Dec 2014

PNN October–December 2014

PNN Pharmacotherapy Line
Oct. 1, 2014 * Vol. 21, No. 190
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 1 issue of JAMA (2014; 312).
Management of S. aureus Bacteremia: Clinical management of Staphylococcus aureus bacteremia should begin with vancomycin and daptomycin, conclude authors of a review article (pp. 1330–41). The group adds that “all adult patients with S aureus bacteremia should undergo echocardiography” and identifies low-risk patients for whom some procedures “can be safely avoided”: “In 9 studies with a total of 4,050 patients, use of transesophageal echocardiography was associated with higher rates of a diagnosis of endocarditis (14%–28%) compared with transthoracic echocardiography (2%–15%). In 4 studies, clinical or transthoracic echocardiography findings did not predict subsequent transesophageal echocardiography findings of endocarditis. Five studies identified clinical or transthoracic echocardiography characteristics associated with low risk of endocarditis (negative predictive values from 93% to 100%). Characteristics associated with a low risk of endocarditis include absence of a permanent intracardiac device, sterile follow-up blood cultures within 4 days after the initial set, no hemodialysis dependence, nosocomial acquisition of S aureus bacteremia, absence of secondary foci of infection, and no clinical signs of infective endocarditis. Of 81 studies of antibiotic therapy for MRSA bacteremia, only 1 high-quality trial was identified. In that study of 246 patients with S aureus bacteremia, daptomycin was not inferior to vancomycin or an antistaphylococcal penicillin, each in combination with low-dose, short-course gentamicin (clinical success rate, 44.2% [53/120] vs 41.7% [48/115]; absolute difference, 2.4% [95% CI, −10.2% to 15.1%]).” (V. G. Fowler Jr, vance.fowler@duke.edu)
Evidence-Based Practice, Uniform Health Care & Shared Decision Making: Two Viewpoint articles explore relationships among evidence-based medicine and processes for reaching clinical decisions.
Principles of evidence-based practice “highlight the desirability of (in most clinical situations) tailoring care to patients’ particular circumstances and their individual values and preferences,” authors write (
pp. 1293–4). Rather than “justifying a drive for uniformity of care,” the group lists three principles that should guide evidence-based practice: “the need for systematic summaries of the best available evidence to guide practice; standards for identifying when clinicians can be confident in evidence and when they cannot; and the recognition that values and preferences are as important as evidence in determining optimal clinical decisions.” (B. Djulbegovic, bdjulbeg@health.usf.edu)
While links between evidence-based medicine and shared decision making “have until recently been largely absent or at best implied,” authors of a second article write that “encouraging signs of interaction are emerging” (
pp. 1295–6): “For example, there has been some integration of the teaching of both, exploration about how guidelines can be adapted to facilitate [shared decision making], and research and resource tools that recognize both approaches. Examples of the latter include research agenda and priority setting occurring in partnership with patients and clinicians to help provide relevant evidence for decision making; and a new evidence criterion for the International Patient Decision Aids Standards requiring citation of systematically assembled and up-to-date bodies of evidence, with their trustworthiness appraised, thus aligning the development of [shared decision making] tools with contemporary requirements for the formulation of evidence-based guidelines. Also, independent flagship conferences focused on the practice of evidence-based health care and on the science of shared decision making are now convening joint meetings.” (V. M. Montori, montori.victor@mayo.edu)
Testing Experimental Ebola Interventions: As treatment begins for the first patient diagnosed with Ebola virus in the U.S., authors explore the science and ethics associated with scarce new agents being tested for this condition (pp. 1299–300): “Clinicians, investigators, and policy makers must deploy novel agents in ways that address pressing scientific questions, prioritize research in populations that will be most scientifically informative as well as most likely to benefit, ensure valid answers through the use of supportive care controls, and protect critical clinical and public health resources from diversion to longer-term aims.” (S. Joffe, joffes@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 © 2014, 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
Oct. 2, 2014 * Vol. 21, No. 191
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 2 issue of the New England Journal of Medicine (2014; 371).
Step-Down COPD Therapy: In a study released in advance of publication (see PNN, Sept. 8), patients with severe chronic obstructive pulmonary disorder (COPD) were able to discontinue inhaled glucocorticoids without increased risk of moderate or severe exacerbations (pp. 1285–94). Lung function decreased during the final step-down, the investigators report, adding these details about the 6-week run-in period and 12-week study: “As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P <0.001); a similar between-group difference (43 ml) was seen at week 52 (P = 0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group.” (H. Magnussen, magnussen@pulmoresearch.de)
“The results of this trial, taken together with the findings of other studies, suggest that the rationale for continuing glucocorticoid therapy in patients who are also taking long-acting bronchodilators should be based on symptomatic improvement attributable to the glucocorticoid rather [than] the prevention of exacerbations,” an editorialist writes (
pp. 1340–1). “They also show that a trial of glucocorticoid withdrawal will not increase the risk of exacerbation, even in patients with severe COPD. The findings may prompt clinicians to consider other preventive interventions, such as daily azithromycin, in patients who continue to have frequent exacerbations while receiving long-acting bronchodilators.” (J. J. Reilly)
Contraception Cost & Teenage Pregnancy: Provision of education and no-cost contraception can reduce pregnancy rates among American teenage girls and women, according to results of the Contraceptive CHOICE Project (pp. 1316–23). The prospective cohort study used long-acting, reversible contraceptive (LARC) methods and education about reversible contraception methods. Following study participants over 2–3 years, researchers identify these results among 15–19 year olds: “Of the 1,404 teenage girls and women enrolled in CHOICE, 72% chose an intrauterine device or implant (LARC methods); the remaining 28% chose another method. During the 2008–2013 period, the mean annual rates of pregnancy, birth, and abortion among CHOICE participants were 34.0, 19.4, and 9.7 per 1,000 teens, respectively. In comparison, rates of pregnancy, birth, and abortion among sexually experienced U.S. teens in 2008 were 158.5, 94.0, and 41.5 per 1,000, respectively.” (J. F. Peipert, peipertj@wudosis.wustl.edu)

>>>PNN NewsWatch
* With the first case of Ebola virus disease now diagnosed in the U.S., CDC has deployed a team of 10 experts to Texas to assist state and local health departments in finding, assessing, and assisting everyone who came into contact with the Ebola patient between the time he became symptomatic (before having symptoms, people with Ebola cannot spread the infection) and the time he was placed in an isolation ward. CDC said yesterday that travelers from Guinea, Liberia, Nigeria, or Sierra Leone should monitor their health for symptoms, fever greater than 101.5 degrees Fahrenheit, severe headache, muscle pain, diarrhea, vomiting, stomach pain, or unexplained bruising or bleeding, for 21 days after travel. They should see a health care provider as soon as any of these symptoms develop, letting them know of their travel history and symptoms, CDC added.
*
FDA is taking steps stimulate development of drugs and devices for rare diseases by awarding 15 grants totaling $19 million, the agency announced this week. One quarter of the grants support pediatric research.
* October is
American Pharmacists Month, and today is the #pharmacist tweet-a-thon. Share how you’ve helped a patient as pharmacists worldwide seek to send the hashtag #pharmacist up the Twitter trending chart.

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 © 2014, 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
Oct. 3, 2014 * Vol. 21, No. 192
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Oct. issue of Pediatrics (2014; 134).
ADHD, Stimulants & Growth: Stimulant treatment of children with attention-deficit/hyperactivity disorder (ADHD) is not associated with differences in adult height or rates of growth, conclude researchers who conducted a longitudinal study using cases and controls from a population-based birth cohort (pp. e935–44). Included in the analysis were 340 cases and 680 controls. Using a parametric penalized spline smoothing method modeled height over time to assess corresponding height velocity and peak height velocity (PHV) age and magnitude, the authors determined: “Neither ADHD itself nor treatment with stimulants was associated with differences in magnitude of PHV or final adult height. Among boys treated with stimulants, there was a positive correlation between duration of stimulant usage before PHV and age at PHV (r = 0.21, P = .01). There was no significant correlation between duration of treatment and change in height Z scores (r = −0.08 for beginning vs end change, r = 0.01 for end vs 24 months later change). Among the 59 ADHD cases treated for ≥3 years, there was a clinically insignificant decrease in mean Z score from beginning (0.48) to end (0.33) of treatment (P = .06).” (E. B. Harstad)
Seizures Around the Time of Vaccinations: An investigation into the etiologies of seizures occurring around the time of childhood vaccinations shows that genetic or structural defects are most often the causes (pp. 658–66). Investigators analyzed medical data for 990 children with seizures after vaccination in the first 2 years of life, with these results: “Follow-up was available for 23 of 26 children (median age: 10.6 years) with epilepsy onset after vaccination. Twelve children developed epileptic encephalopathy, 8 had benign epilepsy, and 3 had encephalopathy before seizure onset. Underlying causes were identified in 15 children (65%) and included SCN1A–related Dravet syndrome (formerly severe myoclonic epilepsy of infancy) or genetic epilepsy with febrile seizures plus syndrome (n = 8 and n = 1, respectively), a protocadherin 19 mutation, a 1qter microdeletion, neuronal migration disorders (n = 2), and other monogenic familial epilepsy (n = 2).” (N. E. Verbeek)
Childhood Vaccination & Adolescent Asthma: “Pertussis immunization in infancy does not increase the risk of asthma medication use in adolescents,” conclude authors who analyzed data on 82,000 Swedish children in a vaccination trial in 1993–94 (pp. 721–8). In a follow-up analysis of nearly 80,000 of the children, investigators determined these odds ratios (ORs) using intention-to-treat and per-protocol methods: “The prevalence rates of various asthma medications for study patients at 15 years of age differed between 4.6% and 7.0%. The crude ORs for any asthma medication and antiinflammatory treatment in pertussis-vaccinated children after intention-to-treat analysis were 0.97 (95% CI: 0.93–1.00) and 0.94 (95% CI: 0.90–0.98), respectively. Corresponding adjusted ORs were 0.99 (95% CI: 0.95–1.03) and 0.97 (95% CI: 0.92–1.01). Similar ORs were found after per-protocol analysis.” (H. Vogt)

>>>Psychiatry Report
Source:
Oct. issue of the American Journal of Psychiatry (2014; 171).
Antidepressant Treatment of Bipolar Disorder: Patients with bipolar disorder should not be treated with antidepressant monotherapy based on results of a study of antidepressant-induced manic switch (pp. 1067–73). “No risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer,” the researchers conclude after conducting a regression analysis of 3,240 patients who started treatment with an antidepressant and had no antidepressant treatment during the previous year: “Nearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio = 2.83, 95% CI = 1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI = 0.54, 1.15), and a decreased risk was observed during the period 3–9 months after treatment initiation (hazard ratio = 0.63, 95% CI = 0.42, 0.93).” (M. Landén, mikael.landen@neuro.gu.se)

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 © 2014, 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
Oct. 6, 2014 * Vol. 21, No. 193
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 4 issue of Lancet (2014; 383).
Pump v. Injections in Insulin Therapy: In a study of patients with poorly controlled type 2 diabetes despite multiple daily injections, insulin pump treatment “can be considered as a safe and valuable treatment option,” researchers report (pp. 1265–72). A multicenter trial conducted at 36 hospitals on four continents found these effects of insulin delivery options on glycosylated hemoglobin in 331 patients: “At 6 months, mean glycated haemoglobin had decreased by 1.1% (SD 1.2; 12 mmol/mol, SD 13) in the pump treatment group and 0.4% (SD 1.1; 4 mmol/mol, SD 12) in the multiple daily injection group, resulting in a between-group treatment difference of –0.7% (95% CI –0.9 to –0.4; –8 mmol/mol, 95% CI –10 to –4, p <0.0001). At the end of the study, the mean total daily insulin dose was 97 units (SD 56) with pump treatment versus 122 units (SD 68) for multiple daily injections (p <0.0001), with no significant difference in bodyweight change between the two groups (1.5 kg [SD 3.5] vs 1.1 kg [3.6], p = 0.322). Two diabetes-related serious adverse events (hyperglycaemia or ketosis without acidosis) resulting in hospital admission occurred in the pump treatment group compared with one in the multiple daily injection group. No ketoacidosis occurred in either group and one episode of severe hypoglycaemia occurred in the multiple daily injection group.” (Y. Reznik, reznik-y@chu-caen.fr)
Rituximab in Nephrotic Syndrome: In 48 patients with childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome, rituximab provided an effective and safe treatment (pp. 1273–81). Compared with placebo and administered once weekly, rituximab had these effects over a 1-year period: “The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223–374) than in the placebo group (101 days, 70–155; hazard ratio: 0.27, 0.14–0.53; p <0.0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p = 0.36).” (K. Iijima, iijima@med.kobe-u.ac.jp)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Industry Sponsorship in Statin Studies: While “discrepancies [have been found] between industry and nonindustry sponsored trials” of statins, a new study of 183 trials shows similar results regardless of sponsorship (g5741). “When all of the existing randomised evidence was synthesised in network meta-analyses, there were clear differences in the LDL cholesterol lowering effects of individual statins at different doses. In general, higher doses resulted in higher reductions in baseline LDL cholesterol levels. Of the 35 unique comparisons available in 37 non-industry sponsored trials, 31 were also available in industry sponsored trials. There were no systematic differences in magnitude between the LDL cholesterol lowering effects of individual statins observed in industry sponsored versus non-industry sponsored trials. In industry sponsored trials, the mean change from baseline LDL cholesterol level was on average 1.77 mg/dL (95% credible interval −11.12 to 7.66) lower than the change observed in non-industry sponsored trials. There was no detectable inconsistency in the evidence network.” (H. Naci, h.naci@lse.ac.uk)

>>>PNN JournalWatch
* Adverse Consequences of Glucocorticoid Medication: Psychological, Cognitive, and Behavioral Effects, in
American Journal of Psychiatry, 2014; 171: 1045–51. (L. L. Judd, ljudd@ucsd.edu)
* The Evolution and Future of ACC/AHA Clinical Practice Guidelines: A 30-Year Journey—A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, in
Circulation, 2014; 130: 1208–17. (A. K. Jacobs)
* Deciphering the Complexities of Atopic Dermatitis: Shifting Paradigms in Treatment Approaches, in
Journal of Allergy and Clinical Immunology, 2014; 134: 769–79. (D. Y. M. Leung, leungd@njhealth.org)
* Challenges to School-Located Vaccination: Lessons Learned, in
Pediatrics, 2014; 134: 803–8. (H. M. Limper)
* Postoperative Atrial Fibrillation: Role of Inflammatory Biomarkers and Use of Colchicine for Its Prevention, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1485. (J. C. Worden, Jarett.worden@gmail.com)
* Does Insulin Therapy for Type 1 Diabetes Mellitus Protect Against Alzheimer’s Disease?, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1494. (G. M. Rdzak, grzegorz.rdzak@ynhh.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 © 2014, 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
Oct. 7, 2014 * Vol. 21, No. 194
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 7 issue of the Annals of Internal Medicine (2014; 161).
NNRTI-Sparing Antiretroviral Therapy: In a Phase III, open-label trial of treatment-naive adults with HIV-1 infection, three nonnucleoside reverse transcriptase inhibitor–sparing initial antiretroviral regimens were effective over a 2-year period, researchers report (pp. 461–71). Regimens containing raltegravir or ritonavir-boosted darunavir were more tolerable than a ritonavir-boosted atazanavir regimen, as shown in these results based on virologic (high HIV-1 RNA levels) or tolerability (drug discontinuation) failures: “Among 1,809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as −10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.” (J. L. Lennox, jlennox@emory.edu)
Conflicts of Interest & Bias in Systematic Reviews: Authors of systematic reviews of neuraminidase inhibitors who have financial conflicts of interest are more likely to present evidence “in a favorable manner” and recommend use of the drugs, a retrospective analysis concludes (pp. 513–8). Two investigators blinded to author information found these patterns in review articles: “Twenty-six systematic reviews were identified, of which 13 examined prophylaxis and 24 examined treatment, accounting for 37 distinct assessments. Among assessments associated with a financial conflict of interest, 7 of 8 (88%) were classified as favorable, compared with 5 of 29 (17%) among those without a financial conflict of interest. Reviewers without financial conflicts of interest were more likely to include statements about the quality of the primary studies than those with financial conflicts of interest.” (A. G. Dunn, a.dunn@unsw.edu.au)
Troponin Levels in CKD & ACS: In patients with chronic kidney disease (CKD) and suspected acute coronary syndrome (ACS), troponin levels are useful in determining prognosis but not in making an ACS diagnosis, according to a review of 23 studies (pp. 502–12). Troponin levels already raised by CKD present challenges to clinicians trying to determine whether patients have ACS, the authors explain, adding these details about the relevant studies: “The sensitivity of troponin T for ACS diagnosis ranged from 71% to 100%, and specificity ranged from 31% to 86% {6 studies; low [strength of evidence (SOE)]}. The sensitivity and specificity of troponin I ranged from 43% to 94% and from 48% to 100%, respectively (8 studies; low SOE). No studies examined how troponin levels affect management strategies. Twelve studies analyzed prognostic value. Elevated levels of troponin I or troponin T were associated with higher risk for short-term death and cardiac events (low SOE). A similar trend was observed for long-term mortality with troponin I (low SOE), but less evidence was found for long-term cardiac events for troponin I and long-term outcomes for troponin T (insufficient SOE). Patients with advanced CKD tended to have worse prognoses with elevated troponin I levels than those without them (moderate SOE).” (E. D. Michos, edonnell@jhmi.edu)

>>>PNN NewsWatch
* Three lots of Ketorolac Tromethamine Injection, USP, 30 mg/mL single-dose vials have been recalled by Sagent Pharmaceuticals because of incorrect expiration dates, FDA said. Lots MP5021, MP5024, and MP5025 were distributed in late September and have expiration dates later than the known stability of the product.
* In Colorado, half of 10 children hospitalized with
unexplained paralysis had enterovirus D68 in nasal secretions, CDC reports. The patients, ages 1–18 years, had spinal cord problems that could be visualized on MRI. The agency also reported that all patients had fever and most had respiratory illness about 1 week before the onset of muscle weakness; none had virus in spinal fluid.

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 © 2014, 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
Oct. 8, 2014 * Vol. 21, No. 195
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 8 issue of JAMA (2014; 312).
Patient Decontamination & Antibiotic Resistance in ICUs: Used unitwide in 16 Dutch intensive-care units (ICUs), selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) were associated with low levels of antibiotic resistance but no differences in 28-day mortality, researchers report (pp. 1429–37). In 2009–13, patients with expected length of ICU stay of more than 48 hours were eligible for the interventions, which were used in 12-month alternating periods. Results showed “lower rectal carriage of antibiotic-resistant gram-negative bacteria and ICU-acquired bacteremia but a more pronounced gradual increase in aminoglycoside-resistant gram-negative bacteria” with SDD than SOD: “In point-prevalence surveys, prevalences of antibiotic-resistant gram-negative bacteria in perianal swabs were significantly lower during SDD compared with SOD; for aminoglycoside resistance, average prevalence was 5.6% (95% CI, 4.6%–6.7%) during SDD and 11.8% (95% CI, 10.3%–13.2%) during SOD (P  < .001). During both interventions the prevalence of rectal carriage of aminoglycoside-resistant gram-negative bacteria increased 7% per month (95% CI, 1%–13%) during SDD (P = .02) and 4% per month (95% CI, 0%–8%) during SOD (P = .046; P = .40 for difference). Day 28-mortality was 25.4% and 24.1% during SOD and SDD, respectively (adjusted odds ratio, 0.96 [95% CI, 0.88–1.06]; P = .42), and there were no statistically significant differences in other outcome parameters or between surgical and nonsurgical patients. Intensive care unit–acquired bacteremia occurred in 5.9% and 4.6% of the patients during SOD and SDD, respectively (odds ratio, 0.77 [95% CI, 0.65–0.91]; P = .002; number needed to treat, 77).” (E. A. N. Oostdijk, e.a.n.oostdijk@umcutrecht.nl)
Editorialists respond to this study by calling for balance in antimicrobial stewardship efforts (
pp. 1403–4): “Despite a large amount of research in this area, clinicians are still unclear on the optimal use of SDD and SOD. For the time being in the United States, SOD seems to be a more reasonable approach for the prevention of pathogenic bacterial overgrowth in critically ill patients. The use of SDD in the United States should probably be avoided until multicenter studies demonstrate the overall efficacy of SDD in hospitals with more widespread background antibiotic resistance.” (M. Kollef, mkollef@dom.wustl.edu)
Antimicrobial Use in U.S. Acute Care Hospitals: Based on 1-day prevalence surveys in U.S. acute care hospitals located in 10 states, investigators quantify antimicrobial use in May through Sept. 2011, reaching this conclusion (pp. 1438–46): “Use of broad-spectrum antimicrobial drugs such as piperacillin–tazobactam and drugs such as vancomycin for resistant pathogens was common, including for treatment of community-onset infections and among patients outside critical care units. Further work is needed to understand the settings and indications for which reducing antimicrobial use can be most effectively and safely accomplished.” (S. S. Magill, smagill@cdc.gov)
Controlling Pandemic Influenza: Responding to studies of the serological and immune effects of an avian influenza A/H7N9 vaccine mixed at point of use with MF59 adjuvant (pp. 1409–19, M J. Mulligan, mark.mulligan@emory.edu; pp. 1420–8, R. B. Belshe, belsherb@slu.edu), editorialists write (pp. 1401–2): “Even though these 2 comprehensive and novel studies provide important relevant information, there is much more to learn. Hemagglutinin inhibition and neutralizing antibody are probably involved in the protective efficacy of influenza vaccines, but it is not known how predictive of protection these assays are for avian influenza, or what levels of antibody response are actually required. Although the priming effect is well established, the immunological markers that predict priming have not been determined for these vaccines in humans. Importantly, the significance and immunological mechanisms of the unexpected effect of prior seasonal vaccination on the response to avian vaccines are unknown. Additional research will continue to clarify these issues, and rigorous studies, like those of Mulligan et al and Belshe et al, will prove especially important in helping to understand and be prepared to respond to the evolving threat potentially posed by pandemic influenza.” (J. J. Treanor, john_treanor@urmc.rochester.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 © 2014, 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
Oct. 9, 2014 * Vol. 21, No. 196
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 9 issue of the New England Journal of Medicine (2014; 371).
Blood Pressure & Glucose Control in Type 2 Diabetes: Continued monitoring of patients in a clinical trial shows that blood-pressure lowering had sustained effects, but intensive glucose control did not, reports the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational Study (ADVANCE-ON) Collaborative Group (pp. 1392–406). “There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events,” the investigators conclude based on these results: “The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8,494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure–lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure–lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P = 0.03) and 0.88 (95% CI, 0.77 to 0.99; P = 0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.” (S. Zoungas)
Influenza in Pregnancy: The high level of morbidity and mortality among pregnant women during the 2010 A/H1N1 pandemic “called attention to questions about influenza during pregnancy and led to a large number of publications and vastly improved knowledge about influenza and its treatment and prevention in this population,” Perspective authors write (pp. 1373–5). “Unfortunately, pregnant women continue to become seriously ill with influenza, and some of them die. Research is needed to further elucidate the reasons why some pregnant women are not vaccinated so that the problems can be addressed. In addition, by implementing the current antiviral treatment recommendations, clinicians can prevent complications in women with influenza. We need to ensure that the information about influenza and pregnancy that has been gained in the 5 years since the 2009 H1N1 pandemic is translated into reductions in the number of illnesses, hospitalizations, and deaths that occur in future influenza seasons.” (S. A. Rasmussen)
Physiological Assessment of Acid–Base Disturbances: The physiological approach to assessment of acid–base disorders is preferable over the physicochemical approach, conclude authors of a review article (pp. 1434–45): “The physicochemical (strong ion or Stewart) approach is complex and often requires cumbersome calculations that cannot be performed at the bedside. Many clinicians think that it does not provide a diagnostic or prognostic advantage and that the large number of parameters used in calculations will increase the magnitude of variability and error. The standard base-excess method accurately quantifies the change in metabolic acid–base status in vivo and is conveniently provided by the blood-gas machine. However, ‘mixed’ acid–base disorders will not be detected by that method without the use of elaborate base-excess partitioning. Therefore, in our view, the physiological approach, considered here, remains the simplest, most rigorous, and most serviceable approach to the assessment of acid–base disorders.” (K. Berend, kenber2@me.com)
Medication Errors as Harbinger: “A frail, elderly man with complicated illnesses, taking high-risk medications, living alone—it was a recipe for disaster,” writes the author of a moving case that begins with problems the patient had administering his medications at home (pp. 1378–9). Already diagnosed with hepatic cancer, the patient spends his final days in the hospital largely because of insurance and procedural delays in getting prior-approval and other authorizations for the home care he needed. (D. Ofri)

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 © 2014, 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
Oct. 10, 2014 * Vol. 21, No. 197
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Oct. 14 issue of the Journal of the American College of Cardiology (2014; 64).
Amiodarone & Anticoagulation in Atrial Fibrillation: In patients with atrial fibrillation who participated in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, those taking amiodarone had “significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when [using] warfarin,” researchers report (pp. 1541–50). Using a Cox model, study investigators assessed propensity scores for those receiving or not receiving amiodarone at the time of randomization: “In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant.” (G. Flaker)
Childhood Adiposity & Adult Ventricular Function: In a study of 1,061 adults ages 24–46 years who had been followed for a mean of 28.0 years, excessive adiposity and elevated blood pressure (BP) in childhood were associated with adverse effects on left ventricular (LV) function in later life (pp. 1580–7). Authors use area under the curve (AUC) values for long-term burden (total AUC) and trends (incremental AUC) of body mass index (BMI) and BP to identify four LV geometric types: “Higher values of BMI and systolic and diastolic BP in childhood and adulthood, as well as total AUC and incremental AUC, were all significantly associated with higher LV mass index and [LV hypertrophy], adjusted for race, sex, and age. In addition, higher values of BMI and BP in childhood and adulthood, total AUC, and incremental AUC were significantly associated with [eccentric hypertrophy] and [concentric hypertrophy] but not with [concentric remodeling]. Importantly, all of these measures of BMI had a consistently and significantly greater influence on [eccentric hypertrophy] than did measures of BP.” (C-C Lai)

>>>Circulation Report
Source:
Oct. 7 issue of Circulation (2014; 130).
Omega-6 Fatty Acids & Mortality: Of the omega-6 polyunsaturated fatty acids (n-6 PUFA), only linoleic acid was significantly and inversely associated with mortality in a study of 2,792 older adults (pp. 1245–53). The participants, aged 65 years or older and free of cardiovascular disease at baseline, had these outcomes during 34,291 person–years of follow-up: “In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic [coronary heart disease] mortality (hazard ratio, 0.51; 95% confidence interval, 0.32–0.82; P trend = 0.001). Circulating gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70–1.34; P trend=0.87).…” (J. Wu, jwu1@georgeinstitute.org.au)

>>>PNN NewsWatch
* While the media focus heavily on Ebola virus, pharmacist.com reports that 600 U.S. cases of enterovirus D68 have parents’ attention.
*
PNN will not be published on Mon., Oct. 13, Columbus 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 © 2014, 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
Oct. 14, 2014 * Vol. 21, No. 198
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. issue of JAMA Internal Medicine (2014; 174).
Bisphosphonates & Breast Cancer: Contrary to observational findings, bisphosphonate therapy in postmenopausal women did not reduce the risk of invasive breast cancer in clinical trials, researchers report (pp. 1550–7). The Fracture Intervention Trial (FIT; 6,459 women 55–81 years old followed a mean of 3.8 years while on alendronate or placebo) and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT; 7,765 women 65–89 years old followed a mean of 2.8 years while on annual I.V. zolendronic acid or placebo) show these patterns: “There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84–1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70–1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89–1.63]).” (T. F. Hue, thue@psg.ucsf.edu)

>>>Lancet Highlights
Source:
Oct. 11 issue of Lancet (2014; 383).
Once-Weekly Dulaglutide v. Once-Daily Liraglutide: Among metformin-treated patients with poorly controlled type 2 diabetes, once-weekly dulaglutide was noninferior to once-daily liraglutide in reduction of glycosylated hemoglobin, and safety and tolerability profiles were similar (pp. 1349–57). In the open-label AWARD-6 trial at 62 international sites, randomization of 599 participants to once-weekly dulaglutide 1.5 mg or once-daily liraglutide 1.8 mg produced these results based on a noninferiority margin of 0.4% in HbA1c levels: “Least-squares mean reduction in HbA1c was –1.42% (SE 0.05) in the dulaglutide group and –1.36% (0.05) in the liraglutide group. Mean treatment difference in HbA1c was –0.06% (95% CI –0.19 to 0.07, pnon-inferiority <0.0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0.34 (SE 1.44) and 0.52 (3.01) events per patient per year, respectively, and no severe hypoglycaemia was reported.” (K. M. Dungan, kathleen.dungan@osumc.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Cost of Universal Meningitis Vaccination: A cost-effectiveness analysis of the Novartis meningitis B vaccine Bexsero shows that “routine infant vaccination is the most effective short term strategy and could be cost effective with a low vaccine price” (g5725). The analysis—from the U.K. National Health Service, personal, and social services perspectives—shows the following: “In the short term, case reduction is greatest with routine infant immunisation (26.3% of cases averted in the first five years). This strategy could be cost effective at 3 pounds (3.8 euros, $4.9) a vaccine dose, given several favourable assumptions and the use of a quality of life adjustment factor. If the vaccine can disrupt meningococcal transmission more cases are prevented in the long term with an infant and adolescent combined programme (51.8% after 30 years), which could be cost effective at £4 a vaccine dose. Assuming the vaccine reduces acquisition by 30%, adolescent vaccination alone is the most favourable strategy economically, but takes more than 20 years to substantially reduce the number of cases.” (H. Christensen, hannah.christensen@bristol.ac.uk)

>>>PNN JournalWatch
* Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected With HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America, in
Clinical Infectious Diseases, 2014; 59: e96–e138. (G. M. Lucas, glucas@jhmi.edu)
* Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2–Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline, in
Journal of Clinical Oncology, 2014; 32: 3307–29. (American Society of Clinical Oncology, guidelines@asco.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 © 2014, 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
Oct. 15, 2014 * Vol. 21, No. 199
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 15 issue of JAMA (2014; 312).
Vitamin D & Hospital Outcomes: Among critically ill patients with vitamin D deficiencies, administration of high doses of vitamin D3 had no significant effects on hospital length of stay, hospital mortality, or 6-month mortality, report researchers from the Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) study (pp. 1520–30). Participants were 492 critically ill adult white patients with serum vitamin D levels of 20 ng/mL or less. Vitamin D3 (540,000 IU orally once and 90,000 IU monthly for 5 months) produced these results for 475 patients included in the final analysis: “The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1–33.3] for vitamin D3 vs 19.3 days [IQR, 11.1–34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%–34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%–41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58–1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%–41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%–49.4%] for placebo; HR, 0.78 [95% CI, 0.58–1.04]; P = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 20.1 days (IQR, 12.9–39.1) for vitamin D3 vs 19.0 days (IQR, 11.6–33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%–38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%–56.2%]) for placebo (HR, 0.56 [95% CI, 0.35–0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%–45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%–60.1%] for placebo; HR, 0.60 [95% CI, 0.39–0.93], P for interaction = .12).” (K. Amrein, karin.amrein@medunigraz.at)
Vancomycin MICs & Staph. aureus Septicemia Mortality: Alternative antistaphylococcal agents may not be needed in patients whose Staphylococcus aureus bacteremia (SAB) isolates fall into the elevated but susceptible vancomycin minimum inhibitory concentration (MIC) range, according to results of a meta-analysis of published literature (pp. 1552–64): “Among 38 included studies that involved 8,291 episodes of SAB, overall mortality was 26.1%. The estimated mortality was 26.8% among SAB episodes (n = 2,740) in patients with high-vancomycin MIC (≥1.5 mg/L) compared with 25.8% mortality among SAB episodes (n = 5,551) in patients with low-vancomycin MIC (<1.5 mg/L) (adjusted risk difference [RD], 1.6% [95% CI, −2.3% to 5.6%]; P = .43). For the highest-quality studies, the estimated mortality was 26.2% among SAB episodes (n = 2,318) in patients with high-vancomycin MIC compared with 27.8% mortality among SAB episodes (n = 4,168) in patients with low-vancomycin MIC (RD, 0.9% [95% CI, −2.9% to 4.6%]; P = .65). In studies that included only methicillin-resistant S aureus infections (n = 7,232), the mortality among SAB episodes (n = 2,384) in patients with high-vancomycin MIC was 27.6% compared with mortality of 27.4% among SAB episodes (n = 4,848) in patients with low-vancomycin MIC (adjusted RD, 1.6% [95% CI, −2.3% to 5.5%]; P = .41). No significant differences in risk of death were observed in subgroups with high-vancomycin MIC vs low-vancomycin MIC values across different study designs, microbiological susceptibility assays, MIC cutoffs, clinical outcomes, duration of bacteremia, previous vancomycin exposure, and treatment with vancomycin.” (A. C. Kalil, akalil@unmc.edu)

>>>PNN NewsWatch
* With CDC announcing this morning that a second health care worker at Texas Presbyterian Hospital has developed a fever and tested positive for Ebola, the need for the steps announced yesterday by the agency was clear. CDC said on Tuesday it is sending an additional team of 16 workers to Dallas to reinforce hospital preparedness for Ebola treatment. The team includes experts who successfully controlled outbreaks of Ebola in Africa in the past two decades, including in health-care settings. The agency also said it has formed a dedicated CDC response team that could travel within a few hours to any hospital with a confirmed patient with Ebola, will host a call for nurses later this week with the American Nurses Assoc., and made plans to stream a live event next week from New York City for frontline health care workers.

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 © 2014, 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
Oct. 16, 2014 * Vol. 21, No. 200
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 16 issue of the New England Journal of Medicine (2014; 371).
Ebola Epidemic: Without “drastic improvements,” the trajectory of cases of Ebola in West Africa will result in thousands of new infections per week in the coming months, conclude authors who assessed the first 9 months of the epidemic using a subset of data from Sept. 14 (pp. 1481–95). A total of 3,343 confirmed and 667 probable cases provide these insights: “The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of [Ebola virus disease]. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R0) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5,740 in Guinea, 9,890 in Liberia, and 5,000 in Sierra Leone, exceeding 20,000 in total.” (C. Donnelly, c.donnelly@imperial.ac.uk)
The “Ebola emergency” requires “immediate action” and an “ongoing strategy,” editorialists write (
pp. 1545–6): “The current Ebola epidemic, which is in grave danger of spiraling out of control, must remain the primary focus of our efforts. We are concerned that without a massive increase in the response, way beyond what is being planned in scale and urgency, alongside the complementary deployment of novel interventions (in particular the use of safe and effective vaccines and therapeutics), it will prove impossible to bring this epidemic under control.
“But we must also look to the future. There will be more epidemics and outbreaks of Ebola and other new or reemerging infections. Yet our response to such events remains slow, cumbersome, poorly funded, conservative, and ill prepared. We have been very lucky with the severe acute respiratory syndrome (SARS), H5N1 and H1N1 influenza, and possibly the Middle East respiratory syndrome coronavirus (MERS-CoV), but this Ebola epidemic shows what can happen when luck escapes us. With a different pathogen and a different transmission route, a similar crisis could strike in New York, Geneva, and Beijing as easily as this one has in West Africa.” (J. J. Farrar)
FDA & Nicotine Regulation: After taking nearly 8 years to announce its intention to regulate e-cigarettes, FDA needs to speed up to ensure safe use of “clean nicotine” and “hasten the demise of lethal combusted tobacco,” Perspective authors conclude (pp. 1469–71): “The FDA has proposed creating a 2-year window before warning labels or product safety and quality standards for e-cigarettes would go into effect. The delay is disturbing, given the variability in product quality and a documented spike in cases of accidental nicotine poisoning. We believe that no product subject to FDA regulation should be exempt (even temporarily) from basic supply-chain monitoring or simple safety devices, such as child-resistant containers, ensuring that they’re as safe as possible.” (N. K. Cobb)
Postherpetic Neuralgia: The case of a 73-year-old woman with postherpetic neuralgia leads to this Clinical Practice conclusion (pp. 1526–33): “If pain relief is inadequate, doses should be increased. Regular follow-up is needed to assess pain relief, side effects, satisfaction with treatment, and activities of daily living. If a patient has an inadequate response to therapy or bothersome side effects, we would consider changing to a tricyclic antidepressant. Referral to a pain specialist should also be considered. It is unfortunate that the patient in the vignette did not receive herpes zoster vaccination, which significantly reduces the risk of postherpetic neuralgia.” (R. W. Johnson, rwjbristol@doctors.org.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 © 2014, 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
Oct. 17, 2014 * Vol. 21, No. 201
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Oct. issue of Chest (2014; 146).
Fluids & Septic Mortality: Earlier use of fluid resuscitation—within 3 hours—in patients with severe sepsis was associated with greater numbers of survivors in a retrospective analysis, researchers report (pp. 908–15). At a quaternary medical intensive-care unit, these results were noted for patients seen in 2007–09 within 6 hours of sepsis onset: “Of 651 patients with severe sepsis and septic shock screened, 594 had detailed fluid data. In a univariate analysis, the median amount of fluid within the first 3 h for survivors at discharge was 2,085 mL (940–4,080 mL) and for nonsurvivors, 1,600 mL (600–3,010 mL; P = .007). In comparison, during the latter 3 h, the median amount was 660 mL (290–1,485 mL) vs 800 mL (360–1,680 mL; P = .09), respectively. After adjusting for confounders, the higher proportion of total fluid received within the first 3 h was associated with decreased hospital mortality (OR, 0.34; 95% CI, 0.15–0.75; P = .008).” (R. Kashyap, Kashyap.Rahul@mayo.edu)
ACE Inhibition & COPD Skeletal Muscle Dysfunction: In 67 patients with chronic obstructive pulmonary disorder (COPD) and resulting quadriceps dysfunction, 3 months of ACE inhibition failed to improve symptoms or exercise performance, a study shows (pp. 932–40). Fosinopril or placebo produced these changes in a primary outcome of quadriceps endurance and atrophy signaling at 3 months and secondary outcomes of quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD): “The treatment group demonstrated a significant reduction in systolic [blood pressure] (∆−10.5 mm Hg; 95% CI, −19.9 to −1.1; P = .03) and serum ACE activity (∆−20.4 IU/L; 95% CI, −31.0 to −9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (∆0.5 s; 95% CI, −13.3 to 14.3; P = .94) or atrogin-1 messenger RNA expression (∆−0.03 arbitrary units; 95% CI, −0.32 to 0.26; P = .84). QMVC improved in both groups (fosinopril: ∆1.1 kg; 95% CI, 0.03–2.2; P = .045 vs placebo: ∆3.6 kg; 95% CI, 2.1–5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51).” (N. S. Hopkinson, n.hopkinson@ic.ac.uk)

>>>Allergy/Immunology Report
Source:
Oct. issue of the Journal of Allergy and Clinical Immunology (2014; 134).
Skin Products & Atopic Dermatitis: Two studies show that emollient enhancement and skin moisturization can prevent atopic dermatitis (AD) in young children. In the first study, parents of high-risk neonates applied full-body emollient therapy at least once per day, resulting in 50% reduction in cumulative incidence of AD (pp. 818–23; E. L. Simpson, simpsone@ohsu.edu). Application of moisturizer lowered sensitization rates in the second study, which included 59 high-risk neonates (pp. 824–30.e6; Y. Ohya, hya-y@ncchd.go.jp">ohya-y@ncchd.go.jp)

>>>PNN NewsWatch
* FDA yesterday approved two new drugs for treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib (Ofev, Boehringer Ingelheim) is an orally active drug whose mechanism of action is not understood; it is believed to interfere with the production of two small proteins, transforming growth factor–beta, and tumor necrosis factor–alpha. In Phase III trials of 1,024 patients with IPF, nintedanib reduced the decline in lung function by 50% compared with those taking placebo and significantly reduced the risk of “adjudicated acute exacerbations” by 68%. The most common adverse effects of nintedanib were diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, decreased weight, and high blood pressure. Pirfenidone (Esbriet, InterMune) is also believed to act on the same two small proteins. In a Phase III trial of 555 patients, 17% of patients receiving pirfenidone had a decline of 10% or more in forced vital capacity, significantly fewer than the 32% of those on placebo. The most common adverse effects of pirfenidone were nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, decreased/loss of appetite, gastroesophageal reflux disease, sinusitis, insomnia, decreased weight, and arthralgia.

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 © 2014, 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
Oct. 20, 2014 * Vol. 21, No. 202
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 18 issue of Lancet (2014; 383).
Trauma & Systemic Immune Responses: The inflammatory response to trauma—and the effects of aging on the process—are increasingly well-understood aspects of care that should be considered at the bedside, according to authors of a review article (pp. 1455–65): “Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.” (R. J. Lilford, R.J.Lilford@warwick.ac.uk)

>>>Gastroenterology Report
Source:
Oct. issue of Gastroenterology (2014; 147).
GI Bleeding & Drug Interactions: A case-series analysis of 114,835 patients with upper gastrointestinal bleeding (UGIB) provides useful insights into risks with nonsteroidal anti-inflammatory drugs (NSAIDs), nonselective (ns) NSAIDs, cyclooxygenase-2 selective inhibitors (COX-2 inhibitors), low-dose aspirin, and other agents commonly used with those drugs (pp. 784–92.e9): “Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9.” (G. M.C. Masclee, g.masclee@erasmusmc.nl)

>>>PNN NewsWatch
* FDA on Friday approved new labeling for Pfizer’s Embeda (morphine sulfate and naltrexone hydrochloride) extended-release (ER) capsules for treatment of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Embeda is the third ER opioid analgesic approved with labeling describing the product’s abuse-deterrent properties consistent with FDA’s 2013 draft guidance. While Embeda has a labeled claim that oral abuse should be reduced with this formulation, FDA emphasized that the possibility of oral abuse is not totally eliminated and any reductions in abuse by the intravenous route will be known only after postmarketing data are available.

>>>PNN JournalWatch
* Pathological Features of Fatty Liver Disease, in
Gastroenterology, 2014; 147: 754–64. (E. M. Brunt, ebrunt@path.wustl.edu)
* Targeting the Low-Hanging Fruit of Neurodegeneration, in
Neurology, 2014; 83: 1470–3. (S. Finkbeiner, sfinkbeiner@gladstone.ucsf.edu)
* Developing a Service Model That Integrates Palliative Care Throughout Cancer Care: The Time Is Now, in
Journal of Clinical Oncology, 2014; 32: 3330–6. (A. H. Partridge, ahpartridge@partners.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 © 2014, 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
Oct. 21, 2014 * Vol. 21, No. 203
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 21 issue of the Annals of Internal Medicine (2014; 161).
Sofosbuvir in Incarcerated Patients With HCV: In a cost-effectiveness analysis performed with a lifetime horizon and societal perspective, treatment of some incarcerated patients with hepatitis C virus (HCV) infections would be cost-effective but in many cases not affordable, researchers report (pp. 546–53). Interventions were no treatment, two-drug therapy with pegylated interferon and ribavirin, and three-drug therapy with those agents plus boceprevir or sofosbuvir. “For inmates with short remaining sentences (<1.5 years), only no treatment or sofosbuvir 3-drug therapy was feasible; for those with long sentences (≥1.5 years; mean, 10 years), all strategies were considered,” the authors report. “The strategies yielded 13.12, 13.57, 14.43, and 15.18 [discounted quality-adjusted life–years (QALYs)], respectively, for persons with long sentences. Sofosbuvir produced the largest absolute reductions in decompensated cirrhosis (16%) and hepatocellular carcinoma (9%), resulting in 2.1 additional QALYs at an added cost exceeding $54,000 compared with no treatment. For persons with short sentences, sofosbuvir cost $25,700 per QALY gained compared with no treatment; for those with long sentences, it dominated other treatments, costing $28,800 per QALY gained compared with no treatment.” (J. D. Goldhaber-Fiebert, jeremygf@stanford.edu)
Diet & Activity Counseling in CVD: Two articles—a clinical guideline and related review—provide useful information for clinicians in counseling patients with risk factors for cardiovascular disease (CVD) about eating a healthy diet and getting more physical activity.
In the guideline, the U.S. Preventive Services Task Force “recommends offering or referring adults who are overweight or obese and have additional CVD risk factors to intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention” (
pp. 587–93; www.uspreventiveservicestaskforce.org).
This recommendation, graded B by the task force, was based on these findings from a review of 74 trials (
pp. 568–78): “At 12 to 24 months, intensive lifestyle counseling in persons selected for risk factors reduced total cholesterol levels by an average of 0.12 mmol/L (95% CI, 0.16 to 0.07 mmol/L) (4.48 mg/dL [CI, 6.36 to 2.59 mg/dL]), low-density lipoprotein cholesterol levels by 0.09 mmol/L (CI, 0.14 to 0.04 mmol/L) (3.43 mg/dL [CI, 5.37 to 1.49 mg/dL]), systolic blood pressure by 2.03 mm Hg (CI, 2.91 to 1.15 mm Hg), diastolic blood pressure by 1.38 mm Hg (CI, 1.92 to 0.83 mm Hg), fasting glucose levels by 0.12 mmol/L (CI, 0.18 to 0.05 mmol/L) (2.08 mg/dL [CI, 3.29 to 0.88 mg/dL]), diabetes incidence by a relative risk of 0.58 (CI, 0.37 to 0.89), and weight outcomes by a standardized mean difference of 0.25 (CI, 0.35 to 0.16). Behavioral changes in dietary intake and physical activity were generally concordant with changes in physiologic outcomes.” (www.ahrq.gov)
Affordability of Health Insurance: Flaws in the U.S. health insurance marketplace as recreated by the Affordable Care Act are analyzed (pp. 599–604): “For this study, premium data for all health plans offered on the state and federal health insurance marketplaces were collected; the after-subsidy cost of premiums for the least-expensive bronze plan for every county in the United States was calculated; and variations in premium affordability by age, income, and geographic area were assessed. Results indicated that—although marketplace subsidies ensure affordable health insurance for most persons in the United States—many individuals with incomes just above the subsidy threshold will lack affordable coverage and will be exempt from the mandate. Furthermore, young individuals with low incomes often pay as much as or more than older individuals for bronze plans. If substantial numbers of younger, healthier adults choose to remain uninsured because of cost, health insurance premiums across all ages may increase over time.” (I. Graetz, igraetz@uthsc.edu)

>>>PNN NewsWatch
* CDC yesterday released “tightened guidance” for health care workers caring for patients with Ebola. Three principles undergird the new advice: rigorous training and practice and competence with personal protective equipment (PPE), no skin exposure when PPE is worn, and supervision of donning and removal of PPE by a trained monitor.

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 © 2014, 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
Oct. 22, 2014 * Vol. 21, No. 204
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 22 issue of JAMA, a theme issue on “Price, Cost, and Competition in Health Care” (2014; 312).
For-Profit Status & Patient Outcomes: When hospitals convert from nonprofit to for-profit status, their net incomes typically rise, but clinical and economic outcomes of patients do not improve, researchers report (pp. 1644–52). A retrospective cohort study of 237 converting hospitals and 631 matched control hospitals reveals these patterns for 1.8 million Medicare fee-for-service patients at converting hospitals and 4.8 million similar patients at control hospitals: “Hospitals that converted to for-profit status were more often small or medium in size, located in the south, in an urban or suburban location, and were less often teaching institutions. Converting hospitals improved their total margins (ratio of net income to net revenue plus other income) more than controls (2.2% vs 0.4% improvement; difference in differences, 1.8% [ 95% CI, 0.5% to 3.1%]; P = .007). Converting hospitals and controls both improved their process quality metrics (6.0% vs 5.6%; difference in differences, 0.4% [95% CI, −1.1% to 2.0%]; P = .59). Mortality rates did not change at converting hospitals relative to controls for Medicare patients overall (increase of 0.1% vs 0.2%; difference in differences, −0.2% [95% CI, −0.5% to 0.2%], P = .42) or for dual-eligible or disabled patients. There was no change in converting hospitals relative to controls in annual Medicare volume (−111 vs −74 patients; difference in differences, −37 [95% CI, −224 to 150]; P = .70), Disproportionate Share Hospital Index (1.7% vs 0.4%; difference in differences, 1.3% [95% CI, −0.9% to 3.4%], P = .26), the proportion of patients with Medicaid (−0.2% vs 0.4%; difference in differences, −0.6% [95% CI, −2.0% to 0.8%]; P = .38) or the proportion of patients who were black (−0.4% vs −0.1%; difference in differences, −0.3% [95% CI, −1.9% to 1.3%]; P = .72) or Hispanic (0.1% vs −0.1%; difference in differences, 0.2% [95% CI, −0.3% to 0.7%]; P = .50).” (K. E. Joynt, kjoynt@partners.org)
Commenting on this and other studies in this theme issue, an editorialist lists what factors might account for improved financial performance at converting hospitals (
pp. 1639–41): “First, converting organizations may be able to increase revenue from private payers. Price increases may be possible if converting hospitals joined a large health care system or more inpatient or outpatient referrals could be obtained. Second, the for-profit organization could be better at reducing costs. Billing and insurance-related services can often be streamlined, and wages higher than market levels might be reduced. Third, some costs might simply be shifted to another level in the organization. The debt of the converting hospital may be serviced at the corporate level rather than the hospital level, which would make the hospital’s balance sheet look better even in the absence of a reduction in the actual debt. Similarly, some of the ‘back office’ costs (such as for billing services or human resource functions) may be paid for centrally. Differentiating among these explanations is a clear need in evaluating the financial outcomes of for-profit conversions.” (D. M. Cutler, dcutler@fas.harvard.edu)
Economics & Transparency in Health Care: Before analyzing results of a study on greater price transparency in health care (pp. 1670–6; N. Sood, nsood@healthpolicy.usc.edu), noted economist Uwe Reinhardt writes that “the much ballyhooed consumer-directed health care strategy [in the U.S.] so far has been more a cruel hoax than a smart and ethically defensible health policy” (pp. 1642–3): “This approach of shifting more of the cost of employment-based health insurance visibly and directly into the household budgets of employees amounts to rationing parts of US health care by price and ability to pay and delegates the bulk of the hoped-for belt-tightening to low-income families. Because the word rationing is anathema in the US debate on health policy, the strategy has been marketed instead under the felicitous label of consumer-directed health care, presumably designed to empower consumers in the health care market to take control of their own health care. However, this strategy, based mainly on economic theory, so far has put the cart before the horse.” (U. E. Reinhardt, reinhard@princeton.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 © 2014, 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
Oct. 23, 2014 * Vol. 21, No. 205
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 23 issue of the New England Journal of Medicine (2014; 371).
Fluoroquinolone-Based, Abbreviated TB Regimens: Three articles and an editorial examine the utility of shortened regimens based on fluoroquinolone therapy for treatment of tuberculosis.
Two moxifloxacin regimens lowered bacterial load in patients with pulmonary tuberculosis, researchers report, but noninferiority was not shown (
pp. 1577–87). In all, 1,931 participants received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks followed by isoniazid plus rifampin (control group) or one of those drugs with moxifloxacin in a continuation phase: “A favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.” (S. H. Gillespie, shg3@st-andrews.ac.uk)
A 4-month, gatifloxacin-based regimen also did not reach noninferiority in the second trial of 1,836 patients (
pp. 1588–98): “At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, −0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from −5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P = 0.04 for interaction) and body-mass index (P = 0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen.” (P. L. Olliaro, lliarop@who.int">olliarop@who.int)
In a third trial (n = 827), 6 months of weekly rifapentine and moxifloxacin was as effective as standard therapy, but again a 4-month regimen was not noninferior (
pp. 1599–608): “In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, −1.8 percentage points; 90% confidence interval [CI], −6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, −4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).” (A. Jindani, ajindani@sgul.ac.uk)
An editorialist examines the role and cost of extensive clinical trials in developing new approaches to tuberculosis therapy (
pp. 1642–3): “Phase 3 trials require enormous financial investment. Although the studies described here have established the capacity for large, multicenter trials across disease-endemic countries, the design and selection of future experimental regimens will need to incorporate a triage process that can mitigate risks while enabling the accelerated development of much-needed treatment-shortening therapies. The disconnect between the phase 2 data that motivated these trials and the phase 3 results reinforces the idea that small sample sizes limit the utility of short trials in predicting the success of treatment-shortening regimens.” (D. F. Warner)

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 © 2014, 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
Oct. 24, 2014 * Vol. 21, No. 206
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Oct. issue of Health Affairs, theme issue on Specialty Pharmaceutical Spending & Policy (2014; 33).
Specialty Pharmaceuticals’ Impact on Health Care Costs: An analysis of the economic aspects of specialty pharmaceuticals highlights “the need for a far-reaching discussion of potential novel approaches to innovation pathways in our quest for both affordability and new technology,” authors write (pp. 1714–20). “The pharmaceutical industry is shifting its focus from blockbuster small molecules to specialty pharmaceuticals. Specialty pharmaceuticals are novel drugs and biologic agents that require special handling and ongoing monitoring, are administered by injection or infusion, and are sold in the marketplace by a small number of distributors. They are frequently identified by having a cost to payers and patients of $600 or more per treatment. The total costs of the new agents are likely to have a substantial impact on overall health care costs and on patients during the next decade, unless steps are taken to align competing interests.… We assess the role of cost-sharing provisions, legislation that is promoting realignment within the market, the role of biosimilars in price competition, and the potential for novel drug development paradigms to help bend the cost curve.” (K. A. Schulman, kevin.schulman@duke.edu)
Cost-Containment Tools for Specialty Pharmaceuticals: With 15% annual growth in the cost of specialty pharmaceuticals, tools for controlling their economic impact must be implemented, authors write (pp. 1736–44): “[Specialty pharmaceutical spending] is expected to account for approximately half ($235 billion) of total annual pharmacy spending by 2018. Among the numerous reasons for the high cost of this heterogeneous group of medications are the increasing size of target patient populations, the high cost of drug development, and a complex and uncoordinated delivery system. In this article we describe the evolution of the specialty market, characterize the current state of specialty medication use, and articulate key challenges and potential solutions. Fully realizing the potential value of the expanding universe of specialty medications will require collaborative efforts to reduce waste and promote value. Those who prescribe, dispense, deliver, and pay for specialty medications will need to employ a combination of traditional and novel management approaches, such as prior authorization, step therapy, tiered formularies, administration at lower-cost sites, and the unique tools being developed for cancer medications.” (W. H. Shrank, william.shrank@cvscaremark.com)

>>>Medical Care Report
Source:
Nov. issue of Medical Care (2014; 52).
Cost Nonadherence in Disabled Medicare Beneficiaries: Cost-related medication nonadherence (CRN) remains high among Medicare beneficiaries with disabilities despite the availability of the Part D benefit, researchers report (pp. 951–6). Annual rates of medication affordability were determined by looking at the 2006–11 experiences of a nationally representative group of Medicare participants younger than 65 and with disabilities. Multivariable regression analysis showed these patterns during 14,091 person–years: “In the 6 years following Part D implementation, the proportion of disabled Medicare beneficiaries reporting CRN ranged from 31.6% to 35.6%, while the reported prevalence of spending less on other basic needs to afford medicines ranged from 17.7% to 21.8%. Across study years, those with multiple chronic conditions had consistently worse affordability problems. In 2011, the prevalence of CRN was 37.3% among disabled beneficiaries with ≥3 morbidities as compared with 28.1% among those with fewer morbidities; for spending less on basic needs, the prevalence was 25.4% versus 15.7%, respectively. There were no statistically detectable changes in either measure when comparing 2011 with 2007.” (H. Naci)

>>>PNN NewsWatch
* CDC this week has released recommendations for performing acute hemodialysis in hospitals for patients with Ebola virus disease; a guidance on waste management for Ebola-contaminated materials; and a factsheet for health professionals to use in determining “could it be Ebola?”

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 © 2014, 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
Oct. 27, 2014 * Vol. 21, No. 207
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 25 issue of Lancet (2014; 383).
Supplementary Polio Vaccine Doses: In the global effort to eradicate poliovirus, a supplemental dose of inactivated poliovirus vaccine (IPV) could be an important tool, a study from India indicates (pp. 1505–12). Children aged 1–4 years who had received oral poliovirus vaccine (OPV) at least 6 months previously were randomized in an open-label trial to IPV 0.5 mL intramuscularly or no vaccine. Results based on proportion of children shedding poliovirus 7 days after a challenge dose of serotype 1 and 3 bivalent OPV (bOPV) showed the following: “Between Aug 19, 2013, and Sept 13, 2013, 450 children were enrolled and randomly assigned into study groups. 225 children received IPV and 225 no vaccine. 222 children in the no vaccine group and 224 children in the IPV group had stool samples available for primary analysis 7 days after bOPV challenge. In the IPV group, 27 (12%) children shed serotype 1 poliovirus and 17 (8%) shed serotype 3 poliovirus compared with 43 (19%) and 57 (26%) in the no vaccine group (risk ratio 0.62, 95% CI 0.40–0.97, p = 0.0375; 0.30, 0.18–0.49, p <0.0001). No adverse events were related to the study interventions.” (N. C. Grassly, n.grassly@imperial.ac.uk)
Retinoid in Congenital Childhood Blindness: A synthetic form of 9-cis-retinyl acetate improved visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations, researchers report (pp. 1513–20). The condition, a severe form of inherited retinal degeneration that leads to blindness, is caused by mutations in those genes, the authors explain. In a Phase Ib trial, affected patients older than 5 years had these safety outcomes and efficacy indicators based on changes in Goldmann visual fields (GVFs) over a 2.2-year follow-up period: “Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6–38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28–683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2–30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients).” (R. K. Koenekoop, robert.koenekoop@mcgill.ca)

>>>PNN NewsWatch
* Late Thursday, FDA approved Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence; Baxter] for treatment of bleeding episodes in adults with acquired hemophilia A. Designated an orphan drug product, Obizur was evaluated in 29 adults with acquired hemophilia A for treatment of a serious bleeding episode. Efficacy was established; no safety concerns arose.
* The case count for
Ebola virus disease in West Africa stands at 10,114, CDC and WHO reported over the weekend. A total of 5,666 cases have been laboratory confirmed, and 4,912 patients have died. Travel-associated or localized transmission cases (27 cases, 10 deaths) have occurred in Mali, Senegal, Nigeria, Spain, and the U.S.

>>>PNN JournalWatch
* Medication Misadventures in Older Adults: Literature from 2013, in
Journal of the American Geriatrics Society, 2014; 62: 1950–3. (J. T. Hanlon, jth14@pitt.edu)
* The Concept of Axial Spondyloarthritis: Joint Statement of the Spondyloarthritis Research and Treatment Network and the Assessment of SpondyloArthritis international Society in Response to the US Food and Drug Administration’s Comments and Concerns, in
Arthritis & Rheumatism, 2014; 66: 2649–56. (A. Deodhar)
* The 340B Drug Discount Program: Hospitals Generate Profits by Expanding To Reach More Affluent Communities, in
Health Affairs, 2014; 33: 1786–92. (R. M. Conti, rconti@uchicago.edu)
* Chinese Water-Pipe Smoking and the Risk of COPD, in
Chest, 2014; 146: 924–31. (C. Bai, bai.chunxue@zs-hospital.sh.cn)

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 © 2014, 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
Oct. 28, 2014 * Vol. 21, No. 208
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from JAMA Internal Medicine (2014; 174).
Statins & Mental Impairment: In a Perspective article, a patient with statin-related cognitive impairment writes that “you’ll live longer” with the drugs “but you might not like it” (10.1001/jamainternmed.2014.5376). The patient noticed that problems he was having focusing went away during periods when he ran out of medication. “Looking back, there are a few things I’d like medical professionals to take away from reading this,” the author writes. “Please take seriously any symptoms your patients think might be related to use of a statin (or any drug); drug company research may not pick up side effects that matter to us. When it comes to known side effects, please make sure we understand what they are. Patients may not know what cognitive impairment is; if we have statin-related cognitive impairment, we’re unlikely to recognize it unless you alert us.” (J. McDonagh, heatherf@pcspeed.com)

>>>Geriatrics Highlights
Source:
Oct. issue of the Journal of the American Geriatrics Society (2014; 62).
Statins & Pain in Older People With Cancer: A “potential benefit of ‘deprescribing’ statins in older people with cancer” is relief of pain, investigators report based on a study of patients at a medical oncology clinic at an Australian hospital (pp. 1900–5). Medication use, comorbidities, and a general pain assessment using the 10-point visual analogue scale (VAS) produced these odds ratios during logistic regression of data from 2009–10: “The prevalence of statin use was 35% (n = 97) in people aged 70 to 79 and 39% (n = 41) in those aged 80 and older. After adjusting for age, sex, Charlson Comorbidity Index, and analgesic use, statin use was associated with self-reported pain (VAS ≥5) (OR = 4.09, 95% CI = 1.32–12.68) in people aged 80 and older but not in those aged 70 to 79. Half of participants using statins (51% n = 70) had a palliative treatment approach. Of the 41 statin users aged 80 and older, 20 (49%) were using statins for primary prevention.” (J. Turner, justin.turner@monash.edu)
Inclusion of Older People in Clinical Trials of New Drugs: Studies of recently approved medications often do not include sufficient numbers of patients older than 65 or older than 75, according to an assessment of data from Europe, the literature, and the WHO International Clinical Trials Registry Platform (pp. 1883–90). Investigators looked randomization patterns and exclusion criteria in trials of drugs for diseases typically associated with aging and for diseases not unique to older adults. Results showed: “In 114 Phase II and III trials of 12 medicines, 43.1% of participants were aged 65 and older, and 16.1% were aged 75 and older. In trials involving diseases characteristically associated with ageing, 57% were aged 65 and older; 22% were aged 75 and older. In trials involving diseases not unique to old age, 9% were aged 65 and older, and 1% were aged 75 and older. Upper age limits were applied in 30.7% of the trials; the frequency did not differ between larger (sample size ≥500) and smaller trials (P = .36), although it was significantly lower in trials involving diseases characteristically associated with aging (18.0%) than in trials of diseases not unique to old age (45.3%; P = .002). Age-sensitive exclusion criteria, based on comorbidity (75.4%), concomitant medication (71.9%), and other criteria correlated with age (60.5%) were applied more frequently in larger trials (P < .02).” (E. Beers, e.beers@umcutrecht.nl)

>>>PNN NewsWatch
* CDC yesterday updated the case definition for Ebola virus disease (EVD). The new definition includes “an epidemiologic risk factor within the 21 days before onset of symptoms” rather than the previous travel to or from affected countries in west Africa. The definition provides also guidance to health professionals and hospitals on how to care for people with confirmed EVD cases.
* At a Public Health Grand Rounds session held at CDC headquarters in Atlanta in conjunction with American Pharmacists Month, the
role of pharmacists in improving the nation’s health was highlighted, pharmacist.com reports. By becoming members of integrated health care teams, pharmacists “have an opportunity” to change the health care system, speakers said. The session is archived on the CDC website.

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 © 2014, 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
Oct. 29, 2014 * Vol. 21, No. 209
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (2014; 37).
Cardiovascular Homeostasis & Diabetes: A review article assesses interactions among natriuretic peptides (NPs), the heart, and adipose tissue and their role in development of diabetes (pp. 2899–908): “Recently, both atrial NP (ANP) and B-type NP (BNP) have emerged as key mediators in the control of metabolic processes including the heart in the network of organs that regulate energy usage and metabolism. Epidemiological studies have shown that ANP and BNP are reduced in people with obesity, insulin resistance, and diabetes, and this deficiency may contribute to enhance their global cardiovascular risk. Moreover, ANP and BNP have receptors in the adipose tissue, enhance lipolysis and energy expenditure, and modulate adipokine release and food intake. Therefore, low ANP and BNP levels may be not only a consequence but also a cause of obesity, and recent prospective studies have shown that low levels of [N-terminal B-type NP] and midregional proANP are a strong predictor of type 2 diabetes onset. Whether ANP and BNP supplementation may result in either cardiovascular or metabolic benefits in humans remains, however, to be established.” (G. Bruno, graziella.bruno@unito.it)
Methazolamide in Type 2 Diabetes: “Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control,” conclude investigators who tested the agent in 76 patients with the disease (pp. 3121–3). Compared with placebo, methazolamide 40 mg twice daily for 24 weeks produced these changes in a primary outcome of placebo-corrected reductions in glycosylated hemoglobin (∆HbA1c): “Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ∆HbA1c of –0.39% (95% CI –0.82, 0.04; P < 0.05) (–4.3 mmol/mol [–9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (~10 units/L), and weight loss (2%) in metformin-cotreated patients.” (V. J. Wacher, vwacher@vervapharma.com)
Contribution of Liraglutide in Insulin Degludec Therapy: A double-blind trial of once-daily insulin degludec/liraglutide (IDegLira) plus metformin versus insulin degludec (IDeg) plus metformin establishes superior control of the combination product and quantifies the contribution of the liraglutide component, researchers report (pp. 2926–33). The 26-week trial produced these results based on a primary end point of A1C change from baseline: “A total of 413 patients were randomized (mean A1C 8.8% [73 mmol/mol]; BMI 33.7 kg/m2). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1C decreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) with IDeg (estimated treatment difference −1.1% [95% CI −1.3, −0.8], −12 mmol/mol [95% CI −14, −9; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs. no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable (24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, and incidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%).” (J. B. Buse, john_buse@med.unc.edu)
Sulfonylureas & Cardiovascular Disease: In women with type 2 diabetes, long-term use of sulfonylureas is associated with increased risk of incident coronary heart disease (CHD), according to an analysis of Nurses’ Health Study data (pp. 3106–13). In 4,902 women with a mean age of 68 years, these results were noted: “We identified 339 incident cases of cardiovascular disease, including 191 cases of CHD and 148 cases of stroke. A longer duration of sulfonylurea use was significantly associated with a higher risk of CHD (P for trend = 0.002); the RRs for CHD were 1.24 (95% CI 0.85–1.81) for patients who used sulfonylurea therapy for 1–5 years, 1.51 (0.94–2.42) for 6–10 years, and 2.15 (1.31–3.54) for >10 years, compared with nonusers. Compared with users of metformin monotherapy, the RR for CHD was 3.27 (1.31–8.17) for those who were treated with the combination of metformin and sulfonylurea. The analysis using propensity score stratification yielded similar results. We did not observe a significant association between sulfonylurea therapy and stroke risk.” (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 © 2014, 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
Oct. 30, 2014 * Vol. 21, No. 210
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Oct. 30 issue of the New England Journal of Medicine (2014; 371).
Clinical Characteristics of Ebola: Clinical presentation and factors associated with survival in early patients with Ebola virus disease (EVD) in Sierra Leone are described (10.1056/NEJMoa1411680): “Of 106 patients in whom EVD was diagnosed, 87 had a known outcome, and 44 had detailed clinical information available. The incubation period was estimated to be 6 to 12 days, and the case fatality rate was 74%. Common findings at presentation included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness (in 60%), diarrhea (in 51%), abdominal pain (in 40%), and vomiting (in 34%). Clinical and laboratory factors at presentation that were associated with a fatal outcome included fever, weakness, dizziness, diarrhea, and elevated levels of blood urea nitrogen, aspartate aminotransferase, and creatinine. Exploratory analyses indicated that patients under the age of 21 years had a lower case fatality rate than those over the age of 45 years (57% vs. 94%, P = 0.03), and patients presenting with fewer than 100,000 [Ebola virus] copies per milliliter had a lower case fatality rate than those with 10 million [Ebola virus] copies per milliliter or more (33% vs. 94%, P=0.003). Bleeding occurred in only 1 patient.” (J. S. Schieffelin, jschieff@tulane.edu)
Simvastatin in ARDS: In contrast to animal studies and Phase II trials, simvastatin therapy in 540 patients with acute respiratory distress syndrome (ARDS) failed to improve clinical outcomes, researchers report (pp. 1695–703). Administered in daily 80-mg doses for 28 days, simvastatin was safe and produced minimal adverse effects, the study shows, producing these results in comparison with placebo: “The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (± SD) number of ventilator-free days (12.6 ± 9.9 with simvastatin and 11.5 ± 10.4 with placebo, P = 0.21) or days free of nonpulmonary organ failure (19.4 ± 11.1 and 17.8 ± 11.7, respectively; P = 0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P = 0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug.” (D. F. McAuley, d.f.mcauley@qub.ac.uk)
Suicidality Warnings on Antidepressants: Two Perspective articles explore the impact of 2004 black-box warnings of suicidality in young people on antidepressants.
Based on evidence available at the time, “FDA had little choice but to issue its black-box warning,” writes one author (
pp. 1666–8). “The FDA was obviously mindful of the need to balance the small risk associated with antidepressant treatment against its proven benefits: an expanded black-box warning issued in 2007 stated that depression itself was associated with an increased risk of suicide. Has this well-intended warning accomplished its task—to educate clinicians about risk without discouraging appropriate treatment of depression?” This author concludes not; he recommends that the warning be removed: “I believe we cannot ignore the weight of these epidemiologic data or the very real possibility that the FDA advisory has unintentionally discouraged depressed patients from seeking treatment and doctors from prescribing antidepressants.” (R. A. Friedman)
An FDA physician asks why this warning was so controversial and concludes that FDA’s actions did not have adverse consequences (
pp. 1668–71). Continued analysis of the massive amount of data about antidepressant use and suicidality during the intervening 10 years “will probably provide additional examples that achieve little beyond reinforcing concerns about something that did not happen,” the author writes. (M. B. Stone)

>>>PNN NewsWatch
* FDA yesterday licensed Trumenba (Wyeth), the first U.S. vaccine for prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B in individuals 10–25 years of age. The action follows recent outbreaks of group B disease on American college campuses; CDC reports that 160 of 500 cases of meningococcal disease in the U.S. in 2012 were caused by serogroup B strains. Trumemba was granted breakthrough status by FDA, which evaluated and approved the product in “well under 6 months,” the agency said.

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 © 2014, 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
Oct. 31, 2014 * Vol. 21, No. 211
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Pharmacist Renal Dosing in Medical Home: The impact of pharmacists’ review of renally dosed medications in a patient-centered medical home are described in a report from an academic health system (10.1002/phar.1508). At a tier 3 PCMH, pharmacists identified 328 patients with estimated glomerular filtration rates below 60 mL/min/sq m. Interventions for 146 patients resulted in the following: “Before intervention, 73% of patients were prescribed an [angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker] and 72% of patients were prescribed aspirin. After the intervention, use of these medications increased to 77% and 82% of patients, respectively. Pharmacist recommendations to adjust medication dosing based on Cockcroft–Gault calculated creatinine clearance were made for 138 medications (0.95 medication per patient); 90 (65.2%) recommendations were accepted by the patients’ physicians.” (S. J. Beatty, beatty.52@osu.edu)
Pharmacists’ Medication Management in Psychiatry: A retrospective review and data analysis provides information about pharmacist delivery of comprehensive medication management (CMM) service for 154 patients with psychiatric disorders in a patient-centered medical home (10.1002/phar.1503). Referrals came from professional and lay sources during the 2011–13 evaluation period. Pharmacist providers included one board-certified psychiatric pharmacist. Pharmacists met with patients to evaluate use of all medications and dietary supplements and other aspects of care, with these economic and other results: “The 154 patients completed 256 CMM visits. A mean of 10.1 medical and psychiatric conditions and 13.7 medications/person were assessed. A mean of 5.6 drug therapy problems/patient were identified. A total net cost savings was estimated to be $90,484.00, with a mean savings of $586.55/patient. The cost of providing the service was estimated at $32,185.93. The return on investment was estimated to be 2.8; thus for every dollar spent on providing the service, $2.80 was estimated to be saved. Patients with mental illnesses may benefit from pharmacist-delivered CMM to help resolve drug therapy problems. Medication management may improve clinical outcomes and reduce costs. In addition, patients valued the opportunity to review their medications with a pharmacist.” (C. D. Cobb, carla.cob@riverstonehealth.org)
Carbapenem Stewardship in Specialty Hospital: In a women’s and children’s hospital in Singapore, an antimicrobial stewardship program improved appropriateness of overall carbapenem prescribing and lowered use in pediatrics, researchers report (10.1002/phar.1490). The prospective, single-center, pre–post intervention found these changes in defined daily doses (DDDs) and days of therapy (DOTs) before and after the ASP’s July 2011 start-up: “Of 404 prescriptions for carbapenems reviewed post-ASP, 70.3% were appropriate compared with those prescribed pre-ASP (55.9%; p = 0.027). Reasons for inappropriate prescribing included inappropriate choice (36.1%) and duration (31.3%). A total of 61.2% of the interventions (213 of 348) were accepted. For pediatrics, there was a significant decrease in DDDs per 100 patient–days by 55.6% from a baseline of 0.9–0.4 (p = 0.013) post-ASP and a reduction in DOTs per 100 patient–days by 46.7% from a baseline of 1.5–0.8 (p = 0.06) post-ASP without significant changes in prescription rates. Pediatrics utilization cost increased from a pre-ASP mean of $175 per 100 patient–days to a peak of $238 (p <0.001) and decreased significantly post-ASP to a mean of $149 (p = 0.01). For obstetrics/gynecology, there were no significant changes in DDDs (0.3 vs 0.3, p = 0.99), DOTs (0.2 vs 0.3, p = 0.36), prescriptions (0.03 vs 0.04, p = 0.38), or cost ($45 vs $52, p = 0.63) per 100 patient–days pre- versus post-ASP.” (V. X. F. Seah, valerie.seah.xf@kkh.com.sg)

>>>PNN NewsWatch
* “Is it Flu or Ebola?” A CDC infographic helps patients and professionals address that question. It focuses on the causative organisms, mechanisms of transmission, susceptible people, and signs and symptoms of the two disease. Key symptom differences include cough, sore throat, and runny or stuffy nose for influenza; ebola is characterized by vomiting or diarrhea developing after 3–6 days, weakness that can be severe, stomach pain, and unexplained bleeding or bruising.

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 © 2014, 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
Nov. 3, 2014 * Vol. 21, No. 212
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 1 issue of Lancet (2014; 383).
Dual Antiplatelets After Stent Implantation: In patients who have received drug-eluting stents (DESs) and had no events during the initial year of dual antiplatelet treatment (DAPT), continuation of DAPT is associated with harm and no apparent benefit, according to findings of the ARCTIC-Interruption trial (pp. 1577–85). At 38 French centers, study participants without contraindication to continued DAPT were randomized to thienopyridine interruption and aspirin monotherapy or continued DAPT for 6–18 months, with these results based on an intention-to-treat primary endpoint of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization: “Between Jan 4, 2011, and March 3, 2012, 1,259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15–18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1.17 [95% CI 0.68–2.03]; p = 0.58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0.5%] patient; HR 0.15 [0.02–1.20]; p = 0.073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0.26 [0.07–0.91]; p = 0.04).” (G. Montalescot, gilles.montalescot@psl.aphp.fr)
Acetaminophen for Low Back Pain: Used in a randomized controlled trial of patients with low back pain, regular or as-needed acetaminophen (paracetamol) did not affect recovery time, researchers report, which brings into “question the universal endorsement of paracetamol in this patient group” (pp. 1586–96). Four weeks of regular or as-needed use of the drug or placebo produced these outcomes in 1,643 patients: “Median time to recovery was 17 days (95% CI 14–19) in the regular group, 17 days (15–20) in the as-needed group, and 16 days (14–20) in the placebo group (regular vs placebo hazard ratio 0.99, 95% CI 0.87–1.14; as-needed vs placebo 1.05, 0.92–1.19; regular vs as-needed 1.05, 0.92–1.20). We recorded no difference between treatment groups for time to recovery (adjusted p = 0.79).” (C. M. Williams, cwilliams@georgeinstitute.org.au)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Sudden Death with TMP-SMX: Used in older patients who are on ACE inhibitors or ARBs, trimethoprim–sulfamethoxazole (co-trimoxazole) is associated with sudden death within 7 days of exposure, a population-based analysis of data from Ontario shows (g6196): “Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1,000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin.” (D. N. Juurlink, dnj@ices.on.ca)

>>>PNN NewsWatch
* CDC this weekend released an algorithm for ambulatory care evaluation of patients with possible Ebola virus disease and an infographic on how the virus is spread.

>>>PNN JournalWatch
* Diagnosis and Treatment of Hyponatremia, in
American Journal of Kidney Diseases, 2014; 64: 681–4. (N. E. Madias, nicolaos.madias@steward.org)
* Hyperosmolar Hyperglycemic State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment, in
Diabetes Care, 2014; 37: 3124–31. (G. E. Umpierrez, geumpie@emory.edu)
* Quitting Tobacco: Let’s Keep Talking to Parents, in
Pediatrics, 2014; 134: 1028–9. (S. J. Balk)
* Overdiagnosis: How Our Compulsion for Diagnosis May Be Harming Children, in
Pediatrics, 2014; 134: 1013–23. (E. R. Coon)
* Provision of Clinical Pharmacist Services for Individuals With Chronic Hepatitis C Viral Infection: Joint Opinion of the GI/Liver/Nutrition and Infectious Diseases Practice and Research Networks of the American College of Clinical Pharmacy, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1512. (R. A. Mohammad, rimam@med.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 © 2014, 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
Nov. 4, 2014 * Vol. 21, No. 213
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 4 issue of the Annals of Internal Medicine (2014; 161).
Cost of Gout Therapies: For patients with gout, allopurinol monotherapy is cost-saving when compared with no treatment, but when it doesn’t work, an analysis shows that the combination of allopurinol plus febuxostat is more cost effective than allopurinol escalation therapy (pp. 617–26). Five urate-lowering treatment strategies were compared using a lifetime horizon and payer perspective, with these results for base-case and sensitivity analyses: “In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol–febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39,400 per quality-adjusted life–year.
“The relative rankings of treatments did not change [in the sensitivity analysis]. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol–febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109,000 per quality-adjusted life–year.” (E. Jutkowitz,
Jutko001@umn.edu)
HCV Retreatment After Relapse: In a small, Phase IIa study, investigators showed that a fixed-dose combination of sofosbuvir and ledipasvir is effective in patients whose hepatitis C virus (HCV) genotype 1 infections have relapsed after sofosbuvir plus ribavirin therapy (pp. 634–8). These results held even in patients with advanced liver disease, the study shows, based on these results: “All 14 patients treated with sofosbuvir plus ledipasvir for 12 weeks achieved a sustained virologic response, including 7 with advanced liver disease (Knodell Histology Activity Index score of 3 or 4) and 1 with a detectable NS5B S282T mutation after sofosbuvir plus ribavirin therapy. Sofosbuvir plus ledipasvir was well-tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a patient with baseline renal insufficiency, hypercholesterolemia, and hypophosphatemia) occurred. There were no grade 4 events or treatment discontinuations.” (S. Kottilil, Pike, skottilil@niaid.nih.gov)
Drug Therapy for Painful Diabetic Neuropathy: While comparative effectiveness is unclear, several medications are effective for short-term management of diabetic neuropathy, authors of a review article conclude (pp. 639–49): “65 randomized, controlled trials involving 12,632 patients evaluated 27 pharmacologic interventions. Approximately one half of these studies had high or unclear risk of bias. Nine head-to-head trials showed greater pain reduction associated with serotonin–norepinephrine reuptake inhibitors (SNRIs) than anticonvulsants (standardized mean difference [SMD], −0.34 [95% credible interval {CrI}, −0.63 to −0.05]) and with tricyclic antidepressants (TCAs) than topical capsaicin 0.075%. Network meta-analysis showed that SNRIs (SMD, −1.36 [CrI, −1.77 to −0.95]), topical capsaicin (SMD, −0.91 [CrI, −1.18 to −0.08]), TCAs (SMD, −0.78 [CrI, −1.24 to −0.33]), and anticonvulsants (SMD, −0.67 [CrI, −0.97 to −0.37]) were better than placebo for short-term pain control. Specifically, carbamazepine (SMD, −1.57 [CrI, −2.83 to −0.31]), venlafaxine (SMD, −1.53 [CrI, −2.41 to −0.65]), duloxetine (SMD, −1.33 [CrI, −1.82 to −0.86]), and amitriptyline (SMD, −0.72 [CrI, −1.35 to −0.08]) were more effective than placebo. Adverse effects included somnolence and dizziness with TCAs, SNRIs, and anticonvulsants; xerostomia with TCAs; and peripheral edema and burning sensation with pregabalin and capsaicin.” (M. H. Murad, murad.mohammad@mayo.edu)
Managing Recurrent Nephrolithiasis: In a clinical guideline, the American College of Physicians makes these recommendations for management of recurrent nephrolithiasis (pp. 659–67; A. Qaseem, aqaseem@acponline.org):
* ACP recommends management with increased fluid intake spread throughout the day to achieve at least 2 L of urine per day to prevent recurrent nephrolithiasis. (weak recommendation, low-quality evidence)
* ACP recommends pharmacologic monotherapy with a thiazide diuretic, citrate, or allopurinol to prevent recurrent nephrolithiasis in patients with active disease in which increased fluid intake fails to reduce the formation of stones. (weak recommendation, moderate-quality evidence)

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 © 2014, 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
Nov. 5, 2014 * Vol. 21, No. 214
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 5 issue of JAMA (2014; 312).
Ipilimumab Plus Sargramostim in Metastatic Melanoma: Overall survival (OS) was extended and toxicity reduced through use of the combination of the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blocker ipilimumab plus sargramostim in patients with unresectable stage III or IV melanoma, compared with ipilimumab alone, researchers report (pp. 1744–53). In an Eastern Cooperative Oncology Group (ECOG) Phase II trial, patients with advanced melanoma, at least one prior therapy, no CNS metastases, and ECOG performance of 0 or 1 had these outcomes: “Median follow-up was 13.3 months (range, 0.03–19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0–not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%–85.5%) compared to 52.9% (95% CI, 43.6%–62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable–0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O’Brien–Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median [progression-free survival] for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9–4.6) vs 3.1 months (95% CI, 2.9–4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%–54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%–67.2%) of patients in the ipilimumab-alone group (2-sided P = .04).” (F. S. Hodi, stephen_hodi@dfci.harvard.edu)
Fecal Microbiota for Recurrent C. difficile Infection: Patients with recurrent or resistant mild to moderate Clostridium difficile infections responded well to one-time or repeat doses of fecal microbiota transplantation (FMT), a study shows (pp. 1772–8). FMT capsules were administered on two consecutive days to 20 patients with at least three infections that had not responded to vancomycin taper or at least two severe episodes requiring hospitalization. Results showed: “No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%–85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%–98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3–6) the day prior to administration to 2 (IQR, 1–3) at day 3 (P = .001) and 1 (IQR, 1–2) at 8 weeks (P < .001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5–7) for overall health and 4.5 (IQR, 3–7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR, 7–9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5–7.3] vs 5 [IQR, 2.8–5]; P = .02).” (I. Youngster, ilan.youngster@childrens.harvard.edu)
Prescription Opioid Overdoses: “A multifaceted approach” is needed for addressing the epidemic of prescription opioid overdoses, authors write in a Viewpoint article, one “that includes states, professional associations, medical boards, nonprofits, clinicians, and the public” (pp. 1733–4). “Policies that focus on a single drug can divert focus from broader, further-reaching interventions, such as maximizing prescription drug monitoring programs, leveraging insurer strategies, improving clinician education and oversight, and expanding access to medication-assisted treatment for opioid addiction. The concerns over Zohydro ER should be seen in the greater context of the opioid epidemic. Singling out one drug for restrictions is not likely to be successful.” (C. M. Jones, Christopher.M.Jones@fda.hhs.gov)

>>>PNN NewsWatch
* Pharmacy will have one of its own—and two GOP-controlled houses—in Congress when the provider-status legislation is reintroduced in 2015. Buddy Carter, a Republican and pharmacist from southeastern Georgia, took that state’s 1st Congressional District in Tuesday’s elections, APhA’s CEO notes in a congratulatory message.

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 © 2014, 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
Nov. 6, 2014 * Vol. 21, No. 215
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 6 issue of the New England Journal of Medicine (2014; 371).
Rituximab in ANCA-Associated Vasculitis: In 115 patients with antineutrophil cytoplasm antibody (ANCA)–associated vasculitides, rituximab produced greater rates of sustained remission at month 28 than did azathioprine, a study from the French Vasculitis Group shows (pp. 1771–80). Study participants had newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide–glucocorticoid regimen. Assignment to rituximab 500 mg on days 0 and 14 and at months 6, 12, and 18 or daily azathioprine until month 22 produced these changes in a primary end point of rate of major relapse at month 28: “Major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P = 0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P = 0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).” (L. Guillevin, loic.guillevin@cch.aphp.fr)
“The real value” of this trial “is the knowledge that a patient with ANCA-associated vasculitis has a low risk of relapse while receiving rituximab maintenance therapy with sparing of immunosuppressive agents and glucocorticoids, as well as a better opportunity for recovery and rehabilitation after this often devastating illness,” an editorialist writes (
pp. 1839–40). “The unmet need for a curative therapy remains, and the rates of adverse events after rituximab treatment in ANCA-associated vasculitis are worrisome. Patients will still require prolonged observation after rituximab withdrawal.” (D. Jayne)
Etanercept Tapering in Early Rheumatoid Arthritis: Tapering etanercept to a reduced dose rather than discontinuing the drug completely produced better disease control but no changes in radiographic progression of early rheumatoid arthritis in 131 patients, researchers report (pp. 1781–92). Following a 52-week, open-label phase of etanercept 50 mg injections plus oral methotrexate 10–25 mg weekly, participants were randomized to continued therapy with 25-mg doses of etanercept, oral methotrexate, or placebo, with these results based on a primary end point of the proportion of patients with sustained remission in the double-blind phase: “More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P = 0.009 for combination therapy vs. methotrexate alone; P <0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P = 0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P = 0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group.” (P. Emery, p.emery@leeds.ac.uk)
Medical Errors After Handoff-Program Implementation: Overall medical error rates and preventable adverse events were reduced following implementation of a handoff program involving residents at nine hospitals (pp. 1803–12). While medication errors were not significantly reduced by the intervention in this pre–post analysis, “the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P <0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P <0.001),” the investigators write. (A. J. Starmer, amy.starmer@childrens.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 © 2014, 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
Nov. 7, 2014 * Vol. 21, No. 216
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Nov. issue of the American Journal of Psychiatry (2014; 171).
Pharmacotherapy of Borderline Personality Disorder: In a randomized, placebo-controlled trial, severity of symptoms of borderline personality disorder were reduced when treated with extended-release quetiapine, but moderate doses of the drug increased the frequency of adverse effects (pp. 1174–82). A total of 95 participants received quetiapine 150 or 300 mg per day or placebo, and these effects of the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder were recorded: “Participants in the low-dosage quetiapine group had significant improvement on the Zanarini scale compared with those in the placebo group. Time to response (defined as a reduction of 50% or more on the Zanarini scale total score) was significantly shorter for both the low-dosage quetiapine group (hazard ratio = 2.54, p = 0.007) and the moderate-dosage quetiapine group (hazard ratio = 2.37, p = 0.011) than for the placebo group. Among participants who completed the study, 82% in the low-dosage quetiapine group were rated as ‘responders’ compared with 74% in the moderate-dosage group and 48% in the placebo group. Treatment-emergent adverse events included sedation, change in appetite, and dry mouth. The overall completion rate for the 8-week double-blind treatment phase was 67% (67% for the low-dosage quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for the placebo group). Participants who experienced sedation were more likely to drop out.” (D. W. Black)
This well-designed study “provides evidence that low-dosage quetiapine (150 mg) is effective in the short-term treatment of some of the core symptoms of borderline personality disorder,” an editorialist writes, and yields estimated effect sizes (–0.79) and number needed to treat (2.9) that “suggest a moderate to large effect on the primary outcome” (
pp. 1139–41). He cautions, “A number of questions remain, notably about whether the response will be maintained over longer periods and about long-term safety, especially in regard to metabolic syndrome. Effectiveness studies need to be conducted to determine the risks and benefits of low-dosage quetiapine in patients with comorbid conditions, as well as to assess this treatment’s possible synergistic effects with evidence-based psychotherapies. Finally, studies assessing functional outcomes, focusing especially on ability to engage in productive work and have meaningful relationships, would be optimal.” (M. Tohen)
Varenicline & Bupropion in Adaptive Smoking Cessation: Smokers not responding to prequit nicotine patch treatments did better on varenicline plus bupropion than varenicline alone, researchers report (pp. 1199–205). Among 222 participants who failed to achieve a 50% reduction in smoking after 1 week of treatment, 12 weeks of varenicline with or without bupropion produced these outcomes: “Both treatments were well tolerated. Participants who received the combination treatment had a significantly higher abstinence rate than those who received varenicline plus placebo (39.8% compared with 25.9%; odds ratio = 1.89; 95% CI = 1.07, 3.35). Combination treatment had a significantly greater effect on abstinence rate in male smokers (odds ratio = 4.26; 95% CI = 1.73, 10.49) than in female smokers (odds ratio = 0.94; 95% CI = 0.43, 2.05). It also had a significantly greater effect in highly nicotine-dependent smokers (odds ratio = 3.51, 95% CI = 1.64, 7.51) than in smokers with lower levels of dependence (odds ratio = 0.71, 95% CI = 0.28, 1.80).” (J. E. Rose)

>>>Pediatrics Report
Source:
Nov. issue of Pediatrics (2014; 134).
Pediatric Medication Errors: Among children younger than 6, analgesics were most commonly involved in medication errors in 2002–12, a study shows (pp. 867–76): “Cough and cold medication errors decreased significantly, whereas the number (42.9% increase) and rate (37.2% increase) of all other medication errors rose significantly…. The number and rate of medication error events decreased with increasing child age, with children <1 year accounting for 25.2% of episodes. Analgesics (25.2%) were most commonly involved in medication errors, followed by cough and cold preparations (24.6%). Ingestion accounted for 96.2% of events, and 27.0% of medication errors were attributed to inadvertently taking or being given medication twice.” (M. D. Smith)

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 © 2014, 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
Nov. 10, 2014 * Vol. 21, No. 217
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 8 issue of Lancet (2014; 383).
Antepartum Dalteparin for Thrombophilia During Pregnancy: In a study of 292 pregnant women at high risk for complications from thrombophilia, antepartum dalteparin failed to reduce the frequency of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications, researchers report (pp. 1673–83). Compared with placebo in an open-label trial in doses of 5,000 IU once daily through week 20 and twice daily through week 37 or later, dalteparin produced these changes in a primary outcome of severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism: “Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17.1%; 95% CI 11.4–24.2%] vs no dalteparin 27/143 [18.9%; 95% CI 12.8–26.3%]; risk difference −1.8% [95% CI −10.6% to 7.1%)) and on-treatment analysis (dalteparin 28/143 [19.6%] vs no dalteparin 24/141 [17.0%]; risk difference +2.6% [95% CI −6.4 to 11.6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19.6%]) than in the no dalteparin group (13/141 [9.2%]; risk difference 10.4%, 95% CI 2.3–18.4; p = 0.01).” (M. A. Rodger, mrodger@ohri.ca)
Alemtuzumab Induction in Kidney Transplantation: With alemtuzumab-based induction treatment in a diverse group of 852 patients undergoing renal transplantation, the risk of biopsy-proven acute rejection was reduced, according to results of the 3C study (pp. 1684–90). Adult patients scheduled for kidney transplantation within 24 hours were assigned to alemtuzumab-based induction treatment (alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone), with these results: “Individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0.42, 95% CI 0.28–0.64; log-rank p <0.0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1.23, 0.59–2.55; p = 0.58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1.02, 0.80–1.29; p = 0.88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1.79, 95% CI 0.66–4.83; p = 0.25).” (3C Study Collaborative Group)

>>>PNN NewsWatch
* The Ebola case count in West Africa has risen to 13,241, CDC reported on Friday, up from 10,114 just 2 weeks ago. The number of deaths has leveled off, rising from 4,912 to 4,950. The number of cases in the U.S. remains at 4 with 1 death.

>>>PNN JournalWatch
* 2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, in
Circulation, 2014; 130: 1749–67. (www.cardiosource.org; my.americanheart.org)
* Avoiding the Perfect Storm: The Biologic and Clinical Case for Reevaluating the 7-Day Expectation for Methicillin-Resistant
Staphylococcus aureus Bacteremia Before Switching Therapy, in Clinical Infectious Diseases, 2014; 59: 1455–61. (R. Kullar, ravina.kullar@gmail.com)
* Prevention of Infections During Primary Immunodeficiency, in
Clinical Infectious Diseases, 2014; 59: 1462–70. (O. Lortholary, livier.lortholary@nck.aphp.fr">olivier.lortholary@nck.aphp.fr)
* Smoking Cessation After Cancer, in
Journal of Clinical Oncology, 2014; 32: 3593–5. (F. Sitas, freddys@nswcc.org.au)
* How Long Is Long Enough? Extended Anticoagulation for the Treatment of Cancer-Associated Deep Vein Thrombosis, in
Journal of Clinical Oncology, 2014; 32: 3596–9. (J. I. Zwicker)
* Heart Failure Assessment at the Community Pharmacy Level: A Feasibility Pilot Study, in
Journal of the American Pharmacists Association, 2014; 54: 634–41. (B. E. Bleske, bbleske@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 © 2014, 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
Nov. 11, 2014 * Vol. 21, No. 218
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. issue of JAMA Internal Medicine (2014; 174).
Treatment of Overt Hepatic Encephalopathy: In 50 patients with acute hepatic encephalopathy (HE), polyethylene glycol 3350–electrolyte solution (PEG) was more effective than lactulose based on a primary outcome of improved HE grade at 24 hours, researchers report (pp. 1727–33). In the HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study, 186 patients were screened and 50 were block randomized to PEG 4 L or standard-of-care lactulose, with these results: “Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in [hepatic encephalopathy scoring algorithm (HESA)] score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P <.01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.” (D. C. Rockey, rockey@musc.edu)
Editorialists comment that this work “has demonstrated that rapid bowel purge may be a cost-effective and successful treatment in the acute setting” (
pp. 1734–5). “Questions remain, particularly comparisons with combined rifaximin–lactulose and use in the chronic setting, but the exploration of PEG treatment opens the opportunity for further studies. Future therapies interfering with ammoniagenesis also show promise and warrant further investigation. While hepatic encephalopathy is a common complication of cirrhosis and can be quite difficult to manage, the evolving therapeutic options hold great promise.” (N. L. Shah, ns3zt@virginia.edu)
Emergency Department Intervention for Drug Use: A “relatively robust brief intervention” failed to improve outcomes in drug users seeking emergency medical treatment, a study shows (pp. 1736–45). At six academic hospitals in the U.S., 1,285 adult patients presenting to the emergency department were screened, and those with scores on the 10-item Drug Abuse Screening Test indicating moderate to severe problems related to drug use were randomized to minimal screening only (MSO; informational pamphlet); screening, assessment, and referral to treatment (SAR); or a brief intervention with telephone boosters (BI-B). Based on a primary outcome of self-reported days of use of the patient-defined primary problem drug during the 30-day period preceding the 3-month follow-up, results showed: “For the primary outcome, estimated differences in number of days of use (95% CI) were as follows: MSO vs BI-B, 0.72 (−0.80 to 2.24), P (adjusted) = .57; SAR vs BI-B, 0.70 (−0.83 to 2.23), P (adjusted) = .57; SAR vs MSO, −0.02 (−1.53 to 1.50), P (adjusted) = .98. There were no significant differences between groups in self-reported days using the primary drug, days using any drug, or heavy drinking days at 3, 6, or 12 months. At the 3-month follow-up, participants in the SAR group had a higher rate of hair samples positive for their primary drug of abuse (265 of 280 [95%]) than did participants in the MSO group (253 of 287 [88%]) or the BI-B group (244 of 275 [89%]). Hair analysis differences between groups at other time points were not significant.” (M. P. Bogenschutz, mbogenschutz@salud.unm.edu)
Medications in Advanced Dementia: “Most nursing home residents with advanced dementia receive medications with questionable benefit that incur substantial associated costs,” conclude investigators who conducted a cross-sectional study of medication use in 5,406 nursing home residents with this condition (pp. 1763–71). Based on data from a nationwide long-term care pharmacy database, 54% of the patients were receiving medications for dementia that are of questionable benefit in nursing home residents with advanced dementia, including cholinesterase inhibitors (36.4% of patients), memantine hydrochloride (25.2%), and lipid-lowering agents (22.4%). The study also showed that residents with advanced dementia in facilities with high use of feeding tubes were more likely to be receiving these medications. (J. Tjia, jennifer.tjia@umassmed.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 © 2014, 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
Nov. 12, 2014 * Vol. 21, No. 219
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 12 issue of JAMA (2014; 312).
Maternal Pertussis Vaccination & Obstetric Outcomes: In a study that examines the safety of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) during pregnancy, only a small but significant increase in risk of horioamnionitis diagnosis (pp. 1897–904). No increased risk of hypertensive disorders of pregnancy or preterm or small-for-gestational-age births was noted, the authors write, adding these findings from two California Vaccine Safety Datalink sites covering 123,494 women with singleton pregnancies: “Vaccination was not associated with increased risks of adverse birth outcomes: crude estimates for preterm delivery were 6.3% of vaccinated and 7.8% of unvaccinated women (adjusted RR, 1.03; 95% CI, 0.97–1.09); 8.4% of vaccinated and 8.3% of unvaccinated had an SGA birth (adjusted RR, 1.00; 95% CI, 0.96–1.06). Receipt of Tdap before 20 weeks was not associated with hypertensive disorder of pregnancy (adjusted RR, 1.09; 95% CI, 0.99–1.20); chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13–1.26).” (E. O. Kharbanda, elyse.o.kharbanda@healthpartners.com)
Whole-Exome Sequencing in Clinical Care: Commenting on two studies that examined whole-exome sequencing among 2,000 primarily pediatric patients (pp. 1870–9; C. M. Eng, ceng@bcm.edu) and 814 patients with undiagnosed but suspected genetic conditions (pp. 1880-7; S. F. Nelson, snelson@ucla.edu), editorialists provide these insights into how clinicians can incorporate this newly available technology into clinical medicine (pp. 1865–7): “The molecular diagnostic yields demonstrated by these 2 studies in JAMA demonstrate what is possible with new technology; they provide a fuller understanding of the phenotypic manifestations of rare genetic disorders and eventually toward targeted therapeutics. Still, challenges remain. One topic only briefly addressed by the two groups is the difficulty of interpreting the clinical significance of genomic variants. Both groups mention a number of resources that were consulted for annotating and curating variants, such as the National Center for Biotechnology Information ClinVar database. It is hoped that clinical laboratories will not only use and benefit from such resources, but will also embrace the concept of a learning health care system in which the contribution of data to such resources is viewed not only as a virtue but an imperative. This practice could be encouraged by journals, regulatory bodies, and funding agencies.” (J. S. Berg, jonathan_berg@med.unc.edu)

>>>Infectious Diseases Report
Source:
Dec. 1 issue of Clinical Infectious Diseases (2014; 59).
B-Antigen Mismatch & Trivalent Influenza Vaccines: In 1999–2012, “the population-level impact of lineage-level mismatch between the vaccine and circulating strains of influenza B viruses [was] substantial, especially among children and adolescents,” researchers report, concluding that “the results provide strong support for the inclusion of both influenza B lineages in seasonal influenza vaccines” (pp. 1519–24). Nationwide data from Finland during this time (with the 2009 pandemic season excluded) show these patterns for 34,788 cases of influenza: “Influenza A accounted for 74.0% and influenza B for 26.0% of all typed viruses. Throughout the 12 seasons, we estimated that 41.7% (3750 of 8993) of all influenza B infections were caused by viruses representing the other genetic lineage than the one in the vaccine. Altogether, opposite-lineage influenza B viruses accounted for 10.8% of all influenza infections in the population, the proportion being highest (16.8%) in children aged 10–14 years and lowest (2.6%) in persons aged ≥70 years.” (T. Heikkinen, terho.heikkinen@utu.fi)
Need for Pediatric Fluconazole Monitoring: Based on finding that 40% of 99 pediatric patients had subtherapeutic levels of fluconazole in a retrospective analysis, investigators conclude that “therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children” (pp. 1527–33). The Dutch study found positive associations of trough levels with fluconazole dose, patient weight, and serum urea concentrations and negative associations with patient age and cancer diagnosis. (J-W C. Alffenaar, j.w.c.alffenaar@umcg.nl)

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 © 2014, 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
Nov. 13, 2014 * Vol. 21, No. 220
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 13 issue of the New England Journal of Medicine (2014; 371).
Treatment of Melanoma: Aspects of melanoma therapy are explored in two research studies and an editorial.
In 495 patients with previously untreated unresectable locally advanced or metastatic
BRAF V600–mutated melanoma, addition of the MEK inhibitor cobimetinib to vemurafenib increased progression-free survival significantly but also produced more toxicity, researchers report (pp. 1867–76). Based on a primary end point of investigator-assessed progression-free survival, patients on vemurafenib with cobimetinib or placebo (control) had these outcomes: “The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P <0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P <0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.” (A. Ribas, aribas@mednet.ucla.edu)
Combined BRAF/MEK inhibition also proved useful in a Phase III trial of 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma with a
BRAF V600E or V600K mutation (pp. 1877–88). Dabrafenib with trametinib or placebo showed these effects: “The median progression-free survival was 9.3 months in the dabrafenib–trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib–trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib–trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib–trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib–trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib–trametinib group.” (G. V. Long, georgina.long@sydney.edu.au)
“The good news is that we now have agents with a much higher potential to induce clinically meaningful melanoma regression, as compared with therapies used before 2010, resulting in improved quality and length of life for many patients,” an editorialist writes (
pp. 1929–30). “The other news illustrated by these reports of BRAF and MEK targeted therapy is that melanoma adapts with astonishing speed and we do not yet know how to stop or channel the evolution of the melanoma in an effective way to help our patients. The future of melanoma therapy will be not only to use combinations that target growth pathways favored by the melanoma at a point in time, but also to develop a rational basis for sequential therapies that address the evolution of the melanoma as it adapts to survive.” (B. D. Curti)
Generic-Drug Costs: Costs of generic drugs are increasing for several reasons, authors of a Perspective article write, including shortages, increased demand, and market monopolies (pp. 1859–62). The authors recommend FDA actions to increase market competition and ensure adequate drug supplies. They also suggest that downstream price manipulation by wholesalers or pharmacies be investigated. (J. D. Alpern)

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 © 2014, 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
Nov. 14, 2014 * Vol. 21, No. 221
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Nov. 18 issue of the Journal of the American College of Cardiology (2014; 64).
Polypill Strategy to Improve Adherence: Use of a fixed-dose combination (FDC) “polypill” in 2,118 patients after myocardial infarction improved medication adherence, compared with the three component drugs administered separately, FOCUS (Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention) study investigators found (pp. 2071–82). Results from Phases 1 and 2 of the trial showed these effects on self-reported Morisky–Green questionnaire (MAQ) and pill counts for the polypill (aspirin 100 mg, simvastatin 40 mg, and ramipril 2.5, 5, or 10 mg) or component drugs: “In Phase 1, overall [cardiovascular (CV)] medication adherence, defined as an MAQ score of 20, was 45.5%. In a multivariable regression model, the risk of being nonadherent (MAQ <20) was associated with younger age, depression, being on a complex medication regimen, poorer health insurance coverage, and a lower level of social support, with consistent findings across countries. In Phase 2 [n = 695], the polypill group showed improved adherence compared with the group receiving separate medications after 9 months of follow-up: 50.8% versus 41% (p = 0.019; intention-to-treat population) and 65.7% versus 55.7% (p = 0.012; per protocol population) when using the primary endpoint, attending the final visit with MAQ = 20 and high pill count (80% to 110%) combined, to assess adherence. Adherence also was higher in the FDC group when measured by MAQ alone (68% vs. 59%, p = 0.049). No treatment difference was found at follow-up in mean systolic blood pressure (129.6 mm Hg vs. 128.6 mm Hg), mean low-density lipoprotein cholesterol levels (89.9 mg/dl vs. 91.7 mg/dl), serious adverse events (23 vs. 21), or death (1, 0.3% in each group).” (J. M. Castellano)
This study “addresses one of the vexing issues of long-term care of patients with [cardiovascular disease],” writes an editorialist (
pp. 2083–5). “Despite the obvious case for prioritized action on secondary prevention, global practice patterns reveal low levels of prescription and adherence. This is an inexcusable failure of the health care system anywhere but is particularly tragic in [low- and middle-income countries], where many young lives that could saved are lost because the ‘lifeguard’ of secondary prevention was not deployed. To move secondary prevention from evidence (efficacy) to action (effectiveness), we need to improve practice patterns of providers, enable uptake and adherence by patients, and, crucially, reconfigure health systems to reliably deliver chronic continuous care, starting with the primary care setting.” (K. S. Reddy)
Dual Antiplatelet Therapy After Stent Implantation: Among 1,399 low-risk SECURITY (Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy) patients, 6 months of dual antiplatelet therapy after drug-eluting-stent implantation was noninferior to 12 months (pp. 2086–97): “The primary composite endpoint [of composite of cardiac death, myocardial infarction, stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium type 3 or 5 bleeding at 12 months] occurred, respectively, in 4.5% versus 3.7% (risk difference 0.8%; 95% confidence interval [CI]: −2.4% to 1.7%; p = 0.469) at 12 months. The upper 95% CI limit was lower than the pre-set margin of 2%, confirming the noninferiority hypothesis (p < 0.05).” (A. Colombo)
QT Intervals & Cardiovascular Events: Among 6,273 participants in MESA (Multi-Ethnic Study of Atherosclerosis), incident cardiovascular events were associated with patients’ QT intervals, researchers report (pp. 2111–9). Study participants had no prior known cardiovascular disease (CVD). Associations between corrected baseline 12-lead ECG QT interval duration (QTcorr) and outcomes showed these patterns: “The mean age at enrollment was 61.7 ± 10 years, and 53.4% of participants were women. Cardiovascular events occurred in 291 participants over a mean follow-up of 8.0 ± 1.7 years. Each 10-ms increase in the baseline QTcorr was associated with incident heart failure (hazard ratio [HR]: 1.25; 95% CI: 1.14 to 1.37), CVD events (HR: 1.12; 95% CI: 1.05 to 1.20), and stroke (HR: 1.19; 95% CI: 1.07 to 1.32) after adjustment for CVD risk factors and potential confounders. There was no evidence of interaction with sex or ethnicity.” (R. Beinart)

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 © 2014, 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
Nov. 17, 2014 * Vol. 21, No. 222
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 15 issue of Lancet (2014; 383).
Combining Simeprevir With Sofosbuvir for Hepatitis C: Investigators looking for interferon-free regimens for hepatitis C virus (HCV) genotype 1 found that, in 167 patients who were treatment naive or had not responded to a pegylated interferon regimen, the combination of simeprevir and sofosbuvir “was efficacious and well tolerated” (pp. 1756–65). The treatment-naive and previously treated cohorts received simeprevir 150 mg and sofosbuvir 400 mg daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, with these results: “[Sustained virological response 12 weeks after stopping treatment (SVR12)] was achieved in 154 (92%) patients (n = 72 [90%, 95% CI 81–96] in cohort 1 and n = 82 [94%, 87–98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n = 52 [31%]), headache (n = 33 [20%]), and nausea (n = 26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3–4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12.” (E. Lawitz, lawitz@txliver.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
ARBs in ST-Segment Elevation Myocardial Infarction: Angiotensin II receptor blockers are promising alternatives to ACE inhibitors in patients with ST-segment elevation myocardial infarction with preserved left ventricular systolic function, according to results of a study of 6,698 patients at 53 Korean hospitals (g6650). Participants underwent percutaneous coronary interventions and had left ventricular ejection fractions of 40% or more when they were divided into ARB, ACE inhibitor, and no-angiotensin-blockade groups. Results showed: “Cardiac death or myocardial infarction occurred in 21 patients (1.8%) in the angiotensin receptor blocker group, 77 patients (1.7%) in the ACE inhibitor group, and 33 patients (3.5%) in the no renin angiotensin system blocker group. After propensity score matching (1,175 pairs), there was no significant difference in the rate of cardiac death or myocardial infarction between the angiotensin receptor blocker group and ACE inhibitor group (21 (1.8%) v 23 (2.0%), adjusted hazard ratio 0.65, 95% confidence interval 0.30 to 1.38; P = 0.65). The angiotensin receptor blocker group had a lower rate of cardiac death or myocardial infarction than the no renin angiotensin system blocker group in matched populations (803 pairs) (14 (1.7%) v 25 (3.1%), 0.35, 0.14 to 0.90; P = 0.03).” (J-Y Hahn, jyhahn@skku.edu)
Anticoagulation During PCI: A meta-analysis of trials conducted “in the era of stents and P2Y12 inhibitors” shows that unfractionated heparin plus a glycoprotein IIb/IIIa(GpIIb/IIIa) inhibitor are the most efficacious treatment while bivalirudin is the safest (g6419). Results from 22 trials of 22,434 patients showed: “In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 (95% confidence interval 1.21 to 1.84), as were bivalirudin (relative risk 1.34 (1.01 to 1.78)) and fondaparinux (1.78 (1.01 to 3.14)). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 (0.30 to 0.74)) or unfractionated heparin (0.58 (0.37 to 0.90)). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. Results were similar in direct comparison meta-analyses.” (S. Bangalore, sripalbangalore@gmail.com)

>>>PNN JournalWatch
* The Role of Air Pollutants in Atopic Dermatitis, in
Journal of Allergy and Clinical Immunology, 2014; 134: 993–9. (K. Ahn, kmaped@skku.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 © 2014, 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
Nov. 18, 2014 * Vol. 21, No. 223
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 18 issue of the Annals of Internal Medicine (2014; 161).
Adverse Effects of NSAIDs in Atrial Fibrillation: In an observational cohort study from Denmark, NSAID use was found to be an independent risk factor for bleeding and thromboembolism in patients with atrial fibrillation (AF) who were receiving antithrombotic therapy (pp. 690–8). Investigators concluded, “Physicians should exercise caution with NSAIDs in patients with AF,” based on these data from Danish nationwide registries for 1997–2011: “Of 150,900 patients with AF (median age, 75 years [interquartile range, 65 to 83 years]; 47% female), 53,732 (35.6%) were prescribed an NSAID during a median follow-up of 6.2 years (interquartile range, 2.1 to 14.0 years). There were 17,187 (11.4%) and 19,561 (13.0%) occurrences of serious bleeding and thromboembolism, respectively. At 3 months, the absolute risk for serious bleeding within 14 days of NSAID exposure was 3.5 events per 1,000 patients compared with 1.5 events per 1,000 patients without NSAID exposure. The risk difference was 1.9 events per 1,000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1,000 patients. Use of NSAIDs was associated with increased absolute risks for serious bleeding and thromboembolism across all antithrombotic regimens and NSAID types. An NSAID dosage above the recommended minimum was associated with a substantially increased hazard ratio for bleeding.” (M. Lamberts, mortenlamberts@gmail.com)
RAS Blockade After Valve Replacement: In patients who have had surgical aortic valve replacement (SAVR) for severe aortic stenosis (AS), blockade of the renin–angiotensin system (RAS) was linked to increased survival rates, researchers report (pp. 699–710). At a single tertiary referral center, retrospective data showed the following outcomes for patients with at least two refills 90 days apart for ACE inhibitors or angiotensin II receptor blockers: “Overall unadjusted estimated survival rates at 1, 5, and 10 years were significantly greater in the RAS blockade group than in the non–RAS blockade group (99%, 90%, and 60% vs. 99%, 81%, and 53%, respectively; P < 0.001). Among propensity-matched patients, estimated survival rates at 1, 5, and 10 years remained significantly greater in the RAS blockade group than in the non–RAS blockade group (99%, 90%, and 71% vs. 96%, 78%, and 49%, respectively; P < 0.001). For the matched cohorts, the groups did not significantly differ in the change in left ventricular mass index (P = 0.37), left ventricular ejection fraction (P = 0.67), or left atrial size (P = 0.43) after SAVR on echocardiographic analysis.” (S. R. Kapadia, kapadis@ccf.org)
Preventing Fractures With Medications: While several medications have been shown in clinical trials to prevent fractures in at-risk patients, comparative effectiveness of the agents remains unclear, according to authors who updated a systematic review (pp. 711–23): “From more than 52,000 titles screened, 315 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.” (C. J. Crandall, ccrandall@mednet.ucla.edu)

>>>PNN NewsWatch
* FDA is looking into the safety of long-term dual antiplatelet therapy in patients with stents based on a report from the American Heart Assoc. meeting, the agency announced on Monday. Results of the Dual Antiplatelet Therapy (DAPT) trial were published in the New England Journal of Medicine and presented at AHA. They showed that treatment for 30 months with dual antiplatelet blood-thinning therapy decreased the risk of heart attacks and clot formation in stents, but there was an increased overall risk of death compared with 12 months of treatment. Dual antiplatelet therapy consisted of aspirin plus either clopidogrel or prasugrel; the drugs were used following implantation of drug-eluting coronary stents.

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 © 2014, 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
Nov. 19, 2014 * Vol. 21, No. 224
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 19 issue of JAMA, a theme issue on cardiovascular disease (2014; 312).
Beta-Blockers & Heart-Failure Outcomes: In a registry-based study of heart failure with preserved ejection fraction (HFPEF), beta-blocker use was “was associated with lower all-cause mortality but not with combined all-cause mortality or heart failure hospitalization,” researchers report (pp. 2008–18). Adding that these drugs should be studied in a large randomized controlled trial, the Swedish Heart Failure Registry investigators provide these details about patients with HFPEF and matched controls identified from a sample of 41,976 patients: “Median follow-up in HFPEF was 755 days, overall; 709 days in the matched cohort; no patients were lost to follow-up. In the matched HFPEF cohort, 1-year survival was 80% vs 79% for treated vs untreated patients, and 5-year survival was 45% vs 42%, with 2,279 (41%) vs 1,244 (45%) total deaths and 177 vs 191 deaths per 1,000 patient–years (hazard ratio [HR], 0.93; 95% CI, 0.86–0.996; P = .04). Beta-blockers were not associated with reduced combined mortality or heart failure hospitalizations: 3,368 (61%) vs 1,753 (64%) total for first events, with 371 vs 378 first events per 1,000 patient–years (HR, 0.98; 95% CI, 0.92–1.04; P = .46). In the matched HFREF cohort, beta-blockers were associated with reduced mortality (HR, 0.89; 95% CI, 0.82–0.97, P=.005) and also with reduced combined mortality or heart failure hospitalization (HR, 0.89; 95% CI, 0.84–0.95; P = .001).” (L. H. Lund, Lars.Lund@alumni.duke.edu)
Agreeing with these authors’ bottom line, editorialists conclude that “more definitive information about whether beta-blocker therapy is effective for preventing important outcomes in HFPEF requires well-designed and well-conducted randomized clinical trials” (
pp. 1977–8). The current study does offer insights that are valuable to clinicians at this time, the editorialists add, writing: “Administrative databases offer important value given their ability to capture information about actual practice and outcomes from across large samples of the population, unrestricted by the constructs of a clinical trial or even an epidemiological cohort design. By design, however, such databases offer limited ability to provide complete information about potentially important confounders. Thus, an attempt to use administrative data to probe the potential efficacy of a therapy is a mismatch of the data to the question. However, for most questions in medicine, only incomplete data are available to guide diagnostic and therapeutic decisions, and observational studies may have a role in assisting with treatment options.” (M. A. Pfeffer, mpfeffer@rics.bwh.harvard.edu)
Long-term Warfarin v. Device Therapy in AF: Among patients with nonvalvular atrial fibrillation, mechanical left atrial appendage (LAA) closure using WATCHMAN device (Boston Scientific) implantation was noninferior and superior to warfarin in a long-term study (pp. 1988–98). In the PROTECT AF study, investigators sought to extend findings from shorter trials that had demonstrated efficacy of the device, which reduces emboli through mechanical LAA closure; the LAA is thought to be the major source of thromboemboli in patients in nonvalvular atrial fibrillation. Study participants were randomized to the device (n = 463) or warfarin (n = 244), with these results: “At a mean (SD) follow-up of 3.8 (1.7) years (2,621 patient–years), there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient–years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient–years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41–1.05), meeting prespecified criteria for both noninferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%). Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient–years for the device group [17/463 patients, 3.7%] vs 2.4 events per 100 patient–years with warfarin [22/244 patients, 9.0%]; hazard ratio [HR], 0.40; 95% CI, 0.21–0.75; P = .005) and all-cause mortality (3.2 events per 100 patient–years for the device group [57/466 patients, 12.3%] vs 4.8 events per 100 patient–years with warfarin [44/244 patients, 18.0%]; HR, 0.66; 95% CI, 0.45–0.98; P = .04).” (V. Y. Reddy, vivek.reddy@mountsinai.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 © 2014, 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
Nov. 20, 2014 * Vol. 21, No. 225
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 20 New England Journal of Medicine (2014; 371).
Crizotinib in Non–Small-Cell Lung Cancer: In 50 Phase I trial patients with advanced ROS1-rearranged non–small-cell lung cancers (NSCLCs), crizotinib showed “marked antitumor activity” (pp. 1963–71). The drug—a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and proto-oncogene receptor tyrosine kinase, MET—was administered in doses of 250 mg twice daily. Results were assessed in relation to tumors’ ROS1 fusion partner status: “The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.” (A. T. Shaw, ashaw1@mgh.harvard.edu)
While NSCLC tumors with genetic rearrangements involving the
ROS1 gene are rare—occurring in 1%–2% of patients with the disease—this study points to the value of differentiation of cancer subtypes and targeted therapies, an editorialist writes (pp. 2030–1): “No longer a single-disease entity, NSCLC is being divided into a collection of molecularly defined tumors, with different clinical characteristics and treatment options. Comprehensive molecular characterization of NSCLCs is critical as more targets are becoming clinically relevant. In addition to the reported studies of targeted agents in EGFR-mutant and ALK- and ROS1-positive tumors, trials are ongoing for patients whose lung cancers carry relatively uncommon alterations, including HER2 and BRAF mutations, RET rearrangements, and FGFR fusions. The study by Shaw et al. proves that it is possible to conduct trials in small subgroups of patients with NSCLC and demonstrate big results.” (K. A. Gold)
Factor IX Gene Therapy in Hemophilia B: In 10 patients with severe hemophilia B, factor IX gene therapy yielded positive efficacy results with no late toxic effects in a 3-year study (pp. 1994–2004). The Phase I dose-escalation trial used low, intermediate, and high doses of a adeno-associated virus serotype 8 vector in three pairs of patients; the other four patients received the high dose. Long-term results showed: “A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1% to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (± SD) of 5.1 ± 1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment.” (A. C. Nathwani, a.nathwani@ucl.ac.uk)
ACIP at 50: “For a half-century, U.S. vaccination efforts have benefited greatly” from the efforts of the CDC’s Advisory Committee on Immunization Practices (ACIP), authors write in a Perspective article (pp. 1953–6). Noting that advisors to governmental health agencies rarely provide “evidence-based guidance on using [marketed] products,” the writers add, “As the ACIP continues to play its influential role, its foremost challenge will be preserving its reputation as an inclusive and credible voice on vaccination. Success requires not simply continued attention to rigorous analyses and high-quality recommendations, but also a similar focus on dissemination of its guidance and its reception by clinicians, parents, and patients. With hesitancy regarding vaccines posing a growing threat to vaccination efforts, insights from the fields of health communication, decision making, and related social and behavioral sciences will be increasingly important to the ACIP’s work and the continued success of U.S. vaccination activities.” (J. L. Schwartz)

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 © 2014, 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
Nov. 21, 2014 * Vol. 21, No. 226
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Nov. issue of Health Affairs, a theme issue on Collaborating for Community Health (2014; 33).
Pharmacy Deserts in Chicago: An analysis of pharmacy locations in Chicago identifies areas of “pharmacy deserts” in low-income neighborhoods where accessibility is poor (pp. 1958–65). Combining geographic locations with data on income and racial/ethnic makeup of residents, investigators found these patterns: “We found that throughout the period 2000–2012 the number of pharmacies was lower in segregated minority communities than in segregated white communities and integrated communities. In 2012 there were disproportionately more pharmacy deserts in segregated black communities, as well as in low-income communities and federally designated Medically Underserved Areas. Our findings suggest that public policies aimed at improving access to prescription medications may need to address factors beyond insurance coverage and medication affordability. Such policies could include financial incentives to locate pharmacies in pharmacy deserts or the incorporation of pharmacies into community health centers in Medically Underserved Areas.” (D. M. Qato, dimaqato@uic.edu)

>>>JAPhA Highlights
Source:
Nov/Dec Journal of the American Pharmacists Assoc. (2014; 54).
Pharmacy Services by Area of Detroit: People living in lower-income and nonwhite areas of Detroit face difficulties obtaining lower-priced generic medications and taking advantage of discount generic drug programs, a study shows (pp. 618–24). A survey of 503 pharmacies in Wayne County, MI, provided data on cost of a 30-day supply of levothyroxine 50 mcg and brand-name atorvastatin 20 mg (Lipitor, Pfizer), availability of generic drug programs, home delivery services, hours of pharmacy operations, and availability of immunization services. Analyzed by ZIP code, the data showed: “The overall results per ZIP code showed that the average cost for levothyroxine was $10.01 ± $2.29 and $140.45 + $14.70 for Lipitor. Per ZIP code, the mean (± SD) percentages of pharmacies offering discount generic drug programs was 66.9% ± 15.0%; home delivery of medications was 44.5% ± 22.7%; and immunization for influenza was 46.7% ± 24.3% of pharmacies. The mean (± SD) hours of operation per pharmacy per ZIP code was 67.0 ± 25.2. ZIP codes with higher household income as well as higher percentage of residents being white had lower levothyroxine price, greater percentage of pharmacies offering discount generic drug programs, more hours of operation per week, and more pharmacy-based immunization services. The cost of Lipitor was not associated with any ZIP code characteristic.” (S. R. Erickson, serick@med.umich.edu)

>>>Medical Care Report
Source:
Dec. issue of Medical Care (2014; 52).
Pharmacy Adherence Interventions: Live calls from the pharmacy decreased patients’ primary medication nonadherence (PMN), but automated reminder calls had no effect on this measure, researchers report (pp. 1050–4). Beginning in 2007 at CVS community pharmacies, automated calls were placed on the third and seventh days after prescriptions were processed but not picked up. Live pharmacist or technician calls began in 2009 to those who had not picked up prescriptions by day 8. Compared with a control group of patients with randomly selected birthdays, the results showed: “The automated intervention included 852,612 patients and 1.2 million prescriptions, with a control group of 9,282 patients and 13,178 prescriptions. The live intervention included 121,155 patients and 139,502 prescriptions with a control group of 2,976 patients and 3,407 prescriptions. The groups were balanced by age, sex, and patterns of prior prescription use. For the automated intervention, 4.2% of prescriptions were abandoned in the intervention group and 4.5% in the control group (P >0.1), with no significant differences for any individual classes of medications. The live intervention was used in a group that had not purchased prescriptions after 8 days and thus had much higher PMN. In this setting 36.9% of prescriptions were abandoned in the intervention group and 41.7% in the control group, a difference of 4.8% (P <0.0001). The difference in abandoned prescriptions for antihypertensives was 6.9% (P <0.0001) but for antihyperlipidemics was only 1.4% (P >0.1).” (M. A. Fischer)

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 © 2014, 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
Nov. 24, 2014 * Vol. 21, No. 227
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 22 issue of Lancet (2014; 383).
Antithrombotics in PCI: In patients undergoing a primary percutaneous coronary intervention, unfractionated heparin outperformed bivalirudin in the HEAT-PPCI trial by significantly reducing major adverse ischemic events without increasing bleeding complications, researchers report (pp. 1849–58). The open-label trial randomized consecutive adults to heparin 70 U/kg or bivalirudin 0.75 mg/kg bolus with 1.75 mg/kg/h infusion, with these effects on a composite efficacy outcome of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularization: “Between Feb 7, 2012, and Nov 20, 2013, 1,829 of 1,917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1,812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8.7%) of 905 patients in the bivalirudin group and 52 (5.7%) of 907 patients in the heparin group (absolute risk difference 3.0%; relative risk [RR] 1.52, 95% CI 1.09–2.13, p = 0.01). The primary safety outcome occurred in 32 (3.5%) of 905 patients in the bivalirudin group and 28 (3.1%) of 907 patients in the heparin group (0.4%; 1.15, 0.70–1.89, p = 0.59).” (R. H. Stables, rod.stables@lhch.nhs.uk)
Antenatal Corticosteroids & Tocolysis: In 29 countries, use antenatal interventions to prevent preterm birth was poor, and corticosteroids were often used at controversial times during pregnancies, a WHO study shows (pp. 1869–77). “Of 303,842 recorded deliveries after 22 weeks’ gestation, 17,705 (6%) were preterm. 3,900 (52%) of 7,547 women who gave birth at 26–34 weeks’ gestation, 94 (19%) of 497 women who gave birth at 22–25 weeks’ gestation, and 2,276 (24%) of 9,661 women who gave birth at 35–36 weeks’ gestation received antenatal corticosteroids. Rates of antenatal corticosteroid use varied between countries (median 54%, range 16–91%; IQR 30–68%). Of 4,677 women who were potentially eligible for tocolysis drugs, 1,276 (27%) were treated with bed rest or hydration and 2,248 (48%) received no treatment. Beta-agonists alone (n = 346, 7%) were the most frequently used tocolytic drug. Only 848 (18%) of potentially eligible women received both a tocolytic drug and antenatal corticosteroids.” (J. P. Vogel, vogeljo@who.int)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Sirolimus After Kidney Transplantation: In a systematic review and meta-analysis of 21 trials of 5,876 patients, use of sirolimus after renal transplantation was associated with reduced risk of cancer but increased risk of mortality (g6679). Trying to sort out conflicting results of previous trials and meta-analyses, the investigators examined published studies and a registry of controlled trials, finding the following: “Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.” (G. A. Knoll, gknoll@ottawahospital.on.ca)

>>>PNN NewsWatch
* FDA on Friday issued final guidances on 503B registration and fees. This section governs outsourcing facilities that compound sterile human drugs.

>>>PNN JournalWatch
* Methodologies for the Development of the Management of Cough: CHEST Guideline and Expert Panel Report, in
Chest, 2014; 146: 1395–402. (R. L. Diekemper, rdiekemper@chestnet.org)
* Dietary Treatment in Adults with Refractory Epilepsy, in
Neurology, 2014; 83: 1978–85. (P. Klein, kleinp@epilepsydc.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 © 2014, 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
Nov. 25, 2014 * Vol. 21, No. 228
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Nov. issue of the Journal of the American Geriatrics Society (2014; 62).
Statin Use in Advanced Dementia: In nursing home residents who progress to advanced dementia, statin use often continues, researchers report (pp. 2095–101). Therapy with such agents in people with life-limiting conditions has been controversial. At all facilities in five states, 2007–08 Minimum Data Sets linked to Medicare denominators and Part D files revealed the following: “Of 10,212 residents, 16.6% (n = 1,699) used statins. Greater odds of statin use were associated with having diabetes mellitus (adjusted odds ratio (AOR) = 1.24, 95% confidence interval (CI) = 1.09–1.40), stroke (AOR = 1.31, 95% CI = 1.16–1.48), and hypertension (AOR = 1.35, 95% CI = 1.18–1.54); hospice enrollment was associated with lower odds (AOR = 0.75, 95% CI = 0.64–0.89). In follow-up, 37.2% (n = 632) discontinued statins. Median time to discontinuation was 36 days (interquartile range 12–110 days). Shorter time to discontinuation was associated with hospitalization in past 30 days (adjusted hazard ratio (AHR) = 1.67, 95% CI = 1.40–1.99) and more daily medications (AHR = 1.02, 95% CI = 1.01–1.04). When statins were discontinued, 15.0% (n = 95) of residents stopped only statins, and 47.5% (n = 300) stopped at least one other medication.” (J. Tjia, jennifer.tjia@umassmed.edu)
Insomnia in Institutionalized Older Patients: Among 4,156 residents of 57 long-term care facilities, use of hypnosedatives and presence of depression were significant predictors of insomnia, according to the Services and Health for Elderly in Long TERm care (SHELTER) study (pp. 2033–9). The facilities, located in eight European countries and Israel, had these patterns of insomnia and treatments for this condition: “The prevalence of insomnia was 24% (range 13–30%), with significant differences between countries (P < .001). More insomnia complaints were reported in older than younger residents (P < .001). Higher rates of insomnia were associated with hypnosedatives and depression in all countries (P < .001) and with stressful life events, fatigue, and pain in most countries (P < .001). No associations were found between insomnia and [activities of daily living], physical activity, or cognitive status. Age, depression, stressful life events, fatigue, pain and hypnosedatives were independent significant predictors of insomnia, controlling for all other variables and for country.” (T. Shochat, tshochat@univ.haifa.ac.il)

>>>Internal Medicine Report
Source:
Early-release article from JAMA Internal Medicine (2014; 174).
Timing of Antiretroviral Therapy: Patients whose HIV-1 infections were not treated with antiretroviral therapy (ART) during the first year had significantly lower rates of normalization of immune status, according to the observational US Military HIV Natural History Study (doi: 10.1001/jamainternmed.2014.4010). Results from 1986 to 2010 showed these patterns: “The median CD4+ count in HIV-1–uninfected populations was approximately 900 cells/µL. Among 1,119 HIV-1–infected participants, CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months vs after 12 months from the [estimated dates of seroconversion (EDS)] (P = .001). Incrementally higher CD4+ recovery (<500, 500–899, and ≥900 cells/µL) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation, dysfunction, and responsiveness to levels approximating those found in HIV-1–uninfected persons. Participants with CD4+ counts of 500 cells/µL or higher at study entry (adjusted odds ratio [aOR], 2.00; 95% CI, 1.51–2.64; P < .001) or ART initiation (aOR, 4.08; 95% CI, 3.14–5.30; P < .001) had significantly increased CD4+ normalization rates compared with other participants. However, even among individuals with a CD4+ count of 500 cells/µL or higher at both study entry and before ART, the odds of CD4+ normalization were 80% lower in those initiating ART after 12 months from the EDS and study entry (aOR, 0.20; 95% CI, 0.07–0.53; P = 001). Initiation of ART within 12 months of EDS vs later was associated with a significantly lower risk of AIDS (7.8% vs 15.3%; P = .002), reduced T-cell activation (percent CD4+HLA-DR+ effector memory T cells, 12.0% vs 15.6%; P = .03), and increased responsiveness to HBV vaccine (67.9% vs 50.9%; P = .07).” (S. K. Ahuja, ahujas@uthscsa.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 © 2014, 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
Nov. 26, 2014 * Vol. 21, No. 229
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 26 issue of JAMA (2014; 312).
Levofloxacin After Kidney Transplantation: Used with the intention of preventing BK virus infection following renal transplant, levofloxacin had no effect on BK viruria but produced adverse effects, including bacterial resistance, researchers report (pp. 2106–14). Three-month courses of levofloxacin 500 mg/d or placebo starting within 5 days after transplantation in 154 participants produced these results: “The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51–1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points [BK viremia, peak viral load, rejection, and patient and allograft survival]. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01–2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76–49.95).” (J. S. Gill, jgill@providencehealth.bc.ca)
Dalteparin v. Unfractionated Heparin in Critically Ill Patients: In a cost-effectiveness study conducted from the payer’s perspective, the low molecular weight heparin (LMWH) dalteparin was more effective and cost less than unfractionated heparin (UFH) among critically ill medical–surgical patients in the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (PROTECT) (pp. 2135–45). The trial, conducted by the Canadian Critical Care Trials Group and the Australia and New Zealand Intensive Care Society Clinical Trials Group, included 2,344 patients at 23 centers. The time horizon was during hospitalization. Cost-effectiveness and sensitivity tests showed the following based on prophylaxis for venous thromboembolism (VTE): “Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1,862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1,862 patients who received UFH (incremental cost, −$1,297 [IQR, −$43,98 to $1,404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH.” (R. A. Fowler, rob.fowler@sunnybrook.ca)
FDA & Drug-Approval-Study Design: Voluntary meetings of pharmaceutical companies with FDA officials during design of pivotal studies nearly always resulted in recommendations that would improve quality of the results, a study shows (pp. 2163–5). “Yet companies are not required to meet with the FDA or follow their recommendations,” the authors write. “One-quarter of [35] approvals [in this analysis] occurred without any meeting, and when such meetings occurred, companies did not comply with one-quarter of recommendations. The FDA endorsed [special protocol assessments] for only 12 of the 35 approvals, suggesting missed opportunities for optimizing study quality.” During meetings for 28 pivotal studies, “FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals (median, 1 [range, 0–7] recommendations per approval),” and companies complied with 40 of these.” (L. M. Schwartz, lisa.schwartz@dartmouth.edu)

>>>PNN NewsWatch
* CDC provides advice for patients for managing diabetes during the holidays, including watching out “for heavy holiday favorites such as hams with a honey glaze, turkey swimming in gravy and side dishes loaded with butter, sour cream, cheese, or mayonnaise. Instead, choose skinless turkey without gravy, or other lean meats.”
*
PNN will not be published on Thurs. and Fri., Nov. 27 and 28, Thanksgiving.

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 © 2014, 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
Dec. 1, 2014 * Vol. 21, No. 230
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 27 issue of the New England Journal of Medicine (2014; 371).
Aortic-Root Therapy in Marfan’s Syndrome: Compared with the standard therapy of beta blockers, losartan yielded no significant difference in aortic-root dilatation over a 3-year period in children and young adults with Marfan’s syndrome (pp. 2061–71). Aortic-root enlargement was measured as change in the maximum aortic-root-diameter z score indexed to body-surface area. Randomized assignment to atenolol or losartan had these effects on that measure and other secondary outcomes: “From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5 ± 6.5 years in the atenolol group and 11.0 ± 6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (± SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (−0.139 ± 0.013 and −0.107 ± 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.” (R. V. Lacro, ron.lacro@cardio.chboston.org)
Noting that these findings differ from previous animal and clinical studies, editorialists write that this study “will stimulate healthy discussion about future directions in research and treatment” (
pp. 2127–8): “These findings indicate that clinicians should continue to consider beta-blockers to be the primary medical therapy for aortic protection in Marfan’s syndrome. Losartan appears to be a reasonable treatment option, especially in patients who cannot take beta-blockers. The risk of harm from losartan appears to be very low, but its efficacy needs to be firmly established before it becomes a first-line therapy.” (J. M. Bowen)

>>>Lancet Highlights
Source:
Nov. 29 issue of Lancet (2014; 383).
Alteplase for Acute Ischemic Stroke: While increasing patients’ risk of early death from intracranial hemorrhage by about 2%, use of alteplase within the first 3.0–4.5 hours after stroke onset is associated with 5%–10% reductions in disability-free survival at 3–6 months, a meta-analysis of 9 trials of 6,756 patients shows (pp. 1929–35). “Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3.0 h resulted in a good outcome for 259 (32.9%) of 787 patients who received alteplase versus 176 (23.1%) of 762 who received control (OR 1.75, 95% CI 1.35–2.27); delay of greater than 3.0 h, up to 4.5 h, resulted in good outcome for 485 (35.3%) of 1,375 versus 432 (30.1%) of 1,437 (OR 1.26, 95% CI 1.05–1.51); and delay of more than 4.5 h resulted in good outcome for 401 (32.6%) of 1,229 versus 357 (30.6%) of 1166 (OR 1.15, 95% CI 0.95–1.40).… Despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3.0 h and about 5% for patients treated after 3.0 h, up to 4.5 h.” (C. Baigent, colin.baigent@ctsu.ox.ac.uk)

>>>PNN JournalWatch
* Recognition and Management of Withdrawal Delirium (Delirium Tremens), in
New England Journal of Medicine, 2014; 371: 2109–13. (M. A. Schuckit, mschuckit@ucsd.edu)
* Effects of Intensive Glycaemic Control on Ischaemic Heart Disease: Analysis of Data From the Randomised, Controlled ACCORD Trial, in
Lancet, 2014; 384: 1936–41. (H. C. Gerstein, gerstein@mcmaster.ca)
* Medication Adherence Among Pediatric Patients With Sickle Cell Disease: A Systematic Review, in
Pediatrics, 2014; 134: 1175–83. (K. E. Walsh)
* Variation in Antimicrobial Prescribing for Otitis Media by Race: Different Wrinkle in Disparity?, in
Pediatrics, 2014; 134: 1204–6. (C. R. Woods)
* Meta-Analysis of Assay Sensitivity and Study Features in Clinical Trials of Pharmacologic Treatments for Osteoarthritis Pain, in
Arthritis & Rheumatology, 2014; 66: 3327–36. (R. H. Dworkin)
* Dietary Intervention in Patients With Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Clinical Trials on Maternal and Newborn Outcomes, in
Diabetes Care, 2014; 37: 3345–55. (L. V. Viana, vercoza@yahoo.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 © 2014, 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
Dec. 2, 2014 * Vol. 21, No. 231
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 2 issue of the Annals of Internal Medicine (2014; 161).
The Socioeconomics of Rehospitalizations: Medicare beneficiaries residing in disadvantaged areas had higher rehospitalization rates following discharge for congestive heart failure, pneumonia, or myocardial infarction in 2004–09, a study shows (pp. 765–74). Analysis of a 5% random sample of 255,744 Medicare patients showed these patterns based the Singh validated area deprivation index (ADI) of their neigborhoods: “The 30-day rehospitalization rate did not vary significantly across the least disadvantaged 85% of neighborhoods, which had an average rehospitalization rate of 21%. However, within the most disadvantaged 15% of neighborhoods, rehospitalization rates increased from 22% to 27% with worsening ADI. This relationship persisted after full adjustment, with the most disadvantaged neighborhoods having a rehospitalization risk (adjusted risk ratio, 1.09 [95% CI, 1.05 to 1.12]) similar to that of chronic pulmonary disease (adjusted risk ratio, 1.06 [CI, 1.04 to 1.08]) and greater than that of uncomplicated diabetes (adjusted risk ratio, 0.95 [CI, 0.94 to 0.97]).” Based on these findings, the authors conclude, “Measures of neighborhood disadvantage, such as the ADI, could potentially be used to inform policy and care after hospital discharge.” (A. J. H. Kind, ajk@medicine.wisc.edu)
Reflecting on this and a study of the effect of clinical and social risk factors on hospital readmissions (
pp. 775–84; S. Keyhani, salomeh.keyhani@va.gov), editorialists “stress that quality assessment should reflect how well hospitals care for their patients regardless of financial circumstances” (pp. 833–4; H. M. Krumholz, harlan.krumholz@yale.edu).
Glycemic Control in Midlife & Cognitive Function: In the community-based ARIC (Atherosclerosis Risk in Communities) study, diabetes prevention and glycemic control in midlife were associated with less cognitive decline in late life, researchers report (pp. 785–93). The prospective cohort study included 13,351 adults aged 48–67 years at baseline in 1990–92. Longitudinal monitoring of glycosylated hemoglobin and cognitive function showed the following: “Diabetes in midlife was associated with a 19% greater cognitive decline over 20 years (adjusted global Z-score difference, −0.15 [;95% CI, −0.22 to −0.08]Winking compared with no diabetes. Cognitive decline was significantly greater among persons with prediabetes (HbA1c level of 5.7% to 6.4%) than among those with an HbA1c level less than 5.7%. Participants with poorly controlled diabetes (HbA1c level ≥7.0%) had greater decline than those whose diabetes was controlled (adjusted global Z-score difference, −0.16; P = 0.071). Longer-duration diabetes was also associated with greater late-life cognitive decline (P for trend < 0.001). Rates of decline did not differ significantly between white and black persons (P for interaction = 0.44).” (E. Selvin, lselvin@jhsph.edu)
Health Information Exchange Use & Effects: While research into the use and effects of health information exchange (HIE) is limited, use of the technology is linked to lower emergency department usage or costs, according to a systematic review of 12 studies (pp. 803–11). Describing the quality of the evidence as “low,” the authors write: “Direct evidence that HIEs were used by providers was reported in 21 studies involving 13 distinct HIE organizations, 6 of which were located in New York, and generally showed usage in less than 10% of patient encounters. Findings from 17 studies of sustainability suggest that approximately one quarter of existing HIE organizations consider themselves financially stable. Findings from 38 studies about attitudes and barriers showed that providers, patients, and other stakeholders consider HIE to be valuable, but barriers include technical and workflow issues, costs, and privacy concerns.” (R. S. Rudin, rrudin@rand.org)

>>>PNN NewsWatch
* A $15 million Center for Medicare & Medicaid Innovation Health Care Innovation Award to Community Care of North Carolina will be used by Joe Moose, PharmD, and colleagues to assess community pharmacy’s role in reducing health care costs, pharmacist.com reports.
*
Correction: In yesterday’s PNN, the Lancet article should have stated that disability-free survival at 3–6 months is increased, not reduced, with alteplase treatment of ischemic stroke.

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 © 2014, 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
Dec. 3, 2014 * Vol. 21, No. 232
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 3 issue of JAMA (2014; 312).
Cation Exchange in Hyperkalemia: In the Phase III HARMONIZE trial of 258 patients with hyperkalemia, “open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours,” compared with placebo, researchers report (pp. 2223–33). Those patients responding to treatment (n = 237) participated in a dose-ranging study using 5, 10, or 15 g daily for 28 days. Results showed: “Compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes.” (M. Kosiborod, mkosiborod@saint-lukes.org)
Zirconium cyclosilicate is “an important new treatment for managing patients with hyperkalemia,” editorialists write, but “many questions remain” (
pp. 2217–8). “The long-term effects and tolerability of zirconium cyclosilicate are unknown, and whether long-term therapy would reduce mortality or allow increased use of [renin–angiotensin–aldosterone system] blockade remains to be determined. Zirconium cyclosilicate is a cation exchanger, delivering a small load of sodium equivalent to potassium removed. Even though no change in blood pressure or urinary sodium excretion was observed in this study, patients receiving higher doses of zirconium cyclosilicate had increased rates of edema and the long-term implications of this adverse effect need to be monitored. Higher dietary intake of potassium is known to lower blood pressure in hypertensive patients and has been associated with lower risk of stroke in the general population but increased risk of mortality in patients with end-stage kidney disease. The effect of zirconium cyclosilicate on this relationship also will need to be defined.” (B. S. Dixon, bradley-dixon@uiowa.edu)
Fenoldopam for Acute Kidney Injury After Cardiac Surgery: The selective dopamine D1 agonist fenoldopam failed to avert the need for renal replacement therapy or risk of 30-day mortality in a trial of 667 patients with acute kidney injury, a study shows (pp. 2244–53). Compared with placebo, fenoldopam increased rates of hypertension, the authors note, adding these details from 2008–13 at 19 Italian cardiovascular intensive-care units: “The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001).” (G. Landoni, landoni.giovanni@hsr.it)
Perioperative Aspirin, Clonidine & Surgical Acute Kidney Injury: Rates of acute kidney injury associated with noncardiac surgery were not affected by perioperative use of aspirin or clonidine, according to a study of patients at 88 centers in 22 countries (pp. 2254–64). Results from the placebo-controlled trial of aspirin for up to 30 days and/or clonidine for 72 hours after surgery showed the following: “Aspirin (n  =  3,443) vs placebo (n  =  3,462) did not alter the risk of acute kidney injury (13.4% vs 12.3%, respectively; adjusted relative risk, 1.10; 95% CI, 0.96–1.25). Clonidine (n  =  3,453) vs placebo (n  =  3,452) did not alter the risk of acute kidney injury (13.0% vs 12.7%, respectively; adjusted relative risk, 1.03; 95% CI, 0.90–1.18). Aspirin increased the risk of major bleeding. In a post hoc analysis, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3% when bleeding was present vs 12.3% when bleeding was absent; adjusted hazard ratio, 2.20; 95% CI, 1.72–2.83). Similarly, clonidine increased the risk of clinically important hypotension. In a post hoc analysis, clinically important hypotension was associated with a greater risk of subsequent acute kidney injury (14.3% when hypotension was present vs 11.8% when hypotension was absent; adjusted hazard ratio, 1.34; 95% CI, 1.14–1.58).” (A. X. Garg, amit.garg@lhsc.on.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 © 2014, 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
Dec. 4, 2014 * Vol. 21, No. 233
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Dec. 4 issue of the New England Journal of Medicine (2014; 371).
Phase I Ebola Vaccine Trial: In 20 healthy adults, a replication-defective recombinant chimpanzee adenovirus type 3–vectored ebolavirus vaccine (cAd3-EBO) produced immune reactions with minimal adverse effects, an NIH research team reports (10.1056/NEJMoa1410863). Results from the sequentially enrolled, dose-escalation trial showed the following: “In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2 × 1011 particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2 × 1011 particle-unit dose than in the group that received the 2 × 1010 particle-unit dose (geometric mean titer against the Zaire antigen, 2037 vs. 331; P = 0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2 × 1011 particle-unit dose than among those who received the 2 × 1010 particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P = 0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P = 0.07).” (J. E. Ledgerwood, ledgerwood@mail.nih.gov)
Despite these positive findings, “difficult decisions on the best dosage and [efficacy] trial design await,” an editorialist writes (
10.1056/NEJMe1414305): “Can traditional phase 2 and 3 efficacy trials be performed in West Africa given the many ethical considerations, community expectations regarding the use of a placebo, and projected vaccine supply? Should the cAd3 and VSV vaccines be compared head-to-head? What should be the target population? And can it all be arranged in time for a human trial, or will we ultimately need to turn to the Food and Drug Administration Animal Rule? The road is still long and there are many challenges, but we are nevertheless one step closer to a solution.” (D. G. Bausch)
Dual Antiplatelet Therapy After Drug-Eluting Stents: Similar to other recently published trials, a study presented at the Am. Heart Assoc. meeting (see PNN, Nov. 19; also see similar trials reported on Nov. 3 and 14) shows that dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent showed benefits but also an increased risk of death (pp. 2155–66). DAPT study investigators randomized patients after 12 months with clopidogrel or prasugrel and aspirin to continue the thienopyridine treatment or placebo for 18 months, with these results: “A total of 9,961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P <0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P <0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P <0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P = 0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P = 0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.” (L. Mauri, lmauri1@partners.org)

>>>PNN NewsWatch
* After 6 years of discussion, FDA yesterday officially scrapped the ABCDX classification of pregnancy and lactation risks, replacing it with three subsections in product labeling of drugs and biologic agents: pregnancy, lactation, and females and males of reproductive potential. The rule takes effect on June 30, 2015; drugs and biologics approved after that date will have the new sections, and labeling for existing agents will be revised gradually, FDA said.
*
Blinatumomab (Blincyto, Amgen), the first anti-CD19 agent, received an accelerated approval from FDA for treatment of the rare Philadelphia chromosome–negative precursor B-cell acute lymphoblastic leukemia. In 185 adults, 32% had complete remission for 6.7 months.

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 © 2014, 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
Dec. 5, 2014 * Vol. 21, No. 234
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. issue of Diabetes Care (2014; 37).
Economic Burden of Elevated Blood Glucose Levels: Prediabetes and diabetes now account for more than $1,000 per American in excess medical costs and reduced productivity, an analysis shows, demonstrating the “importance of finding ways to reduce the burden of prediabetes and diabetes through prevention and treatment,” conclude authors (pp. 3172–9). Using three large data sources for commercially insured patients, Medicare beneficiaries, and those discharged from hospitals, the investigators calculated these costs for 2012: “The economic burden associated with diagnosed diabetes (all ages) and undiagnosed diabetes, gestational diabetes, and prediabetes (adults) exceeded $322 billion in 2012, consisting of $244 billion in excess medical costs and $78 billion in reduced productivity. Combined, this amounts to an economic burden exceeding $1,000 for each American in 2012. This national estimate is 48% higher than the $218 billion estimate for 2007. The burden per case averaged $10,970 for diagnosed diabetes, $5,800 for gestational diabetes, $4,030 for undiagnosed diabetes, and $510 for prediabetes.” (T. M. Dall, tim.dall@ihs.com)
These data provide “information that is vitally important for the policy makers for each state to know and reflect upon and then to consider and enact effective policies to address the situation,” editorialists write (
pp. 3137–8). “How much more information do we need in order to act at a local, state, and federal level? The crisis is worsening—the time to act is now. These data clearly should signal a call for action.” (W. T. Cefalu, cefaluwt@pbrc.edu)

>>>Pharmacotherapy Report
Source:
Early-release article from Pharmacotherapy (2014; 34).
New Drugs of Abuse: Authors review “clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom” (10.1002/phar.1522): “Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases.” (M. A. Rech, mrech@lumc.edu)

>>>Circulation Highlights
Source:
Dec. 2 issue of Circulation (2014; 130).
Cannabis-Associated Angiopathy: The case of a 42-year-old man with crescendo transient ischemic attacks manifest as right hemiparesis illustrates the arterial complications of cannabis use, researchers report (pp. 2069–70). The patient has used cannabis daily for more than 20 years when he developed symptoms over a period of less than 48 hours. Multifocal intracranial stenosis was evident on MRI and sonography that affected the bilateral middle and left posterior cerebral arteries. The patient was hospitalized for 4 days and discharged on antiplatelet therapy with aspirin 100 mg daily and instructions to discontinue cannabis use. Neuroimaging at 3 months showed complete reversal of the stenosis. (G. Tsivgoulis, tsivgoulisgiorg@yahoo.gr)

>>>PNN NewsWatch
* FDA has approved a new indication for ruxolitinib (Jakafi, Incyte Corp.): treatment of patients with polycythemia vera who do not respond adequately to or cannot tolerate hydroxyurea.
*
FDA has resolved criminal and civil actions related to interstate shipment of compounded methylprednisolone in 2013 by Main Street Family Pharmacy in Newbern, TN. The pharmacy’s owner, David A. Newbaker, and the LLC pharmacy each pleaded guilty to single counts of misdemeanor criminal violations of federal drug laws.

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 © 2014, 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
Dec. 8, 2014 * Vol. 21, No. 235
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 6 issue of Lancet (2014; 384).
Ponesimod in Chronic Plaque Psoriasis: The oral sphingosine 1-phosphate receptor 1 modulator ponesimod provided “significant clinical benefit” in patients with chronic plaque psoriasis at week 16 and during maintenance therapy, a study shows (pp. 2036–45). In this Phase II trial, patients with psoriasis area and severity index (PASI) scores higher than 10 received ponesimod 20 or 40 mg or placebo once daily for 16 weeks. Responders were randomized a second time to maintenance ponesimod therapy or placebo. Results showed: “Of 326 patients initially randomised (20 mg ponesimod n = 126, 40 mg ponesimod n = 133, and placebo n = 67) PASI75 was achieved at week 16 in 58 (46.0%), 64 (48.1%), and nine (13.4%), respectively. The treatment effect was significant for the two ponesimod doses (both p <0.0001). Of 219 patients who entered the maintenance period, PASI75 was achieved by week 28 in 35 (71.4%) of 49 who continued on 20 mg ponesimod and 41 (77.4%) of 53 on 40 mg ponesimod, and in 19 (42.2%) of 45 who swapped from 20 mg to placebo and 19 (40.4%) of 47 from 40 mg to placebo. Ponesimod was associated with dyspnoea, raised liver enzyme concentrations, and dizziness.” (D. D’Ambrosio, daniele.dambrosio@actelion.com)
Chikungunya Virus-Like Particle Vaccine Safety: An open-label Phase I trial demonstrates immunogenicity, safety, and tolerability of chikungunya virus-like particle vaccine in 25 healthy adults (pp. 2046–52). Participants received vaccinations in three sequential dose groups at weeks 0, 4, and 20, with follow-up through week 44. Results showed: “All injections were well tolerated, with no serious adverse events reported. Neutralising antibodies were detected in all dose groups after the second vaccination (geometric mean titres of the half maximum inhibitory concentration: 2,688 in the 10 µg group, 1,775 in the 20 µg group, and 7,246 in the 40 µg group), and a significant boost occurred after the third vaccination in all dose groups (10 µg group p = 0.0197, 20 µg group p <0.0001, and 40 µg group p <0.0001). 4 weeks after the third vaccination, the geometric mean titres of the half maximum inhibitory concentration were 8,745 for the 10 µg group, 4,525 for the 20 µg group, and 5,390 for the 40 µg group.” (J. E. Ledgerwood, ledgerwood@mail.nih.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 349).
Asthma & Prenatal, Early-Life Antibiotic Exposure: Analysis of Swedish children born in 2006–10 shows that associations of asthma and antibiotic exposure in utero and during early life can be explained by confounding factors that are shared within families, researchers report (g6979). In a nationwide prospective population-based cohort study, 493,785 children (180,894 of whom were eligible for sibling analyses), investigators found these patterns for antibiotic and asthma medications prescriptions: “Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55).” (A. K. Örtqvist, Anne.ortqvist@ki.se)

>>>PNN JournalWatch
* Clinical Approach and Management for Selected Fungal Infections in Pulmonary and Critical Care Patients, in
Chest, 2014; 146: 1658–66. (A. H. Limper, limper.andrew@mayo.edu)
* Where There Is Smoke…There Is Sleep Apnea: Exploring the Relationship Between Smoking and Sleep Apnea, in
Chest, 2014; 146: 1673–80. (V. Krishnan, vkrishnan@metrohealth.org)
* Perioperative Beta Blockade in Noncardiac Surgery: A Systematic Review for the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, in
Journal of the American College of Cardiology, 2014; 64: 2406–25. (reprints@elsevier.com)
* 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, in
Circulation, 2014; 130: e199–267. (C. T. January)

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 © 2014, 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
Dec. 9, 2014 * Vol. 21, No. 236
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. issue of JAMA Internal Medicine (2014; 174).
Treatment of Community-Acquired Pneumonia: Compared with a beta-lactam–macrolide regimen, beta-lactam monotherapy failed to achieve noninferiority in a trial of 580 immunocompetent adults with moderately severe community-acquired pneumonia (pp. 1894–901). Conducted at six acute care Swiss hospitals, the trial used open-label, randomized assignment of participants to identify these outcomes in 2009–13: “After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13–0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59–1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80–1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82–1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.” (N. Garin)
Pharmacogenomic Evidence & FDA Labeling: Biomarker testing recommendations made in FDA-approved labeling “may be premature,” according to an analysis of the clinical evidence supporting the advice (pp. 1938–44). The authors identified drug labels describing use of a biomarker and assessed the supporting evidence for its clinical validity and utility. Results showed: “Of the 119 drug-biomarker combinations, only 43 (36.1%) had labels that provided convincing clinical validity evidence, whereas 18 (15.1%) provided convincing evidence of clinical utility. Sixty-one labels (51.3%) made recommendations about how clinical decisions should be based on the results of a biomarker test; 36 (30.3%) of these contained convincing clinical utility data. A full description of supporting studies was included in 13 labels (10.9%).” (B. Wang)
Buprenorphine Taper in Prescription Opioid Dependence: Ongoing buprenorphine maintenance therapy proved more efficacious than tapered dosing in a 14-week trial of 113 patients with prescription opioid dependence, researchers report (pp. 1947–54). In 2009–13, illicit opioid use determined by urinalysis and patient report was as follows in maintenance and taper groups: “During the trial, the mean percentage of urine samples negative for opioids was lower for patients in the taper group (35.2% [95% CI, 26.2%–44.2%]) compared with those in the maintenance group (53.2% [95% CI, 44.3%–62.0%]). Patients in the taper group reported more days per week of illicit opioid use than those in the maintenance group once they were no longer receiving buprenorphine (mean use, 1.27 [95% CI, 0.60–1.94] vs 0.47 [95% CI, 0.19–0.74] days). Patients in the taper group had fewer maximum consecutive weeks of opioid abstinence compared with those in the maintenance group (mean abstinence, 2.70 [95% CI, 1.72–3.75] vs 5.20 [95% CI, 4.16–6.20] weeks). Patients in the taper group were less likely to complete the trial (6 of 57 [11%] vs 37 of 56 [66%]; P < .001). Sixteen patients in the taper group reinitiated buprenorphine treatment after the taper owing to relapse.” (D. A. Fiellin)
Antidiabetic Drug Choices: The recommended initial agent for diabetes, metformin is begun in only 57.8% of newly diagnosed patients, according to a retrospective cohort study of patients in the Aetna database for 2009–13 (pp. 1955–62). Risks of addition of a second agent or intensification of therapy were associated with initial use of medications other than metformin, the study found. “These findings have significant implications for quality of life and medication costs,” the group concludes. (S. A. Berkowitz)

>>>PNN NewsWatch
* The ASHP Midyear Clinical Meeting is under way in Anaheim, CA. Free live CPE programs are available today and tomorrow at ashp.org as part of the ASHP Advantage offerings; all begin at 11:30 a.m. EST.

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 © 2014, 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
Dec. 10, 2014 * Vol. 21, No. 237
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Dec. 15 issue of Clinical Infectious Diseases (2014; 59).
HCV Resistance to MK-5172/Pegylated Interferon/Ribavirin: Data from a Phase II trial of the protease inhibitor MK-5172 provides insights into the mechanisms of virologic failure in patients with hepatitis C virus (HCV) genotype 1 infection (pp. 1657–65). Study participants were treatment-naive and noncirrhotic when they received various doses of MK-5172 plus pegylated interferon alfa/ribavirin (peg-IFN/RBV): “Six of 266 (2.3%) MK-5172 recipients satisfied prespecified criteria for virologic failure, all with genotype 1a infection. Five patients with virologic failure were in the MK-5172 100-mg arm, including 4 patients with low plasma MK-5172 levels documented during triple therapy. Variants associated with >4-fold loss of potency were detected in 3 of the 4 patients with genotype 1a breakthrough while on MK-5172. The fifth patient had undetectable HCV-RNA levels at the end of triple therapy but subsequently broke through during the peg-IFN/RBV tail 16 weeks after completion of MK-5172. Three patients had D168 variants at virologic failure, including 2 with the D168A variant associated with a 95-fold loss of potency. The sole apparent relapse was actually a genotype 3a reinfection in the MK-5172 200-mg group.” (A. Y. M. Howe, anita_howe@merck.com)
Procalcitonin in Chronic Kidney Disease: Noting that “procalcitonin (PCT) has been shown to be a useful surrogate marker in identifying patients with various bacterial infections,” authors discuss use of PCT in patients with chronic kidney disease or renal replacement therapy (pp. 1761–7): “PCT has been studied as a diagnostic marker in differentiating bacterial pneumonia from other respiratory conditions such as chronic obstructive pulmonary disease exacerbations or viral pneumonia. Differentiating bacterial from nonbacterial pneumonia using PCT has shown to reduce antibiotic usage, length of stay, and antibiotic-related adverse effects. PCT has also been studied in patients with sepsis in an effort to reduce unnecessary antibiotic usage and decrease the length of antibiotic therapy. This article focuses on the use of PCT in patients with various degrees of chronic kidney disease in addition to various forms of dialysis, as chronic kidney disease may alter baseline levels of PCT and thus result in inappropriate use of PCT in this population.” (E. Grace, eegrace@presby.edu)

>>>Oncology Highlights
Source:
Dec. 10 issue of the Journal of Clinical Oncology (2014; 32).
Treatment of Breast Cancer in Premenopausal Women: In premenopausal women with axillary node-negative, hormone receptor–positive breast cancer tumors measuring 3 cm or less, ovarian function suppression (OFS) plus tamoxifen produced “more menopausal symptoms and sexual dysfunction,” contributing “to inferior self-reported health-related quality of life,” researchers report (pp. 3948–58). The study, closed early, was underpowered to reach conclusions about survival; available results showed the following: “In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for [disease-free survival] (5-year rate: 87.9% v 89.7%; log-rank P = .62) or [overall survival] (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up.” (A. J. Tevaarwerk, at4@medicine.wisc.edu)
Amrubicin in Small-Cell Lung Cancer: The third-generation anthracycline and topoisomerase II inhibitor amrubicin “did not improve survival when compared with topotecan in the second-line treatment of patients with” small-cell lung cancer (SCLC), a study shows (pp. 4012–9). Among 637 patients with refractory or sensitive SCLC, these efficacy results were noted: “Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001).” (J. von Pawel, j.pawel@asklepios.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 © 2014, 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
Dec. 11, 2014 * Vol. 21, No. 238
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 11 New England Journal of Medicine (2014; 371).
Angiotensin Blockade in Autosomal-Dominant Polycystic Kidney Disease: Two articles and an editorial examine management of hypertension in patients with autosomal-dominant polycystic kidney disease (ADPKD).
Compared with standard blood-pressure control in 558 patients with early ADPKD, “rigorous blood-pressure control” with lisinopril and telmisartan “was associated with a slower increase in total kidney volume, no overall change in the estimated [glomerular filtration rate (GFR)], a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion,” investigators conclude (
pp. 2255–66). They note that dizziness and lightheadedness were more common among those with a low blood-pressure target range (95/60 to 110/75 mm Hg) than among those with standard targets (120/70 to 130/80 mm Hg). (R. W. Schrier, robert.schrier@ucdenver.edu)
In 486 patients with late ADPKD and stage 3 kidney disease, monotherapy with ACE inhibitors was as effective as combination therapy with an angiotensin II receptor blocker (ARB), researchers report (
pp. 2267–76). Based on a composite primary outcome of time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR, lisinopril with or without telmisartan produced these results: “There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril–telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups.” (V. E. Torres, torres.vicente@mayo.edu)
“These two studies provide important guidance for the care of patients with ADPKD,” write editorialists (
pp. 2329–31). “They show that blood pressure can be controlled with ACE inhibitors, drugs that have an acceptable safety profile. They suggest that rigorous blood-pressure control, early in the disease process, may slow cyst growth and reduce the left-ventricular-mass index, but this approach is complicated by increased dizziness. The studies again dissociate kidney-volume growth from a decline in renal function, emphasizing the importance of hard outcomes in clinical trials involving patients with ADPKD. Despite these limitations, the studies indicate that, with careful medical care, including meticulous attention to blood pressure, the prognosis for patients with ADPKD remains good.” (D. H. Ellison)
Achieving Health Equity: Responding to articles with mixed results on racial and ethnic disparities among Medicare Advantage Plan enrollees (pp. 2288–97; J. Z. Ayanian, ayanian@umich.edu), and quality and equity of care in U.S. hospitals (pp. 2298–308; A. N. Trivedi, amal_trivedi@brown.edu), an editorialist makes these points (pp. 2331–2): “These divergent findings illustrate that reducing racial and ethnic disparities in health outcomes is more difficult than simply standardizing the care provided to patients. Indeed, although it is a positive step that improvements are being made in processes of care in hospitals, providing standardized care for a limited set of inpatient measures is unlikely to lead to equity in health outcomes. Inpatient processes, such as the administration of aspirin, represent a narrow slice of time and depend primarily on technical actions of the health care team rather than on patients. In comparison, to improve outcomes such as control of blood pressure, cholesterol, and glucose, clinicians must work closely with patients over a period of years to ensure that they take their medications, consume healthful diets, and are physically active.” (M, H. Chin)

>>>PNN NewsWatch
* FDA has licensed Human Papillomavirus 9-valent Vaccine, Recombinant (Gardasil 9, Merck Sharp & Dohme), increasing by five the number of HPV types covered by immunization. The product is approved for use in females ages 9 through 26 and males ages 9 through 15 for prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58, and for prevention of genital warts caused by HPV types 6 or 11. It has the potential to prevent 90% of these cancers.

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 © 2014, 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
Dec. 12, 2014 * Vol. 21, No. 239
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Dec. issue of the Journal of Allergy and Clinical Immunology (2014; 134).
Asthma Control & Medicine Beliefs: Among urban minority adults, negative beliefs about inhaled corticosteroids (ICSs) and positive views about complementary and alternative medicine (CAM) were associated uncontrolled asthma, researchers report (pp. 1252–9). A psychometric instrument used for testing 304 adults and 33 audio-recorded primary care visits provided these results: “Psychometric testing of the instrument identified 17 items representing ICS beliefs (alpha = .59) and CAM endorsement (alpha = .68). Test–retest analysis demonstrated a high level of reliability (intraclass correlation coefficient = 0.77 for CAM items and 0.79 for ICS items). We found high rates of CAM endorsement (93%), negative ICS beliefs (68%), and uncontrolled asthma (69%). CAM endorsement was significantly associated with uncontrolled asthma (P = .04). Qualitative data analysis provided preliminary evidence for the instrument’s clinical utility in that knowledge of ICS beliefs and CAM endorsement prompted providers to initiate discussions with patients.” The authors conclude, “A brief self-administered instrument that identifies beliefs and behaviors that likely undermine ICS adherence might be a leveraging tool to change the content of communications during clinic visits.” (M. George, mgeorge@nursing.upenn.edu)
Adherence & Inhaler Reminders: Compared with behavioral intervention or standard care, inhaler reminders were effective for improving medication adherence among patients with uncontrolled asthma who were seen in a primary care clinic (pp. 1260–8.e3). The 6-month cluster-randomized trial test two brief general practitioner (GP)–delivered interventions aimed at improving adherence and asthma control: inhaler reminders and feedback (IRF) and/or personalized adherence discussions (PADs). Compared with usual care, these interventions produced the following results among patients with suboptimal Asthma Control Test (ACT) scores: “A total of 43 GPs enrolled 143 patients with moderate-severe asthma (mean age, 40.3 ± 15.2 years; ACT score, 14.6 ± 3.8; fluticasone propionate dose, 718 ± 470 µg). Over 6 months, adherence was significantly higher in the IRF group than in non-IRF groups (73% ± 26% vs 46% ± 28% of prescribed daily doses; P < .0001), but not between PAD and non-PAD groups. Asthma control improved overall (mean change in ACT score, 4.5 ± 4.9; P < .0001), with no significant difference among groups (P = .14). Severe exacerbations were experienced by 11% of the patients in IRF groups and 28% of the patients in non-IRF groups (P = .013; after adjustment for exacerbation history; P = .06).” (J. M. Foster, j.m.foster@woolcock.org.au)

>>>Chest Highlights
Source:
Dec. issue of Chest (2014; 146).
Statins in the ICU: Authors of a point/counterpoint exchange debate the wisdom of continuing or stopping statin therapy in patients admitted to intensive-care units (pp. 1431–3, 1433–5, 1435–6, 1436–7). Proponents of continuing statins argue this prevents “unintentional discontinuation of medications for chronic disease,” which they say “is a risk with hospitalization and an even greater risk with ICU admission.” They also maintain that statins could influence short-term outcomes of some critical illnesses. Taking the opposing view, a second set of authors writes, “For most critical illnesses, there is insufficient evidence to warrant continuation of treatment with statins in the ICU setting” and conclude that the drugs could be unsafe and ineffective. The proponents disagree, but the countering authors conclude, “Over the past decades, we have been baited with mechanistically promising antiinflammatory and other treatments, such as anti-tumor necrosis factor therapies, IL-1ra, and drotrecogin alfa, which have all failed to benefit patients. We are, sadly, left without specific therapies for common critical illnesses, such as sepsis or [acute respiratory distress syndrome]. Understandably, we are eager for new therapies.” (A. H. Flannery, alex.flannery@uky.edu; S. Q. Simpson, ssimpson3@kumc.edu)

>>>PNN NewsWatch
* FDA has approved the first clinical test for confirming the presence of human T-cell lymphotropic virus-I/II antibodies, the MP Diagnostics HTLV Blot 2.4.

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 © 2014, 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
Dec. 15, 2014 * Vol. 21, No. 240
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 13 issue of Lancet (2014; 384).
Meningococcal Vaccines & Carriage Rates: In a Phase III trial of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination, meningococcal carriage rates in 18–24-year-olds were not reduced at 1 month after vaccinations, but were lower during 12 months after vaccination, suggesting a herd effect that might affect transmission if vaccination were widely implemented (pp. 2123–31). Based on a primary outcome of cross-sectional carriage of meningococci as determined by oropharyngeal swabs, the researchers found these effects of vaccination: “Between Sept 21 and Dec 21, 2010, 2,954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1.2, 95% CI 0.8–1.7) or MenACWY-CRM (0.9, [0.6–1.3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18.2% [95% CI 3.4–30.8] carriage reduction), capsular groups BCWY (26.6% [10.5–39.9] carriage reduction), capsular groups CWY (29.6% [8.1–46.0] carriage reduction), and serogroups CWY (28.5% [2.8–47.5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39.0% (95% CI 17.3–55.0) carriage reduction for serogroup Y and 36.2% (15.6–51.7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified.” (R. C. Read, R.C.Read@soton.ac.uk)
Impetigo Treatments in Endemic Settings: A short course of oral trimethoprim–sulfamethoxazole (co-trimoxazole) proved noninferior to intramuscular benzathine benzylpenicillin in a trial of indigenous Australian infants and children with purulent or crusted non-bullous impetigo (pp. 2132–40). Block randomization to once- or twice-daily oral co-trimoxazole or a single dose of intramuscular benzathine benzylpenicillin yielded these results: “Between Nov 26, 2009, and Nov 20, 2012, 508 patients were randomly assigned to receive benzathine benzylpenicillin (n = 165 [156 analysed]), twice-daily co-trimoxazole for 3 days (n = 175 [173 analysed]), or once-daily co-trimoxazole for 5 days (n = 168 [161 analysed]). Treatment was successful in 133 (85%) children who received benzathine benzylpenicillin and 283 (85%) who received pooled co-trimoxazole (absolute difference 0.5%; 95% CI −6.2 to 7.3), showing non-inferiority of co-trimoxazole (10% margin). Results for twice-daily co-trimoxazole for 3 days and once-daily co-trimoxazole for 5 days were similar. Adverse events occurred in 54 participants, 49 (90%) of whom received benzathine benzylpenicillin.” (A. C. Bowen, asha.bowen@menzies.edu.au)

>>>PNN NewsWatch
* FDA on Friday expanded the approved indications of ramucirumab (Cyramza, Lilly) to include treatment of patients with metastatic nonsmall-cell lung cancer.

>>>PNN JournalWatch
* Establishing School-Centered Asthma Programs, in
Journal of Allergy and Clinical Immunology, 2014; 134: 1223–30. (S. J. Szefler, stanley.szefler@childrenscolorado.org)
* Surrogate Outcomes for ESRD Risk: The Case for a 30% Reduction in Estimated GFR Over 2 Years, in
American Journal of Kidney Diseases, 2014; 64: 845–7. (J. M. Sontrop, jsontro@uwo.ca)
* Advances in Therapy for HIV/Hepatitis C Virus–Coinfected Patients in the Liver Transplant Setting, in
Clinical Infectious Diseases, 2014; 60: 108–16. (N. A. Terrault, norah.terrault@ucsf.edu)
* Development and Future of the American Society of Clinical Oncology’s Quality Oncology Practice Initiative, in
Journal of Clinical Oncology, 2014; 32: 3907–13. (D. W. Blayney, dblayney@stanford.edu)
* Functional Disorders in the Neurology Section of
ICD-11: A Landmark Opportunity, in Neurology, 2014; 83: 2299–301. (J. Stone, Jon.Stone@ed.ac.uk)
* Keeping Kidneys Safe: The Pharmacist’s Role in NSAID Avoidance in High-Risk Patients, in
Journal of the American Pharmacists Association, 2015; 55: e15–e25. (A B. Pai)

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 © 2014, 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
Dec. 16, 2014 * Vol. 21, No. 241
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Dec. issue of the American Journal of Psychiatry (2014; 171).
Biomarker for Antidepressant Response: Patient levels of C-reactive protein (CRP) may provide “an accessible peripheral blood biomarker” that could be used in personalizing the choice of antidepressants in major depressive disorder, a study concludes (pp. 1278–86). In the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, CRP was measured in 241 adult men and women with major depressive disorder who were randomly allocated to escitalopram or nortriptyline therapy. Results on the Montgomery-Åsberg Depression Rating Scale (MADRS) showed the following: “CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: beta = 3.27, 95% CI = 1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome.” (R. Uher)
Brain Methylation in Antidepressant Pharmacogenetics: In a study of 232 first-generation Mexican Americans with major depressive disorder, pharmacogenetic variation that affects a brain-methylation site was associated with differences in responses to antidepressants, researchers report (pp. 1297–309). During 8 weeks of treatment with desipramine 50–200 mg/d or fluoxetine 10–40 mg/d, outcome measures on the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory showed these patterns: “Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral = 0.95).” (M-L Wong)

>>>Neurology Report
Source:
Dec. issue of Neurology (2014; 83).
Biomarkers for Migraine in Older Adults: Adiponectin levels were higher in older men and women with migraine than in control patients, a study shows, but after adjustment, the prevalence of migraine “was significantly associated with total adiponectin only in older men, suggesting the association may be confounded or absent in older women” (pp. 2211–8). In the case–control Atherosclerosis Risk in Communities Study, adiponectin and leptin levels were monitored beginning at visit 1 in 1987–89, and a standardized headache questionnaire was administered in 1993–95. Longitudinal results showed the following: “Of the 981 participants, the mean age at baseline was 52.8 years (SE 0.3); 131 fulfilled migraine criteria. Crude, mean total adiponectin levels were greater in men and women with migraine (8.1 µg/mL, SE 0.5) as compared to those without migraine (7.0 µg/mL, SE 0.2) (p = 0.031). After adjustments, the odds of migraine were increased by 88% with each SD increase in total adiponectin in men (odds ratio [OR] 1.86; 95% confidence interval [CI] 1.15, 3.01; p = 0.011), but not in women (OR 1.05; 95% CI 0.80, 1.37; p = 0.728; p interaction = 0.029). Similar results were demonstrated for [high molecular weight] adiponectin. Crude and adjusted leptin levels were not associated with migraine.” (B. L. Peterlin, lpeterlin@jhmi.edu)

>>>PNN NewsWatch
* Pharmacies can now implement testing programs for syphilis, thanks to the first-ever CLIA waiver granted by FDA for a rapid screening test for the spirochete. Ease of use and accuracy of the Syphilis Health Check (VEDA LAB) was demonstrated in a study of fingerstick samples of whole blood from 417 participants collected over 4 months from typical CLIA-waived sites such as physician offices, FDA said.

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 © 2014, 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
Dec. 17, 2014 * Vol. 21, No. 242
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 17 issue of JAMA (2014; 312).
Low-Dose Aspirin in Primary Cardiovascular Prevention: In a group of older Japanese patients with multiple atherosclerotic risk factors, daily low-dose aspirin had no significant effect on their risks of having cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction, researchers report (pp. 2510–20). In the Japanese Primary Prevention Project (JPPP), 14,464 patients aged 60–85 years with hypertension, dyslipidemia, or diabetes mellitus were randomized to open-label, enteric-coated aspirin 100 mg/d or no aspirin. Results showed: “The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55–5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% [95% CI, 2.40%–3.20%] for aspirin vs 2.96% [95% CI, 2.58%–3.40%] for no aspirin; hazard ratio [HR], 0.94 [95% CI, 0.77–1.15]; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 [95% CI, 0.19–0.47] for aspirin vs 0.58 [95% CI, 0.42–0.81] for no aspirin; HR, 0.53 [95% CI, 0.31–0.91]; P = .02) and transient ischemic attack (0.26 [95% CI, 0.16–0.42] for aspirin vs 0.49 [95% CI, 0.35–0.69] for no aspirin; HR, 0.57 [95% CI, 0.32–0.99]; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 [95% CI, 0.67–1.11] for aspirin vs 0.51 [95% CI, 0.37–0.72] for no aspirin; HR, 1.85 [95% CI, 1.22–2.81]; P = .004).” (Y. Ikeda)
Entecavir for Prevention of HBV Reactivation in Untreated Diffuse Large B-Cell Lymphoma: Addition of entecavir yielded significantly better outcomes, compared with lamivudine, in 121 patients who were seropositive for hepatitis B virus (HBV) surface antigen and were being treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma (pp. 2521–30). At 10 Chinese medical centers, daily entecavir 0.5 mg or lamivudine 100 mg beginning 1 week before R-CHOP and continuing for 6 months after chemotherapy completion showed these results based on a primary efficacy end point of the incidence of HBV-related hepatitis: “The rates were significantly lower for the entecavir group vs the lamivudine group for HBV-related hepatitis (0% vs 13.3%, respectively; difference between groups, 13.3% [95% CI, 4.7% to 21.9%]; P = .003), HBV reactivation (6.6% vs 30%; difference, 23.4% [95% CI, 10.2% to 36.6%]; P = .001), and chemotherapy disruption (1.6% vs 18.3%; difference, 16.7% [95% CI, 6.4% to 27.0%]; P = .002). Of the 61 patients in the entecavir group, 15 (24.6%) experienced treatment-related adverse events. Of 60 patients in the lamivudine group, 18 (30%) experienced treatment-related adverse events (difference between entecavir and lamivudine groups, 5.4% [95% CI, −10.5% to 21.3%]; P = .50).” (H. Huang)
“For HBV carriers as well as patients with cleared HBV infection, entecavir prophylaxis can be recommended to reduce the rate of HBV reactivation and hepatitis,” editorialists write (
pp. 2505–7). “For patients unable to receive antiviral prophylaxis, HBV DNA viral loads must be closely monitored during and after completion of chemotherapy. A more nuanced approach may be possible, in which patients at low risk for HBV reactivation can be identified and preferentially followed up with surveillance alone, such as those who are seropositive for both the core antibody and surface antibody. The answer to this question warrants ongoing investigation, as does the definition of the optimal duration of prophylactic antiviral therapy. The screening for and management of patients infected with HBV who receive chemotherapy should be viewed as nothing less than optimal care of patients with lymphoma.” (J. S. Abramson)

>>>PNN NewsWatch
* FDA yesterday named 14 members—12 voting and 2 nonvoting—to its Pharmacy Compounding Advisory Committee.

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 © 2014, 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
Dec. 18, 2014 * Vol. 21, No. 243
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 18 issue of the New England Journal of Medicine (2014; 371).
Cytisine for Smoking Cessation: Compared with nicotine-replacement therapy, the nicotinic partial agonist cytisine was superior for smoking cessation based on self-reported continuous abstinence for up to 6 months, researchers report (pp. 2353–62). In New Zealand, 1,310 adult daily smokers who called a national quitline participated in an open-label, pragmatic, noninferiority trial. After calling the quitline, participants received either coupons for nicotine-replacement products redeemable at community pharmacies or cytisine tablets by courier. Results showed: “At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders.” (N. Walker, n.walker@auckland.ac.nz)
Describing cytisine as “a tobacco treatment hiding in plain sight,” an editorialist explains that “the challenge [in bringing an old drug to market for a new indication] is to protect public health while retaining cytisine’s affordability for consumers” (
pp. 2429–30): “Unfortunately, in the United States and Western Europe there is now no direct pathway through the regulatory and pharmaceutical market structure for a potentially useful drug with cytisine’s unconventional history. The solution will require creative collaboration among a range of stakeholders. These include regulators, pharmaceutical companies, government agencies that fund research, and both public and private organizations whose mission is to improve global public health. A first step might be to convene these stakeholders and challenge them to identify a way forward.” (N. A. Rigotti)
Interferon-free HCV Regimen After Liver Transplant: Among 34 liver-transplant recipients with recurrent hepatitis C virus (HCV) genotype 1 infection, an interferon-free regimen (NS5A inhibitor ombitasvir with ritonavir-boosted protease inhibitor ABT-450 [ABT-450/r], nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin) “was associated with a low rate of serious adverse events and a high rate of sustained virologic response,” a study shows (pp. 2375–82). Initial ribavirin doses and later dose modifications for anemia were at the discretion of the investigator. Based on a primary efficacy end point of sustained virologic response at 12 weeks after the end of 24 weeks of treatment, results showed: “Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study.” (P. Y. Kwo, pkwo@iu.edu)

>>>PNN NewsWatch
* FDA yesterday approved finafloxacin otic suspension (Xtoro, Alcon) for treatment of acute otitis externa. Cure rates among 560 clinical trial participants with confirmed Pseudomonas aeruginosa or Staphylococcus aureus were 70% versus 37% with vehicle only. Adverse effects were pruritus and nausea.
* Eight pharmacists were among 14 people arrested by federal authorities on Wednesday and charged with crimes related to
contaminated medications produced in 2012 by the New England Compounding Center in Framingham, MA, the Boston Globe reports.

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 © 2014, 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
Dec. 19, 2014 * Vol. 21, No. 244
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Jan. issue of Medical Care (2015; 53).
Patient-Focused Drug Development: A new initiative at FDA, patient-focused drug development (PFDD) “has the potential to change product development in fundamental ways,” authors write (pp. 9–17). PFDD seeks “to bring patient perspectives into an earlier stage of product development.” The goal is to provide “context for benefit–risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications.… Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development.” The authors conclude, “Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development.” (E. M. Perfetto)
PCORI CER Methods Project: Development and improvement of comparative effectiveness research (CER) methods through activities of the Patient-Centered Outcomes Research Institute (PCORI) are described (pp. 2–8): “PCORI’s Methods Program is building a research portfolio to address the gaps in the field of patient-centered CER identified in the [final] Methodology Report. The first iteration of the Methods Program Funding Announcement is largely based on the research areas and gaps identified by the Methodology Committee and articulates 6 broad research areas of programmatic interest. These are: (1) research into patient engagement strategies and measurement, including ethical issues related to participation in research; (2) methods to identify patient-centered and patient-reported outcomes and measure them appropriately; (3) methods for research topic generation and prioritization; (4) the improvement of analytic methods of importance to PCORI, including causal inference, heterogeneity of treatment effects, and missing data; (5) methods related to cluster-randomized trials, registries, and studies of devices and diagnostics; and (6) methods related to the capture and use of data collected from multiple data sources across multiple health care systems. In September 2013, PCORI awarded the first 19 projects under the Methods Program. The Methods Program portfolio now comprises 41 projects in a range of methods areas.” (R. Fleurence, rfleurence@pcori.org)
Disparities in Individualized Care for Diabetes: After assessing care provided to patients with diabetes as recorded in the National Health and Nutrition Examination Survey for 2007–10, investigators conclude that “individualized goals for diabetes care may unearth greater racial/ethnic disparities in clinical performance compared with uniform goals” (pp. 25–31). “Diabetes performance measures should include individualized goals to prevent worsening disparities in diabetes outcomes,” the group adds based on these findings for individualized A1C and LDL cholesterol goals in the survey: “More Hispanics were recommended an individualized A1C <7.0% compared with whites (54% vs. 42%, P = 0.008). Fewer blacks and Hispanics were recommended an individualized LDL <70 mg/dL than whites (21% and 19% vs. 28%, P = 0.02 and 0.001). Fewer Hispanics had adequate individualized A1C control (56% vs. 68%, P <0.001), and fewer blacks and Hispanics had adequate individualized LDL control (31% and 36% vs. 51%, P ≤0.001 and P = 0.004). A uniform A1C <7% goal did not reveal disparities in glycemic control; individualized A1C and LDL, blood pressure <140/90 mm Hg, and nonsmoking was achieved by few adults (18%), and fewer blacks and Hispanics than whites (6% and 11% vs. 22%, P <0.001 and P = 0.005).” (N. Laiteerapong)

>>>Health Affairs Report
Source:
Dec. issue of Health Affairs, a special issue on children’s health (2014; 33).
Medical Complexity & Medicaid: Authors present “a business case” on how achieve cost savings among pediatric Medicaid beneficiaries with medically complex conditions (pp. 2199–206). “Reductions in hospital and emergency department use … could underwrite investments in outpatient and community care,” the article shows. (J. G. Berry, jay.berry@childrens.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 © 2014, 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
Dec. 22, 2014 * Vol. 21, No. 245
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 19 issue of Lancet (2014; 384).
HPV Vaccine in Women Older Than 25: Writing that “adult women who remain at risk of cervical cancer can also be vaccinated,” investigators report efficacy of human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine in women older than 25 years (pp. 2213–27). The age-stratified study population (45% each in the 26–35 and 36–45 age groups and 10% older than 45) received HPV 16/18 vaccine or control, with this impact on a primary outcome of vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18: “The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5,752 women were included in the total vaccinated cohort (n = 2,881 vaccine, n = 2,871 control), and 4,505 in the according-to-protocol cohort for efficacy (n = 2,264 vaccine, n = 2,241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81.1%, 97.7% CI 52.1–94.0), in the 26–35 years age group (83.5%, 45.0–96.8), and in the 36–45 years age group (77.2%, 2.8–96.9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79.1%, 97.7% CI 27.6–95.9) and HPV 45 (76.9%, 18.5–95.6]) Serious adverse events occurred in 285 (10%) of 2,881 women in the vaccine group and 267 (9%) of 2,871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination.” (S. R. Skinner, rachel.skinner@health.nsw.gov.au)
GLP-1 Agonists & Insulin in Type 2 Diabetes: The combination of glucagon-like peptide-1 (GLP-1) agonist and basal insulin in patients with type 2 diabetes “can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia or weight gain,” conclude authors of a review and meta-analysis (pp. 2228–34): “Of 2,905 identified studies, 15 were eligible and were included in our analysis (N = 4,348 participants). Compared with other anti-diabetic treatments, GLP-1 agonist and basal insulin combination treatment yielded an improved mean reduction in glycated haemoglobin (HbA1c) of −0.44% (95% CI −0.60 to −0.29), an improved likelihood of achieving the target HbA1c of 7.0% or lower (relative risk [RR] 1.92; 95% CI 1.43 to 2.56), no increased relative risk of hypoglycaemia (0.99; 0.76 to 1.29), and a mean reduction in weight of −3.22 kg (−4.90 to −1.54). Furthermore, compared with basal-bolus insulin regimens, the combination treatment yielded a mean reduction in HbA1c of −0.1% (−0.17 to −0.02), with lower relative risk of hypoglycaemia (0.67, 0.56 to 0.80), and reduction in mean weight (−5.66 kg; −9.8 to −1.51).” (R. Retnakaran, rretnakaran@mtsinai.on.ca)

>>>PNN NewsWatch
* FDA approved on Friday three products containing new drugs: ceftolozane/tazobactam (Zerbaxa, Cubist) for treatment of complicated intra-abdominal infections and complicated urinary-tract infections in adults; ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets (Viekira Pak, AbbVie) for treatment of patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis; and olaparib (Lynparza, AstraZeneca) for treatment for women with advanced ovarian cancer associated with defective BRCA genes, as detected by an FDA-approved test.

>>>PNN JournalWatch
* Efficacy of Beta Blockers in Patients With Heart Failure Plus Atrial Fibrillation: An Individual-Patient Data Meta-Analysis, in
Lancet, 2014; 384: 2235–43. (D. Kotecha, d.kotecha@bham.ac.uk)
* Comparison of Nurse Staffing Measurements in Staffing-Outcomes Research, in
Medical Care, 2015; 53: 10.1097/MLR.0b013e318277eb50. (S. H. Park)
* Risk Prediction Models for Postoperative Delirium: A Systematic Review and Meta-Analysis, in
Journal of the American Geriatrics Society, 2014; 62: 2383–90. (L. C. C. van Meenen, lauravanmeenen@gmail.com)
* Shared Medical Appointments to Screen for Geriatric Syndromes: Preliminary Data from a Quality Improvement Initiative, in
Journal of the American Geriatrics Society, 2014; 62: 2415–9. (S. G. May, suepattra@gmail.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 © 2014, 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
Dec. 23, 2014 * Vol. 21, No. 246
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Dec. issue of the Journal of the American Geriatrics Society (2014; 62).
Evidence Regarding Health Outcomes With Polypharmacy: Data from observational studies that examined the relationship between polypharmacy and health outcomes in community-dwelling older persons are “mixed,” investigators conclude, adding, “Because of the challenge of confounding, randomized controlled trials of medication discontinuation may provide more-definitive evidence regarding this relationship than observational studies can provide” (pp. 2261–72). A systematic review of literature published since 1946 provided these insights into adverse outcomes in relation to the number of medications being used per person: “Of the 50 studies identified, the majority that were rated good in terms of their adjustment for comorbidity demonstrated relationships between polypharmacy and a range of outcomes, including falls, fall outcomes, fall risk factors, adverse drug events, hospitalization, mortality, and measures of function and cognition. However, a number of these studies failed to demonstrate associations, as did a substantial proportion of studies rated fair or poor.” (T. Fried, terri.fried@yale.edu)
Sleep Duration & Vitamin D Levels: Among 1,614 adults in Korea aged 60–80 years, serum vitamin D levels were positively associated with self-reported daily sleep duration, a study shows (pp. 2327–32). Data from the Korean National Health and Nutrition Examination Survey 2010 for noninstitutionalized older adults showed these patterns among four sleep quartiles (≤4 h, 5–6 h, 7–8 h, ≥9 h): “Mean serum vitamin D levels of subjects in the Q1, Q2, Q3, and Q4 groups were 44.18, 48.08, 48.83, and 51.78 nmol/L, respectively. On multivariate linear regression analysis, subjects in the Q2 (B = 3.80, 95% confidence interval (CI) = 0.42–7.19), Q3 (B = 4.89, 95% CI = 1.54–8.24), and Q4 (B = 5.18, 95% CI = 0.78–9.58) groups had significantly higher serum vitamin D levels than subjects in the Q1 group.” (J. W. Kang, kjw002@yuhs.ac)

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2014; 161).
Blood Pressure Reduction in Mild Hypertension: Treatment of patients with mild hypertension (140–159 over 90–99 mm Hg) is likely beneficial in reducing stroke and mortality risk, conclude investigators who conducted a systematic review and meta-analysis (10.7326/M14-0773): “Individual-patient data involved 10 comparisons from trials where most patients had diabetes, and aggregate data involved 3 comparisons from trials of patients without diabetes. The average blood pressure reduction was about 3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to 1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes, 0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78 (CI, 0.67 to 0.92) for total deaths. Results were similar in secondary analyses. Withdrawal from treatment due to adverse effects was more common in the active groups.” (J. Sundström)
For diagnosing hypertension, ambulatory blood pressure monitoring is “the reference standard for confirming elevated office [blood pressure] screening results to avoid misdiagnosis and overtreatment of persons with isolated clinic hypertension,” according to an updated systematic review from the U.S. Preventive Services Task Force (
10.7326/M14-1539; M. A. Piper)

>>>PNN NewsWatch
* Operating under its accelerated-approval program, FDA yesterday approved nivolumab (Opdivo, Bristol-Myers Squibb) for treatment of patients with unresectable or metastatic melanoma who no longer respond to other drugs. The PD-1–protein inhibitor was tested in 120 patients; 32% of those on nivolumab had tumor shrinkage, and one-third of responders had an effect that lasted more than 6 months.
*
Peramivir (Rapivab, BioCryst) was also approved by FDA on Monday; its indication is treatment of influenza infections in adults. The drug is the third neuraminidase inhibitor on the US market. Efficacy was established in 297 patients with confirmed influenza; combined influenza symptoms were alleviated 21 hours sooner in those on the drug. Efficacy of the oral agent could not be established in patients with serious influenza requiring hospitalization.

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 © 2014, 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
Dec. 24, 2014 * Vol. 21, No. 247
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 24/31 issue of JAMA (2014; 312).
Antenatal Supplements in Rural Bangladesh: Compared with an iron–folic acid product, use of antenatal multiple micronutrient supplements lowered the number of stillbirths and significantly reduced preterm births and low birth weights among women in rural Bangladesh, researchers report (pp. 2649–58). The test formulation contained 15 micronutrients and was provided to those randomized to the investigational arm for daily administration from early pregnancy to 12 weeks postpartum. Results showed: “Among the 22,405 pregnancies in the multiple micronutrient group and the 22,162 pregnancies in the iron–folic acid group, there were 14,374 and 14,142 live-born infants, respectively, included in the analysis. At 6 months, multiple micronutrients did not significantly reduce infant mortality; there were 764 deaths (54.0 per 1,000 live births) in the iron–folic acid group and 741 deaths (51.6 per 1,000 live births) in the multiple micronutrient group (relative risk [RR], 0.95; 95% CI, 0.86–1.06). Multiple micronutrient supplementation resulted in a non–statistically significant reduction in stillbirths (43.1 vs 48.2 per 1000 births; RR, 0.89; 95% CI, 0.81–0.99; P = .02) and significant reductions in preterm births (18.6 vs 21.8 per 100 live births; RR, 0.85; 95% CI, 0.80–0.91; P < .001) and low birth weight (40.2 vs 45.7 per 100 live births; RR, 0.88; 95% CI, 0.85–0.91; P < .001).” (K. P. West, Jr.)
Metformin in Type 2 Diabetes & Kidney Disease: Metformin use in patients with type 2 diabetes and chronic kidney disease can be cautiously expanded, according to authors who conducted a systematic review on the risk of lactic acidosis in this population (pp. 2668–75). Assessment of 65 studies, case series, retrospective studies, meta-analyses, and a clinical trial showed the following: “Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30–60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person–years to 10 per 100,000 person–years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus—use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use.” (S. E. Inzucchi)
Effect of Medical Home in High-Risk Children: Among 201 children with chronic illness who required frequent emergency department and hospital visits, comprehensive care provided in an enhanced medical home reduced serious illnesses and costs, a study shows (pp. 2640–8). In Houston in 2011–13, these effects on clinical outcomes and resource use were noted: “Comprehensive care decreased both the rate of children with a serious illness (10 per 100 child–years vs 22 for usual care; rate ratio [RR], 0.45 [95% CI, 0.28–0.73]), and total hospital and clinic costs ($16,523 vs $26,781 per child–year, respectively; cost ratio, 0.58 [95% CI, 0.38–0.88]). In analyses of net monetary benefit, the probability that comprehensive care was cost neutral or cost saving was 97%.” Rates were reduced for serious illness, emergency department visits, hospitalizations, pediatric intensive care stays, and number of hospital days. (R. A. Mosquera)

>>>PNN NewsWatch
* FDA yesterday granted a new indication for liraglutide (recombinant) injection: chronic weight management in addition to a reduced-calorie diet and physical activity. Novo Nordisk will market the drug for this use under the tradename Saxenda.
*
PNN will not be published on Thurs. and Fri., Dec. 25 and 26, Christmas.

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 © 2014, 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
Dec. 29, 2014 * Vol. 21, No. 248
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Annual humorous articles from the holiday issue of BMJ (2014; 349).
Men Are Idiots: Analysis of winners of the Darwin Award over a 20-year period shows a preponderance of men engaging in idiotic risk-taking behaviors, researchers report, thus supporting the “male idiot theory” (g7094). “Winners of the Darwin Award must eliminate themselves from the gene pool in such an idiotic manner that their action ensures one less idiot will survive,” the group notes, adding that “males are significantly more likely to receive the award than females (P<0.0001).” Some reasons for the disparity include lack of intelligence and alcohol abuse: “For example, the office workers watching a construction worker demolishing a car park in the adjacent lot must have wondered about the man’s intelligence. After two days of office speculation—how does he plan to remove the final support to crash the car park down safely?—they discovered, on the third day, that he didn’t have a plan. The concrete platform collapsed, crushing him to death and flattening his mini-excavator.
“In addition, alcohol may play an important part in many of the events leading to a Darwin Award. It is conceivable that the sex difference is attributable to sociobehavioural differences in alcohol use. Anecdotal data support the hypothesis that alcohol makes men feel ‘bulletproof’ after a few drinks, and it would be naive to rule this out. For example, the three men who played a variation on Russian roulette alternately taking shots of alcohol and then stamping on an unexploded Cambodian land mine. (Spoiler alert: the mine eventually exploded, demolishing the bar and killing all three men.) Unfortunately the data on alcohol consumption are incomplete and do not permit testing for sex differences after adjustment for differences in alcohol consumption between the sexes.” (B. A. D. Lendrem,
ben.lendrem@gmail.com)
“Weekend Effect” in Palliative Care: Patients in a German palliative care unit were 18% more likely to die on weekends and holidays than on normal workdays, a retrospective analysis indicates (g7370). Data from 1997 through 2008 show the following: “A total of 2,565 admitted patients and 1,325 deaths were recorded. Of the deaths, 448 (33.8%) occurred on weekends and public holidays. The mortality rate on weekends and public holidays was 18% higher than that on working days (mortality rate ratio 1.18, 95% confidence interval 1.05 to 1.32; P = 0.005).” (J. Gaertner, jan.gaertner@uniklinik-freiburg.de)
Magazine Age in Waiting Rooms: A cohort study in a general practice waiting room in New Zealand confirms that patients are correct when they complain that that magazines are old, but this is more the result of pilfering than placement (g7262). Comparison of gossipy magazines (those with five or more celebrity photographs on the cover) and nongossipy magazines shows these patterns: “47 of the 82 magazines with a visible date on the front cover were aged less than 2 months. 28 of these 47 (60%) magazines and 10 of the 35 (29%) older magazines disappeared (P = 0.002). After 31 days, 41 of the 87 (47%, 95% confidence interval 37% to 58%) magazines had disappeared. None of the 19 nongossipy magazines (the Economist and Time magazine) had disappeared compared with 26 of the 27 (96%) gossipy magazines (P < 0.001). All 15 of the most gossipy magazines and all 19 of the nongossipy magazines had disappeared by 31 days. The study was terminated at this point.” (B. Arroll, bruce.arroll@auckland.ac.nz)

>>>PNN JournalWatch
* Standards of Medical Care in Diabetes—2015, in
Diabetes Care, 2015; 38(suppl 1).
* Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes, in
Diabetes Care, 2015; 38: 140–9. (S. E. Inzucchi, silvio.inzucchi@yale.edu)
* Point–Counterpoint: Should Sulfonylureas Remain an Acceptable First-Line Add-on to Metformin Therapy in Patients With Type 2 Diabetes? Yes, They Continue to Serve Us Well! and No, It’s Time to Move On!, in
Diabetes Care, 2015; 38: 166–9 (M. J. Abrahamson, martin.abrahamson@joslin.harvard.edu) and 170–5 (S. Genuth, smg15@case.edu)
* Vaccine for Atherosclerosis, in
Journal of the American College of Cardiology, 2014; 64: 2779–91. (Prediman K. Shah)
* Beta-Trace Protein: A Marker of GFR and Other Biological Pathways, in
American Journal of Kidney Diseases, 2015; 65: 131–46. (C. A. White, cw38@queensu.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 © 2014, 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
Dec. 30, 2014 * Vol. 21, No. 249
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Jan. issue of Diabetes Care (2015; 38).
Evidence Level in Diabetes Standards: Analyzing the evidence levels that support recommendations in the American Diabetes Association’s Standards of Medical Care in Diabetes, authors find increasingly higher-quality support, “although nearly half of recommendations continue to reflect expert opinion or conflicting or limited evidence from smaller studies” (pp. 6–8). These positive trends “should be considered in light of two developments in diabetes care,” the investigators write: “Up to 49% of people with diabetes [in the U.S.] still did not meet the targets for glycemic control, blood pressure, and/or LDL cholesterol level” and a “growing recognition of the need to tailor population-level recommendations to individual patients with a wide range of concurrent conditions, personal preferences, and health goals.” The writers continue: “Continuing therapeutic advances, the aging U.S. population, and the ongoing epidemics of obesity and sedentary lifestyles all present challenges to clinicians, policy makers, and evidence-based guideline makers. These challenges will require careful consideration of the existing evidence, new approaches to tailoring evidence to individual patients, and expansion of the evidence base in a way that will continue to make diabetes care recommendations more evidence-based and also more widely implemented.” (R. W. Grant, richard.w.grant@kp.org)
Antidiabetic Therapies & Cancer: In contrast to meta-analyses of observational studies, assessment of the German Disease Analyzer database found no reduced risk of cancer with metformin therapy in patients with type 2 diabetes, compared with insulin or sulfonylurea monotherapy (pp. 59–65). Randomized controlled trials have also failed to support findings from observational studies, the researchers report, and their study sought to avoid time-related bias that had compromised interpretation of observational findings. The study sample covered 22,556 patients over a median follow-up period of 4.8 years during which 1,446 patients developed cancer. Results showed: “In multivariable adjusted models, hazard ratios were 1.09 (95% CI 0.87–1.36) for sulfonylurea monotherapy, 1.14 (95% CI 0.85–1.55) for insulin monotherapy, and 0.94 (95% CI 0.67–1.33) for other diabetes medications compared with metformin monotherapy. Results were similar for comparison of first diabetes medications.” (B. Kowall, bernd.kowall@ddz.uni-duesseldorf.de)
Severity of Hypoglycemia With Hypoglycemic Drugs: Clinical characteristics are identified that may be helpful in individualizing therapy and avoiding more severe episodes of hypoglycemia during medication treatment of altered glucose levels, according to an analysis of data from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (pp. 22–8). Among 12,537 participants with high cardiovascular risk and impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes, these predictors of severe and nonsevere hypoglycemia were noted during addition of insulin glargine to monotherapy or no therapy: “During a median follow-up period of 6.2 years, 28% of participants reported nonsevere hypoglycemia, and 3.8% reported severe hypoglycemia. Prior use of a sulfonylurea and allocation to glargine independently predicted a higher risk for both categories of participants. Nonsevere events were independently associated with younger age, lower BMI, the presence of diabetes, and higher baseline HbA1c level. Severe events were associated with older age, hypertension, higher serum creatinine level, and lower cognitive function, but not baseline glycemic status. Progressively higher on-treatment HbA1c level was associated with a lower risk of nonsevere events in both treatment groups; a lower risk of severe events in the glargine group, and a higher risk of severe events with standard care.” (M. C. Riddle, riddle@ohsu.edu)
Automated Internet Behavioral Weight-Loss Program: In 154 adults with elevated BMIs (25–45 kg/m2), an automated Internet-based weight-loss program produced significantly greater results, a study shows (pp. 9–15). The behavioral intervention, with weekly videos and automated feedback, produced a mean loss of 5.5 kg over 3 months, compared with 1.3 kg with Internet-based education about eating and activity. (J. G. Thomas, jthomas4@lifespan.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 © 2014, 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
Dec. 31, 2014 * Vol. 21, No. 250
Providing news and information about medications and their proper use

>>>
PNN’s Top 10 for 2014
Halfway through the 2010 decade, pharmacists find plenty of medication challenges to address but lots of obstacles too. Here’s how 2014 treated them and their patients.
1 Infectious Diseases Cause Sickness, Deaths: With severe influenza seasons as bookends, 2014 had plenty of pestilence. Media coverage fanned hysteria in the U.S. over a handful of patients with Ebola, while the West Africa case count and deaths rose to 20,081 and 7,842 at year’s end. Enterovirus cases surged in the fall (Oct. 7, 10), and a multiyear influenza vaccine analysis demonstrated the need for two B antigens (Nov. 12).
2 Antibiotic Stewardship: Overuse of anti-infective agents persisted (May 13), leading to resistance despite pharmacists’ collaborative efforts in antibiotic stewardship programs (May 14, Sept. 15). The possibility of a cure in those with hepatitis C virus was threatened by a huge gap in costs of the new HCV drugs between low-income and developed countries (May 15) and the need for more clinical testing in difficult-to-treat patients (May 22).
3 Pharmacists Seek Medicare Recognition: The big news in the profession was introduction of a bill calling for addition of pharmacists to the Medicare Part B provider list for services in medically underserved communities (Mar. 12). A strong coalition formed to spearhead this effort (Mar. 4), and op-ed pieces published in lay media called for support of pharmacists as “capable providers in an incapable system.” When Congress reconvenes in Jan., a reintroduced bill will find a pharmacist in the House and GOP control of the Senate, thanks to Republicans’ midyear election sweep (Nov. 5).
4 FDA Has Banner Year of Approvals: With 41 approvals of new molecular entities, FDA topped the 21st century records of 39 new drugs in 2012 and 36 in 2004. Dalbavancin (Dalvance, Durata Therapeutics) became the first agent approved as a Qualified Infectious Disease Product (May 27, June 5), and a report looked at reasons for denials and delays by the agency (Jan. 22).
5 Pharmacy Compounding Sequelae Continue: The legal system continued its response to the 2012 compounding-driven fungal meningitis epidemic, with eight pharmacists charged criminally (Dec. 18). The new compounding law was implemented (July 2, 8; Dec. 17).
6 Advances in Clinical Medicine: Plenty of new guidelines were released even as controversy continued over the ones for lipids (Jan. 28) and hypertension (Feb. 5, Apr. 9) released in late 2013. Early goal-directed sepsis management promised to usher in a new era (May 1). Polypills for cardiovascular conditions (Feb. 7, Aug. 11, Nov. 18) and HIV (May 15, July 17) offered better adherence, while polypharmacy presented problems(Dec. 23).
7 Digital Medicine & Genomic Biomarkers: Electronic health records were implemented as Obamacare incentives kicked in (Jan. 27). Health information exchanges expanded (Dec. 2), and electronic medication packaging could assist with adherence (Sept. 24). Pharmacogenomics continued to be controversial, with some saying FDA labeling for related biomarkers was premature (Dec. 9), even as studies pointed to ways such information could greatly enhance personalized drug therapy (Sept. 30, Dec. 14).
8 Placing the Patient—Warts & All—at the Center of Care: Many studies examined ways of empowering patients and placing them at the center of patient care, even as evidence showed that their lifestyle choices presented problems that medications could only paper over (see Statins & Gluttony, July 8).
9 Weed and Cigs and Oxy, Oh My: While CVS pulled tobacco products (Feb. 6), patients’ habits were particularly problematic in the abuse of tobacco and e-cigarettes (Aug. 13) , marijuana (May 27, Aug. 26, Sept. 11), opioid analgesics (Jan. 7, Apr. 24, May 13, May 29, Nov. 5), and new drugs of abuse (Dec. 5).
10 Pharmacists Moving on Up: Pharmacists’ direct patient care efforts were noteworthy, including outcomes in hospitals with cardiovascular-credentialed pharmacists (June 13), Medicare Annual Wellness Visits (July 29), and Project IMPACT Diabetes (Sept. 16). CDC officials recognized the expanding roles of pharmacists (Oct. 28), and the CMS Innovation Center granted $15 million for a North Carolina study of community pharmacy’s reduction of health costs (Dec. 2).

>>>PNN NewsWatch
* PNN will not be published on Thurs. and Fri., Jan. 1 and 2, New Year’s.

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 © 2014, 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.