Jun 2016

PNN April–June 2016

PNN Pharmacotherapy Line
Apr. 1, 2016 * Vol. 23, No. 63
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Apr. issue of Pediatrics (2016; 137).
Rebound Infantile Hemangiomas After Propranolol: Factors predicting rebound growth of infantile hemangiomas (IH) following therapy with propranolol are identified in a multicenter retrospective cohort study (10.1542/peds.2015-1754). About one quarter of patients experienced rebound growth, the researchers report, particularly girls, those 12–15 months of age at discontinuation, and those having deep IH component: “A total of 997 patients were enrolled. The incidence of rebound growth was 231 of 912 patients (25.3%). Mean age at initial rebound was 17.1 months. The odds of rebound among those who discontinued therapy at <9 months was 2.4 (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.3 to 4.5; P = .004) compared with those who discontinued therapy between 12 to 15 months of life. Female gender, location on head and neck, segmental pattern, and deep or mixed skin involvement were associated with rebound on univariate analysis. With multivariate analysis, only deep IHs (OR: 3.3; 95% CI: 1.9 to 6.0; P < .001) and female gender (OR: 1.7; 95% CI: 1.1 to 2.6; P = .03) were associated. Of those with rebound growth, 83% required therapeutic modification including 62% of patients with modifications in their propranolol therapy.” (S. D. Shah, sonal.shah@ucsf.edu)
Important questions remain concerning rebound hemangiomas growth and beta-blocker therapy, editorialists write (
10.1542/peds.2015-3739): “Is there a dose-response relationship between [oral propranolol (OP)] and IH rebound? Should varied recommendations (weight-based dose and/or treatment duration) be used for IH of different rebound risk? Does OP therapy prolong the proliferative potential of IH? Does the duration of therapy needed to minimize rebound correlate with age at treatment initiation? The field is ripe with opportunities for further study. In the meantime, the results of this large cohort review … will help guide clinicians in optimizing OP therapy and minimizing rebound growth in select higher-risk lesions.” (A. J. Mancini, amancini@northwestern.edu)
Community Pharmacy Partnership in Asthma Intervention: In areas where hospital resources are limited, partnering with community pharmacies can improve population-level asthma outcomes among children hospitalized with asthmatic disorders, a study shows (10.1542/peds.2015-0039). Making sure patients have medications in hand at discharge is an important element in this strategy, the authors add, reporting these results with rapid-cycle improvement methods: “During the intervention period, the median percentage of patients with asthma who received medications in-hand increased from 0% to 82%. A key intervention was the expansion of the medication in-hand program to all patients. Additional changes included expanding team to evening stakeholders, narrowing the number of community partners, and building electronic tools to support key processes. The mean percentage of patients with asthma discharged from the satellite who had a readmission or emergency department revisit within 90 days of their index admission decreased from 18% to 11%.” (H.S. Sauers-Ford)
Varicella Vaccine Effectiveness With 1 or 2 Doses: In a matched case–control study, children who received two doses of varicella vaccine had better protection against community transmission of the causative virus (10.1542/peds.2015-2802). At locations in California and Pennsylvania, investigators found: “One-dose [vaccine effectiveness (VE)] (1-dose versus unvaccinated) was 75.6% (95% confidence interval [CI], 38.7%–90.3%) in preventing any clinically diagnosed varicella and 78.1% (95% CI, 12.7%–94.5%) against moderate or severe, clinically diagnosed disease (≥50 lesions). Among subjects aged ≥4 years, 2-dose VE (2-dose versus unvaccinated) was 93.6% (95% CI, 75.6%–98.3%) against any varicella and 97.9% (95% CI, 83.0%–99.7%) against moderate or severe varicella. Incremental effectiveness (2-dose versus 1-dose) was 87.5% against clinically diagnosed varicella and 97.3% against laboratory-confirmed varicella.” (D. Perella)

>>>PNN NewsWatch
* FDA has approved defibrotide sodium (Defitelio, Jazz Pharmaceuticals) to treat adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after hematopoietic stem cell transplantation.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 4, 2016 * Vol. 23, No. 64
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 2 issue of Lancet (2016; 387).
First-Line Bevacizumab for Pleural Mesothelioma: Overall survival (OS) was significantly improved by addition of bevacizumab to pemetrexed/cisplatin therapy in a group of patients with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, researchers report (pp. 1405–14). At 73 hospitals in France, these results were recorded in an open-label, phase 3 trial of pemetrexed plus cisplatin with (PCB) or without (PC) bevacizumab: “From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18.8 months [95% CI 15.9–22.6]) than with PC (16.1 months [14.0–17.9]; hazard ratio 0.77 [0.62–0.95]; p = 0.0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC.” (G. Zalcman, gerard.zalcman@aphp.fr)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Pioglitazone & Bladder Cancer: Pioglitazone but not rosigliazone use appears to be linked to higher risks of bladder cancer, according to results of a large population study conducted using the U.K. Clinical Practice Research Databank (i1541). Assessing 145,806 patient records for 2000–13 with follow-up into 2014, the investigators found these results using Cox proportional hazards: “The cohort generated 689,616 person years of follow-up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100,000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100,000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100,000 person years; 1.10, 0.83 to 1.47). Duration-response and dose-response relations were observed for pioglitazone but not for rosiglitazone.” (L. Azoulay, laurent.azoulay@mcgill.ca)
Diabetes Progression & Antidiabetic Therapies: Patients with type 2 diabetes who are treated with metformin-based triple therapy have significantly lower risks of progression to blindness but also greater risks of hypoglycemia, according to an open cohort study conducted in 1,243 U.K. primary care practices (i1450). Data from the QResearch files for 469,688 English patients in 2007–15 led authors to this conclusion regarding monotherapy and combination therapy with glitazones, gliptins, metformin, sulphonylureas, insulin, and other hypoglycemic agents: “We have found lower risks of hyperglycaemia among patients prescribed dual therapy involving metformin with either gliptins or glitazones compared with metformin alone. Compared with metformin monotherapy, triple therapy with metformin, sulphonylureas, and either gliptins or glitazones was associated with an increased risk of hypoglycaemia, which was similar to the risk for dual therapy with metformin and sulphonylureas. Compared with metformin monotherapy, triple therapy with metformin, sulphonylureas, and glitazones was associated with a reduced risk of blindness. These results, while subject to residual confounding, could have implications for the prescribing of hypoglycaemic drugs.” (J. Hippisley-Cox, Julia.hippisley-cox@nottingham.ac.uk)

>>>PNN JournalWatch
* Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial, in
Diabetes Care, 2016; 39: 596–602. (J. Wahren, john.wahren@ki.se)
* Type 1 Diabetes and Polycystic Ovary Syndrome: Systematic Review and Meta-analysis, in
Diabetes Care, 2016; 39: 639–48. (H. F. Escobar-Morreale, hectorfrancisco.escobar@salud.madrid.org)
* Management of Neonates Born to Mothers With Graves’ Disease, in
Pediatrics, 2016; 137: 10.1542/peds.2015-1878. (D. C. M. van der Kaay)
* Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis, in
Pediatrics, 2016; 137: 10.1542/peds.2015-1784. (T. Lahiri)
* Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders, in
American Journal of Psychiatry, 2016; 173: 344–61. (C. E. Wilcox)
* Nabilone for the Management of Pain, in
Pharmacotherapy, 2016; 36: 273–86. (C. C. Tsang, cotsang@toh.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 5, 2016 * Vol. 23, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Apr. 5 issue of the Annals of Internal Medicine (2016; 164).
ACP Calls for Action on Prescription Drug Prices: The American College of Physicians last week issued two position papers in response to the rapid escalation in prices of prescription drugs (10.7326/M15-2768). In “Stemming the Escalating Cost of Prescription Drugs,” ACP makes seven recommendations, including improving transparency in pricing, cost, and comparative value of all pharmaceutical products; eliminating restriction on use of quality-adjusted life–years in research funded by the Patient-Centered Outcomes Research Institute; allowing Medicare and other publicly funded health programs to negotiate volume discounts on prescription drug prices and pursue bulk purchasing agreements; permitting safe reimportation of medications and increasing competition among brand-name and generic sole-source drugs; and opposing extension of market or data exclusivity periods for small-molecule, generic, orphan, and biologic drugs.
An ACP policy on formularies and pharmacy benefit management supports use of a “drug’s effectiveness, safety, and ease of administration rather than solely … cost” in formulary decisions and in evaluations of physician prescribing patterns. The College also “recommends that formularies should be constructed so that physicians have the option of prescribing drugs that are not on the formulary (based on objective data to support a justifiable, medically indicated cause) without cumbersome prior authorization requirements.” (H. Daniel,
hdaniel@mail.acponline.org)
Oral Prednisolone in Acute Gout: A study from four emergency departments (EDs) in Hong Kong supports use of oral prednisolone as a first-line alternative to indomethacin in patients with acute gout (pp. 464–71). Seeking to confirm results of two recent randomized trials with small sample sizes, investigators compared the two drugs in 416 adult patients presenting with acute gout, with these results: “376 patients completed the study. Equivalent and clinically significant within-group reductions in mean pain score were observed with indomethacin and prednisolone in the ED (approximately 10 mm [rest] and 20 mm [activity]) and from days 1 to 14 (approximately 25 mm [rest] and 45 mm [activity]). No major adverse events occurred during the study. During the ED phase, patients in the indomethacin group had more minor adverse events than those in the prednisolone group (19% vs. 6%; P < 0.001). During days 1 to 14, 37% of patients in each group had minor adverse events.” (T. H. Rainer, rainerth@cardiff.ac.uk)
ESAs & HRQOL in Anemia of Chronic Kidney Disease: In patients with anemia of chronic kidney disease (CKD), use of erythropoietin-stimulating agents (ESAs) to achieve higher hemoglobin target levels does not result in “important differences” in health-related quality of life (HRQOL), authors of a systematic review and meta-analysis conclude (pp. 472–8): “Of 17 eligible studies, 13 reported [Short Form-36 Health Survey (SF-36)] outcomes and 4 reported [Kidney Dialysis Questionnaire (KDQ)] outcomes. Study populations consisted of patients not undergoing dialysis (n = 12), those undergoing dialysis (n = 4), or a mixed sample (n = 1). Only 4 studies had low risk of bias. Pooled analyses showed that higher hemoglobin targets resulted in no statistically or clinically significant differences in SF-36 or KDQ domains. Differences in HRQOL were further attenuated in studies at low risk of bias and in subgroups of dialysis recipients.” (N. Tangri, ntangri@sogh.mb.ca)
Sharing Clinical Trial Data: The International Committee of Medical Journal Editors is calling for authors of clinical trials to “share with others the deidentified individual-patient data underlying the results presented in the article (including tables, figures, and appendices or supplementary material) no later than 6 months after publication” (pp. 505–6; D. B. Taichman, dtaichman@acponline.org).

>>>PNN NewsWatch
* FDA on Friday alerted health professionals and patients not to use unexpired drug products that are intended to be sterile that were produced by Medaus Pharmacy in Birmingham, AL, due to lack of sterility assurance. Medaus’s products were distributed nationwide and internationally.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 6, 2016 * Vol. 23, No. 66
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
JAMA articles released in conjunction with ACC.16.
Muscle-Related Statin Intolerance: In patients with statin intolerance secondary to muscle-related adverse effects, the PCSK9 inhibitor evolocumab provides a more effective alternative than ezetimibe, according to results of the GAUSS-3 randomized clinical trial (10.1001/jama.2016.3608). Patients received atorvastatin 20 mg or placebo in the 24-week crossover phase A of the trial, followed in phase B by subcutaneous evolocumab 420 mg monthly or oral ezetimibe 10 mg daily for 24 weeks.
Results showed: “Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).” (S. E. Nissen,
nissens@ccf.org)
Citing the impressive “legacy effect of statins,” editorialists write, “PCSK9 inhibitors are just starting out. Whether PCSK9 inhibitors will have the same impressive long-term outcomes will not be known for many years” (
10.1001/jama.2016.3670). “There are several arguments against [treatment of statin-intolerant patients with PCSK9 inhibitors]. First, PCSK9 inhibitors are not approved for this indication. Although preliminary results are encouraging and large, long-term outcome trials are well under way, PCSK9 inhibitors have not yet been shown to reduce cardiovascular events. Second, one-fifth of the statin-intolerant patients in GAUSS-3 still reported muscle-related adverse effects while taking evolocumab. Third, a 1-year supply of either alirocumab or evolocumab currently costs approximately $14,000.” (D. D. Waters, david.waters@ucsf.edu)
Losmapimod in Acute Myocardial Infarction: In the phase 3 LATITUDE-TIMI 60 trial, the p38 MAPK inhibitor losmapimod did not reduce the risk of major ischemic cardiovascular events in patients hospitalized with myocardial infarction (MI), compared with placebo (10.1001/jama.2016.3609). “The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” the authors conclude. “The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91–1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo.” (M. L. O’Donoghue, modonoghue@partners.org)

>>>PNN NewsWatch
* FDA yesterday approved Inflectra (infliximab-dyyb, Celltrion/Hospira), biosimilar to Remicade, for several indications.
* New warnings are being added to
saxagliptin and alogliptin labels cautioning of increased risk of heart failure in patients using the drugs, especially those with heart or kidney disease. Health professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control, FDA advised.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 7, 2016 * Vol. 23, No. 67
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Apr. 7 issue of the New England Journal of Medicine (2016; 374).
Antenatal Betamethasone for Late Preterm Delivery: In pregnant women at risk for late preterm delivery, betamethasone significantly reduced the rate of neonatal respiratory complications, compared with placebo (pp. 1311–20). Study participants had singleton pregnancies and were at 34 weeks to 36 weeks 5 days of their pregnancies on study admission. Two injections of betamethasone or placebo 24 hours apart produced these outcomes based on a primary outcome of neonatal respiratory complications in the first 72 hours after birth: “The primary outcome occurred in 165 of 1,427 infants (11.6%) in the betamethasone group and 202 of 1,400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P = 0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P <0.001).” (C. Gyamfi–Bannerman, cg2231@cumc.columbia.edu)
“Do the benefits of using antenatal glucocorticoids before late preterm birth outweigh the risks?” editorialists ask (
pp.1376–7). Perhaps, as “the potential benefits may be underestimated” by this trial, which excluded women with multiple gestations and diabetes and therefore were at highest risk. However, the frequency of neonatal hypoglycemia with glucocorticoids is a concern, they add, noting: “Neonatal hypoglycemia has been reported to be the only independent risk factor for later developmental delay among moderate or late preterm infants.” (C. A. Crowther)
Pioglitazone After Ischemic Stroke/TIA: Testing the impact of lowered insulin resistance in patients without diabetes who had ischemic stroke or transient ischemic attack (TIA), investigators found a lower risk of a primary outcome of fatal or nonfatal stroke or myocardial infarction with pioglitazone treatment (pp. 1321–31). A total of 3,876 patients with recent ischemic stroke or TIA received pioglitazone dosed to a target of 45 mg/d or placebo. Results showed: “By 4.8 years, a primary outcome had occurred in 175 of 1,939 patients (9.0%) in the pioglitazone group and in 228 of 1,937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P = 0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P <0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P = 0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P <0.001), edema (35.6% vs. 24.9%, P <0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P = 0.003).” (W. K. Kernan, walter.kernan@yale.edu)
“Insulin-sensitizing drugs have been exalted as metabolic saviors and vilified as a threat to public health,” an editorialist writes (
pp. 1378–9). Referring to a line from a Grateful Dead tune, he notes, “The trip has been long and strange, but it may yet lead to strategies for improving the health of people like Jerry Garcia, whose premature death was related to insulin resistance.” (C. F. Semenkovich)
Chemotherapy in Low-Grade Glioma: Progression-free survival and overall survival were improved among 251 patients with grade 2 glioma who received combination chemotherapy in addition to radiation therapy, compared with radiation alone, a study shows (pp. 1344–55). From a median follow-up period of 11.9 years, researchers report: “Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P = 0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%.” (J. C. Buckner, buckner.jan@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 8, 2016 * Vol. 23, No. 68
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (2016; 149).
Warfarin Therapy in AF/CKD: In patients with end-stage chronic kidney disease (CKD), treatment of atrial fibrillation (AF) with warfarin has an “unfavorable risk/benefit ratio,” researchers report based on a systematic review and meta-analysis (pp. 951–9). Those with non-end-stage CKD have a more favorable benefit scenario, the groups writes, adding these details: “Thirteen publications from 11 cohorts (six retrospective and five prospective) including >48,500 total patients with >11,600 warfarin users were included in the meta-analysis. In patients with AF and non-end-stage CKD, warfarin resulted in a lower risk of ischemic stroke/thromboembolism (HR, 0.70; 95% CI, 0.54–0.89; P = .004) and mortality (HR, 0.65; 95% CI, 0.59–0.72; P <.00001), but had no effect on major bleeding (HR, 1.15; 95% CI, 0.88–1.49; P = .31). In patients with AF and end-stage CKD, warfarin had no effect on the risks of stroke (HR, 1.12; 95% CI, 0.69–1.82; P = .65) and mortality (HR, 0.96; 95% CI, 0.81–1.13; P = .60), but increased the risks of major bleeding (HR, 1.30; 95% CI, 1.08–1.56; P = .005).” (J. Lee)
Oral Anticoagulation for AF With Other Stroke Risk Factors: Patients with atrial fibrillation (AF) and one additional risk factor for stroke have an improved prognosis when treated with oral anticoagulation (OAC), according to an analysis of data on 8,962 patients in 2000–10 (pp. 960–8). Risk factors include congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or thromboembolism, vascular disease, age 65–74 years, and sex category (CHA2DS2-VASc score = 1 in men, 2 in women). Comparing the 53% of patients who received with OAC against the rest of this group, the investigators found: “Over a follow-up of 979 ± 1,158 days, 151 (7%) had a major adverse event (stroke/systemic thromboembolism/death). Prescription of OAC was not associated with a better prognosis for stroke/systemic thromboembolism/death for patients in the ‘low-risk’ category (ie, CHA2DS2-VASc score = 0 for men or 1 for women; adjusted hazard ratio [HR], 0.68; 95% CI, 0.35–1.31; P = .25). OAC use was independently associated with a better prognosis in patients with AF with a single additional stroke risk factor (ie, CHA2DS2-VASc score = 1 in men, 2 in women; adjusted HR, 0.59; 95% CI, 0.40–0.86; P = .007).” (L. Fauchier)
Azithromycin in Treatment-Resistant Cough: Other than a possible benefit in patients with asthma, 8 weeks of therapy with the macrolide azithromycin in those with treatment-resistant chronic cough was not beneficial, a study shows (pp. 1052–60). Using the Leicester Cough Questionnaire (LCQ) score for evaluation, investigators randomized 44 patients with treatment-resistant cough to azithromycin 250 mg three times per week or placebo, with these results: “There was a clinically important improvement in LCQ score with azithromycin (mean change, 2.4; 95% CI, 0.5 to 4.2) but not placebo (mean change, 0.7; 95% CI, −0.6 to 1.9), but the between-group difference was not statistically significant (P = .12). There were no significant between-group differences for any of the secondary outcome measures. Looking at subgroups of responders, there was a large and significant improvement in LCQ score in patients with chronic cough and a concurrent diagnosis of asthma who were treated with azithromycin (mean, 6.19; 95% CI, 4.06 to 8.32).” (T. Harrison)

>>>Cardiology Report
Source:
Apr. 12 issue of the Journal of the American College of Cardiology (2016; 67).
Aspirin Dose in PPI-Treated Patients on Dual Antiplatelet Therapy: In the COGENT trial, gastroprotection with PPIs was important in patients with coronary artery disease receiving both low- and high-dose aspirin therapy as part of a dual antiplatelet therapy regimen (pp. 1661–71). Over a median follow-up period of 110 days, “randomization to PPI therapy reduced 180-day Kaplan–Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group,” the researchers report. Compared with low-dose aspirin, high-dose aspirin was associated with similar risks of composite gastrointestinal events and major adverse cardiac events. (M. Vaduganathan)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 11, 2016 * Vol. 23, No. 69
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 9 issue of Lancet (2016; 387).
Pembrolizumab for Nonsmall-Cell Lung Cancer: New “data establish pembrolizumab as a new treatment option … and validate the use of PD-L1 selection” in previously treated, PD-L1-positive, advanced nonsmall-cell lung cancer, authors conclude based on a study of 1,034 patients (pp. 1540–50). The open-label, phase 2/3 trial compared two doses of pembrolizumab with docetaxel, each administered every 3 weeks, with these results: “Median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58–0.88; p = 0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49–0.75; p <0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74–1.05; p = 0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66–0.94; p = 0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38–0.77; p = 0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36–0.70; p <0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44–0.78; p = 0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45–0.78; p <0.0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).” (R. S. Herbst, roy.herbst@yale.edu)
Daratumumab in Refractory Multiple Myeloma: In an ongoing study that to date has included 106 heavily pretreated and refractory patients with multiple myeloma, daratumumab monotherapy is showing “encouraging efficacy … with a favourable safety profile,” researchers report (pp. 1551–60). Based on a primary endpoint of overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR), the investigators found these results with the novel CD38-targeted monoclonal antibody: “Patients received a median of five previous lines of therapy (range 2–14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8–38.9)—three (2.8%, 0.6–8.0) had a stringent CR, ten (9.4%, 4.6–16.7) had a very good PR, and 18 (17.0%, 10.4–25.5) had a PR. The median time to first response was 1.0 month (range 0.9–5.6). Median duration of response was 7.4 months (95% CI 5.5–not estimable) and progression-free survival was 3.7 months (95% CI 2.8–4.6). The 12-month overall survival was 64.8% (95% CI 51.2–75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7–not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation.” (S. Lonial, sloni01@emory.edu)

>>>PNN JournalWatch
* Worldwide Trends in Diabetes Since 1980: A Pooled Analysis of 751 Population-Based Studies With 4.4 Million Participants, in
Lancet, 2016; 387: 1513–30. (NCD Risk Factor Collaboration)
* Early Administration of Epinephrine (Adrenaline) in Patients With Cardiac Arrest With Initial Shockable Rhythm in Hospital: Propensity Score Matched Analysis, in
BMJ, 2016; 353: i1577. (M. Donnino, mdonnino@bidmc.harvard.edu)
* Family-Based Approaches to Cardiovascular Health Promotion, in
Journal of the American College of Cardiology, 2016; 67: 1725–37. (R. Vedanthan)
* Contemporary Reviews in Cardiovascular Medicine: Peripartum Cardiomyopathy, in
Circulation, 2016; 133: 1397–409. (Z. Arany, zarany@mail.med.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 12, 2016 * Vol. 23, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. issue of and early-release articles from JAMA Internal Medicine (2016; 176).
Polypharmacy in Older Patients: “Pharmacists, nurses, and other health care professionals can be creatively engaged to systematize the process of medication monitoring and follow-up, complementing the role of the physician,” editorialists write (pp.482–3) in response to a study of medication use in older patients released in advance of print (see PNN, Mar, 22; pp. 473–82; D. M. Qato, dimaqato@uic.edu). Three changes are needed for the inappropriate use of drugs to be reduced: a comprehensive, portable, and truly informative medication list that the patient helps to maintain, a team approach to monitoring medication effectiveness and adverse effects, and real patient engagement, supported by the whole health care team, the writers note, adding “None of this is easy, but it is achievable. Advances in technology and meaningful use requirements set the stage for a truly useful, ‘living’ medication list. The growth of the patient-centered medical home creates a foundation for team-based care. Readmission penalties and the assumption of financial risk by health systems are aligning incentives to keep patients healthy and happy by increasing their engagement in their care.” (M. A. Steinman, mike.steinman@ucsf.edu)
Preventing Hospital Readmissions: About one quarter of hospital readmissions are preventable, a study finds, and acting to improve this metric will require “improved communication among health care teams and between health care professionals and patients, greater attention to patients’ readiness for discharge, enhanced disease monitoring, and better support for patient self-management,” authors conclude (pp. 484–93). Over 12 months in 2012–13, 1,000 general medicine patients readmitted at 12 U.S. academic medical centers had these characteristics: “269 (26.9%) [readmissions] were considered potentially preventable. In multivariable models, factors most strongly associated with potential preventability included emergency department decision making regarding the readmission (aOR, 9.13; 95% CI, 5.23–15.95), failure to relay important information to outpatient health care professionals (aOR, 4.19; 95% CI, 2.17–8.09), discharge of patients too soon (aOR, 3.88; 95% CI, 2.44–6.17), and lack of discussions about care goals among patients with serious illnesses (aOR, 3.84; 95% CI, 1.39–10.64). The most common factors associated with potentially preventable readmissions included emergency department decision making (affecting 9.0%; 95% CI, 7.1%–10.3%), inability to keep appointments after discharge (affecting 8.3%; 95% CI, 4.1%–12.0%), premature discharge from the hospital (affecting 8.7%; 95% CI, 5.8%–11.3%), and patient lack of awareness of whom to contact after discharge (affecting 6.2%; 95% CI, 3.5%–8.7%).” (A. D. Auerbach, andrew.auerbach@ucsf.edu)
Despite lowering readmissions by nearly 10%, a large-scale effort targeting high-risk patients failed to achieve goal reductions set by CMS, according to a report released in advance of print (
10.1001/jamainternmed.2016.0833). The quasi-experimental evaluation used personalized transitional care—including education, medication reconciliation, follow-up telephone calls, and linkage to community resources—to produce these outcomes among older Medicare fee-for-service beneficiaries residing near an academic medical center: “The adjusted readmission rate decreased from 21.5% to 19.5% in the target population and from 21.1% to 21.0% in the control population, a relative reduction of 9.3%. The number needed to treat to avoid 1 readmission was 50. In a difference-in-differences analysis using a logistic regression model, the odds of readmission in the target population decreased significantly more than that of the control population in the intervention period (odds ratio, 0.90; 95% CI, 0.83–0.99; P = .03). In a comparative interrupted time series analysis of the difference in monthly adjusted admission rates, the target population decreased an absolute −3.09 (95% CI, −6.47 to 0.29; P = .07) relative to the control population, a similar but nonsignificant effect.” (L. I. Horwitz, leora.horwitz@nyumc.org)

>>>PNN NewsWatch
* FDA yesterday approved the breakthrough, orphan agent venetoclax (Venclexta, AbbVie/Genentech) for second-line treatment of chronic lymphocytic leukemia with 17p deletion.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 13, 2016 * Vol. 23, No. 71
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Apr. 12 issue of JAMA (2016; 315).
Dexmedetomidine in Agitated Delirium: Addition of dexmedetomidine to standard care of agitated delirium in patients on mechanical ventilation in intensive care units (ICUs) resulted in more ventilator-free hours on day 7, researchers report (pp. 1460–8). In the Dexmedetomidine to Lessen ICU Agitation (DahLIA) parallel-group study, 74 adult patients in 15 ICUs in Australia and New Zealand were randomized to titrated dexmedetomidine or placebo, with these results: “Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P <.001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007).” (M. C. Reade, m.reade@uq.edu.au)
While the clinical benefits demonstrated in the DahLIA trial are important and the study demonstrates clinical advantages of dexmedetomidine in many ICU patients with complications, editorialists add that the “study must be viewed with a wide-angle lens looking back 15 years to appreciate its place among this genre of articles that have changed the view of the patient and the scenery of the ICU” (
pp. 1455–6): “In 2001, when the Confusion Assessment Method-ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) validation studies were published, only about 10 articles per year appeared on ICU delirium. At that time, the concept of ‘ICU psychosis’ was still widely used, incorrectly suggesting that confusion among ICU patients may have been an innocent bystander accompanying critical illness. Subsequent reports have added to the understanding of delirium among critically ill patients, and to the armamentarium of tools and prognostic information available to clinicians, such that today, an estimated 300 articles on ICU delirium are published each year.” (E. W. Ely, wes.ely@vanderbilt.edu)
Secondary Infections Among ICU Patients With Sepsis: In a Dutch prospective observational study of admissions to ICUs in 2011–13 at two hospitals, secondary infections in patients admitted for sepsis were more common among those with higher disease severity but contributed “only modestly to overall mortality” (pp. 1469–79). “The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection,” the authors add. (L. A. van Vught, l.a.vanvught@amc.uva.nl)
DIY Mobile App for Diabetes: Lessons from the Nightscout Project are examined in a Viewpoint article (pp. 1447–8). The do-it-yourself, patient-designed mobile app enables remote monitoring of continuous glucose monitoring systems using mobile technology. The project began when a programmer developed computer code to monitor his son’s results during the school day. It rapidly expanded to about 40 users through a Facebook group. In 18 months, this group has grown to include 15,000 members in the U.S. and 4,000 in other countries. Issues of safety, legal liability, regulatory challenges, and access are discussed in the article, which concludes, “As the Nightscout Project continues to develop and unfold, the questions it raises should lead to greater opportunities for patients and their families to help drive innovation in the health care delivery system.” (J. M. Lee, joyclee@umich.edu)

>>>PNN NewsWatch
* Presence of undeclared sibutramine, desmethylsibutramine, and/or phenolphthalein in Super Herbs could present a “significant risk” to patients with histories of coronary artery disease, congestive heart failure, arrhythmias, or stroke, FDA said. Promoted for weight loss, the dietary supplement is being recalled and discontinued by the manufacturer.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 14, 2016 * Vol. 23, No. 72
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Apr. 14 issue of the New England Journal of Medicine (2016; 374).
FDA Response to Prescription Opioid Abuse: Writing as the Department of Health and Human Services rolls out a campaign to cope with opioid misuse, FDA officials describe these issues as requiring response by that agency (pp. 1480–5):
* Balancing individual need and societal risk
* Meeting the need for timely action
* Reviewing labeling and postmarketing surveillance requirements
* Prioritizing abuse-deterrent formulations and overdose treatments
* Addressing the lack of nonopioid alternatives for pain management
* Creating clear guidelines for opioid use
* Managing pain in children
* Developing a better evidence base
“Nationally, the annual number of deaths from opioid overdoses now exceeds the number of deaths caused by motor vehicle accidents,” the authors conclude. “Regardless of whether we view these issues from the perspective of patients, physicians, or regulators, the status quo is clearly not acceptable. As the public health agency responsible for oversight of pharmaceutical safety and effectiveness, we recognize that this crisis demands solutions. We are committed to action, and we urge others to join us.” (R. M. Califf)
Fusion in Lumbar Spinal Stenosis: Two studies in this issue report negative or mixed results with the addition of fusion to decompression surgery for lumbar spinal stenosis (pp. 1413–23, P. Försth, peter.forsth@surgsci.uu.se; pp. 1424–34, Z. Ghogawala, zoher.ghogawala@lahey.org). Editorialists note that surgeries using both decompression and fusion increased in number during 2002–07, while surgical decompression surgeries declined during that period (pp. 1478–9). “The goal of surgery in lumbar spinal stenosis is to improve walking distance and to relieve pain by decompression of nerve roots,” the editorialists conclude. “The addition of instrumented fusion—’just to be sure’—for the treatment of the most frequent forms of lumbar spinal stenosis does not create any added value for patients and might be regarded as an overcautious and unnecessary treatment.” (W. C. Peul)
Treating Diabetic Sensory and Motor Neuropathy: “Agents that have proved to be effective in randomized trials involving patients with distal predominantly sensory neuropathy and that are most commonly used for treatment include pregabalin or gabapentin, tricyclic antidepressants, and [serotonin–norepinephrine reuptake inhibitors],” concludes the author of a case vignette on diabetic sensory and motor neuropathy (pp. 1455–64). Based on the clinical and overall situation of a 65-year-old woman with a 5-year history of type 2 diabetes, the author notes: “Since this patient has a sleep disturbance, pregabalin or gabapentin may be appropriate first choices, but monitoring will be required for weight gain, fluid retention, and diminished glycemic control. It would be best to start with lower doses (e.g., 75 mg of pregabalin twice daily) and to adjust the dose upward if there is no reduction in pain within the first 2 weeks. If there is no response after 1 month of treatment, a switch to an agent from another drug class would be advisable. If the vitamin B12 level is below 450 pg per milliliter, supplementation with oral methylcobalamin (2000 µg per day) could be initiated, although there are as yet no data that show that supplementation reduces neuropathy in the absence of frank deficiency. Alpha lipoic acid can be given to relieve pain (starting at a twice-daily oral dose of 300 mg), although formal studies of its use in this regard have not been conducted.” (A. I. Vinik, vinikai@evms.edu)
Metronidazole-Associated Encephalopathy: MRI images of metronidazole-associated encephalopathy are presented in an Images in Clinical Medicine article (p. 1465). The patient had been taking 500-mg doses of the drug three times daily for more than 3 weeks when dysarthria and gait instability—hallmark signs of this condition—resulted in a fall at home. “Risk factors [for metronidazole-associated encephalopathy] include liver dysfunction and a prolonged course of metronidazole (typical cumulative dose, >20 g),” the author writes. “MRI of the brain is usually diagnostic and typically reveals a symmetric, enhanced [fluid-attenuated inversion recovery (FLAIR)] signal in the dentate nuclei of the cerebellum.” (D. Farmakiotis, dfarmakiotis@windowslive.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 15, 2016 * Vol. 23, No. 73
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
May 1 issue of Clinical Infectious Diseases (2016; 62).
Reversing HCV Epidemic Through Antiviral Therapy: Scaled-up treatment with direct-acting antivirals (DAAs) could help stem an epidemic of hepatitis C virus (HCV) among men who have sex with men (MSM) in the U.K., an epidemiologic study shows (pp. 1072–80). Moderately effective behavioral interventions are also needed, the group reports, adding this analysis based on data from a dynamic HCV transmission model that considered HIV-diagnosed MSM in the U.K. Collaborative HIV Cohort (UK CHIC): “HCV prevalence among HIV-positive MSM in UK CHIC increased from 7.3% in 2004 to 9.9% in 2011, whereas primary incidence was flat (1.02–1.38 per 100 person–years). Over the next decade, modeling suggests 94% of infections are attributable to high-risk individuals, comprising 7% of the population. Without treatment, HCV chronic prevalence could have been 38% higher in 2015 (11.9% vs 8.6%). With current treatment and sustained virological response rates (status quo), chronic prevalence is likely to increase to 11% by 2025, but stabilize with DAA introduction in 2015. With DAA scale-up to 80% within 1 year of diagnosis (regardless of disease stage), and 20% per year thereafter, chronic prevalence could decline by 71% (to 3.2%) compared to status quo in 2025. With additional behavioral interventions, chronic prevalence could decline further to <2.5% by 2025.” (N. K. Martin, natasha-martin@ucsd.edu)
Prior-Year Influenza Vaccination & High-Dose Vaccine: Regardless of vaccination in the previous year with either high-dose inactivated influenza vaccine (IIV-HD) or inactivated influenza vaccine (IIV-SD), older adults benefit from use of IIV-HD the following year (Y2), researchers report (pp. 1092–9). A subset of year 1 (Y1) patients in a clinical trial were randomized to standard-dose or high-dose vaccine in Y2, with these effects on vaccine efficacy (VE), hemagglutination inhibition (HAI) titers, and safety: “Of 14,500 Y1 participants, 7,643 reenrolled in Y2. Relative to participants who received IIV-SD both seasons, VE was higher for IIV-HD vaccinees in Y2 (28.3% overall; 25.1% for Y1 IIV-HD, Y2 IIV-HD; and 31.6% for Y1 IIV-SD, Y2 IIV-HD). In multivariate logistic regression models, Y1 vaccine was not a significant modifier of Y2 VE (P = .43), whereas Y2 IIV-HD remained significantly associated with lower influenza risk (P = .043). Compared to administration of IIV-SD in both years, postvaccination HAI titers were significantly higher for patterns that included IIV-HD in Y2. No safety concerns were raised with IIV-HD revaccination.” (C. A. DiazGranados, carlos.diazgranados@sanofipasteur.com)
Contemporary Pertussis Vaccines: A systematic review and meta-analysis shows similar effects of currently available formulations of acellular pertussis (aP) and whole-cell (wP) pertussis vaccines during the first 3 years following vaccination (pp. 1100–10). Using a primary outcome of pertussis infections based on WHO clinical case definitions, the study found these outcomes in patients completing more than three doses of a primary series of aP or wP vaccine formulations: “Meta-analysis of 2 aP vaccine efficacy studies (assessing the 3-component GlaxoSmithKline and 5-component Sanofi-Pasteur formulations) yielded an overall aP vaccine efficacy of 84% (95% confidence interval [CI], 81%–87%). Meta-analysis of 3 wP vaccine effectiveness studies (assessing the Behringwerke, Pasteur/Mérieux, and SmithKline Beecham formulations) yielded an overall wP vaccine effectiveness of 94% (95% CI, 88%–97%) (both I2 = 0%).” (S. B. Omer, somer@emory.edu)
Durability of Tetanus/Diphtheria Immunity: In 546 adults, investigators find “durable levels of protective antitoxin immunity” against tetanus and diphtheria in most patients (pp. 1111–8): “Antibody responses to tetanus declined with an estimated half-life of 14 years (95% confidence interval, 11–17 years), whereas antibody responses to diphtheria were more long-lived and declined with an estimated half-life of 27 years (18–51 years). Mathematical models combining antibody magnitude and duration predict that 95% of the population will remain protected against tetanus and diphtheria for ≥30 years without requiring further booster vaccination.” (M. K. Slifka, slifkam@ohsu.edu)

>>>PNN NewsWatch
* Particulate matter has prompted Hospira to recall one lot of 50% Magnesium Sulfate Injection.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 18, 2016 * Vol. 23, No. 74
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 16 issue of Lancet (2016; 387).
Oral Misoprostol For Labor Induction: For pregnant women with unfavorable cervix requiring induction of labor, oral misoprostol is as effective a Foley catheter, researchers report (pp. 1619–28). In the PROBAAT-II trial at 29 Dutch hospitals, open-label randomization to oral misoprostol 50 mcg once every 4 hours or transcervical Foley catheter produced these results: “Between July, 2012, and October, 2013, we randomly assigned 932 women to oral misoprostol and 927 women to Foley catheter. The composite primary outcome [of asphyxia or postpartum hemorrhage] occurred in 113 (12.2%) of 924 participants in the misoprostol group versus 106 (11.5%) of 921 in the Foley catheter group (adjusted relative risk 1.06, 90% CI 0.86–1.31). Caesarean section occurred in 155 (16.8%) women versus 185 (20.1%; relative risk 0.84, 95% CI 0.69–1.02, p = 0.067). 27 adverse events were reported in the misoprostol group versus 25 in the Foley catheter group. None were directly related to the study procedure.” (M. L. G. ten Eikelder, m.teneikelder@gmail.com)
Eribulin in Advanced Liposarcoma, Leiomyosarcoma: Building on favorable phase 2 findings, phase 3 investigators conclude that “eribulin could be a treatment option for advanced soft-tissue sarcoma” based on its improvement in overall survival compared with active control (pp. 1629–37). Previously treated adults with intermediate- or high-grade advanced liposarcoma or leiomyosarcoma had these responses after randomization to eribulin mesylate or dacarbazine: “[In 2011–13], we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13.5 months [95% CI 10.9–15.6] vs 11.5 months [9.6–13.0]; hazard ratio 0.77 [95% CI 0.62–0.95]; p = 0.0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators.” (P. Schöffski, patrick.schoffski@uzleuven.be)
Geographic Patterns of Use of & Barriers to Access to Opioids: Despite increases in use of opioid analgesics in many countries, barriers to access to the drugs continue to contribute to low use in several parts of the world, a study shows, including Africa, Asia, Central America, the Caribbean, South America, and eastern and southeastern Europe (pp. 1644–56). Calculations of defined daily doses for statistical purposes (S-DDD) per million inhabitants per day show these patterns for 2001–13: “The S-DDD of opioid analgesic use more than doubled worldwide between 2001–03 and 2011–13, from 1,417 S-DDD (95% CI −732 to 3,565; totalling about 3.01 billion defined daily doses per annum) to 3,027 S-DDD (−1,162 to 7,215; totalling about 7.35 billion defined daily doses per annum). Substantial increases occurred in North America (16,046 S-DDD [95% CI 4,032–28,061] to 31,453 S-DDD [8,121–54,785]), western and central Europe (3,079 S-DDD [1,274–4,883] to 9,320 S-DDD [3,969–14,672]), and Oceania (2,275 S-DDD [763–3,787] to 9,136 S-DDD [2,508–15,765]). Countries in other regions have shown no substantial increase in use. Impediments to use included an absence of training and awareness in medical professionals, fear of dependence, restricted financial resources, issues in sourcing, cultural attitudes, fear of diversion, international trade controls, and onerous regulation. Higher number of impediments reported was significantly associated with lower use (unadjusted incidence rate ratio 0.39 [95% CI 0.29–0.52]; p <0.0001), but not when adjusted for gross domestic product and human development index (0.91 [0.73–1.14]; p = 0.4271).” (S. Berterame, stefano.berterame@incb.org)

>>>PNN JournalWatch
* Should the Benefit of Adjuvant Chemotherapy in Colon Cancer Be Re-Evaluated?, in
Journal of Clinical Oncology, 2016; 34: 1297–9. (B. Glimelius, bengt.glimelius@igp.uu.se)
* Does Atopic Dermatitis Cause Food Allergy? A Systematic Review, in
Journal of Allergy and Clinical Immunology, 2016; 137: 1071–8. (C. Flohr, carsten.flohr@kcl.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 19, 2016 * Vol. 23, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Apr. 19 issue of the Annals of Internal Medicine (2016; 164).
First-Line Drug Treatment of Type 2 Diabetes: Metformin outperforms sulfonylureas for initial pharmacotherapy in patients with type 2 diabetes, according to a systematic review and meta-analysis of 179 trials and 25 observational studies (10.7326/M15-2650). Authors cite metformin’s relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality in reaching this conclusion. “On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies,” the group writes, adding these details: “Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that [dipeptidyl peptidase-4 (DPP-4)] inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, [glucagon-like peptide-1 (GLP-1)] receptor agonists, and [sodium–glucose cotransporter 2 [SGLT-2] inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors.” (N. M. Maruthur, maruthur@jhmi.edu)
Rheumatoid Arthritis With Tight Control: Early, temporary combination therapy in patients with rheumatoid arthritis provides optimal 10-year outcomes, a study shows, and “drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes” (pp. 523–31). A comparison of four strategies (sequential monotherapy [strategy 1], step-up combination therapy [strategy 2], or initial combination therapy with prednisone [strategy 3] or with infliximab [strategy 4], all followed by targeted treatment to lower disease activity) produced these results: “195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean [Health Assessment Questionnaire (HAQ)] score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp–van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81).” (I. M. Markusse, I.M.Markusse@lumc.nl)
BMI & Body Fat: A cohort study from Manitoba sheds light on the complicated relationships among body mass index (BMI), total body fat, and mortality (pp. 532–41). In adults 40 years or older undergoing bone mineral density (BMD) testing, results showed independent associations of low BMI and high body fat with increased mortality: “The final cohort included 49,476 women (mean age, 63.5 years; mean BMI, 27.0 kg/m2; mean body fat, 32.1%) and 4,944 men (mean age, 65.5 years; mean BMI, 27.4 kg/m2; mean body fat, 29.5%). Death occurred in 4,965 women over a median of 6.7 years and 984 men over a median of 4.5 years. In fully adjusted mortality models containing both BMI and body fat percentage, low BMI (hazard ratio [HR], 1.44 [95% CI, 1.30 to 1.59] for quintile 1 and 1.12 [CI, 1.02 to 1.23] for quintile 2) and high body fat percentage (HR, 1.19 [CI, 1.08 to 1.32] for quintile 5) were associated with higher mortality in women. In men, low BMI (HR, 1.45 [CI, 1.17 to 1.79] for quintile 1) and high body fat percentage (HR, 1.59 [CI, 1.28 to 1.96] for quintile 5) were associated with increased mortality.” (W. D. Leslie, bleslie@sbgh.mb.ca)

>>>PNN NewsWatch
* Health professionals should not to use “sterile” drug products from Pharmakon Pharmaceuticals Inc., in Noblesville, IN, FDA warned yesterday, due to a lack of sterility assurance and other quality issues.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 20, 2016 * Vol. 23, No. 76
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Apr. 19 issue of JAMA (2016; 315).
Pharmacist-Prescribed Birth Control: New laws in Oregon and California that enable pharmacist prescribing of oral contraceptives do not go far enough, argue authors of a Viewpoint article (pp. 1567–8). “The new laws’ requirement of a prescription by a pharmacist replaces one barrier to women’s access to contraceptive health services with another,” the group writes. “While the United States, Canada, and most European countries require prescriptions for hormonal birth control, some other countries (eg, Portugal, Russian Federation, South Korea) provide hormonal contraception without a prescription. In a worldwide survey, the United States was one of 45 countries requiring a prescription, whereas women in 106 other countries could obtain oral contraceptive pills over the counter. Importantly, international comparative studies on availability of contraceptives have determined that more restrictive policies do not confer health advantages to women.” (Y. T. Yang, ytyang@gmu.edu)
Opioids for Chronic Pain: The “CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016” advocates use of nonopioids as initial therapy for chronic pain and other approaches for reducing risks associated with long-term opioid therapy (pp. 1624–45). CDC officials provide this summary of their 12 recommendations for prescribing of opioids for chronic pain: “Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.” (D. Dowell, ddowell@cdc.gov)
In one of two editorials accompanying publication of the CDC guideline, a writer argues that “zero pain is not the goal” (
pp. 1575–7). “The reduction of suffering is—and that is something more complex than analgesia alone,” he adds. “Pain management will never be easy or straightforward, but it is an intrinsic element of any effort to reduce patients’ suffering. The problem is not inappropriate pressures exerted from measurement of patients’ assessment of their pain control: it is the difficulty of knowing what to do with the information that patients are in pain. The CDC guidelines offer important recommendations for addressing that issue.” (T. H. Lee, thomas.lee@pressganey.com)
Financing of care for pain management and addiction treatment plays a major role in the opioid problem, a second editorialist adds (
pp. 1577–9): “Of critical importance is adequate coverage by Medicare, Medicaid, and private insurance for medication-assisted treatment for opioid addiction, including methadone and buprenorphine. There needs to be widespread recognition that these effective treatments are not substitution of one addiction for another but rather are medications that, like insulin for diabetes mellitus, allow patients to live productively, managing their disease. This requires changing language associated with addiction, undoing discriminatory policies affecting those taking methadone or buprenorphine, and countering negative attitudes toward people with addiction.” (Y. Olsen, yolsen@ibrinc.org)

>>>PNN NewsWatch
* FDA is expanding its award-winning “The Real Cost” campaign to educate rural, white male teenagers about the negative health consequences associated with smokeless tobacco use. Messages on the dangers of nicotine addiction, gum disease, tooth loss, and several cancers are being highlighted through advertisements in 35 U.S. markets specifically selected to reach the campaign’s target audience.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 21, 2016 * Vol. 23, No. 77
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Apr. 21 issue of the New England Journal of Medicine (2016; 374).
ACE/Renin Regulation in Heart Failure: Among 2,336 patients with chronic heart failure, addition of the renin inhibitor aliskiren to enalapril “led to more adverse events without an increase in benefit,” researchers report (pp. 1521–32). In the single-blind ATMOSPHERE trial, participants were randomized to one or both drugs. A composite outcome of death from cardiovascular causes or hospitalization for heart failure showed these results: “After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P = 0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P = 0.009) and an elevated potassium level (17.1% vs. 12.5%, P <0.001).” (J. J. V. McMurray, john.mcmurray@glasgow.ac.uk)
Stroke Risk After TIAs/Minor Stroke: Stratification of the risks of recurrent stroke and treatment based on this risk appear necessary in patients who have transient ischemic attacks (TIAs) or minor strokes, a study shows (pp. 1533–42). Finding “a lower risk of cardiovascular events after TIA than previously reported,” investigators identified these indicators of recurrent stroke risk: “From 2009 through 2011, we enrolled 4,789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan–Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan–Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD2 score of 6 or 7 were each associated with more than a doubling of the risk of stroke.” (P. Amarenco, pierre.amarenco@aphp.fr)
“This study should prompt health care providers and policymakers to make necessary changes in systems of stroke care in order to deliver the most effective care not only to patients with acute stroke, but also to those with a TIA or minor stroke,” editorialists write (
pp. 1577–9). “The TIAregistry.org results support the value of organizing specialized units for the care of patients with a TIA or minor stroke where rapid diagnostic evaluations and evidence-based preventive treatments by stroke specialists can be initiated promptly and lead to reduced early and late risks of stroke. Our patients and the public deserve access to the best we can provide to prevent stroke.” (R. L. Sacco)
Results With Readmissions: Hospitals are responding to incentives for reducing readmissions similarly to patterns observed with previous programs involving financial penalties, HHS officials write based on analysis of data from 2007 to 2015 (pp. 1543–51). An interrupted time-series model was used to determine that lower readmission rates were not the result of manipulation of the system through use of observation units: “We analyzed data from 3387 hospitals. From 2007 to 2015, readmission rates for targeted conditions declined from 21.5% to 17.8%, and rates for nontargeted conditions declined from 15.3% to 13.1%. Shortly after passage of the ACA, the readmission rate declined quickly, especially for targeted conditions, and then continued to fall at a slower rate after October 2012 for both targeted and nontargeted conditions. Stays in observation units for targeted conditions increased from 2.6% in 2007 to 4.7% in 2015, and rates for nontargeted conditions increased from 2.5% to 4.2%. Within hospitals, there was no significant association between changes in observation-unit stays and readmissions after implementation of the [the Affordable Care Act].” (R. B. Zuckerman, rachael.zuckerman@hhs.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 22, 2016 * Vol. 23, No. 78
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Apr. issue of Health Affairs, a theme issue on Patients’ & Consumers’ Use Of Evidence (2016; 35).
Targeted Services & Medication Adherence: Benefits managers in Connecticut seeking to improve medication adherence found beneficial the combination of value-based insurance design (VBID) and requirements to participate in evidence-based preventive services (pp. 637–46). VBID lowered patient costs for targeted high-value primary and chronic disease preventive services but required that participants receive the services. Beneficiaries not participating in the program or removed for noncompliance with its requirement had to pay a premium surcharge. Results showed: “To evaluate [the program’s] efficacy in [curbing cost growth and improving health], we compared changes in service use and spending after implementation of the program to trends among employees of six other states. Compared to employees of other states, Connecticut employees were similar in age and sex but had a slightly higher percentage of enrollees with chronic conditions and substantially higher spending at baseline. During the program’s first two years, the use of targeted services and adherence to medications for chronic conditions increased, while emergency department use decreased, relative to the situation in the comparison states. The program’s impact on costs was inconclusive and requires a longer follow-up period.” (R. A. Hirth, rhirth@umich.edu)
“Boot Camp Translation” to Reinvent the Wheel of Medical Evidence: By converting complex medical guidelines into “locally relevant messages,” the High Plains Research Network’s Community Advisory Council has provided useful information to communities of eastern Colorado and other areas, researchers report (pp. 613–8): “The Colorado Clinical and Translational Sciences Institute tested the Boot Camp Translation process on multiple topics in communities throughout the United States from 2012 to 2015. During that period the institute used the process more than twenty-five times, addressing the topics of cancer prevention, hypertension, asthma, diabetes, and mental health. Multiple studies show that use of the process has led to improvement in cancer testing, asthma management, and hypertension control. Policies that support the translation of medical evidence into local programs will improve the health of patients.” (J. M. Westfall, jack.westfall@ucdenver.edu)

>>>Medical Care Highlights
Source:
May issue of Medical Care (2016; 54).
Prescribed Opioid Dosage & Overdose Deaths: No “clear cut-point in opioid dosage” was found in a study of prescribed dosages and overdose deaths, but “lowering the recommended dosage threshold below the 100 [morphine-equivalent mg (MEM)] used in many recent guidelines would affect proportionately few patients not at risk for overdose while potentially benefitting many of those at risk for overdose,” authors conclude (pp. 435–41). In a nested case–control study with risk-set sampling of controls, investigators used data from the Veterans Health Administration for patients prescribed opioids and having diagnoses of chronic pain to make these observations about those dying from opioid overdose (cases): “The average prescribed opioid dosage was higher (P <0.001) for cases (mean = 98.1 MEM, SD = 112.7; median = 60, interquartile range, 30–120), than controls (mean = 47.7 MEM, SD=65.2; median = 25, interquartile range, 15–45). In a ROC analysis, dosage was a moderately good ‘predictor’ of opioid overdose death, indicating that, on average, overdose cases had a prescribed opioid dosage higher than 71% of controls.” (A. S. B. Bohnert, amybohne@med.umich.edu)
“Unsubstantiated claims misled a generation of physicians into believing that [chronic opioid therapy] could be prescribed without untoward risks of addiction and overdose among chronic pain patients,” editorialists write (
pp. 426–9). “We are facing the worst man-made epidemic in modern medical history. Iatrogenic drug addiction and overdose have resulted from well-intentioned but ill-advised efforts to care for chronic pain patients by indiscriminate long-term prescribing of opioid analgesics. We need health care leaders, state and Federal regulatory bodies, and professional societies to act immediately and forcefully to address this epidemic.” (M. R. Von Korff, vonkorff@ghc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 25, 2016 * Vol. 23, No. 79
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 23 issue of Lancet (2016; 387).
Social Norm Feedback & Antibiotic Prescribing: In England, social-norm feedback to high prescribers of antibiotics by the country’s chief medical officer substantially reduced use of the drugs, researchers report, making this a low-cost and nationally effective tool for antimicrobial stewardship (pp. 1743–52). The trial used a randomized 2-by-2 design to assign high prescribing general practitioners (GPs) to intervention or no intervention groups, followed by rerandomization to a patient-centered letter. Results showed: “Letters were sent to 3,227 GPs in the intervention group. Between October, 2014, and March, 2015, the rate of antibiotic items dispensed per 1,000 population was 126.98 (95% CI 125.68–128.27) in the feedback intervention group and 131.25 (130.33–132.16) in the control group, a difference of 4.27 (3.3%; incidence rate ratio [IRR] 0.967 [95% CI 0.957–0.977]; p <0.0001), representing an estimated 73,406 fewer antibiotic items dispensed. In December, 2014, GP practices were re-assigned to patient-focused intervention (n = 777) or control (n = 804) groups. The patient-focused intervention did not significantly affect the primary outcome measure between December, 2014, and March, 2015 (antibiotic items dispensed per 1,000 population: 135.00 [95% CI 133.77–136.22] in the patient-focused intervention group and 133.98 [133.06–134.90] in the control group; IRR for difference between groups 1.01, 95% CI 1.00–1.02; p = 0.105).” (M. Hallsworth, michael.hallsworth@behaviouralinsights.co.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Beta Blockers in Heart Failure: Beta blockers should be used in patients with reduced-fraction heart failure (HFrEF) in sinus rhythm regardless of age or gender, according to authors of an individual patient data meta-analysis (i1855). Among 13,833 participants in 11 trials, these outcomes were identified: “Compared with placebo, beta blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P = 0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by beta blockers, although this effect was attenuated at older ages (interaction P = 0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give beta blockers, 15.6% in those receiving placebo).” (D. Kotecha, d.kotecha@bham.ac.uk)
Drugs for Rheumatoid Arthritis: For pharmacotherapy of rheumatoid arthritis, “triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic [disease modifying antirheumatic drugs (DMARDs)] with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients,” concludes a Cochrane systematic review (i1777). Based on results from 158 trials, the investigators report: “Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab.” (G. S. Hazlewood, glenhazlewood@gmail.com)

>>>PNN JournalWatch
* Predicting Progression in CKD: Perspectives and Precautions, in
American Journal of Kidney Diseases, 2016; 67: 779–86. (A. Levin, alevin@providencehealth.bc.ca)
* The Geriatrics in Primary Care Demonstration: Integrating Comprehensive Geriatric Care into the Medical Home: Preliminary Data, in
Journal of the American Geriatrics Society, 2016; 64: 875–9. (P. A. Engel, peter.engel@va.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 26, 2016 * Vol. 23, No. 80
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Apr. issue of the Journal of the American Geriatrics Society (2016; 64).
Antipsychotics in Hospital Delirium: The evidence base supporting use of antipsychotics in older patients with delirium during hospitalization is lacking, according to results of a systematic review and meta-analysis (pp. 705–14). “Additional methodologically rigorous studies using standardized outcome measures are needed,” the authors conclude, based on these findings: “Screening of 10,877 eligible records identified 19 studies. In seven studies comparing antipsychotics with placebo or no treatment for delirium prevention after surgery, there was no significant effect on delirium incidence (OR = 0.56, 95% confidence interval (CI) = 0.23–1.34, I2 = 93%). Using data reported from all 19 studies, antipsychotic use was not associated with change in delirium duration, severity, or hospital or ICU [length of stay], with high heterogeneity among studies. No association with mortality was detected (OR = 0.90, 95% CI = 0.62–1.29, I2 = 0%).” (K. J. Neufeld, kneufel2@jhmi.edu)
Geriatric Syndrome After Discharge to Nursing Homes: Nine geriatric syndromes in hospitalized older adults transferred to skilled nursing facilities (SNFs) occur commonly and often coexist, researchers report (pp. 715–22). Noting that information on the syndromes is often not communicated by the hospital to the SNF, the authors make these observations about weight loss, lack of appetite, incontinence, and pain; depression; delirium; cognitive impairment; and falls and pressure ulcers: “Geriatric syndromes were prevalent in more than 90% of hospitalized adults referred to SNFs; 55% met criteria for three or more coexisting syndromes. The most-prevalent syndromes were falls (39%), incontinence (39%), loss of appetite (37%), and weight loss (33%). In individuals who met criteria for three or more syndromes, the most common triad clusters were nutritional syndromes (weight loss, loss of appetite), incontinence, and depression. Treating hospital physicians commonly did not recognize and document geriatric syndromes in discharge summaries, missing 33% to 95% of syndromes present according to research personnel.” (S. P. Bell, susan.p.bell@vanderbilt.edu)
Vitamin D Supplements During Weight Loss: Among postmenopausal women initially deficient in vitamin D, supplementation with vitamin D3 2000 IU/d during weight loss decreased leg strength and did not change lean mass or bone mineral density (BMD), a study shows (pp. 769–78). Twelve-month results of a lifestyle-based weight loss intervention with randomization to vitamin D3 or placebo showed the following: “Change in 25(OH)D was significantly different between the vitamin D and placebo groups at 12 months (13.6 ng/mL vs −1.3 ng/mL, P < .001), but no differences in change in lean mass (−0.8 kg vs −1.1 kg, P = .53) or BMD of the spine (−0.01 g/cm2 vs 0.0 g/cm2, P = .82) or right femoral neck (both −0.01 g/cm2, P = .49) were detected between the groups. Leg strength decreased in the vitamin D group but not in the placebo group (−2.6 pounds vs 1.8 pounds, P = .03). In women randomized to vitamin D, achieving repletion (25(OH)D ≥ 32 ng/mL) did not alter results.” (A. McTiernan, amctiern@fhcrc.org)
Inappropriate Use of Antimuscarinic Medications: Among Medicare Advantage Prescription Drug Plan members aged 65 and older, potentially inappropriate medications (PIM) for overactive bladder (OAB) was prevalent and associated with increased total health care costs, according to retrospective analysis of medical and pharmacy claims data (pp. 779–87): “Of members initiated on an antimuscarinic OAB medication, 31.1% had a drug–drug or drug–disease or syndrome interaction. Dementia was the most common disease or syndrome interaction (11.3%), followed by constipation (8.6%) and delirium (2.9%). Paroxetine (2.6%), amitriptyline (2.2%), cyclobenzaprine (1.7%), and meclizine (1.6%) were the most common interacting medications. Subjects in the PIM group had greater healthcare costs over 12 months of follow-up ($12,001) than those in the non-PIM group ($9,373) after controlling for baseline characteristics (P < .001). There was no difference between the PIM and the non-PIM groups in odds of discontinuing OAB treatment at 12 months after controlling for baseline characteristics (odds ratio = 0.98, 95% confidence interval = 0.89–1.07, P = .63).” (B. T. Suehs, bsuehs6@humana.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 27, 2016 * Vol. 23, No. 81
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Apr. 26 issue of JAMA (2016; 315).
Prediction Rule for Dual Antiplatelet Therapy: Investigators find that a clinical decision tool performed well in predicting the need for continuation of dual antiplatelet therapy 1 year after percutaneous coronary intervention (PCI) and should be evaluated further (pp. 1735–49). The rule, which assesses late ischemic and bleeding risks, “showed modest accuracy in derivation and validation cohorts,” the authors write, adding these details based on data from 11,648 randomized DAPT Study patients and 8,136 PROTECT trial participants: “The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; −1 point for age 65 to younger than 75 years; and −2 points for age 75 years or older. Among the high score group (score ≥2, n = 5,917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], −3.0% [95% CI, −4.1% to −2.0%], P <.001) compared with the low score group (score <2, n = 5,731; 1.7% vs 2.3%; RD, −0.7% [95% CI, −1.4% to 0.09%], P = .07; interaction P <.001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, −0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2,848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding.” (R. W. Yeh, ryeh@bidmc.harvard.edu)
“To reach their full potential, the goal for prediction models should not end with their publication,” editorialists write (
pp. 1713–4). “Journals are already filled with articles that include prediction models, yet few of these are routinely used in clinical practice. This partially is explained because, in the past, risk calculation has not been user-friendly. However, in an era of electronic health records, clinical decision aids can be built to automatically calculate probabilistic estimates and provide those estimates to clinicians at the point of care. But accurate risk prediction alone is only a start of the process; such probabilistic estimation needs to be actionable and linked to clear decisions. Based on different combinations of estimated risks and benefits, clinicians need a clear menu of care management strategies. It is also necessary to continue to enhance educational efforts for practitioners and patients to better understand the benefits and limitations of these models.” (E. D. Peterson, eric.peterson@duke.edu)
Sublingual Immunotherapy Tablet in Allergic Asthma: Acting primarily through a reduction in moderate exacerbations, house dust mite (HDM) sublingual allergen immunotherapy (SLIT) can enable adults with allergy-related asthma to reduce doses of inhaled corticosteroid (ICS) (pp. 1715–25). “Addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points,” the authors conclude. (J. C. Virchow, j.c.virchow@med.uni-rostock.de)
This study is especially valuable “given its focus on an important patient population with highly relevant end points,” editorialists write (
pp. 1711–2). “As research continues and these therapies enter clinical practice, the goal should be to optimize each patient’s immunotherapy regimen and disease control, taking personal preferences into account, and ideally to develop additional patient profiling using specific biomarkers to further personalize the use of these treatment options.” (R. A. Wood, rwood@jhmi.edu)

>>PNN NewsWatch
* Oral fluconazole in pregnancy is being evaluated by FDA for possible association with miscarriage.
* Citing presence of particulate matter,
Fresenius Kabi USA is recalling lot 6111504 of Sensorcaine-MPF (bupivacaine HCl) Injection, USP, 0.75%, 7.5 mg/mL, 30 mL fill in a 30 mL vial.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 28, 2016 * Vol. 23, No. 82
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Apr. 28 issue of the New England Journal of Medicine (2016; 374).
Oral Ixazomib for Multiple Myeloma: In a phase 3 trial of 722 patients with relapsed, refractory, or relapsed and refractory multiple myeloma, addition of the oral proteasome inhibitor ixazomib to a regimen of lenalidomide and dexamethasone produced significantly longer progression-free survival, researchers report (pp. 1621–34). Ixazomib plus lenalidomide–dexamethasone (ixazomib group) or placebo plus lenalidomide–dexamethasone (placebo group) produced these findings: “Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P = 0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups.” (P. Moreau, philippe.moreau@chu-nantes.fr)
Ebola Vaccines: Two studies report clinical trial results with different types of Ebola vaccine.
A single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine boosted with modified vaccinia Ankara (MVA) strain produced B-cell and T-cell immune responses to
Zaire ebolavirus (ZEBOV) superior to those induced by the ChAd3 vaccine alone, a phase 1 study shows (pp. 1635–46): “No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by [a recombinant vesicular stomatitis virus–based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV)] vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5.” (A. V. S. Hill, adrian.hill@ndm.ox.ac.uk)
In an open-label, dose-escalation phase 1 trial, rVSV-ZEBOV vaccine was reactogenic and immunogenic after a single dose (
pp. 1647–60). Further study is warranted, the authors concluded, based on these findings: “No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in [one study site].” (M. M. Addo, m.addo@uke.de)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 29, 2016 * Vol. 23, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
May issue of the Diabetes Care (2016; 39).
Losing the War Against Diabetes: A global effort to understand both individual- and population-level factors will be required to win not just the battle but also the war against diabetes, according to the presenter of the 2015 Kelly West Award Lecture (pp. 653–63): “For example, preliminary data show that thin people in low- and middle-income countries such as India commonly experience type 2 diabetes. Global studies comparing these thin Asian Indians with other high-risk groups such as Pima Indians, a population with a high mean BMI, suggest that type 2 diabetes may not be a single pathophysiological entity. Pima Indians may represent the well-studied phenotype of poor insulin action (type 2A), whereas Asian Indians represent the grossly understudied phenotype of poor insulin secretion (type 2B). This has major implications for diagnosis, prevention, and treatment and highlights the mismatch between where diabetes burdens occur (i.e., low- and middle-income countries) and where research happens (i.e., high-income countries). Correcting this imbalance will advance our knowledge and arsenal to win the global war against diabetes.” (K. M. Venkat Narayan, knaraya@emory.edu)
Intensive Diabetes Treatment & Cardiovascular Outcomes: Thirty-year follow-up of the Diabetes Control and Complications Trial (DCCT) show that intensive diabetes therapy during the 6.5 years of the trial produced “long-term beneficial effects on the incidence of cardiovascular disease in type 1 diabetes,” researchers report (pp. 686–93). The 1,441 patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study, yielding these results: “During 30 years of follow-up in DCCT and EDIC, 149 cardiovascular disease events occurred in 82 former intensive treatment group subjects versus 217 events in 102 former conventional treatment group subjects. Intensive therapy reduced the incidence of any cardiovascular disease by 30% (95% CI 7, 48; P = 0.016), and the incidence of major cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) by 32% (95% CI −3, 56; P = 0.07). The lower HbA1c levels during the DCCT/EDIC statistically account for all of the observed treatment effect on cardiovascular disease risk. Increased albuminuria was also independently associated with cardiovascular disease risk.” (R. Gubitosi-Klug, rose.gubitosi-klug@case.edu)
Intensive Glycemic Control & Cardiovascular Outcomes: After 9 years of monitoring high-risk patients with type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, investigators conclude that a mean of 3.7 years of intensive glycemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death (pp. 701–8). Results of the follow-on ACCORDION trial show that among 8,601 people monitored for a median of 8.8 years, intensive glucose lowering was associated with a 49% increase in cardiovascular mortality during the active phase of the trial; this decreased to a 20% increase during follow-up, remaining statistically elevated (95% CI 1.03, 1.39; P = 0.02). (H. C. Gerstein, gerstein@mcmaster.ca)
Intensive Glucose Control & Preventing End-Stage Kidney Disease: Patients with type 2 diabetes who are managed with intensive glucose control have long-term reductions in the risk of end-stage kidney disease (ESKD), according to results of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (pp. 694–700). No evidence of increased risks of cardiovascular events or death was found in the study, which reports these results: “A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26).” (V. Perkovic, vperkovic@georgeinstitute.org.au)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 2, 2016 * Vol. 23, No. 84
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 30 issue of Lancet (2016; 387).
COPD Treatment in Heightened Cardiovascular Risk: In patients with moderate chronic obstructive pulmonary disease and heightened cardiovascular risk, addition of vilanterol to fluticasone therapy was well tolerated but failed to improve mortality, cardiovascular outcomes, or exacerbations, researchers report (pp. 1817–26). Fluticasone alone or in combination “seemed to reduce FEV1 decline,” the authors add, noting these details from the SUMMIT trial of 16,485 patients 40–80 years of age: “Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0.88 [95% CI 0.74–1.04]; 12% relative reduction; p = 0.137) or the components (fluticasone furoate, HR 0.91 [0.77–1.08]; p = 0.284; vilanterol, 0.96 [0.81–1.14]; p = 0.655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2.4] vs 46 mL per year [2.5] for placebo, difference 8 mL per year [95% CI 1–15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1–14]), but not vilanterol (difference −2 mL per year [95% CI −8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0.93 [95% CI 0.75–1.14]) with similar findings for fluticasone furoate (0.90 [0.72–1.11]) and vilanterol (0.99 [0.80–1.22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups.” (J. Vestbo, jorgen.vestbo@manchester.ac.uk)
Early Low-Dose Hydrocortisone in Premies: A study of 1,072 extremely preterm neonates (less than 28 weeks’ gestation at birth) shows significantly improved rates of survival without bronchopulmonary dysplasia at 36 weeks’ gestation in those treated with prophylactic low-dose hydrocortisone compared with placebo (pp. 1827–36). “This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates,” the authors conclude based on these results: “Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1.48, 95% CI 1.02–2.16, p = 0.04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6–200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24–25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1.87, 95% CI 1.09–3.21, p = 0.02).” (O. Baud, olivier.baud@rdb.aphp.fr)

>>>PNN NewsWatch
* FDA on Friday approved pimavanserin (Nuplazid, Acadia), the first drug approved to treat hallucinations and delusions associated with psychosis sometimes experienced by those with Parkinson’s disease.
*
FDA on Friday also approved the first generic version of Crestor (rosuvastatin calcium). It will be marketed by Watson Pharmaceuticals with three indications: hypertriglyceridemia, primary dysbetalipoproteinemia, and homozygous familial hypercholesterolemia.
* A federal judge has entered an order of permanent injunction against Paul W. Franck, owner of numerous
compounding pharmacies in Florida, FDA announced. The order prohibits Franck from manufacturing, holding, and distributing sterile drug products until he complies with the FD&C Act and its regulations, in addition to other requirements, the agency said.

>>>PNN JournalWatch
* Diabetes in Pregnancy and Childhood Cognitive Development: A Systematic Review, in
Pediatrics, 2016; 137: 10.1542/peds.2015-4234. (A. A. Adane)
* Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis, in
Pediatrics, 2016; 137: 10.1542/peds.2015-4089. (R. A. Al Khalifah)
* Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis, in
Diabetes Care, 2016; 39: 833–46. (F. B. Hu, nhbfh@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 3, 2016 * Vol. 23, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 3 issue of the Annals of Internal Medicine (2016; 164).
Gradual Versus Abrupt Smoking Cessation: Smokers have higher abstinence rates when they stop use abruptly rather than tapering, a study shows (pp. 585–92). This result holds even among smokers who express an initial preference for tapering, the authors note, adding these details from a 697-participant trial of behavioral therapy plus nicotine replacement therapy (NRT): “At 4 weeks, 39.2% (95% CI, 34.0% to 44.4%) of the participants in the gradual-cessation group were abstinent compared with 49.0% (CI, 43.8% to 54.2%) in the abrupt-cessation group (relative risk, 0.80 [CI, 0.66 to 0.93]). At 6 months, 15.5% (CI, 12.0% to 19.7%) of the participants in the gradual-cessation group were abstinent compared with 22.0% (CI, 18.0% to 26.6%) in the abrupt-cessation group (relative risk, 0.71 [CI, 0.46 to 0.91]). Participants who preferred gradual cessation were significantly less likely to be abstinent at 4 weeks than those who preferred abrupt cessation (38.3% vs 52.2%; P = 0.007).” (N. Lindson-Hawley, nicola.lindson-hawley@phc.ox.ac.uk)
“These findings call into question whether clinicians should encourage the practice of gradual reduction before a quit date in smokers who are ready to quit, including those who prefer reduction as a treatment strategy,” editorialists write (
pp. 622–3). “Although not a primary focus, prequit nicotine patches and combined short-acting NRT with nicotine patches after quitting were used in this trial. Prequit NRT has been shown in some studies to be advantageous. This trial adds to the evidence of benefit for using nicotine patches before a quit date. Further, the continued benefit of combination NRT adds to the growing evidence that combined, as opposed to single, NRT could become the standard of care for medicinal nicotine use.” (M. B. Steinberg, michael.steinberg@rutgers.edu)
Influenza Vaccine in Surgical Patients: A retrospective cohort study from Kaiser Permanente Southern California supports recommendations to vaccinate surgical inpatients against influenza (pp. 593–9). The analysis showed no increased risk of adverse outcomes among patients receiving the vaccine in comparison with those who did not: “Of the 42,777 surgeries included in adjusted analyses, vaccine was administered during hospitalization in 6,420. No differences were detected between the vaccinated and unvaccinated groups in risk for inpatient visits (rate ratio [RR], 1.12 [95% CI, 0.96 to 1.32]), ED visits (RR, 1.07 [CI, 0.96 to 1.20]), postdischarge fever (RR, 1.00 [CI, 0.76 to 1.31]), or clinical evaluations for infection (RR, 1.06 [CI, 0.99 to 1.13]). A marginal increase in risk for outpatient visits (RR, 1.05 [CI, 1.00 to 1.10]; P = 0.032) was found.” (S. Y. Tartof)
PCSK9 Monoclonal Antibodies for ACS: Authors of a review article examine use of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies in patients with acute coronary syndrome (pp. 600–7): “Acute coronary events induce a dynamic increase of PCSK9 levels that may play a role in plaque vulnerability of both culprit and nonculprit coronary vessels. Growing evidence highlights a potential key role of PCSK9 antibodies in managing acute coronary syndrome. This review describes the influence of PCSK9 antibodies on plaque composition and instability, as well as the pharmacokinetic profile and the potential anti-inflammatory and antithrombotic mechanisms associated with PCSK9 inhibition that may confer benefits during the early phase of acute coronary syndrome. The authors posit a rationale for the use of PCSK9 antibodies in patients with acute coronary syndrome and highlight the need for further investigation in this area.” (E. P. Navarese, elianonavarese@gmail.com)
An editorialist provides this cautionary note (
pp. 624–5; M. S. Lauer, michael.lauer@nih.gov), “Even if we could map a network for all of the probably thousands of scientists and institutions behind the work on PCSK9 inhibitors, we have a long way to go before we can declare that we have found another ‘cure’ like ipilimumab and ivacaftor.”

>>>PNN NewsWatch
* FDA’s “This Free Life” campaign, launched yesterday, targets the 800,000 of 2 million lesbian, gay, bisexual and transgender (LGBT) young adults ages 18–24 who smoke socially. The group has a twofold greater rate of tobacco use as other young adults.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 4, 2016 * Vol. 23, No. 86
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
May 3 issue of JAMA (2016; 315).
Inappropriate Outpatient Antibiotic Prescriptions: In the U.S. in 2010–11, 3 in 10 of antibiotic prescriptions for outpatients were likely not appropriate, a survey finds (pp. 1864–73). The authors call for increased antibiotic stewardship efforts in ambulatory care settings based on the following data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey: “Of the 184,032 sampled visits, 12.6% of visits (95% CI, 12.0%–13.3%) resulted in antibiotic prescriptions. Sinusitis was the single diagnosis associated with the most antibiotic prescriptions per 1,000 population (56 antibiotic prescriptions [95% CI, 48–64]), followed by suppurative otitis media (47 antibiotic prescriptions [95% CI, 41–54]), and pharyngitis (43 antibiotic prescriptions [95% CI, 38–49]). Collectively, acute respiratory conditions per 1,000 population led to 221 antibiotic prescriptions (95% CI, 198–245) annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1000 population, among all conditions and ages combined in 2010–2011, an estimated 506 antibiotic prescriptions (95% CI, 458–554) were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate antibiotic prescriptions.” (K. E. Fleming-Dutra, ftu2@cdc.gov)
“The White House National Action Plan for Combating Antibiotic-Resistant Bacteria established a goal of reducing outpatient antibiotic use by 50% by 2020, but until now estimates of the proportion of inappropriate use were unknown,” editorialists write (
pp. 1839–41). “Now that baseline estimates about outpatient antibiotic prescribing have been determined, future work needs to focus on interventions targeting both clinicians and patients to help reach the national goal. It will be critical to continue to evaluate progress in improving antibiotic use in conjunction with widespread adoption of antibiotic stewardship activities in the outpatient setting.” (S. E. Cosgrove, scosgro1@jhmi.edu)
Locally Advanced Pancreatic Cancer: In 442 patients with locally advanced pancreatic cancer controlled after 4 months of induction chemotherapy, LAP07 investigators found no difference in overall survival based on treatment with chemoradiotherapy versus chemotherapy alone or with maintenance gemcitabine versus gemcitabine plus erlotinib (pp. 1844–53). “With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5–18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9–17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79–1.34; P = .83),” the authors write. “Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3–15.3 months) and was 11.9 months (95% CI, 10.4–13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97–1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.” (P. Hammel, pascal.hammel@aphp.fr)
These results provide “progress but no precision,” an editorialist writes, concluding that “the LAP07 trial contributes important new information to help guide treatment decisions for patients with locally advanced pancreas cancer” (
pp. 1837–8). “Ideally, future pancreatic cancer trials will identify molecular markers that better predict responsiveness to specific treatments including radiation and will allow for more focused approaches to treatment selection. In the meantime, chemoradiation need not constitute an essential component of the therapeutic backbone.” (D. Schrag, deb_schrag@dfci.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday warned that compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with use of aripiprazole. Dose reduction or drug discontinuation eliminates the urges, the agency added.
*
FDA has approved a brand name change for the antidepressant Brintellix (vortioxetine) to Trintellix to decrease the risk of prescribing and dispensing errors resulting from name confusion with the anticoagulant Brilinta (ticagrelor).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 5, 2016 * Vol. 23, No. 87
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
May 5 issue of the New England Journal of Medicine (2016; 374).
Antiarrhythmics in Out-of-Hospital Cardiac Arrest: In a double-blind, placebo-controlled study of patients in cardiac arrest outside the hospital, “neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo,” Resuscitation Outcomes Consortium (ROC) investigators conclude (pp. 1711–22). All participants had shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock and vascular access. Per-protocol analysis showed these results: “3,026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1,059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], −0.4 to 7.0; P = 0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, −1.0 to 6.3; P = 0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, −3.2 to 4.7; P = 0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P = 0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo.” (P. J. Kudenchuk)
Much more important than drug interventions in this situation is bystander-initiated cardiopulmonary resuscitation (CPR), editorialists conclude (
pp. 1781–2): “We commend the ROC investigators for their efforts to provide scientific evidence to support emergency care, and we agree with the Institute of Medicine recommendations that research must continue, with efforts to coordinate emergency care and quickly implement best practices on the basis of contemporary data. Finally, we emphasize the benefit of bystander-initiated CPR, for which the current trial showed an absolute survival benefit of almost 10 percentage points, eclipsing any effect of drug intervention.” (J. A. Joglar)
Rosuvastatin in Cardiac Surgery: Use of perioperative rosuvastatin during cardiac surgeries showed no benefits over placebo and produced higher rates of acute kidney injury, researchers report (pp. 1744–53). Among 1,922 patients undergoing elective procedures, rosuvastatin 20 mg daily or placebo produced these outcomes based on a primary outcome of postoperative atrial fibrillation within 5 days after surgery and myocardial injury within 120 hours after surgery: “The rate of postoperative atrial fibrillation did not differ significantly between the rosuvastatin group and the placebo group (21.1% and 20.5%, respectively; odds ratio 1.04; 95% confidence interval [CI], 0.84 to 1.30; P = 0.72), nor did the area under the troponin I–release curve (102 ng × hour per milliliter and 100 ng × hour per milliliter, respectively; between-group difference, 1%; 95% CI, −9 to 13; P = 0.80). Subgroup analyses did not indicate benefit in any category of patient. Rosuvastatin therapy did not result in beneficial effects on any of the secondary outcomes but was associated with a significant absolute (± SE) excess of 5.4 ± 1.9 percentage points in the rate of postoperative acute kidney injury
(P = 0.005).” (Z. Zheng,
zhengzhe@fuwai.com)
Ozanimod in Ulcerative Colitis: Ozanimod (RPC1063), an oral sphingosine-1-phosphate receptor 1 and 5 agonist, produced a slightly higher rate of clinical remission of ulcerative colitis than did placebo in a phase 2 trial of 197 adults (pp. 1754–62). A primary outcome of clinical remission “occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P = 0.048 and P = 0.14, respectively, for the comparison of the two doses of ozanimod with placebo),” the authors report. “Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory.” (W. J. Sandborn, wsandborn@ucsd.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 6, 2016 * Vol. 23, No. 88
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
May issue of Chest (2016; 149).
Nurse Practitioner-Delivered Critical Care: Outcomes in an adult medical intensive-care unit (ICU) were similar when care was delivered by acute care nurse practitioners (ACNPs) versus teams of residents, a study shows (pp. 1146–54). In 2011–13, these results were recorded based on a primary end point of 90-day survival: “Among 9,066 admissions, there was no difference in 90-day survival for patients cared for by ACNP or resident teams (adjusted hazard ratio [HR], 0.94; 95% CI, 0.85-1.04; P = .21). Although patients cared for by ACNPs had lower ICU mortality (6.3%) than resident team patients (11.6%; adjusted OR, 0.77; 95% CI, 0.63-0.94; P = .01), hospital mortality was not different (10.0% vs 15.9%; adjusted OR, 0.87; 95% CI, 0.73-1.03; P = .11). ICU length of stay was similar between the ACNP and resident teams (3.4 ± 3.5 days vs 3.7 ± 3.9 days [adjusted OR, 1.01; 95% CI, 0.93-1.1; P = .81]), but hospital length of stay was shorter for patients cared for by ACNPs (7.9 ± 11.2 days) than for resident patients (9.1 ± 11.2 days) (adjusted OR, 0.87; 95% CI, 0.80-0.95; P = .001).” (J. S. Landsperger)
“The accumulated evidence suggests that properly trained and supervised nonphysician prescribing providers can provide high-quality critical care,” editorialists write (
pp. 1119–20). “The question remains: ‘Where and when should they provide care?’ It appears that properly trained advanced practice providers that can effectively communicate with a supervising board-certified intensivist should provide care wherever patient need exists and they are credentialed to provide it.” (C. M. Lilly)
Bisphosphonates & Atrial Fibrillation/Flutter: Older men using bisphosphonates had higher rates of atrial fibrillation/flutter (AF) than control patients, according to the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study (pp. 1173–80). The prospective observational study included 2,911 men with a mean age of 76 years. Logistic regression analysis of data based on overnight in-home polysomnography showed these results for the community-dwelling men: “A total of 123 (4.2%) men were current bisphosphonate users. Prevalent nocturnal AF was present in 138 participants (4.6%). After multivariable adjustment, there was a significant association between current bisphosphonate use and prevalent AF (OR, 2.33; 95% CI, 1.13–4.79). In the subset of men with moderate to severe [sleep-disordered breathing], this association was even more pronounced (OR, 3.22; 95% CI, 1.29–8.03). However, the multivariable-adjusted relationship between bisphosphonate use and incident AF did not reach statistical significance (adjusted hazard ratio, 1.53; 95% CI, 0.96–2.45).” (S. R. Thadani)

>>>Circulation Report
Source:
May 3 issue of Circulation (2016; 133).
U.S. v. International Lipids Guidelines: A review compares the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline with Adult Treatment Panel III and international guidelines (pp. 1795–806): “The 2013 ACC/AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from other international guidelines.” (M. Nayor, mnayor@partners.org)

>>>PNN NewsWatch
* FDA yesterday issued a final rule banning sales of previously unregulated nicotine-delivery and tobacco products to those under 18 years of age. The rule extends the agency’s authority to all tobacco products, including e-cigarettes, cigars, hookah tobacco and pipe tobacco, among others. “This historic rule helps implement the bipartisan Family Smoking Prevention and Tobacco Control Act of 2009 and allows the FDA to improve public health and protect future generations from the dangers of tobacco use through a variety of steps, including restricting the sale of these tobacco products to minors nationwide,” the agency said in a news release.
*
FDA is also reminding health professionals and patients not to use drugs intended to be sterile that were produced by compounding pharmacy Medaus Inc., of Birmingham, AL, due to lack of sterility assurance.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 9, 2016 * Vol. 23, No. 89
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 7 issue of Lancet (2016; 387).
Atezolizumab in Metastatic Urothelial Carcinoma: In a phase 2 trial of 486 patients with locally advanced and metastatic urothelial carcinoma, the programmed death ligand 1 (PD-L1) inhibitor atezolizumab “showed durable activity and good tolerability,” researchers report (pp. 1909–20). “Increased levels of PD-L1 expression on immune cells were associated with increased response,” the group adds. “This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.” (J. E. Rosenberg, rosenbj1@mskcc.org)
Tocilizumab in Giant Cell Arteritis: A study of tocilizumab shows that inhibition of interleukin-6 receptors is effective in induction and maintenance of remission in patients with giant cell arteritis (pp. 1921–7). The phase 2 trial evaluated I.V. tocilizumab 8 mg/kg every 4 weeks plus prednisolone in 30 patients, with these results: “17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11–79; p = 0.0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36–94; p = 0.0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7–17; p <0.0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p = 0.0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events.” (P. M. Villiger, peter.villiger@insel.ch)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
DPP-4 Inhibitors/Sulfonylureas & Risk of Hypoglycemia: To avoid hypoglycemia, sulfonylurea doses should be decreased when a dipeptidyl peptidase-4 (DPP-4) inhibitor is added in type 2 diabetes, a systematic review and meta-analysis shows (i2231). This approach also needs more study, the authors add, based on these results: “10 studies were included, representing a total of 6,546 participants (4,020 received DPP-4 inhibitors plus sulphonylureas, 2,526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The [number needed to harm (NNH)] was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94).” (F. Salvo, francesco.salvo@u-bordeaux.fr)

>>>PNN JournalWatch
* Executive Summary: Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, in
Clinical Infectious Diseases, 2016; 62: 1197–202. (T. F. Barlam, tamar.barlam@bmc.org)
* Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine, in
Journal of the American College of Cardiology, 2016; 67: 2161–76. (N. Sayed)
* Pediatric Insomnia, in
Chest, 2016; 149: 1332–9. (K. M. Brown)
* Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial, in
American Journal of Psychiatry, 2016; 173: 499–508. (M. Fava)
* Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation, in
American Journal of Psychiatry, 2016; 173: 509–16. (R. G. Ross)
* Adverse Geriatric Outcomes Secondary to Polypharmacy in a Mouse Model: The Influence of Aging, in
The Journals of Gerontology: Series A, 2016; 71: 571–7. (S. Hilmer, sarah.hilmer@sydney.edu.au)
* What’s Next for Dyslipidemia Management? The 2013 ACC/AHA Guidelines, the NLA Recommendations, and Beyond, in
Journal of the American Pharmacists Association, 2016; 56: 284–92. (Y. L. Phan, y.phan@usciences.edu)
* Reversal Agents for Use with Direct and Indirect Anticoagulants, in
American Journal of Health-System Pharmacy, 2016; 73: S27–S48. (M. A. Smythe, maureen.smythe@beaumont.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 10, 2016 * Vol. 23, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May issue of JAMA Internal Medicine (2016; 176).
Market Changes & Opioid Dispensing/Overdose: Following two key changes in the opioid market, opioid dispensing and prescription opioid overdoses declined, but heroin overdose rates continued to increase, a study shows (pp. 978–87). In 2010, Oxycontin was reformulated to make the product resistant to crushing or dissolving, and propoxyphene was withdrawn from the U.S. market. Evaluation of claims from a large American insurer showed these patterns for 31.3 million adult members in 2003–12: “Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, −32.2 mg morphine-equivalent dose per member per quarter [95% CI, −38.1 to −26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was −11.3 (95% CI, −12.4 to −10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, −8.19 (95% CI, −9.30 to −7.08) for propoxyphene, and −16.2 (95% CI, −18.8 to −13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, −1.10 per 100,000 members per quarter [95% CI, −1.47 to −0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100,000 members per quarter [95% CI, −0.01 to 0.53]).” (M. R. Larochelle, marc.larochelle@bmc.org)
Supporting limits on the duration of opioid prescriptions, editorialists write, “Although mandated limits on opioid prescriptions for acute pain would not address all aspects of the epidemic, such limits are likely to be an essential part of the solution (
pp. 583–4). “The sixth recommendation of the March 2016 guidelines from the Centers for Disease Control and Prevention on prescribing opioids for chronic pain has started this process by providing specific advice to limit the duration of opioid prescriptions. It states, in part, ‘When opioids are used for acute pain,… [t]hree days or less will often be sufficient; 7 days will rarely be needed.’ Policies that mandate restrictive prescribing of opioids should balance the effective treatment of pain with reducing societal harm from these dangerous and addictive medications.” (B. T. Bateman, bbateman@partners.org)
HBV Vaccine Response in Patients with HIV-1 Infection: Double doses of hepatitis B virus (HBV) vaccine given in a 4-dose series to patients with HIV infection “improved long-term immune response compared with the standard regimen,” researchers report (pp. 603–10). The open-label trial compared 3 intramuscular standard-dose (20-µg) injections of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group); 4 intramuscular double-dose (40-µg) injections at weeks 0, 4, 8, and 24 (IM40 × 4 group), or 4 intradermal low-dose (4-µg) injections at weeks 0, 4, 8, and 24 (ID4 × 4 group). Results showed: “Among the 437 patients randomized, 426 received at least 1 dose of vaccine. Of these, 287 were men (67.4%) and they had a mean (SD) age of 42.9 (9.7) years. The percentage of responders at month 42 was 41% (95% CI, 33%–49%) in the IM20 × 3 group, 71% (95% CI, 64%–79%) in the IM40 × 4 group (P < .001 vs the IM20 × 3 group), and 44% (95% CI, 35%–53%) in the ID4 × 4 group (P = .64 vs IM20 × 3 group). Fifteen percent of the patients had [hepatitis B surface antibody] titers of less than 10 mIU/mL at 33.1 months in the IM40 × 4 group, 8.7 months in the IM20 × 3 group, and 6.8 months in the ID4 × 4 group.” (O. Launay, odile.launay@aphp.fr)
A “Culture of Culturing”: In older adults residing in nursing homes, “indiscriminant use of urinalysis and urine cultures among … residents without urinary symptoms” should not be used as a way of “avoiding the hard but satisfying challenge of assessing the frail older patient” for other causes of behavioral changes, authors of a Less Is More article write (pp. 587–8; H. L. Wald, Heidi.wald@ucdenver.edu)

>>>PNN NewsWatch
* PharMEDium Services, LLC is voluntarily recalling the codes/lots of sterile preparations compounded with a single recalled lot of Fresenius Kabi Sensorcaine-MPF (bupivacaine HCl) to the hospital level, FDA announced yesterday, because of particulate matter found during reserve sample inspection.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 11, 2016 * Vol. 23, No. 91
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
May 10 issue of JAMA (2016; 315).
Fluids for Mild Gastroenteritis in Children: Treatment failures are greater with use of electrolyte maintenance solutions in children with mild gastroenteritis than when dilute apple juice is used for initial oral rehydration followed by preferred fluids, researchers report (pp. 1966–74). Addressing the lack of evidence for use of electrolyte maintenance solution in children with minimally dehydrated children, the study concludes that the apple juice/preferred fluid approach may be an appropriate alternative in high-income countries: “Among 647 randomized children (mean age, 28.3 months; 331 boys [51.1%]; 441 (68.2%) without evidence of dehydration), 644 (99.5%) completed follow-up. Children who were administered dilute apple juice experienced treatment failure less often than those given electrolyte maintenance solution (16.7% vs 25.0%; difference, −8.3%; 97.5% CI, − to −2.0%; P <.001 for inferiority and P = .006 for superiority). Fewer children administered apple juice/preferred fluids received intravenous rehydration (2.5% vs 9.0%; difference, −6.5%; 99% CI, −11.6% to −1.8%). Hospitalization rates and diarrhea and vomiting frequency were not significantly different between groups.” (S. B. Freedman, stephen.freedman@albertahealthservices.ca)
Macitentan & New Ischemic Digital Ulcers in Systemic Sclerosis: In international trials of patients with systemic sclerosis and active digital ulcers, the endothelin-1 blocker macitentan failed to reduce development of new ulcers over a 16-week period (pp. 1975–88). Results from the DUAL-1 and DUAL-2 trials “do not support the use of macitentan for the treatment of digital ulcers in this patient population,” the authors write based on these findings: “In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, −0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [−0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, −0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, −0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.” (D. Khanna, khannad@med.umich.edu)
ADHD in Adolescents: Extended-release methylphenidate and amphetamine formulations, atomoxetine, and extended-release guanfacine improve symptoms of attention-deficit/hyperactivity disorder (ADHD) in adolescents, conclude authors of a systematic review and meta-analysis (pp. 1997–2008). Based on results of 16 randomized controlled trials and 1 meta-analysis of 2,668 adolescents, the authors conclude: “Psychosocial treatments incorporating behavior contingency management, motivational enhancement, and academic, organizational, and social skills training techniques were associated with inconsistent effects on ADHD symptoms and greater benefit for academic and organizational skills. Additional treatment studies in adolescents, including combined pharmacological and psychosocial treatments, are needed.” (E. Chan, eugenia.chan@childrens.harvard.edu)

>>>PNN NewsWatch
* The possibility of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) occurring in patients taking olanzapine is being added to product labeling, FDA said yesterday. DRESS may start as a rash but can progress to fever, swollen lymph nodes, swollen face, and eosinophilia. The condition can result in injury to internal organs— including the liver, kidneys, lungs, heart, or pancreas—and has a mortality rate of up to 10%.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 12, 2016 * Vol. 23, No. 92
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
May 12 issue of the New England Journal of Medicine (2016; 374).
Serious Asthma Events with Fluticasone + Salmeterol: Compared with fluticasone alone, patients with persistent asthma had fewer severe asthma exacerbations when the long-acting beta-agonist (LABA) salmeterol was added to a maintenance regimen, a study shows (pp. 1822–30). Risks of serious asthma-related events were statistically similar between the two groups, the authors write, adding these details: “Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone–salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone–salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P = 0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone–salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5,834 patients (8%) in the fluticasone–salmeterol group, as compared with 597 of 5,845 patients (10%) in the fluticasone-only group (P <0.001).” (D. A. Stempel, david.a.stempel@gsk.com)
While this study leaves several important questions unanswered, an editorialist writes that these practical conclusions can be drawn from its results (
pp. 1887–8): “It is clear that among patients with asthma who have not had life-threatening episodes in the past and are highly adherent to their drug regimen, it is likely that the use of salmeterol together with fluticasone in a single inhaler is safe. For these patients and this combination, the black-box warning should be lifted. This is an important result, and it stresses once again that most patients with asthma, and especially those without serious episodes, can reach high levels of symptom control and avoid frequent exacerbations by simply using their inhalers every day.” (F. D. Martinez)
Symptoms in Smokers with Preserved Pulmonary Function: While many current and former smokers have respiratory symptoms but do not meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD), bronchodilators and glucocorticoids are being used without any evidence base for efficacy or safety, researchers report (pp. 1811–21). Among 2,736 current or former smokers and controls who had never smoked, respiratory symptoms as measured with the COPD Assessment Test and other assessment tools showed these results: “Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (± SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27 ± 0.67 vs. 0.08 ± 0.31 and 0.03 ± 0.21 events, respectively, per year; P <0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to [high-resolution computed tomographic scans] than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.” (P. G. Woodruff, prescott.woodruff@ucsf.edu)
The results of this and other studies show that “smoking itself should be considered the disease and should be approached in all its complexity,” an editorialist writes (
pp. 1885–6). Referring to an analysis showing that smokers with symptoms “are treated like patients with COPD, but they do not have COPD according to our current definition,” the author notes: “Since our treatment database was derived only from people with airflow obstruction, we should probably limit recommendations to the diagnosis and treatment of the spirometrically confirmed COPD that is defined according to current guidelines. These new studies help us define this new cohort of patients with chronic respiratory symptoms without obstruction. It is now up to us to figure out how to treat them in order to help reduce symptoms and prevent exacerbations.” (L. M. Fabbri)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 13, 2016 * Vol. 23, No. 93
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
May 15 issue of Clinical Infectious Diseases (2016; 62).
Central Line–Associated Bloodstream Infections: In oncology settings, antimicrobial-resistant Escherichia coli and Enterococcus faecium have emerged as “significant pathogens” in central line–associated bloodstream infection (CLABSI), a study shows (pp. 1203–9). “Practices for antimicrobial prophylaxis and empiric antimicrobial therapy should be regularly assessed in conjunction with contemporary antimicrobial resistance data,” the authors conclude. National Healthcare Safety Network (NHSN) data from 2009 to 2012 show these CLABSI incidence rates per 1,000 central line–days: “4,654 CLABSIs were reported to NHSN from 299 adult oncology units. The most common organisms causing CLABSI in oncology locations were coagulase-negative staphylococci (16.9%), Escherichia coli (11.8%), and Enterococcus faecium (11.4%). Fluoroquinolone resistance was more common among E. coli CLABSI in oncology than nononcology locations (56.5% vs 41.5% of isolates tested; P <.0001) and increased significantly from 2009–2010 to 2011–2012 (49.5% vs 60.4%; P = .01). Furthermore, rates of CLABSI were significantly higher in oncology compared to nononcology locations for fluoroquinolone-resistant E. coli (rate ratio, 7.37; 95% confidence interval [CI], 6.20–8.76) and vancomycin-resistant E. faecium (rate ratio, 2.27, 95% CI, 2.03–2.53). However, resistance rates for some organisms, such as Klebsiella species and Pseudomonas aeruginosa, were lower in oncology than in nononcology locations.” (I. See, isee@cdc.gov)
Stillbirth Following Influenza Vaccination During Pregnancy: In a cohort study from Australia, administration of the seasonal trivalent influenza vaccine during pregnancy is associated with lower risks of stillbirth (pp. 1221–7). Among 58,008 births in 2012–13 with birth at or after 20 weeks’ gestation and Apgar scores of 0 at 1 and 5 minutes, these associations were noted based on receipt of influenza vaccine: “A total of 5,076 (8.8%) pregnant women received trivalent influenza vaccine and 377 stillbirths occurred. There were 5.0 and 3.0 stillbirths per 100,000 pregnancy–days among unvaccinated and vaccinated women, respectively. After adjustment, stillbirth was 51% less likely among vaccinated vs unvaccinated mothers (aHR, 0.49; 95% confidence interval [CI], .29–.84). The largest relative reduction in stillbirths was observed for births occurring just after influenza season (aHR, 0.33; 95% CI, .12–.88).” (A. K. Regan, annette.regan@health.wa.gov.au)
Timing of Antibiotic Therapy in Enterococcal Septicemia: Hospitalized patients who develop enterococcal bloodstream infections (EBSI) fare better when antibiotic therapy is started within 48 hours, researchers report (pp. 1242–50). In a retrospective cohort analysis of adults in 2010–14, mortality rates at 30 days were lower with early treatment: “Overall, 190 patients were included. A breakpoint in time to appropriate therapy was identified at 48.1 hours, where 30-day mortality was substantially increased (14.6% vs 45.3%; P <.001). Patients receiving appropriate therapy after 48.1 hours also experienced higher in-hospital mortality and longer EBSI duration. After adjustment for severity of illness and comorbidity, delayed therapy ≥48.1 hours was associated with a 3-fold increase in 30-day mortality (risk ratio, 3.16 [95% confidence interval, 1.96–5.09]). Vancomycin resistance was the only independent predictor of delayed therapy.” (M. J. Rybak, m.rybak@wayne.edu)

>>>Oncology Highlights
Source:
May 20 issue of the Journal of Clinical Oncology (2016; 34).
Vitamin D Levels & Melanoma: Among patients with melanoma, lower vitamin D levels were associated with poorer outcomes, and the relationship held even after adjusting for higher C-reactive protein (CRP) levels (pp. 1741–7): “A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024),” the authors report. “On univariate analysis, lower vitamin D was associated with poorer overall (P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates.” (J. E. Lee, jelee@mdanderson.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 16, 2016 * Vol. 23, No. 94
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Hospital Value-Based Purchasing & Patient Mortality: Alternative models with evidence of improved patient outcomes should be considered instead of hospital value-based purchasing (HVBP) programs, investigators conclude based on a study of U.S. 30-day risk-adjusted mortality rates for acute myocardial infarction, heart failure, or pneumonia among 2.4 million patients admitted during 2008–13 (i2214). In data from 2,919 hospitals in the HVBP program and 1,348 ineligible hospitals used as controls, these patterns of outcomes were noted: “Mortality rates of incentivized conditions in hospitals participating in the HVBP program declined at −0.13% for each quarter during the preintervention period and −0.03% point difference for each quarter during the post-intervention period. For non-HVBP hospitals, mortality rates declined at −0.14% point difference for each quarter during the preintervention period and −0.01% point difference for each quarter during the post-intervention period. The difference in the mortality trends between the two groups was small and non-significant (difference in difference in trends −0.03% point difference for each quarter, 95% confidence interval −0.08% to 0.13% point difference, P = 0.35). In no subgroups of hospitals was HVBP associated with better outcomes, including poor performers at baseline.” (A. K. Jha, ajha@hsph.harvard.edu)
Low-Dose Estrogens in Combined Oral Contraception: Used for combination oral contraception, levonorgestrel in lower estrogen doses was associated with the lowest risks of three serious adverse events in a study of nearly 5 million women in France (i2002). Analyzing the French national health insurance database in 2010–12, researchers report: “The cohort generated 5,443,916 women years of oral contraceptive use, and 3,253 events were observed: 1,800 pulmonary embolisms (33 per 100,000 women years), 1,046 ischaemic strokes (19 per 100,000 women years), and 407 myocardial infarctions (7 per 100,000 women years). After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% confidence interval 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel. Levonorgestrel combined with 20 µg oestrogen was associated with a statistically significantly lower risk than levonorgestrel with 30–40 µg oestrogen for each of the three serious adverse events.” (A. Weill, alain.weill@cnamts.fr)

>>>Lancet Highlights
Source:
May 14 issue of Lancet (2016; 387).
Analgesia for Renal Colic: In a controlled trial, I.M. NSAIDs proved to be the best emergency department treatment for patients with moderate to severe renal colic (pp. 1999–2007). At a tertiary care hospital in Qatar, analysis of I.M. diclofenac, I.V. morphine, and I.V. paracetamol (acetaminophen) showed these results for a primary outcome of proportion of participants achieving at least a 50% reduction in initial pain score at 30 min after analgesia: “Compared to morphine, diclofenac was significantly more effective in achieving the primary outcome (odds ratio [OR] 1.35, 95% CI 1.05–1.73, p = 0.0187), whereas no difference was detected in the effectiveness of morphine compared with intravenous paracetamol (1.26, 0.99–1.62, p = 0.0629).” (S. A. Pathan, drsameer_pathan@live.com)

>>>PNN NewsWatch
* FDA has issued MedWatch alerts concerning serious adverse effects with fluoroquinolones that outweigh benefits for most patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options; counterfeit products labeled as carmustine in some foreign countries; and presence of sildenafil in some SOS Telecom prescription drugs, including nitroglycerin.

>>>PNN JournalWatch
* Toward Precision Medicine and Health: Opportunities and Challenges in Allergic Diseases , in
Journal of Allergy and Clinical Immunology, 2016; 137: 1289–300. (S. J. Galli, sgalli@stanford.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 17, 2016 * Vol. 23, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 17 issue of the Annals of Internal Medicine (2016; 164).
Preventing Major Depression in Primary Care: A personalized program aimed at preventing depression among patients in primary care settings yielded modest but nonsignificant reductions in risk, a study from Spain shows (pp. 656–65). Primary care physicians (PCPs) at 10 centers in 7 cities “communicated individual risk for depression and personal predictors of risk and developed a psychosocial program tailored to prevent depression,” the authors report. Among 3,326 adult patients who were not depressed at baseline, these outcomes were observed over an 18-month period: “At 18 months, 7.39% of patients in the intervention group (95% CI, 5.85% to 8.95%) developed major depression compared with 9.40% in the control (usual care) group (CI, 7.89% to 10.92%) (absolute difference, −2.01 percentage points [CI, −4.18 to 0.16 percentage points]; P = 0.070). Depression incidence was lower in the intervention centers in 5 cities and similar between intervention and control centers in 2 cities.” (J. Á. Bellón, jabellon@uma.es)
Uncertainty in Treatment Rankings From Network Meta-analyses: Authors and readers should be cautious about interpreting treatment rankings based on network meta-analyses, according to an evaluation of the uncertainty of these studies (pp. 666–73). Using data from 58 network meta-analyses of 1,308 randomized trials and 404 interventions, the investigators found these Bayesian results for the surface under the cumulative ranking curve (SUCRA) and its 95% credible interval (95% CrI): “The median width of the 95% CrIs of the SUCRA was 65% (first to third quartile, 38% to 80%). In 28% of networks, there was a 50% or greater probability that the best-ranked treatment was actually not the best. No evidence showed a difference between the best-ranked intervention and the second and third best-ranked interventions in 90% and 71% of comparisons, respectively. In 39 networks with 6 or more interventions, the median probability that 1 of the top 2 interventions was among the bottom 2 was 35% (first to third quartile, 14% to 59%).” (L. Trinquart, ludovic.trinquart@aphp.fr)
Using Network Meta-analyses for Clinical Practice Guidelines: Using network meta-analysis of first-line treatments for primary open-angle glaucoma (POAG) as a case report, researchers conclude that this technique is useful “for timely recommendations when multiple treatment options are available” (pp. 674–82). Eligible randomized controlled trials (RCTs) and major updates of American Academy of Ophthalmology guidelines since 1991 were used to determine the following: “Guidelines were grouped together on the basis of literature search dates, and RCTs that existed at 1991, 1995, 1999, 2004, and 2009 were analyzed. The outcome of interest was intraocular pressure (IOP) at 3 months. Only the latest guideline made a specific recommendation: prostaglandins. Network meta-analyses showed that all treatments were superior to placebo in decreasing IOP at 3 months. The mean reductions (95% credible intervals [CrIs]) for the highest-ranking class compared with placebo were as follows: 1991: beta-blockers, 4.01 (CrI, 0.48 to 7.43); 1995: alpha-2-adrenergic agonists, 5.64 (CrI, 1.73 to 9.50); 1999: prostaglandins, 5.43 (CrI, 3.38 to 7.38); 2004: prostaglandins, 4.75 (CrI, 3.11 to 6.44); 2009: prostaglandins, 4.58 (CrI, 2.94 to 6.24).” (T. Li, tli19@jhu.edu)
Support of Benefit-Based Tailored Treatment for Lipids: Writing in an Ideas and Opinions article, authors maintain that recently published reports of nonstatin lipid-lowering medications do not challenge the 2013 lipid guidelines issued by the American College of Cardiology and the American Heart Association (pp. 683–4): “In fact, this new clinical evidence, which is not based on treatment to LDL cholesterol targets, reinforces the importance of cardiovascular risk and the secondary importance of LDL cholesterol levels. The controversy surrounding this new evidence provides an opportunity to review important principles in applying clinical trial results to real-world clinical care and shows why guidelines should move away from treatment targets based on a single measure of risk—such as blood pressure or hemoglobin A1c level—and toward more global, benefit-based tailored treatment.” (T. P. Hofer, thofer@umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 18, 2016 * Vol. 23, No. 96
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
May 17 issue of JAMA (2016; 315).
Prophylactic High-Dose Erythropoietin in Very Preterm Infants: Neurodevelopmental outcomes at 2 years were statistically similar in very preterm infants who received placebo or prophylactic early high-dose recombinant human erythropoietin (rhEPO), researchers report (pp. 2079–85). The infants were born at 26 to 31 weeks’ gestation and were randomly assigned to rhEPO 3,000 IU/kg or placebo at various timepoints in the first 42 hours after birth. Results showed: “Among 448 preterm infants randomized (mean gestational age, 29.0 [range, 26.0–30.9] weeks; 264 [59%] female; mean birth weight, 1210 [range, 490–2,290] g), 228 were randomized to rhEPO and 220 to placebo. Neurodevelopmental outcome data were available for 365 (81%) at a mean age of 23.6 months. In an intention-to-treat analysis, mean [Mental Development Index] was not statistically significantly different between the rhEPO group (93.5 [SD, 16.0] [95% CI, 91.2 to 95.8]) and the placebo group (94.5 [SD, 17.8] [95% CI, 90.8 to 98.5]) (difference, −1.0 [95% CI, −4.5 to 2.5]; P = .56). No differences were found between groups in the secondary outcomes.” (G. Natalucci)
Communicating with Surrogates of Critically Ill Patients: Differences between a physician’s and a surrogate’s perceptions of prognosis for critically ill patients “were common … and were related to misunderstandings by surrogates about physicians’ assessments of patients’ prognoses and differences in beliefs about patients’ prognoses,” a study shows (pp. 2086–94). For 174 critically ill patients, including 75 who died, these differences in prognostic estimates were noted: “Surrogates’ prognostic estimates were much more accurate than chance alone, but physicians’ prognostic estimates were statistically significantly more accurate than surrogates’ (C statistic, 0.83 vs 0.74; absolute difference, 0.094; 95% CI, 0.024–0.163; P = .008). Among 71 surrogates interviewed who had beliefs about the prognosis that were more optimistic than that of the physician, the most common reasons for optimism were a need to maintain hope to benefit the patient (n = 34), a belief that the patient had unique strengths unknown to the physician (n = 24), and religious belief (n = 19).” (D. B. White, whitedb@upmc.edu)
Acid and/or Lymphocytes in GERD? Findings from a Preliminary Communication indicate that the pathophysiologic mechanisms in acute gastroesophageal reflux disease (GERD) may be T lymphocyte–predominant esophageal inflammation and basal cell and papillary hyperplasia in response to refluxed acid rather than direct effects of acid on tissue (pp. 2104–12). Among 12 patients with reflux esophagitis who were successfully treated with proton pump inhibitors (PPIs), 24-hour esophageal pH and impedance monitoring and esophagoscopy showed the following: “At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0–2) at baseline vs 1 (1–2) at both 1 week [P = .005] and 2 weeks [P = .002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by [confocal laser endomicroscopy]), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; ∆, 16.2% [95% CI, 4.4%-26.5%], P = .005), mucosal impedance decreased (mean: 2671.3 Ω at baseline to 1508.4 Ω at 2 weeks; ∆, 1162.9 Ω [95% CI, 629.9-1695.9], P = .001), and all patients had evidence of esophagitis.” (K. B. Dunbar)
“Shifting the model of the pathogenesis of esophagitis from a 1-dimensional focus on chemical injury to one of cytokine-mediated inflammation, sometimes culminating in caustic injury to the distal esophageal mucosa with mucosal erosion and neutrophil-mediated inflammation, … opens the door to explaining other phenotypes of GERD that have emerged in recent years,” writes an editorialist (
pp. 2077–8). “This is not a one-size-fits-all disease.” (P. J. Kahrilas).

>>>PNN NewsWatch
* Nevada-based Well Care Compounding Pharmacy has issued a voluntary statewide recall of all sterile compounded products because of FDA concerns over sterility assurance.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 19, 2016 * Vol. 23, No. 97
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
May 19 issue of the New England Journal of Medicine (2016; 374).
Rate v. Rhythm Control in AF: In patients with new-onset postoperative atrial fibrillation, strategies using heart-rate or rhythm control produced similar statistical and clinical outcomes, with “neither treatment strategy [showing] a net clinical advantage over the other,” researchers report (pp. 1911–21). Based on a primary end point of total number of days of hospitalization within 60 days after randomization, the study showed: “Postoperative atrial fibrillation occurred in 695 of the 2,109 patients (33.0%) who were enrolled preoperatively; of these patients, 523 underwent randomization. The total numbers of hospital days in the rate-control group and the rhythm-control group were similar (median, 5.1 days and 5.0 days, respectively; P = 0.76). There were no significant between-group differences in the rates of death (P = 0.64) or overall serious adverse events (24.8 per 100 patient–months in the rate-control group and 26.4 per 100 patient–months in the rhythm-control group, P = 0.61), including thromboembolic and bleeding events. About 25% of the patients in each group deviated from the assigned therapy, mainly because of drug ineffectiveness (in the rate-control group) or amiodarone side effects or adverse drug reactions (in the rhythm-control group). At 60 days, 93.8% of the patients in the rate-control group and 97.9% of those in the rhythm-control group had had a stable heart rhythm without atrial fibrillation for the previous 30 days (P = 0.02), and 84.2% and 86.9%, respectively, had been free from atrial fibrillation from discharge to 60 days (P = 0.41).” (A. C. Gelijns, annetine.gelijns@mountsinai.org)
These findings “support the concept that the initial goal should be rate control because no clear benefit of the more complex rhythm-control strategy was observed,” an editorialist writes (
pp. 1977–8). “Efforts to restore sinus rhythm should be reserved for patients in whom rate control cannot be achieved or for those who are hemodynamically unstable or highly symptomatic.” (H. Calkins)
Danazol for Telomere Diseases: In a phase 1/2 study in patients with genetic defects in telomere maintenance and repair, the synthetic sex hormone danazol 800 mg/d performed better than expected, not just stopping decline but actually producing telomere elongation (pp. 1922–31): “After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol— elevated liver-enzyme levels and muscle cramps— of grade 2 or less occurred in 41% and 33% of the patients, respectively.” (D. M. Townsley, townsleydm@nhlbi.nih.gov)
“Elongation of telomeres through androgen treatment may have applications in the treatment or prevention of other diseases linked to defective telomere maintenance,” writes an editorialist (
pp. 1978–80). “The effect of this treatment on lung and liver in older patients with these disorders needs to be examined.… More information about the role of telomerase and telomeres in the biology of various normal, premalignant, and malignant cells is urgently needed.” (P. M. Lansdorp)

>>>PNN NewsWatch
* The first in a new class of PD-1/PD-L1 inhibitors, atezolizumab (Tecentriq, Genentech) was approved yesterday by FDA for patients with locally advanced or metastatic urothelial carcinoma whose disease has worsened during or following platinum-containing chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before (neoadjuvant) or after (adjuvant) surgical treatment.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 20, 2016 * Vol. 23, No. 98
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source:
June American Journal of Kidney Diseases (2016; 67).
Statins & Kidney Disease Outcomes: Looking at statin therapy in adult patients not on dialysis, investigators find that the drugs “may modestly reduce proteinuria and rate of [estimated glomerular filtration rate (eGFR] decline” but otherwise do not reduce the risk of kidney failure events (pp. 881–92). A systematic review and meta-analysis of 57 eligible studies of 143,888 participants showed the following: “Statin treatment did not produce an apparent beneficial effect for kidney failure events (OR, 0.98; 95% CI, 0.87–1.10; P = 0.7) or end-stage renal disease events (OR, 0.98; 95% CI, 0.90–1.07; P = 0.7). However, mean difference for rate of decline in eGFR (0.41 [95% CI, 0.11–0.70] mL/min/1.73 m2 per year slower in statin recipients) and standardized mean difference for change in proteinuria or albuminuria (−0.65 [95% CI, −0.94 to −0.37] standard deviation units, statin recipients vs controls) were statistically significant. In addition, statin therapy significantly reduced the risk for cardiovascular events (OR, 0.69; 95% CI, 0.61–0.79; P <0.001) in patients with chronic kidney disease.” (J. Lv, jichenglv75@gmail.com)
Tolvaptan & Neurocognitive Function: Rapid motor movements and other indicators of neurocognitive function improve when tolvaptan reverses chronic hyponatremia, a phase 3b study shows, but benefits disappear when serum sodium concentrations return to low baseline (pp. 893–901). In 57 adults aged 50 or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia, these outcomes of tolvaptan versus placebo therapy were noted: “Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P <0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04–0.51; P = 0.03).” (J. G. Verbalis, verbalis@georgetown.edu)
Sodium Restriction in Kidney Transplant Recipients With RAAS Blockade: “In stable kidney transplant recipients receiving [renin-angiotensin-aldosterone system (RAAS)] blockade, dietary sodium restriction effectively reduces [blood pressure (BP)] without affecting [estimated glomerular filtration rate (eGFR)],” researchers report (pp. 936–44). The 22 participants received 6 weeks of regular-sodium or low-sodium diets, with these results: “Sodium excretion decreased from 164 ± 50 mmol/24 h during the regular-sodium diet to 87 ± 55 mmol/24 h during the low-sodium diet (mean difference, −77 [95% CI, −110 to −44] mmol/24 h; P <0.001). Sodium restriction significantly reduced systolic BP from 140 ± 14 to 129 ± 12 mm Hg (mean difference, −11 [95% CI, −14 to −7] mm Hg; P <0.001), diastolic BP from 86 ± 8 to 79 ± 8 mm Hg (mean difference, −7 [95% CI, −10 to −5] mm Hg; P <0.001). We found no significant effect on natural log (ln)-transformed [urinary albumin excretion (UAE)] (mean difference, −0.03 [95% CI, −0.6 to 0.6] ln(mg/24 h); P = 0.9) or eGFR.” (L. V. de Vries, l.v.de.vries@umcg.nl)

>>>Allergy/Immunology Report
Source:
May issue of the Journal of Allergy and Clinical Immunology (2016; 137).
Costs & Outcomes in Step-Down Asthma Care: Similar outcomes are produced at less cost when therapy is stepped down in patients with controlled asthma, according to an analysis of data from the US Medical Expenditure Panel Survey for 2000–10 (pp. 1373–9.e3): “Overall, 29.9% of patients meeting the inclusion criteria (n = 4,235) were eligible for step down; 89.4% (95% CI, 86.4% to 92.4%) of those who stepped down had preserved asthma control compared with 83.5% (95% CI, 79.9% to 87.0%) of those who were similarly eligible for step down but maintained their treatment level. The average monthly asthma-related cost savings was $34.02/mo (95% CI, $5.42/mo to $61.24/mo) with step down compared with maintenance of the treatment level.” (M. A. Rank, rank.matthew@mayo.edu)

>>>PNN NewsWatch
* Reacting to a patient death, FDA is reminding clinicians that oral ketoconazole tablets have not been indicated for skin and nail infections since FDA removed the indication in 2013.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 23, 2016 * Vol. 23, No. 99
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 21 issue of Lancet (2016; 387).
NSAIDs v. Acetaminophen in Osteoarthritic Pain: A network meta-analysis challenges use of monotherapy with paracetamol (acetaminophen) in patients with osteoarthritis (pp. 2093–105). “On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose,” the group concludes. “We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients.” (S. Trelle, sven.trelle@ctu.unibe.ch)
Vaginal Progesterone Prophylaxis for Preterm Birth: While producing no negative outcomes during pregnancy or after birth, vaginal progesterone “was not associated with reduced risk of preterm birth” in a group of 1,228 pregnant women, researchers report (pp. 2106–16). Doses of 200 mg daily taken by women at increased risk of preterm birth from 22–24 to 34 weeks’ gestation (n = 618) were compared with placebo (n = 610), yielding these results: “In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0.86, 95% CI 0.61–1.22) or neonatal outcome (OR 0.62, 0.38–1.03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97.3 [SD 17.9] vs 97.7 [17.5]; difference in means −0.48, 95% CI −2.77 to 1.81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p = 0.27).” (J. E. Norman, k jane.norman@ed.ac.uk)
Nifedipine v. Atosiban for Threatened Preterm Birth: The calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban produced similar obstetric and neonatal outcomes in a study of threatened preterm birth conducted in the Netherlands and Belgium (pp. 2117–24). Women participating in the APOSTEL III trial were at weeks 25–34 of pregnancy at baseline. The composite primary outcome included adverse perinatal outcomes (perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis); results showed: “Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0.91, 95% CI 0.61–1.37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2.20, 95% CI 0.91–5.33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups.” (M. A. Oudijk, m.a.oudijk@amc.uva.nl)

>>>PNN JournalWatch
* Ledipasvir–Sofosbuvir: A Once-Daily Oral Treatment Option for Chronic Hepatitis C Virus Genotype 1 Infection, in
Pharmacotherapy, 2016; 36: 10.1002/phar.1748. (L. Holle, lisa.holle@uconn.edu)
* Bazedoxifene and Conjugated Equine Estrogen: A Combination Product for the Management of Vasomotor Symptoms and Osteoporosis Prevention Associated with Menopause, in
Pharmacotherapy, 2016; 36: 10.1002/phar.1749. (E. M. Umland, elena.umland@jefferson.edu)
* Dynamics of Microtubules and Their Associated Proteins: Recent Insights and Clinical Implications, in
Neurology, 2016; 86: 1911–20. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
*Despite Federal Legislation, Shortages of Drugs Used in Acute Care Settings Remain Persistent and Prolonged, in
Health Affairs, 2016; 35: 798–804. (A. K. Venkatesh, arjun.venkatesh@yale.edu)
* Steady Increase in Prices for Oral Anticancer Drugs After Market Launch Suggests A Lack of Competitive Pressure, in
Health Affairs, 2016; 35: 805–12. (C. S. Bennette, cb11@uw.edu)
* Income Inequities and Medicaid Expansion Are Related to Racial and Ethnic Disparities in Delayed or Forgone Care Due to Cost, in
Medical Care, 2016; 54: 555–61. (C. R. Clark)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 24, 2016 * Vol. 23, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-online content from JAMA Internal Medicine (2016; 176).
Opioid Analgesics for Low Back Pain: With a bottom line that “the efficacy of opioid analgesics in acute low back pain is unknown,” authors of a systematic review and meta-analysis paint a bleak picture based on available evidence (10.1001/jamainternmed.2016.1251): “For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short-term pain relief but the effect is not likely to be clinically important within guideline recommended doses. Evidence on long-term efficacy is lacking.” (A. J. McLachlan, andrew.mclachlan@sydney.edu.au)
Patent Troll Legislation: A proposed bill being considered by the U.S. Congress could affect legal maneuvers that impede timely access to generic drugs, according to authors of a Viewpoint article (10.1001/jamainternmed.2016.1867): “Patent reform legislation was recently introduced in Congress—the Protecting American Talent and Entrepreneurship Act of 2015 (PATENT Act) in the Senate and Innovation Act in the House—to curb the effects of nonpracticing entities or, as they are more colorfully known, ‘patent trolls.’ Nonpracticing entities are organizations that acquire and hold patents, often not developing technology related to their patents, and use their patent rights to sue companies that are developing and selling allegedly infringing products. Patent trolls, though a thorn to large technology companies, are less prevalent in the health care field. However, the legislation has nonetheless been strongly contested by the biopharmaceutical industry because current efforts to restrict patent trolls represent the latest in a series of initiatives to bring restraint to the patent system—and specifically have an impact on poorly innovative drug patents that manufacturers traditionally rely on to maintain profits by delaying timely generic drug competition.” (C. L. Treasure)

>>>Rheumatology Report
Source:
May issue of Arthritis & Rheumatology (2016; 68).
Biosimilar Use in South Korea: Use of biosimilar infliximab was low during its introduction into South Korea, researchers report, but use of other agents was affected (pp. 1076–9). Looking for patterns with applicability to other countries as the biosimilar process ramps up, authors analyzed claims data for 2009 through 2014, bookending the introduction of biosimilar infliximab in 2012. Results showed: “In total, 20,976 TNF inhibitor users were identified from the South Korean claims database, including 983 with a prescription claim for biosimilar infliximab. Among all of the claims for any version of infliximab, the proportion of biosimilar infliximab claims increased to 19% through March 2014. Before November 2012, each month there were 33 (95% confidence interval [95% CI] 32, 35) more infliximab claims, 44 (95% CI 40, 48) more etanercept claims, and 50 (95% CI 47, 53) more adalimumab claims. After November 2012, there were significant changes in the slopes for trend in usage, with additional increases in the use of branded and biosimilar infliximab (9 more claims per month, 95% CI 2, 17) and decreases in the use of etanercept (−52 claims per month, 95% CI −66, −38) and adalimumab (−21 claims per month, 95% CI −35, −6).” (S. C. Kim, skim62@partners.org)
Incident Diabetes Mellitus, Glucocorticoids & RA: In patients with rheumatoid arthritis (RA), use of glucocorticoids (GC) within the last 6 months “is a clinically important and quantifiable risk factor for [diabetes mellitus (DM)],” a study shows (pp. 1089–98). A cohort analysis of the U.K. Clinical Practice Research Datalink (CPRD) and the U.S. National Data Bank for Rheumatic Diseases (NDB) shows these patterns of risk for incident DM: “The hazard ratio (HR) was 1.30 (95% confidence interval [95% CI] 1.17–1.45) and 1.61 (95% CI 1.37–1.89) in current GC users compared to nonusers in the CPRD and the NDB, respectively. A range of conventional statistical models consistently confirmed increases in risk with the GC dosage and duration. The [weighted cumulative dose] model showed that recent GC use contributed the most to the current risk of DM, while doses taken >6 months previously did not influence current risk. In the CPRD, 5 mg of prednisolone equivalent dose for the last 1, 3, and 6 months was significantly associated with HRs of 1.20, 1.43, and 1.48, respectively, compared to nonusers.” (W. G. Dixon, Will.Dixon@manchester.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 25, 2016 * Vol. 23, No. 101
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
May 24/31 issue of JAMA (2016; 315).
Sodium Excretion & Cardiovascular Disease in CKD: Analyzing the effects of sodium intake on development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD), investigators find a linear relationship between higher urinary sodium excretion and increased risk of CVD (pp. 2200–10). While some data have indicated a possible J-shaped curve, these authors found no CVD benefit from moderate intake of sodium among those enrolled in the Chronic Renal Insufficiency Cohort Study from 2003 to 2013: “Among 3,757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2,894 mg/24 hours) to highest (≥4,548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09–1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03–1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08–3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001).” (J. He, jhe@tulane.edu)
This “well-designed and -conducted study … adds to the growing body of evidence suggesting that patients with CKD have health consequences associated with a particular aspect of their diet,” editorialists write (
pp. 2173–4). “Recommendations for sodium intake among patients with CKD should be based on replication of these results and most of all experimental studies. It is time to launch representative, large-scale clinical trials of dietary interventions for persons with CKD. If the results reported [in this study] are validated in experimental studies, efforts to influence sodium intake in persons with CKD could save many lives and medical costs. As Sir William Osler, MD, an admired physician, said, ‘Patients should have rest, food, fresh air, and exercise—the quadrangle of health.’ Recommendations regarding the types and amounts of food people eat, and the amount of sodium consumed, should be guided by evidence that these dietary intakes will promote human health.” (N. R. Powe)
Treating Opioid Use Disorders: Calling for “a stronger treatment system for opioid use disorders,” Viewpoint authors write that federal money will not be enough to address the opioid epidemic (pp. 2165–6): “The Centers for Medicare & Medicaid Services has begun supporting state substance abuse treatment delivery system innovation through the Innovator Accelerator Program (IAP), providing a modest investment in technical assistance to help states strengthen delivery systems. The IAP includes support to help states engage in outcome tracking and quality improvement.…
“Funding more treatment services is necessary to address the nation’s addiction challenge, but it is not sufficient. By building effective systems of care that track outcomes and integrate expanded access within other evidence-based public health strategies, the federal government can make meaningful progress against this epidemic.” (B. Saloner)
Persistent Rash in TPN: A JAMA Clinical Challenge article presents the case of a 50-year-old man with generalized alopecia and erythematous, scaly rash on the face and scalp that developed about 8 months after beginning total parenteral nutrition (pp. 2223–4). Past medical history was significant for history of metastatic mucinous appendiceal adenocarcinoma, a desquamating rash on his face that had spread to his scalp, inguinal region, and perineum over the past 4 months, and no improvement in the rash despite multiple rounds of oral fluconazole, topical antibiotic ointment, and intravenous antibiotics. What would you recommend be done next: skin biopsy, trace element levels, topical steroid cream, or paraneoplastic panel? (V. G. Fowler Jr., vance.fowler@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 26, 2016 * Vol. 23, No. 102
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
May 26 issue of the New England Journal of Medicine (2016; 374).
Primary Results of the HOPE-3 Trial: In three articles and an editorial, primary results of the Heart Outcomes Prevention Evaluation (HOPE)–3 trial are presented.
During a median follow-up period of 5.6 years, blood-pressure-lowering with candesartan 16 mg/d plus hydrochlorothiazide 12.5 mg/d was statistically similar to placebo for lowering rates of major cardiovascular events among 12,705 participants at intermediate risk who did not have cardiovascular disease at baseline (
pp. 2009–20). Based on coprimary outcomes of (1) composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke or (2) those factors plus resuscitated cardiac arrest, heart failure, and revascularization, the investigators found: “The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P = 0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P = 0.02 and P = 0.009, respectively, for trend in the two outcomes).” (E. M. Lonn, eva.lonn@phri.ca)
Lipid lowering proved more beneficial, the HOPE-3 investigators report (
pp. 2021–31, pp. 2032–43). In the same population as above and again with 5.6 years’ follow-up, “Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease,” the group concludes in the second article. The final article, comparing those patients on rosuvastatin and candesartan/hydrochlorothiazide with those on dual placebo, also found significant benefits of treatment: “The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P = 0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P = 0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups.” (S. Yusuf, yusufs@mcmaster.ca)
“The results of the HOPE-3 trial suggest that rosuvastatin at a dose of 10 mg per day is more effective in preventing cardiovascular events than is candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day in this relatively low-risk population,” editorialists conclude (
pp. 2085–7). “Although these results do not exclude the possibility that more effective therapy for blood-pressure lowering might be beneficial in a relatively low-risk, older population, they provide support for the use of statins as a safe and effective intervention to prevent cardiovascular events in such patients.” The writers add, “The results of the comparison of the effects of the combined intervention (rosuvastatin and candesartan plus hydrochlorothiazide) with placebo generally agreed with the results for the separate interventions. There was no evidence of harm or synergy between the two interventions. Although the addition of blood-pressure lowering to rosuvastatin therapy appeared to provide more benefit than that observed with rosuvastatin alone in the subgroup of participants who were in the upper third of systolic blood pressure levels, the P value for interaction was not significant.” (W. C. Cushman)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 27, 2016 * Vol. 23, No. 103
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
June issue of Diabetes Care (2016; 39).
Metabolic Surgery for Type 2 Diabetes: Presenting 11 articles on use of metabolic surgery in type 2 diabetes (T2D), journal editors write (pp. 857–60): “In the centerpiece of this collection, Rubino et al. report new evidence-based guidelines for surgical treatment of T2D, writing on behalf of 48 voting delegates (75% are nonsurgeons) of the 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference organized in collaboration with major diabetes organizations. These recommendations, endorsed thus far by 45 international professional societies [see Table 1, Rubino et al.], reflect a large body of evidence demonstrating that several gastrointestinal (GI) operations initially designed to promote weight loss (bariatric surgery) can improve glucose homeostasis more effectively than any known pharmaceutical or behavioral approach, causing durable remission in many patients with T2D. Formally ratified by an unprecedented array of societies representing diverse medical and surgical specialties from around the world, these new guidelines can serve as a global reference for the use and study of GI surgery as an intentional treatment option for T2D (‘metabolic surgery&rsquoWinking.” (W. T. Cefalu, cefaluwt@pbrc.edu)
Lipid Lowering & CVD in Type 1 Diabetes: In patients with type 1 diabetes without history of cardiovascular disease (CVD), lipid-lowering therapy (LLT) for primary prevention was associated with reduced risk of CVD and cardiovascular death, researchers report (pp. 996–1003). Analysis of the Swedish National Diabetes Register in a propensity score-based study showed the following for 24,230 individuals with type 1 diabetes in 2006–08: “The propensity score allowed balancing of all 32 covariates, with no differences between treated and untreated after accounting for propensity score. Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50–0.72), all-cause death 0.56 (0.48–0.64), fatal/nonfatal stroke 0.56 (0.46–0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66–0.92), fatal/nonfatal coronary heart disease 0.85 (0.74–0.97), and fatal/nonfatal CVD 0.77 (0.69–0.87).” (C. Hero, christel.hero@vgregion.se)
Addition of Liraglutide to Insulin in Type 1 Diabetes: In a 12-week study, liraglutide added to insulin in 72 patients with type 1 diabetes (T1D and overweight/obesity had “modest reductions of weekly mean glucose levels with significant weight loss, small insulin dose reductions, and frequent gastrointestinal side effects” (pp. 1027–35). “These findings do not justify the use of liraglutide in all patients with T1D,” the group concludes based on these results: “In the 1.2-mg and 1.8-mg groups, the mean weekly reduction in average blood glucose was −0.55 ± 0.11 mmol/L (10 ± 2 mg/dL) and −0.55 ± 0.05 mmol/L (10 ± 1 mg/dL), respectively (P < 0.0001), while it remained unchanged in the 0.6-mg and placebo groups. In the 1.2-mg group, HbA1c fell significantly (−0.78 ± 15%, −8.5 ± 1.6 mmol/mol, P < 0.01), while it did not in the 1.8-mg group (−0.42 ± 0.15%, −4.6 ± 1.6 mmol/mol, P = 0.39) and 0.6-mg group (−0.26 ± 0.17%, −2.8 ± 1.9 mmol/mol, P = 0.81) vs. the placebo group (−0.3 ± 0.15%, −3.3 ± 1.6 mmol/mol). Glycemic variability was reduced by 5 ± 1% (P <0.01) in the 1.2-mg group only. Total daily insulin dose fell significantly only in the 1.2-mg and 1.8-mg groups (P <0.05). There was a 5 ± 1 kg weight loss in the two higher-dose groups (P <0.05) and by 2.7 ± 0.6 kg (P <0.01) in the 0.6-mg group vs. none in the placebo group. In the 1.2- and 1.8-mg groups, postprandial plasma glucagon concentration fell by 72 ± 12% and 47 ± 12%, respectively (P <0.05). Liraglutide led to higher gastrointestinal adverse events (P < 0.05) and ≤1% increases (not significant) in percent time spent in hypoglycemia (<55 mg/dL, 3.05 mmol/L).” (P. Dandona, pdandona@kaleidahealth.org)
Excluding Young Women From Antidiabetic Trials: “Exclusion criteria [for antidiabetic drug trials] affecting women of childbearing potential are often disproportionate to risk to the participant and fetus,” conclude authors of an analysis of phase 2/3 studies that included adults 18–40 years of age (pp. 1004–9; R. S. Legro, rsl1@psu.edu).

>>>PNN NewsWatch
* PNN is moving! Please note the new address and voice telephone number in the below boilerplate.
*
PNN will not be published on Mon., May 30, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 31, 2016 * Vol. 23, No. 104
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 28 issue of Lancet (2016; 387).
Sustained-Release Dexamphetamine in Heroin/Cocaine Dependence: In 73 methadone treatment–refractory heroin-dependent patients, sustained-release dexamphetamine proved to be “a well accepted, effective, and safe agonist pharmacotherapy,” researchers report (pp. 2226–34). “Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management,” the authors add. In the multicenter controlled trial, Dutch patients at heroin-assisted treatment centers who had failed at least two treatments for cocaine dependence received 12 weeks of daily, supervised prescription of oral sustained-release dexamphetamine 60 mg or placebo in addition to co-prescribed methadone and heroin, with these results: “Sustained-release dexamfetamine treatment resulted in significantly fewer days of cocaine use than placebo treatment (mean 44.9 days [SD 29.4] vs 60.6 days [24.3], respectively [95% CI of difference 3.1–28.4]; p = 0.031; Cohen’s standardised effect size d = 0.58). One or more adverse events were reported by 28 (74%) patients in the dexamfetamine group and by 16 (46%) patients in the placebo group. Most adverse events were transient and well-tolerated.” (M. Nuijten, mascha.nuijten@brijder.nl)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Dabigatran v. Warfarin in Atrial Fibrillation: Compared with outcomes as quantified in controlled trials of dabigatran and warfarin, investigators find similar efficacy figures in a U.S. health database of patients receiving routine care but underestimated rates of major bleeding, especially with warfarin (i2607). Estimates from controlled trials were used to predict annual rates of thromboembolism (composite outcome of primary inpatient diagnosis codes for ischemic or ill-defined stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, and systemic embolism) and major bleeding (composite outcome of codes occurring in an inpatient setting for hemorrhagic stroke; major upper, lower, or unspecified gastrointestinal bleed; and major urogenital or other bleed), with these results: “6,516 (30%) and 15,418 (70%) of patients initiated dabigatran and warfarin, respectively. Annual event rates per 100 patients were 1.7 for thromboembolism and 4.6 for major bleeding. For thromboembolism, calibration of estimates from randomized controlled trials was similar to calibration for model based predictions; however, trial estimates for major bleeding consistently underestimated the rate of bleeding among patients in routine care. Underestimation of bleeding rates was particularly pronounced in warfarin initiators with high HAS-BLED scores, where event rates were underestimated by up to 4.0 per 100 patient years. Harrell’s c indices for discrimination for thromboembolism or major bleeding in dabigatran and warfarin initiators ranged between 0.59 and 0.66 for randomized controlled trial predictions, and between 0.52 and 0.70 for cross validated model based predictions.” (S. V. Wang, swang27@partners.org)

>>>PNN NewsWatch
* FDA on Friday approved once-monthly daclizumab (Zinbryta; Biogen, Abbvie) for self-administered, subcutaneous treatment for relapsing forms of multiple sclerosis. The agent should generally be reserved for third-line treatment because of safety concerns, including a black-box warning about hepatic injury, including autoimmune hepatitis, and other immune-mediated disorders.
*
Axumin is newly FDA-approved radionuclide product indicated for PET imaging in men with suspected prostate cancer recurrence.
*
FDA last week approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence.

>>>PNN JournalWatch
* Norovirus Infections in Long-Term Care Facilities, in
Journal of the American Geriatrics Society, 2016; 64: 1097–103. (S. Rajagopalan, srajagopalan@ph.lacounty.gov)
* Length of Stay in the Emergency Department and Occurrence of Delirium in Older Medical Patients, in
Journal of the American Geriatrics Society, 2016; 64: 1114–9. (P. Porrino, paolapo1985@yahoo.it)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 1, 2016 * Vol. 23, No. 105
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (2016; 173).
Cannabis Use Disorder: With “attitudes toward marijuana changing,” the prevalent occurrence of DSM-5 cannabis use disorder “suggest the need to improve prevention and educate the public, professionals, and policy makers about possible harms associated with cannabis use disorders and available interventions,” researchers report (pp. 588–99). The National Epidemiologic Survey on Alcohol and Related Conditions–III for 2012–13 shows the following: “The prevalences of 12-month and lifetime cannabis use disorder were 2.5% and 6.3%. Among those with 12-month and lifetime diagnoses, the mean days of marijuana use per year were 225.3 (SE = 5.7) and 274.2 (SE = 3.8). The odds of 12-month and lifetime cannabis use disorder were higher for men, Native Americans, unmarried individuals, those with low incomes, and young adults (e.g., among those age 18–24 years versus ≥45: odds ratio for 12-month disorder, 7.2; 95% confidence interval, 5.5–9.5). Cannabis use disorder was associated with other substance use disorders, affective disorders, anxiety, and personality disorders. Twelve-month cannabis use disorder was associated with disability. As disorder severity increased, virtually all associations became stronger. Only 13.2% with lifetime cannabis use disorder participated in 12-step programs or professional treatment.” (D. S. Hasin)
“Given the shifting cannabis legal and sociocultural environment, clinicians require accurate information to guide practice development,” editorialists write (
pp. 551–3). “When seen in light of a growing body of neurodevelopmental work on the effects of cannabis on adolescent brain maturation processes, concerns about the potential harms associated with cannabis use and cannabis use disorder require public health vigilance. The findings from Hasin and colleagues help to address this gap and make a strong case for the need to enhance cannabis prevention and education efforts.” (W. M. Compton)
Mortality & Psychotropic Use in Schizophrenia: Patients with schizophrenia have lower mortality rates with moderate- and high-dose antipsychotic and antidepressant use but higher rates with long-term, high-dose benzodiazepines, a study shows (pp. 600–6). In Sweden, prospectively collected data from national databases show the following in 2006–10 for 21,492 individuals with schizophrenia diagnoses: “Compared with no exposure, both moderate (adjusted hazard ratio = 0.59, 95% CI = 0.49–0.70) and high (adjusted hazard ratio = 0.75, 95% CI = 0.63–0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio = 0.85, 95% CI = 0.73–0.98), and high exposure, even lower (adjusted hazard ratio = 0.71, 95% CI = 0.59–0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 [95% CI=1.50–2.03]).” (J. Tiihonen)

>>>Pediatrics Report
Source:
June issue of Pediatrics (2016; 137).
Improving Vaccine Delivery: While practitioners reported more improvements in immunization practices when financial incentives or a virtual learning collaborative was offered, objective measurements showed little change in immunization coverage of those in their practices (10.1542/peds.2015-4603). In a cluster-randomized trial conducted across the U.S. in 2013–14, data from 3,147 patient records in 32 practices were as follows for practices with either pay for performance (P4P) or the Vaccinator Toolkit: “Practices in the study arms reported similar [quality improvement] activities (~6 to 7 activities). We found no difference in [percentage of all needed vaccines received] between P4P and [virtual quality improvement technical support] (mean ± SE, 90.7% ± 1.1% vs 86.1% ± 1.3%, P = 0.46). Likewise, there was no difference in odds of being [up to date] between study arms (adjusted odds ratio 1.02, 95% confidence interval 0.68 to 1.52, P = .93).” (L. Y. Fu)

>>>PNN NewsWatch
* FDA has granted accelerated approval for obeticholic acid (Ocaliva, Intercept Pharmaceuticals) for treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 2, 2016 * Vol. 23, No. 106
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
June 2 issue of the New England Journal of Medicine (2016; 374).
Preventing Catheter-Associated Urinary Tract Infection: In the Agency for Healthcare Research and Quality–funded Comprehensive Unit-based Safety Program, catheter-associated urinary tract infections (UTI) were reduced in intervention general acute care units but not in intensive care units (ICUs) (pp. 2111–9). The program included dissemination of information to sponsor organizations and hospitals, data collection, and guidance on key technical and socioadaptive factors in the prevention of catheter-associated UTI. Results during baseline (3 months), implementation (2 months), and sustainability (12 months) periods were as follows: “Data were obtained from 926 units (59.7% were non-ICUs, and 40.3% were ICUs) in 603 hospitals in 32 states, the District of Columbia, and Puerto Rico. The unadjusted catheter-associated UTI rate decreased overall from 2.82 to 2.19 infections per 1,000 catheter–days. In an adjusted analysis, catheter-associated UTI rates decreased from 2.40 to 2.05 infections per 1,000 catheter–days (incidence rate ratio, 0.86; 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). Among non-ICUs, catheter use decreased from 20.1% to 18.8% (incidence rate ratio, 0.93; 95% CI, 0.90 to 0.96; P <0.001) and catheter-associated UTI rates decreased from 2.28 to 1.54 infections per 1,000 catheter–days (incidence rate ratio, 0.68; 95% CI, 0.56 to 0.82; P <0.001). Catheter use and catheter-associated UTI rates were largely unchanged in ICUs. Tests for heterogeneity (ICU vs. non-ICU) were significant for catheter use (P = 0.004) and catheter-associated UTI rates (P = 0.001).” (S. Saint, saint@med.umich.edu)
“The multiplicity of reasons for fever in patients in the ICU is another reason why catheter-associated UTI rates in ICUs may not have declined,” writes an editorialist (
pp. 2168–9). “Changes to the National Healthcare Safety Network (NHSN) definition of catheter-associated UTI accounted for substantial increases in rates of catheter-associated UTI beginning in 2012 and substantial reductions in catheter-associated UTI rates in 2015. In March 2012, NHSN changed the fever requirement from a subjective definition requiring attribution to catheter-associated UTI to an objective definition of the presence of fever regardless of its clinical source. Thus, it is likely that the NHSN rates reported here by both ICUs and non-ICUs underestimate the program’s influence. In contrast, reverse causation is noted for the analysis of later cohorts from the On the CUSP: Stop CAUTI program, since they will benefit from the 2015 definition change that excludes yeast and restricts catheter-associated UTIs to cases with cultures with higher colony counts (≥105 colony-forming units [CFU] per milliliter vs. the current count of ≥103 CFU per milliliter).” (S. S. Huang)
Clinical Trials Embedded Into Usual Care: Experiences during four clinical trials that used extant electronic health record (EHR) systems provide fodder for a review of randomized comparative effectiveness research conducted during usual patient care (pp. 2152–8): “The goals of randomized comparative effectiveness trials can be realized by the integration of randomized treatment assignment within the usual care ecosystem and by the collection of baseline and outcome data by traditional observational study methods (i.e., from the patient’s EHR rather than from specific study-visit forms). As such, the limitations of these point-of-care studies are inherited from the observational substrate; trials conducted in this manner are not traditional full-strength pragmatic studies stripped of technique but rather should be considered observational comparative effectiveness studies that are enhanced by randomization.” (P. W. Lavori, lavori@stanford.edu)
E-Cigarettes & Smoking Cessation: A case vignette of a 29-year-old man who smokes 1.5 packs per day is used to discuss the potentially beneficial use of e-cigarettes in smoking cessation programs (pp. 2172–4; J. S. Yeh).

>>>PNN NewsWatch
* FDA yesterday approved Netspot, the first kit for the preparation of gallium Ga 68 dotatate injection, a radioactive diagnostic probe that will help locate tumors during PET imaging in adult and pediatric patients with rare somatostatin receptor positive neuroendocrine tumors.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 3, 2016 * Vol. 23, No. 107
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
June issue of the Journal of the American College of Cardiology (2016; 67).
Vitamin D & Cardiac Function in Heart Failure: In the VINDICATE (VitamIN D treatIng patients with Chronic heArT failurE) study, high-dose 25 (OH) vitamin D3 (cholecalciferol) did not improve 6-minute walk times after 1 year in participants with chronic heart failure (HF) secondary to left ventricular (LV) systolic dysfunction, researchers report (pp. 2593–603). Secondary end points were improved, including LV structure and function, by supplementation with 4,000 IU daily of vitamin D3: “One year of high-dose vitamin D3 supplementation did not improve 6-min walk distance at 1 year, but was associated with a significant improvement in cardiac function (LV ejection fraction +6.07% [95% confidence interval (CI): 3.20 to 8.95; p <0.0001]); and a reversal of LV remodeling (LV end diastolic diameter -2.49 mm [95% CI: -4.09 to -0.90; p = 0.002] and LV end systolic diameter -2.09 mm [95% CI: -4.11 to -0.06 p = 0.043]).” (K. K. Witte)
Gut-Generated TMAO & Atherosclerotic Burden: Fasting plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, are independent predictors of a high atherosclerotic burden in patients with coronary artery disease (CAD), according to data obtained from 353 consecutive patients (pp. 2620–8). Atherosclerotic CAD had been detected in study participants in 2012–14. Analysis of high-sensitivity cardiac troponin T (hs-cTnT) levels, SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores, and lesion characteristics provided these associations with fasting plasma TMAO levels: “In this prospective cohort study, the median TMAO level was 5.5 µM (interquartile range [IQR]: 3.4 to 9.8 µM), the median SYNTAX score was 11.0 (IQR: 4.0 to 18.5), and 289 (81.9%), 40 (11.3%), and 24 (6.8%) patients had low (0 to 22), intermediate (23 to 32), and high (≥33) SYNTAX scores, respectively. Plasma TMAO levels correlated (all p <0.0001) with the SYNTAX score (r = 0.61), SYNTAX score II (r = 0.62), and hs-cTnT (r = 0.29). Adjusting for traditional risk factors, body mass index, medications, lesion characteristic, renal function, and high-sensitivity C-reactive protein, elevated TMAO levels remained independently associated with a higher SYNTAX score (odds ratio [OR]: 4.82; p <0.0001), SYNTAX score II (OR: 1.88; p = 0.0001), but were not associated with subclinical myonecrosis (OR: 1.14; p = 0.3147). Elevated TMAO level was an independent predictor of the presence of diffuse lesions, even after adjustments for traditional risk factors and for hs-cTnT (OR: 2.05; 95% confidence interval: 1.45 to 2.90; p = 0.0001).” (V. Senthong)

>>>Circulation Highlights
Source:
May 31 issue of Circulation (2016; 133).
Value-Based Purchasing Programs: As a result of federal laws, Medicare and private-payer value-based payments (VBPs) are becoming more important in health care financing, but results with the approach have been modest thus far, authors of a review article write (pp. 2197–205): “Much of the policy attention has been on programs such as accountable care organizations and bundled payments; yet, [VBP] or pay-for-performance, defined as providers being paid fee-for-service with payment adjustments up or down based on value metrics, remains a core element of value payment in Medicare Access and CHIP Reauthorization Act and will likely remain so for the foreseeable future. This review article summarizes the current state of VBP programs and provides analysis of the strengths, weaknesses, and opportunities for the future. Multiple inpatient and outpatient VBP programs have been implemented and evaluated; the impact of those programs has been marginal. Opportunities to enhance the performance of VBP programs include improving the quality measurement science, strengthening both the size and design of incentives, reducing health disparities, establishing broad outcome measurement, choosing appropriate comparison targets, and determining the optimal role of VBP relative to alternative payment models. VBP programs will play a significant role in healthcare delivery for years to come, and they serve as an opportunity for providers to build the infrastructure needed for value-oriented care.” (W. B. Borden, wborden@mfa.gwu.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 © 2016, 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
June 6, 2016 * Vol. 23, No. 108
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 4 issue of Lancet (2016; 387).
Timing of Procedural Indomethacin: Rectal indomethacin should be given before endoscopic retrograde cholangiopancreatography (ERCP) to all patients rather than afterwards based on risk, according to results of a 2,600-patient study conducted in China (pp. 2293–301). Based on a primary outcome of overall occurrence of post-ECRP pancreatitis, results were as follows for preprocedural rectal indomethacin (indometacin) 100 mg within 30 minutes of the prcoedure: “Overall, post-ERCP pancreatitis occurred in 47 (4%) of 1,297 patients assigned to universal indometacin and 100 (8%) of 1,303 patients assigned to risk-stratified indometacin (relative risk 0.47; 95% CI 0.34–0.66; p <0.0001). Post-ERCP pancreatitis occurred in 18 (6%) of 305 high-risk patients in the universal group and 35 (12%) of 281 high-risk patients in the risk-stratified group (p = 0.0057). Post-ERCP pancreatitis was also less frequent in average-risk patients in the universal group (3% [29/992]), in which they received indometacin, than in the risk-stratified group (6% [65/1,022]), in which they did not receive the drug (p = 0.0003). Other than pancreatitis, adverse events occurred in 41 (3%; two severe) patients in the universal indometacin group and 48 (4%; one severe) patients in the risk-stratified group. The most common adverse events were biliary infection (22 [2%] patients vs 33 [3%] patients) and gastrointestinal bleeding (13 [1%] vs ten [1%]).” (Y. Pan, yanglinpan@hotmail.com)
Predicting AF Bleeding Risk Using Biomarker-Based ABC: A biomarker-based risk score performed well in predicting bleeding risk in patients with atrial fibrillation who were receiving anticoagulants (pp. 2302–11). Compared with the HAS-BLED and ORBIT scores, the ABC-bleeding score showed these results in decision support: “The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66–0.70] vs 0.61 [0.59–0.63] vs 0.65 [0.62–0.67], respectively; ABC-bleeding vs HAS-BLED p <0.0001 and ABC-bleeding vs ORBIT p = 0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68–0.73] vs 0.62 [0.59–0.64] for HAS-BLED vs 0.68 [0.65–0.70] for ORBIT; ABC-bleeding vs HAS-BLED p <0.0001 and ABC-bleeding vs ORBIT p = 0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores.” (Z. Hijazi, Ziad.Hijazi@ucr.uu.se)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Cardiovascular Safety of Methylphenidate: Children and young people have greater risks of myocardical infarction and arrthythmias when methylphenidate therapy is first started, according to an analysis of a South Korean insurance database (i2550). These outcomes were noted for 1,224 patients with incident cardiovascular event and first prescriptions for methylphenidate: “Increased risk of arrhythmia was observed in all exposed time periods—that is, periods of treatment with methylphenidate—(incidence rate ratio 1.61, 95% confidence interval 1.48 to 1.74), and the risk was highest in the children who had congenital heart disease. No significant risk of myocardial infarction was observed for all exposed time periods (1.33, 0.90 to 1.98), though risk was higher in the early risk periods between eight and 56 days after the start of treatment with methylphenidate. No significant increased risk was observed for hypertension, ischemic stroke, or heart failure.” (N. L. Pratt, Nicole.Pratt@unisa.edu.au)

>>>PNN NewsWatch
* FDA is looking at risk of serious burns and potential permanent scarring with use of Zecuity (sumatriptan iontophoretic transdermal system) patch for migraine headaches.

>>>PNN JournalWatch
* Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A Meta-analysis, in
Pediatrics, 2016; 137: 10.1542/peds.2015-4496. (S. V. Kaiser)

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 © 2016, 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
June 7, 2016 * Vol. 23, No. 109
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 7 issue of the Annals of Internal Medicine (2016; 164).
DPP-4 Inhibitors & Hospitalization for Heart Failure: Users of saxagliptin, sitagliptin, and other inhibitors of dipeptidyl peptidase-4 (DPP-4) had no increased risk of hospitalization for heart failure (hHF) in a cohort study, researchers report (pp. 705–14). Data from 18 health insurance and health-system data partners in the FDA Mini-Sentinel program showed these hospitalization patterns for adults with type 2 diabetes: “78,553 saxagliptin users and 298,124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)–stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score–matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles.” (S. Toh, darren_toh@harvardpilgrim.org)
An editorialist likes the data-sharing approach of this study and calls for more such efforts addressing uncertainties (
pp. 771–2): “In a country with a health care system as partitioned as that of the United States, sharing complementary data resources could go a long way toward answering safety and effectiveness questions quickly and more definitively, linking clinical trial investigation with real-world experience, eliminating waste and redundancy in research data collection, and incorporating the voices of patients and other stakeholders. My compliments to Toh and colleagues and others who work to achieve this vision.” (J. V. Selby, jvselby@pcori.org)
Monotherapy v. Metformin-Based Therapy in Type 2 Diabetes: Safety and effectiveness data support use of metformin over sulfonylureas for monotherapy in patients with type 2 diabetes, according to authors of a systematic review and meta-analysis (pp. 740–51). “Results for add-on therapies to metformin were similar to those for monotherapies,” the group adds based on these findings: “Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, [glucagon-like peptide-1 (GLP-1)] receptor agonists, and [sodium–glucose cotransporter 2 (SGLT-2)] inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors.” (N. M. Maruthur, maruthur@jhmi.edu)
Fracture Risk in Parathyroidectomy v. Bisphosphonates: In primary hyperparathyroidism (PHPT), surgical therapy reduced fracture risk but bisphosphonate management was not superior to observation, a retrospective cohort study shows (pp. 715–23). Data from an integrated health system show that “total hip [bone mineral density (BMD)] increased transiently in women with parathyroidectomy (4.2% at <2 years) and bisphosphonates (3.6% at <2 years) and declined progressively in both women and men without these treatments (−6.6% and −7.6%, respectively, at >8 years). In 6,272 patients followed for fracture, the absolute risk for hip fracture at 10 years was 20.4 events per 1,000 patients who had parathyroidectomy and 85.5 events per 1,000 patients treated with bisphosphonates compared with 55.9 events per 1,000 patients without these treatments.” (M. W. Yeh, myeh@mednet.ucla.edu)

>>>PNN NewsWatch
* OTC antacid products containing aspirin can cause serious bleeding, FDA warned consumers yesterday.

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 © 2016, 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
June 8, 2016 * Vol. 23, No. 110
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
June 7 issue of JAMA (2016; 315).
American Obesity Trends: Research articles on adults and children and an accompanying editorial explore trends in obesity in the U.S.
In the 2005–14 decade, obesity rates increased to 35.0% for men and 40.4% for women, including class 3 obesity in 5.5% and 9.9% of men and women, respectively (
pp. 2284–91). The nationally representative National Health and Nutrition Examination Survey (NHANES) showed these patterns: “For the years 2013–2014, the overall age-adjusted prevalence of obesity was 37.7% (95% CI, 35.8%–39.7%); among men, it was 35.0% (95% CI, 32.8%–37.3%); and among women, it was 40.4% (95% CI, 37.6%–43.3%). The corresponding prevalence of class 3 obesity overall was 7.7% (95% CI, 6.2%–9.3%); among men, it was 5.5% (95% CI, 4.0%–7.2%); and among women, it was 9.9% (95% CI, 7.5%-12.3%). Analyses of changes over the decade from 2005 through 2014, adjusted for age, race/Hispanic origin, smoking status, and education, showed significant increasing linear trends among women for overall obesity (P = .004) and for class 3 obesity (P = .01) but not among men (P = .30 for overall obesity; P = .14 for class 3 obesity).” (K. M. Flegal, kflegal@cdc.gov)
Obesity among young American children increased until 2003–04, according to analysis of NHANES surveys in 1988–94 through 2013–14 (
pp. 2292–9): “In this nationally representative study of US children and adolescents aged 2 to 19 years, the prevalence of obesity in 2011–2014 was 17.0% and extreme obesity was 5.8%. Between 1988–1994 and 2013–2014, the prevalence of obesity increased until 2003–2004 and then decreased in children aged 2 to 5 years, increased until 2007–2008 and then leveled off in children aged 6 to 11 years, and increased among adolescents aged 12 to 19 years.” (C. L. Ogden, cogden@cdc.gov)
“The obesity epidemic in the United States is now 3 decades old, and huge investments have been made in research, clinical care, and development of various programs to counteract obesity,” an editorialist notes (
pp. 2277–8). “However, few data suggest the epidemic is diminishing. Perhaps it is time for an entirely different approach, one that emphasizes collaboration with the food and restaurant industries that are in part responsible for putting food on dinner tables.” (J. W. Zylke, jody.zylke@jamanetwork.org)
Specialty-Based Global Payments: An Oncology Care Model (OCM) provides a template for a “new phase in payment reform,” the specialty-based global payment, according to authors of a Viewpoint article (pp. 2271–2). “The OCM creates a spending target that covers all Medicare Part A services (hospital, skilled nursing facility, hospice, and some home health) and Part B services (physician and some home health), as well as certain Part D expenditures, incurred during a 6-month episode starting at the initiation of chemotherapy,” write the authors. “Historically, 52% to 71% of total spending occurred during this period, depending on the type of cancer. Similar to Medicare’s bundled payment initiatives, the OCM spending target is based on an episode of care (6 months in the OCM). And similar to the Medicare accountable care organization programs, the OCM covers spending across the care continuum and is based on continued fee-for-service payments to clinicians and health care organizations. To date, more than 450 practices intend to participate in the OCM.…
“Another example is the Medicare Comprehensive End-Stage Renal Disease (ESRD) Care Model, in which physicians and dialysis organizations assume responsibility for a budget for beneficiaries with ESRD. Although there are potential pitfalls of using smaller budgets, carefully designed incentives appropriately targeted to a specialty may offer a compromise between fee-for-service and wholesale risk contracts.” (Z. Song,
zirui_song@post.harvard.edu)

>>>PNN NewsWatch
* FDA is warning that taking higher-than-recommended doses of OTC or prescription loperamide (Imodium) through abuse or misuse can cause potentially fatal cardiac arrhythmias. The risk is increased when loperamide is taken at high doses with interacting drugs.
*
Step 2 60 Gold is being recalled to the consumer level by Body Shot Bar because of undeclared sibutramine, 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 © 2016, 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
June 9, 2016 * Vol. 23, No. 111
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
June 9 issue of the New England Journal of Medicine (2016; 374).
Genomics in AML: Reacting to research into driver mutations associated with genomic subgroups in patients with acute myeloid leukemia (AML) (pp. 2209–21; P. J. Campbell, pc8@sanger.ac.uk), editorialists write that the results can be used to design mechanism-based clinical trials of the disease (pp. 2282–4): “Mutational studies involving large cohorts of patients with AML and with other malignant conditions can be used to better inform our understanding of cancer pathogenesis and improve risk stratification. Such studies can also help in the development of precision-medicine strategies that use genomic data to improve our ability to match individual patients with the best therapy for their disease. The clonal phylogeny of AML is not random but follows distinct roads characterized by unique initiating and transforming events—and that has made all the difference.” (A. D. Viny)
Indacaterol–Glycopyrronium in COPD: For preventing exacerbations of chronic obstructive pulmonary disease (COPD), the combination of indacaterol and glycopyrronium was more effective than salmeterol–fluticasone in patients with a history of such problems during the prior year (pp. 2222–34). The 52-week study used a primary outcome of annual rate of COPD exacerbations to make these findings: “A total of 1,680 patients were assigned to the indacaterol–glycopyrronium group, and 1,682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium showed not only noninferiority but also superiority to salmeterol–fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P = 0.003). The indacaterol–glycopyrronium group had a longer time to the first exacerbation than did the salmeterol–fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P <0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P <0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P <0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P = 0.046). The effect of indacaterol–glycopyrronium versus salmeterol–fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol–glycopyrronium group and 4.8% in the salmeterol–fluticasone group (P = 0.02).” (J. A. Wedzicha, j.wedzicha@imperial.ac.uk)
Exome Sequencing in Neurometabolic Disorders: Deep clinical phenotyping of 41 probands with intellectual developmental disorder and unexplained metabolic phenotypes produced insights into pathophysiology of the conditions at the molecular or cellular level (pp. 2246–55): “We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).” (C. D. van Karnebeek, cvankarnebeek@cw.bc.ca)

>>>PNN NewsWatch
* Pharmavite LLC is recalling specific lots of Nature Made products due to possible Salmonella or Staphylococcus aureus contamination. Affected vitamin products are listed in an online news release.

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 © 2016, 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
June 10, 2016 * Vol. 23, No. 112
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
June 15 issue of Clinical Infectious Diseases (2016; 62).
Statin Use and Hospital Length of Stay for CAP: Statin use by adults with community-acquired pneumonia (CAP) had no effect on hospital length of stay (LOS) or in-hospital mortality, researchers report (pp. 1471–8). At five hospitals in Chicago and Nashville, TN, proportional subdistribution hazards models showed these associations between statin use and hospital LOS: “Of 2,016 adults enrolled, 483 (24%) were statin users; 1,533 (76%) were nonusers. Statin users were significantly older, had more comorbidities, had more years of education, and were more likely to have health insurance than nonusers. Multivariable regression demonstrated that statin users and nonusers had similar LOS (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], .88–1.12), as did those in the propensity-matched groups (HR, 1.03; 95% CI, .88–1.21). No significant associations were found between statin use and LOS or in-hospital mortality, even when stratified by pneumonia severity.” (F. Havers, fhavers@cdc.gov)
Fecal Microbial Transplants, Antibiotic Resistance & Recurrent C. diff: Fecal microbiota transplantation (FMT) is effective for eradication of antibiotic-resistant organisms and elimination of antibiotic resistance (ABR) genes in patients with recurrent Clostridium difficile infection (RCDI), a study shows (pp. 1479–86). Data from 20 patients with RCDI, 3 donors, and 87 libraries from the Human Microbiome Project showed these patterns of resistance, genes, and transplant effects: “RCDI patients had a greater number and diversity of ABR genes compared with donors and healthy controls. Beta-lactam, multidrug efflux pumps, fluoroquinolone, and antibiotic inactivation ABR genes were increased in RCDI patients, although donors primarily had tetracycline resistance. RCDI patients were dominated by Proteobacteria with Escherichia coli and Klebsiella most prevalent. FMT resulted in a resolution of symptoms that correlated directly with a decreased number and diversity of ABR genes and increased Bacteroidetes and Firmicutes with reduced Proteobacteria. ABR gene profiles were maintained in recipients for up to a year following FMT.” (L. C. McDonald, ljm3@cdc.gov)
The CDC is working to develop Microbiome Disruption Indices (MDIs) to increase understanding of how microbiome status can be used to “tailor antibiotic stewardship and infection control decisions,” editorialists write (
pp. 1487–8): “The goal is to develop standardized criteria that characterize the major human microbiomes (beginning with the large intestine) with regard to their vulnerability to [multidrug-resistant organisms (MDROs)] colonization and, once colonized, to MDRO dominance that increases the risk for infection or transmission of the MDRO to other patients. In addition, such indices can communicate the disruptive potential of various drugs, including antibiotics. Potential MDIs include compositional indices of diversity, species richness, the presence or absence of protective species and, as demonstrated here …, measurement of the resistome. In addition, MDIs may include indices of the functional status of the microbiome based on either an inferred metagenomics approach (ie, predicting major metabolic pathways present) or a more direct metabolomics approach (ie, direct measurement of metabolites). With these indices in use, a patient’s status of disruption could be ascertained, and as a patient reaches a threshold suggesting extreme vulnerability to colonization, special reverse isolation precautions could be instituted to prevent the acquisition of new resistance traits and MDROs while preemptive microbiome restoration is considered to achieve improved indices.” (L. C. McDonald, ljm3@cdc.gov)

>>>PNN NewsWatch
* In partnership with international regulatory and law enforcement agencies, FDA this week took action against 4,402 websites that illegally sell potentially dangerous, unapproved prescription drugs to U.S. consumers, the agency announced yesterday. This effort was part of Operation Pangea IX, the Ninth Annual International Internet Week of Action (IIWA), a global cooperative effort, led by INTERPOL, to combat the unlawful sale and distribution of illegal and potentially counterfeit medical products on the internet.

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 © 2016, 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
June 13, 2016 * Vol. 23, No. 113
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 11 issue of Lancet (2016; 387).
Rituximab in Chemotherapy for Burkitt’s Lymphoma: Addition of rituximab to dose-dense chemotherapy improved 3-year event-free survival (EFS) rates among 260 adults with Burkitt’s leukemia or lymphoma, researchers report (pp. 2402–11). In an open-label, phase 3 trial, patients were randomized to intravenous rituximab and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone, with these results: “With a median follow-up of 38 months (IQR 24–59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66–82]) than did those in the no rituximab group (62% [53–70]; log-rank p stratified by treatment group = 0.024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0.59 for EFS (95% CI 0.38–0.94; p = 0.025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3–4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3.31 days per cycle [95% CI 3.01–3.61] vs 3.38 days per cycle [3.05–3.70]) events.” (V. Ribrag, vincent.ribrag@gustaveroussy.fr)
Ixmyelocel-T in Ischemic Heart Failure: In the phase 2b ixCELL-DCM trial, “transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes,” a study concludes (pp. 2412–21). Ixmyelocel-T is multicellular therapy produced from patients’ own bone marrow that expands two specific cell lines. Based on a primary endpoint of composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure, the authors report these results for patients at 31 clinical centers: “The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0.63 [95% CI 0.42–0.97]; p = 0.0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p = 0.0197).” (A. N. Patel, Amit.Patel@hsc.utah.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Policy Options for Cardiovascular Screening: A simulation of the community-dwelling population of England shows that universal screening for primary prevention of cardiovascular disease “seems less effective than alternative strategies [that] incorporate population-wide approaches,” authors conclude (i2793). “The most equitable strategy would be the combination of the population-wide intervention and concentrated screening, followed by concentrated screening alone and the population-wide intervention,” the writers note. “Universal screening had the least apparent impact on socioeconomic inequalities in health.” (C. Kypridemos, c.kypridemos@liverpool.ac.uk)

>>>PNN NewsWatch
* FDA on Friday licensed Vaxchora (PaxVax Bermuda), a vaccine for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas.

>>>PNN JournalWatch
* Emerging Resistance, New Antimicrobial Agents … but No Tests! The Challenge of Antimicrobial Susceptibility Testing in the Current US Regulatory Landscape, in
Clinical Infectious Diseases, 2016; 63: 83–8. (R. M. Humphries, rhumphries@mednet.ucla.edu)
* The Critically Ill Kidney Transplant Recipient: A Narrative Review, in
Chest, 2016; 149: 1546–55. (E. Canet)
* Sleep Telemedicine: An Emerging Field’s Latest Frontier, in
Chest, 2016; 149: 1556–65. (B. G. Fields)
* Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement, in
Journal of Clinical Oncology, 2016; 34: 2182–90. (S. Jain, guidelines@asco.org)
* Controversies Regarding Lipid Management and Statin Use for Cardiovascular Risk Reduction in Patients With CKD, in
American Journal of Kidney Diseases, 2016; 67: 965–77. (H. Kramer, hkramer@luc.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 © 2016, 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
June 14, 2016 * Vol. 23, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June issue of JAMA Internal Medicine (2016; 176).
Potential Savings Through Therapeutic Substitution: The potential for reductions in drug costs through therapeutic substitution could be substantial, researchers report, “if it can be implemented in a way that does not negatively affect quality of care” (pp. 769–75). Analysis of prescribed medications in 107,132 individuals included in the nationally representative Medical Expenditure Panel Survey (2010–12) shows these possibilities for cost savings: “In the included drug classes, the majority of the drugs were generics, with a total of 93.5 billion standardized doses compared with 47.4 billion standardized doses of branded drugs. Total expenditure of the branded drugs accounted for $147 (95% CI, $137–$156) billion compared with $62.7 (95% CI, $58.9–$66.5) billion for the generics. Between 2010 and 2012, an estimated $73.0 (95% CI, $67.6–$78.5) billion in total excess expenditure and $24.6 (95% CI, $22.6–$26.5) billion in out-of-pocket excess expenditure was attributable to branded drug overuse. The excess was present across numerous drug classes throughout many aspects of medicine and equates to 9.6% of total and 14.1% of out-of-pocket prescribed medicine expenses. The drug classes with the highest excess expenditure included statins ($10.9 [SE, $0.41] billion), atypical antipsychotics ($9.99 [SE, $1.03] billion), proton pump inhibitors ($6.12 [SE, $0.38] billion), selective serotonin reuptake inhibitors ($6.08 [SE, $0.49] billion), and angiotensin receptor blockers ($5.53 [SE, $0.35] billion).” (M. E. Johansen, mikejoha3@gmail.com)
“To achieve the benefits of within-class substitution, we need wider adoption of systematic protocols, aligned with physician judgment, as to when such substitutions are beneficial and when not,” writes an editorialist (
p. 776). “This work is not easy; it requires close collaboration between physicians and pharmacists, but the financial savings will be large.” (J. S. Ross)
Options for Increasing Generic Drug Use: Two articles and an editorial examine use of generic medications.
Two interventions— limiting interactions with pharmaceutical marketing and directed educational outreach—are ways of increasing use of generic drugs and thereby slowing the rate of increase of health care costs, according to authors who conducted a national survey of physicians (
pp. 845–7). Randomly selected internists and specialists reported wide acceptance of generic drugs as effective, safe, and preferred agents. “Still, generic skepticism remains common, particularly among physicians who reported pharmaceutical sales representatives as sources of the last times they learned about generic drugs becoming available,” the authors found. (A. S. Kesselheim, akesselheim@partners.org)
Redesign of default options in electronic health records increased the generic prescribing rate by 23.1 percentage points at a tertiary care health system, a study shows (
pp. 847–8). “The opt-out rate for generic levothyroxine was 22.1% after the intervention, compared with less than 2% among other medications, likely reflecting physician recognition that generic and brand-name levothyroxine may differ in formulation,” the authors conclude. “This provides a real-world illustration of what has been a hypothesis in the health care context: that the effectiveness of defaults in changing behavior is appropriately mitigated in the setting of strongly held preferences.” (M. S. Patel, mpatel@upenn.edu)
“This new evidence of the continuing conflict between brand-name and generic drugs has several immediate policy implications,” editorialists write (
pp. 733–4): those interested in improving the value of health care should work to improve physician and patient understanding of generics, the FDA and the generic drug industry must maintain high standards of bioequivalence and quality, and the recent high-visibility and inordinate price hikes have the potential to “damage the credibility of the entire industry.” (J. M. Sharfstein, joshua.sharfstein@jhu.edu)

>>>PNN NewsWatch
* Zecuity manufacturer Teva Pharmaceuticals has decided to temporarily suspend sales, marketing, and distribution to investigate the cause of burns and scars associated with the Zecuity patch (sumatriptan iontophoretic transdermal system), FDA said yesterday.

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 © 2016, 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
June 15, 2016 * Vol. 23, No. 115
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
June 14 issue of JAMA (2016; 315).
Aspirin & ARDS in Emergency Department: In a phase 2b trial of patients presenting to the emergency department at risk for acute respiratory distress syndrome (ARDS), aspirin was no better than placebo at preventing development of ARDS at 7 days, researchers report (pp. 2406–14). Testing for benefits of early aspirin administration in at-risk patients, the authors found these results for 390 patients: “The median (IQR) hospital length of stay was 6 (3–10) days. Administration of aspirin, compared with placebo, did not significantly reduce the incidence of ARDS at 7 days (10.3% vs 8.7%, respectively; odds ratio, 1.24 [92.6% CI, 0.67 to 2.31], P = .53). No significant differences were seen in secondary outcomes: ventilator-free to day 28, mean (SD), 24.9 (7.4) days vs 25.2 (7.0) days (mean [90% CI] difference, −0.26 [−1.46 to 0.94] days; P = .72); ICU length of stay, mean (SD), 5.2 (7.0) days vs 5.4 (7.0) days (mean [90% CI] difference, −0.16 [−1.75 to 1.43] days; P = .87); hospital length of stay, mean (SD), 8.8 (10.3) days vs 9.0 (9.9) days (mean [90% CI] difference, −0.27 [−1.96 to 1.42] days; P = .79); or 28-day survival, 90% vs 90% (hazard ratio [90% CI], 1.03 [0.60 to 1.79]; P = .92) or 1-year survival, 73% vs 75% (hazard ratio [90% CI], 1.06 [0.75 to 1.50]; P = .79). Bleeding-related adverse events were infrequent in both groups (aspirin vs placebo, 5.6% vs 2.6%; odds ratio [90% CI], 2.27 [0.92 to 5.61]; P = .13).” (D. J. Kor, kor.daryl@mayo.edu)
“ARDS continues to have significant mortality and morbidity for critically ill patients, but improved understanding of the pathogenesis of this syndrome continues to provide the potential to identify successful drug therapies to improve outcomes from ARDS in the future,” editorialists write (
pp. 2403–5). These study results should be used by the NIH Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, the US Critical Illness and Injury Trials Group (USCIITG), and others. (J. D. Christie, jchristi@upenn.edu)
Long-Acting Opioids & Mortality in Chronic Noncancer Pain: Findings from a retrospective cohort study of the Tennessee Medicaid database show a significantly increased risk of all-cause mortality among patients with chronic noncancer pain who were prescribed opioids (pp. 2415–23). In comparison with those given anticonvulsants or cyclic antidepressants, opioids were associated with a 64% increase in mortality and more out-of-hospital deaths from causes other than unintentional overdose. (W. A. Ray, wayne.ray@vanderbilt.edu)
Drug Treatments of Obesity: “Phentermine–topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss” in a systematic review and meta-analysis of 28 trials of 29,018 patients, investigators write (pp. 2424–34). Orlistat, lorcaserin, and naltrexone–bupropion were also more effective than placebo for producing weight loss after 1 year of therapy. (S. Singh, sis040@ucsd.edu)

>>>PNN NewsWatch
* Meeting in Baltimore, the ASHP House of Delegates acted on some 25 policies and referred a resolution on assisted suicide and a new business item on nonacademic hours required for licensure by some state boards of pharmacy to the organization’s Board of Directors. One policy approved by the House calls for ASHP “to advocate that Congress ban direct-to-consumer advertising for prescription drugs and medication-containing devices.”
* In other news from the ASHP Summer Meeting,
Sister Mary Louise Degenhart, ASC, MBA, FASHP, received the Harvey A. K. Whitney Award, addressing the topic, “Pharmacy: A Profession of Hope” in her lecture. R. David Anderson, BSPharm, ScD(Hon), and the late Toby Clark, MSc, FASHP, FFIP, were made honorary members of ASHP.
*
FDA yesterday said it has strengthened the existing warning about the risk of acute kidney injury with canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR), adding language about acute kidney injury and recommendations to minimize this risk.
* The
AspireAssist medical device (Aspire Bariatrics), approved yesterday by FDA, is a surgically implanted tube in the stomach that drains a portion of stomach contents after each meal. It is indicated for use in morbidly obese patients (BMI, 35–55 kg/sq m) who have failed to achieve and maintain weight loss through nonsurgical means.

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 © 2016, 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
June 16, 2016 * Vol. 23, No. 116
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
June 16 New England Journal of Medicine (2016; 374).
Alteplase Doses in Acute Ischemic Stroke: Based on rates of death and disability at 90 days in a predominantly Asian population, low-dose alteplase produced similar results as standard-dose alteplase in patients with acute ischemic stroke, ENCHANTED researchers report (pp. 2313–23). Among 3,310 patients randomized in a 2-by-2 open-label design, I.V. alteplase 0.6 or 0.9 mg/kg produced these results: “The primary outcome [of death or disability at 90 days] occurred in 855 of 1,607 participants (53.2%) in the low-dose group and in 817 of 1,599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P = 0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P = 0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P = 0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P = 0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P = 0.07).” (C. S. Anderson, canderson@georgeinstitute.org.au)
“As systems of stroke care develop, less expensive but still effective therapies need to be available, especially when families must first purchase them for the physician to administer,” an editorialist writes (
pp. 2389–90). “Using less effective therapies to save short-term costs will only increase the costs of long-term care for disabled stroke survivors. In the Disney movie Enchanted, Robert Philip observes: ‘It’s tempting to see things the way you wish they were instead of how they are.’ ENCHANTED shows us how things really are and supports the continued use of guideline-based thrombolytic therapy for Asians with acute stroke.” (C. Sila)
Tenofovir & Perinatal Hep B Transmission: Used during the third trimester and postpartum in mothers with high viral loads, tenofovir disoproxil fumarate (TDF) prevented mother-to-child transmission of hepatitis B virus (HBV), a study shows (pp. 2324–34). Based on primary outcomes of viral transmission rates and birth defects, study results showed the following for TDF 300 mg/d used from 30–32 weeks’ gestation until postpartum week 4: “At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (P <0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of the infants [5 of 97] vs. 18% [18 of 100], P = 0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P = 0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2% [2 of 95 infants] and 1% [1 of 88], respectively; P = 1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% [44 of 97 women] vs. 30% [30 of 100], P = 0.03).…” (C. Q. Pan, panc01@nyu.edu)
Comprehensive Primary Care Initiative: Midpoint results of the 4-year, multipayer Comprehensive Primary Care Initiative show “progress in transforming the delivery of primary care “ but no cost savings or improved quality of care or patient experience, authors write (pp. 2345–56; S. B. Dale, sdale@mathematica-mpr.com).
Achieving “the quadruple aim of improving health, containing costs, enhancing the experience of patients, and improving work life for primary care physicians” will require “more fundamental changes … in the structure and culture of primary care,” editorialists respond (
pp. 2390–2). “The Comprehensive Primary Care Initiative provides a down payment on the promotion of such changes, but much more remains to be learned from this initiative and others about how to implement large-scale changes that make primary care better for patients and more satisfying for physicians and their teams.” (J. Z. Ayanian)

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 © 2016, 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
June 17, 2016 * Vol. 23, No. 117
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
June issue of Gastroenterology (2016; 150).
Oral Contraceptive Use & Crohn Disease Complications: Women with Crohn disease (CD) on long-term oral contraceptives (OCs) were at greater risk for CD complications requiring surgery in a study from Sweden (pp. 1561–7.e1). Investigators found these risks for females aged 16 to 51 years in the Swedish National Patient Register in 2002–13: “We identified 482 incident cases of surgery among 4,036 patients with CD, with a median follow-up period of 58 months. Compared with nonusers, the [multivariable-adjusted hazard ratios (MV-adjusted HRs)] for surgery were 1.14 (95% confidence interval [CI], 0.80–1.63) for past users and 1.30 (95% CI, 0.89–1.92) for current users. The risk of surgery increased with longer duration of use (Ptrend = .036) and higher prescribed daily dose (Ptrend = .016). Specifically, for women with more than 3 years of OC use, the MV-adjusted HR for surgery was 1.68 (95% CI, 1.06–2.67). The association was confined to the combination type of OC. We estimated that for every 83 patients with CD receiving [combination OCs] for at least 1 year, 1 extra surgery is required. The rate of steroid prescriptions did not appear to increase with past or current use of OCs, compared with patients who have not taken OCs (all Pcomparisons > .20).” (H. Khalili, hkhalili@mgh.harvard.edu)
This study “provides another important potential risk of estrogen-containing contraception,” editorialists write (
pp. 1518–20). “If estrogen-containing oral contraceptives are also associated with an increased risk of surgery in patients with CD, this may ‘tip the scales’ away from routine use of these agents in women with CD. With the currently available data, progestin-only containing oral contraceptives (which have not been shown to increase VTE or surgical complication of CD) or intrauterine devices with or without progestin should be considered in women with CD as first-line contraceptive agents.” (M. D. Long, millie_long@med.unc.edu)

>>>Allergy/Immunology Report
Source:
June issue of the Journal of Allergy and Clinical Immunology (2016; 137).
Idelalisib in Allergic Rhinitis: A selective inhibitor of phosphatidylinositol 3-kinase p110-delta, idelalisib was well tolerated and reduced allergic responses after a challenge in a phase 1 study of 41 patients with allergic rhinitis (pp. 1733–41). Allergic symptoms induced by grass pollen were as follows in patients on idelalisib 100 mg or placebo for 7 days: “Idelalisib treatment was well tolerated. Mean total nasal symptom scores were lower during the combined idelalisib treatment periods compared with placebo (treatment difference [idelalisib − placebo], −1.78; 95% CI, −2.53 to −1.03; P < .001). Statistically significant differences were also observed for the combined treatment periods for total symptom scores, nasal airflow, nasal secretion weight, and nasal congestion scores. The percentage of ex vivo–activated basophils (CD63+/CCR3+ cells; after stimulation with grass pollen) was substantially lower for idelalisib-treated compared with placebo-treated subjects. Plasma CCL17 and CCL22 levels were reduced after idelalisib treatment.” (K. D. Puri, kpuri@Celgene.com)

>>>Rheumatology Highlights
Source:
June issue of Arthritis & Rheumatology (2016; 68).
TNF Inhibitors & Ischemic Stroke: Tumor necrosis factor inhibitor (TNFi) therapy does not appear to exacerbate the increased risk of ischemic stroke observed among patients with rheumatoid arthritis, according to a study from Britain (pp. 1337–45). Whether the drugs affect mortality after ischemic stroke was unclear, however, in these data for 2001–09 in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis: “To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD–treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person–years of observation, respectively (incidence rate 175 versus 173 per 100,000 person–years). After adjustment for confounders, there was no association between ever-exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54–1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03–1.21] and 0.60 [95% CI 0.16–2.28], respectively).” (K. L. Hyrich, kimme.hyrich@manchester.ac.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 © 2016, 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
June 20, 2016 * Vol. 23, No. 118
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 18 issue of Lancet (2016; 387).
Neuropsychiatric Safety of Smoking Interventions: In the EAGLES trial, neuropsychiatric adverse effects were not increased among patients with or without psychiatric conditions receiving varenicline or bupropion, compared with nicotine patch or placebo, researchers report (pp. 2507–20). All active therapies were more effective than placebo for achieving abstinence, and varenicline was more effective than nicotine patch or bupropion, according to these results among 8,144 participants: “In the non-psychiatric cohort, 13 (1.3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2.2%) of 989 in the bupropion group, 25 (2.5%) of 1,006 in the nicotine patch group, and 24 (2.4%) of 999 in the placebo group. The varenicline–placebo and bupropion–placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were −1.28 (95% CI −2.40 to −0.15) and −0.08 (−1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were −1.07 (−2.21 to 0.08) and 0.13 (−1.19 to 1.45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6.5%) of 1,026 participants in the varenicline group, 68 (6.7%) of 1,017 in the bupropion group, 53 (5.2%) of 1,016 in the nicotine patch group, and 50 (4.9%) of 1,015 in the placebo group. The varenicline–placebo and bupropion–placebo RDs were 1.59 (95% CI −0.42 to 3.59) and 1.78 (−0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (−0.81 to 3.25) and 1.42 (−0.63 to 3.46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3.61, 95% CI 3.07 to 4.24), nicotine patch (1.68, 1.46 to 1.93), and bupropion (1.75, 1.52 to 2.01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2.07 [1.75 to 2.45] and 2.15 [1.82 to 2.54], respectively).” (R. M. Anthenelli, ranthenelli@ucsd.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Polypharmacy & Blood-Thinning Effects in AF: Among patients with atrial fibrillation who were taking more than 5 medications, apixaban was more effective than warfarin in the ARISTOTLE study and “at least just as safe,” investigators write (i2868). The trial included 18,201 participants who received apixaban 5 mg twice daily or individualized warfarin (target INR, 2.0–3.0), with these effects based on number of concomitant drugs: “Each patient used a median of six drugs (interquartile range 5–9); polypharmacy (≥5 drugs) was seen in 13,932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0–5, 6–8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P <0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0–5, 6–8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction = 0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction = 0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin.” (J. J. Focks, Jeroen.Jaspersfocks@radboudumc.nl)

>>>PNN JournalWatch
* Advances and Highlights in Mechanisms of Allergic Disease in 2015, in
Journal of Allergy and Clinical Immunology, 2016; 137: 1681–96. (C. A. Akdis, akdisac@siaf.uzh.ch)
* Omega-3 Fatty Acids Contribute to the Asthma-Protective Effect of Unprocessed Cow’s Milk, in
Journal of Allergy and Clinical Immunology, 2016; 137: 1699–706.e13. (M. J. Ege, markus.ege@med.lmu.de)
* Cognitive Reserve and Postoperative Delirium in Older Adults, in
Journal of the American Geriatrics Society, 2016; 64: 1341–6. (J. Verghese, joe.verghese@einstein.yu.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 © 2016, 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
June 21, 2016 * Vol. 23, No. 119
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 21 issue of the Annals of Internal Medicine (2016; 164).
Aspirin for CVD, Cancer Prevention: Four articles present a decision analysis and three supporting reviews of prophylactic aspirin efficacy and adverse effects.
Among adults aged 40 to 79 years, initiation of low-dose aspirin prophylaxis has the greatest potential for positive net benefit in the prevention of cardiovascular disease (CVD), according to a decision analysis conducted by the U.S. Preventive Services Task Force (
pp. 777–86). Using evidence from the below systematic reviews, the authors found these relative effects on CVD and colorectal cancer (CRC) prevention and risks of gastrointestinal (GI) and cerebral hemorrhages: “Lifetime net quality-adjusted life–years are positive for most adults initiating aspirin at ages 40 to 69 years, and life expectancy gains are expected for most men and women initiating aspirin at ages 40 to 59 years and 60 to 69 years with higher CVD risk. Harms may exceed benefits for persons starting aspirin in their 70s and for many during the first 10 to 20 years of use.”
Results of the sensitivity analysis showed that findings were “most sensitive to the relative risk for hemorrhagic stroke and CVD mortality but are affected by all relative risk estimates, baseline GI bleeding incidence and case-fatality rates, and disutilities associated with aspirin use.” (AHRQ website,
www.ahrq.gov)
In primary prevention of CVD, aspirin’s effects are modest and evident at doses of 100 mg per day or less, researchers report, with older adults having greater relative benefits in prevention of myocardial infarction (MI) (
pp. 804–13): “Two good-quality and 9 fair-quality randomized, controlled trials were identified. In analyses of all doses, aspirin reduced the risk for nonfatal [MI] (relative risk [RR], 0.78 [95% CI, 0.71 to 0.87]) but not nonfatal stroke; aspirin showed little or no benefit for all-cause or cardiovascular mortality. Benefits began within the first 5 years. Older adults achieved greater relative MI reduction, but no other effect modifications were found in analyzed subpopulations. In trials with aspirin doses of 100 mg or less per day, the reduction in nonfatal MI benefit persisted (absolute risk reduction, 0.15 to 1.43 events per 1,000 person–years) and a 14% reduction in nonfatal stroke benefit was noted, but no benefit was found for all-cause mortality (RR, 0.95 [CI, 0.89 to 1.01]) or cardiovascular mortality (RR, 0.97 [CI, 0.85 to 1.10]).” (AHRQ website, www.ahrq.gov)
Data on incidence of cancer obtained in CVD primary prevention trials fail to show clear evidence of aspirin’s effectiveness for prevention of cancer (
pp. 814–25). Aspirin prophylaxis might reduce the incidence of CRC and “perhaps mortality approximately 10 years after initiation,” the authors conclude based on these findings: “In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n = 103,787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n = 72,926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n = 14,033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n = 47,464).” (AHRQ website, www.ahrq.gov)
Assessment of GI bleeding risks and expected benefits is needed before aspirin is used because of a highly variable absolute bleeding rates among patients, the third review concludes (
pp. 826–35). Age, gender, and risk factors affect bleeding risk, the authors note, adding these details from their assessment of available evidence: “In CVD primary prevention studies, very-low-dose aspirin use (≤100 mg daily or every other day) increased major [GI] bleeding risk by 58% (odds ratio [OR], 1.58 [95% CI, 1.29 to 1.95]) and hemorrhagic stroke risk by 27% (OR, 1.27 [CI, 0.96 to 1.68]). Projected excess bleeding events with aspirin depend on baseline assumptions. Estimated excess major bleeding events were 1.39 (CI, 0.70 to 2.28) for GI bleeding and 0.32 (CI, −0.05 to 0.82) for hemorrhagic stroke per 1000 person-years of aspirin exposure using baseline bleeding rates from a community-based observational sample. Such events could be greater among older persons, men, and those with CVD risk factors that also increase bleeding risk.” (AHRQ website, www.ahrq.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 © 2016, 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
June 22, 2016 * Vol. 23, No. 120
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
June 21 issue of JAMA (2016; 315).
Plant-Based Therapies for Menopausal Symptoms: Phytoestrogen supplements improve hot flashes and vaginal dryness symptoms among women in menopause, according to results of a systematic review and meta-analysis, but the agents have no significant effect on the frequency of night sweats (pp. 2554–63). Results from 62 studies of 6,653 women produced these findings and led authors to conclude that more rigorous trials are needed: “Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, −1.31 [95% CI, −2.02 to −0.61]) and vaginal dryness score (pooled mean difference of changes, −0.31 [95% CI, −0.52 to −0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, −2.14 [95% CI, −5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, −0.79 [−1.35 to −0.23]) and vaginal dryness score (pooled mean difference of changes, −0.26 [−0.48 to −0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality.” (T. Muka, t.muka@erasmusmc.nl)
Protein-Based Risk Score for Cardiovascular Outcomes: Compared with the refit Framingham secondary event risk score, a score based on levels of 9 circulating proteins was better at predicting cardiovascular outcomes in patients with stable coronary heart disease (CHD), but the measure “still provided only modest discriminative accuracy,” researchers report (pp. 2532–41). Data from the Heart and Soul study provided a derivation cohort, while those in the HUNT-3 study from Norway were used as a validation cohort, with these results: “In the derivation cohort, C statistics were 0.66 for refit Framingham, 0.74 for 9-protein, and 0.75 for refit Framingham plus 9-protein models. In the validation cohort, C statistics were 0.64 for refit Framingham, 0.70 for 9-protein, and 0.71 for refit Framingham plus 9-protein models. Adding the 9-protein risk score to the refit Framingham model increased the C statistic by 0.09 (95% CI, 0.06–0.12) in the derivation cohort, and in the validation cohort, the C statistic was increased by 0.05 (95% CI, 0.02–0.09). Compared with the refit Framingham model, the integrated discrimination index for the 9-protein model was 0.12 (95% CI, 0.08–0.16) in the derivation cohort and 0.08 (95% CI, 0.05–0.10) in the validation cohort. In analysis of paired samples among 139 participants with cardiovascular events after the second sample, absolute within-person annualized risk increased more for the 9-protein model (median, 1.86% [95% CI, 1.15%–2.54%]) than for the refit Framingham model (median, 1.00% [95% CI, 0.87%–1.19%]) (P = .002), while among 375 participants without cardiovascular events, both scores changed less and similarly (P = .30).” (P. Ganz, peter.ganz@ucsf.edu)
“Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making,” editorialists write in response to this study (
pp. 2525–6). “To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies. If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described. If some of these proteins are true risk factors, rather than simply risk markers, then they could serve as targets for future therapies. The quest for personalized or precision medicine is an important one, and [this] work by Ganz et al is a welcome step in that direction.” (M. S. Sabatine, msabatine@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 © 2016, 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
June 23, 2016 * Vol. 23, No. 121
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
June 23 New England Journal of Medicine (2016; 374).
PET-CT–Guided Therapy of Advanced Hodgkin’s Lymphoma: Similar efficacy and fewer adverse effects resulted from bleomycin discontinuance in patients with advanced Hodgkin’s lymphoma based on interim positron-emission tomography–computed tomography (PET-CT) (pp. 2419–29). Patients with newly diagnosed conditions received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by an interim PET-CT scan. Patients with negative findings were randomized to continue ABVD or omit bleomycin (AVD group); those with positive findings received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).
While the results fell “just short of the specified noninferiority margin,” the authors reported these overall encouraging results from bleomycin omission: “A total of 1,214 patients were registered; 937 of the 1,119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin’s lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.” (P. Johnson,
johnsonp@soton.ac.uk)
Reacting to these study results, an editorialist describes a path forward in “fine-tuning the treatment of Hodgkin’s lymphoma” (
pp. 2490–2): “Ideally, tweaks to the criteria for interim PET interpretation in combination with new molecular prognostic markers will more precisely identify the high-risk population. However, new prognostic markers will not increase cure rates; only new treatments can do that. New agents that have the potential to improve outcomes for patients with Hodgkin’s lymphoma in the near term are the antibody–drug conjugate brentuximab vedotin and the PD-1 inhibitors nivolumab and pembrolizumab. When and how to incorporate these agents into the treatment of Hodgkin’s lymphoma is the goal of multiple ongoing trials.” (N. L. Bartlett)
“Normal” BMIs in Adolescence Associated with CVD, Deaths: In an observational analysis of body-mass index (BMI) data for 2.3 million Israeli adolescents in 1967–2010, BMIs in the 50th to 74th percentiles but in the normal range were linked to greater cardiovascular and all-cause mortality in young adulthood and midlife (pp. 2430–40). “We could not determine whether an increased BMI in adolescence is an independent risk factor, is mediated by adult obesity, or both,” the authors conclude. “The secular shift to the right in the distribution of adolescent BMI and the rising prevalence of overweight and obesity among adolescents may account for a substantial and increasing future burden of cardiovascular disease, particularly coronary heart disease.” (G. Twig, gilad.twig@gmail.com)

>>>PNN NewsWatch
* CDC’s Advisory Committee on Immunization Practices (ACIP) yesterday voted that intranasal live attenuated influenza vaccine (LAIV) should not be used during the 2016–17 season. ACIP continues to recommend annual influenza vaccination, with either the inactivated influenza vaccine (IIV) or recombinant influenza vaccine, for everyone 6 months and older. Overall vaccine effectiveness (VE) for the 2015–16 strains was 49%, ACIP learned from CDC staff during the meeting, but for LAIV the VE figure was 3% (95% CI, –49% to 37%) against any influenza virus in children 2 to 17 years of age. IIV formulations were 63% effective (95% CI, 52–72%). These data follow the two preceding seasons in which the VE for LAIV had been poor or lower than expected.

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 © 2016, 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
June 24, 2016 * Vol. 23, No. 122
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Early-online article from and June issue of Health Affairs, a theme issue on Behavioral Health with numerous articles on substance-use disorders (2016; 35).
PDMPs & Opioid-Related Deaths: Opioid-related overdose deaths were reduced by an average of 1.12 per 100,000 population in the year after state implementation of prescription drug monitoring programs, researchers report (10.1377/hlthaff.2015.1496). Looking at the start-up of these programs in all states except Missouri, the authors found: “In adjusted analyses we found that a state’s implementation of a program was associated with an average reduction of 1.12 opioid-related overdose deaths per 100,000 population in the year after implementation. Additionally, states whose programs had robust characteristics—including monitoring greater numbers of drugs with abuse potential and updating their data at least weekly—had greater reductions in deaths, compared to states whose programs did not have these characteristics. We estimate that if Missouri adopted a prescription drug monitoring program and other states enhanced their programs with robust features, there would be more than 600 fewer overdose deaths nationwide in 2016, preventing approximately two deaths each day.” (S. W. Patrick, stephen.patrick@vanderbilt.edu)
PDMPs & Physician Opioid Prescribing: Sustained reductions in opioid prescribing are identified in an analysis of data from 24 states in 2001–10 (pp. 1045–51): “We found that the implementation of a prescription drug monitoring program was associated with more than a 30 percent reduction in the rate of prescribing of Schedule II opioids. This reduction was seen immediately following the launch of the program and was maintained in the second and third years afterward. Effects on overall opioid prescribing and prescribing of non-opioid analgesics were limited. Increased use of these programs and the adoption of new policies and practices governing their use may have contributed to sustained effectiveness. Future studies are needed to evaluate the policies’ comparative effectiveness.” (Y. Bao, yub2003@med.cornell.edu)

>>>Medical Care Report
Source:
July issue of Medical Care (2016; 54).
Benefits to Medicaid of Physician Practice Integration: Physician practice groups formed through alignments with hospitals and health systems are more likely to participate in Medicaid programs, a study shows (pp. 714–8). In 2009–15, office-based U.S. physician practices showed these participation trends: “Independent (nonintegrated) physician practices are still the most common organizational type, but their share is declining as the share of practices integrated with a health system increases 3-fold between 2009 and 2015. Although >80% of practices that are part of a health system accept Medicaid, <60% of independent practices will see these patients. Vertically integrating with a health system makes it more likely a practice will start seeing Medicaid patients.” (M. R. Richards)
Early Adopters of Dabigatran: Cardiologists and younger physicians more quickly began prescribing dabigatran after the anticoagulant was marketed, according to investigators who studied Pennsylvania physicians (pp. 725–32). Focusing on 3,911 doctors who regularly prescribed anticoagulants, the authors identified these adoption patterns: “We identified 5 distinct adoption trajectories: 3.7% rapidly and extensively adopted dabigatran (adopting in ≤3 mo with 45% of prescriptions) and 13.4% were rapid and moderate adopters (≤3 mo with 20% share). Two groups accounting for 21.6% and 16.1% of physicians, respectively, were slower to adopt (6–10 mo post-introduction) and dabigatran accounted for <10% share. Nearly half (45.2%) of anticoagulant prescribers did not adopt dabigatran. Cardiologists were much more likely than primary care physicians to rapidly adopt [odds ratio (OR) = 12.2; 95% confidence interval (CI), 9.27–16.1] as were younger prescribers (age 36–45 y: OR = 1.49, 95% CI, 1.13–1.95; age 46–55: OR = 1.34, 95% CI, 1.07–1.69 vs. >55 y).” (W-H Lo-Ciganic)
Mortality in Safety-Net Hospitals: Safety-net hospitals (SNHs) had similar medical and surgical mortality measures as other hospitals in a longitudinal study of data from 2006–11 (pp. 648–56). A small gap in surgical mortality rates in early years diminished in later years of the study. (H. J. Jiang)

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 © 2016, 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
June 27, 2016 * Vol. 23, No. 123
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 25 issue of Lancet (2016; 387).
Platelet Transfusion After Antiplatelet Cerebral Bleed: Added to standard care, platelet transfusion seemed inferior in 190 patients taking antiplatelet drugs who had acute spontaneous primary intracerebral hemorrhage (pp. 2605–13). Conducted at 41 European sites, adult patients were enrolled in the trial if they were within 6 hours of symptom onset and had used antiplatelet therapy for at least the prior 7 days. Results of the open-label trial were as follows: “The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2.05, 95% CI 1.18–3.56; p = 0.0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay.” (Y. B. Roos, y.b.roos@amc.uva.nl)
Subcutaneous Tocilizumab in Systemic Sclerosis: Mixed results in the phase 2 faSScinate trial provide direction for a phase 3 study of the use of tocilizumab in adult patients with systemic sclerosis (pp. 2630–40). A greater number of serious infections and one patient death in the tocilizumab group complicate interpretation of the limited efficacy benefits: “We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was −3.92 in the tocilizumab group and −1.22 in the placebo group (difference −2.70, 95% CI −5.85 to 0.45; p = 0.0915). The least squares mean change at 48 weeks was −6.33 in the tocilizumab group and −2.77 in the placebo group (treatment difference −3.55, 95% CI −7.23 to 0.12; p = 0.0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p = 0.0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.” (D. Khanna, khannad@med.umich.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Prolonged Dual Antiplatelet Therapy in Stable Coronary Disease: “Real-world” patients had outcomes during prolonged dual therapy after myocardial infarction similar to participants in clinical trials, a study shows (i3163). The PEGASUS-TIMI-54 trial criteria were used to select 1,676 individuals from those with MI noted in electronic health records in the CALIBER database, with these results: “Generalisation from CALIBER’s target subgroup to all 7,238 real world patients who were stable at least one year after acute [MI] showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10,000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10,000 patients treated per year.” (A. Timmis, a.d.timmis@qmul.ac.uk)

>>>PNN JournalWatch
* Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971–2015: A Systematic Review and Bayesian Meta-Analysis, in
Arthritis & Rheumatology, 2016; 68: 1432–41. (M. M. Ward, wardm1@mail.nih.gov)
* Antihypertensive Therapy in Females: A Clinical Review Across the Lifespan, in
Pharmacotherapy, 2016; 36: 638–51. (J. C. Marrs, joel.marrs@ucdenver.edu)
* A Review of Antiviral and Antifungal Use and Safety During Pregnancy, in
Pharmacotherapy, 2016; 36: 668–78. (J. M. Cottreau, jessica.cottreau@rosalindfranklin.edu)
* Ramucirumab: A Vascular Endothelial Growth Factor Receptor-2 Inhibitor With Activity in Several Malignancies, in
American Journal of Health-System Pharmacy, 2016; 73: 957–68. (A. Glode, ashley.glode@ucdenver.edu)
* Pediatric Asthma Medication Therapy Management Through Community Pharmacy and Primary Care Collaboration, in
Journal of the American Pharmacists Association, 2016; 56: 10.1016/j.japh.2016.03.007. (C. L. Bradley, cbradley@highpoint.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 © 2016, 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
June 28, 2016 * Vol. 23, No. 124
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source:
June issue of the Journal of the American Geriatrics Society (2016; 64).
Brief Scale for Identifying Medication Problems: Using four structured questionnaires administered in homes of community-dwelling older patients, investigators validated a brief scale for prospectively identifying the need for assistance with medication management (pp. 1195–202). In five North Carolina counties, a retrospective cross-sectional and a 3-year longitudinal study produced these results among 4,136 individuals: “Characteristics associated with need for help taking medications were aged 80 and older, being male, living with others, having four or more chronic conditions, and impaired cognitive or functional status (c-statistic 0.94, 77.1% sensitivity, 87.9% specificity). Predictors of new need for help with medications 3 years later included aged 75 and older at baseline, being male, and impaired cognitive and functional status (c-statistic 0.75).” (B. D. Jamerson, bjamers@gmail.com)
Antipsychotic Drugs & Hip Fractures: Among 906,422 people born before 1945 and living in Norway in 2005–10, use of antipsychotic medications doubled the risk of hip fracture, a study shows (pp. 1203–9). Using a nationwide cohort design, researchers report these results based on national prescription and hip fracture registries: “Thirty-nine thousand nine hundred thirty-eight (4.4%) participants experienced a primary hip fracture. Greater risk of hip fracture was associated with exposure to any antipsychotic (SIR = 2.1, 95% confidence interval (CI) = 1.9–2.1), first-generation antipsychotics (SIR = 2.0, 95% CI = 1.8–2.2), second-generation antipsychotics (SIR = 2.2, 95% CI = 1.9–2.4), prolactin-sparing antipsychotics (SIR = 2.4, 95% CI = 1.8–3.1) and prolactin-elevating antipsychotics (SIR = 2.0, 95% CI = 1.9–2.2).” (M. S. Bakken, marit.bakken@uib.no)
Interventions for Inappropriate Prescribing in Community-Dwelling Older Adults: Organizational (pharmacist interventions), professional (computerized clinical decision support systems), and multifaceted approaches are effective for reducing potentially inappropriate prescribing (PIP) among community-dwelling older adults, according to results of a systematic review and narrative synthesis of published literature (pp. 1210–22). “Ongoing assessment of interventions to reduce PIP is needed in community-dwelling older adults, particularly in relation to preventing initiation of PIP,” the authors conclude based on these results: “Twelve randomized controlled trials were identified with baseline PIP prevalence of 18% to 100%. Four of six organizational interventions reported a reduction in PIP, particularly through pharmacists conducting medication reviews. Evidence of the effectiveness of multidisciplinary teams was weak. Both of the two professional (targeting prescriber’s directly) interventions were computerized clinical decision support interventions and were effective in decreasing new PIP but not existing PIP. Three of four multifaceted approaches were effective in reducing PIP. The risk of bias was often high, particularly in reporting selection bias.” (B. Clyne, barbaraclyne@rcsi.ie)
Inflammatory Biomarkers & Cognitive Decline: In the Ginkgo Evaluation of Memory Study, inflammatory biomarkers were not useful for identifying individuals at risk of cognitive decline (pp. 1171–7). Authors recommend future study of pentraxin 3 and serum amyloid P as markers of vascular inflammation, adiponectin for assessing metabolic function, and the modified Mini-Mental State Examination for cognitive function. (M. Sharma, msharma04@gmail.com)

>>>PNN NewsWatch
* Medtronic has filed for FDA approval of its artificial pancreas device for treating patients with type 1 diabetes, according to media reports. Presentations at the recent American Diabetes Association Scientific Sessions included late-breaking pivotal trial results of the Hybrid Closed Loop system, pivotal trial results for the company’s fourth generation sensor, and further study of the company’s SmartGuard technology. The artificial pancreas is the focus of nine article in a special section of the July issue of Diabetes Care (“The Artificial Pancreas in 2016: A Digital Treatment Ecosystem for Diabetes&rdquoWinking. Six other articles in that issue present personalized medicine approaches from a Diabetes Care symposium at the ADA meeting.

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 © 2016, 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
June 29, 2016 * Vol. 23, No. 125
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
June 29 issue of JAMA (2016; 315).
Blood Pressures & Cardiovascular Outcomes in Advanced Age: Among patients aged 75 years or older, intensive systolic blood pressure (SBP) control produced significantly better cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT), researchers report (pp. 2673–82). Based on a primary cardiovascular disease composite outcome of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes, intensive (SBP < 120 mm Hg) and standard (<140 mm Hg) control produced these results: “Among 2,636 participants (mean age, 79.9 years; 37.9% women), 2,510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51–0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49–0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89–1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97–3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76–2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99–2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98–2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65–1.29]).” (J. D. Williamson, jwilliam@wakehealth.edu)
Editorialists make these recommendations to clinicians managing hypertension in patients 75 years or older (
pp. 2669–70): “Although the story is incomplete, the available evidence supports a stepwise approach to treatment beginning with an initial SBP goal of less than 140 mm Hg. If lowering SBP to that level is tolerated well, further titration with careful monitoring should be considered to achieve an SBP goal of less than 130 mm Hg. The choice of antihypertensive medications can vary depending on clinician and patient preference, considering that several studies have shown that the major benefit of treatment depends on BP lowering rather than type of antihypertensive medication used.11 In general, however, the preferred first-line drugs should be diuretics, calcium antagonists, angiotensin receptor antagonists, and angiotensin-converting enzyme inhibitors. Beta-receptor antagonists are also valuable as first-line agents in patients with coronary heart disease, arrhythmias, and heart failure. Combination drug preparations are useful because therapy often will involve multiple drugs. Since older persons with SBP less than 110 mm Hg while standing were excluded in SPRINT, the risk of syncope and falls may have been underestimated, and particular attention should be given to avoidance of orthostatic hypotension with treatment.” (A. V. Chobanian, achob@bu.edu)
Mood & Heart Failure: In a trial terminated early, escitalopram failed to significantly improve all-cause mortality, hospitalizations, or depression among patients with chronic systolic heart failure and depression (pp. 2683–93). The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was stopped after 18 of 24 planned months when these results were noted in the treatment and placebo groups: “The primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92).” (C. E. Angermann, angermann_c@ukw.de)

>>>PNN NewsWatch
* FDA yesterday approved a fixed-dose combination tablet containing sofosbuvir and a new drug, velpatasvir (Epclusa, Gilead), to treat adult patients with chronic hepatitis C virus (HCV) both with and without cirrhosis. For patients with moderate to severe (decompensated) cirrhosis, Epclusa is approved for use in combination with ribavirin. Epclusa, approved under FDA’s priority review program, is the first drug product for treatment of all six HCV genotypes.

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 © 2016, 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
June 30, 2016 * Vol. 23, No. 126
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
June 30 New England Journal of Medicine (2016; 374).
Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine: Assessing a study showing waning efficacy of a three-dose regimen of the RTS,S/AS01 malaria vaccine and rebound (negative efficacy) infections at year 5 (pp. 2519–29 ; P. Bejon, pbejon@kemri-wellcome.org), editorialists caution against jumping to a conclusion (pp. 2596–7): “[This] trial evaluated only a three-dose regimen, which has not been recommended by the [World Health Organization (WHO)], and the field site for the trial had substantially lower rates of malaria transmission than many of the sites in the phase 3 trial. Fortunately, three other sites participating in the phase 3 trial are extending surveillance beyond the fourth year and include cohorts receiving either a three-dose or four-dose regimen; these sites will provide an important resource to test and better understand the findings of this trial.… In the meantime, it would be unwise to postpone the planning of the WHO-recommended pilot implementation studies, which will be designed to yield data of importance to decisions regarding the deployment of this vaccine.” (J. Clemens)
Midostaurin in Advanced Systemic Mastocytosis: Midostaurin, a multikinase inhibitor of KIT D816V, “showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia,” researchers report (pp. 2530–41). Oral midostaurin 100 mg twice daily produced these outcomes in the open-label trial: “The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were −59% and −58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.” (J. Gotlib, jason.gotlib@stanford.edu)
Pembrolizumab in Advanced Merkel-Cell Carcinoma: The aggressive skin cancer Merkel-cell carcinonoma responded to first-line treatment with pembrolizumab, which blocks the programmed death 1 immune inhibitory pathway (pp. 2542–52). Based on a primary end point of objective response rate using the Response Evaluation Criteria in Solid Tumors, version 1.1, instrument, the investigators found these results with pembrolizumab 2 mg/kg every 3 weeks: “A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.” (S. L. Topalian, stopali1@jhmi.edu)

>>>PNN NewsWatch
* FDA yesterday cleared for marketing the Xpert Carba-R Assay (Cepheid), an infection control aid that tests patient specimens to detect specific genetic markers associated with bacteria that are resistant to carbapenem antibiotics. The assay tests only for genetic material; it does not detect bacteria, carbapenemase activity, or other possible nonenzymatic causes of carbapenem resistance.

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 © 2016, 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.