outcomes in 473 randomly assigned patients: “Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0.712, 96% CI 0.56–0.906; one-sided p value 0.0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0.709, 95% CI 0.524–0.959; two-sided p value 0.025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group.” (B. G. M. Durie, bdurie@myeloma.org)
Intensified Methotrexate in Plaque-Type Psoriasis: Compared with placebo, an intensified subcutaneous methotrexate dosing schedule produced a favorable 52-week risk–benefit profile in 120 patients with moderate-to-severe plaque-type psoriasis, the METOP trial shows (pp. 528–37). The phase 3 trial included patients who had been diagnosed at least 6 months and were methotrexate-naive. Starting doses of 17.5 mg/week with escalation to 22.5 mg/week permitted after 8 weeks of therapy produced these findings: “At week 16, a [Psoriasis Area and Severity Index] 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3.93, 95% CI 1.31–11.81; p = 0.0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period.” (K. Reich, kreich@dermatologikum.de)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Treatment of WHO Group II Anovulation: For first-line treatment of women with WHO group II anovulation who wish to conceive, clomiphene plus metformin are superior to clomiphene alone in terms of ovulation and pregnancy, according to a systematic review and meta-analysis of 57 trials of 8,082 women (j138): “All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively).” (R. Wang, r.wang@adelaide.edu.au)

>>>PNN NewsWatch
*
FDA warned last week of rare but serious allergic reactions with skin antiseptic products containing chlorhexidine gluconate. The agency is requesting that manufacturers add a warning about this risk to products’ Drug Facts labels.

>>>PNN JournalWatch
* Atrial Fibrillation and Ventricular Arrhythmias: Sex Differences in Electrophysiology, Epidemiology, Clinical Presentation, and Clinical Outcomes, in
Circulation, 2017; 135: 593–608. (A. M. Gillis, amgillis@ucalgary.ca
* Bleeding Disorders in Congenital Syndromes, in
Pediatrics, 2017; 139: e20154360. (S. N. Sarangi) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 7, 2017 * Vol. 24, No. 25
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. 7 issue of the Annals of Internal Medicine (2017; 166).
High-Risk Prescribing & Dual Health System Use: As reported in PNN when the this research was first released (Dec. 6), U.S. veterans with dementia who have access to both VA and outside services are at high risk of potentially unsafe medication (PUM) prescribing (pp. 157–63). A retrospective cohort study of VA and Medicare Part D data shows these patterns of prescribing among 75,829 veterans with dementia based on HEDIS high-risk medication in older adults (PUM-HEDIS), any daily exposure to prescriptions with a cumulative Anticholinergic Cognitive Burden (ACB) score of 3 or higher (PUM-ACB), any antipsychotic prescription (PUM-antipsychotic), and any PUM exposure (any-PUM): “Compared with VA-only users, dual users had more than double the odds of exposure to any-PUM (odds ratio [OR], 2.2 [95% CI, 2.2 to 2.3]), PUM-HEDIS (OR, 2.4 [CI, 2.2 to 2.8]), and PUM-ACB (OR, 2.1 [CI, 2.0 to 2.2]). The odds of PUM-antipsychotic exposure were also greater in dual users (OR, 1.5 [CI, 1.4 to 1.6]). Dual users had an adjusted average of 44.1 additional days of any-PUM exposure (CI, 37.2 to 45.0 days).” (J. M. Thorpe, Joshua.Thorpe@va.gov)
Noting that the VA pharmacy system is “perfectly designed to achieve the outcomes it gets,” an editorialist writes (
pp. 221–2): “Thorpe and colleagues note that the VA system has a robust integrated pharmacy and medical record system available in all of the VA health care settings—a system clearly built to achieve better outcomes. Yet when using 3 indicators of unsafe medications among veterans with dementia, the researchers found that approximately 4 of every 10 VA-only users still received potentially harmful medications. Anticholinergic medications were the most commonly prescribed drugs but have long been known to be potentially harmful for elderly persons. The Office of Inspector General of the U.S. Department of Health and Human Services has shown that the leading cause of adverse events in hospitals and skilled nursing facilities is related to medications, many of which induce delirium due to their anticholinergic properties. Yet we as a profession continue to prescribe these medications for our elderly patients. Again, the prioritization of choice holds us back from building a better system.” (D. R. Gifford, dgifford@ahca.org)
Discharge Thresholds in Acute Decompensated Heart Failure: Reacting to a systematic review of discharge natriuretic peptides (NPs) thresholds in hospitalized patients with acute decompensated heart failure (HF) (pp. 180–90; C. A. Umscheid, craig.umscheid@uphs.upenn.edu), editorialists describe the difficulty in generating sufficient evidence to determine the utility of these biomarkers in real-world practice (pp. 223–4): “For one, it is not clear whether patients who do not achieve target NP levels during hospitalization fail to do so due to inadequate treatment (in either intensity or duration) or because their underlying HF is too severe to respond adequately to standard interventions. The former suggests that a strategy focused on intensifying therapy with a ‘discharge goal’ of achieving a specific NP target would likely be beneficial. In the latter case, such efforts are unlikely to be fruitful, other than simply identifying patients at the highest risk. It is unclear whether all admitted patients with HF would be risk-stratified in a similar manner by NP levels. Inclusion of admitted patients with de novo HF reduces the overall risk of the cohort. In addition, it is not clear what ‘intensified treatment’ in the face of failure to achieve NP goals should entail—more diuretics? Higher doses of neurohormonal drugs or vasodilators? Longer length of stay or intensified postdischarge follow-up? At present, our limited options for treating hospitalized patients with HF significantly limit our ability to intensify therapy even in patients identified as being at higher risk.” (D. J. Whellan, david.whellan@jefferson.edu)
Metformin in Chronic Diseases: Metformin use in patients with diabetes plus moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment improves outcomes, a systematic review shows (pp. 191–200): “Metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.” (M. J. Crowley, matthew.crowley@dm.duke.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 8, 2017 * Vol. 24, No. 26
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 7 issue of JAMA (2017; 317).
Treatment of Pituitary Adenomas: Dopamine agonists are first-line therapy for prolactinomas, review authors conclude (pp. 516–24). Other pituitary adenomas initially require surgery followed by medical therapy only when not cured, they write, adding these details: “Prolactinomas account for 32% to 66% of adenomas and present with amenorrhea, loss of libido, galactorrhea, and infertility in women and loss of libido, erectile dysfunction, and infertility in men; they are generally treated with the dopamine agonists cabergoline and bromocriptine. Growth hormone–secreting tumors account for 8% to 16% of tumors and usually present with enlargement of the lips, tongue, nose, hands, and feet and are diagnosed by elevated insulin-like growth factor 1 levels and growth hormone levels; initial treatment is surgical. Medical therapy with somatostatin analogues, cabergoline, and pegvisomant is often also needed. Adrenocorticotropic hormone (ACTH)–secreting tumors account for 2% to 6% of adenomas and are associated with obesity, hypertension, diabetes, and other morbidity. Measurement of a late-night salivary cortisol level is the best screening test but petrosal sinus sampling for ACTH may be necessary to distinguish a pituitary from an ectopic source. The primary treatment of Cushing disease (hypercortisolism due to ACTH-producing adenomas, which is the cause in approximately 65% of the cases of hypercortisolism) is adenoma resection and medical therapies including ketoconazole, mifepristone, and pasireotide. Hyperthyroidism due to thyroid-stimulating hormone–secreting tumors accounts for 1% of tumors and is treated with surgery and somatostatin analogues if not surgically cured. Clinically nonfunctioning adenomas account for 15% to 54% of adenomas and present with mass effects; surgery is generally required, although incidentally found tumors can be followed if they are asymptomatic.” (M. E. Molitch, molitch@northwestern.edu)
e-Discontinuation: “Prescribers need to be able to e-discontinue prescriptions, just as easily as they can e-prescribe them,” Viewpoint authors write (pp. 469–70): “ CancelRx was first defined by the National Council for Prescription Drug Programs and was published as part of the SCRIPT standard for e-prescribing in the Federal Register by the Centers for Medicare & Medicaid Services in 2010. However, this approach was not incorporated into the ‘meaningful use’ program for electronic health record (EHR) incentive payments, which might have encouraged uptake. Changes to meaningful use under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) included rules that required EHRs to include the ability to cancel prescriptions and other features of the SCRIPT 10.6 standard.…
“Adding e-discontinuation functionality has the potential to help reduce medication errors and take fuller advantage of e-prescribing technology.” (S. Fischer,
sfischer@rand.org)
Global Vaccine Injury Compensation: “Establishing a global compensation system could build confidence in the processes that lead to the development of vaccines deployed in low-resource settings, relieve vaccine manufacturers of liability concerns that impede vaccine investments, and facilitate effective responses to global public health threats like Ebola and Zika,” according to authors of a Viewpoint article that reviews three models for addressing vaccine injury (pp. 471–2). After discussing approaches in which patients or manufacturers bear the costs of injuries, the authors write: “The third approach, a no-fault compensation system for adverse events attributed to vaccination, balances these competing principles. Under a no-fault vaccine injury compensation system, governments compensate individuals who are harmed by properly manufactured vaccines instead of requiring them to use legal or other processes against manufacturers. A no-fault system acknowledges that a community that promotes immunization, knowing individuals will be injured, must share the burden of the cost of injuries. This approach also acknowledges that manufacturers are a critical part of vaccine access and that they must have a basic level of economic certainty. It fulfills the utilitarian and communitarian expectations of a democratic society. Yet no-fault compensation systems for vaccine injury prevail in only 19 jurisdictions worldwide including the United States.” (S. F. Halabi, sfh9@georgetown.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 9, 2017 * Vol. 24, No. 27
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 9 issue of the New England Journal of Medicine (2017; 376).
Thromboprophylaxis After Knee Arthroscopy/Casting: Use of low-molecular-weight heparins for a few days after knee arthroscopy or for the full duration of lower-leg casting is not supported by results of the POT-KAST and POT-CAST trials (pp. 515–25). Compared with no anticoagulation, prophylactic doses of low-molecular-weight heparin for 8 days after arthroscopy in the POT-KAST trial or during the full period of casting immobilization in the POT-CAST trial produced these results: “In the POT-KAST trial, 1,543 patients underwent randomization, of whom 1,451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, −0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, −0.6 to 0.7). In the POT-CAST trial, 1,519 patients underwent randomization, of whom 1,435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection.” (S. C. Cannegieter, s.c.cannegieter@lumc.nl)
Despite these findings, clinicians will likely consider it prudent to anticoagulate some higher-risk patients during and following knee arthroscopy, an editorialist writes, adding that the real question could be whether the patient really needs the procedure (
pp. 576–7): “There is no indication to routinely treat all patients undergoing knee arthroscopy or lower-leg casting with prophylactic anticoagulation. For patients at increased risk for venous thromboembolism, the use of some prophylactic treatment makes intuitive sense but is not evidence-based. The appropriate prevention strategy to consider for these patients — including the type of drug, dose, and duration of treatment — is unknown. Given the large number of arthroscopic knee surgeries and the reported overall limited benefit of these procedures in diminishing pain and improving physical function, another effective strategy to consider in the prevention of venous thromboembolism is a critical reevaluation as to which patients truly need arthroscopic knee surgery.” (S. Moll)
Red-State Medicaid Expansions & ACA Repeal/Reform: Even in GOP-leaning “red states,” the benefits of Medicaid expansion of benefits under the Affordable Care Act (ACA) are associated with overall support for the controversial law, results of a four-state survey show (e7). Compared with Texas — where Medicaid was not expanded — low-income individuals residing in Arkansas, Kentucky, and Louisiana felt that overall the law helped rather than hurt them personally. “Of course, a person’s sense of whether he or she has been helped by the law is inherently subjective and may be influenced by social desirability bias, political partisanship, and numerous other factors,” the authors write. “So what lessons can be drawn from subjective evaluations such as these? In part, the results are useful evidence that even in the most conservative region in the country, many people report substantial benefits from the law and are willing to directly credit the ACA for those changes. These subjective valuations are consistent with the findings of multiple other studies that used more traditional evaluative approaches and have shown large gains in access to care and affordability from Medicaid expansion.” (B. D. Sommers)

>>>PNN NewsWatch
* Citing presence of particulate matter, Exela Pharma Sciences, in association with marketer X-Gen Pharmaceuticals, is voluntarily recalling lot number PLND1613 of
Ibuprofen Lysine Injection, 20 mg /2 mL (10 mg/mL), vials to the hospital or user level, FDA said yesterday.
*
FDA also notes on its website the recall of Kingsway Trading’s Well Balance Xanthium & Siler Combo (Bi Yan Pian) batches 130401 and 150201 because they contain ephedra alkaloids.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 10, 2017 * Vol. 24, No. 28
Providing news and information about medications and their proper use

>>>Cardiology Report
Source: Feb. issue of the Journal of the American College of Cardiology (2017; 69).
Aspirin Formulation & Resistance in Type 2 Diabetes: Aspirin resistance in patients with type 2 diabetes is frequently the result of incomplete bioavailability of enteric formulations, according to a 40-patient, triple-crossover study (doi 10.1016/j.jacc.2016.11.050). Participants received plain aspirin 325 mg, delayed-release, enteric-coated (EC) aspirin, and a modified-release lipid-based aspirin (PL2200) in separate phases of the trial. Antiplatelet activity as measured by the rate and extent of inhibition of serum thromboxane B2 (TXB2) generation showed these patterns: “The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin–treated subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0–t [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB2, with marked interindividual variability.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
In patients without diabetes, high patient weight can also contribute to aspirin nonresponsiveness, an editorialist adds (
doi 10.1016/j.jacc.2016.11.049). “Together, these data suggest that diabetes and obesity are independent and possibly additive determinants of poor aspirin responsiveness, limiting the duration and/or degree of platelet COX-1 suppression, and possibly requiring different dosing strategies, well beyond the uncertain effects of aspirin formulations.” (C. Patrono, carlo.patrono@rm.unicatt.it)

>>>Chest Highlights
Source: Feb. issue of Chest (2017; 151).
Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD: In two phase 3 trials, a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology was superior to placebo and the components administered separately in a total of 3,718 patients with moderate-to-very severe COPD, PINNACLE-1 and -2 researchers report (pp. 340–57): “At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms).” (F. J. Martinez)

>>>PNN NewsWatch

*
FDA yesterday approved the corticosteroid deflazacort (Emflaza, Marathon Pharmaceuticals) to treat patients age 5 years and older with the rare genetic disorder Duchenne muscular dystrophy. This is the first FDA approval of any corticosteroid to treat patients with this condition, which causes progressive muscle deterioration and weakness, and the first approval of deflazacort for any use in the United States, the agency said.
* CareFusion is recalling the
Alaris Syringe Pump because of a faulty Air-In-Line (AIL) sensor, which may generate a false alarm and cause the syringe pump to stop supplying the infusion to the patient, FDA said.
*
Tom Price, MD, congressman from Georgia, was approved early this morning as Pres. Trump’s Secretary of Health and Human Services in a 52–47 party-line vote, STAT news reports. As a former practicing orthopedic surgeon, Price brings a unique outlook on Medicare and Medicaid policies to the position. He has been a staunch opponent of the Affordable Care Act, which the GOP plans to repeal or modify. Price is a member of a “conservative, fringe medical group,” the Washington Post reports. The article said the Association of American Physicians and Surgeons is opposed to Medicare and mandatory vaccinations; the article has a link to a Price video from the group’s 2011 annual meeting in which he said quality is a “buzzword” used by “Washington bureaucrats and the left … to disrupt [the] patient–family–physician relationship.”

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 13, 2017 * Vol. 24, No. 29
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 11 issue of Lancet (2017; 389).
Thrombolytic Removal of Intraventricular Hemorrhage: In 500 patients with severe stroke caused by intraventricular hemorrhage and with a routine extraventricular drain, irrigation with alteplase did not improve functional outcomes but appeared to be safe, a study shows (pp. 603–11). Based on results obtained in 2009–15, the investigators conclude, “Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.” (D. F. Hanley, dhanley@jhmi.edu)
Masitinib for Severely Symptomatic Indolent Systemic Mastocytosis: In a phase 3 trial of adults with severely symptomatic indolent or smouldering systemic mastocytosis, a myeloid neoplasm, masitinib is an effective and well tolerated (pp. 612–20). The KIT and LYN kinase inhibitor was compared with placebo using a dose-minimization design based on severe symptoms of the lifelong disorder, with these results: “Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n = 71) or placebo (n = 64). By 24 weeks, masitinib was associated with a cumulative response of 18.7% in the primary endpoint (122.6 responses of 656.5 possible responses [weighted generalised estimating equation]) compared with 7.4% for placebo (48.9 of 656.5; difference 11.3%; odds ratio 3.6; 95% CI 1.2–10.8; p = 0.0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).” (O. Hermine, hermine@gmail.com">ohermine@gmail.com)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Reduced-Dose Anticoagulants in Atrial Fibrillation: In a study of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin, a nonsignificant statistical trend showed possible poorer efficacy with apixaban and better safety results with dabigatran, researchers report (j510). Using individual data from three Danish nationwide registries, the investigators determined: “Among 55,644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n = 4,400; dabigatran n = 8,875; rivaroxaban n = 3,476; warfarin n = 38,893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.” (T. B. Larsen, tobl@rn.dk)

>>>PNN JournalWatch
* Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension, in
Chest, 2017; 151: 468–80. (H-A Ghofrani) 
* Intrathecal Amphotericin B: A 60-Year Experience in Treating Coccidioidal Meningitis, in
Clinical Infectious Diseases, 2017; 64: 519–24. (E. J. C. Goldstein) 
* Antineoplastic Treatment of Advanced-Stage Non–Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011), in
Journal of Clinical Oncology, 2017; 35: 529–35. (C. J. Bradley, cathy.bradley@ucdenver.edu
* Acute Asthma, Prognosis, and Treatment, in
Journal of Allergy and Clinical Immunology, 2017; 139: 438–47. (J. E. Fergeson, jfergeso@health.usf.edu
* Don’t Pass the Salt: Evidence to Support Avoidance of High Salt Intake in CKD, in
American Journal of Kidney Diseases, 2017; 69: 175–8. (A. K. Leonberg-Yoo, Amanda.Leonberg-Yoo@uphs.upenn.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 14, 2017 * Vol. 24, No. 30
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. issue of JAMA Internal Medicine (2017; 177).
Beta-Blockers After AMI in Older Nursing Home Residents: Among a cohort of nursing home residents in 2007–10, use of beta-blockers after acute myocardial infarction (AMI) was associated with “considerable mortality benefit” but also declines in functional status, particularly in those with poor cognitive and functional status at baseline, researchers report (pp. 254–62). Minimum Data Set 2.0 figures and data from Medicare Parts A and D show these associations based on beta-blocker use in long-stay residents of nursing homes aged 65 years or older: “The initial cohort of 15,720 patients (11,140 women [70.9%] and 4,580 men [29.1%]; mean [SD] age, 83 [8] years) included 8,953 new beta-blocker users and 6,767 nonusers. The propensity-matched cohort included 5,496 new users of beta-blockers and an equal number of nonusers for a total cohort of 10,992 participants (7,788 women [70.9%]; 3,204 men [29.1%]; mean [SD] age, 84 [8] years). Users of beta-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02–1.28), with a number needed to harm of 52 (95% CI, 32–141). Conversely, beta-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67–0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98–1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from beta-blockers (OR, 1.34; 95% CI, 1.11–1.61 and OR, 1.32; 95% CI, 1.10–1.59, respectively). In contrast, little evidence of functional decline due to beta-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89–1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77–1.26) and intermediate (OR, 1.05; 95% CI, 0.86–1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of beta-blockers were similar across all subgroups.” (M. A. Steinman, mike.steinman@ucsf.edu)
After listing limitations of data analyses in an area where higher-quality evidence is needed, an editorialist writes, “A randomized clinical trial for frail older adults with cognitive and functional impairment to examine guideline-recommended medications for AMI is needed to address biases inherent in observational studies” (
pp. 262–3). “Furthermore, a trial for discontinuation of beta-blocker therapy in the population of elders with life-limiting illness would be prudent given the changing benefits and risks of treatment across levels of cognitive and functional impairment. The Palliative Care Research Cooperative Group’s discontinuation trial for statin therapy among adults with life-limiting illness provides a useful model for such a study. Regardless of the state of the science, all clinicians should consider improving their approach to communication regarding initiating (and discontinuing) therapy for those in the last quarter of their life.” (J. Tjia, jennifer.tjia@umassmed.edu)
Trust but Verify: Commenting on two randomized controlled trials (RCTs) that show no effects of programs designed to enhance care of high-use veterans through interdisciplinary efforts (pp. 166–75; D. M. Zulman, dzulman@stanford.edu) and improve antibiotic prescribing patterns (pp. 176–83; H. C. Bucher, heiner.bucher@usb.ch), an editorialist reiterates the need for randomized controlled trials in assessment of quality improvement efforts (pp. 162–3). “These 2 RCTs demonstrate the importance of rigorous study design. Common sense doesn’t always prove to be right. Preintervention–postintervention observational designs can be mistaken, especially when there is no concurrent control. Just as we would not accept a drug as efficacious without a randomized clinical design, quality improvement interventions benefit from rigorous evaluation methodology. As the Russian proverb says: trust but verify.” (M. H. Katz, mkatz@dhs.lacounty.gov)
Fish Oil or Aspirin in Arteriovenous Fistula Failure: In the randomized Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study, neither aspirin nor fish oil supplementation significantly reduced failure rates of new arteriovenous fistulae within 12 months of surgery in patients requiring hemodialysis (pp. 184–93; A. B. Irish, ashley.irish@health.wa.gov.au)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 15, 2017 * Vol. 24, No. 31
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 14 issue of JAMA (2017; 317).
Scalp Cooling After Breast Cancer Chemotherapy: Women who used a scalp-cooling device kept more of their hair during chemotherapy for breast cancer, according to two studies and a related editorial.
During chemotherapy with a taxane and/or anthracycline, 142 women with stage 1 or 2 breast cancer “were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling,” researchers conclude (
pp. 596–605). Adding that longer-term efficacy and safety data are needed, the group adds these details regarding results: “Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%–60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%–7.6%) (success rate difference, 50.5%; 95% CI, 40.5%–60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events.” (J. Nangia, nangia@bcm.edu)
Scalp cooling during nonanthracycline adjuvant chemotherapy was hair sparing among 122 women with stage 1 or 2 breast cancer, a second study shows (
pp. 606–14): “Hair loss of 50% or less (Dean score of 0–2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%–75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P < .001). Three of 5 quality-of-life measures were significantly better 1 month after the end of chemotherapy in the scalp cooling group. Of patients who underwent scalp cooling, 27.3% (95% CI, 18.0%–36.6%) reported feeling less physically attractive compared with 56.3% (95% CI, 31.9%–80.6%) of patients in the control group (P = .02). Of the 106 patients in the scalp cooling group, 4 (3.8%) experienced the adverse event of mild headache and 3 (2.8%) discontinued scalp cooling due to feeling cold.” (H. S. Rugo, hope.rugo@ucsf.edu)
With mortality benefits of adjuvant chemotherapy well established in breast cancer, “the time has come” to address adverse effects of the drugs, writes an editorialist (
pp. 587–8): “Chemotherapy has been a mainstay of adjuvant therapy for breast cancer and has contributed to a reduction in breast cancer–related mortality. However, with the introduction of targeted therapies, it is appealing to imagine a future in which chemotherapy is no longer necessary and some of the distressing adverse effects of cancer treatments can be avoided. Until that time, identifying interventions, such as scalp cooling for the prevention of chemotherapy-induced alopecia, that reduce or eliminate treatment-associated toxic effects will help ease the distress associated with chemotherapy and may, as a result, improve outcomes for patients with breast cancer.” (D. L. Hershman, dlh23@cumc.columbia.edu)
Sublingual Grass Pollen Immunotherapy: Two years of sublingual grass pollen immunotherapy failed to improve nasal responses to allergen challenge at a 3-year follow-up, report researchers who studied 92 adult patients with moderate to severe seasonal allergic rhinitis (pp. 615–25). Comparing the major allergen Phleum p 5 with placebo controls, participants received daily sublingual tablets and monthly injections, with these results: “In the intent-to-treat population, mean [total nasal symptom] score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).” (S. R. Durham, s.durham@imperial.ac.uk)

>>>PNN NewsWatch
* Synergy Rx Pharmacy is voluntarily recalling all lots of
Human Chorionic Gonadotropin 5,000 units/vial and 11,000 units/vial to the retail level due to a lack of sterility assurance, according to an announcement posted on the FDA website.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 16, 2017 * Vol. 24, No. 32
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 16 New England Journal of Medicine (2017; 376).
Baricitinib in Rheumatoid Arthritis: An oral reversible inhibitor of Janus kinases JAK1 and JAK2, baricitinib was more effective than placebo or adalimumab in treating 1,307 patients with active rheumatoid arthritis, a phase 3 trial shows (pp. 652–62). In the 52-week study, results based on 20% improvement in the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), Disease Activity Score for 28 joints (DAS28), Health Assessment Questionnaire–Disability Index, and Simplified Disease Activity Index at week 12 were as follows: “More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P <0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the [modified Sharp score] at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P <0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P = 0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol.” (P. C. Taylor, peter.taylor@kennedy.ox.ac.uk)
ED Opioid Prescribing & Risk of Long-Term Use: In the nation’s emergency departments, physicians vary widely in their rates of prescribing of opioid analgesics, report researchers, who also found increased risks of long-term opioid use among opioid-naive patients who were seen by high-intensity opioid prescribers (pp. 663–73). A retrospective analysis of Medicare beneficiaries with index emergency department visits in 2008–11 showed these rates of prescribing and long-term opioid use: “Our sample consisted of 215,678 patients who received treatment from low-intensity prescribers and 161,951 patients who received treatment from high-intensity prescribers. Patient characteristics, including diagnoses in the emergency department, were similar in the two treatment groups. Within individual hospitals, rates of opioid prescribing varied widely between low-intensity and high-intensity prescribers (7.3% vs. 24.1%). Long-term opioid use was significantly higher among patients treated by high-intensity prescribers than among patients treated by low-intensity prescribers (adjusted odds ratio, 1.30; 95% confidence interval, 1.23 to 1.37; P <0.001); these findings were consistent across multiple sensitivity analyses.” (M. L. Barnett, mbarnett@hsph.harvard.edu)
FDA Regulation of Prescription Drugs: FDA officials review the current regulatory operations of the agency, reaching this conclusion (pp. 674–82): “Many of the FDA’s benefit–risk assessments and decisions are straightforward, but sometimes the FDA is confronted with a difficult set of benefits, risks, and uncertainties. Particularly in these situations, the FDA and the drug company may reach different conclusions based on the same facts, or there may be differences of opinion among the members of the FDA’s review team. The FDA encourages transparent, robust scientific discussions among its staff and has processes for handling differences of opinion. There is also a process for drug companies to appeal an FDA decision. Such situations can be highly charged and can elicit strong public reactions, with some people criticizing the FDA for being too conservative and delaying access to new drugs, and others criticizing the FDA for being too lenient and approving drugs on the basis of limited data. We believe that the new structured framework for benefit–risk assessment will facilitate a better understanding of the data and uncertainties underlying drug approvals and will make this information more transparent to the public.” (H. V. Joffe, hylton.joffe@fda.hhs.gov)

>>>PNN NewsWatch
*
FDA yesterday approved the injectable agent brodalumab (Siliq, Valeant Pharmaceuticals) for treatment of adults with moderate-to-severe plaque psoriasis.
* Bird flu is spreading in China, according to an article in the
Sydney Morning Herald. Some 79 people died of H7N9 influenza last month, Chinese government sources say.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 17, 2017 * Vol. 24, No. 33
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Feb. 15 issue of Clinical Infectious Diseases (2017; 64).
Mumps Outbreak in Highly Vaccinated University Community: Illustrating how outbreaks can occur in a highly vaccinated population, investigators report 56 cases of mumps from New York City, all linked back to a university community (pp. 408–12). “On 14 January 2014, a vaccinated student presented with parotitis. Mumps immunoglobulin M (IgM) testing was negative and reverse-transcription polymerase chain reaction (RT-PCR) testing was not performed, resulting in a missed diagnosis and the start of an outbreak at a New York City (NYC) university,” the group writes. “Fifty-six NYC residents with mumps were identified with onset between 12 January and 30 April 2014. Fifty-three cases (95%) were university students, 1 (2%) was a staff member, and 2 (4%) had epidemiologic links to the university. The median age was 20 years (range 18–37 years). All cases had parotitis. Three cases were hospitalized, including 1 of 2 cases with orchitis. Fifty-four (96%) cases had received ≥1 mumps-containing vaccine, 1 (2%) was unvaccinated due to religious exemption, and 1 (2%) had unknown vaccination status. Two of the 44 (5%) cases tested by serology were mumps IgM positive, and 27 of the 40 (68%) tested by RT-PCR were positive.” (L. N. Patel)
Diabetes, Insulin Therapy, Hospitalization for Infection & 28-Day Mortality Risk: In the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, community-dwelling adults aged 45 years or older had increased risk of hospitalization for infection when they had been diagnosed with diabetes, and the odds were increased further if they were on insulin therapy (pp. 435–42). The prospective cohort study followed 30,239 participants from 2003 to 2012, identifying these patterns: “Among 29,683 patients from the REGARDS study with complete follow-up, 7,375 had diabetes. Over a median follow-up period of 6.5 years, we identified 2,593 first and 3,411 total infection hospitalizations. In adjusted analyses, participants with diabetes had an increased hazard of infection (hazard ratio, 1.50; 95% confidence interval [CI], 1.37–1.64) compared with those without diabetes. Participants with diabetes hospitalized for infection did not have an increased odds of death within 28 days (odds ratio, 0.94; 95% CI, .67–1.32). Participants receiving insulin therapy had greater hazard of infection (hazard ratio, 2.18; 95% CI, 1.90–2.51) but no increased odds of mortality (odd ratio, 1.07; 95% CI, .67–1.71).” (J. P. Donnelly)

>>>Oncology Highlights
Source: Feb. 20 issue of the Journal of Clinical Oncology (2017; 35).
Viral Status & Sorafenib Effects in Advanced Hepatocellular Cancer: The overall survival (OS) benefit of sorafenib varies depending on patients’ hepatitis status, according to results from the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial (pp. 622–8). Among 1,643 patients who received sorafenib, hazard ratios based on hepatitis C virus (HCV) or hepatitis B virus (HBV) status were as follows: “Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for ‘other’ treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.” (P. Johnson, Philip.Johnson@liverpool.ac.uk)
Personal Genomic Testing for Cancer Risk: When patients learn through genomic testing that they have elevated cancer risks, they do not change their health-related behaviors, a study shows (pp. 636–44; S. W. Gray, stagray@coh.org).

>>>PNN NewsWatch
* A reasonably good match between circulating influenza viruses and strains in the 2016–17 vaccine is reported in yesterday’s
MMWR. Overall vaccine effectiveness is preliminarily estimated at 48% against medically attended acute respiratory infection and 43% overall. As of early Nov. 2016, vaccination rates were 37% in pediatric patients, 37% in adults aged 18–64 years, 57% among older adults, and 47% among pregnant women.
*
PNN will not be published on Mon., Feb. 20, Presidents Day.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 21, 2017 * Vol. 24, No. 34
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. 21 issue of the Annals of Internal Medicine (2017; 166).
Primary Care–Based Opioid Use Disorder Therapy: “Greater integration of medication-assisted treatment (MAT) for opioid use disorder (OUD) in U.S. primary care settings would expand access to treatment for this condition,” write authors of a review article on this topic (pp. 268–78): “Models for integrating MAT into primary care vary in structure. This article summarizes findings of a technical report for the Agency for Healthcare Research and Quality describing MAT models of care for OUD, based on a literature review and interviews with key informants in the field. The report describes 12 representative models of care for integrating MAT into primary care settings that could be considered for adaptation across diverse health care settings. Common components of existing care models include pharmacotherapy with buprenorphine or naltrexone, provider and community education, coordination and integration of OUD treatment with other medical and psychological needs, and psychosocial services and interventions. Models vary in how each component is implemented. Decisions about adopting MAT models of care should be individualized to address the unique milieu of each implementation setting.” (P. T. Korthuis, korthuis@ohsu.edu)
Editorialists write that primary care clinicians will need training in three areas to improve care of patients with OUD: biology of opioid use disorder, rationale for and efficacy of treatment options, and identification of the spectrum of patients for whom their practice can provide effective treatment (
pp. 307–8). “Federally funded services, such as the Providers’ Clinical Support System for Medication-Assisted Treatment, can provide education, mentoring, and support,” the article continues. “Internists have had a profound effect on developing, researching, disseminating, and implementing the most effective treatments for opioid use disorder. Primary care practices now have a road map to follow to help address the pressing health crisis presented by the current epidemic.” (E. J. Edelman, ejennifer.edelman@yale.edu)
Oral Treatment of Type 2 Diabetes: As reported earlier in PNN (see Jan. 3), the American College of Physicians recommends first-line use of metformin for oral pharmacologic treatment of adults with type 2 diabetes in an update to its 2012 guideline (pp. 279–90). ACP recommends that clinicians (A. Qaseem, aqaseem@acponline.org):
* Prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)
* Consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered (Grade: weak recommendation; moderate-quality evidence), and select with patients among medications after discussing benefits, adverse effects, and costs.

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Vitamin D Prevention of Respiratory Infections: Supplements of vitamin D protect against acute respiratory tract infections, according to results of a systematic review and meta-analysis (i6583). A 12% reduction in risk was found overall, with greater protective effects in those with lower baseline vitamin D levels (<12 nmol/L) and in those who did not receive bolus supplements of the nutrient. (A. R. Martineau, a.martineau@qmul.ac.uk)

>>>PNN JournalWatch
* Risk of Heart Failure After Community Acquired Pneumonia: Prospective Controlled Study With 10 Years of Follow-up, in
BMJ, 2017; 356: j413. (D. T. Eurich, deurich@ualberta.ca
* The Scientific Basis of Guideline Recommendations on Sugar Intake: A Systematic Review, in
Annals of Internal Medicine, 2017; 166: 257–67. (B. C. Johnston, bradley.johnston@sickkids.ca
* Systematic Review of the Prevalence of Medication Errors Resulting in Hospitalization and Death of Nursing Home Residents, in
Journal of the American Geriatrics Society, 2017; 65: 433–42. (J. E. Ibrahim, joseph.ibrahim@monash.edu
* Pharmacotherapeutic Considerations for Individuals with Down Syndrome, in
Pharmacotherapy, 2017; 37: 214–20. (E. Hefti, erikheft@buffalo.edu
* Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know, in
Pharmacotherapy, 2017; 37: 236–48. (S. E. Conway, susan-conway@ouhsc.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 22, 2017 * Vol. 24, No. 35
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 21 issue of JAMA (2017; 317).
Effects of Testosterone Replacement in Older Men: Clinical benefits of testosterone replacement in older men with low levels of the hormone are examined.
Rather than a decrease in noncalcified coronary artery plaque volume, researchers found increases in this cardiovascular risk indicator in older men using testosterone gel for 1 year (
pp. 708–16). In the Testosterone Trials (TTrials), conducted in 2010–14, coronary computed tomographic angiography yielded these results for 138 men with low serum testosterone levels and symptoms suggestive of hypogonadism: “At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis.… Testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003).” (P. J. Snyder, pjs@mail.med.upenn.edu)
In the same study, 492 older men with low testosterone and age-associated memory impairment (AAMI) had no improvements in memory or cognitive function during 1 year of testosterone gel, compared with placebo (
pp. 717–27). “There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88),” the authors write. “Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89).” (P. J. Snyder, pjs@mail.med.upenn.edu)
“It is unlikely that the limited efficacy shown by the TTrials meets the mandate of the 2004 Institute of Medicine report to warrant public funding for a powerful, long-term, large randomized clinical trial for evaluating testosterone,” editorialists write (
pp. 699–701). “In September 2015 the FDA mandated that testosterone manufacturers undertake longer-term safety and efficacy trials for off-label use of testosterone for aging men. If such a study proceeds, it could provide a valuable extension to the short-term safety of the TTrials supported by the manufacturers who have reaped large financial benefit from the boom in testosterone sales. In any case, with the results of [these] studies …, the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed.” (D. J. Handelsman, djh@anzac.edu.au)
Fibrinogen Concentrate in High-Risk Cardiac Surgery: Intraoperative blood loss was unchanged in 120 patients receiving fibrinogen concentrate during high-risk cardiac surgery, a placebo-controlled study shows (pp. 738–47). In the Netherlands, those undergoing elective, high-risk procedures received fibrinogen concentrate targeted to a postinfusion plasma fibrinogen level of 2.5 g/L or placebo, with these results: “Median blood loss in the fibrinogen group was 50 mL (interquartile range [IQR], 29–100 mL) compared with 70 mL (IQR, 33–145 mL) in the control group (P = .19), the absolute difference 20 mL (95% CI, −13 to 35 mL). There were 6 cases of stroke or transient ischemic attack (4 in the fibrinogen group); 4 myocardial infarctions (3 in the fibrinogen group); 2 deaths (both in the fibrinogen group); 5 cases with renal insufficiency or failure (3 in the fibrinogen group); and 9 cases with reoperative thoracotomy (4 in the fibrinogen group).” (S. Bilecen, s.bilecen@umcutrecht.nl)

>>>PNN NewsWatch
* On Friday, a U.S. district court judge entered a consent decree of permanent injunction against
Pick and Pay Inc./Cili Minerals, a manufacturer and distributor of drugs and dietary supplements, and its owner, Anton S. Botha, requiring the business to immediately cease operations until it comes into compliance with federal laws, FDA said yesterday in a news release. Products were sold online, FDA said, and also at a retail location in Lafayette, LA.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 23, 2017 * Vol. 24, No. 36
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 23 issue of the New England Journal of Medicine (2017; 376).
Lanadelumab in Hereditary Angioedema Prophylaxis: In a phase 1b, ascending-dose trial, the kallikrein inhibitor lanadelumab reduced cleavage of high-molecular-weight kininogen and attacks of angioedema in 37 patients with hereditary angioedema with C1 inhibitor deficiency (pp. 717–28). Investigators describe the following pharmacodynamic profile of the new drug based on two administration periods 14 days apart: “No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.” (A. Banerji, abanerji@partners.org)
“Kallikrein inhibition with lanadelumab given by fortnightly subcutaneous injection would be convenient and widely accessible,” writes an editorialist (
pp. 788–9). “Early safety indications are encouraging, with no indication of antibody formation or the anaphylactoid events associated with short-term inhibition of kallikrein; therefore, self-administration could be feasible. Most exciting, [this] preliminary study … suggests an unprecedented level of protection against angioedema. If this proves reproducible in larger studies currently under way, and if the treatment will be affordable, lanadelumab could herald a transformation in the way that we manage hereditary angioedema and in the life prospects for families affected by this devastating disorder.” (H. J. Longhurst)
Tight Glycemic Control in Critically Ill Children: Tight glycemic control was not beneficial in a 35-center trial of 713 patients, researchers report (pp. 729–41). Comparing target blood glucose ranges of 80–100 versus 150–180 mg/dL, results showed: “The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm.… In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P = 0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P <0.001). Patients in the lower-target group also had higher rates of health care–associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P = 0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days.” (M. S. D. Agus, michael.agus@childrens.harvard.edu)
Minimizing Health Risks of Recreational Cannabis: “We should be skeptical of people who claim to know what the net effect of cannabis legalization on public health will be,” the author of a Perspective article concludes (pp. 705–7). “Much will depend on implementation decisions, but jurisdictions’ ability to minimize health risks will also depend on how they respond to new information and other sources of uncertainty.” (B. Kilmer)

>>>PNN NewsWatch
* Organic Herbal Supply, Inc. has voluntarily recalled of all lots of
XtraHRD Natural Male Enhancement capsules after an FDA analysis showed the product contains tadalafil, the agency said.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 24, 2017 * Vol. 24, No. 37
Providing news and information about medications and their proper use

>>>Medical Care Report
Source: Mar. issue of Medical Care (2017; 55).
Readmissions in Safety-Net Hospitals: Safety-net hospitals (SNHs) have more barriers to reduction of readmissions, according to a national survey, yet are less likely to use readmission-reduction strategies (pp. 229–35). Responses from a survey of 980 of 1,600 U.S. acute care hospitals in 2013–14 showed these results: “SNHs were more likely to report patient-related barriers, including lack of transportation, homelessness, and language barriers compared with non-SNHs (P-values <0.001). Despite reporting more barriers, SNHs were less likely to use e-tools to share discharge summaries (70.1% vs. 73.7%, P <0.04) or verbally communicate (31.5% vs. 39.8%, P <0.001) with outpatient providers, track readmissions by race/ethnicity (23.9% vs. 28.6%, P <0.001), or enroll patients in postdischarge programs (13.3% vs. 17.2%, P <0.001). SNHs were also less likely to use discharge coordinators, pharmacists, and postdischarge programs. When we examined the use of strategies within SNHs, we found trends to suggest that high-performing SNHs were more likely to use several readmission strategies.” (J. F. Figueroa, jfigueroa@hsph.harvard.edu)
Predictors of Overdose Among Medicaid Beneficiaries: A study demonstrates how claims data can be used to identify Medicare patients at risk for opioid overdoses (pp. 291–8). Such findings could be used to restrict opioid prescribing or dispensing or make referrals to treatment, the authors conclude based on these data for adults in the Pennsylvania Medicaid program in 2007–12: “A total of 372,347 Medicaid enrollees with 583,013 new opioid treatment episodes were included in the cohort. Opioid overdose was higher among those with abuse (1.5%) compared with those without (0.2%, P <0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%) misuse compared with those without (0.2%, P <0.001). Abuse [adjusted rate ratio (ARR), 1.52; 95% confidence interval (CI), 1.10–2.10), probable misuse (ARR, 1.98; 95% CI, 1.46–2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48–2.09) were associated with significantly more events of opioid medication overdose compared with those without.” (G. Cochran, gcochran@pitt.edu)
Patient Perceptions of Deprescribing: The Patient Perceptions of Deprescribing questionnaire provides “a novel, multidimensional instrument to measure patients’ attitudes and experiences related to medication discontinuation that can be used to determine how to best involve patients in deprescribing decisions,” researchers report (pp. 306–13). The instrument includes dimensions of “Medication Concerns,” “Provider Knowledge,” “Interest in Stopping Medicines,” “Unimportance of Medicines,” and “Patient Involvement in Decision-Making.” (A. Linsky, amy.linsky@va.gov)

>>>Health Affairs Highlights
Source: Feb. issue of Health Affairs (2017; 36).
End-of-Life Spending & Length of Hospice Service: Seeking to better define the impact of hospice care on end-of-life spending, investigators assessed costs in Medicare regions with high expenditures (pp. 328–36). Results for 2004–11 demonstrated both the potential of cost savings and the limitations of the intervention: “Longer periods of hospice service were associated with decreased end-of-life expenditures for patients residing in regions with high average expenditures but not for those in regions with low average expenditures. Hospice use accounted for 8 percent of the expenditure variation between the highest and the lowest spending quintiles, which demonstrates the powers and limitations of hospice use for saving on costs.” (S. Wang, shiyi.wang@yale.edu)

>>>PNN NewsWatch
* Don’t look for Medimmune’s
live attenuated influenza virus vaccine to return soon -- and maybe never, based on discussions this week at a CDC Advisory Committee on Immunization Practices meeting. Problems with effectiveness of the H1N1 component of the vaccine began after the 2009 pandemic, STAT reports based on a company presentation. While solutions are under study, ACIP won’t likely be willing to reinstate recommendations to use of the product until data are available from one or more H1N1-dominated influenza seasons. Panel members wondered aloud how long the company will stick with the product given that uncertainty.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 27, 2017 * Vol. 24, No. 38
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 25 issue of Lancet (2017; 389).
Terminal Room Disinfection & Pathogen Control: Enhanced disinfection of the last hospital room occupied by discharged patients who had infections or colonizations with certain pathogens is an effective means of decreasing infection risk in hospitals, researchers report (pp. 805–14). At nine hospitals in the southeastern U.S., 21,395 patients with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Clostridium difficile, or multidrug-resistant Acinetobacter were studied. The rooms from which the patients were discharged were disinfected using one of four strategies, and patients admitted into those rooms were considered infected. Results showed that the incidence of target organisms was lower when ultraviolet (UV) light was added to standard cleaning regimens (quaternary ammonium disinfectant except for C. difficile, for which bleach was used). Addition of bleach or disinfecting UV light to these cleaning strategies did not significantly lower the incidence of infection or colonization of exposed patients. (D. J Anderson, deverick.anderson@duke.edu)
Risk Information & Taster Sessions in Smoking Cessation: Delivery of personalized risk information and an invitation to a no-commitment “come and try it” taster session increased cessation rates among smokers in the U.K., a study shows (pp. 823–33). The letter used information from a screening questionnaire and the patient’s medical record to personalize their risks of smoking; at the taster sessions, information was provided about the National Health Service Stop Smoking Services (SSSs), address participant concerns, and encourage signing up for cessation services. Results showed: “Recruitment, collection of baseline data, delivery of the intervention, and follow up of participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned 4,384 smokers to the intervention group (n = 2,636) or the control group (n = 1,748); 4,383 participants comprised the intention-to-treat population. Attendance at the first session of an SSS course was significantly higher in the intervention group than in the control group (458 [17.4%] vs 158 [9.0%] participants; unadjusted odds ratio 2.12 [95% CI 1.75–2.57]; p <0.0001).” (H. Gilbert, hazel.gilbert@ucl.ac.uk)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Off-Label Antidepressant Use: At primary practices in Quebec, use of prescribed antidepressants for off-label indications were often not supported by “strong scientific evidence,” according to analysis of records from 2003 to 2015 (j603). Results showed: “106,850 antidepressant prescriptions were written by 174 physicians for 20,920 adults. By class, tricyclic antidepressants had the highest prevalence of off-label indications (81.4%, 95% confidence interval, 77.3% to 85.5%), largely due to a high off-label prescribing rate for amitriptyline (93%, 89.6% to 95.7%). Trazodone use for insomnia was the most common off-label use for antidepressants, accounting for 26.2% (21.9% to 30.4%) of all off-label prescriptions. For only 15.9% (13.0% to 19.3%) of all off-label prescriptions, the prescribed drug had strong scientific evidence for the respective indication. For 39.6% (35.7% to 43.2%) of off-label prescriptions, the prescribed drug did not have strong evidence but another antidepressant in the same class had strong evidence for the respective indication. For the remaining 44.6% (40.2% to 49.0%) of off-label prescriptions, neither the prescribed drug nor any other drugs in the class had strong evidence for the indication.” (J. Wong, jenna.wong@mail.mcgill.ca)

>>>PNN NewsWatch
*
Advanced Pharma, doing business as Avella of Houston, is conducting a voluntary recall of all unexpired sterile injectable products labeled “latex free” produced at its Houston location between Sept. 2016 and mid-February. The recall, extending to the user level (hospitals and institutions), results from possible synthetic latex and/or natural latex in the products.

>>>PNN JournalWatch
* Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action, in
Diabetes Care, 2017; 40: 419–30. (K. Cusi, kenneth.cusi@medicine.ufl.edu)
* Women in Leadership and the Bewildering Glass Ceiling, in
American Journal of Health-System Pharmacy, 2017; 74: 312–24. (M. A. Chisholm-Burns, mchisho3@uthsc.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 28, 2017 * Vol. 24, No. 39
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Feb. issue of the Journal of the American Geriatrics Society (2017; 65).
Improving Warfarin Use in Older Adults: Two studies and an editorial show benefits of using warfarin in older adults, but risks always weight on clinicians’ decisions. 
In older adults with atrial fibrillation (AF), more than 40% were not placed on oral anticoagulants (OACs) at discharge despite a very high stroke risk, researchers report (
pp. 241–8). Based on findings from two large community cohorts of patients with AF, the group concludes, “Dominant reasons [for not using OACs] included fall risk, poor prognosis, older age, and dementia. These individuals’ high 1-year mortality rate confirmed their high level of comorbidity. To improve anticoagulation decisions and outcomes in this population, future research should focus on strategies to mitigate fall risk, improve assessment of risks and benefits of anticoagulation in individuals with AF, and determine whether newer anticoagulants are safer in complex elderly and frail individuals.” (A. S. Go, alan.s.go@kp.org)
Among veterans aged 65 years or older, discontinuance of warfarin after diagnosis of dementia was followed by a significant increase in stroke and mortality, a study shows (
pp. 249–56). Based on new diagnoses of dementia in 2007 or 2008, patients with at least a 6-month history of warfarin therapy for nonvalvular atrial fibrillation had these outcomes: “After a diagnosis of dementia, 405 individuals (16%) persisted on warfarin therapy. Unadjusted Cox proportional hazards analysis demonstrated a protective effect of warfarin in prevention of ischemic stroke (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.46–0.89, P = .008), major bleeding (HR = 0.72, 95% CI = 0.55–0.94, P = .02), and all-cause mortality (HR = 0.66, 95% CI = 0.55–0.79, P < .001). Using propensity score matching, the protective effect of continuing warfarin persisted in prevention of stroke (HR = 0.74, 95% CI = 0.54–0.996, P = .047) and mortality (HR = 0.72, 95% CI = 0.60–0.87, P < .001), with no statistically significant decrease in risk of major bleeding (HR = 0.78, 95% CI = 0.61–1.01, P = .06).” (A. R. Orkaby, aorkaby@partners.org)
“Even under the most ideal circumstances of care, there will continue to be large numbers of older adults with atrial fibrillation who are not treated with warfarin or for whom therapy will be discontinued once started,” writes an editorialist (
pp. 236–7). “The opportunity to provide safer and highly effective oral anticoagulant therapy is an extremely attractive prospect for both providers and the complex older patients under their care. Unfortunately, this will never be the case for warfarin.” (J. H. Gurwitz)

>>>Diabetes Highlights
Source: Mar. issue of the Diabetes Care (2017; 40).
Tackling the Prandial Problem: A review article author “proposes that a greater proportion of available resources be directed to basic and clinical research on the prandial problem” (pp. 291–300): “Both basal and postprandial elevations contribute to the hyperglycemic exposure of diabetes, but current therapies are mainly effective in controlling the basal component. Inability to control postprandial hyperglycemia limits success in maintaining overall glycemic control beyond the first 5 to 10 years after diagnosis, and it is also related to the weight gain that is common during insulin therapy. The ‘prandial problem’—comprising abnormalities of glucose and other metabolites, weight gain, and risk of hypoglycemia—deserves more attention. Several approaches to prandial abnormalities have recently been studied, but the patient populations for which they are best suited and the best ways of using them remain incompletely defined. Encouragingly, several proof-of-concept studies suggest that short-acting glucagon-like peptide 1 agonists or the amylin agonist pramlintide can be very effective in controlling postprandial hyperglycemia in type 2 diabetes in specific settings.” (M. C. Riddle, riddlem@ohsu.edu)

>>>PNN NewsWatch
*
Endo Pharmaceuticals is recalling one lot of Edex (alprostadil for injection) 10 mcg to the consumer level because of a defect in the crimp caps used in the manufacture of the product lot. This defect has the potential to lead to a loss of container closure integrity and thereby result in loss of sterility assurance.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 1, 2017 * Vol. 24, No. 40
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 28 issue of JAMA (2017; 317).
Antithrombotic Drug Use & Subdural Hematoma: Use of low-dose aspirin, vitamin K antagonists (VKAs), direct oral anticoagulants, and combined antithrombotic drug treatment is associated with increased risk of subdural hematoma, according to analysis of regional and national data from Denmark (pp. 836–46). “The highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug,” the authors conclude. “The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.” Among 5.2 million people in Denmark, 10,010 patients with first-ever subdural hematomas had these implicating factors compared with matched controls: “Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15–1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57–2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31–2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38–4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40–4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49–14.02]).… The largest increase [in incidence] was among older patients (>75 years; n = 4,441) who experienced an increase from 55.1 per 100,000 person–years to 99.7 per 100,000 person–years (P < .001 for trend).” (D. Gaist, dgaist@health.sdu.dk)
Subsequent Neoplasm Risk in Childhood Cancer Survivors: Lower rates of subsequent neoplasms among 23,603 childhood cancer survivors from the 1990s are associated with radiation exposure reduced from 1970s levels, researchers report (pp. 814–24). Analysis of data from pediatric tertiary hospitals in the U.S. and Canada showed these patterns for 1970 through 1999, with follow-up through the end of 2015: “Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for 1990s), as did median dose (30 Gy [interquartile range, 24–44] for 1970s vs 26 Gy [interquartile range, 18–45] for 1990s). Fifteen-year cumulative incidence of subsequent malignancies decreased by decade of diagnosis (2.1% [95% CI, 1.7%–2.4%] for 1970s, 1.7% [95% CI, 1.5%–2.0%] for 1980s, 1.3% [95% CI, 1.1%–1.5%] for 1990s). Reference absolute rates per 1,000 person–years were 1.12 (95% CI, 0.84–1.57) for subsequent malignancies, 0.16 (95% CI, 0.06–0.41) for meningiomas, and 1.71 (95% CI, 0.88–3.33) for nonmelanoma skin cancers for survivors with reference characteristics (no chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years).” (L. M. Turcotte, turc0023@umn.edu)
Early Complications of Type 1 vs. Type 2 Diabetes: In patients diagnosed with diabetes before age 20, those with type 1 conditions have fewer early complications and comorbidities than those with type 2 diabetes, but such problems are common in both patient types, a study shows (pp. 825–35). In 2,018 participants followed from diagnosis in 2002 to 2015, these outcomes were observed in 2011–15: “After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease (odds ratio [OR], 2.58; 95% CI, 1.39–4.81; P=.003), retinopathy (OR, 2.24; 95% CI, 1.11–4.50; P = .02), and peripheral neuropathy (OR, 2.52; 95% CI, 1.43–4.43; P = .001), but no significant difference in the odds of arterial stiffness (OR, 1.07; 95% CI, 0.63–1.84; P = .80) and hypertension (OR, 0.85; 95% CI, 0.50–1.45; P = .55).” (D. Dabelea, dana.dabelea@ucdenver.edu)

>>>PNN NewsWatch
*
FDA on Tuesday approved elotristat ethyl (Xermelo, Lexicon Pharmaceuticals) as the first and only orally administered therapy for treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. The new drug targets overproduction of serotonin by metastatic neuroendocrine tumors. It will be distributed by specialty pharmacies beginning Mar. 6.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 2, 2017 * Vol. 24, No. 41
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 2 issue of the New England Journal of Medicine (2017; 376).
Treatment of Thyroid Deficiency in Pregnancy: Levothyroxine therapy was ineffective for improving offspring cognitive function when administered during pregnancy to mothers with subclinical hypothyroidism or hypothyroxinemia, researchers report (pp. 815–25). Compared with placebo, levothyroxine administered at 8–20 weeks’ gestation produced these outcomes based on children’s IQ at 3–5 years of age or at death in those younger than 3 years: “A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.” (B. M. Casey, brian.casey@utsouthwestern.edu)
While these findings “indicate that screening and treatment for subclinical hypothyroidism, if performed well into the second trimester of pregnancy, are unlikely to be beneficial,” drug administration at an earlier point in pregnancy remains a reasonable option, editorialists write (
pp. 876–7): “Because more than 75% of women in the United States have their first prenatal visit before 12 weeks of gestation, earlier treatment appears to be feasible. We continue to endorse the recent guidelines of the American Thyroid Association, since the early initiation of low-dose levothyroxine therapy for subclinical hypothyroidism may be of benefit, is inexpensive, and is unlikely to be harmful.” (D. S. Cooper)
Anti–Interleukin-31 Receptor A Antibody for Atopic Dermatitis: Targeting of the interleukin-31 receptor A was effective for reducing pruritus symptoms in 264 patients with moderate-to-severe atopic dermatitis, a phase 2 study shows (pp. 826–35). Based on a primary end point of percentage improved (lowered) scores on the pruritus visual-analogue scale at week 12, subcutaneous nemolizumab every 4–8 weeks showed these results: “At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were −43.7% in the 0.1-mg group, −59.8% in the 0.5-mg group, and −63.1% in the 2.0-mg group, versus −20.9% in the placebo group (P <0.01 for all comparisons). Changes on the [Eczema Area and Severity Index] were −23.0%, −42.3%, and −40.9%, respectively, in the nemolizumab groups, versus −26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were −7.5%, −20.0%, and −19.4% with nemolizumab, versus −15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group.” (T. Ruzicka, thomas.ruzicka@med.uni-muenchen.de)
“New therapies [such as nemolizumab] should be included as part of a comprehensive approach that includes education on skin care and trigger avoidance, psychological support to enhance adherence and reduce itching, and treatment of the already established mental health and sleep disorders,” writes an editorialist (
pp. 878–9). “Data from larger long-term studies and pediatric trials are needed to fully understand how these new agents will fit into the management of atopic dermatitis. It will be important to evaluate how quickly patients have disease flares after stopping the agents and whether the addition of topical agents may provide more effective or longer remission.” (L. C. Schneider)

>>>PNN NewsWatch
*
FDA yesterday approved Odactra (Merck, Sharp & Dohme; Catalent Pharma), the first sublingually administered allergen extract for treatment of house dust mite–induced allergic rhinitis, with or without conjunctivitis, in people 18 through 65 years of age.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 3, 2017 * Vol. 24, No. 42
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source: Mar. issue of Pediatrics (2017; 139).
Improving Adolescent Immunization Rates: Practical approaches for optimizing adolescent immunizations are offered in a clinical report from the American Academy of Pediatrics (AAP; 10.1542/peds.2016-4187): “With the expansion of the adolescent immunization schedule during the past decade, immunization rates notably vary by vaccine and by state. Addressing barriers to improving adolescent vaccination rates is a priority. Every visit can be viewed as an opportunity to update and complete an adolescent’s immunizations. It is essential to continue to focus and refine the appropriate techniques in approaching the adolescent patient and parent in the office setting. Health care providers must continuously strive to educate their patients and develop skills that can help parents and adolescents overcome vaccine hesitancy. Research on strategies to achieve higher vaccination rates is ongoing, and it is important to increase the knowledge and implementation of these strategies. This clinical report focuses on increasing adherence to the universally recommended vaccines in the annual adolescent immunization schedule of the American Academy of Pediatrics, the American Academy of Family Physicians, the Centers for Disease Control and Prevention, and the American Congress of Obstetricians and Gynecologists. This will be accomplished by (1) examining strategies that heighten confidence in immunizations and address patient and parental concerns to promote adolescent immunization and (2) exploring how best to approach the adolescent and family to improve immunization rates.” (H. H. Bernstein)
In an accompanying clinical report, AAP reviews vaccines recommended for administration during the adolescent years and discusses evidence supporting the need for immunization (
10.1542/peds.2016-4186): “The adolescent period heralds the pediatric patient’s transition into adulthood. It is a time of dynamic development during which effective preventive care measures can promote safe behaviors and the development of lifelong health habits. One of the foundations of preventive adolescent health care is timely vaccination, and every visit can be viewed as an opportunity to update and complete an adolescent’s immunizations.” (H. H. Bernstein)
Overdoses Among Children of Mothers Prescribed Opioids: Based on a study showing a “markedly increased risk of overdose” among young children whose mothers are prescribed opioids, researchers conclude, “Physicians, pharmacists, and parents should take measures to mitigate the risk of opioid-related harm to children, such as prescribing smaller quantities, emphasizing the importance of secure medication storage, and the prompt disposal of unused opioids” (10.1542/peds.2016-2887). The study compared 103 children with opioid overdose with 412 matched controls. Results showed: “Children with an opioid overdose were far more likely to have a mother who received a prescription opioid (unadjusted odds ratio, 2.41; 95% confidence interval, 1.68–3.45) and who was prescribed antidepressants. The most commonly implicated overdose opioids were codeine (53.4%), oxycodone (32.0%), and methadone (15.5%).” (Y. Finkelstein)

>>>Psychiatry Highlights
Source: Mar. issue of the American Journal of Psychiatry (2017; 174).
Mood Switch Rates During Acute Bipolar Treatment: Mood switches among patients with bipolar II depression were similar for two commonly used medications in a 16-week study of 142 participants, and combination therapy produced higher discontinuance rates without improvement in responses (pp. 266–76). Random assignment to lithium, sertraline, or both produced these changes in mood at patient visits: “Twenty participants (14%) experienced a switch during the study period (hypomania, N = 17; severe hypomania, N = 3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N = 89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response.” (L. L. Altshuler)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 6, 2017 * Vol. 24, No. 43
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Congenital Heart Defects With SSRI Use During Pregnancy: Use of SSRIs by pregnant women during the cardiogenesis phase of fetal development can lead to congenital heart defects when the mother or child has certain variants in folate, homocysteine, or transsulfuration pathways, a study shows (j832). Using data from the U.S. National Birth Defects Prevention Study on 1,180 liveborn infants with congenital heart defects and 1,644 controls born in 1997–2008, investigators found these correlations of outcomes with single nucleotide polymorphism panels: “For women who reported taking SSRIs periconceptionally, maternal SHMT1 (rs9909104) GG and AG genotypes were associated with a 5.9 and 2.4 increased risk of select congenital heart defects in offspring, respectively, versus the AA genotype ([Bayesian false discovery probabilities (BFDP)] = 0.69). Compared with the AA genotype, BHMT (rs492842 and rs542852) GG and AG genotypes were associated with twice the risk of congenital heart defects (BFDP = 0.74 and 0.79, respectively). MGST1 (rs2075237) CC and AC genotypes were associated with an increased risk compared with the GG genotype (8.0 and 2.8, respectively; BFDP = 0.79). Single nucleotide polymorphism in infant genes in the folate (MTHFS rs12438477), homocysteine (TRDMT1 rs6602178 and GNMT rs11752813) and transsulfuration (GSTP1 rs7941395 and MGST1 rs7294985) pathways were also associated with an increased risk of congenital heart defects.” (W. Nembhard, wnnembhard@uams.edu)
Immunosuppression & Serious Infections During Pregnancy: Among 4,961 pregnant women with systemic inflammatory conditions, use of high-dose steroids is associated with an increased risk of serious infections, while risks are similar among those on steroids, nonbiologic agents, or TNF inhibitors, researchers report (j895). In an observational cohort study based on public and private insurance program data, the authors found: “The crude incidence rates of serious infections per 100 person years among 2,598 steroid users, 1,587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose–response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose = 0.019, P = 0.02).” (R. J. Desai, rdesai@bwh.harvard.edu)
>>>PNN NewsWatch
* In the first
FDA approval of a product for nocturnal polyuria, the agency has OK’d desmopressin acetate (Noctiva; Renaissance Lakewood, Serenity Pharmaceuticals) nasal spray for adults who awaken at least two times per night to urinate. The product carries a boxed warning about severe hyponatremia risk, and a Medication Guide must be dispensed with prescriptions.

>>>PNN JournalWatch
* Neuraminidase Inhibitors During Pregnancy and Risk of Adverse Neonatal Outcomes and Congenital Malformations: Population Based European Register Study, in
BMJ, 2017; 356: j629. (S. Graner, Sofie.graner@ki.se)
* Intra-articular Corticosteroids Versus Intra-articular Corticosteroids Plus Methotrexate in Oligoarticular Juvenile Idiopathic Arthritis: A Multicentre, Prospective, Randomised, Open-Label Trial, in
Lancet, 2017; 389: 909–16. (A. Ravelli, angeloravelli@gaslini.org)
* Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology, in
American Journal of Psychiatry, 2017; 174: 216–29. (O. D. Howes) 
* Treatment of Prescription Opioid Use Disorder in Pregnant Women, in
American Journal of Psychiatry, 2017; 174: 208–14. (C. Guille) 
* Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-3271. (C. Cazeiro) 
* Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors, in
Pediatrics, 2017; 139: 10.1542/peds.2016-1450. (C. Unegbu) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 7, 2017 * Vol. 24, No. 44
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Mar. 7 issue of the Annals of Internal Medicine (2017; 166).
Anakinra in Chronic Fatigue Syndrome: Symptoms of chronic fatigue syndrome (CFS) were not improved by 4 weeks of subcutaneous anakinra therapy, researchers report (10.7326/M16-2391). Cytokine inhibition was tested in 50 women aged 18–59 years of age with CFS and severe fatigue, with these results during 4 weeks of treatment and 20 weeks of follow-up: “At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in … fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).” (M. E. Roerink, Megan.Roerink@radboudumc.nl)
Moving Health Care to a Single-Payer System: With the process of repealing and replacing Obamacare under way, authors of an opinion article advocate moving toward a single-payer system as a solution to the high overhead associated with billing and payment under current processes (10.7326/M17-0302): “The president has promised universal coverage and reduced deductibles and copayments, all within tight budgetary constraints. That is a tall order and unlikely to be filled by proposals that Republicans have offered thus far.…
“The economic case for single-payer reform is compelling. Private insurers’ overhead currently averages 12.4% versus 2.2% in traditional Medicare. Reducing overhead to Medicare’s level would save approximately $220 billion this year. Single-payer reform could also sharply reduce billing and paperwork costs for physicians, hospitals, and other providers. For example, by paying hospitals lump-sum operating budgets rather than forcing them to bill per patient, Scotland and Canada have held hospital administrative costs to approximately 12% of their revenue versus 25.3% in the United States. Simplified, uniform billing procedures could reduce the money and time that physicians spend on billing-related documentation.” (S. Woolhandler,
swoolhan@hunter.cuny.edu)
Pay-for-Performance Programs: Paying for performance in health care leads to improved processes but not to better health outcomes, authors of a systematic review conclude (pp. 341–53). Data from 69 studies of pay-for-performance (P4P) programs show the following: “Low-strength evidence suggested that P4P programs in ambulatory settings may improve process-of-care outcomes over the short term (2 to 3 years), whereas data on longer-term effects were limited. Many of the positive studies were conducted in the United Kingdom, where incentives were larger than in the United States. The largest improvements were seen in areas where baseline performance was poor. There was no consistent effect of P4P on intermediate health outcomes (low-strength evidence) and insufficient evidence to characterize any effect on patient health outcomes. In the hospital setting, there was low-strength evidence that P4P had little or no effect on patient health outcomes and a positive effect on reducing hospital readmissions.” (D. Kansagara, kansagar@ohsu.edu)

>>>Health Affairs Highlights
Source: Mar. issue of Health Affairs, a theme issue on Delivery System Innovation (2017; 36).
Value-Based Insurance Design & Med Adherence: Patients with high-deductible health plans require value-based insurance designs to avoid reduced medication adherence, an analysis indicates (pp. 516–23): “We found that the value-based plan offset reductions in medication adherence associated with switching to a deductible plan. The value-based plan appeared particularly beneficial for patients who started with low levels of medication adherence. Patients with additional clinical complexity or vulnerable populations living in neighborhoods with lower socioeconomic status, however, did not show adherence improvements and might not be taking advantage of value-based insurance design provisions.…” (M. E. Reed, mary.e.reed@kp.org)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 8, 2017 * Vol. 24, No. 45
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 7 issue of JAMA (2017; 317).
Opioid Agonist for Dependence Treatment: Long-term maintenance therapy with methadone or buprenorphine is more effective in patients with dependence than opioid taper or psychological treatments alone, according to a summary of a Cochrane review (pp. 967–8): “For patients who are dependent on prescription opioids, long-term maintenance of opioid agonists is associated with less prescription opioid use and better adherence to medication and psychological therapies for opioid dependence compared with opioid taper or psychological treatments alone. Methadone maintenance was not associated with differences in therapeutic efficacy compared with buprenorphine maintenance treatment. Evidence quality was low to moderate.” (S. Nielsen, suzanne.nielsen@unsw.edu.au)
Diet & Mortality: Many U.S. deaths attributed to heart disease, stroke, or type 2 diabetes are associated with poor diet, according to data from the National Health and Nutrition Examination Surveys for 1999–2002 and 2009–12 (pp. 912–24). Overall, 48.6% of deaths of men from cardiometabolic disease and 41.8% of deaths of women from these causes were associated with suboptimal dietary factors. The pattern held in various age, race/ethnicity, and education subgroups. These patterns were noted for consumption of 10 foods or nutrients that have been associated with cardiometabolic diseases: “The largest numbers of estimated diet-related cardiometabolic deaths were related to high sodium (66,508 deaths in 2012; 9.5% of all cardiometabolic deaths), low nuts/seeds (59,374; 8.5%), high processed meats (57,766; 8.2%), low seafood omega-3 fats (54,626; 7.8%), low vegetables (53,410; 7.6%), low fruits (52,547; 7.5%), and high [sugar-sweetened beverages (SSBs)] (51,694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (−20.8% relative change [95% UI, −18.5% to −22.8%]), nuts/seeds (−18.0% [95% UI, −14.6% to −21.0%]), and excess SSBs (−14.5% [95% UI, −12.0% to −16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]).” (R. Micha, renata.micha@tufts.edu)
“The findings reported by Micha et al appear correct—a substantial proportion of [cardiometabolic disease (CMD)] deaths are associated with suboptimal diet, and improving diet quality could help prevent a large fraction of CMD deaths and reduce health disparities,” conclude editorialists (
pp. 908–9). “There is some precedence, such as from trials of the Mediterranean diet plus supplemental foods, that modification of diet can reduce cardiovascular disease risk by 30% to 70%. Yet estimation of downstream benefits is complex and imprecise. Whether the authors overestimated or underestimated the potential effects of improved diet, the likely benefits are substantial and justify policies designed to improve diet quality.” (N. T. Mueller, noeltmueller@jhu.edu)
Lipoprotein Lipase Gene Variants & Coronary Artery Disease: People with rare, damaging mutations in the gene for lipoprotein lipase (LPL) have an increased risk of higher triglyceride levels and early-onset coronary artery disease (CAD), a study shows (pp. 937–46). Case–control genomic and clinical cohorts showed these associations: “Among 46,891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%–0.46%) carried a damaging mutation in LPL, including 105 of 32,646 control participants (0.32%) and 83 of 14,245 participants with early-onset CAD (0.58%). Compared with 46,703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6–34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35–2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39–1.64; P = 1.1 × 10−22) per 1-SD increase in triglycerides.” (S. Kathiresan, skathiresan1@mgh.harvard.edu)

>>>PNN NewsWatch
*
A&H Focal Inc. is voluntarily recalling all lots marketed as dietary supplements for male sexual enhancement since January 2014 because FDA tests show they contain phosphodiesterase-5 inhibitors.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 9, 2017 * Vol. 24, No. 46
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 9 issue of the New England Journal of Medicine (2017; 376).
Long-Term Imatinib Outcomes in CML: Among patients with newly diagnosed chronic myeloid leukemia (CML), the selective BCR-ABL1 kinase inhibitor imatinib was effective and had no unacceptable cumulative or late toxic effects over 11 years of follow-up, a Novartis-funded study shows (pp. 917–27). The trial, an open-label multicenter crossover study, compared imatinib and interferon alfa plus cytarabine, with these outcomes based on overall survival, response to treatment, and serious adverse events: “The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment.” (A. Hochhaus, andreas.hochhaus@med.uni-jena.de)
“Although the journey to cancer cure has just begun, the use of imatinib to treat CML has pointed oncology in a new direction,” concludes an editorialist (
pp. 982–3). “The development of imatinib fundamentally altered the field of oncology. Priorities shifted from agents that were active on dividing cells to understanding the biology of individual types of cancer. Once genetic analysis of tumors began, nearly all the cancer types had more complex genetic abnormalities than did CML, but the complexity gave rise to a revolution in cancer nosology. We now recognize that the grouping of tumors on the basis of the appearance of a hematoxylin and eosin–stained tissue fragment examined under a light microscope lumps together entities that are distinct both genetically and clinically. Lung cancer is now considered to be at least eight or nine entities, and the number of variants is continuing to expand. That is the good news. The bad news is that the inherent genetic instability of many cancers also facilitates the development of resistance to these interventions. In some instances, new genetic abnormalities create vulnerabilities that can be attacked by new agents.” (D. L. Longo)
Access Problems With Medicaid Expansion: While increased insurance coverage was evident in the second year after 29 states and the District of Columbia expanded Medicaid programs under the Affordable Care Act, wait times for appointments also climbed, researchers report, suggesting persistence of access problems (pp. 947–56). Among 60,766 U.S. adults ages 18–64 years with low incomes, uninsurance rates fell by 8.2 percentage points in expansion states in the second year of increased coverage, compared with nonexpansion states. Rates of Medicaid coverage increased by 15.6 percentage points. Expansion states showed fewer reports of inability to afford needed follow-up care (3.4 percentage points less than nonexpansion states), and reports of worrying about how to pay medical bills dropped by 7.9 percentage points. However, reports of longer wait times climbed by 2.6 percentage points in expansion states, compared with nonexpansion jurisdictions. (S. Miller, amille@umich.edu)

>>>PNN NewsWatch
* Only about one-third of
smokers hospitalized for myocardial infarction and other serious heart conditions received proven smoking-cessation therapy while they were in the hospital, according to research scheduled for presentation at next week’s American College of Cardiology’s 66th Annual Scientific Session. The findings come from a study of 282 U.S. hospitals and 36,675 patients in 2004–14. Of patients who received smoking-cessation therapy, about 20% were given the nicotine patch, which was the most commonly given treatment, and about 10% received professionally delivered smoking-cessation counseling. Few patients received medication or other forms of nicotine replacement therapy such as nicotine gum or lozenges.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 10, 2017 * Vol. 24, No. 47
Providing news and information about medications and their proper use

>>>Chest Highlights
Source: Mar. issue of Chest (2017; 151).
Asthma—Catching Up With the Evidence? In a retrospective cohort study of adolescents and adults with asthma in British Columbia, inappropriate use of short-acting beta-agonists (SABAs) declined over time but increased over the course of the disease, researchers report (pp. 612–8). Examination of the administrative health database for the province showed these trends between 2002 and 2013 for those between ages 15 and 67 years: “Three hundred fifty-six thousand, one hundred twelve patients (56.5% female sex; mean age, 30.5 years) contributed 2.6 million patient-years. In 7.3% of the patient-years, SABAs were prescribed inappropriately. This proportion dropped by a relative rate of 5.3% per year (P <.001). In the first year of asthma, 6.3% of patients had indicators of inappropriate SABA use, which dropped within the first 3 years but increased thereafter. Excessive prescription of SABAs increased rapidly during the time course of asthma (change of 23.3% per year; P <.001) and by age (change of 5.1% per year; P <.001).” (M. Sadatsafavi)
Management of Chronic Hypersensitivity Pneumonitis: Assessed retrospectively for effectiveness in patients with chronic hypersensitivity pneumonitis (cHP), use of either mycophenolate mofetil (MMF) or azathioprine (AZA) was associated with improvements in lung function, a study shows (pp. 619–25). Experiences at four interstitial lung disease centers showed these patterns: “Seventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco) % predicted were declining at a mean rate of 0.12% (P <.001) and 0.10% (P <.001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in Dlco of 4.2% (P <.001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).” (J. Morisset)

>>>Cardiology Report
Source: Mar. 14 issue of the Journal of the American College of Cardiology (2017; 69).
Rheumatoid Arthritis & Heart Failure: Patients diagnosed with rheumatoid arthritis (RA) are at increased risk of developing heart failure (HF), a Swedish study shows, with symptoms developing quickly that were not explainable by increased risk of ischemic heart disease (pp. 1275–85). Implicating inflammatory factors associated with RA, investigators found a 25% increased risk of HF that was evident quickly after RA onset. (Ä. Mantel, angla.mantel@ki.se)
“Although effective treatments for heart failure targeting inflammation are at least years away, an immediate clinical implication of the association of rheumatoid arthritis and heart failure is the potential for improved diagnosis of left ventricular dysfunction,” writes an editorialist (
pp. 1286–7; P. Heidenreich).

>>>PNN NewsWatch
* A study of 43,145 men followed for a mean of 3.3 years shows beneficial effects of
phosphodiesterase-5 inhibitors following myocardial infarction (MI). In research scheduled for next week’s American College of Cardiology’s 66th Annual Scientific Session, Andersson et al. found that Swedish men who had prescriptions filled for the erectile dysfunction drugs had a 30% lower all-cause mortality rate and a 36% reduced risk of hospitalization for heart failure after an incident MI.
* Another
ACC presentation reports increased risk of stroke and heart failure among U.S. marijuana users. Kalla et al. studied adults aged 18–55 years with records in the Nationwide Inpatient Sample 2009–10, finding a 10% increased risk of heart failure and 24% increased risk of cerebrovascular accident among cannabis users after correcting for potentially confounding factors.
*
Regeneca Worldwide, division of VivaCeuticals, is conducting a nationwide recall of all of its herbal and dietary supplement products pursuant to a consent decree entered by the federal court for the Central District of California, FDA announced yesterday. This recall applies to all lot numbers produced from June 1, 2011, to Feb. 8, 2017.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 13, 2017 * Vol. 24, No. 48
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Mar. 11 issue of Lancet (2017; 389).
Quarter-Dose Quadpills for Hypertension: In a small trial, quarter-doses of four antihypertensive agents combined in one tablet showed promise for additive effects in the control of high blood pressure, researchers report (pp. 1035–42). Testing irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg, the group found these effects among 21 patients with hypertension: “The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–23), and office blood pressure was reduced by 22/13 mm Hg (p <0.0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p = 0.0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n = 4,721 participants) of one drug at quarter-dose and six trials (n = 312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p <0.0001), and there were no side-effects from either regimen.” (C. K. Chow, cchow@georgeinstitute.org.au)
“Obtaining the full public health benefit of polypills will require education, advocacy, endorsement, and implementation by key global agencies such as WHO and national clinical bodies, as well as endorsement from governments,” authors of a related article write (
pp. 1066–74). “The evidence clearly shows polypills improve adherence and cardiovascular disease risk factors for patients with indications for use of polypill components—ie, those with established cardiovascular disease or at high risk. However, the implementation of polypills into clinical practice has many challenges. The clinical trials literature provides insights into the clinical impact of a polypill strategy, including cost-effectiveness, safety of use, substantial improvement in adherence, and better risk factor control than usual care. Despite the clear need for such a strategy and the available clinical data backing up the use of the polypill in different patient populations, challenges to widespread implementation, such as an absence of government reimbursement and poor physician uptake (identified from on the ground experience in countries following commercial rollout), have greatly obstructed real-world implementation.” (R. Webster, rwebster@georgeinstitute.org.au)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Insulin Initiation in Primary Care: A novel, nurse-centered model of care improved insulin initiation rates among patients with type 2 diabetes in a cluster-randomized trial in Australia (j783). The Stepping Up model involved a practice nurse leading insulin initiation and mentoring by registered nurses with diabetes educator credentials, with these results in 266 patients at 74 practices: “HbA1c improved in both arms, with a clinically significant between arm difference (mean difference −0.6%, 95% confidence interval −0.9% to −0.3%), favouring the intervention. At 12 months, in intervention practices, 105/151 (70%) of participants had started insulin, compared with 25/115 (22%) in control practices (odds ratio 8.3, 95% confidence interval 4.5 to 15.4, P <0.001). Target HbA1c (≤7% (53 mmol/mol)) was achieved by 54 (36%) intervention participants and 22 (19%) control participants (odds ratio 2.2, 1.2 to 4.3, P = 0.02). Depressive symptoms did not worsen at 12 months (PHQ-9: −1.1 (3.5) v −0.1 (2.9), P = 0.05).” (J. Furler, j.furler@unimelb.edu.au)

>>>PNN JournalWatch
* 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis, in
Clinical Infectious Diseases, 2017; 64: 701–6. (A. R. Tunkel) 
* The Role of Stewardship in Addressing Antibacterial Resistance: Stewardship and Infection Control Committee of the Antibacterial Resistance Leadership Group, in a special supplement to
Clinical Infectious Diseases, 2017; 64(suppl 1): S36–40. (D. J. Anderson) 
* Improving the Management of COPD in Women, in
Chest, 2017; 151: 686–96. (C. R. Jenkins) 
* Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association, in
Circulation, 2017; 135: e604–33. (A. N. Raval) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 14, 2017 * Vol. 24, No. 49
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Mar. issue of JAMA Internal Medicine (2017; 177).
Language & Diabetes Care: Researchers and editorialists examine antidiabetic medication adherence and glycemic control based on language discordance between patients and providers. 
Limited English proficiency (LEP) Latino patients with diabetes were significantly less likely to adhere to newly prescribed antidiabetic agents than other groups, a study shows, including English-speaking Latinos (
pp. 371–9). Observational data from 2006 through 2012 at a large integrated health care delivery system showed that Spanish fluency of the physician and availability of interpreters were insufficient to improve LEP’s primary medication adherence (never dispensed), early-stage persistence (dispensed only once), late-stage persistence (two or more cycles dispensed, but discontinued within 24 months), or inadequate overall medication supply (more than 20% of time with insufficient medication supply during first 24 months). (A. Fernández, alicia.fernandez@ucsf.edu)
A second study, using a pre–post, difference-in-differences design, found that switching LEP Latino patients from language-discordant primary-care providers (PCPs) to language-concordant care improved clinical outcomes (
pp. 380–7). In 2007–13, Kaiser Northern California adult patients with diabetes who identified as Latino had these clinical outcomes based on patient–PCP language concordance: “Overall, 1,605 LEP Latino adults with diabetes (mean [SD] age, 60.5 [13.1] years) were included in this study, and there was a significant net improvement in glycemic and LDL control among patients who switched from language-discordant PCPs to concordant PCPs relative to those who switched from one discordant PCP to another discordant PCP. After adjustment and accounting for secular trends, the prevalence of glycemic control increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control decreased by 4% (95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95% CI, 1% to 17%; P = .03). No significant changes were observed in SBP control. Prevalence of LDL control increased 15% (95% CI, 7% to 24%; P < .001) among LEP Latinos who switched from concordant to discordant PCPs. Risk factor control did not worsen following a PCP switch in any group.” (A. J. Karter, andy.j.karter@kp.org)
“As the US health care system evolves to more accountable care organizations with integrated health systems, care of the most vulnerable must be prioritized,” editorialists write (
pp. 313–5). “Latinos with LEP who have diabetes represent such a population, as evidenced not only by their language status but by their socioeconomic disadvantage. There is a need to integrate greater granularity on social determinants into the medical record to provide more precision patient–clinician interactions. Metrics for our health care system need to include an equity outcome that sets a high bar for the most vulnerable patients. Healthcare outcomes of LEP Latinos with diabetes would be an excellent system measure of health equity.” (E. J. Pérez-Stable, eliseo.perez-stable@nih.gov)
Outcomes Data Imbalance Among Antidiabetic Drugs: FDA requirements for randomized controlled trial data on adverse cardiovascular events for new antidiabetic drugs have created an imbalance in available information, a Viewpoint author writes, such that “there is no longer more evidence for the cardiovascular benefit of metformin than there is for some of the newer second-line drugs” (pp. 301–2): “At what point can newer drugs be used instead of metformin as first-line agents? Although direct comparisons between metformin and newer agents in randomized clinical trials with primary cardiovascular outcomes are the best way to address this question, no such studies are under way, as evidenced by studies that have been registered at clinicaltrials.gov as of November 2016.” (J. Flory, jaf9052@med.cornell.edu)
Better Adult Pneumococcal Vaccine Needed: “A new [pneumococcal] vaccine exclusively for older adults and those who are immunocompromised is needed,” Viewpoint authors suggest (pp. 303–4). “Simply creating a new vaccine with additional serotypes and administering it to both children and adults is unlikely to solve this problem. A compelling solution is to develop a conjugate vaccine for exclusive use in adults while continuing to use PCV13 and PPV23 in children.” (D. M. Weinberger, daniel.weinberger@yale.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 15, 2017 * Vol. 24, No. 50
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 14 issue of JAMA (2017; 317).
Adequacy of Anticoagulation & Stroke: When ischemic stroke occurs, patients with atrial fibrillation who are adequately anticoagulated have lower odds of developing moderate or severe symptoms and of dying during hospitalization for the event, a study shows (pp. 1057–67). In the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study, retrospective analysis of data from 1,622 hospitals in 2012–15 showed these patterns based on participation in the Get With the Guidelines–Stroke program: “Of 94,474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7,176 (7.6%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥2) and 8,290 (8.8%) were receiving non–vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79,008 patients (83.6%) were not receiving therapeutic anticoagulation; 12,751 (13.5%) had subtherapeutic warfarin anticoagulation (INR <2) at the time of stroke, 37,674 (39.9%) were receiving antiplatelet therapy only, and 28,583 (30.3%) were not receiving any antithrombotic treatment. Among 91,155 high-risk patients (prestroke CHA2DS2-VASc score ≥2), 76,071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeutic warfarin (15.8% [95% CI, 14.8%–16.7%]) and NOACs (17.5% [95% CI, 16.6%–18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI, 26.6%–27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%–25.3%]), or subtherapeutic warfarin (25.8% [95% CI, 25.0%–26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%–7.0%]) and NOACs (6.3% [95% CI, 5.7%–6.8%]) compared with those receiving no antithrombotic therapy (9.3% [95% CI, 8.9%–9.6%]), antiplatelet therapy only (8.1% [95% CI, 7.8%–8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%–9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51–0.60], 0.65 [0.61–0.71], and 0.88 [0.84–0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67–0.85], 0.79 [0.72–0.88], and 0.83 [0.78–0.88], respectively).” (Y. Xian, ying.xian@duke.edu)
Getting to Goal in Type 2 Diabetes: “Patient-centered diabetes management can be accomplished with lifestyle modification and combination therapy,” write the authors of a Viewpoint on managing type 2 diabetes in 2017 (pp. 1015–6). “Metformin is an optimal first-line agent; newer GLP1 and SGLT2 agents have efficacy for glucose lowering coupled with weight loss and potential cardiovascular risk reduction; and insulin therapy is generally safe and effective for patients not controlled with noninsulin agents. In younger, healthy, newly diagnosed patients, a hemoglobin A1c level less than 7% should be the goal; in older individuals with comorbidities, less stringent goals with a focus on safety and avoidance of hypoglycemia are critical. Antihyperglycemic therapy should be combined with evidence-based treatment of cholesterol and blood pressure for cardiovascular risk reduction. Although the cardiovascular benefits of SGLT2 and GLP1 agents merit consideration, these medications are not replacements for statin therapy or blood pressure management for reducing the risk of cardiovascular disease.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
Efficacy Endpoints in Diabetes Studies: Achieving glycemic control in patients with type 2 diabetes is not a valid predictor of reduced risk of complications of the disease, according to Viewpoint authors who argue for use of heart disease and mortality outcomes in studies of the disease (pp. 1017–8; H. M. Krumholz, harlan.krumholz@yale.edu).

>>>PNN NewsWatch
* A U.S. district judge yesterday entered a consent decree of permanent injunction against
EonNutra LLC, CDSM LLC and HABW LLC, manufacturers and distributors of unapproved drugs and dietary supplements, and their owner, Michael Floren, requiring Floren’s businesses to immediately cease operations until they come into compliance with federal laws, FDA said.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 16, 2017 * Vol. 24, No. 51
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 16 issue of the New England Journal of Medicine (2017; 376).
Pembrolizumab in Advanced Urothelial Carcinoma: Used as second-line therapy in 542 patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab extended overall survival by approximately 3 months with a lower rate of treatment-related adverse events, compared with chemotherapy, the KEYNOTE-045 trial shows (pp. 1015–26). The drug, a highly selective, humanized monoclonal IgG4-kappa isotype antibody against programmed death 1 (PD-1), produced these results in an open-label, phase 3 comparison with paclitaxel, docetaxel, or vinflunine: “The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P = 0.002). The median overall survival among patients who had a tumor [PD-1 ligand] combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P = 0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P = 0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P = 0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).” (J. Bellmunt, joaquim_bellmunt@dfci.harvard.edu)
This trial “will have a practice-changing effect,” an editorialist writes, adding that PD-1 and PD-L1 inhibitors are active as first-line therapy (
pp. 1073–4). “Indeed, they are being investigated in randomized phase 3 trials assessing their use as first-line therapy in combination with platinum-based chemotherapy (NCT02853305 and NCT02807636) and cytotoxic T-lymphocyte–associated 4 (CTLA-4)–inhibiting immune modulators (NCT02516241 and NCT03036098) and as adjuvant therapy after surgery for high-risk disease (NCT02450331 and NCT02632409).” (G. Sonpavde)
Radiation + Temozolomide in Older Patients with Glioblastoma: Compared with short-course radiotherapy alone, the combination of radiotherapy with temozolomide nearly doubled survival time in some patients 65 years or older with newly diagnosed glioblastoma, researchers report (pp. 1027–37): “A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P <0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P <0.001). Among 165 patients with methylated O6-methylguanine–DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P <0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P = 0.055; P = 0.08 for interaction). Quality of life was similar in the two trial groups.” (J. R. Perry, james.perry@sunnybrook.ca)

>>>PNN NewsWatch
*
FDA is warning that eluxadoline (Viberzi, Allergan), used to treat irritable bowel syndrome with diarrhea, should not be used in patients who do not have a gallbladder. An FDA review found these patients have an increased risk of developing serious pancreatitis that could result in hospitalization or death. Among 120 reports received by FDA of serious cases of pancreatitis or death, some patients also had sphincter of Oddi spasm (n = 6) or abdominal pain (n = 16).

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 17, 2017 * Vol. 24, No. 52
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Apr. 1 issue of Clinical Infectious Diseases (2017; 64).
Influenza Vaccine Booster Doses in Transplant Recipients: Solid organ transplant recipients (SOTR) have an increased antibody response when a booster influenza vaccine dose is administered 5 weeks after the initial standard-dose injection, according to findings from the TRANSGRIPE 1–2 trial (pp. 829–38). The phase 3, open-label study randomly assigned 499 SOTR to 1 or 2 influenza vaccine doses, with these results: “Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups.” (E. Cordero)
HPV Vaccine Responses 6 Years After 1, 2, or 3 Doses: A study from Fiji shows effectiveness of human papillomavirus (HPV) vaccine after only 2 doses and suggests that a single dose might be sufficient (pp. 852–9). Testing a single dose of a bivalent HPV vaccine in 200 girls from two main ethnic groups in Fiji, investigators found these levels of neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 at 28 days based on the current and previously administered vaccines: “After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695–2896]; 2D: 1476 [95% CI, 1019–2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396–5783]; 2D: 2951 [95% CI, 1984–4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511–4530]; 2D: 3275 [95% CI, 2452–4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445–888]; 2D: 606 [95% CI, 462–862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously.” (Z. Q. Toh)
PPIs & Listeriosis: Prescribed proton pump inhibitors (PPIs) place patients at increased risk of listeriosis, report researchers who looked at 721 cases and matched controls in the Danish national registry (pp. 845–51): “The adjusted OR for current use of PPIs and development of listeriosis was 2.81 (95% confidence interval [CI], 2.14–3.69). PPI usage up to 90 days before the index date remained statistically significant. Subgroup analyses revealed increasing ORs with decreasing age and level of comorbidity and an increased OR for concurrent glucocorticoid treatment (OR, 4.61; 95% CI, 3.01–7.06). No significant association was found for current use of histamine-2-receptor antagonists (adjusted OR, 1.82; 95% CI, 0.89–3.71).” (A. K. Jensen)

>>>Oncology Highlights
Source: Mar. 20 issue of the Journal of Clinical Oncology, a theme issue on genomics in hematologic malignancies (2017; 35).
Genomics in Defining the Biology of Hematologic Malignancies: “Each hematologic malignancy discussed [in this issue] has complex genetics caused by the combinatorial diversity of somatic genetic mutations,” authors of an overview article write of the special issue (pp. 927–8). “However, many malignancies are associated with frequent disruption of a single biologic process, such as Janus kinase 2 signaling in myeloproliferative neoplasms, the mRNA spliceosome in myelodysplastic syndrome, and mitogen-activated protein kinase signaling in multiple myeloma. Clinical genetics offers the potential for improved disease classification, prognostication, identification of predictors of therapeutic response, and evaluation of the depth of disease remission. The articles in this issue, written by international authorities in the field, emphasize the translation of this increased genomic understanding to the clinic, with the practicing hematologist and oncologist in mind.” (B. L. Ebert)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 20, 2017 * Vol. 24, No. 53
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Early-release articles from the New England Journal of Medicine (2017; 376).
Targeting PCSK9 in Cholesterol Management: In articles released in conjunction with the American College of Cardiology’s 66th Annual Scientific Session, researchers and an editorialist examine the effects of medications that target the gene for proprotein convertase subtilisin–kexin type 9 (PCSK9).
Evolocumab reduced risks of cardiovascular events among 27,564 participants in the FOURIER clinical trial, reported investigators at the ACC meeting (
doi: 10.1056/NEJMoa1615664). A primary composite efficacy end point of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization, evolocumab produced these outcomes in comparison with placebo in patients with atherosclerotic cardiovascular disease whose LDL cholesterol remained above 70 mg/dL during statin therapy: “At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P <0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1,344 patients [9.8%] vs. 1,563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P <0.001) and the key secondary end point [of cardiovascular death, MI, or stroke] (816 [5.9%] vs. 1,013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P <0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).” (M. S. Sabatine, msabatine@partners.org)
“The FOURIER trial is a landmark trial providing formal evidence that treatment targeted at PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved by lipid-lowering treatment alone,” an editorialist writes (
doi: 10.1056/NEJMe1703138). “However, in this trial, the duration of evolocumab treatment was rather short [median, 2.2 years]. The efficacy, with regard to atherosclerotic cardiovascular disease, of PCSK9 inhibition treatment that is started shortly after an acute event still needs to be determined, as does the efficacy of the treatment in other categories of high-risk patients. End-point studies of alirocumab and other monoclonal antibodies against PCSK9 (bococizumab and LY3015014) are under way, and an RNA interference therapeutic agent that inhibits PCSK9 synthesis and lowers plasma LDL cholesterol levels has been tested in a phase 1 study.” (R. P. F. Dullaart)
In the phase 2 ORION-1 trial, inclisiran lowered PCSK9 and LDL cholesterol in 501 patients with high cardiovascular risk and elevated LDL cholesterol levels (
doi: 10.1056/NEJMoa1615758). The RNA interference therapeutic agent produced these results: “Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P <0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.” (K. K. Ray, k.ray@imperial.ac.uk)

>>>PNN JournalWatch
* Targeted Strategies Directed at the Molecular Defect: Toward Precision Medicine for Select Primary Immunodeficiency Disorders, in
Journal of Allergy and Clinical Immunology, 2017; 139: 715–25. (T. A. Fleisher, tfleishe@mail.nih.gov
* Geriatric Infectious Diseases: Current Concepts on Diagnosis and Management, in
Journal of the American Geriatrics Society, 2017; 65: 631–41. (T. T. Yoshikawa, Toyoshikawa@cdrewu.edu

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 21, 2017 * Vol. 24, No. 54
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Mar. 21 issue of the Annals of Internal Medicine (2017; 166).
Intensive Blood Pressure Treatment in Older Adults: Treating older adults aggressively to blood pressures below a target of 150/90 mm Hg has advantages that outweigh problems such as hypotension, syncope, and greater medication burden, according to a systematic review and clinical guidelines released by the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP). 
Improved health outcomes were evident among participants of 21 randomized controlled trials and 3 observational studies, review authors note (
pp. 419–29): “Nine trials provided high-strength evidence that BP control to less than 150/90 mm Hg reduces mortality (relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]), cardiac events (RR, 0.77 [CI, 0.68 to 0.89]), and stroke (RR, 0.74 [CI, 0.65 to 0.84]). Six trials yielded low- to moderate-strength evidence that lower targets (≤140/85 mm Hg) are associated with marginally significant decreases in cardiac events (RR, 0.82 [CI, 0.64 to 1.00]) and stroke (RR, 0.79 [CI, 0.59 to 0.99]) and nonsignificantly fewer deaths (RR, 0.86 [CI, 0.69 to 1.06]). Low- to moderate-strength evidence showed that lower BP targets do not increase falls or cognitive impairment.” (D. Kansagara, kansagar@ohsu.edu)
ACP and AAFP make these recommendations based on the available evidence (
pp. 430–7; A. Qaseem, aqaseem@acponline.org):
* ACP and AAFP recommend that clinicians initiate treatment in adults aged 60 years or older with systolic blood pressure persistently at or above 150 mm Hg to achieve a target systolic blood pressure of less than 150 mm Hg to reduce the risk for mortality, stroke, and cardiac events. (Grade: strong recommendation, high-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.
* ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in adults aged 60 years or older with a history of stroke or transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for recurrent stroke. (Grade: weak recommendation, moderate-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.
* ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk, based on individualized assessment, to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for stroke or cardiac events. (Grade: weak recommendation, low-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.
Editorialists outline characteristics of programs that have produced large improvements in blood pressure (BP) and have the potential to lower hypertension-related morbidity and mortality in older adults (
pp. 445–6): “On the basis of these recommendations, providers who wish to prevent hypertension-related morbidity and mortality by implementing high-value, population-based practices should develop an office-based program with the following features: high-fidelity BP measurement support, including office BP measurement conducted by well-trained staff, resources for training patients in home monitoring or the availability of ambulatory BP monitoring, and ongoing quality assurance efforts; routine assessment of global [cardiovascular disease (CVD)] risk in all patients aged 40 years or older and in younger individuals with multiple risk factors or extreme elevations of a single risk factor; provider training in shared decision making for hypertension treatment and CVD risk reduction in general; creation of a registry to track patients receiving hypertension treatment (and other forms of CVD risk reduction); and use of non–visit-based follow-up for patients with moderate to severe hypertension who have had treatment initiation or changes (to monitor effectiveness and potential adverse effects).” (M. Pignone, pignone@austin.utexas.edu)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 22, 2017 * Vol. 24, No. 55
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 21 issue of JAMA (2017; 317).
Consumer Advertising & Testosterone Use: Increased levels of direct-to-consumer advertising (DTCA) were associated with increased testosterone testing, new initiations of therapy with the hormone, and initiation without recent testing, according to a study of 75 designated market areas (DMAs) in the U.S. (pp. 1159–66). Insurance claims from 2009–13 showed these patterns in relation to Nielsen-measured DTCA for the 75 largest DMAs: “Of 17,228,599 commercially insured men in the 75 DMAs, 1,007,990 (mean age, 49.6 [SD, 11.5] years) had new serum testosterone tests and 283,317 (mean age, 51.8 [SD, 11.3] years) initiated testosterone treatment. Advertising intensity varied by geographic region and time, with the highest intensity seen in the southeastern United States and with months ranging from no ad exposures to a mean of 13.6 exposures per household. Nonbranded advertisements were common prior to 2012, with branded advertisements becoming more common during and after 2012. Each household advertisement exposure was associated with a monthly increase in rates of new testosterone testing (rate ratio [RR], 1.006; 95% CI, 1.004–1.008), initiation (RR, 1.007; 95% CI, 1.004–1.010), and initiation without a recent test (RR, 1.008; 95% CI, 1.002–1.013). Mean absolute rate increases were 0.14 tests (95% CI, 0.09–0.19), 0.05 new initiations (95% CI, 0.03–0.08), and 0.02 initiations without a recent test (95% CI, 0.01–0.03) per 10,000 men for each monthly ad exposure over the entire period.” (J. B. Layton, blayton@unc.edu)
“As learned intermediaries, physicians are supposed to protect consumers from the potential adverse effects of drug advertisements,” writes an editorialist (
pp. 1124–5). “However, when clinical indications are weak or uncertain, signals of harm are suggestive but unproven, and patient demand is strong, physicians may not be able to provide that protection. In a recent observational study, DTCA was associated with an increase in statin prescribing that was largest among patients with the lowest cardiovascular risk—precisely the opposite of what would be desired from the perspective of cardiovascular risk reduction. Findings like these suggest that DTCA of prescription drugs as currently regulated in the United States is unlikely to yield consistent public health gains.” (R. L. Kravitz, rlkravitz@ucdavis.edu)
Dabigatran, Warfarin & Risk of Osteoporotic Fractures: In a retrospective cohort study, use of dabigatran rather than warfarin was associated with a lower risk of osteoporotic fractures among patients in Hong Kong with nonvalvular atrial fibrillation (NVAF), researchers report (pp. 1151–8). Results from 2010–14 showed the following associations: “Among 51,496 patients newly diagnosed with NVAF, 8,152 new users of dabigatran (n = 3,268) and warfarin (n = 4,884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person–years; ARD per 100 person–years, −0.68 [95% CI, −0.38 to −0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person–years; ARD per 100 person–years, −3.15 [95% CI, −2.40 to −3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person–years; ARD per 100 person–years, −0.04 [95% CI, 0.67 to −0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001).” (I. C. K. Wong, i.wong@ucl.ac.uk)

>>>PNN NewsWatch
*
Safinamide (Xadago, Newron Pharmaceuticals) tablets have been approved by FDA as an add-on treatment for patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. The drug is an MAO-B inhibitor; because of the risk of serotonin syndrome and other serious interactions, safinamide is contraindicated in patients taking other MAO inhibitors, opioids, dextromethorphan, amphetamine, methylphenidate, cyclobenazprine, some antidpressants, or St. John’s wort.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 23, 2017 * Vol. 24, No. 56
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 23 issue of the New England Journal of Medicine (2017; 376).
Pregabalin in Acute and Chronic Sciatica: After 8 weeks of pregabalin therapy, intensity of leg pain associated with sciatica was not altered, researchers report, and adverse effects were higher in comparison with placebo (pp. 1111–20). With doses of pregabalin of up to 600 mg/d for up to 8 weeks and evaluation through week 52, results showed: “A total of 209 patients underwent randomization, of whom 108 received pregabalin and 101 received placebo; after randomization, 2 patients in the pregabalin group were determined to be ineligible and were excluded from the analyses. At week 8, the mean unadjusted leg-pain intensity score was 3.7 in the pregabalin group and 3.1 in the placebo group (adjusted mean difference, 0.5; 95% confidence interval [CI], −0.2 to 1.2; P = 0.19). At week 52, the mean unadjusted leg-pain intensity score was 3.4 in the pregabalin group and 3.0 in the placebo group (adjusted mean difference, 0.3; 95% CI, −0.5 to 1.0; P = 0.46). No significant between-group differences were observed with respect to any secondary outcome at either week 8 or week 52. A total of 227 adverse events were reported in the pregabalin group and 124 in the placebo group. Dizziness was more common in the pregabalin group than in the placebo group.” (C. Lin, aclin@georgeinstitute.org.au)
“These results indicate failure of the drug to improve this condition; however, the design of the trial does not exclude a possible benefit in chronic sciatica,” editorialists write (
pp. 1169–70). “This trial highlights a need in the field of pain treatment — namely, to identify biomarkers that could link the efficacy of a drug with the biologic causes of diverse types of pain.” (N. Attal)
Efficacy of Low-Cost, Heat-Stable Oral Rotavirus Vaccine: In a study of infants in Niger, an oral rotavirus vaccine had an efficacy of 66.7% against severe rotavirus gastroenteritis (pp. 1121–30). The live, oral bovine rotavirus pentavalent vaccine was administered in three doses at 6, 10, and 14 weeks of age in a placebo-controlled trial, with these results: “Among the 3,508 infants who were included in the per-protocol efficacy analysis, there were 31 cases of severe rotavirus gastroenteritis in the vaccine group and 87 cases in the placebo group (2.14 and 6.44 cases per 100 person–years, respectively), for a vaccine efficacy of 66.7% (95% confidence interval [CI], 49.9 to 77.9). Similar efficacy was seen in the intention-to-treat analyses, which showed a vaccine efficacy of 69.1% (95% CI, 55.0 to 78.7). There was no significant between-group difference in the risk of adverse events, which were reported in 68.7% of the infants in the vaccine group and in 67.2% of those in the placebo group, or in the risk of serious adverse events (in 8.3% in the vaccine group and in 9.1% in the placebo group); there were 27 deaths in the vaccine group and 22 in the placebo group. None of the infants had confirmed intussusception.” (R. F. Grais, rebecca.grais@epicentre.msf.org)
“Rotavirus gastroenteritis is the leading cause of diarrhea-associated hospitalization and death in children younger than 5 years of age,” editorialists write, “with more than 85% of the approximately 200,000 annual rotavirus deaths occurring in Africa and Asia” (
pp. 1170–2). “During the past three decades, remarkable progress has been made in reducing mortality from diarrheal disease, but the goal of ending such deaths cannot be achieved without aggressive implementation of a comprehensive approach to diarrhea prevention and treatment, including providing access of rotavirus vaccines to every child regardless of economic status. Increased availability of low-cost, programmatically suitable vaccines in abundant supply will be key to achieving this goal.” (M. Santosham)
C1 Inhibition in Hereditary Angioedema Attacks: Self-administered subcutaneous CSL830, a C1 inhibitor, reduced the frequency of acute angioedema attacks among 90 patients with type I or II hereditary angioedema in a phase 3 trial (pp. 1131–40). Compared with placebo, two doses of the drug “reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month; 95% CI, –4.21 to –2.81; P <0.001 for both comparisons),” the authors write. (H. Longhurst, hilary.longhurst@bartshealth.nhs.uk)

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 24, 2017 * Vol. 24, No. 57
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source: Mar. issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Aspirin-Exacerbated Respiratory Disease: “Aspirin-exacerbated respiratory disease (AERD) is characterized by adult-onset asthma and severe chronic eosinophilic rhinosinusitis with nasal polyposis,” write authors of a review article (pp. 764–6). “AERD is not consistently associated with atopy, although serum total IgE levels can be increased. Steady-state levels of urinary or nasal lavage fluid mast cell activation products (histamine and tryptase) and leukotriene (LT) E4, the stable metabolite of the cysteinyl leukotrienes (cysLTs), exceed those found in patients with aspirin-tolerant asthma and sinonasal disease.” (J. A. Boyce, jboyce@partners.org)
Automated Identification of New Patients With AERD: Patients with previously undiagnosed aspirin-exacerbated respiratory disease (AERD) can be identified using an informatics algorithm, a study shows (pp. 819–25.e6). All three clinical features of AERD — asthma, nasal polyposis, and respiratory reactions to cyclooxygenase-1 inhibitors/NSAIDs — are noted in electronic health records (EHRs), the authors explain. Using an informatics algorithm to search EHRs of adults in the Partners Healthcare system over a 10-year period, they found: these patterns among those with asthma, nasal polyps, and record of respiratory (cohort A) or unspecified (cohort B) reactions to NSAIDs: “Our algorithm identified 731 ‘possible AERD’ cases, of which 638 were not in our AERD patient registry. Chart review of cohorts A (n = 511) and B (n = 127) demonstrated a positive predictive value of 78.4% for ‘clinical AERD,’ which rose to 88.7% when unspecified reactions were excluded. Of those with clinical AERD, 12.4% had no mention of AERD by any treating caregiver and were classified as ‘undiagnosed AERD.’ ‘Undiagnosed AERD’ cases were less likely than ‘diagnosed AERD’ cases to have been seen by an allergist/immunologist (38.7% vs 93.2%; P <.0001).” (K. N. Cahill, kncahill@partners.org)
Capsaicin-Evoked Cough Responses in Asthma: Neuronal dysfunction is the likely mechanism of exaggerated capsaicin-evoked cough responses in patients with mild-to-moderate asthma, researchers report, and nonatopic asthmatic patients had the highest cough responses (pp. 771–9.e10). Compared with healthy volunteers, patients with stable asthma had these reactions to capsaicin inhalational challenge: “Ninety-seven patients with stable asthma (median age, 23 years [interquartile range, 21–27 years]; 60% female) and 47 healthy volunteers (median age, 38 years [interquartile range, 29–47 years]; 64% female) were recruited. Asthmatic patients had higher Emax and lower ED50 values than healthy volunteers. Emax values were 27% higher in female subjects (P = .006) and 46% higher in patients with nonatopic asthma (P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than nonatopic asthmatic patients (P = .04). The ED50 value was 65% lower in female patients (P = .0001) and 71% lower in all asthmatic patients (P = .0008). ED50 values were also influenced by asthma control and serum IgE levels, whereas Emax values were related to 24-hour cough frequency. Age, body mass index, FEV1, PC20, fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters.” (J. A. Smith, jacky.smith@manchester.ac.uk)

>>>PNN NewsWatch
* The
APhA House of Delegates convenes this weekend at the Association’s Annual Meeting & Exposition in San Francisco. Pharmacy’s only professionwide policy-setting body is considering three topics: Patient Access to Pharmacist-Prescribed Medications, Pharmacists’ Role Within Value-Based Payment Models, and Pharmacy Performance Networks. Delegates to the House have submitted several items of new business to be considered, including expansion of the statement on equal employment opportunity for pharmacists to include all pharmacy personnel, drug disposal, on-label indication and medication safety, work schedules (to include meal and rest breaks, on-site dependent care, and flexible spending accounts), support for clinically validated blood pressure measurement devices, and pharmacy technician education, training, and development (to include completion of an educational/training program and certification by 2027).

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 27, 2017 * Vol. 24, No. 58
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Mar. 25 issue of Lancet (2017; 389).
Sirukumab in Refractory Rheumatoid Arthritis: In the phase 3 SIRROUND-T study, the interleukin-6 inhibitor sirukumab relieved disease symptoms with minimal adverse effects among 878 patients with active rheumatoid arthritis refractory or intolerant to previous treatment with at least one anti-TNF drug (pp. 1206–17). Participants received subcutaneous sirukumab or placebo every 2 or 4 weeks, with these results: “The proportions of patients who achieved [20% improvement in American College of Rheumatology criteria (ACR20) scores] at week 16 were 117 (40%) of 292 with 50 mg sirukumab every 4 weeks, and 132 (45%) of 292 with 100 mg sirukumab every 2 weeks versus 71 (24%) of 294 with placebo; differences compared with placebo were 0.16 (95% CI 0.09–0.23) for 50 mg sirukumab every 4 weeks and 0.21 (0.14–0.29) for 100 mg sirukumab every 2 weeks (both p <0.0001). Adverse event incidences in the 24-week placebo-controlled period were similar across groups (at least one event occurred for 182 patients assigned to placebo [62%, including early escape patients switched to sirukumab at week 18] of 294; 194 [66%] of 292 with 50 mg sirukumab every 4 weeks; and 207 [71%] of 292 with 100 mg sirukumab every 2 weeks). The most common adverse events in this period were injection-site erythema (four [1%] with placebo, 22 [8%] with 50 mg sirukumab every 4 weeks, and 41 [14%] with 100 mg sirukumab every 2 weeks). At week 52, of all patients receiving sirukumab including those reassigned from placebo, the most common adverse events were again injection-site erythema (33 [8%] of 416 with 50 mg sirukumab every 4 weeks and 66 [16%] of 418 with 100 mg sirukumab every 2 weeks).” (P. P. Tak, paul-peter.x.tak@gsk.com)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Alcohol & Cardiovascular Diseases: “Heterogeneous associations … between level of alcohol consumption and the initial presentation of cardiovascular diseases” suggest the need for “a more nuanced approach to the role of alcohol in prevention of cardiovascular disease is necessary,” according to authors of a population-based cohort study (j909). Using medical records of 1.9 million adults without cardiovascular disease at baseline, the authors found: “114,859 individuals received an incident cardiovascular diagnosis during follow-up. Non-drinking was associated with an increased risk of unstable angina (hazard ratio 1.33, 95% confidence interval 1.21 to 1.45), myocardial infarction (1.32, 1.24 to1.41), unheralded coronary death (1.56, 1.38 to 1.76), heart failure (1.24, 1.11 to 1.38), ischaemic stroke (1.12, 1.01 to 1.24), peripheral arterial disease (1.22, 1.13 to 1.32), and abdominal aortic aneurysm (1.32, 1.17 to 1.49) compared with moderate drinking (consumption within contemporaneous UK weekly/daily guidelines of 21/3 and 14/2 units for men and women, respectively). Heavy drinking (exceeding guidelines) conferred an increased risk of presenting with unheralded coronary death (1.21, 1.08 to 1.35), heart failure (1.22, 1.08 to 1.37), cardiac arrest (1.50, 1.26 to 1.77), transient ischaemic attack (1.11, 1.02 to 1.37), ischaemic stroke (1.33, 1.09 to 1.63), intracerebral haemorrhage (1.37, 1.16 to 1.62), and peripheral arterial disease (1.35; 1.23 to 1.48), but a lower risk of myocardial infarction (0.88, 0.79 to 1.00) or stable angina (0.93, 0.86 to 1.00).” (S. Bell, scb81@medschl.cam.ac.uk)

>>>PNN NewsWatch
*
FDA on Thursday granted accelerated approval to avelumab (Bavencio, EMD Serono) for first-line treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma. This is the first FDA-approved treatment for this rare, aggressive form of skin cancer.?
* At the APhA Annual Meeting & Exhibition in San Francisco,
Daniel A. Hussar, BSPharm, MS, PhD, received the Remington Honor Medal.The long-time professor at the Philadelphia College of Pharmacy is well-known for his advocacy in pharmacy and his articles and presentation on new drugs.

>>>PNN JournalWatch
* Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis, in
Journal of the American Geriatrics Society, 2017; 65: 490–5. (S. Nayak, smita.nayak@swedish.org
* Review: Breaking From Bisphosphonates, in
Arthritis & Rheumatology, 2017; 69: 494–8. (M. Seton) 

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 28, 2017 * Vol. 24, No. 59
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Mar. Journal of the American Geriatrics Society (2017; 65).
High-Dose Vitamin D for Preventing Respiratory Infections: Administered to older adults residing in long-term care facilities, high-dose vitamin D supplements given once monthly reduced the frequency of acute respiratory infection (ARI) but also increased falls without an increase in fractures, researchers report (pp. 496–503). Participants assigned to the high-dose group received monthly supplements of vitamin D3 100,000 IU. Outcomes were compared with participants who received placebo if they were receiving vitamin D3 400–1000 IU/d as part of usual care or vitamin D3 12,000 IU monthly if they were on lower doses as part of usual care. Results showed: “Participants (55 high dose, 52 standard dose) were randomized and included in the final analysis. The high-dose group had 0.67 ARIs per person–year and the standard-dose group had 1.11 (incidence rate ratio (IRR) = 0.60, 95% confidence interval (CI) = 0.38–0.94, P = .02). Falls were more common in the high-dose group (1.47 per person–year vs 0.63 in standard-dose group; IRR = 2.33, 95% CI = 1.49–3.63, P < .001). Fractures were uncommon and similar in both groups (high dose 0.10 vs standard dose 0.19 per person–year; P = .31). Mean trough 25-hydroxyvitamin D levels during the trial were 32. ng/mL in the high-dose group and 25.1 ng/mL in the standard-dose group. There was no hypercalcemia or kidney stones in either group.” (A. A. Ginde, adit.ginde@ucdenver.edu)
Vitamin D Deficiency, Incident Frailty & Cardiometabolic Diseases: In a prospective longitudinal cohort study conducted from 1994 through 2008, low vitamin D levels were associated with development of incident frailty, but the relationship was no longer significant after accounting for the presence of cardiometabolic diseases (pp. 619–24). Concluding that “future studies should explore mechanisms to explain this relationship,” the authors report these findings based on serum circulating 25-hydroxyvitamin D (25[OH]D) concentrations: “Incidence rate of frailty was 32.2 per 1,000 person–years in participants with 25(OH)D < 10 ng/mL, compared to 12.9 per 1,000 person–years in those with 25(OH)D ≥ 30 ng/mL (mean follow-up = 8.5 ± 3.7 years). In cumulative incidence analyses, those with lower 25(OH)D exhibited higher frailty incidence, though differences were non-significant (P = .057). In regression models adjusted for demographics, smoking, and season, 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) was associated with nearly three-times greater frailty incidence (hazard ratio (HR) = 2.77, 95% CI = 1.14, 6.71, P = .02). After adjusting for BMI, the relationship of 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) with incident frailty persisted, but was attenuated after further accounting for cardiometabolic diseases (HR = 2.29, 95% CI = 0.92, 5.69, P = .07).” (R. R. Kalyani, rrastogi@jhmi.edu)
Delirium Prevention Strategies in Older Adults: Delirium-friendly preprinted postoperative orders (PPOs) for individuals with hip fracture, used by regular nursing staff in a tertiary-care hospital, significantly lowered the occurrence of postoperative delirium but made no difference with respect to length of stay, discharge site, or in-hospital mortality, a study shows (pp. 567–73). The PPOs provided doses of medications for nighttime sedation, analgesia, and nausea and called for attention to catheter removal and bowel movements, producing these results: “Orthopedic nurses adhered reasonably well with delirium-friendly PPOs. Of 283 participants, 42% developed postoperative delirium, with significantly less delirium in the intervention group (intervention 33%, control 51%, P = .001). The effect of the intervention was stronger in individuals with preexisting dementia (intervention 60%, control 97%, P < .001). Participants with postoperative delirium had longer hospital stays and were more likely to die or be discharged to a nursing home, but there was no significant between-group difference in these outcomes.” (S. Freter, susan.freter@nshealth.ca)

>>>PNN NewsWatch
*
Niraparib (Zejula, Tesaro) has been approved by FDA for maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a complete or partial response to platinum-based chemotherapy. The drug is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 29, 2017 * Vol. 24, No. 60
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 28 issue of JAMA (2017; 317).
Vitamin D, Calcium Supplementation & Cancer Incidence in Older Women: Administered to older women in a 4-year trial, dietary supplementation with vitamin D3 and calcium produced no significant difference in all-type cancer incidence, researchers report (pp. 1234–43). Nonmelanoma skin cancers were excluded from the analysis, which showed these results for 2,000 IU/d of vitamin D3 and 1,500 mg/d of calcium: “Among 2,303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2,064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%]; P = .06). Kaplan–Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group).” (J. Lappe, jmlappe@creighton.edu)
“Fortunately, large-scale, general-population, high-dose vitamin D supplementation trials designed to overcome many of the limitations of previous trials are ongoing,” editorialists write (
pp. 1217–8). “The largest of these trials, the Vitamin D and Omega-3 Trial (VITAL; NCT01169259), a 5-year trial of supplemental vitamin D (2,000 IU/d) for the primary prevention of cancer and cardiovascular disease in a racially/ethnically diverse cohort of nearly 26,000 men and women across the United States, is expected to provide results soon regarding the role of supplementation for nonskeletal outcomes and the overall balance of benefits and risks. As ongoing large-scale trials report their findings, an improved understanding of these important relationships should come to light.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
For-Profit Medical Schools: A Viewpoint author reviews the “sea change” in medical education resulting from the recent openings of schools such as the one at California Northstate U., where a pharmacy school had earlier begun enrolling pharmacy students (pp. 1209–12): “Characterized by a tuition-dependent business model, the new for-profit medical schools will probably continue to evolve. Indeed, for-profit medical schools are unlikely to maintain their investment allure absent growth of the tuition-paying base. Gradual expansion of the total active enrollment to levels maintained by some of the largest not-for-profit medical schools is therefore to be expected. Potential loss of quality in the face of quantity would have to be guarded against by way of the reaccreditation process. The new for-profit medical schools may also give consideration to a growing presence in the online distance learning space. Enticing as digital education might be as a means of expanding the tuition-paying base, the hands-on requirements of the discipline may prove constraining. Whatever business model emerges, it is all but certain that the old adage ‘there’s no profit like not-for-profit’ is no more.” (E. Y. Adashi, eli_adashi@brown.edu)

>>>PNN NewsWatch
*
FDA yesterday approved dupilumab injection (Dupixent, Regeneron Pharmaceuticals) for treatment of adults with moderate-to-severe atopic dermatitis. The drug is intended for patients whose eczema is not controlled adequately by topical therapies, or those for whom topical therapies are not advisable; it can be used with or without topical corticosteroids.
* The
APhA House of Delegates on Monday approved policies or business items on patient access to pharmacist-prescribed medications, pharmacists’ role within value-based payment models, pharmacy performance networks, and drug disposal, pharmacist.com reports. Installed as APhA president was Nancy Alvarez, PharmD, BCPS, FAPhA, of Chapman U. Michael Hogue, PharmD, FAPhA, FNAP, of Samford U. is the new speaker of the APhA House.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 30, 2017 * Vol. 24, No. 61
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 30 New England Journal of Medicine (2017; 376).
Extended Treatment of Venous Thromboembolism: In the phase 3 EINSTEIN CHOICE trial, patients with venous thromboembolism who had completed 6–12 months of anticoagulation had lower risks of a recurrent event when they received prophylactic or treatment doses of rivaroxaban than with low-dose aspirin, researchers report (pp. 1211–22). All participants “were in equipoise regarding the need for continued anticoagulation,” the group writes. A primary efficacy outcome of symptomatic recurrent fatal or nonfatal venous thromboembolism and a principal safety outcome of major bleeding showed: “A total of 3,365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1,107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1,127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1,131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P <0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.” (J. I. Weitz, weitzj@taari.ca)
“The emergence of rivaroxaban and other direct oral anticoagulant agents has altered the standard of care among patients with venous thromboembolism,” editorialists write (
pp. 1279–80). “For patients without cancer, the use of direct oral anticoagulant agents might be considered as first-line treatment for those with acute venous thromboembolism. Full-dose treatment could be continued for a minimum of 3 to 6 months. In patients in whom there is equipoise with respect to continuing anticoagulant therapy beyond this period, the use of a reduced-intensity direct oral anticoagulant agent might be considered. Clinicians who choose this strategy can be confident of excellent efficacy and low bleeding risk similar to that observed with aspirin or placebo.” (M. A. Crowther)
HPV Vaccination During Pregnancy: Quadrivalent human papillomavirus (HPV) vaccination of women during pregnancy showed no adverse outcomes in an analysis of Danish registries (pp. 1223–33). Data from 2006 to 2013 showed the following: “In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1,665 exposed pregnancies and 220 cases among 6,660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1,852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1,774 exposed pregnancies and 407 cases among 7,096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7,072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1,768 exposed pregnancies and 783 cases among 7,072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2,004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21).” (N. M. Scheller, nims@ssi.dk)
This “carefully conducted postlicensure safety study of HPV vaccine … is a model for others to emulate,” an editorialist adds (
pp. 1280–2). “In the case of HPV vaccine or other vaccines that are not intended for pregnant women but are inadvertently administered to them, postmarketing safety evaluations assume great importance.” (K. M. Edwards)

>>>PNN NewsWatch
* The first drug for primary progressive multiple sclerosis (PPMS),
ocrelizumab (Ocrevus, Genentech) was approved yesterday by FDA for treatment of adults with relapsing forms of multiple sclerosis and PPMS.
*
Envy Me is recalling all lots of LaBri’s Body Health Atomic, a weight-loss dietary supplement, because of undeclared sibutramine.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 31, 2017 * Vol. 24, No. 62
Providing news and information about medications and their proper use

>>>Diabetes Report
Source: Apr. issue of Diabetes Care, with a special section on Emerging Science and Concepts for Management of Diabetes and Aging (2017; 40).
Diabetes & Aging: Discussing the challenges of treating diabetes in older adults, authors introducing the special section write, “The difficulty results from having continued gaps in research that investigates diabetes in older adults, the age-group with the highest prevalence rates of diabetes and the fastest growing segment of the population,” (pp. 440–3). “We also recognize that given the exclusion of older participants from most traditional randomized controlled trials of diabetes interventions, treatment decisions are often made with much uncertainty and need to be individualized. Therefore, future research should allow and account for the complexity of older adults. Beyond broadening the inclusion criteria for randomized controlled trials, we will increasingly need comparative effectiveness studies to assess safety and efficacy of therapies in older adults with diabetes who are particularly vulnerable to adverse effects from overtreatment. Older adults with diabetes are a heterogeneous population ranging from the robust to the frail and represent unique challenges and considerations for both the clinician and researcher that will need to be urgently addressed in the future.” (R. R. Kalyani, rrastogi@jhmi.edu)
Atherosclerotic Disease in Older Adults With Diabetes: Authors present a pragmatic approach to management of atherosclerotic cardiovascular disease (ASCVD) in older adults with diabetes (pp. 476–84): “Older adults with diabetes are at higher risk for [ASCVD] than younger adults with diabetes and older adults without diabetes. The rationale to implement ASCVD risk–lowering therapies in older adults with diabetes is compelling. Recommendations for lifestyle modification, lipid-lowering therapy, blood pressure management, blood glucose control, and aspirin therapy are often based on studies that show their efficacy in younger populations. However, the risks associated with each of these interventions increase with age, and favorable risk-to-benefit ratios demonstrated in younger adults with diabetes are less certain in older populations. The variability in health status among older adults is pertinent. Those with robust health are more likely to tolerate and derive benefit from many therapies when compared with those who have more complex health including frailty. Age- and/or frailty-stratified data to help clarify these relationships are sparse. In this Perspective, current recommendations for modifying ASCVD risk are described with a review of the pertinent literature that guides their application in older adults.” (M. T. Korytkowski, mtk7@pitt.edu)
Lixisenatide in Older Adults With Type 2 Diabetes: In the GetGoal-O Trial, the addition of lixisenatide to current regimens (including insulin) in nonfrail older adults whose type 2 diabetes was not adequately controlled was significantly more effective than placebo (pp. 485–93). A total of 350 patients without risk of malnutrition and without moderate-to-severe cognitive impairment were randomized in the 24-week trial, with these results: “HbA1c decreased substantially with lixisenatide (−0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P <0.0001). Mean reduction in 2-h [postprandial plasma glucose] was significantly greater with lixisenatide (−5.12 mmol/L) than with placebo (−0.07 mmol/L; P <0.0001). A greater decrease in body weight was observed with lixisenatide (−1.47 kg) versus placebo (−0.16 kg; P <0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo.” (G. S. Meneilly, meneilly@mail.ubc.ca)

>>>PNN NewsWatch
* Medicaid enrollees might benefit from policies that require review and justification for use of
methadone for pain, according to investigators who analyzed the effects of methadone’s preferred status in North Carolina and Florida. Compared with South Carolina, where methadone is not a preferred drug, North Carolina and Florida had significantly higher rates of fatal and nonfatal methadone overdose among Medicaid beneficiaries in 2012–13. The report of this research is in this week’s MMWR.

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 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.