Sep 2016

PNN July–September 2016

PNN Pharmacotherapy Line
July 1, 2016 * Vol. 23, No. 127
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
July issue of Pediatrics (2016; 138).
Febrile Seizure Risk After Vaccination: Concomitant administration of the trivalent inactivated influenza vaccine (IIV3) and some routine childhood vaccines significantly increases infants’ and children’s risk of febrile seizures (FS), but the absolute risk increase is small, a study shows (10.1542/peds.2016-0320). Seeking to examine reasons for an increased risk observed in 2010–11, investigators examined postvaccination FS rates during the 2006–07 through 2010–11 influenza seasons, with these results: “Only [pneumococcal conjugate vaccine (PCV)] 7-valent had an independent FS risk (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.00 to 3.91). IIV3 had no independent risk (IRR, 0.46; 95% CI, 0.21 to 1.02), but risk was increased when IIV3 was given with either PCV (IRR, 3.50; 95% CI, 1.13 to 10.85) or a diphtheria-tetanus-acellular-pertussis (DTaP)–containing vaccine (IRR, 3.50; 95% CI, 1.52 to 8.07). The maximum estimated absolute excess risk due to concomitant administration of IIV3, PCV, and DTaP-containing vaccines compared with administration on separate days was 30 FS per 100,000 persons vaccinated.” (J. Duffy)
This absolute risk translates into one extra case of FS per decade in the typical pediatric practice, editorialists write in concluding that these vaccines can and should be administered concomitantly (
10.1542/peds.2016-0976): “The benefits of giving these vaccines simultaneously include decreased office visits associated with painful vaccines, decreased episodes of vaccine-associated fussiness, and, most important, the assurance that children will be fully immunized and protected from infections that carry real morbidity and mortality. It is well established that the vaccines we miss when we fail to give all the vaccines we can (simultaneously at each health care visit) may never be administered to some children, thus leaving them at risk for the diseases the vaccines prevent. It goes without saying that influenza, diphtheria, tetanus, pertussis, and pneumococcal infections may result in serious illness. These infections also have the potential to cause fevers and febrile seizures.… The risk from these diseases far outweighs the risk from the vaccines. Fortunately, because of the surveillance and research of the [Vaccine Safety Datalink], we no longer need to wonder how often adverse events happen after vaccinations; instead, we can measure them scientifically, and studies like that by Duffy et al increase our confidence in vaccines.” (M. H. Sawyer)
Pertussis Antibodies in Premature Neonates: Infants born to mothers vaccinated against pertussis in the third trimester may still have antibodies even when born prematurely, researchers report (10.1542/peds.2015-3854). Neonatal pertussis toxin antibody and filamentous hemoagglutinin (FHA) concentrations during the months after delivery were measured for vaccinated and unvaccinated mothers: “Mothers of 31 (19%) of 160 premature infants had received combined tetanus, diphtheria, 5-component acellular pertussis, inactivated polio vaccine in pregnancy. Compared with infants of unvaccinated mothers, those born to vaccinated mothers had significantly higher antibody concentrations at 2 months for all measured vaccine antigens (P < .001). The number of days between maternal vaccination and delivery and immunoglobulin G concentration at 2 months of age was positively correlated for pertussis toxin (P = .011) and FHA (P = .001). After primary immunization, infants of vaccinated mothers had significantly lower antibody concentrations for FHA (P = .003) compared with infants of unvaccinated mothers; these differences had resolved by 12 months of age.” (A. Kent)

>>>PNN NewsWatch
* In declining to accept an appeal of a Ninth Circuit case, the U.S. Supreme Court earlier this week let stand a decision allowing state boards of pharmacy to require pharmacies to dispense emergency contraceptives regardless of pharmacists’ religious objections. The decision presents challenges in situations where an objecting pharmacist typically practices alone or a pharmacy or pharmacy chain is owned by individuals who object to certain therapies based on religious beliefs. The case emanated from Washington State, where the board requires pharmacies to ensure that patients have full and timely access to medications, including emergency contraceptives, SeattlePI.com reports.
*
PNN will not be published on Mon., July 4, Independence Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 5, 2016 * Vol. 23, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 5 issue of the Annals of Internal Medicine (2016; 165).
Pharmacist-Led Chronic Disease Management: Pharmacists caring for patients with chronic diseases produce potentially better indicators of physiologic goal attainment with similar amounts of resource utilization, according to results of a systematic review of 65 patient populations in 63 American studies (pp. 30–40): “Pharmacist-led care was associated with similar numbers of office visits, urgent care or emergency department visits, and hospitalizations (moderate-strength evidence) and medication adherence (low-strength evidence) compared with usual care (typically continuing a prestudy visit schedule). Pharmacist-led care increased the number or dose of medications received and improved study-selected glycemic, blood pressure, and lipid goal attainment (moderate-strength evidence). Mortality and clinical events were similar (low-strength evidence). Evidence on patient satisfaction was mixed and insufficient. The reporting of harms was limited.” (N. Greer, nancy.greer@va.gov)
Escalating Cost of Prescription Drugs: The American College of Physicians calls for action regarding prescription drug prices, value, and spending in a policy position paper (pp. 50–2): “Prescription drugs play an important part in treating and preventing disease. However, the United States often pays more for some prescription drugs than other developed countries, and the high price and increasing costs associated with prescription medication is a major concern for patients, physicians, and payers. Pharmaceutical companies have considerable flexibility in how they price drugs, and the costs that payers and patients see are dependent on how payers are able to negotiate discounts or rebates. Beyond setting list prices are issues of regulatory approval, patents and intellectual property, assessment of value and cost-effectiveness, and health plan drug benefits. These issues are linked, and comprehensive efforts will be needed to affect how drugs are priced in the United States.” (H. Daniel, hdaniel@mail.acponline.org)
HIV Preexposure Prophylaxis in Injection Drug Users: Used with frequent screening and prompt treatment when needed, HIV preexposure prophylaxis (PrEP) in people who inject drugs (PWID) “can reduce HIV burden among PWID and provide health benefits for the entire U.S. population, but, at current drug prices, it remains an expensive intervention both in absolute terms and in cost per [discounted quality-adjusted life–years (QALYs)] gained,” researchers conclude (pp. 10–9). Results of cost-effectiveness analysis provide these base-case and sensitivity-analysis results: “PrEP+screen+[antiretroviral therapy (ART)] dominates other strategies, averting 26,700 infections and reducing HIV prevalence among PWID by 14% compared with the status quo. Achieving these benefits costs $253,000 per QALY gained. At current drug prices, total expenditures for PrEP+screen+ART could be as high as $44 billion over 20 years.…
“Cost-effectiveness of the intervention is linear in the annual cost of PrEP and is dependent on PrEP drug adherence, individual transmission risks, and community HIV prevalence.” (C. L. Bernard,
clb210@stanford.edu)

>>>PNN JournalWatch
* Dupilumab Efficacy and Safety in Adults With Uncontrolled Persistent Asthma Despite Use of Medium-to-High-Dose Inhaled Corticosteroids Plus a Long-Acting Beta-2 Agonist: A Randomised Double-Blind Placebo-Controlled Pivotal Phase 2b Dose-Ranging Trial, in
Lancet, 2016; 388: 31–44. (S. Wenzel, wenzelse@upmc.edu)
* Romiplostim in Children With Immune Thrombocytopenia: A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study, in
Lancet, 2016; 388: 45–54. (M. D. Tarantino, mtarantino@ilbcdi.org)
* Safety of Reduced Antibiotic Prescribing for Self Limiting Respiratory Tract Infections in Primary Care: Cohort Study Using Electronic Health Records, in
BMJ, 2016; 354: i3410. (M. C. Gulliford, martin.gulliford@kcl.ac.uk)
* Impact of Statin Related Media Coverage on Use of Statins: Interrupted Time Series Analysis With UK Primary Care Data, in
BMJ, 2016; 353: i3283. (K. Bhaskaran, krishnan.bhaskaran@lshtm.ac.uk)
* Discontinuation and Restarting in Patients on Statin Treatment: Prospective Open Cohort Study Using a Primary Care Database, in
BMJ, 2016; 353: i3305. (Y. Vinogradova, Yana.Vinogradova@nottingham.ac.uk)
* A Framework for Extending Psychiatrists’ Roles in Treating General Health Conditions, in
American Journal of Psychiatry, 2016; 173: 658–63. (E. R. Vanderlip)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 6, 2016 * Vol. 23, No. 129
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
July 5 issue of JAMA (2016; 316).
Deutetrabenazine in Huntington Disease: In 90 patients with chorea associated with Huntington disease, a deuterium-containing form of tetrabenazine improved motor signs at 12 weeks compared with placebo, researchers report (pp. 40–50). Deutetrabenazine attenuates CYP2D6 metabolism, increasing active metabolite half-lives, and produced these results over 12 weeks: “In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2–12.9) to 7.7 (95% CI, 6.5–8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2–14.3) to 11.3 (95% CI, 10.0–12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P <.001).” (S. Frank, sfrank2@bidmc.harvard.edu)
“Although the minimal clinically important difference for the total maximal chorea score is not established, some data suggest that the effect sizes reported in this study and in [a] prior tetrabenazine trial are clinically meaningful,” editorialists write (
pp. 33–5). “Although the minimal clinically important difference for the total maximal chorea score is not established, some data suggest that the effect sizes reported in this study and in the prior tetrabenazine trial are clinically meaningful. In both studies, subjective improvement was noted by patients or clinicians, and in clinical practice, tetrabenazine clearly reduces chorea. In addition, because the duration of the trial was relatively short, consisting of only 12 weeks of therapy, the sustainability of benefit over a longer time course is not known. These and other issues regarding a comparison of deutetrabenazine and tetrabenazine should be addressed by the ongoing ARC-HD (Alternatives for Reducing Chorea in Huntington Disease; NCT01897896) study, which will examine the safety and tolerability of patients with Huntington disease taking tetrabenazine and switching to deutetrabenazine and will also include patients from this current deutetrabenazine study who chose to switch to open-label deutetrabenazine.” (M. Geschwind, michael.geschwind@ucsf.edu)
Pharmacogenomics of Clopidogrel in Stroke, TIAs: CYP2C19 genotype plays a key role in the efficacy of clopidogrel when used with aspirin in patients with minor ischemic stroke or transient ischemic attack, a study concludes (pp. 70–8). In 2,933 Chinese patients at 73 sites in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) randomized trial, these results were noted for three CYP2C19 major alleles (*2, *3, *17): “After day 90 follow-up, clopidogrel–aspirin reduced the rate of new stroke in [1,207] noncarriers but not in [1,726] carriers of the loss-of-function alleles (P = .02 for interaction; events among noncarriers, 41 [6.7%] with clopidogrel–aspirin vs 74 [12.4%] with aspirin; hazard ratio [HR], 0.51 [95% CI, 0.35–0.75]; events among carriers, 80 [9.4%] with clopidogrel–aspirin vs 94 [10.8%] with aspirin; HR, 0.93 [95% CI, 0.69 to 1.26]). Similar results were observed for the secondary composite efficacy outcome (noncarriers: 41 [6.7%] with clopidogrel-aspirin vs 75 [12.5%] with aspirin; HR, 0.50 [95% CI, 0.34–0.74]; carriers: 80 [9.4%] with clopidogrel-aspirin vs 95 [10.9%] with aspirin; HR, 0.92 [95% CI, 0.68–1.24]; P = .02 for interaction). The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the clopidogrel–aspirin group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin only group; P = .78 for interaction).” (Y. Wang, yongjunwang1962@gmail.com)

>>>PNN NewsWatch
* Pfizer has agreed to add disclosures of a serious risk of addiction to its promotional materials for opioid products, the Washington Post reports. “The company also will acknowledge there is no good research on opioids’ effectiveness beyond 12 weeks,” the article states. “Though Pfizer does not sell many opioids compared with other industry leaders, its action sets it apart from companies that have been accused of fueling an epidemic of opioid misuse through aggressive marketing of their products.”
* The
Absorb GT1 Bioresorbable Vascular Scaffold System, approved yesterday by FDA, is the first fully absorbable stent indicated for treatment of coronary artery disease. The stent releases everolimus to limit the growth of scar tissue and is gradually absorbed by the body in approximately 3 years.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 7, 2016 * Vol. 23, No. 130
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
July 7 issue of the New England Journal of Medicine (2016; 375).
Adaptive Randomization Trials: Articles examine and apply adaptive randomization trial techniques as responsive ways of conducting clinical research.
Editorialists note that the adaptive approach, as used in the Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2 (I-SPY 2 TRIAL), allowed investigators to react clinical results as they were available rather than “creating a fixed framework of statistical assumptions that determines sample size and power” (
pp. 83–4). “This adaptive approach potentially allows for faster and more flexible trial design,” the writers add. As applied in breast cancer research, adaptive designs address “a growing dissatisfaction with trials of adjuvant therapy that are large, take many years to complete, and often result in very small improvements in outcome.” (L. A. Carey)
In the phase 2 I-SPY 2 trial, the tyrosine kinase inhibitor neratinib produced higher rates of pathological complete response than did standard chemotherapy with trastuzumab in women with HER2-positive, hormone-receptor–negative breast cancer (
pp. 11–22). Participants were categorized based on biomarker subtypes and combinations of subtypes (signatures). Enrollment was stopped when Bayesian analysis showed probability of success in a phase 3 trial as 85% or greater or less than 10% for each biomarker. Results indicated: “Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor–negative signature. Among patients with HER2-positive, hormone-receptor–negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%.” (L. J. Esserman, laura.esserman@ucsf.edu)
In a second part of the I-SPY 2 trial, “veliparib–carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer,” researchers report (
pp. 23–34). Veliparib is a poly(ADP-ribose) polymerase (PARP) inhibitor. It was tested with adaptive design similar to the above method, producing these results: “With regard to triple-negative breast cancer, veliparib–carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib–carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib–carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib–carboplatin was greater than that of the control.” (L. J. Esserman, laura.esserman@ucsf.edu)
“More widespread use of adaptive trial designs could accelerate the discovery process, especially if coupled with other evolving trial concepts, such as large, simple trials,” write authors of a review article (
pp. 65–74). “Advances in adaptive trial design will require further dissemination and acceptance of the sometimes complex statistical methods. There is an intuitive appeal of adaptive trial design and its attempt to identify the patients who are most likely to derive benefit from a therapy, and this feature will resonate well with most doctors and patients.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday issued draft guidances for next-generation sequencing (NGS) technologies. NGS can scan a person’s DNA to detect genomic variations that may determine whether a person has or is at risk of disease or may help to inform treatment decisions, FDA said, noting that the action is in support of the President’s Precision Medicine Initiative.
*
Dream Body Weight Loss is voluntarily recalling all lots of Dream Body Extreme Gold 800 mg 30 gold capsules, Dream Body 450 mg 30 white capsules, and Dream Body Advanced 400 mg 30 purple capsules to the consumer level, FDA said. Agency sampling and testing showed the products contain sibutramine.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 8, 2016 * Vol. 23, No. 131
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
July 5 Journal of the American College of Cardiology (2016; 68).
Nonstatin Therapies for LDL-Cholesterol Lowering: Evidence-based recommendations for clinicians are offered for addition of nonstatin therapies in reducing LDL cholesterol levels in primary and secondary prevention patients (pp. 92–125). Algorithms in a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents offer guidance in a variety of clinical situations: “Since the publication of the 2013 ACC/AHA cholesterol guidelines, [randomized controlled trials] evaluating the safety and efficacy of non-statin therapies (including large trials of ezetimibe and extended-release niacin with laropiprant added to moderate-dose statins in higher-risk patients) have provided important information regarding the potential benefits and harms of these agents in [atherosclerotic cardiovascular disease (ASCVD)] risk reduction when used in combination with evidence-based statin therapy. In addition, the approval of 2 PCSK9 inhibitors for LDL-C lowering in specific high-risk patients has resulted in gaps in expert guidance regarding the role of available non-statin therapies. This expert consensus decision pathway addresses current gaps in care for LDL-C lowering to reduce ASCVD risk, and recommendations build on the evidence base established by the 2013 ACC/AHA cholesterol guideline. The algorithms endorse the 4 evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guidelines and assume that the patient is currently taking or has attempted to take a statin, given that this is the most effective initial therapy. Recommendations attempt to provide practical guidance for clinicians and patients regarding the use of non-statin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with new agents for ASCVD risk reduction.” (www.acc.org)

>>>Chest Highlights
Source:
July issue of Chest (2016; 150).
Implantable Treprostinil Delivery System: A fully implantable treprostinil delivery system used in 60 patients with severe pulmonary arterial hypertension (PAH) produced “a low rate of catheter-related complications and a high rate of patient satisfaction” during a mean of 12.1 ± 4.4 months of testing (pp. 27–34). Results showed: “Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient–days.… The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months’ postimplantation (P <.0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions.” (R. C. Bourge)

>>>Circulation Report
Source:
July 5 issue of Circulation (2016; 134).
Rivaroxaban v. Warfarin in Worsening Renal Failure: In 12,612 patients with atrial fibrillation, those with on-treatment worsening renal failure (WRF) had lower rates of stroke and systemic embolism without increased bleeding risk when on rivaroxaban compared with dose-adjusted warfarin, researchers report (pp. 37–47). ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) investigators report these results: “Baseline characteristics were generally similar between patients with stable renal function (n = 9,292) and WRF (n = 3,320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient–years; P = 0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient–years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P = 0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban.” (C. B. Fordyce, christopher.fordyce@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 11, 2016 * Vol. 23, No. 132
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 9 issue of Lancet (2016; 388).
Variation in Quality of Care by Day & Time of Admission: The “weekend effect” of poorer care for patients who present at hospitals on the weekends or at night is a “simplification,” researchers report based on a study showing varying quality of stroke care in several weekly patterns (pp. 170–7). Using data from the Sentinel Stroke National Audit Programme for 74,307 adults aged 16 years or older admitted for hospital care for ischemic or primary intracerebral hemorrhage, the investigators found these patterns in care quality based on 30-day postadmission survival: “Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35–66% [16/46–232/350]; coefficient of variation 18.2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1.03, 95% CI 0.95–1.13), but patients admitted overnight on weekdays had lower odds of survival (0.90, 0.82–0.99).” (B. D. Bray, benjamin.bray@kcl.ac.uk)
Weekend Specialist Care: In a June 2014 point-prevalence study, mortality risk for emergency admissions did not differ between Sunday and Wednesday (pp. 178–86). Analysis of eligible hospital trusts in England showed these patterns of self-reported care and related outcomes: “127 of 141 eligible acute hospital trusts agreed to participate; 115 (91%) trusts contributed data to the point prevalence survey. Of 34,350 clinicians surveyed, 15,537 (45%) responded. Substantially fewer specialists were present providing care to emergency admissions on Sunday (1,667 [11%]) than on Wednesday (6,105 [42%]). Specialists present on Sunday spent 40% more time caring for emergency patients than did those present on Wednesday (mean 5.74 h [SD 3.39] vs 3.97 h [3.31]); however, the median specialist intensity on Sunday was only 48% (IQR 40–58) of that on Wednesday. The Sunday to Wednesday intensity ratio was less than 0.7 in 104 (90%) of the contributing trusts. Mortality risk among patients admitted at weekends was higher than among those admitted on weekdays (adjusted odds ratio 1.10, 95% CI 1.08–1.11; p <0.0001). There was no significant association between Sunday to Wednesday specialist intensity ratios and weekend to weekday mortality ratios (r −0.042; p = 0.654).” (J. Bion, j.f.bion@bham.ac.uk)

>>>PNN NewsWatch
* The first retinoid approved for nonprescription use, adapalene (Differin Gel 0.1%, Galderma) was approved by FDA on Friday for once-daily topical treatment of acne in people 12 years of age and older. Adapalene, approved for prescription use in 1996, is the first new agent for OTC therapy for acne marketed since the 1980s, FDA said.

>>>PNN JournalWatch
* Point–Counterpoint on Evidence-Based Medicine, in
Journal of the American College of Cardiology, 2016; 68: 204–13 (D. J. Sheridan) and 214–6 (J. E. Brush, Jr.)
* Management of Periprocedural Anticoagulation: A Survey of Contemporary Practice, in
Journal of the American College of Cardiology, 2016; 68: 217–26. (G. C. Flaker)
* Risk of Procedural Hemorrhage, in
Chest, 2016; 150: 237–46. (J. P. Kress)
* Persistent Challenges in Pediatric Pulmonary Hypertension, in
Chest, 2016; 150: 226–36. (R.l K. Hopper)
* Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-Generation Beta-Lactam/Beta-Lactamase Inhibitor Combinations, in
Clinical Infectious Diseases, 2016; 63: 234–41. (R. A. Bonomo, robert.bonomo@va.gov)
* Zika Virus: Implications for Public Health, in
Clinical Infectious Diseases, 2016; 63: 227–33. (D. Focosi, d.focosi@ao-pisa.toscana.it)
* Selection of Optimal Adjuvant Chemotherapy Regimens for [HER2] –Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: [ASCO] Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline, in
Journal of Clinical Oncology, 2016; 34: 2416–27 (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, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 12, 2016 * Vol. 23, No. 133
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July issue of JAMA Internal Medicine (2016; 176).
Opioids for Low Back Pain: Used for treatment of chronic low back pain, opioid analgesics “provide modest short-term pain relief,” authors of a systematic review and meta-analysis conclude, “but the effect is not likely to be clinically important within guideline recommended doses” (pp. 958–68). Concluding that “evidence on long-term efficacy is lacking” and that the overall efficacy “in acute low back pain is unknown,” the authors report: “Of 20 included [randomized controlled trials] of opioid analgesics (with a total of 7,925 participants), 13 trials (3,419 participants) evaluated short-term effects on chronic low back pain, and no placebo-controlled trials enrolled patients with acute low back pain. In half of these 13 trials, at least 50% of participants withdrew owing to adverse events or lack of efficacy. There was moderate-quality evidence that opioid analgesics reduce pain in the short term; mean difference (MD), −10.1 (95% CI, −12.8 to −7.4). Meta-regression revealed a 12.0 point greater pain relief for every 1 log unit increase in morphine equivalent dose (P = .046). Clinically important pain relief was not observed within the dose range evaluated (40.0–240.0-mg morphine equivalents per day). There was no significant effect of enrichment study design.” (A. J. McLachlan, andrew.mclachlan@sydney.edu.au)
Hospital Prescribing of Opioids: Among Medicare beneficiaries, appropriate use of opioid analgesics soon after hospital admission may lead to inappropriate prescribing of the agents at discharge, according to an analysis of pharmacy claims data and hospital average performance on pain-related Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) measures (pp. 990–7). Investigators used a 20% random sample of Medicare beneficiaries hospitalized in 2011 who had no opioid prescriptions in the 60 days before hospitalization. Results showed: “Among 623,957 hospitalizations, 92,882 (14.9%) were associated with a new opioid claim. Among those hospitalizations with an associated opioid claim within 7 days of hospital discharge, 32,731 (42.5%) of 77,092 were associated with an opioid claim after 90 days postdischarge. Across 2,512 hospitals, the average adjusted rate of new opioid use within 7 days of hospitalization was 15.1% (interquartile range, 12.3%–17.4%; interdecile range, 10.5%–20.0%). A hospital’s adjusted rate of new opioid use was modestly positively associated with the percentage of its inpatients reporting that their pain was always well managed (increase from 25th to the 75th percentile in the HCAHPS measure was associated with an absolute increase in new opioid use of 0.89 percentage points or a relative increase of 6.0%; P <.001).” (A. B. Jena, jena@hcp.med.harvard.edu)
Liraglutide Added to High-Dose Insulin: In 71 patients with type 2 diabetes uncontrolled by high-dose insulin therapy, liraglutide “improved glycemic control, decreased body weight, and enhanced treatment satisfaction,” a 6-month study shows (pp. 939–47). “Further studies are warranted to confirm these findings and evaluate the long-term risk and benefit of this treatment option,” the writers conclude. (I. Lingvay, ildiko.lingvay@utsouthwestern.edu)
Intensive Treatment & Severe Hypoglycemia: Intensive glycemic therapy used in adults with type 2 diabetes is unnecessary about 20% of the time, according to authors who retrospectively analyzed data from the OptumLabs Data Warehouse for 2001–13 (pp. 969–78). “The risk-adjusted probability of intensive treatment was 25.7% (95% CI, 25.1%–26.2%) in patients with low clinical complexity and 20.8% (95% CI, 19.4%–22.2%) in patients with high clinical complexity,” the authors report. “Among patients with high clinical complexity, intensive treatment nearly doubles the risk of severe hypoglycemia.” (R. G. McCoy, mccoy.rozalina@mayo.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first focused ultrasound device to treat essential tremor in patients who have not responded to medication. ExAblate Neuro (InSightec) uses magnetic resonance images taken during the procedure to deliver focused ultrasound to destroy tissue in the thalamus thought to be responsible for causing tremors. Treated patients have a 50% improvement in tremors and motor function.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 13, 2016 * Vol. 23, No. 134
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
July 12 issue of JAMA (2016; 316).
Need for Condoms During Suppressive Antiretroviral Therapy: No cases of HIV transmission were observed in serodiscordant couples who did not use condoms during vaginal or anal sex when the HIV-infected partner was on antiretroviral therapy (ART) that reduced serum HIV-1 RNA loads to less than 200 copies/mL, researchers report (pp. 171–81). In the PARTNER (Partners of People on ART—A New Evaluation of the Risks) study, rates of within-couple HIV transmission for heterosexuals and men who have sex with men (MSM) during periods of sex without condoms and adequate viral suppression were as follows: “Among 1,166 enrolled couples, 888 (mean age, 42 years [IQR, 35–48]; 548 heterosexual [61.7%] and 340 MSM [38.3%]) provided 1,238 eligible couple–years of follow-up (median follow-up, 1.3 years [IQR, 0.8–2.0]). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5–6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15–71), with MSM couples reporting approximately 22,000 condomless sex acts and heterosexuals approximately 36,000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple–years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple–years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple–years of follow-up.” (A. Rodger, alison.rodger@ucl.ac.uk)
Given these results, clinicians can provide cautionary guidance to patients wanting the option of condomless sex, editorialists write (
pp. 149–51): “Clinicians can indicate that the risk of HIV transmission appears small in the setting of continued viral suppression, emphasizing that the duration the HIV-infected partner needs to be virologically suppressed before achieving optimal protection is unknown, although appears to be for at least 6 months, based on the best available data. Moreover, clinicians need to be clear that even though the overall risk for HIV transmission may be small, the risk is not zero and the actual number is not known, especially for higher-risk groups such as MSM. Although more research is needed with larger numbers of couples and longer follow-up, it is not known if or when such data will emerge. Consequently, for now, clinicians and public health officials must share the data that exist in an honest and understandable way so that serodiscordant couples can be fully informed when individualizing their decision making about sexual practices.” (E. S. Daar, edaar@labiomed.org)
2016 HIV Recommendations for Adults: The International Antiviral Society–USA provides updated guidelines for use of antiretroviral agents in adults with established HIV infection (pp. 191–210): “Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an [integrase strand transfer inhibitor] plus 2 [nucleoside reverse transcriptase inhibitors]. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available [antiretroviral drugs] can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.” (H. F. Günthard, huldrych.guenthard@usz.ch)

>>>PNN NewsWatch
* FDA has approved lifitegrast ophthalmic solution (Xiidra, Shire US) for treatment of signs and symptoms of adults with dry eye disease. Lifitegrast is the first medication in a new class of lymphocyte function-associated antigen 1 antagonists.
* Alere Inc. is initiating a voluntary withdrawal of the
Alere INRatio and INRatio2 PT/INR Monitoring System, FDA said yesterday. The agency was not satisfied that a software solution effectively addressed a 2014 issue regarding use of the device in patients with certain diseases, FDA said, prompting the request for market withdrawal.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 14, 2016 * Vol. 23, No. 135
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
July 14 New England Journal of Medicine (2016; 375).
Drugs v. Ablation in Ventricular Tachycardia: In 259 patients with recurrent ventricular tachycardia despite an implantable cardioverter–defibrillator (ICD), ablation yielded better results than escalation of antiarrhythmic drugs, researchers report (pp. 111–21). In the Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial, survivors of myocardial infarction with ischemic cardiomyopathy and an ICD were randomly assigned to catheter ablation or escalated drug therapy for recurrent tachycardia, with these results on a composite outcome of death, three or more documented episodes of ventricular tachycardia within 24 hours (ventricular tachycardia storm), or appropriate ICD shock: “During a mean (± SD) of 27.9 ± 17.1 months of follow-up, the primary outcome occurred in 59.1% of patients in the ablation group and 68.5% of those in the escalated-therapy group (hazard ratio in the ablation group, 0.72; 95% confidence interval, 0.53 to 0.98; P = 0.04). There was no significant between-group difference in mortality. There were two cardiac perforations and three cases of major bleeding in the ablation group and two deaths from pulmonary toxic effects and one from hepatic dysfunction in the escalated-therapy group.” (J. L. Sapp, john.sapp@nshealth.ca)
“The results of the VANISH trial indicate that it is appropriate to offer catheter ablation to patients with ischemic cardiomyopathy, an ICD, and recurrent ventricular tachycardia while taking amiodarone,” editorialists write (
pp. 173–4). “For patients who have ventricular tachycardia while taking another antiarrhythmic drug or no antiarrhythmic drug, catheter ablation does not appear to be superior to treatment with amiodarone. These results also emphasize the need for better antiarrhythmic therapies in this group of patients.” (M. E. Cain)
Olanzapine for Chemotherapy-Induced Nausea and Vomiting: In previously untreated patients undergoing highly emetogenic chemotherapy, olanzapine was significantly better than placebo for preventing nausea and vomiting, according to a phase 3 trial (pp. 134–42). Used in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3–receptor antagonist, olanzapine produced these results in patients receiving cisplatin or cyclophosphamide–doxorubicin: “In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P = 0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P = 0.002), and the overall 120-hour period (37% vs. 22%, P = 0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P <0.001), 67% versus 52% (P = 0.007), and 64% versus 41% (P <0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2.” (R. M. Navari, rmnavari@gmail.com)
Ipilimumab After Allogeneic Transplantation: In a phase 1/1b trial, administration of ipilimumab proved feasible in 28 patients with relapsed hematologic cancer after allogeneic hematopoietic stem-cell transplantation (HSCT) (pp. 143–53): “Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood.” (M. S. Davids, matthew_davids@dfci.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 15, 2016 * Vol. 23, No. 136
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Aug. 1 issue of Clinical Infectious Diseases (2016; 63).
Anti-MRSA Antibiotics in CAP: Antibiotics reserved for treating methicillin-resistant Staphylococcus aureus (MRSA) are overused for empiric therapy of community-acquired pneumonia (CAP), according to a prospective surveillance study of hospitalized adults (pp. 300–9). Results showed a very low prevalence of S. aureus and specifically MRSA in the multicenter study: “Among 2,259 adults hospitalized for CAP, 37 (1.6%) had S. aureus identified, including 15 (0.7%) with MRSA and 22 (1.0%) with MSSA; 115 (5.1%) had Streptococcus pneumoniae. Vancomycin or linezolid was administered to 674 (29.8%) patients within the first 3 days of hospitalization. Chronic hemodialysis use was more common among patients with MRSA (20.0%) than pneumococcal (2.6%) and all-cause non-S. aureus (3.7%) CAP. Otherwise, clinical features at admission were similar, including concurrent influenza infection, hemoptysis, multilobar infiltrates, and prehospital antibiotics. Patients with MRSA CAP had more severe clinical outcomes than those with pneumococcal CAP, including intensive care unit admission (86.7% vs 34.8%) and in-patient mortality (13.3% vs 4.4%).” (W. H. Self, wesley.self@vanderbilt.edu)
Race, Gender in Hep C Treatment: Black patients and younger women were underrepresented in cohorts of Veterans Administration patients with hepatitis C virus (HCV) infections who received treatment with direct-acting antiviral agents (DAA), a study shows (pp. 291–9). In VA facilities nationwide, these unexplained differences emerged: “Of the 145,596 patients seen in the current DAA era, 17,791 (10.2%) received treatment during the first 16 months of DAA approval. Black patients had 21% lower odds of receiving DAA than whites (odds ratio [OR] = 0.79; 95% confidence interval [CI], .75, .84). Overall, women were as likely to receive treatment as men (OR = 0.99; 95% CI, .90–1.09). However, the odds of receiving DAAs were 29% lower for younger women compared with younger men (OR = 0.71, 95% CI, .54–.93). Similar to the DAA cohort, black patients had significantly lower odds of receiving treatment than whites (OR = 0.74, 95% CI, .69–.79) in the previous treatment era. The racial difference between the 2 eras did not reach statistical significance.” (F. Kanwal, kanwal@bcm.edu)

>>>Oncology Highlights
Source:
July 20 issue of the Journal of Clinical Oncology (2016; 34).
Adherence & Disease-Free Survival in Breast Cancer: Among participants in the Breast International Group (BIG) 1-98 clinical trial, adherence and persistence with tamoxifen (Tam) and letrozole (Let) therapy was associated with greater odds of disease-free survival (DFS), researchers report (pp. 2452–9). The four-arm study examined 5 years of Tam, Let, or the agents in sequence, with these outcomes based on compliance with dosage and duration of therapy: “Both aspects of low adherence (early cessation of letrozole and a compliance score of <90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event.” (J. H. Chirgwin, chirgwin@tpg.com.au)
Aspirin for Secondary Colorectal Cancer Prevention: Retrospective national cancer registry and prescription data from Norway for people with colorectal cancer (CRC) shows an independent association between aspirin use and improved CRC-specific survival (CSS) and overall survival (OS) (pp. 2501–8): “A total of 2,071 deaths (32.9%, all causes) occurred among [6,102] aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01).” (K. Taskén, kjetil.tasken@ncmm.uio.no)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 18, 2016 * Vol. 23, No. 137
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 16 issue of Lancet (2016; 388).
Rituximab in RA: In a 12-month, open-label trial of 295 patients with rheumatoid arthritis, initial treatment with rituximab was noninferior to TNF inhibitor therapy and cost saving, researchers report (pp. 239–47). Participants had active disease that responded inadequately to nonbiological therapy. IV rituximab 1 g on days 1 and 15 and after 26 weeks if needed was compared with subcutaneous adalimumab 40 mg every other week or subcutaneous etanercept 50 mg per week, with these results: “After 12 months, the change in [28-joint-count disease activity score] for patients assigned to rituximab was −2.6 (SD 1.4) and TNF inhibitor was −2.4 (SD 1.5), with a difference within the prespecified non-inferiority margin of −0.19 (95% CI −0.51 to 0.13; p = 0.24). The health-related costs associated with the rituximab strategy were lower than the TNF inhibitor strategy (£9,405 vs £11,523 per patient, p <0.0001). 137 (95%) of 144 patients in the rituximab group and 143 (95%) of 151 patients in the TNF inhibitor group had adverse events. 37 serious adverse events occurred in patients receiving rituximab compared with 26 in patients receiving TNF inhibitors, of which 27 were deemed to be possibly, probably, or definitely related to the treatment (15 vs 12, p = 0.5462). One patient in each group died during the study.” (D. Porter, duncan.porter@glasgow.ac.uk)
Adjuvant S-1 for Pancreatic Cancer: Adjuvant S-1 chemotherapy should be the new standard care in Japanese patients with resected pancreatic cancer, authors conclude based on a 387-patient, open-label, noninferiority, phase 3 trial (pp. 248–57). Results with S-1 versus gemcitabine were as follows: “On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44–0.72, pnon-inferiority <0.0001, p <0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6–30.8) in the gemcitabine group and 44.1% (36.9–51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group.” (N. Boku, nboku@ncc.go.jp)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Hypoglycemia with Sulfonylureas: Sulfonylureas should be used cautiously in patients with severely reduced renal function, authors of a research study conclude based on the frequency of hypoglycemic events observed among 120,803 patients with records in the Clinical Practice Research Datalink database in 2004–12 (i3625). Those with renal function less than 30 mL/min/1.73 sq m and the overall population had increased risk of hypoglycemic events. “This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation,” the authors conclude. (F. de Vries, f.devries@uu.nl)
Diabetes Treatments & Heart Failure: The risks of cardiovascular disease, heart failure, and all-cause mortality vary considerably among available antidiabetic drugs, researchers report (i3477). In the U.K. QResearch database, glitazones and gliptins produced the lowest risk among adults treated in 2007–15. (J. Hippisley-Cox, Julia.hippisley-cox@nottingham.ac.uk)

>>>PNN NewsWatch
* PharmaTech LLC, of Davie, FL, is voluntarily recalling all nonexpired lots of Diocto Liquid, a docusate sodium solution distributed by Rugby, FDA announced on Saturday. The agency confirmed the product has been contaminated with Burkholderia cepacia, which has been linked to an outbreak in five states.

>>>PNN JournalWatch
* The Role of the Inflammasome in Patients With Autoinflammatory Diseases, in
Journal of Allergy and Clinical Immunology, 2016; 138: 3–14. (H. M. Hoffman, hahoffman@ucsd.edu)
* Anticholinergic Medication Use and Risk of Fracture in Elderly Adults with Depression, in
Journal of the American Geriatrics Society, 2016; 64: 1492–7. (R. R. Aparasu, rraparasu@uh.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 19, 2016 * Vol. 23, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 19 issue of the Annals of Internal Medicine (2016; 165).
Treating Insomnia: Several articles, including a clinical guideline, examine treatment of chronic insomnia in adults.
Short-term benefits are evident for eszopiclone, zolpidem, and suvorexant in insomnia, but long-term efficacy is unknown, and the drugs “may cause cognitive and behavioral changes and may be associated with infrequent but serious harms,” authors of an evidence report conclude (
pp. 103–12). From 35 randomized controlled trials lasting at least 4 weeks, these results were obtained: “Eszopiclone, zolpidem, and suvorexant improved short-term global and sleep outcomes compared with placebo, although absolute effect sizes were small (low- to moderate-strength evidence). Evidence for benzodiazepine hypnotics, melatonin agonists, and antidepressants, and for most pharmacologic interventions in older adults, was insufficient or low strength. Evidence was also insufficient to compare efficacy within or across pharmacotherapy classes or versus behavioral therapy. Harms evidence reported in trials was judged insufficient or low strength; observational studies suggested that use of hypnotics for insomnia was associated with increased risk for dementia, fractures, and major injury. The FDA documents reported that most pharmacotherapies had risks for cognitive and behavioral changes, including driving impairment, and other adverse effects, and they advised dose reduction in women and in older adults.” (T. J. Wilt, tim.wilt@va.gov)
Compared with inactive controls, cognitive behavioral therapy for insomnia (CBT-I) has shown evidence of effectiveness in clinical trials, authors of a second evidence report conclude (
pp. 113–24). In 60 trials with low to moderate risk of bias, CBT-I “improved posttreatment global and most sleep outcomes, often compared with information or waitlist controls (moderate-strength evidence). Use of CBT-I improved several sleep outcomes in older adults (low- to moderate-strength evidence). Multicomponent behavioral therapy improved several sleep outcomes in older adults (low- to moderate-strength evidence). Stimulus control improved 1 or 2 sleep outcomes (low-strength evidence). Evidence for other comparisons and for harms was insufficient to permit conclusions.” (M. Brasure, brasu001@umn.edu)
Based on these evidence reports, the American College of Physicians makes two recommendations in the clinical practice guideline (
pp. 125–33; A. Qaseem, aqaseem@acponline.org):
* Recommendation 1: ACP recommends that all adult patients receive CBT-I as the initial treatment for chronic insomnia disorder. (Grade: strong recommendation, moderate-quality evidence)
* ACP recommends that clinicians use a shared decision-making approach, including a discussion of the benefits, harms, and costs of short-term use of medications, to decide whether to add pharmacological therapy in adults with chronic insomnia disorder in whom CBT-I alone was unsuccessful. (Grade: weak recommendation, low-quality evidence)
In implementing CBT-I, “A face-to-face intervention has the greatest evidence of efficacy and should be available in medical settings for those who need it,” editorialists write (
pp. 149–50). “Unfortunately, that is not the world in which we live. Work arounds include subsidizing CBT-I therapists to work in medical clinics, providing services via telemedicine, or improving referral access in behavioral health settings. Stepped-care models to manage patient demand for CBT-I have been proposed, but mechanisms for funding and disseminating such models are poorly developed. The ideal solution would involve having CBT-I available to patients in the setting where they usually receive medical care.…
“Unless access to and unencumbered payment for value-based behavioral interventions, such as CBT-I, in medical settings become a reality, patients with chronic insomnia will continue to receive suboptimal treatment and experience suboptimal outcomes. Patients, the health system, and society will also bear the cost burden of increased health care use by and reduced productivity of these ineffectively treated patients.” (R. G. Kathol,
roger-kathol@cartesiansolutions.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 20, 2016 * Vol. 23, No. 139
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
July 19 issue of JAMA (2016; 316).
Buprenorphine Implants for Illicit Opioid Use: In a study with “an exceptionally high response rate in the control group,” buprenorphine implants were not more effective than continued sublingual buprenorphine in opioid-dependent patients with stable abstinence (pp. 282–90). The study population was recruited at 21 U.S. sites in 2014–15; all were on stable doses of daily sublingual buprenorphine for 6 months or more. Based on a primary end point of between-group difference in proportion of responders, investigators found these results during a 6-month comparison: “Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non–implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively.” (R. N. Rosenthal, rrosenthal@chpnet.org)
“The approval of this new buprenorphine implant formulation provides a unique new tool to address the complex, often chronic and relapsing opioid use disorders,” editorialists write (
pp. 277–9). “This novel implant system may help buttress patients’ decision-making deficits that are a core component of the addiction by making these lifesaving medication adherence decisions far more infrequent. However, buprenorphine implants are currently approved by the US Food and Drug Administration for only up to 1 year of treatment for a subgroup of patients who have already achieved and sustained prolonged clinical stability while receiving low to moderate doses of oral transmucosal buprenorphine, a caveat clearly stated in the product label. Even so, this novel approach to delivering care may open up treatment for new, previously difficult-to-reach populations or for those in the criminal justice system. Although further research is needed to determine which populations would benefit the most from these new formulations, the potential of these agents to have a positive role in the current opioid crisis is undeniable.” (W. M. Compton, wcompton@nida.nih.gov)
Management of Opioid Use Disorder: In a synopsis article, authors present and discuss a clinical guideline developed in British Columbia (pp. 338–9). It makes three recommendations (A. S. Cifu, adamcifu@uchicago.edu):
* Opioid withdrawal alone is not recommended for treatment of opioid use disorder in most patients because of increased risks of overdose death and infectious disease, particularly HIV through intravenous drug use, following detoxification (moderate-quality evidence; strong recommendation).
* In the absence of contraindications, medically supervised opioid agonist treatment should be offered to patients. Buprenorphine/naloxone is the preferred first-line treatment. Methadone is an alternative in certain patient populations (high-quality evidence; strong recommendation).
* Psychosocial supports tailored to patient needs may be offered as an adjunct to medical treatment (moderate-quality evidence; conditional recommendation).
Outcomes with Hypoglycemic Agents in Type 2 Diabetes: Results of a network meta-analysis support recommendations of the American Diabetes Association for first-line treatment of adults with type 2 diabetes with metformin and “selection of additional therapies based on patient-specific considerations” (pp. 313–24). Metformin lowered A1C levels as well as or better than other agents, while all drugs produced similar efficacy and safety outcomes when added to metformin. (G. F. M. Strippoli, gfmstrippoli@gmail.com)

>>>PNN NewsWatch
* Consumers experiencing hair loss, hair breakage, balding, itching, and rash associated with the use of WEN, a Chaz Dean Cleansing Conditioner product, should stop use and seek medical care, FDA said yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 21, 2016 * Vol. 23, No. 140
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
July 21 New England Journal of Medicine (2016; 375).
Extended Aromatase-Inhibitor Adjuvant Therapy: In 1,918 postmenopausal women with hormone-receptor–positive early breast cancer, 10 years of adjuvant aromatase inhibitor therapy produced significantly improved rates of disease-free survival and contralateral breast cancer, researchers report, compared with placebo (pp. 209–19). Letrozole administered for an additional 5 years did not alter overall survival rates, the group notes: “After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P = 0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P = 0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P = 0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.” (P. E. Goss, pgoss@mgh.harvard.edu)
Lack of an effect on overall survival in this trial “should not be surprising,” editorialists write (
pp. 274–5): “The participants, who in most cases underwent randomization approximately 10 years after the time of diagnosis, have passed the peak risk of recurrence and a considerable proportion of their remaining risk as well. In any event, avoiding a new diagnosis of invasive breast cancer is a benefit in itself. However, the absence of a survival effect will be considered as oncologists and patients with breast cancer weigh the risks and benefits of the use of long-term adjuvant endocrine therapy.” (R. T. Chlebowski)
Meningococcal B Vaccine Immunogenicity: Used on a compassionate basis, a multicomponent meningococcal serogroup B (4CMenB) vaccine produced no immunogenic response in one third of college students vaccinated during a meningococcal outbreak in 2013–14, a study shows (pp. 220–8): “Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson’s correlation,0.64; P <0.001) but not with the response to the 5/99 strain (Pearson’s correlation,−0.06; P = 0.43).” (N. E. Basta, nebasta@umn.edu)
“The regulatory approval and clinical use of vaccines for pathogens that cause outbreaks will remain challenging,” observes an editorialist (
pp. 275–8). “4CMenB will not be the last vaccine for which a traditional, pivotal, double-blind, randomized, controlled trial with hard clinical end points is difficult, if not impossible, to generate. At one end of this spectrum are vaccines such as 4CMenB, for which the severity of the illness (despite treatment) and the existence of presumed correlates could make a compelling case for the use of the statutory accelerated pathway for product approval. At the other end, the alternate, accelerated approval pathway may be required to accommodate vaccines targeting pandemic threats or limited outbreaks.” (J. H. Kim)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 22, 2016 * Vol. 23, No. 141
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
July issue of Health Affairs, a theme issue on ACA Coverage, Health Spending & More (2016; 35).
Medication Reconciliation, Readmissions & Costs: An insurer-initiated, pharmacist-conducted medication reconciliation program reduced hospital readmissions and saved $2 for every $1 in costs, researchers report (pp. 1222–9). Pharmacists visited high-risk patients in their homes or contacted them by telephone to identify and resolve medication-related problems, with these results: “Program participants had a 50 percent reduced relative risk of readmission within thirty days of discharge and an absolute risk reduction of 11.1 percent. The program saved $2 for every $1 spent. These results represent real-world evidence that insurer-initiated, pharmacist-led care transition programs, focused on but not limited to medication reconciliation, have the potential to both improve clinical outcomes and reduce total costs of care.” (J. M. Polinski, jennifer.polinski@cvscaremark.com)
Medical Marijuana Laws & Part D Medication Use: In states with medical marijuana laws, use of certain prescription drugs by Medicare Part D beneficiaries fell after marijuana became available (pp. 1230–6): “Using data on all prescriptions filled by Medicare Part D enrollees from 2010 to 2013, we found that the use of prescription drugs for which marijuana could serve as a clinical alternative fell significantly, once a medical marijuana law was implemented. National overall reductions in Medicare program and enrollee spending when states implemented medical marijuana laws were estimated to be $165.2 million per year in 2013. The availability of medical marijuana has a significant effect on prescribing patterns and spending in Medicare Part D.” (W. D. Bradford, bradfowd@uga.edu)
“Me-Too” Brand-Name Drugs & Specialty Drugs: In two articles, costs of brand-name drugs in the same therapeutic category as agents with generic alternatives and of specialty pharmaceuticals are examined. In the first article, investigators find, “In 2013 patient copayments averaged 10.5 times more for two commonly prescribed brand-name medications versus generic therapeutic alternatives” (pp. 1237–40; N. M. Gastala, reizinee@gmail.com).
The proportion of prescription drugs reimbursed at $600 or more per 30-day fill nearly quadrupled between 2003 and 2014, the second article reports (
pp. 1241–6; S. B. Dusetzina; usetzina@unc.edu">Dusetzina@unc.edu): “Over this time period, fills for specialty drugs increased by 198 percent and spending for the drugs increased by 292 percent, as percentages of total drug fills and spending. Median out-of-pocket spending increased by 46 percent for specialty drugs and decreased by 57 percent for nonspecialty drugs during this time.”

>>>Medical Care Highlights
Source:
Aug. issue of Medical Care (2016; 54).
Financial Stress & Nonadherence in Diabetes: Health care providers should talk with patients with diabetes about reasons for cost-related nonadherence (CRN), according to authors who found perceived financial stress expressed by one half of these patients and health care and food insecurity in one fifth (pp. 796–803). Data from the 2013 National Health Interview Study of 34,557 individuals showed these relationships among perceived financial stress, financial insecurity with health care, food insecurity, and cost-reducing strategies on CRN: “Overall, 11% (n = 4,158) of adults reported diabetes; 14% with diabetes reported CRN, compared with 7% without diabetes. Greater perceived financial stress [prevalence ratio (PR) = 1.07; 95% confidence interval (CI), 1.05–1.09], financial insecurity with health care (PR = 1.6; 95% CI, 1.5–1.67), and food insecurity (PR = 1.30; 95% CI, 1.2–1.4) were all associated with a greater likelihood of CRN. Asking the doctor for a lower cost medication was associated with a lower likelihood of CRN (PR = 0.2; 95% CI, 0.2–0.3), and 27% with CRN reported this. Other cost-reducing behavioral strategies (using alternative therapies, buying prescriptions overseas) were associated with a greater likelihood of CRN.” (M. R. Patel)
Person-Centered Wellness Home: Wellness care is different from medical care, authors write, and pairing person-centered wellness homes with patient-centered medical homes could be synergistic (pp. 735–7; T. J. Mielenz).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 25, 2016 * Vol. 23, No. 142
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 23 issue of Lancet (2016; 388).
Early Rheumatoid Arthritis Treatment: Getting tocilizumab started quickly in patients newly diagnosed with rheumatoid arthritis is more important than initiation of methotrexate as described in current standards, according to authors of a clinical study of 317 patients (pp. 343–55). For 2 years, investigators at 21 Dutch rheumatology departments randomly assigned newly diagnosed patients to tocilizumab 8 mg/kg I.V. every 4 weeks with a maximum of 800 mg per dose, methotrexate orally 10 mg/week with stepped increases to a maximum of 30 mg per week until remission or dose-limiting toxicity, or both drugs, with these results: “For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1.13, 95% CI 1.00–1.29, p = 0.06 for tocilizumab plus methotrexate vs methotrexate, 1.14, 1.01–1.29, p = 0.0356 for tocilizumab vs methotrexate, and p = 0.59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study.” (J. W. G. Jacobs, j.w.g.jacobs@umcutrecht.nl)
Aspirin & Early Recurrent Stroke: Aspirin is a key element in successful prevention of recurrent stroke in the first few days after transient ischemic attack (TIA) or ischemic stroke, researchers report, warranting public education efforts (pp. 365–75). Effects of aspirin and dipyridamole on secondary prevention of stroke were identified in three postevent time periods, as follows: “We pooled data for 15,778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8,452 participants in the aspirin group had an ischaemic stroke vs 175 of 7,326; hazard ratio [HR] 0.42, 95% CI 0.32–0.55, p <0.0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8,452 vs 110 of 7,326; 0.29, 0.20–0.42, p <0.0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6,691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5,726 in the control group, HR 0.07, 95% CI 0.02–0.31, p = 0.0004; at 0–6 weeks, 14 vs 60 participants, 0.19, 0.11–0.34, p <0.0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0.42, 0.26–0.70, p = 0.0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0.97, 0.84–1.12, p = 0.67; severity mRS shift OR 1.00, 0.77–1.29, p = 0.97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0.90, 95% CI 0.65–1.25, p = 0.53; mRS shift OR 0.90, 0.37–1.72, p = 0.99), but dipyridamole did reduce risk thereafter (0.76, 0.63–0.92, p = 0.005), particularly of disabling or fatal ischaemic stroke (0.64, 0.49–0.84, p = 0.0010).” (P. M. Rothwell, peter.rothwell@clneuro.ox.ac.uk)

>>>PNN NewsWatch
* Talon Compounding Pharmacy (TCP) voluntarily recalled all lots of lyophilized HCG and sermorelin aseptically compounded and packaged by TCP and that remain within expiry due to FDA concern over a lack of sterility assurance, the agency said on Friday. The sterile products were distributed to patients and providers nationwide between January 18 and July 18 of this year.

>>>PNN JournalWatch
* Colistin Use in Patients With Reduced Kidney Function, in
American Journal of Kidney Diseases, 2016; 68: 296–306. (E. Fiaccadori, enrico.fiaccadori@unipr.it)
* Olodaterol for the Treatment of Chronic Obstructive Pulmonary Disease, in
American Journal of Health-System Pharmacy, 2016; 73: 1135–43. (W. H. Ramadan, wramadan@lau.edu.lb)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 26, 2016 * Vol. 23, No. 143
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source:
July issue of the Journal of the American Geriatrics Society (2016; 64).
Warfarin & All-Cause Mortality in AF: Among older community-dwelling adults in Italy with varying levels of health and function, treatment of atrial fibrillation (AF) with anticoagulation was associated with lower all-cause mortality rates over a 2-year period, researchers report (pp. 1416–24). Assessments with the Multidimensional Prognostic Index (MPI) based on information collected using the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA) showed these outcomes and associations in 2005–13: “Higher MPI-SVaMA scores were associated with lower rates of warfarin treatment and higher 3-year mortality. After adjustment for propensity score quintiles, warfarin treatment was significantly associated with lower 2-year mortality in individuals with MPI-SVaMA-1 (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.50–0.82), MPI-SVaMA-2 (HR = 0.68, 95% CI = 0.55–0.85), and MPI-SVaMA-3 (HR = 0.55, 95% CI = 0.44–0.67). Heterogeneity analyses confirmed that the effect of warfarin treatment was not different between MPI-SVaMA groups (P for heterogeneity = .48).” (A. Pilotto, alberto.pilotto@galliera.it)
Mortality & Glucose, BP & Cholesterol Control in the Very Old: Among patients with type 2 diabetes who were aged 80 or older, low glycosylated hemoglobin (HbA1c), blood pressure (BP), and total cholesterol (TC) were associated with higher mortality in an analysis of a U.K. primary care database (pp. 1425–31). Outcomes from 25,966 patients were as follows in this population-based cohort study: “There were 4,490 deaths during follow-up (median 2.0 years; mortality 104.7 per 1,000 person–years). Mortality in participants with low (<6.0% (<42 mmol/mol)) or high (≥8.5% (≥69 mmol/mol)) HbA1c was similar to that in those with the reference HbA1c (8.0–8.4% (64–68 mmol/mol)). Mortality was lowest in individuals with HbA1c of 7.0–7.4% (53–57 mmol/mol) (80.9 per 1,000 person–years, adjusted hazard ratio (aHR) = 0.80, 95% confidence interval (CI) = 0.70–0.91, P = .001). Mortality was higher in individuals with lower BP (e.g., <130/70 mmHg, 151.7 per 1,000 person–years, aHR = 1.52, 95% CI = 1.34–1.72, P <.001 vs reference BP <150/90 mmHg) and in the lowest TC category (<3.0 mmol/L, 138.7 per 1,000 person–years, aHR = 1.42, 95% CI = 1.24–1.64, P <.001 vs reference TC 4.5–4.9 mmol/L). The relationship between TC and mortality varied according to sex and prescription of lipid-lowering drugs.” (S. Hamada, hamada.shota@kcl.ac.uk)
Nursing Home Polypharmacy & Mortality: In a prospective observational cohort study of six nursing homes (NHs) in Israel, the number of drugs being used by residents was not associated with 2-year mortality rates (pp. 1432–8). Among 558 fully dependent and 206 mobile residents with dementia requiring institutional care, these outcomes were observed: “At baseline, 268 residents were taking five or fewer drugs per day, 202 were taking six or seven, and 294 were taking eight or more. In the multivariate analysis, the likelihood of dying within 2 years in the group taking six or seven drugs per day (odds ratio (OR = 0.95, 95% CI = 0.63–1.43) and in those taking eight or more (OR = 1.20, 95% CI = 0.78–1.84) was similar to that of those taking five or fewer. Variables at baseline independently associated with greater mortality were male sex (OR = 1.75, 95% CI = 1.24–2.46), older age (OR = 1.07, 95% CI = 1.04–1.10), higher Charlson Comorbidity Index (OR = 1.17, 95% CI = 1.04–1.30), and taking anticoagulant (OR = 1.78, 95% CI = 1.01–3.13) or antihyperglycemic medication (OR = 1.69, 95% CI = 1.12–2.53). Variables at baseline independently associated with lower mortality were higher body mass index (OR = 0.99, 95% CI = 0.93–0.99) and taking lipid-lowering medication (OR = 0.54, 95% CI = 0.36–0.80) and selective serotonin reuptake inhibitors or serotonin–norepinephrine reuptake inhibitors (OR = 0.52, 95% CI = 0.37–0.75).” (A. Schlesinger, agata.schlesinger@gmail.com)
Predicting Pneumonia: Electronic medical record data can be used to stratify older adults’ risks of developing pneumonia, a study shows (pp. 1439–47). “Age, sex, chronic obstructive pulmonary disease, congestive heart failure, body mass index, and use of inhaled or oral corticosteroids were critical predictors in all prognostic indices,” the authors report. (M. L. Jackson, jackson.ml@ghc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 27, 2016 * Vol. 23, No. 144
Providing news and information about medications and their proper use

>>>Nephrology Report
Source:
Aug. issue of the American Journal of Kidney Diseases (2016; 68).
Pain, Kidney Function Decline & Mortality: Among a nationally representative cohort of U.S. veterans, investigators found a prevalence of pain and analgesic prescription use, and pain was associated with increased rates of reduced kidney function, faster rates of decline in kidney function, and higher mortality (pp. 240–6). Data for more than 2.3 million veterans from 2004 to 2006 showed these patterns: “~60% of veterans reported pain of any severity during the baseline period. The most commonly prescribed analgesics were opioids. In a dose–response relationship, veterans reporting moderate or severe pain had a higher risk for faster [estimated glomerular filtration rates (eGFRs)] decline compared with those reporting none (ORs of 1.11 [95% CI, 1.09–1.14] and 1.17 [95% CI, 1.13–1.21] for moderate and severe pain, respectively). In combined analyses, veterans reporting moderate or severe pain both had 30% higher risk of the combined outcome (incident eGFR, 60 mL/min/1.73 m2 or death) compared with those reporting none (HRs of 1.30 [95% CI, 1.28–1.31] and 1.30 [95% CI, 1.28–1.32] for moderate and severe pain, respectively).” (J. L. T. Chen, joline.chen@va.gov)
Epoetin Alfa Titration Practices After Labeling Changes: Following labeling revisions for epoetin alfa (EPO) and implementation of a prospective payment system, EPO doses declined significantly, a study of Medicare patients shows (pp. 266–76). “Facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates,” the authors report, adding these details about 70,000 patients clustered in about 1,300 dialysis facilities: “Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels <10 g/dL (July–October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5–10.8 g/dL) but within-patient hemoglobin standard deviations were similar (~0.68 g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups.” (J. T. Molony, jmolony@cdrg.org)
Aspirin Use & Outcomes in Kidney Transplant Recipients: In stable renal transplant recipients with no history of cardiovascular disease (CVD), aspirin use was not associated with changes in CVD or mortality outcomes in a post-hoc analysis of data from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial (pp. 277–86). Comparing 981 aspirin users with 981 matched nonusers, the investigators found: “During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92–1.58], 0.92 [95% CI, 0.69–1.23], 1.19 [95% CI, 0.81–1.74], 1.03 [0.82–1.31], and 1.11 [95% CI, 0.88–1.38], respectively).” (D. E. Weiner, dweiner@tuftsmedicalcenter.org)

>>>PNN NewsWatch
* FDA yesterday approved safety labeling changes for fluoroquinolones to enhance warnings about their association with disabling side effects involving tendons, muscles, joints, nerves, and the central nervous system and limiting use of the drugs in those with less serious bacterial infections. These adverse effects can occur hours to weeks after exposure to fluoroquinolones and may be permanent, FDA said. While fluoroquinolone use in serious conditions such as anthrax, plague, and bacterial pneumonia is warranted, FDA said use in patients with acute bacterial sinusitis, acute exacerbation of chronic bronchitis and uncomplicated urinary tract infections should be reserved for those with no other options.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 28, 2016 * Vol. 23, No. 145
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
July 28 issue of the New England Journal of Medicine (2016; 375).
Cardiac, Renovascular Complications in Type 2 Diabetes: Two research articles and an editorial examine progress in pharmacotherapeutic reductions of complications of type 2 diabetes.
In the LEADER trial, participants taking liraglutide had significantly lower composite rates of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke compared with those on placebo, researchers report (
pp. 311–22). Among 9,340 patients with type 2 diabetes and high cardiovascular risk, the primary composite outcome of first occurrence of the above events showed the following during a median follow-up of 3.8 years: “The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4,668 patients [13.0%]) than in the placebo group (694 of 4,672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P <0.001 for noninferiority; P = 0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P = 0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P = 0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.” (J. B. Buse, john_buse@med.unc.edu)
EMPA-REG OUTCOME investigators found slower rates of progression of kidney disease and fewer clinically relevant renal events among participants on empagliflozin than among those on placebo, a second study notes (
pp. 323–34): “Incident or worsening nephropathy occurred in 525 of 4,124 patients (12.7%) in the empagliflozin group and in 388 of 2,061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P <0.001). Doubling of the serum creatinine level occurred in 70 of 4,645 patients (1.5%) in the empagliflozin group and in 60 of 2,323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4,687 patients (0.3%) in the empagliflozin group and in 14 of 2,333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.” (C. Wanner, wanner_c@ukw.de)
After noting that previous trials “have come close yet have not shown similar results” with regard to cardiovascular and microvascular benefits in type 2 diabetes, editorialists conclude (
pp. 380–2): “Although there may have been differences among the participants that account for the positive results in the EMPA-REG OUTCOME and LEADER trials, such differences alone do not fully explain the results. We are left with differences that appear encouraging, yet are not a ‘home run’ with regard to the management of diabetes. In the coming years, controlled and comparative effectiveness trials that uniformly combine newer agents with older agents may help to delineate an even more effective treatment plan for the millions of people whose lives are affected by type 2 diabetes.” (J. R. Ingelfinger)

>>>PNN NewsWatch
* FDA yesterday approved the glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide (Adlyxin, Sanofi), a once-daily injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes.
* The International Pharmaceutical Federation yesterday released
“Responding to disasters: Guidelines for pharmacy,” the first global guidelines that support continued access to medicines and pharmacy expertise during natural disasters, such as floods, heat waves, and earthquakes, The document describes actions under each of the four phases of an emergency — prevention/risk mitigation, preparation/readiness, response, and recovery.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
July 29, 2016 * Vol. 23, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Aug. issue of Diabetes Care (2016; 39).
Prandial Add-On Options for Basal Insulin Glargine Therapy: Short-acting glucagon-like peptide-1 receptor agonists may be preferred for add-on intensification during basal insulin therapy, according to an analysis of GetGoal Duo-2 trial data (pp. 1318–28). In overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1–3 oral antidiabetic drugs, lixisenatide once daily or insulin glulisine once or thrice daily produced these changes in glycosylated hemoglobin levels, weight, and hypoglycemic events: “Baseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m2). HbA1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
Saxagliptin & Hypoglycemia: Among 16,492 patients with type 2 diabetes in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study, risk factors for hypoglycemia were identified that clinicians can use to “better tailor antidiabetic therapy,” investigators conclude (pp. 1329–37). Over a median of 2.1 years, these associations were noted for any hypoglycemia (glucose level <54 mg/dL) or major hypoglycemia (requiring extended assistance): “At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P <0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia.” (I. Raz, ntv502@netvision.net.il)
Fatty Acid Intake & Type 2 Diabetes: Compared with diets high in carbohydrates (CHO) or in polyunsaturated fatty acids (PUFA), diets high in cis-monounsaturated fatty acids (MUFA) improve metabolic risk factors in patients with type 2 diabetes (T2D), according to a systematic review and meta-analysis (pp. 1448–57): “We identified 24 studies totaling 1,460 participants comparing high-MUFA to high-CHO diets and 4 studies totaling 44 participants comparing high-MUFA to high-PUFA diets. When comparing high-MUFA to high-CHO diets, there were significant reductions in fasting plasma glucose (WMD −0.57 mmol/L [95% CI −0.76, −0.39]), triglycerides (−0.31 mmol/L [−0.44, −0.18]), body weight (−1.56 kg [−2.89, −0.23]), and systolic blood pressure (−2.31 mmHg [−4.13, −0.49]) along with significant increases in HDL cholesterol (0.06 mmol/L [0.02, 0.10]). When high-MUFA diets were compared with high-PUFA diets, there was a significant reduction in fasting plasma glucose (−0.87 mmol/L [−1.67, −0.07]). All of the outcomes had low to medium levels of heterogeneity, ranging from 0.0 to 69.5% for diastolic blood pressure (Phet = 0.011).” (F. B. Hu, frank.hu@channing.harvard.edu)

>>>PNN NewsWatch
* Steps FDA is taking to protect the blood supply from Zika virus are outlined in a statement issued yesterday, including cessation of blood collections in Florida’s Miami–Dade and Broward counties.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 1, 2016 * Vol. 23, No. 147
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Adverse Outcomes & New EHR Systems in Hospitals: Among Medicare beneficiaries hospitalized during “go live” periods of implementation of new electronic health records (EHRs) in 17 U.S. hospitals, investigators found “no overall negative association of such implementation on short term inpatient mortality, adverse safety events, or readmissions” (i3835). Compared with events at 399 control hospitals in the same hospital referral region, study hospitals had these performance results during 90 days before and 90 days after implementation of EHRs: “Before and after implementation, characteristics of admissions were similar in both study and control hospitals. Among study hospitals, unadjusted 30 day mortality (6.74% to 7.15%, P = 0.06) and adverse safety event rates (10.5 to 11.4 events per 1,000 admissions, P = 0.34) did not significantly change after implementation of EHRs. There was an unadjusted decrease in 30 day readmission rates, from 19.9% to 19.0% post-implementation (P = 0.02). In difference-in-differences analysis, however, there was no significant change in any outcome between pre-implementation and post-implementation periods (all P ≥0.13).” (A. B. Jena, jena@hcp.med.harvard.edu)
“The biggest challenge to the usefulness of these results lies in the study’s design,” an editorialist writes (
i3941). “The ‘difference-in-differences’ design used here is generally considered strong but contains a hidden assumption—that hospitals can be treated like machines: mechanical, linear systems in which, when one component changes, all other components continue to operate as before. This is never the case for complex sociotechnical systems. In such systems, you can’t change only one thing—any intervention sets in motion a tangled web of other changes, some intended some not, some compensatory, some not; the ramifying influences of these effects and their feedbacks are not easily predicted or well captured in a global average.” (R. L. Wears, wears@ufl.edu)

>>>Lancet Highlights
Source:
July 30 issue of Lancet (2016; 388).
Olaratumab in Soft-Tissue Sarcoma: Potentially “suggesting a … shift in the treatment of soft-tissue sarcoma,” olaratumab with doxorubicin significantly increased median overall survival in patients with advanced soft-tissue sarcoma, compared with doxorubicin alone, researchers report (pp. 488–97). The open-label phase 1b/2 study at 16 U.S. sites yielded these respective results among 15 and 133 patients: “Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1–8.3) with olaratumab plus doxorubicin and 4.1 months (2.8–5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44–1.02, p = 0.0615). Median overall survival was 26.5 months (20.9–31.7) with olaratumab plus doxorubicin and 14.7 months (9.2–17.1) with doxorubicin (stratified HR 0.46, 0.30–0.71, p = 0.0003). The objective response rate was 18.2% (9.8–29.6) with olaratumab plus doxorubicin and 11.9% (5.3–22.2) with doxorubicin (p = 0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients).” (W. D. Tap, tapw@mskcc.org)

>>>PNN JournalWatch
* Colistin Use in Patients With Reduced Kidney Function, in
American Journal of Kidney Diseases, 2016; 68: 296–306. (E. Fiaccadori, enrico.fiaccadori@unipr.it)
* The Phenomenology of Major Depression and the Representativeness and Nature of DSM Criteria, in
American Journal of Psychiatry, 2016; 173: 771–80. (K. S. Kendler)
* The Digital Divide and Patient Portals: Internet Access Explained Differences in Patient Portal Use for Secure Messaging by Age, Race, and Income, in
Medical Care, 2016; 54: 772–9. (I. Graetz)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 2, 2016 * Vol. 23, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 2 issue of the Annals of Internal Medicine (2016; 165).
Cardiovascular Events & Tyrosine Kinase Inhibitors: In a nationwide study from Sweden, investigators uncover evidence of increased risk of arterial and venous events in patients receiving tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) (pp.161–6). The risk of myocardial infarction was elevated with two second-generation agents, compared with imatinib, according to the retrospective cohort study based on analysis of population-based registries: “896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1,000 person–years, respectively) than in those receiving imatinib (8 per 1,000 person–years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred.” (T. Dahlén, torsten.dahlen@karolinska.se)
Prophylactic Medications & Breast Cancer Risk: In a grand rounds summary, an oncologist and an internist present factors to discuss with women seeking prophylactic medications for increased risk of breast cancer (pp. 194–204): “Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown to reduce the risk for estrogen receptor–positive breast cancer and are approved by the U.S. Food and Drug Administration (FDA) for this indication. However, neither medication reduces the risk for estrogen receptor–negative breast cancer or all-cause mortality. The [U.S. Preventive Services Task Force in 2013] concluded that postmenopausal women with an estimated 5-year risk for breast cancer of 3% or greater will probably have more net benefit than harm and recommends that clinicians engage in shared, informed decision making about these medications. The American Society of Clinical Oncology issued a practice guideline on use of pharmacologic interventions for breast cancer in 2013. It recommends that women aged 35 years or older at increased risk, defined as a 5-year absolute risk for breast cancer of 1.66% or greater, discuss breast cancer prevention medications with their primary care practitioner. The Society includes the aromatase inhibitor exemestane in addition to tamoxifen and raloxifene as a breast cancer prevention medication, although exemestane is not FDA approved for this indication.” (R. B. Burns, rburns@bidmc.harvard.edu)
Emergence of Zika Virus: With yesterday’s CDC briefing on a Zika virus (ZIKV) outbreak in Miami as a backdrop, authors of a review article summarize all that remains unknown about this pathogen (pp. 175–83): “ZIKV is yet another arbovirus that is rapidly emerging on a global scale, on the heels of a chikungunya epidemic in the Americas that began in 2013. A ZIKV epidemic that began in Brazil in 2015 has now spread rapidly to more than 30 countries in the Americas and the Caribbean, infecting more than 2 million inhabitants. This epidemic currently continues unabated. The explosive nature of recent outbreaks and concerning links to Guillain–Barré syndrome and microcephaly are incompletely understood. Also unknown is the relative importance of sexual transmission of ZIKV and asymptomatic ZIKV infections to the overall burden of transmission. The limited understanding of ZIKV presents an enormous challenge for responses to this rapidly emerging threat to human health. This article reviews the existing literature on ZIKV and proposes critical questions for vaccine development and other areas of needed research.” (K. B. Anderson, ande7622@umn.edu)

>>>PNN NewsWatch
* Sage Products is voluntarily initiating a nationwide recall of one lot of Comfort Shield Barrier Cream Cloths (product code 7503; lot number 53957; expiration date 3/6/2018) to the distributor and health care facility/user level, FDA said yesterday. The recall is being initiated due to product contamination with Burkholderia cepacia, which can cause serious, potentially life-threatening infections in hospitalized or immunocompromised patients as well as certain other patient groups.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 3, 2016 * Vol. 23, No. 149
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Aug. 2 issue of JAMA (2016; 316).
Liraglutide in Advanced Heart Failure: The cardioprotective effects of glucagon-like peptide 1 (GLP-1) agonists seen in early clinical trials did not translate into greater clinical stability among patients hospitalized for advanced heart failure with reduced left ventricular ejection fraction (LVEF), according to results of a phase 2 study (pp. 500–8). Subcutaneous doses of the GLP-1 agonist liraglutide or placebo showed no differences in posthospitalization clinical stability, as reflected in these results: “Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52–68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%–33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054–4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57–2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89–1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively).” (K. B. Margulies, ken.margulies@uphs.upenn.edu)
Early Vasopressin in Septic Shock: While the use of early vasopressin in adults with septic shock failed to reduce the number of kidney failure–free days in a comparison with standard-of-care norepinephrine, a nonsignificant reduction in the need for renal replacement therapy may justify larger trials, VANISH investigators conclude (pp. 509–18). In 18 U.K. intensive care units, these results were recorded in a four-arm trial that also included hydrocortisone with the two vasopressors: “A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, −2.3% [95% CI, −13.0% to 8.5%]). The median number of kidney failure–free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to –24) in the vasopressin group and 13 days (IQR, 1 to –25) in the norepinephrine group (difference, −4 days [95% CI, −11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, −9.9% [95% CI, −19.3% to −0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, −3.3% to 8.2%]).” (A. C. Gordon, anthony.gordon@imperial.ac.uk)
Health Care Reform in the U.S.: In the first scholarly article authored by a sitting U.S. president, Pres. Obama assesses progress in health care reform under his Affordable Care Act, concluding that “policy makers should build on progress made by the Affordable Care Act by continuing to implement the Health Insurance Marketplaces and delivery system reform, increasing federal financial assistance for Marketplace enrollees, introducing a public plan option in areas lacking individual market competition, and taking actions to reduce prescription drug costs” (pp. 525–32). “Although partisanship and special interest opposition remain, experience with the Affordable Care Act demonstrates that positive change is achievable on some of the nation’s most complex challenges.” (B. Obama, press@who.eop.gov)
In one of four accompanying editorials, the
JAMA Editor calls on the U.S. presidential candidates to submit their ideas about health care reform before the election (pp. 492–3; H. Bauchner, howard.bauchner@jamanetwork.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 4, 2016 * Vol. 23, No. 150
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Aug. 4 New England Journal of Medicine (2016; 375).
Adalimumab for Hidradenitis Suppurativa: Among 307 patients with hidradenitis suppurativa in the PIONEER I and 326 in PIONEER II trials, adalimumab produced significantly higher clinical responses than did placebo, with similar adverse effects (pp. 422–34). Patients with the painful, chronic inflammatory skin disease received placebo or the TNF-alpha inhibitor in doses of 40 mg weekly for 12 weeks during period 1 followed by reassignment to adalimumab 40 mg or placebo weekly or every 2 weeks for 24 weeks, with these results: “Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P = 0.003) and 58.9% versus 27.6% in PIONEER II (P <0.001). Patients receiving adalimumab had significantly greater improvement than the placebo groups in rank-ordered secondary outcomes (lesions, pain, and the modified Sartorius score for disease severity) at week 12 in PIONEER II only. Serious adverse events in period 1 (excluding worsening of underlying disease) occurred in 1.3% of patients receiving adalimumab and 1.3% of those receiving placebo in PIONEER I and in 1.8% and 3.7% of patients, respectively, in PIONEER II. In period 2, the rates of serious adverse events were 4.6% or less in all the groups in both studies, with no significant between-group differences.” (A. B. Kimball, harvardskinstudies@gmail.com)
Asthma Risk in Amish and Hutterite Farm Children: Compared with children raised on Hutterite farms, Amish children have significantly lower rates of asthma and allergic sensitization despite much higher home levels of endotoxin, researchers report (pp. 411–21). “The Amish environment provides protection against asthma by engaging and shaping the innate immune response,” the authors conclude based on these findings: “Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling.” (D. Vercelli, donata@email.arizona.edu)
An editorialist examines possible mechanisms involved in and implications of these study results (
pp. 477–9): “The findings of Stein et al. support the notion that exposure to microbe-rich farm dust directs an alternative, proinflammatory, innate immune response involving transcriptional pathways and mediators, including nuclear factor kappa-B and IRF7, that prevents the emergence of asthma. It should be pointed out that microbial products may also act through [toll-like receptors] and MyD88 to activate the formation of regulatory T cells that enforce tolerance at mucosal surfaces. Thus, both long-term, low-level activation of innate immune cells and possibly T-cell–related immune regulatory mechanisms may contribute to the protective effects of the Amish farm dust against asthma.” (T. A. Chatila)
Defining and Using Pragmatic Trials: Pragmatic trials emerged in response to concerns that “many [clinical] trials did not adequately inform practice because they were optimized to determine efficacy,” review article authors write (pp. 454–63). Compared with explanatory trials that examine a physiological or clinical hypothesis, pragmatic trials “inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice,” the authors note. “The original PRECIS (Pragmatic–Explanatory Continuum Indicator Summary) tool attempted to clarify the concept of pragmatism and provided a guide, scoring system, and graphical representation of the pragmatic features of a trial. Features included the recruitment of investigators and participants, the intervention and its delivery, follow-up, and the determination and analysis of outcomes.” (I. Ford, ian.ford@glasgow.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 5, 2016 * Vol. 23, No. 151
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Aug. issue of Pediatrics (2016; 138).
Safety of 9-Valent HPV Vaccine: In seven phase 3 trials, the overall safety profile of 9-valent human papillomavirus (9vHPV) vaccine was similar to that of quadrivalent HPV (qHPV) vaccine, except for an increased risk of injection-site adverse events (AEs), researchers report (10.1542/peds.2015-4387). The study evaluates the three-dose 9vHPV regimen in more than 15,000 participants with these results: “The most common AEs (≥5%) experienced by 9vHPV vaccine recipients were injection-site AEs (pain, swelling, erythema) and vaccine-related systemic AEs (headache, pyrexia). Injection-site AEs were more common in 9vHPV vaccine than qHPV vaccine recipients; most were mild-to-moderate in intensity. Discontinuations and vaccine-related serious AEs were rare (0.1% and <0.1%, respectively). Seven deaths were reported; none were considered vaccine related. The proportions of pregnancies with adverse outcome were within ranges reported in the general population.” (E. D. Moreira Jr.)
Sports & Nonmedical Opioid Use: In the Monitoring the Future study, eighth and 10th graders had lower risks of lifetime nonmedical prescription opioid use (NPOU) or heroin use (10.1542/peds.2016-0677). Cross-sections of the 191,682 participants showed these longitudinal patterns: “The trends in NPOU and lifetime heroin use among adolescents who engage in sports and exercise has declined between 1997 and 2014. Logistic regression analyses found that adolescents who engage in sports and exercise had lower odds of reporting lifetime NPOU and heroin use compared with adolescents who did not engage in these activities during the past year.” (P. Veliz)

>>>Psychiatry Highlights
Source:
Aug. American Journal of Psychiatry (2016; 173).
SSRIs & Statins: The antidepressant effects of SSRIs are enhanced during concomitant statin therapy, a study shows (pp. 807–15). A nationwide cohort study conducted in Denmark adds to similar evidence from preclinical and clinical trials: “The authors identified 872,216 incident SSRI users, of whom 113,108 (13.0%) used a statin concomitantly. Compared with SSRI treatment alone, the combined use of an SSRI and a statin was associated with a significantly lower risk for both psychiatric hospital contacts (adjusted hazard ratio = 0.75 (95% CI = 0.69, 0.82) and psychiatric hospital contacts due to depression (adjusted hazard ratio = 0.64, 95% CI = 0.55, 0.75). Compared with SSRI treatment alone, the concomitant use of SSRIs and statins was not associated with significant increases in all-cause mortality (adjusted hazard ratio = 1.04, 95% CI = 0.96, 1.12) or suicidal behavior (adjusted hazard ratio = 0.85, 95% CI = 0.61, 1.18).” (O. Köhler)
Adolescent Marijuana Use & Subclinical Psychotic Symptoms: Regular marijuana use increases substantially the risk of subclinical psychotic symptoms among adolescent boys, according to a longitudinal study of 1,009 first and seventh graders who self-reported use at ages 13 to 18 (pp. 781–9): “For each year adolescent boys engaged in regular marijuana use, their expected level of subsequent subclinical psychotic symptoms rose by 21% and their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. The effect of prior regular marijuana use on subsequent subclinical psychotic symptoms persisted even when adolescents stopped using marijuana for a year. These effects were after controlling for all time-stable and several time-varying confounds. No support was found for reverse causation.” (J. Bechtold)

>>>PNN NewsWatch
* FDA yesterday said U.S. Marshals have seized more than 100 cases of products labeled as containing kratom. Consumption of kratom, distributed by Nature Therapeutics, can lead respiratory depression, vomiting, nervousness, weight loss, and constipation, the agency warned in urging consumers to avoid the plant-derived agent.
* “Rare diseases are no longer a neglected niche of the pharmaceutical business; they are a tantalizing moneymaking opportunity,” writes a
Washington Post reporter in asking whether 1983 Orphan Drug Act has backfired. “More than 400 treatments have been approved since the law passed. Last year, nearly half of all novel drugs approved were treatments for orphan diseases.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 8, 2016 * Vol. 23, No. 152
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 6 issue of Lancet (2016; 388).
High-Dose Cytarabine in Mantle Cell Lymphoma: In adults age 65 or younger with mantle cell lymphoma, immunotherapy with high-dose cytarabine followed by autologous stem-cell transplantation (ASCT) should be the standard of care, according to European Mantle Cell Lymphoma Network investigators (pp. 565–75). In a phase 3 trial conducted in 128 European hem-onc hospitals or practices these results were found in patients with untreated stage II–IV mantle cell lymphoma: “Of 497 patients (median age 55 years [IQR 49–60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4–6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3–not reached], 5 year rate 65% [95% CI 57–71]) than in the control group (3.9 years [3.2–4.4], 40% [33–46]; hazard ratio 0.56; p = 0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241 vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups.” (M. Dreyling, Martin.Dreyling@med.uni-muenchen.de)
Stem-Cell Transplantation in Aggressive Multiple Sclerosis: A report of a phase 2 trial describes “the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs,” authors write (pp. 576–85). Autologous hemopoietic stem-cell transplantation (aHSCT) produced these results in the single-arm trial at three Canadian hospitals: “Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient–years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9–12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6–84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.” (H. L Atkins, hatkins@ohri.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 353).
Blood Pressure & Complications in Type 2 Diabetes: A population-based cohort study based on Swedish national registries supports lower systolic blood pressures in patients with type 2 diabetes with no prior cardiovascular disease (i4070): “The group with the lowest systolic blood pressure (110–119 mm Hg) had a significantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% confidence interval 0.64 to 0.91; P = 0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P = 0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P = 0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P = 0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P = 0.03) compared with the reference group (130–139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality.” (S. Adamsson Eryd, samuel.adamssoneryd@registercentrum.se)

>>>PNN JournalWatch
* Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders, in
Pediatrics, 2016; 138: 10.1542/peds.2015-4256. (H. E. Hoyme)
* Improving Discharge Efficiency in Medically Complex Pediatric Patients, in
Pediatrics, 2016; 138: 10.1542/peds.2015-3832. (A. M. Statile)
* A Test in Context: Neprilysin—Function, Inhibition, and Biomarker, in
Journal of the American College of Cardiology, 2016; 68: 639–53. (A. Bayes-Genis)
* Treatment of Higher-Risk Patients With an Indication for Revascularization: Evolution Within the Field of Contemporary Percutaneous Coronary Intervention, in
Circulation, 2016; 134: 422–31. (A. J. Kirtane, akirtane@columbia.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 9, 2016 * Vol. 23, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. issue of JAMA Internal Medicine (2016; 176).
Drug Therapy & Conduction Disease: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), lisinopril use was associated with reduced incidence of first episodes of conduction system disease, researchers report (pp. 1085–92). In a secondary analysis of data on 21,004 ambulatory individuals 55 years or older with hypertension and at least one other cardiac risk factor, these associations were noted for amlodipine besylate, lisinopril, or chlorthalidone use and incident first-degree conduction disease: “Among the 1,114 participants who developed any conduction defect, 389 developed [left bundle branch block], 570 developed [right bundle branch block], and 155 developed intraventricular conduction delay. Compared with chlorthalidone, randomization to lisinopril was associated with a significant 19% reduction in conduction abnormalities (hazard ratio [HR], 0.81; 95% CI, 0.69–0.95; P  =  .01). Treatment with amlodipine, however, was not associated with a significant difference in conduction outcome events (HR, 0.94; 95% CI, 0.81–1.09; P  = .42). Similarly, pravastatin treatment was not associated with a reduced adjusted risk for incident disease compared with usual hyperlipidemia treatment (HR, 1.13; 95% CI, 0.95–1.35; P  =  .18). Increased age (HR, 1.47; 95% CI, 1.34–1.63; P <.001), male sex (HR, 0.59; 95% CI, 0.50–0.73; P <.001), white race (HR, 0.59; 95% CI, 0.50–0.70; P <.001), diabetes (HR, 1.23; 95% CI, 1.07–1.42; P = .003), and left ventricular hypertrophy (HR, 3.20; 95% CI, 2.61–3.94; P <.001) were also independently associated with increased risk for conduction system disease.” (G. M. Marcus, marcusg@medicine.ucsf.edu)
Statins, LDL Levels & Major Adverse Cardiac Events: Patients taking statins and achieving LDL cholesterol (LDL-C) levels of 70–100 mg/dL had lower risk of adverse cardiac outcomes than those with higher levels, according to an observational cohort study from Israeli health plan (pp. 1105–13). Among 4.3 million members, those with ischemic heart disease aged 30–84 years had these outcomes: “The cohort with at least 80% adherence included 31,619 patients, for whom the mean (SD) age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking statin treatment. Overall, there were 9,035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1,000 persons per year). The adjusted incidence of adverse outcomes was not different between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97–1.07; P = .54), but it was lower with moderate vs high LDL-C (HR, 0.89; 95% CI, 0.84–0.94; P < .001). Among 54,884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02–1.10; P = .001) in the low vs moderate groups and 0.87 (95% CI, 0.84–0.91; P = .001) in the moderate vs high groups.” (M. Leibowitz, leibowm@clalit.org.il)
Bleeding & Thrombosis in Older Adults Taking VKAs: Patients older than 80 have a small increase in bleeding risk while on vitamin K antagonists (VKAs) but a sharp increase in thrombosis risk, according to authors of a matched cohort study of older Dutch patients (pp. 1176–83): “During 6,419 observation–years, 713 of the 3,313 patients (1,394 men and 1,919 women) had 1,050 bleeding events. The risk of bleeding was not significantly increased in patients aged 80 to 89 years (event rate per 100 patient–years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89–1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05–1.50) compared with patients aged 70 to 79 years (ER, 14.8). The point estimates for major bleeding (including fatal) were comparable for patients aged 80 to 89 years (ER, 1.0; HR, 1.09; 95% CI, 0.60–1.98) and those 90 years or older (ER, 1.1; HR, 1.20; 95% CI, 0.65–2.22) compared with those aged 70 to 79 years (ER, 0.9). The increase in bleeding risk was sharper in men than in women. Eighty-five patients (2.6%) developed a thrombotic event. Risk of thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22–3.75) and 80s (HR, 1.75; 95% CI, 1.002–3.05) than for patients in their 70s. Vitamin K antagonist control became significantly poorer with rising age, which partly explained the increased bleeding risk in patients 90 years or older, but most of the increased risk of thrombosis was not mediated by VKA control.” (H. A. M. Kooistra, h.a.m.kooistra@umcg.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 10, 2016 * Vol. 23, No. 154
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Aug. 9 issue of JAMA (2016; 316).
INR Stability During Long-term Warfarin Therapy: Only 26% of patients on long-term warfarin therapy had stable INR values over a 6-month period, according to data obtained from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (pp. 661–3). By comparison, among those stable during the 6-month period, 34% remained stable over the following year, while 36% had one or more “extreme” INR values, the authors report. The study group comprised 3,749 patients with a mean age of 75 years; 43% were women. Results based on an assumption of an INR target range of 2–3 showed the following: “968 patients (26%) had 80% or more of INR values in 2.0–3.0 range during the first 6 months (median No. of INR measurements, 8 [interquartile range {IQR}, 6–10]) (Table). Of patients with stable INRs during the first 6 months, 34% (95% CI, 31%–37%) remained stable over the subsequent year (median No. of INR measurements, 13 [IQR, 10–16]). Prior stability explained a small amount of variation in subsequent stability (R2, 11% [95% CI, 9%–13%]). Stability during the baseline period had limited predictive ability of stability over the subsequent year (C index, 0.61 [95% CI, 0.59–0.62]).” (E. D. Peterson, eric.peterson@duke.edu)
Screening for Lipid Disorders in Children and Adolescents: A recommendation statement and related editorial provide guidance for clinicians in screening pediatric patients for lipid disorders. Two review articles provide the evidence basis for the discussion (multifactorial dyslipidemia: pp. 634–44, familial hypercholesterolemia: pp. 645–55; P. Lozano, lozano.p@ghc.org).
Evidence regarding screening for lipid disorders in children and adolescents is insufficient to make a recommendation, according to the U.S. Preventive Services Task Force (USPSTF) (
pp. 625–33). In an update to its 2007 recommendation, USPSTF advises: “Evidence on the quantitative difference in diagnostic yield between universal and selective screening approaches, the effectiveness and harms of long-term treatment and the harms of screening, and the association between changes in intermediate outcomes and improvements in adult cardiovascular health outcomes are limited. Therefore, the USPSTF concludes that the balance of benefits and harms cannot be determined.” (K. Bibbins-Domingo, chair@uspstf.net)
“A system is still needed for identifying high-risk patients,” editorialists write, noting that an estimated 525,600 infants are born in the U.S. annually with familial hypercholesterolemia (FH) (
pp. 589–91). “Considering that all newborns undergo screening for phenylketonuria, which has a prevalence of 1 in 10,000, it seems reasonable that clinicians should also perform screening to detect FH (and pediatric lipid disorders), a disease that is far more common and is known to cause early morbidity and mortality. The USPSTF rightfully acknowledges that “clinical decisions involve more considerations than evidence alone.” Accordingly, when high-quality [randomized controlled trial] data are lacking, clinicians who provide care for children and adolescents should make the best use of the available evidence to make reasonable inferences that can inform decision making for their patients and their families.” (E. M. Urbina, elaine.urbina@cchmc.org)
Kidney Disease in Patients With Diabetes: The overall prevalence of kidney disease among U.S. adults with diabetes did not change over the past three decades, a study shows, but the prevalence of albuminuria decreased while that for reduced estimated glomerular filtration rate (eGFR) increased (pp. 602–10). Data from the National Health and Nutrition Examination Surveys from 1988 through 2014 also showed the following: “Significant heterogeneity in the temporal trend for albuminuria was noted by age (P = .049 for interaction) and race/ethnicity (P = .007 for interaction), with a decreasing prevalence of albuminuria observed only among adults younger than 65 years and non-Hispanic whites, whereas the prevalence of reduced GFR increased without significant differences by age or race/ethnicity.” (I. H. de Boer, deboer@u.washington.edu)

>>>PNN NewsWatch
* Possible Burkholderia cepacia contamination has prompted recall of a number of PharmaTech drug and dietary supplement (vitamin) products, FDA said yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 11, 2016 * Vol. 23, No. 155
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Aug. 11 issue of the New England Journal of Medicine (2016; 375).
Extended Thromboprophylaxis with Betrixaban: Extended-duration betrixaban and a standard regimen of enoxaparin protected similarly against thrombosis in acutely ill medical patients in a trial of 7,513 patients, researchers report (pp. 534–44). Two cohorts of patients had suggestions of benefits with extended betrixaban, as noted in these study results for patients with elevated d-dimer levels (cohort 1), elevated d-dimer level or an age of 75 years or more (cohort 2), and all enrolled patients (overall population cohort): “In cohort 1, the primary efficacy outcome [of a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism] occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P = 0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P = 0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P = 0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P = 0.55).” (A. T. Cohen, alexander.cohen@kcl.ac.uk)
Migalastat in Fabry’s Disease: An oral pharmacologic chaperone that stabilizes specific mutant forms of alpha-galactosidase provided no advantage over placebo in 67 patients with Fabry’s disease (pp. 545–55). Deficiency of this X-linked enzyme leads to accumulation of glycosphingolipids, the authors note, leading to multisystem disease and early death in those with the disease. Double-blind migalastat or placebo was provided on a randomized basis for 6 months (stage 1) followed by open-label migalastat for 6–12 months, with these results based on a primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months: “The primary end-point analysis, involving patients with mutant alpha-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P = 0.30). Among patients with suitable mutant alpha-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were –0.30 ± 0.66 and −1.51 ± 1.33 ml per minute per 1.73 m2 of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (−7.7 g per square meter; 95% confidence interval [CI], −15.4 to –0.01), particularly when left ventricular hypertrophy was present (−18.6 g per square meter; 95% CI, −38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased.” (D. P. Germain, dominique.germain@uvsq.fr)
Dietary Sodium and Cardiovascular Disease Risk: In a Sounding Board article, authors examine the challenges Americans face in reducing sodium intake to lessen their risks of cardiovascular disease given the amount of salt added to foods by the industry (pp. 580–6): “Nearly half of Americans are already trying to reduce their dietary sodium, and most want low-sodium foods. Yet sodium levels are high before food reaches the kitchen or table, and the sodium density of the U.S. diet has changed little despite consumer education encouraging individual behavior change. Most of the sodium consumed is already in the foods we purchase and cannot be removed by consumers. By reducing the amount of sodium in foods, manufacturers and food-service operators can give consumers more control over their sodium intake. Reducing the average sodium intake by just 400 mg per day could potentially avert as many as 28,000 deaths and save $7 billion in health care costs annually in the United States. Reducing population sodium intake, through reducing excess sodium in manufactured and restaurant food in the United States, represents an important opportunity to prevent heart disease and stroke and reduce health care costs.” (M. E. Cogswell)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 12, 2016 * Vol. 23, No. 156
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Aug. issue of Chest (2016; 150).
Errors in Inhaler Use: Among patients treated with metered-dose inhalers (MDIs) and dry powder inhalers (DPIs), “incorrect … technique is unacceptably frequent and has not improved over the past 40 years, pointing to an urgent need for new approaches to education and drug delivery,” authors of a systematic review write (pp. 394–406). In articles published between 1975 and 2014, these outcomes were noted for the first and second 20-year periods: “Data were extracted from 144 articles reporting on a total number of 54,354 subjects performing 59,584 observed tests of technique. The most frequent MDI errors were in coordination (45%; 95% CI, 41%–49%), speed and/or depth of inspiration (44%; 40%–47%), and no postinhalation breath-hold (46%; 42%–49%). Frequent DPI errors were incorrect preparation in 29% (26%–33%), no full expiration before inhalation in 46% (42%–50%), and no postinhalation breath-hold in 37% (33%–40%). The overall prevalence of correct technique was 31% (28%–35%); of acceptable, 41% (36%–47%); and of poor, 31% (27%–36%). There were no significant differences between the first and second 20-year periods of scrutiny.” (J. Sanchis)
Pulmonary Arterial Hypertension-Specific Therapy: Monotherapy targeting pulmonary arterial hypertension (PAH) is better than placebo or “conventional therapy” in terms of improved outcomes in mortality, exercise capacity, functional class, and hemodynamic status, a meta-analysis shows (pp. 353–66). Combination therapy further improves patients’ exercise capacity, functional class, and hemodynamic status but without significant changes in mortality and with more adverse effects: “In total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95% CI, 0.33 to 0.76]; P = .001), 6-min walk test (mean difference, 31.10 m [95% CI, 25.40 to 36.80]; P <.00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95% CI, 1.51 to 4.07]; P = .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96 m [95% CI, 15.35 to 24.57]; P <.00001), functional class (OR, 1.65 [95% CI, 1.20 to 2.28]; P = .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95% CI, 1.54 to 2.61]; P <.00001) but not for mortality reduction (OR, 0.98 [95% CI, 0.57 to 1.68]; P = .94).” (Y-f Jiang)

>>>Circulation Report
Source:
Aug. 9 issue of Circulation (2016; 134).
Drugs & Heart Failure: Based on a review of dozens of medications that can produce or exacerbate heart failure (HF), an American Heart Association panel makes nine recommendations and reaches this conclusion (pp. e32–69): “Polypharmacy is a significant concern in patients with HF because of the burden of both cardiovascular and noncardiovascular conditions. It is not unusual to have medications ordered and adjusted by different clinicians, many times with minimal consideration for drug–drug or drug–condition interactions, or to have prescriptions filled at different pharmacies. The following strategies may be helpful in detecting inappropriate and potentially hazardous medications that could exacerbate HF.” Ideas include establishing “a team management approach in which a healthcare provider acts as ‘captain’ of the medications and instructs patients to notify this individual whenever a medication is changed or added to the medication list. Ideally, this call should made before the product is purchased or the prescription is filled.” (http://professional.heart.org/statements)

>>>PNN NewsWatch
* FDA yesterday issued a revised draft guidance to improve dietary supplement companies’ new dietary ingredient (NDI) premarket safety notifications to the agency. These notifications help identify safety concerns before products reach consumers. FDA said the draft guidance clarifies several important points that were misunderstood or not fully explained in a 2011 version, describes the public health significance of the recommendations, and requests additional comment for use in developing a final guidance.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 15, 2016 * Vol. 23, No. 157
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Physical Activity & Disease Risk: Significant reductions in risks of five common diseases were associated with physical activity several times greater than currently recommended levels, authors of a systematic review and Bayesian dose–response meta-analysis write (i3857): “174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000–4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level [about 150 minutes/week of brisk walking or 75 minutes/week of running]) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3,600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9,000 to 12,000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity <600 MET minutes/week), the risk reduction for those in the highly active category (≥8,000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty interval 0.829 to 0.900) for breast cancer; 21% (0.789, 0.735 to 0.850) for colon cancer; 28% (0.722, 0.678 to 0.768) for diabetes; 25% (0.754, 0.704 to 0.809) for ischemic heart disease; and 26% (0.736, 0.659 to 0.811) for ischemic stroke.” (M. H. Forouzanfar, forouzan@uw.edu)
Blood Pressure Variability & Cardiovascular Disease: Long-term variability in blood pressure carries cardiovascular and mortality risks similar to those with elevated cholesterol levels, according to results of a systematic review and meta-analysis of 19 observational cohort studies and 17 clinical trial cohorts (i4098). The investigators concluded that “future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date” based on these study results: “Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively).” (R. J. Stevens, richard.stevens@phc.ox.ac.uk)

>>>PNN NewsWatch
* Consumers should stop use of DHZC-2 tablets (Ton Shen Health) and return them to the place of purchase, FDA said on Friday. The product, sold mostly in the Chicagoland area, may be contaminated with lead, the agency said.

>>>PNN JournalWatch
* Economic Downturns, Universal Health Coverage, and Cancer Mortality In High-Income and Middle-Income Countries, 1990–2010: A Longitudinal Analysis, in
Lancet, 2016; 388: 684–95. (M. Maruthappu, maruthappu@post.harvard.edu)
* Commonalities and Distinctions Between Alcoholic and Nonalcoholic Fatty Liver Disease, in
Gastroenterology, 2016; 150: 1695–7 (theme issue on this topic). (A. J. Sanyal)
* Executive Summary: Management of Adults With Hospital-Acquired and Ventilator-Associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society, in
Clinical Infectious Diseases, 2016; 63: 575–82. (A. C. Kalil, akalil@unmc.edu)
* Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline, in
Journal of Clinical Oncology, 2016; 34: 2784–96. (American Society of Clinical Oncology, guidelines@asco.org)
* Multidisciplinary Interventions in the Management of Atopic Dermatitis, in
Journal of Allergy and Clinical Immunology, 2016; 138: 325–34. (J. S. LeBovidge, jennifer.lebovidge@childrens.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 16, 2016 * Vol. 23, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-online article from and the Aug. 16 issue of the Annals of Internal Medicine (2016; 165).
LAIV v. IIV in Hutterite Children: In a study conducted in 52 Hutterite colonies in Canada, children were protected similarly against influenza by intranasal live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV), researchers report (10.7326/M16-0513). The results failed to support a hypothesis of LAIV superiority over IIV, but neither were they consistent with inferior protection found in surveillance data that led the CDC to not recommend use of LAIV in the upcoming influenza season. The cluster randomized blinded trial was conducted over three influenza seasons from 2012 to 2015. Findings for 1,186 children and adolescents receiving the vaccine and 3,425 community members who did not were as follows: “Mean vaccine coverage among children in the LAIV group was 76.9% versus 72.3% in the IIV group. Influenza virus infection occurred at a rate of 5.3% (295 of 5560 person–years) in the LAIV group versus 5.2% (304 of 5810 person–years) in the IIV group. The hazard ratio comparing LAIV with IIV for influenza A or B virus was 1.03 (95% CI, 0.85 to 1.24).” (M. Loeb, loebm@mcmaster.ca)
Health Care Service Value by Advanced Practice Clinicians & Physicians: Nurse practitioners and physician assistants provided an equivalent amount of low-value health care services compared with physicians in a study that dispels the ideas about care provided for common conditions by advanced practice clinicians (APCs) (pp. 237–44). Data from the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS), 1997 to 2011 produce these measures of care value for patients presenting with upper respiratory infections (URIs), back pain, or headache: “12,170 physician and 473 APC office-based visits and 13,359 physician and 2,947 APC hospital-based visits were identified. Although office-based clinicians saw similar patients, hospital-based APCs saw younger patients (mean age, 42.6 vs. 45.0 years; P <0.001), and practiced in urban settings less frequently (49.7% vs. 81.7% of visits; P <0.001) than hospital-based physicians. Unadjusted and adjusted results revealed that APCs ordered antibiotics, CT or MRI, radiography, and referrals as often as physicians in both settings. Stratification suggested that self-identified [primary care provider (PCP)] APCs ordered more services than PCP physicians in the hospital-based setting.” (J. N. Mafi, jmafi@mednet.ucla.edu)
“Various studies have shown that APCs may provide comparable or even superior care, especially under circumstances in which the additional clinical acumen gained by more training and experience may not be required,” an editorialist writes (
pp. 290–1). “Perhaps URIs, headache, and low back pain are additional examples of the more extensive training of primary care physicians not contributing to higher value care.… A better understanding of these issues may guide more informed ascertainment of the competencies required for skillful primary care in different settings and patient populations.” (E. C. Rich, ERich@mathematica-mpr.com)
Naloxone Coprescription for Primary Care Patients: In primary care patients who are prescribed long-term opioid therapy for pain, providers may prioritize the coprescribing of naloxone based on presence of established risk factors, a study shows (pp. 245–52). In a nonrandomized and possibly nongeneralizable study conducted at six safety-net primary care clinics in San Francisco over a 2-year period, investigators found these results when providers and staff were trained and supported in naloxone coprescribing: “38.2% of 1,985 patients receiving long-term opioids were prescribed naloxone. Patients prescribed higher doses of opioids and with an opioid-related [emergency department (ED)] visit in the past 12 months were independently more likely to be prescribed naloxone. Patients who received a naloxone prescription had 47% fewer opioid-related ED visits per month in the 6 months after receipt of the prescription (incidence rate ratio [IRR], 0.53 [95% CI, 0.34 to 0.83]; P = 0.005) and 63% fewer visits after 1 year (IRR, 0.37 [CI, 0.22 to 0.64]; P <0.001) compared with patients who did not receive naloxone. There was no net change over time in opioid dose among those who received naloxone and those who did not (IRR, 1.03 [CI, 0.91 to 1.27]; P = 0.61).” (P. Coffin, phillip.coffin@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 17, 2016 * Vol. 23, No. 159
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Aug. 16 issue of JAMA (2016; 316).
Abaloparatide & New Vertebral Fractures: The risk of new vertebral fractures among postmenopausal women with osteoporosis was reduced with treatment with a selective activator of the parathyroid hormone type 1 receptor, researchers report (pp. 722–33). Comparing subcutaneous abaloparatide with placebo, ACTIVE study investigators found these differences based on a primary end point of percentage of participants with new vertebral fracture: “Among 2,463 women (mean age, 69 years [range, 49–86]), 1,901 completed the study. New morphometric vertebral fractures occurred in 0.58% (n = 4) of the abaloparatide group, 4.22% (n = 30) of the placebo group (risk difference [RD] vs placebo, −3.64 [95% CI, −5.42 to −2.10]; relative risk, 0.14 [95% CI, 0.05–0.39]; P <.001), and 0.84% (n = 6) of the teriparatide group. The Kaplan–Meier estimated event rate for nonvertebral fracture was 2.7% for abaloparatide, 4.7% for placebo (RD, −2.01 [95% CI, −4.02 to −0.00]; hazard ratio [HR], 0.57 [95% CI, 0.32–1.00]; P = .049), and 3.3% for teriparatide. [bone mineral density] increases were greater with abaloparatide than with placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) than with teriparatide (6.4%) with an RD of −2.96 (95% CI, −5.12 to −0.87; P = .006).” (P. D. Miller, millerccbr@aol.com)
With nearly half of white women over 50 years of age expected to have an osteoporotic fracture during their remaining lifetime, editorialists write that abaloparatide has potential but unproven utility as a “second-in-class” agent (
pp. 715–6): “There is a limit to how much bone strength can improve by reducing resorption in the absence of stimulating formation and rebuilding bone microarchitecture. Additional anabolic osteoporosis therapies are needed, particularly ones that have improved safety, efficacy, ease of administration, and cost compared with teriparatide. Ultimately, which therapy is selected for osteoporosis treatment may be less important than identifying and initiating an approved treatment. The bar is high for any preventive treatment—in the efforts to prevent a fracture that may or may not ever occur, prescribers do not want to prescribe a therapy that causes a new problem. The way forward for fracture prevention involves not only the development of better therapies to prevent fracture and easier delivery systems but also improved adoption of existing osteoporosis therapies for patients with prior fractures and minimization of adverse effects, particularly those associated with long-term use.” (A. R. Cappola, acappola@mail.med.upenn.edu)
Cost-effectiveness of PCSK9 Inhibitor Therapy: To reach a quality-adjusted life–year (QALY) threshold of $100,000 in patients with heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD), the cost of marketed PCSK9 inhibitors would need to fall by $10,000 per year, a study shows (pp. 743–53). Using the Cardiovascular Disease Policy Model to simulate U.S. adults aged 35–94 years of age, these results were generated assuming a wholesale cost of $14,350 per year and using a lifetime horizon and health-system perspective: “Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 [lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke)] at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000–$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000–$1,539,000). Reducing annual drug costs to $4,536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38% increase over 2015 prescription drug expenditures). In contrast, initiating statins in these high-risk populations in all statin-tolerant individuals who are not currently using statins was estimated to save $12 billion.” (K. Bibbins-Domingo, kirsten.bibbins-domingo@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 18, 2016 * Vol. 23, No. 160
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Aug. 18 issue of the New England Journal of Medicine (2016; 375).
Analgesics & Asthma in Young Children: Countering an idea that acetaminophen use is associated with asthma in children, a study finds no difference between that drug and ibuprofen when used on an as-needed basis in patients aged 12–59 months with mild persistent asthma (pp. 619–30). NIH/NHLBI AsthmaNet investigators conducting the trial assigned 300 children to receive acetaminophen or ibuprofen for fever or pain over a 48-week period, with these results: “Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P = 0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P = 0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P = 0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P = 0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P = 0.94), or adverse events.” (W. Phipatanakul, wanda.phipatanakul@childrens.harvard.edu)
This trial, lacking a placebo group, “does not directly answer the question of whether the use of acetaminophen or ibuprofen, as compared with no drug use, can worsen asthma,” an editorialist writes (
pp. 684–5): “As stated by the authors, the inclusion of a placebo group would have been unethical in this case, and thus this question may never be answered definitively. However, the outcome rates over the course of this trial (0.81 asthma exacerbations per participant in the acetaminophen group and 0.87 asthma exacerbations per participant in the ibuprofen group) appear to be approximately the same as the outcome rates in other trials involving children in this age group, which suggests that there is no significant increase in symptoms associated with the use of either acetaminophen or ibuprofen. Given the difficulties of designing a trial with a true placebo group, this may be the best answer we can get in this age group.” (A. A. Litonjua)
Obeticholic Acid in Primary Biliary Cholangitis: The farnesoid X receptor agonist obeticholic acid produced beneficial changes in serum markers in patients with primary biliary cholangitis, compared with placebo, but its use was also associated with more serious adverse events (pp. 631–43). Based on a primary end point of alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level, the POISE trial shows: “Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5–10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P <0.001 for both comparisons). Patients in the 5–10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, −113 and −130 U per liter, respectively, vs. −14 U per liter; P <0.001 for both comparisons) and total bilirubin level (−0.02 and −0.05 mg per deciliter [−0.3 and −0.9 µmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 µmol per liter]; P <0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5–10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5–10-mg group, 11% in the 10-mg group, and 4% in the placebo group.” (F. Nevens, frederik.nevens@uzleuven.be)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 19, 2016 * Vol. 23, No. 161
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source:
Aug. 20 issue of the Journal of Clinical Oncology (2016; 34).
Disease Monitoring Costs in Metastatic Breast Cancer: In older women with metastatic breast cancer (MBC), “extreme” use of monitoring tests that have little clinical utility was common and has the potential to drive up health care costs, researchers report (pp. 2820–6). Women (n = 2,460) identified in the SEER-Medicare database as having MBC in 2002–11 and undergoing disease monitoring showed these patterns of extreme use of disease-monitoring tests (serum tumor markers [STMs] and radiographic imaging): “924 (37.6%) [women] were extreme users of disease-monitoring tests. Factors significantly associated with extreme use were hormone receptor–negative MBC (odds ratio [OR], 1.63; 95% CI, 1.27 to 2.08), history of a positron emission tomography scan (OR, 2.92; 95% CI, 2.40 to 3.55), and more frequent oncology office visits (OR, 3.14; 95% CI, 2.49 to 3.96). Medical costs per year were 59.2% higher in extreme users. Extreme users were more likely to use emergency department and hospice services at the end of life.” (M. K. Accordino, mkg2134@cumc.columbia.edu)
“We are fortunate to have a rapidly expanding armamentarium of therapies that improve survival for women with MBC,” editorialists write (
pp. 2807–9). “However, as our patients live for longer, we must remain mindful of our limited resources and allocate costs across the disease trajectory from diagnostic tests to therapeutics to palliative interventions. Given the choice between spending limited dollars on extreme use of tests that do not have an impact on outcomes and spending them on newer therapies that improve health, the answer is clear.” (T. J. Smith, tsmit136@jhmi.edu)
CML Life Expectancy After Imitinib: Following introduction of imatinib mesylate and subsequently marketed tyrosine kinase inhibitors (TKIs), life expectancy of patients with chronic myeloid leukemia (CML) increased and approached that of the general population, a study shows, adding “this will be an important message to convey to patients” (pp. 2851–7). Data in the Swedish Cancer Registry from 1973 to 2013 reflect these increases in life expectancy and loss in expectation of life: “A total of 2,662 patients with CML were diagnosed between 1973 and 2013. Vast improvements in the life expectancy of these patients were seen over the study period; larger improvements were seen in the youngest ages. The great improvements in life expectancy translated into great reductions in the loss in expectation of life. Patients of all ages diagnosed in 2013 will, on average, lose < 3 life-years as a result of CML.” (H. Bower, hannah.bower@ki.se)

>>>Infectious Diseases Report
Source:
Sept. 1 issue of Clinical Infectious Diseases (2016; 63).
Fluconazole Prophylaxis in Premie Candidiasis: In an analysis of all randomized, placebo-controlled trials of prophylactic fluconozole in premature infants, investigators find that the intervention is safe, effective, and not increasing resistance (pp. 604–10). Patient-level data obtained from study investigators were assessed for invasive candidiasis (IC) or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates, with these results: “Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30–.78), 0.20 (95% CI, .08–.51), and 0.28 (95% CI, .18–.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups.” (D. K. Benjamin, danny.benjamin@duke.edu)
Pneumococcal Vaccines & Otitis Media: Pneumoccal and other cases of otitis media declined in children younger than 3 years of age following widespread introduction of pneumococcal conjugated vaccines 7 and 13, according to a study from Israel (pp. 611–8; R. Dagan, rdagan@bgu.ac.il).

>>>PNN NewsWatch
* Arbor Pharmaceuticals yesterday announced a voluntary recall of three lots (005C16, 006C16 and 007C16, expiration date 02/2018) of Cetylev (acetylcysteine) effervescent tablets for oral solution 500 mg because of an inadequate seal of the blister pack, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 22, 2016 * Vol. 23, No. 162
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Feedback & Behavioral Change in Primary Care Prescribing: Interventions that can be delivered using electronic health records can reduce high-risk prescribing in primary care practices, a study shows (i4079). In Scotland, 262 practices were randomized to usual care (emailed educational materials), usual care plus feedback (five quarterly reports), or usual care plus feedback and a behavioral change component. Based on a primary outcome of patient-level composite of six prescribing measures relating to high-risk use of antipsychotics, NSAIDs, and antiplatelets, 15-month results showed: “In the primary analysis, high risk prescribing as measured by the primary outcome fell from 6.0% (3,332/55,896) to 5.1% (2,845/55,872) in the usual care arm, compared with 5.9% (3,341/56,194) to 4.6% (2,587/56,478) in the feedback only arm (odds ratio 0.88 (95% confidence interval 0.80 to 0.96) compared with usual care; P = 0.007) and 6.2% (3,634/58,569) to 4.6% (2,686/58,582) in the feedback plus behavioural change component arm (0.86 (0.78 to 0.95); P = 0.002). In the pre-specified secondary analysis of change in trend within each arm, the usual care educational intervention had no effect on the existing declining trend in high risk prescribing. Both types of feedback were associated with significantly more rapid decline in high risk prescribing after the intervention compared with before.” (B. Guthrie, b.guthrie@dundee.ac.uk)
Pioglitazone & Bladder Cancer: Supporting results from other recent trials, a retrospective cohort study finds no association between use of pioglitazone for type 2 diabetes and risk of bladder cancer (i3903). Data from Finland, the Netherlands, Sweden, and the U.K. show these risk patterns among 56,337 patients who initiated pioglitazone therapy and 317,109 matched control patients who used other antidiabetic drugs: “In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean followup time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40,000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort).” (P. Korhonen, pasi.korhonen@epidresearch.com)
Ultrasound Monitoring in Early Rheumatoid Arthritis: When treated with currently recommended agents, people with early rheumatoid arthritis do not need routine ultrasound monitoring, researchers report (i4205). Tight-control therapy was guided by changes in ultrasound images in the 238-patient study from Norway, but results were similar to those with conventional tight-control approaches. The authors conclude, “The findings highlight the need for randomised trials assessing the clinical application of medical technology.” (E. A. Haavardsholm, e.a.haavardsholm@medisin.uio.no)

>>>PNN NewsWatch
* Sagent Pharmaceuticals is recalling one lot of Oxacillin for Injection, USP, 10 g (lot OXT512; expiration date March 2017) because a single vial was found to contain iron oxide particulate matter, FDA announced on Friday.

>>>PNN JournalWatch
* Association Between Payments From Manufacturers of Pharmaceuticals to Physicians and Regional Prescribing: Cross Sectional Ecological Study, in
BMJ, 2016; 354: i4189. (W. Fleischman, wf3@buffalo.edu)
* Quality of Care Provided by a Comprehensive Dementia Care Comanagement Program, in
Journal of the American Geriatrics Society, 2016; 64: 1724–30. (L. A. Jennings, lajennings@mednet.ucla.edu)
* An Interprofessional Approach to Reducing the Risk of Falls Through Enhanced Collaborative Practice, in
Journal of the American Geriatrics Society, 2016; 64: 1701–7. (E. Eckstrom, eckstrom@ohsu.edu)
* History of Meningococcal Outbreaks in the United States: Implications for Vaccination and Disease Prevention, in
Pharmacotherapy, 2016; 36: 880–92. (P. Balmer, Paul.Balmer@pfizer.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 23, 2016 * Vol. 23, No. 163
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source:
Aug. Journal of the American Geriatrics Society (2016; 64).
Treatment Patterns with Antidementia Drugs: Medicare data show that older patients who develop late dementia are less likely to be treated with antidementia drugs, researchers report (pp. 1540–8). Prescription fills for cholinesterase inhibitors (ChEIs) or memantine in the year after diagnosis of dementia showed these patterns among 433,559 Part A, B, or D beneficiaries with dementia in 2009 and a subset of 185,449 people with incident dementia: “Treatment with antidementia drugs occurred in 55.8% of all participants with dementia and 49.3% of those with incident dementia. There was no difference between ChEIs and memantine use according to dementia severity (measured as death within first year or living in residential care vs in a community setting) even though memantine is not indicated in mild disease. In incident cases, initiation of treatment was lower in residential care (relative risk (RR) = 0.82, 95% confidence interval (CI) = 0.81–0.83) and with more comorbidities (RR = 0.96, 95% CI = 0.96–0.96). Sixty percent of participants were managed in primary care alone. Seeing a neurologist (RR = 1.07, 95% CI = 1.06–1.09) or psychiatrist (RR = 1.17, 95% CI = 1.16–1.19) was associated with higher likelihood of treatment than seeing a primary care provider alone, and seeing geriatrician was associated with with lower likelihood (RR = 0.96, 95% CI = 0.93–0.99). Across the United States, the proportion of newly diagnosed individuals started on antidementia treatment varied from 32% to 66% across hospital referral regions.” (J. P. W. Bynum, julie.bynum@dartmouth.edu)
Medicare Expenditures Before and After Alzheimer’s Diagnosis: Medicare expenditures increase even before beneficiaries are diagnosed with Alzheimer’s disease and related dementia (ADRD) or mild cognitive impairment (MCI), an analysis shows (pp. 1549–57). A 5% sample of the Medicare claims files for 2009–13 showed these expenditures and usage during the 24 months before and after new diagnoses for ADRD or MCI: “Medicare expenditures were 42% higher in participants with ADRD ($10,622 vs $15,091, P <.001) and 41% higher in those with MCI ($9,728 vs $13,691, P <.001) during the year before diagnosis than in matched controls. Medicare expenditures of participants with ADRD increased to $27,126 for the first 12 months immediately after diagnosis and decreased to $17,257 during the 12 months after that. For participants with MCI, average Medicare expenditures were $20,386 for the 12 months after diagnosis and $14,286 for the 12 months after that. Use of inpatient care, postacute skilled nursing facility care, and home health care increased substantially after diagnosis of ADRD or MCI.” (P-J Lin, plin@tuftsmedicalcenter.org)
Preventing Hospital-Acquired Adverse Drug Reactions: The incidence of hospital-acquired adverse drug reactions (ADRs) and medication costs were reduced significantly among older patients through application of the Screening Tool of Older Persons’ Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) criteria, according to a single-blind cluster randomized trial (pp. 1558–66). At a tertiary referral hospital in southern Ireland, presentation of STOPP/START criteria to intervention physicians had these effects on ADRs: “One or more ADRs occurred in 78 of the 372 control participants (21.0%; median age 78, interquartile range (IQR) 72–84) and in 42 of the 360 intervention participants (11.7%; median age 80, IQR 73–85) (absolute risk reduction = 9.3%, number needed to treat = 11). The median [length of stay] in the hospital was 8 days (IQR 4–14 days) in both groups. At discharge, median medication cost was significantly lower in the intervention group (73.16 euros, IQR 38.68–121.72 euros) than in the control group (90.62 euros, IQR 49.38–162.53 euros) (Wilcoxon rank test Z statistic = −3.274, P < .001).” (D. O’Mahony, denis.omahony@ucc.ie)

>>>PNN NewsWatch
* One lot of a product used for emergency eye rinsing after an injury is being recalled for possible Klebsiella pneumoniae contamination (Eyesaline Eyewash solution, Honeywell, lot F16091-61), FDA said.
*
FDA yesterday permitted marketing of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and ImPACT Pediatric medical devices, used for assessing cognitive function after suspected brain injury.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 24, 2016 * Vol. 23, No. 164
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Aug. 23 issue of JAMA (2016; 316).
High Cost of U.S. Prescription Drugs: The high cost of prescription drugs in the U.S. is the results of policies “granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits,” authors write (pp. 858–71). To counter this situation—the U.S. has double the per-capita spending on prescription drugs of 19 other industrialized nations ($858 versus $400)—the group recommends, “The most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.”
This conclusion is based on these findings from a review of peer-reviewed medical and health policy literature from 2005 to mid-2016: “The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear.” (A. S. Kesselheim,
akesselheim@partners.org)
Colistin-Resistant Superbug: In a news article, an infectious disease expert discusses strategies for decreasing the risk of morbidity and mortality from a colistin-resistant Escherichia coli (pp. 806–7). Restricting use of colistin in agriculture is one important step, said Barbara E. Murray, MD, of the U. Texas Health Science Center at Houston. “China is one of the world’s highest users of colistin in agriculture,” Murray said. “In France, 90% of farms in the pig industry report using colistin during the postweaning period. Belgium, Spain, Austria, Sweden, Germany, Vietnam, the Netherlands. It’s used all over the world in animal food. I was really surprised to read that it was in products going to animals in the European Union because they had banned a lot of antibiotic use already in animals because of their prior experience with vancomycin-resistant enterococci.”
Noting that “it’s quite early” in emergence of
mcr-1–carrying E. coli, Murray recommends: “There’s certainly some increased funding for surveillance and I think that will trickle down to increased funding for investigator-initiated studies. The Generating Antibiotics Incentives Now (GAIN) Act is prolonging the patent life on certain antibiotics. The FDA … now has a rapid pathway for agents that fill an unmet need. The FDA has also gotten the signal that when it’s a crisis situation, [it] may need to consider approving agents with smaller studies. Because you don’t have hundreds and hundreds of patients out there—thank goodness—[who] are infected with these multidrug-resistant organisms.” (J. Abbasi)

>>>PNN NewsWatch
* Mylan earned $1.7 billion last year for 3.6 million U.S. prescriptions for EpiPens, an analysis in the Washington Post shows. The company is under scrutiny because of increases for a pair of the prefilled syringes from $94 in 2007 to $609 in mid-May. An article in the New York Times notes, “EpiPens are a perfect example of a health care nightmare. They’re also just a typical example of the dysfunction of the American health care system.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 25, 2016 * Vol. 23, No. 165
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Aug. 25 issue of the New England Journal of Medicine (2016; 375).
70-Gene Signature & Chemotherapy in Early-Stage Breast Cancer: Nearly half of women with early-stage breast cancer who are at high risk may not need chemotherapy, according to a phase 3 study based on determination of genomic risk with a 70-gene signature test (pp. 717–29). The test, MammaPrint, was used to determine genomic risk, while clinical risk was estimated with a modified version of Adjuvant! Online. Among 6,694 women, these results were identified: “A total of 1,550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor–positive, human epidermal growth factor receptor 2–negative, and either node-negative or node-positive disease.” (F. Cardoso, mindact@eortc.be)
This MINDACT (Microarray in Node-negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial “shows how a well-coordinated and highly collaborative multinational team of investigators can efficiently conduct a potentially practice-changing study,” editorialists write (
pp. 790–1). “This is a research model that will be even more critical as we advance toward precision medicine. In the clinic today, these results could allow some doctors and patients to choose to avoid chemotherapy if they have carefully considered their own tolerance for toxicity, risk, and uncertainty. When we were in training, a standard refrain from our mentors was never to order a test if we lacked a plan for how we would use the result. On the basis of the MINDACT study, clinicians may consider ordering the 70-gene signature for patients in line for chemotherapy who hope to forgo it on the basis of a possibly low genomic risk. What doctors and their patients do with the results of such testing will be highly individualized — and will inevitably be finessed by the findings from future studies.” (C. A. Hudis)
Noting that the derivation of the 70-gene signature test was published 14 years ago and that this clinical trial began in 2007, the author of a Perspective article writes that such “new tests may be ‘-omic’ and based on relatively new technologies, but they have been introduced through an established process of determining analytic validity … and then clinical validity” (
pp. 711–3). “Initial studies were interpreted by panels of experts, and the use of the tests was introduced into guidelines. Large-scale randomized trials such as this one are being performed to assess and refine clinical utility and thus refine the guidelines. The new tests are being compared with and tested in the context of previous decision tools, such as clinical prognostic indexes and immunohistochemistry results. The new tests add to, but do not replace, the information from these prior tools. This process is the usual one followed by clinical science, rather than a radical departure from proven models.” (D. J. Hunter)
Inotuzumab Ozogamicin in ALL: In the global, phase 3 INO-VATE ALL trial of 218 patients with relapsed or refractory acute lymphoblastic leukemia, “The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease,” authors write (pp. 740–53). Progression-free and overall survival were longer with the anti-CD22 antibody, but “veno-occlusive liver disease was a major adverse event” associated with the drug. (H. M. Kantarjian, hkantarjian@mdanderson.org)
Daratumumab in Multiple Myeloma: Compared with bortezomib plus dexamethasone, the CD38 human IgG-kappa monoclonal antibody daratumumab significantly increased progression-free disease when given in combination with the other drugs, researchers report (pp. 754–66). The three-drug regimen “was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone,” the CASTOR investigators add. (A. Palumbo, appalumbo@yahoo.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 26, 2016 * Vol. 23, No. 166
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Early-release article from and Aug. issue of Health Affairs (2016; 35).
ACA Coverage & Prescription Use, Patient Costs: Medicaid and private insurance coverage provided under the Affordable Care Act (ACA) “has increased treatment rates while reducing out-of-pocket spending, particularly for people with chronic conditions” by “reducing financial barriers to care,” a study shows (10.1377/hlthaff.2016.0091). Prescription transaction data for 6.7 million people using prescription drugs were analyzed for changes in coverage, prescription fills, plan spending, and out-of-pocket costs, with these results: “We found a 30 percent reduction in the proportion of this population that was uninsured in 2014 compared to 2013. Uninsured people who gained private coverage filled, on average, 28 percent more prescriptions and had 29 percent less out-of-pocket spending per prescription in 2014 compared to 2013. Those who gained Medicaid coverage had larger increases in fill rates (79 percent) and reductions in out-of-pocket spending per prescription (58 percent). People who gained coverage who had at least one of the chronic conditions detailed in our study saw larger decreases in out-of-pocket spending compared to those who did not have at least one condition.” (A. W. Mulcahy, amulcahy@rand.org)
Synchronized Prescription Refills & Medication Adherence: Medicare patients with low baseline medication adherence represent an especially promising group for prescription synchronization programs, researchers report (pp. 1504–12). Among randomly selected Medicare Advantage patients receiving mail-order refills for common maintenance antihypertensive, lipid-lowering, or antidiabetic medications, these results were recorded during 12 months of prescription synchronization: “On average, the absolute increase in the proportion of patients deemed adherent during follow-up was 3–10 percentage points for the intervention group, compared to 1–5 percentage points for the control group. Patients with poorer baseline adherence showed larger increases in the absolute proportion deemed adherent in intervention (23–26 percentage points) compared to a control group (13–15 percentage points). Synchronizing refills might be a promising intervention to improve adherence to maintenance medications, especially among Medicare patients with low baseline adherence.” (J. A. Doshi, jdoshi@mail.med.upenn.edu)
Minority Access to Health Profession Careers: Reflecting on his roots in a segregated southwest Georgia town, a former U.S. Surgeon General brings attention to the lack of diversity in health profession education (pp. 1532–5): “A fundamental requirement for a strong nation is a healthy population. For the United States, this means having sufficient numbers and sufficient diversity of health professionals in urban and rural communities across the country to promote healthy lifestyles and a culture of wellness, and to care for people who are afflicted by illness or injury. In the US health care system, greater racial and ethnic diversity is essential to providing high-quality care, promoting the cultural competence of health professionals, and developing the trust and confidence in health professionals needed by the people served by the system.
“There are no longer separate waiting rooms for white and black patients in Blakely. We’ve made some progress. But if we do not invest sufficiently today in the education of young health professionals, although we now sit in the same room, we may have a very long wait.” (L. W. Sullivan,
sullivan@pemsm.com)

>>>Medical Care Highlights
Source:
Sept. issue of Medical Care (2016; 54).
Price Caps & Generic Competition: An Ontario study shows that “continuously reducing price-caps [on prescription drugs] may have the unintended consequence of forcing generic firms to exit [markets]” (pp. 884–90). “A small manufacturer or a manufacturer in a market with ≥3 competitors or in an older market was more likely to exit,” the authors report. (W. Zhang)

>>>PNN NewsWatch
* U.S. Surgeon General Vivek H. Murthy, MD, MBA, yesterday sent letters to 2.3 million health professionals asking for a “commitment to turn the tide on the opioid crisis.” A pledge, pocket guide, and other campaign materials are online at turnthetiderx.org.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 29, 2016 * Vol. 23, No. 167
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 27 issue of Lancet (2016; 388).
Antidepressants in Children & Adolescents: Used for treating major depressive disorder, antidepressants “do not seem to offer a clear advantage for children and adolescents,” authors of a network meta-analysis conclude (pp. 881–90). “Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated,” the group adds based on these findings from 34 eligible trials of 5,260 participants and 14 antidepressants: “The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0.51, 95% credible interval [CrI] −0.99 to −0.03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0.31, 95% CrI 0.13 to 0.95) and imipramine (0.23, 0.04 to 0.78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5.49, 1.96 to 20.86; 3.19, 1.01 to 18.70; and 2.80, 1.20 to 9.42, respectively). In terms of heterogeneity, the global I2 values were 33.21% for efficacy and 0% for tolerability.” (A. Cipriani, andrea.cipriani@psych.ox.ac.uk)
Congenital Zika Virus Syndrome: Many babies born with Zika virus congenital syndrome have normal head circumferences and mothers do not always have the characteristic rash, a case series shows, indicating the need for revision of the screening criteria (pp. 891–7). Investigators reviewed the cases of all 1,501 liveborn infants reported to the Brazilian Ministry of Health suspected of having the syndrome as of Feb. 27, 2016, finding the following: “899 [cases] were discarded. Of the remainder 602 cases, 76 were definite, 54 highly probable, 181 moderately probable, and 291 somewhat probable of congenital Zika virus syndrome. Clinical, anthropometric, and survival differences were small among the four groups. Compared with these four groups, the 899 discarded cases had larger head circumferences (mean Z scores −1.54 vs −3.13, difference 1.58 [95% CI 1.45–1.72]); lower first-week mortality (14 per 1,000 vs 51 per 1,000; rate ratio 0.28 [95% CI 0.14–0.56]); and were less likely to have a history of rash during pregnancy (20.7% vs 61.4%, ratio 0.34 [95% CI 0.27–0.42]). Rashes in the third trimester of pregnancy were associated with brain abnormalities despite normal sized heads. One in five definite or probable cases presented head circumferences in the normal range (above −2 SD below the median of the InterGrowth standard) and for one third of definite and probable cases there was no history of a rash during pregnancy. The peak of the epidemic occurred in late November, 2015.” (C. G. Victora, cvictora@equidade.org)
Pathology of Congenital Zika Syndrome: Pathology results from five fatal cases of congenital Zika syndrome show a number of brain aberrations associated with infection of glial cells by the causative virus (pp. 898–904). U.S. CDC analysis showed the following: “Viral antigens were localised to glial cells and neurons and associated with microcalcifications in all three fatal cases with microcephaly. Antigens were also seen in chorionic villi of one of the first trimester placentas. Tissues from all five cases were positive for Zika virus RNA by [reverse transcription polymerase chain reaction], and sequence analyses showed highest identities with Zika virus strains isolated from Brazil during 2015.” The authors conclude: “These findings provide strong evidence of a link between Zika virus infection and different congenital central nervous system malformations, including microcephaly as well as arthrogryposis and spontaneous abortions.” (S. R. Zaki, szaki@cdc.gov)

>>>PNN NewsWatch
* FDA on Friday expanded its recommendation for Zika virus testing of blood products to include the entire U.S. and its territories.
* When
programmable syringe pumps are used to infuse therapies at low rates, serious clinical consequences can result from inconsistent flow, FDA is warning.

>>>PNN JournalWatch
* New Perspectives in Rheumatology: Avoiding Antimalarial Toxicity, in
Arthritis & Rheumatology, 2016; 68: 1805–9. (J. T. Rosenbaum, jtrosenb@lhs.org)
* ASHP National Survey of Pharmacy Practice in Hospital Settings: Monitoring and Patient Education—2015, in
American Journal of Health-System Pharmacy, 2016; 73: 1307–30. (C. A. Pedersen, craig.pedersen@virginiamason.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 30, 2016 * Vol. 23, No. 168
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2016; 165).
Sacubitril–Valsartan in Heart Failure With Reduced Ejection Fraction: In a cost-effectiveness analysis partially funded by the VA, sacubitril–valsartan therapy provided “reasonable value in reducing cardiovascular mortality and morbidity in patients with [New York Heart Association (NYHA)] class II to IV heart failure,” a study concludes (10.7326/M16-0057). The assessment used a Markov decision model and a lifetime horizon and societal perspective. Based on data from clinical trials, observational analysis, and reimbursement claims, the investigators calculated these measures of life–year, quality-adjusted life–years (QALYs), costs, heart failure hospitalizations, and incremental cost-effectiveness ratios: “The sacubitril–valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional QALY, and $29,203 in incremental costs, equating to a cost per QALY gained of $47,053. The cost per QALY gained was $44,531 in patients with NYHA class II heart failure and $58,194 in those with class III or IV heart failure.” The sensitivity analysis showed: “Sacubitril–valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120,623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100,000 per QALY gained.” (A. T. Sandhu, ats114@stanford.edu)
Editorialists hope that this article will move the needle on the number of physicians prescribing this drug combination, despite “the plethora of articles and P values concerning sacubitril–valsartan published over the past 3 years [having] had minimal impact on prescribing behaviors” (
10.7326/M16-1932): “This experience has important lessons for those who believe that publishing numerous articles will meaningfully influence clinical practice. Many physicians are too busy caring for patients to spend time reading research reports on new and unfamiliar drugs. Furthermore, even if physicians were to read the findings of a new study, they are likely to encounter data that are presented in an opaque and unpersuasive manner. For many, publications are simply a way that researchers talk to each other rather than communicating with physicians who are responsible for the care of most patients. This is a lesson the academic clinical community needs to hear and take to heart.” (M. Packer, milton.packer@baylorhealth.edu)
Disability Insurance & Opioid-Related Mortality: “Welfare reform and the medicalization of social support through disability insurance programs may have contributed to increased opioid-related mortality since the mid-1990s,” authors of an opinion piece write (10.7326/M16-0918). “As disability rates have increased, so has the proportion of disability attributable to musculoskeletal problems—conditions that are increasingly likely to be treated with opioid analgesics,” the group notes. “After remaining flat for the preceding 20 years, the proportion of disability awards to persons with back pain and other musculoskeletal conditions increased from 13.4% in 1994 to 36.1% in 2014. This increase does not seem to have been accompanied by increasing incidence of these conditions. During the same period, trends in self-reported persistent back pain have largely been flat.” (N. B. King)
Regulation of Electronic Cigarettes: Differing views about electronic cigarettes in the U.S. and U.K. are examined in this article (10.7326/M16-1345). While “the Royal College of Physicians has reaffirmed its position that e-cigarettes should be promoted as harm-reducing substitutes for combustible tobacco,” the FDA has exercised regulatory authority by setting a minimum age for purchase, banning free samples, and regulating vending machines. (M. B. Steinberg, michael.steinberg@rutgers.edu)

>>>PNN NewsWatch
* FDA yesterday announced a new product recall and expanded a previous warning. Impax Laboratories, Inc. is recalling one lot of Lamotrigine Orally Disintegrating Tablets (ODT) 200 mg (NDC 0115-1529-08, lot #502240) to the retail level because 10-count blister cards may contain 100-mg tablets. Following up on a warning about DHZC-2 tablets (see PNN, Aug. 15), the agency said it is investigating to see if other Life Rising products also have elevated lead levels.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Aug. 31, 2016 * Vol. 23, No. 169
Providing news and information about medications and their proper use

>>>Diabetes Care Report
Source:
Sept. issue of Diabetes Care (2016; 39).
Insulin Injection Into Lipohypertrophic Tissue: Lipohypertrophy (LHT), common in insulin-treated patients, can interfere with insulin absorption and action, a study shows, leading to “profound deterioration in postprandial glucose control” and more variability in glycemic control (pp. 1486–92). In 13 patients with type 1 diabetes, insulin injections into LHT or normal adipose tissue (NAT) yielded these euglycemic clamp findings: “Compared with NAT, LHT reduced insulin absorption (mean area under the insulin concentration curve [AUCINS0–4h] 131 vs. 165 h * mU/L [LHT vs. NAT]; Cmax 61 vs. 79 mU/L, P <0.02, respectively) and effect (areas under glucose infusion rate [GIR] curves [AUCGIR0–4h 625 vs. 775 mg/kg, P <0.05]) but increased intrasubject variability ([coefficient of variation] AUCINS0–4h 52 vs. 11%, Cmax 55 vs. 15%, AUCGIR0–4h 57 vs. 23%, all P <0.01). Postprandial blood glucose (BG) concentrations were ≥26% higher with LHT (AUCBG0–5h 731 vs. 513 mg * h/dL, BGmax 199 vs. 157 mg/dL, 2-h BG 150 vs. 104 mg/dL, 5-h BG 145 vs. 81 mg/dL, all P <0.05) and maximum concentrations occurred later. Hypoglycemia (BG ≤50 mg/dL) occurred numerically less frequently with LHT injection (two vs. six patients), whereas profound hyperglycemia (BG ≥300 mg/dL) only occurred with LHT injection (two patients). Tmax-INS did not differ between LHT and NAT in either study.” (T. Heise, tim.heise@profil.com)
Transdermal Buprenorphine for Neuropathic Pain: Used in patients with diabetic peripheral neuropathic pain (DPNP), transdermal buprenorphine effectively reduces severity of pain and other symptoms, researchers report, but nausea and constipation must be managed proactively (pp. 1493–500). A trial of 186 participants compared dose-titrated transdermal buprenorphine with placebo, with these results: “A high proportion of patients did not complete the study (buprenorphine 37 of 93, placebo 24 of 93). The main reason for premature withdrawal in the buprenorphine group was adverse events commonly due to untreated nausea and/or vomiting. Among the per-protocol population, more patients in the buprenorphine group (86.3%) experienced a 30% reduction in average versus baseline pain at week 12 than those in the placebo group (56.6%, P <0.001). A nonsignificant trend favored the buprenorphine group within the intention-to-treat analysis of the same end point (51.7% vs. 41.3%, P = 0.175).” (R. W. Simpson, richard.simpson@iinet.net.au)
Intensification of Diabetes Therapy After Metformin Failure: Among Cleveland Clinic patients newly diagnosed with type 2 diabetes, substantial numbers of patients who fail initial metformin therapy are not placed on intensified antidiabetic therapy within 6 months (pp. 1527–34). In 2005–13, those failing to reach A1C goals during 3 months of metformin therapy had these 6-month outcomes: “Treatment was intensified early in 62%, 69%, and 72% of patients when poor glycemic control was defined as an A1C >7%, >7.5%, and >8%, respectively. The probability of undergoing an early intensification was greater the higher the A1C category. Time until A1C goal attainment was shorter among patients who received early intensification regardless of the A1C goal (all P < 0.05).” (K. M. Pantalone, pantalk@ccf.org)
Supplementing Metformin Therapy in Type 2 Diabetes: Compared with lixisenatide, liraglutide produced better glycemic control when added to metformin therapy in a 26-week, open-label trial of 404 patients with type 2 diabetes (pp. 1501–9; M. Nauck, michael.nauck@rub.de).

>>>PNN NewsWatch
* FDA has approved etanercept-szzs (Erelzi, Sandoz), a biosimilar to the Enbrel brand of etanercept, for treatment of several inflammatory diseases, including use as monotherapy or in combination with methotrexate in patients with moderate to severe rheumatoid arthritis.
* Ton Shen Health/Life Rising Corporation is expanding its recall of
DHZC-2 tablets to all lots purchased before August 24 of this year because they have the potential to be contaminated with elevated levels of lead, FDA said yesterday. The recalled product, sold in 1.6-ounce bottles, have the UPC code 616042102727 and were sold nationwide in retail stores and distributed through mail orders.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 1, 2016 * Vol. 23, No. 170
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Sept. 1 issue of the New England Journal of Medicine (2016; 375).
Acquired Resistance to PD-1 Blockade in Melanoma: “Immune escape” mechanisms that allow metastatic melanoma tumors to acquire resistance to anti–programmed death 1 (PD-1) therapy include defects in the pathways involved in interferon-receptor signaling and in antigen presentation, a study shows (pp. 819–29). In four patients with metastatic melanoma who initially responded to pembrolizumab but had disease progression months to years later, analysis of paired baseline and relapsing lesions showed the following: “Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.” (A. Ribas, aribas@mednet.ucla.edu)
“The ability of whole-exome sequencing to identify mechanisms of both innate and acquired resistance has potential clinical applications,” an editorialist writes (
pp. 888–9). “As our knowledge of the host–tumor interactions at both the genomic and biologic levels increases, we inch closer to the time when extensive genomic analysis coupled with immune profiling will be applied to patients with cancer at the time of diagnosis and at relapse, to aid in selection of the combination therapy that is most likely to bring about eradication of an individual patient’s tumor — the ultimate goal of precision medicine.” (C. B. Bifulco)
Antiretroviral Therapy for Prevention of HIV-1 Transmission: Among 1,763 HIV Prevention Trials Network (HPTN) 052 trial participants, HIV-1 transmission to sexual partners was significantly reduced by early antiretroviral therapy (ART) (pp. 830–9). Those in the early-ART group received treatment when CD4+ counts were at 350–550 cells/cu mm, while the delayed-ART group began treatment at 250 cells/cu mm. Results showed: “Index participants were followed for 10,031 person–years; partners were followed for 8,509 person–years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.” (M. S. Cohen, mscohen@med.unc.edu)
Adding Salmeterol to Initial Pediatric Asthma Therapy: Commenting on a study showing serious adverse events when fluticasone was added to salmeterol in children with asthma (pp. 840–9; D. A. Stempel, david.a.stempel@gsk.com), editorialists write that “no evidence [supports] the use of a combined inhaler as first-line preventive therapy in children, and this fact needs to be emphasized because such use is increasingly creeping into practice” (pp. 889–91; A. Bush).

>>>PNN NewsWatch
* FDA yesterday announced class-wide changes to drug labeling, including patient information, to help inform health professionals and patients of the serious risks associated with the combined use of certain opioid medications and benzodiazepines. The boxed warnings and patient-focused Medication Guides for nearly 400 prescription opioid analgesics, opioid-containing cough products, and benzodiazepines will present information about the serious risks associated with concomitant use of these medications, including extreme sleepiness, respiratory depression, coma, and death.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 2, 2016 * Vol. 23, No. 171
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Sept. issue of Pediatrics (2016; 138).
Vaccine Delays, Refusals, and Patient Dismissals: Vaccine-refusing parents increased in number between 2006 and 2013, a survey of pediatricians shows, and these families are more frequently being dismissed from practices because of continued refusals (10.1542/peds.2016-2127). The American Academy of Pediatrics Periodic Surveys from 2006 and 2013 show these patterns of vaccine delays, refusals, and dismissals: “The proportion of pediatricians reporting parental vaccine refusals increased from 74.5% in 2006 to 87.0% in 2013 (P <.001). Pediatricians perceive that parents are increasingly refusing vaccinations because parents believe they are unnecessary (63.4% in 2006 vs 73.1% in 2013; P = .002). A total of 75.0% of pediatricians reported that parents delay vaccines because of concern about discomfort, and 72.5% indicated that they delay because of concern for immune system burden. In 2006, 6.1% of pediatricians reported ‘always’ dismissing patients for continued vaccine refusal, and by 2013 that percentage increased to 11.7% (P = .004).” (D. W. Kimberlin, dkimberlin@peds.uab.edu)
Intussusception Rates Before and After Rotavirus Vaccine: Hospitalizations for intussusception increased among children aged 8–11 weeks after introduction of the rotavirus vaccination, a period that corresponds to recommended time for first doses of the vaccine, researchers report (10.1542/peds.2016-1082). However, they conclude, “Given the magnitude of declines in rotavirus disease compared with this small increase in intussusception, the benefits of rotavirus vaccination outweigh the increase risk of intussusception.” Data for 26 states for 2000–13 showed increases in intussusception hospitalization rates over baseline of 46% to 101% for this age group in all but 2 years. (J. E. Tate)
“When discussing rotavirus vaccine with parents, pediatricians should acknowledge and discuss any potential risks, including intussusception, noting that the risk is low but can be serious when it occurs,” editorialists write (
10.1542/peds.2016-1952). “While acknowledging vaccination risks, it is paramount as pediatricians that we also communicate to parents and families the enormous benefits of rotavirus vaccination in preventing rotavirus disease in the United States.” (E. B. Walter, walte002@mc.duke.edu)

>>>Psychiatry Report
Source:
Sept. American Journal of Psychiatry (2016; 173).
Preventing Relapse in Body Dysmorphic Disorder: Among 58 patients with body dysmorphic disorder who responded during an open-label phase of escitalopram therapy, delayed time to relapse and fewer relapses were observed with the drug during double-blind, placebo-controlled continuation therapy (pp. 887–95). After a 14-week initial phase with 100 participants, Phase 2 lasted for 6 months and produced these results: “In phase 1, 67.0% of treated subjects and 81.1% of subjects who completed phase 1 responded to escitalopram. Body dysmorphic disorder severity (in both the intent-to-treat and the completer groups) and insight, depressive symptoms, psychosocial functioning, and quality of life significantly improved from baseline to end of phase 1. In phase 2, time to relapse was significantly longer with escitalopram than with placebo treatment (hazard ratio = 2.72, 95% CI = 1.01–8.57). Phase 2 relapse proportions were 18% for escitalopram and 40% for placebo. Among escitalopram-treated subjects, body dysmorphic disorder severity significantly decreased over time during the continuation phase, with 35.7% of subjects showing further improvement. There were no significant group differences in body dysmorphic disorder severity or insight, depressive symptoms, psychosocial functioning, or quality of life.” (K. A. Phillips)
Citalopram Dosage Risk Mitigation: An FDA safety recommendation to limit citalopram doses to 40 mg/d has had unintended clinical consequences among patients formerly taking much higher doses of the drug, a VA study shows (pp. 896–902; T. S. Rector).

>>>PNN NewsWatch
* The CDC yesterday released 2015 U.S. obesity maps. All states have more than 20% of the population in the ≥30 kg/sq m category. More than 35% of people in Alabama, Louisiana, Mississippi, and West Virginia have obesity.
*
PNN will not be published on Mon., Sept. 5, Labor Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 6, 2016 * Vol. 23, No. 172
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 6 issue of the Annals of Internal Medicine (2016; 165).
Long-Term Pioglitazone Treatment in Nonalcoholic Steatohepatitis: In patients with prediabetes/type 2 diabetes and nonalcoholic steatohepatitis (NASH), pioglitazone is safe and effective, a study shows, affirming the drug’s correction of causative metabolic defects (pp. 305–15). With a primary outcome of nonalcoholic fatty liver disease activity scores in 2 histologic categories without worsening of fibrosis, the study showed: “Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P <0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, −0.5 [CI, −0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, −7 percentage points [CI, −10 to −4 percentage points]; P <0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P <0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).” (K. Cusi, Kenneth.Cusi@medicine.ufl.edu)
This study “extends previous observations of the therapeutic benefits of pioglitazone in NASH to include patients with impaired glucose regulation,” editorialists write (
pp. 373–4). “Unfortunately, use of pioglitazone beyond 18 months did not provide significant additional resolution of fibrosis, but it may retard further progression. Whether physicians should include pioglitazone in the therapeutic arsenal for diabetic patients with NASH is unclear on the basis of this [randomized controlled trial]. However, long-term confirmatory studies are unlikely to be performed given the impracticability and risk of serial liver biopsies. We believe that physicians should consider adding pioglitazone to their toolboxes when facing patients with NASH and diabetes, but the primary obstacle to the widespread use of pioglitazone remains its safety profile. Thus, treatment should be considered for patients at the greatest risk (those with NASH and fibrosis) and should be balanced against the common risk for weight gain and the uncommon risks for fracture and heart failure.” (E. Vilar-Gomez, eduardovilar2000@yahoo.com)

>>>Lancet Highlights
Source:
Sept. 3 issue of Lancet (2016; 388).
Single-Inhaler Triple Therapy in COPD: In the 14-country TRILOGY trial, use of a single inhaler that delivered two long-acting bronchodilators and a corticosteroid yielded clinical benefits over inhaled corticosteroid/long-acting beta-2-agonist treatment (pp. 963–73). Among 1,368 patients in 2014–16, these outcomes were noted for inhaled beclometasone dipropionate 100 mcg (BPD) and formoterol fumarate 6 mcg (FF) twice daily or step-up to BDP 100 mcg, FF 6 mcg, and glycopyrronium bromide 12.5 mcg (GB) twice daily for 52 weeks via pressurized metered-dose inhaler: “At week 26, BDP/FF/GB improved pre-dose FEV1 by 0.081 L (95% CI 0.052–0.109; p <0.001) and 2-h post-dose FEV1 by 0.117 L (0.086–0.147; p <0.001) compared with BDP/FF. Mean [Transition Dyspnea Index] focal scores at week 26 were 1.71 for BDP/FF/GB and 1.50 for BDP/FF, with a difference of 0.21 (95% CI −0.08 to 0.51; p = 0.160). Adjusted annual moderate-to-severe exacerbation frequencies were 0.41 for BDP/FF/GB and 0.53 for BDP/FF (rate ratio 0.77 [95% CI 0.65–0.92]; p = 0.005), corresponding to a 23% reduction in exacerbations with BDP/FF/GB compared with BDP/FF. Adverse events were reported by 368 (54%) patients with BDP/FF/GB and 379 (56%) with BDP/FF. One serious treatment-related adverse event occurred (atrial fibrillation) in a patient in the BDP/FF/GB group.” (D. Singh, dsingh@meu.org.uk)

>>>PNN JournalWatch
* Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis, in
American Journal of Psychiatry, 2016; 173: 876–86. (B. Helfer)
* Recommendations for Prevention and Control of Influenza in Children, 2016–2017, in
Pediatrics, 2016; 10.1542/peds.2016-2527. (Am. Academy of Pediatrics Committee on Infectious Diseases)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 7, 2016 * Vol. 23, No. 173
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Sept. 6 issue of JAMA (2016; 316).
Primary TB Screening: In an evidence report conducted for the U.S. Preventive Services Task Force (USPSTF), researchers find no studies comparing screening for latent tuberculosis infection (LTBI) versus no screening (pp. 970–83). However, treatment of those identified with LTBI reduced the risk of active tuberculosis (TB) among the populations studied. Both the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs) were “moderately sensitive and highly specific within countries with low TB burden,” the group concludes. (L. C. Kahwati, lkahwati@rti.org)
Based on this evidence, the USPSTF made a B recommendation to screen for LTBI in populations at increased risk (
pp. 962–9): “The USPSTF found adequate evidence that accurate screening tests for LTBI are available, treatment of LTBI provides a moderate health benefit in preventing progression to active disease, and the harms of screening and treatment are small. The USPSTF has moderate certainty that screening for LTBI in persons at increased risk for infection provides a moderate net benefit.” Risk is increased among immunocompromised patients, but USPSTF did not review evidence for these groups since TB testing is part of the standard of care for their conditions. Other high-risk groups include those homeless within the past year, prisoners, and residents of long-term care facilities. (K. Bibbins-Domingo, chair@uspstf.net)
“The USPSTF recommendations on screening for TB provide a service by focusing discussions on how to expand efforts on targeted testing and treatment of LTBI among adults seen in primary care settings,” editorialists write (
pp. 931–3). “There will be challenges with implementation of these recommendations because of the current inability to precisely define individuals at high risk for progression to active TB. The recommendations also highlight the need for new and better tools for control of TB, including LTBI. In the short run, implementation science (operational research) will be needed to help facilitate the best ways of implementing the USPSTF recommendations. In the long run and to overcome the challenge of LTBI, new tools are needed including new and better diagnostic tests, biomarkers that have a high predictive value for identifying which patients are at risk for progression to active disease, and shorter, more effective, and better-tolerated regimens for treatment of LTBI. Such advancements will not be made without substantial investments in TB research by funders, including foundations and, most importantly, the United States and other governments from high- and middle-income countries.” (H. M. Blumberg, henry.m.blumberg@emory.edu)
Bevacizumab Nasal Spray for Epistaxis: In the first of two studies of intranasal management of epistaxis, topical bevacizumab was no better than placebo at reducing the duration of monthly epistaxis episodes in 80 consecutive patients with hereditary hemorrhagic telangiectasia (HHT) (pp. 934–42). Results of a phase 2, dose-ranging study showed: “Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1–436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8–406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8–327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3–291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee.” (S. Dupuis-Girod, sophie.dupuis-girod@chu-lyon.fr)
In the North American Study of Epistaxis in HHT, placebo was equivalent to topical intranasal bevacizumab, estriol, or tranexamic acid for epistaxis frequency (
pp. 943–51). “Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0–14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]),” the authors report. “Drug therapy did not significantly reduce epistaxis frequency (P = .97).” (K. J. Whitehead, kevin.whitehead@hsc.utah.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 8, 2016 * Vol. 23, No. 174
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Sept. 8 issue of the New England Journal of Medicine (2016; 375).
Adalimumab in Active Noninfectious Uveitis: In a phase 3 trial, adalimumab provided an effective, safe glucocorticoid-sparing option for treatment of noninfectious uveitis in adults (pp. 932–43). Compared with placebo, adalimumab was “associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo,” the authors conclude. Study participants had failed therapy with prednisone for 2 or more weeks before randomization to placebo or adalimumab in a loading dose of 80 mg followed by 40 mg every 2 weeks. Results showed: “The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P <0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8 vs. 13.6 serious adverse events per 100 person–years).” (G. J. Jaffe, glenn.jaffe@duke.edu)
Acute Sinusitis in Adults: Watchful waiting with a “wait and see” or “safety net” antibiotic prescription is a reasonable approach to care of the adult patient with acute sinusitis, according to the author of a Clinical Practice article, especially when return of the patient to the clinic is not assured (pp. 962–70). After reviewing the case of a 28-year-old woman with persistent symptoms over a 12-day period, the author makes these recommendations: “If antibiotic therapy is chosen as the initial treatment, I would prescribe amoxicillin at a dose of 1000 mg orally three times a day for 5 days, unless the patient had coexisting conditions that would warrant the use of amoxicillin–clavulanate. If the patient is allergic to penicillin, I would prescribe doxycycline at a daily dose of 200 mg for 5 days.
“I would recommend the use of analgesics or nasal glucocorticoids as needed for facial pain, pressure, or fullness. Nasal congestion is also relieved by topical glucocorticoids, and (on the basis of clinical experience) the patient may benefit from the use of nasal decongestant spray such as oxymetazoline for no more than 5 days to limit the risk of rebound congestion. The use of a nasal rinse with saline may be helpful if the patient has purulent nasal drainage, especially if the drainage is difficult for her to expel. Antihistamines should be reserved for patients with known allergies to inhalants or prominent allergic symptoms. Oral glucocorticoids are not recommended.” (R. M. Rosenfeld,
richard.rosenfeld@downstate.edu)
Positive Primary Outcomes in Clinical Trials: When clinical trials achieve significant positive results in their designated primary outcome, the reader should ask several key questions to determine whether the evidence is sufficient to modify medical practice, according to authors of a “Changing Face of Clinical Trials” review article (pp. 971–9). In addition to providing 11 questions that must be asked about the reader’s own situation, the authors provide this advice: “If the efficacy and safety outcomes of the trial are convincingly met, the next step is to evaluate its overall quality and internal validity. It must also be determined whether the findings translate into treatment effectiveness (and net clinical benefit) in real-world patients. However, caution is required when data from nonrandomized registries are used to confirm or refute trial findings, given the potential for selection bias and residual confounding when such registries are used. At the same time, gauging the cost-effectiveness of treatments across different types of health care systems will determine the level of reimbursement (which in turn will affect the adoption of a new therapy).” (S. J. Pocock, stuart.pocock@lshtm.ac.uk)

>>>PNN NewsWatch
* United Exchange Corp. of Cerritos, CA, a primary source vendor of the Rugby-branded Eye Irrigating Solution and Major-branded Eye Wash, is voluntarily recalling products due to microbial contamination.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 9, 2016 * Vol. 23, No. 175
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
Sept. 13 issue of the Journal of the American College of Cardiology (2016; 68).
Edoxaban in Patients With AF at Risk of Falling: As an alternative to warfarin in patients with atrial fibrillation who are increased risk of falling, edoxaban provides “an even greater absolute reduction in severe bleeding and mortality,” according to results from the ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48) trial (pp. 1169–78). Among 900 patients judged by investigators to be at increased risk of falls, these results were found during the trial: “After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio [HRadj]: 1.88; 95% confidence interval [CI]: 1.49 to 2.38; p < 0.001), major bleeding (HRadj: 1.30; 95% CI: 1.04 to 1.64; p = 0.023), life-threatening bleeding (HRadj: 1.67; 95% CI: 1.11 to 2.50; p = 0.013), and all-cause death (HRadj: 1.45; 95% CI: 1.23 to 1.70; p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj: 1.16; 95% CI: 0.89 to 1.51; p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin.” (J. Steffel)
Sex & 6- or 24-Month Dual-Antiplatelet Therapy Duration: Seeking data relevant to the debate over the optimal duration of dual-antiplatelet therapy (DAPT) for men and women after percutaneous coronary intervention (PCI), researchers report “similar adjusted 2-year ischemic and bleeding outcomes” regardless of gender and despite varying clinical presentations (pp. 1780–9). Based on a primary efficacy endpoint of composite of death, myocardial infarction, or cerebrovascular accident at 24-month follow-up in PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study), the authors found: “Women (n = 459 [23.3%]) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome but had a lower severity of coronary artery disease. After adjustment, prolonged DAPT, compared with 6-month treatment, did not reduce the primary endpoint in both men (adjusted hazard ratio: 1.080; 95% confidence interval: 0.766 to 1.522; p = 0.661) and women (adjusted hazard ratio: 1.013; 95% confidence interval: 0.588 to 1.748; p = 0.962) (interaction p = 0.785). No sex disparity was identified across multiple secondary ischemic endpoints, including overall or cardiovascular mortality, myocardial infarction, and stent thrombosis. There was also no clear sex-related effect on clinically relevant bleeding, including Bleeding Academic Research Consortium type 3 or 5, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales.” (G. Gargiulo)

>>>Chest Highlights
Source:
Sept. issue of Chest (2016; 150).
E-Cigarettes & Oxidative Stress, Vascular Function: After single use, both traditional tobacco cigarettes and e-cigarettes produced unfavorable effects on markers of oxidative stress and flow-mediated dilation (FMD), a crossover study of healthy smokers and nonsmokers shows (pp. 606–12): “Smoking both e-cigarettes and traditional cigarettes led to a significant increase in the levels of soluble NOX2-derived peptide and 8-iso-prostaglandin F2-alpha and a significant decrease in nitric oxide bioavailability, vitamin E levels, and FMD. Generalized estimating equation analysis confirmed that all markers of oxidative stress and FMD were significantly affected by smoking and showed that the biologic effects of e-cigarettes vs traditional cigarettes on vitamin E levels (P = .413) and FMD (P = .311) were not statistically different. However, e-cigarettes seemed to have a lesser impact than traditional cigarettes on levels of soluble NOX2-derived peptide (P = .001), 8-iso-prostaglandin F2-alpha (P = .046), and nitric oxide bioavailability (P = .001).” (R. Carnevale)

>>>PNN NewsWatch
* In “an unprecedented public health achievement,” all 155 countries and territories using oral poliovirus vaccines (OPVs) in 2015 synchronized cessation of use of the trivalent product earlier this year, according to this week’s Morbidity and Mortality Weekly Report. They switched mostly to bivalent OPV.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 12, 2016 * Vol. 23, No. 176
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Outcomes With Atrial Fibrillation: “Interventions aimed at reducing outcomes beyond stroke are warranted in patients with atrial fibrillation,” conclude authors of a systematic review and meta-analysis that found an associated increased risk of death and of cardiovascular and renal disease (i4482): “104 eligible cohort studies involving 9,686,513 participants (587,867 with atrial fibrillation) were identified. Atrial fibrillation was associated with an increased risk of all cause mortality (relative risk 1.46, 95% confidence interval 1.39 to 1.54), cardiovascular mortality (2.03, 1.79 to 2.30), major cardiovascular events (1.96, 1.53 to 2.51), stroke (2.42, 2.17 to 2.71), ischaemic stroke (2.33, 1.84 to 2.94), ischaemic heart disease (1.61, 1.38 to 1.87), sudden cardiac death (1.88, 1.36 to 2.60), heart failure (4.99, 3.04 to 8.22), chronic kidney disease (1.64, 1.41 to 1.91), and peripheral arterial disease (1.31, 1.19 to 1.45) but not haemorrhagic stroke (2.00, 0.67 to 5.96). Among the outcomes examined, the highest absolute risk increase was for heart failure. Associations between atrial fibrillation and included outcomes were broadly consistent across subgroups and in sensitivity analyses.” (A. Odutayo, ayodele.odutayo@bnc.ox.ac.uk)
Health Outcomes During 2008 Financial Crisis: Other than a consistent increased risk of suicide and other adverse mental health outcomes, researchers looking at changes in health outcomes in Europe during the 2008 financial crisis found heterogeneous effects (i4588). Better empirical studies of such problems during such times are needed, the authors conclude, based on these findings of a systematic review: “41 studies met the inclusion criteria, and focused on suicide, mental health, self rated health, mortality, and other health outcomes. Of those studies, 30 (73%) were deemed to be at high risk of bias, nine (22%) at moderate risk of bias, and only two (5%) at low risk of bias, limiting the conclusions that can be drawn. Although there were differences across countries and groups, there was some indication that suicides increased and mental health deteriorated during the crisis. The crisis did not seem to reverse the trend of decreasing overall mortality. Evidence on self rated health and other indicators was mixed.” (C. Stavropoulou, C.Stavropoulou@city.ac.uk)

>>>Lancet Highlights
Source:
Sept. 10 issue of Lancet (2016; 388).
Global Burden of Viral Hepatitis: Based on an increased burden and relative rank between 1990 and 2013 despite availability of vaccines and treatments, Global Burden of Disease researchers conclude that viral hepatitis provides an “important opportunity to improve public health” (pp. 1081–8): “Between 1990 and 2013, global viral hepatitis deaths increased from 0.89 million (95% uncertainty interval [UI] 0.86–0.94) to 1.45 million (1.38–1.54); [years of life lost] from 31.0 million (29.6–32.6) to 41.6 million (39.1–44.7); [years lived with disability] from 0.65 million (0.45–0.89) to 0.87 million (0.61–1.18); and [disability-adjusted life-years] from 31.7 million (30.2–33.3) to 42.5 million (39.9–45.6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990.” (J. D. Stanaway, stanaway@uw.edu)

>>>PNN NewsWatch
* Novo Nordisk Inc. is recalling six batches of the GlucaGen HypoKit in the U.S. because of two customer complaints from the U.K. and Portugal involving detached needles on the syringe with Sterile Water for Injection, FDA said on Friday.

>>>PNN JournalWatch
* Long-Term P2Y
12-Receptor Antagonists in Post-Myocardial Infarction Patients: Facing a New Trilemma?, in Journal of the American College of Cardiology, 2016; 68: 1223–32. (D. Alexopoulos)
* Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications, in
Circulation, 2016; 134: 752–72. (D. Z. I. Cherney, david.cherney@uhn.ca)
* 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease, in
Circulation, 2016; 134: e123–55. (G. N. Levine)
* Duration of Dual Antiplatelet Therapy: A Systematic Review for the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, in
Circulation, 2016; 134: e156–78. (Evidence Review Committee Members)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 13, 2016 * Vol. 23, No. 177
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. issue of JAMA Internal Medicine (2016; 176).
Antibiotic Duration in CAP: Recommendations calling for personalized, often shorter durations of antibiotic therapy can be safely implemented in patients hospitalized for community-acquired pneumonia, researchers report (pp. 1257–65). The 2007 Infectious Diseases Society of America/American Thoracic Society guidelines call for at least 5 days of treatment with antibiotic discontinuance when patients are afebrile for 48–72 hours and meet no more than one CAP-associated instability criteria (systolic blood pressure <90 mm Hg, heart rate >100/min, respiratory rate >24/min, arterial oxygen saturation <90%, or Pao2 <60 mm Hg in room air). At four Spanish teaching hospitals in 2012–13, randomly assigned intervention patients (n = 162) were managed using these guidelines and compared with 150 control patients, with these results: “In the intent-to-treat analysis, clinical success was 48.6% (71 of 150) in the control group and 56.3% (90 of 162) in the intervention group at day 10 (P = .18) and 88.6% (132 of 150) in the control group and 91.9% (147 of 162) in the intervention group at day 30 (P = .33). The mean (SD) CAP symptom questionnaire scores were 24.7 (11.4) vs 27.2 (12.5) at day 5 (P = .10) and 18.6 (9.0) vs 17.9 (7.6) at day 10 (P = .69). In the per-protocol analysis, clinical success was 50.4% (67 of 137) in the control group and 59.7% (86 of 146) in the intervention group at day 10 (P = .12) and 92.7% (126 of 137) in the control group and 94.4% (136 of 146) in the intervention group at day 30 (P = .54). The mean (SD) CAP symptom questionnaire scores were 24.3 (11.4) vs 26.6 (12.1) at day 5 (P = .16) and 18.1 (8.5) vs 17.6 (7.4) at day 10 (P = .81).” (A. Uranga, ane.urangaecheverria@osakidetza.eus)
Advocating a “new antibiotic mantra” that “shorter is better,” an editorialist writes that patients should no longer be told to keep taking antibiotics until all are gone (
pp. 1254–5): “The ultimate goal is to customize duration of therapy to the patient’s response. So what should we do when patients are given a prescription for a fixed duration of therapy and their symptoms resolve before they complete the course? Here we need to change the dogma: patients should no longer be told to keep taking the antibiotic. Patients should be told that if their symptoms resolve before completing the antibiotic they should communicate with their physician to determine if they can stop therapy early. Health care professionals should be encouraged to allow patients to stop antibiotic treatment as early as possible on resolution of symptoms of infection. Ultimately, we should replace the old dogma of continuing therapy past resolution of symptoms with a new, evidence-based dogma of ‘shorter is better.’” (B. Spellberg, bspellberg@dhs.lacounty.gov)
Antibiotics During Asthma-Exacerbation Hospitalizations: Overuse of antibiotics by hospital-based clinicians when caring for patients with asthma exacerbations “suggest a significant opportunity to improve patient safety, reduce the spread of resistance, and lower spending through greater adherence to guideline recommendations,” investigators conclude (pp. 1397–400). Analysis of the Premier Alliance database shows these usage patterns at 577 U.S. hospitals in 2013–14 where 51,951 adult patients with asthma or acute respiratory failure/asthma were seen: “Antibiotics were prescribed on the first hospital day in 21,248 (40.9%) and at any point during the hospitalization in 30,226 patients (58.2%). Median duration of inpatient antibiotic treatment was 3 days (interquartile range, 2–4 days). The most commonly prescribed antibiotics were macrolides (9633 [18.5%]), quinolones (8362 [16.1%]), third-generation cephalosporins (4420 [8.5%]), and tetracyclines (1858 [3.6%]). Treatment rates varied across hospitals.” The authors conclude, “In this large national sample, we found that 58.2% of patients hospitalized for asthma received antibiotics in the absence of documentation of an indication for antibiotic therapy. These findings build on prior research restricted to US emergency departments that reported that 18% to 22% of patients with asthma were given a prescription for an antibiotic on emergency department discharge.…
“We hope these results prompt hospital-based clinicians to examine local treatment patterns and attract the attention of professional societies and government agencies charged with promoting antimicrobial stewardship.” (P. K. Lindenauer,
peter.lindenauer@baystatehealth.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 14, 2016 * Vol. 23, No. 178
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Sept. 13 issue of JAMA (2016; 316).
Value & Volume in Health Care: Individual physicians may benefit from understanding the actual costs of care and the outcomes achieved in specific patients with defined clinical conditions, a study shows (pp. 1061–72). Quality and outcome measures in 2012–16 at the University of Utah Health Care were analyzed to identify high variability in 1.7 million patient visits and 34,000 inpatient discharges, and three selected clinical projects provided information on reduction of costs and improvement in quality of care: “Professional costs accounted for 24.3% of total costs for inpatient episodes ($114.4 million of $470.4 million) and 41.9% of total costs for outpatient visits ($231.7 million of $553.1 million). For Medicare severity diagnosis related groups with the highest total direct costs, cost variability was highest for postoperative infection (CV = 1.71) and sepsis (CV = 1.37) and among the lowest for organ transplantation (CV ≤ 0.43). For total joint replacement, a composite quality index was 54% at baseline (n = 233 encounters) and 80% 1 year into the implementation (n = 188 encounters) (absolute change, 26%; 95% CI, 18%–35%; P <.001). Compared with the baseline year, mean direct costs were 7% lower in the implementation year (95% CI, 3%–11%; P <.001) and 11% lower in the postimplementation year (95% CI, 7%–14%; P <.001). The hospitalist laboratory testing mean cost per day was $138 (median [IQR], $113 [$79–160]; n = 2,034 encounters) at baseline and $123 (median [IQR], $99 [$66–147]; n = 4,276 encounters) in the evaluation period (mean difference, −$15; 95% CI, −$19 to −$11; P < 001), with no significant change in mean length of stay. For a pilot sepsis intervention, the mean time to anti-infective administration following fulfillment of systemic inflammatory response syndrome criteria in patients with infection was 7.8 hours (median [IQR], 3.4 [0.8–7.8] hours; n = 29 encounters) at baseline and 3.6 hours (median [IQR], 2.2 [1.0–4.5] hours; n = 76 encounters) in the evaluation period (mean difference, −4.1 hours; 95% CI, −9.9 to −1.0 hours; P = .02).” (V. S. Lee, vivian.lee@hsc.utah.edu)
These “findings offer proof of concept that improving value by patient condition can lead to lower costs and better quality—at the same time,” editorialists write (
pp. 1047–8). After explaining that the “period of voluntary experimentation with new payment models is coming to an end,” the authors assess the Utah study findings: “Even with limited outcomes and cost data, the results reported by Lee and colleagues are impressive. For total joint replacement, for example, clinical outcomes were improved while costs declined by 11%. One key step toward better quality and efficiency was modifying physical therapists’ schedules so that virtually all patients were out of bed on the day of surgery—a change that was associated with a 9.5% decrease in average length of stay. This is the kind of improvement that occurs when teams focus on defined conditions for which patients have similar needs. Such opportunities for improvement are almost impossible to recognize when physical therapy is managed as a single program serving a heterogeneous population as is typical at hospitals.” (T. H. Lee, thomas.lee@pressganey.com)
Colchicine & Prevention of Cardiovascular Events: Available evidence indicates that colchicine has a cardioprotective effect but would create numerous cases of gastrointestinal adverse events during long-term therapy, a JAMA Clinical Evidence Synopsis shows (pp. 1106–7). Use of colchicine in 1,000 patients at risk of myocardial infarction for 3 years “may be associated with 46 (95% CI, 25–54) fewer myocardial infarctions,” but 110 (4–299) patients would have nausea, vomiting, or diarrhea. (L. G. lars.hemkens@usb.ch)

>>>PNN NewsWatch
* The Center for Pharmacy Practice Accreditation has accredited the specialty pharmacy practice model of KloudScript, Inc., a community-led specialty pharmacy care network, in partnership with one of its community pharmacy members, Doc’s Pharmacy. The announcement marks the first time a specialty-at-retail service provider and pharmacy provider have jointly received this accreditation, the group said.
* With 18 cases of fair-associated
swine flu (H3N2) infections reported in Ohio and Michigan during August, the CDC is providing information on how people can interact safely with animals at fairs.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 15, 2016 * Vol. 23, No. 179
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Sept. 15 issue of the New England Journal of Medicine (2016; 375).
Shingles Vaccine in Adults 70 or Older: Among adults aged 70 years or older, a new shingles vaccine under development by GlaxoSmithKline Biologicals reduced the risk of herpes zoster and postherpetic neuralgia in a phase 3 trial (pp. 1019–32). The product, a herpes zoster subunit vaccine (HZ/su) containing recombinant varicella–zoster virus glycoprotein E and the AS01B adjuvant system, was administered in the ZOE-70 (Zoster Efficacy Study in Adults 70 Years of Age or Older) trial to participants at the same sites used in the ZOE-50 trial of patients aged 50 or older. Two doses of HZ/su or placebo given 2 months apart produced these responses: “In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6,950 participants) or placebo (6,950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person–years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P <0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P <0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P <0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups.” (T. C. Heineman, thomas.heineman@genocea.com)
Public health challenges—including the difficulty with two doses and getting patients with a prescription to the pharmacy for Part D administration—will need to be addressed if the new shingles vaccine is to achieve its potential, editorialists write (
pp. 1079–80): “Despite the 2008 recommendations for the zoster vaccine, by 2014 only 27.9% of adults 60 years of age or older reported being vaccinated. In the early years after vaccine approval, supply constraints limited uptake. In more recent years, the supply has been sufficient, and the reasons for the continued poor uptake include provider challenges (e.g., cost, storage of the frozen formulation, and complex Medicare reimbursement), limited public awareness of the disease and vaccine, a lack of requirements for adult vaccination, and the focus on acute medical care over prevention among practitioners caring for adult patients. Although HZ/su may address some of these issues, such as easier storage requirements for a nonreplicating product, it will have its own challenges, including the two-dose schedule and the higher reactogenicity. Thus, the full public health value of herpes zoster vaccines will not be realized unless we identify and address barriers to delivery and uptake.” (K. M. Neuzil)
Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia: Younger adults with B-lineage, CD20-positive, Ph-negative acute lymphoblastic leukemia (ALL) responded well to addition of rituximab to the ALL chemotherapy protocol, researchers report (pp. 1044–53). Random assignment of 209 patients to standard ALL therapy or rituximab-supplemented therapy yielded these results: “After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P = 0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group.” (H. Dombret, herve.dombret@sls.aphp.fr)

>>>PNN NewsWatch
* Virtus Pharmaceuticals Opco II is voluntarily recalling seven batches of hyoscyamine sulfate 0.125 mg tablets, sublingual tablets, and orally disintegrating tablets to the consumer level because of superpotent and subpotent test results.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 16, 2016 * Vol. 23, No. 180
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Oct. 1 issue of Clinical Infectious Diseases (2016; 63).
Patient Sharing & Carbapenem-Resistant Enterobacteriaceae: In Illinois, hospitals with greater connectedness (centrality) to other hospitals are more likely to have patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE), a study shows (pp. 889–93). “Centrality had a greater effect on CRE rates in rural counties, which do not have [long-term acute care hospitals (LTACHs)],” the authors conclude based on these findings from a statewide hospital discharge dataset: “Higher CRE rates were observed among facilities with greater patient sharing, as measured by degree centrality. Each additional hospital connection (unit of degree) conferred a 6% increase in CRE rate in rural facilities (relative risk [RR] = 1.056; 95% confidence interval [CI], 1.030–1.082) and a 3% increase among Chicagoland and non-Chicago urban facilities (RR = 1.027; 95% CI, 1.002–1.052 and RR = 1.025; 95% CI, 1.002–1.048, respectively). Sharing 4 or more patients with LTACHs was associated with higher CRE rates, but this association may have been due to chance (RR = 2.08; 95% CI, .85–5.08; P = .11).” (M. J. Ray, michael.j.ray@illinois.gov)
Multidrug-Resistant Uropathogens: The increasing importance of multidrug resistance in management of outpatient urinary tract infections (UTIs) is reviewed (pp. 960–5): “As treatment options for multidrug-resistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim–sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.” (E. B. Hirsch, e.hirsch@neu.edu)

>>>Oncology Highlights
Source:
Sept. 20 issue of the Journal of Clinical Oncology (2016; 34).
Obesity, Smoking & Cancer Risk: The influence of obesity on cancer risk is greater in nonsmokers than smokers, and risk information provided to patients based on their smoking status, authors of a commentary argue (pp. 3237–9). “There is a clear difference in the effect estimate of BMI on total cancer risk in smokers versus nonsmokers for various reasons, including true causality, confounding, reverse causation, and different mixture of cancers,” the writers explain. “Yet regardless of the reasons, for clinical communication for risk prediction, it is inappropriate to provide a single effect estimate, which would be neither predictive for a smoker, nor a nonsmoker. For example, if the relative risk estimate of cancer associated with obesity is 1.0 in smokers, 2.0 in nonsmokers, and 1.4 in the entire population—which is determined by the relative prevalence of smokers and nonsmokers—ignoring a person’s smoking status and telling this individual that his or her relative risk is 1.4 would be incorrect. For communicating risk, an obese nonsmoker should be aware that his or her cancer risk is two-fold relative to a nonsmoking lean person. The relevance of BMI for a smoker is more complicated and would require a more nuanced message.” (E. Giovannucci, egiovann@hsph.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday said it has taken action against 55 major national retail chains, tobacco specialty stores and online retailers, by issuing the first warning letters for selling newly regulated tobacco products, such as e-cigarettes, e-liquids, and cigars, to minors. The agency last month began enforcing new federal regulations making it illegal nationwide to these tobacco products to anyone under age 18 in person and online, and requiring retailers to check photo ID of anyone under age 27, among other restrictions. During compliance checks, minors were able to purchase some of these newly regulated tobacco products in a variety of youth-appealing flavors, including bubble gum, cotton candy, and gummy bear.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 19, 2016 * Vol. 23, No. 181
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 17 issue of Lancet (2016; 388).
Adalimumab for Preventing Uveitic Flare: Adding to the evidence from a phase 3 trial reported recently in the New England Journal of Medicine (see PNN, Sept. 8), researchers report, “Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids” (pp. 1183–92). Among 226 intention-to-treat patients, a primary efficacy endpoint of time to treatment failure based on new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity showed: “Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8.3 months; hazard ratio 0.57, 95% CI 0.39–0.84; p = 0.004). The 40th percentile for time to treatment failure was 4.8 months in the placebo group and 10.2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group).” (Q. D. Nguyen, quan.nguyen@unmc.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
E-cigarettes in Quit Attempts: In the Smoking Toolkit Study, repeated cross-sectional household surveys in England show that electronic cigarette use was positively associated with quit attempts (i4645). Nicotine-replacement therapy (NRT) had a negative effect on quit attempts, and other interventions showed no significant effects: “The success rate of quit attempts increased by 0.098% (95% confidence interval 0.064 to 0.132; P <0.001) and 0.058% (0.038 to 0.078; P <0.001) for every 1% increase in the prevalence of e-cigarette use by smokers and e-cigarette use during a recent quit attempt, respectively. There was no clear evidence for an association between e-cigarette use and rate of quit attempts (beta 0.025; 95% confidence interval −0.035 to 0.085; P = 0.41), use of NRT bought over the counter (beta 0.006; −0.088 to 0.077; P = 0.89), use of prescription treatment (beta −0.070; −0.152 to 0.013; P = 0.10), or use of behavioural support (beta −0.013; −0.102 to 0.077; P = 0.78). A negative association was found between e-cigarette use during a recent quit attempt and use of NRT obtained on prescription (beta −0.098; −0.189 to −0.007; P = 0.04).” (E. Beard, e.beard@ucl.ac.uk)
Hyperglycemia & Adverse Perinatal Outcomes: Evidence does not support a clear threshold at which hyperglycemia is associated with adverse perinatal outcomes, according to a systematic review and meta-analysis of 25 reports of 207,172 women (i4694): “There were positive linear associations with caesarean section, induction of labour, large for gestational age, macrosomia, and shoulder dystocia for all glucose exposures across the distribution of glucose concentrations. There was no clear evidence of a threshold effect. In general, associations were stronger for fasting concentration than for post-load concentration. For example, the odds ratios for large for gestational age per 1 mmol/L increase of fasting and two hour post-load glucose concentrations (after a 75 g OGTT) were 2.15 (95% confidence interval 1.60 to 2.91) and 1.20 (1.13 to 1.28), respectively. Heterogeneity was low between studies in all analyses.” (D. Farrar, iane.Farrar@bthft.nhs.uk">Diane.Farrar@bthft.nhs.uk)

>>>PNN JournalWatch
* Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis, in
Clinical Infectious Diseases, 2016; 63: e147–95. (P. Nahid, pnahid@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 20, 2016 * Vol. 23, No. 182
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and the Sept. 20 issue of the Annals of Internal Medicine (2016; 165).
H1N1 Influenza Vaccine & Congenital Malformations: Administered to pregnant women during the 2009 swine-flu pandemic, GlaxoSmithKline’s monovalent AS03-adjuvanted H1N1 influenza vaccine “did not seem to be linked to overall congenital malformation in offspring” when intrafamily factors were considered, researchers report, “although risk increases for specific malformations could not be ruled out completely” (10.7326/M16-0139). In a population-based cohort study from Sweden, these patterns of congenital malformations were identified for live babies born between Oct. 1, 2009, and Oct. 1, 2011: “Congenital malformation was observed in 2,037 (4.97%) exposed offspring and 9,443 (4.78%) unexposed offspring. Adjusted risk for congenital malformation was 4.98% in exposed offspring versus 4.96% in unexposed offspring (risk difference, 0.02% [95% CI, −0.26% to 0.30%]). The corresponding risk differences were 0.16% (CI, −0.23% to 0.56%) for vaccination during the first trimester and 0.10% (CI, −0.41% to 0.62%) for vaccination in the first 8 weeks. Using siblings as comparators yielded no statistically significant risk differences.” (J. F. Ludvigsson, jonasludvigsson@yahoo.com)
Multicomponent Quality Improvement in Diabetes: Implementing a multicomponent quality improvement (QI) strategy for achieving diabetes care goal is possible even in resource-challenged clinics, according to a study from India and Pakistan (pp. 399–408). In a pragmatic, open-label trial, 1,146 patients with type 2 diabetes and poor cardiometabolic profiles had these outcomes when randomized to a multicomponent QI strategy using nonphysician care coordinators and decision-support electronic health records or usual care: “Median diabetes duration was 7.0 years; 6.8% and 39.4% of participants had preexisting cardiovascular and microvascular disease, respectively; mean HbA1c level was 9.9%; mean BP was 143.3/81.7 mm Hg; and mean LDLc level was 122.4 mg/dL. Over a median of 28 months, a greater percentage of intervention participants achieved the primary outcome [of HbA1c + BP and/or LDLc goals] (18.2% vs. 8.1%; relative risk, 2.24 [95% CI, 1.71 to 2.92]). Compared with usual care, intervention participants achieved larger reductions in HbA1c level (−0.50% [CI, −0.69% to −0.32%]), systolic BP (−4.04 mm Hg [CI, −5.85 to −2.22 mm Hg]), diastolic BP (−2.03 mm Hg [CI, −3.00 to −1.05 mm Hg]), and LDLc level (−7.86 mg/dL [CI, −10.90 to −4.81 mg/dL]) and reported higher [health-related quality of life] and treatment satisfaction.” (N. Tandon, nikhil_tandon@hotmail.com)
Binge-Eating Disorder in Adults: Drug and nondrug therapies are effective in patients with binge-eating disorders, report authors of a systematic review and meta-analysis (pp. 409–20): “Therapist-led cognitive behavioral therapy, lisdexamfetamine, and second-generation antidepressants (SGAs) decreased binge-eating frequency and increased binge-eating abstinence (relative risk, 4.95 [95% CI, 3.06 to 8.00], 2.61 [CI, 2.04 to 3.33], and 1.67 [CI, 1.24 to 2.26], respectively). Lisdexamfetamine (mean difference [MD], −6.50 [CI, −8.82 to −4.18]) and SGAs (MD, −3.84 [CI, −6.55 to −1.13]) reduced binge-eating–related obsessions and compulsions, and SGAs reduced symptoms of depression (MD, −1.97 [CI, −3.67 to −0.28]). Headache, gastrointestinal upset, sleep disturbance, and sympathetic nervous system arousal occurred more frequently with lisdexamfetamine than placebo (relative risk range, 1.63 to 4.28). Other forms of cognitive behavioral therapy and topiramate also increased abstinence and reduced binge-eating frequency and related psychopathology. Topiramate reduced weight and increased sympathetic nervous system arousal, and lisdexamfetamine reduced weight and appetite.” (K. A. Brownley, kbrownle@med.unc.edu)

>>>PNN NewsWatch
* FDA has announced the 2016 Naloxone App Competition, a public contest focused on developing innovative technologies to combat the epidemic of opioid overdose. Computer programmers, public health advocates, clinical researchers, entrepreneurs, and innovators are invited to create a mobile phone application that can connect opioid users experiencing an overdose with nearby carriers of the antidote naloxone, thereby increasing the likelihood of timely administration and overdose reversal.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 21, 2016 * Vol. 23, No. 183
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Sept. 20 issue of JAMA (2016; 316).
Second-Line Rheumatoid Arthritis Therapies: In patients with rheumatoid arthritis who do not respond adequately to initial therapy with an anti-TNF biologic agent, addition of a non-TNF-targeting biologic drug yields better outcomes than adding a second TNF inhibitor, researchers report (pp. 1172–80). Randomization of 300 nonresponding patients in 2009–12 to a non–TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment yielded these results for persistent disease activity (disease activity score in 28 joints–erythrocyte sedimentation rate [DAS28-ESR]) and European League Against Rheumatism (EULAR) scores: “Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27–3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003).” (J-E Gottenberg, jacques-eric.gottenberg@chru-strasbourg.fr)
Physician Buprenorphine Capacity: U.S. physicians are treating far fewer patients with buprenorphine than allowed under DEA limits, according to an analysis of 90% of community pharmacy prescriptions (pp. 1211–2). The Symphony Health Solutions’ Integrated Dataverse showed these patterns among prescribers of the drug, used for treating opioid use disorders, in the seven states with the most buprenorphine-waivered physicians: “We identified 3,234 buprenorphine prescribers with 245,016 patients receiving a new prescription of buprenorphine. Prescribers’ median monthly patient census was 13 patients (interquartile range [IQR], 5–36), and median episode duration was 53 days (IQR, 20–120). Twenty-two percent of prescribers had monthly censuses of 1 to 3 patients, 49% had 4 to 30 patients, 20% had 31 to 75 patients, and 9% had more than 75 patients.” The investigators conclude that availability of more experienced prescribers to novice prescribers and of substance abuse counseling to patients could help to resolve barriers to wider drug availability. (B. D. Stein, stein@rand.org)
Antimicrobial Resistance: To reduce the effects of multidrug-resistant pathogens, clinicians should change the way they prescribe antimicrobial agents, and public health interventions should continue, according to a review of 103 published articles (pp. 1193–204): “The increase in [antimicrobial resistance (AMR)] has been driven by a diverse set of factors, including inappropriate antibiotic prescribing and sales, use of antibiotics outside of the health care sector, and genetic factors intrinsic to bacteria. The problem has been exacerbated by inadequate economic incentives for pharmaceutical development of new antimicrobial agents. A range of specific AMR concerns, including carbapenem- and colistin-resistant gram-negative organisms, pose a clinical challenge. Alternative approaches to address the AMR threat include new methods of antibacterial drug identification and strategies that neutralize virulence factors.” (H. D. Marston, hilary.marston@nih.gov)
Performance Improvement: In the first of a new series in JAMA on performance improvement, the case of a 90-year-old woman without peripheral intravenous access adequate for antibiotic administration involves erroneous placement of a dialysis catheter instead a conventional central line (pp. 1207–8; T. Minnier, minnierte@upmc.edu).

>>>PNN NewsWatch
* FDA on Monday granted accelerated approval to eteplirsen (Exondys 51, Sarepta Therapeutics) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). It is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with DMD.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 22, 2016 * Vol. 23, No. 184
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Early-release article from and Sept. 22 issue of New England Journal of Medicine (2016; 375).
Anti-Xa Antidotal Effects of Andexanet Alfa: In patients with acute major bleeding associated with use of factor Xa inhibitors, andexanet alfa produced effective hemostasis in 79%, researchers report (pp. 1131–41). Participants in the open-label, single-group study were 67 patients with onset of acute major bleeding within 18 hours after administration of a factor Xa inhibitor. A bolus of andexanet followed by a 2-h infusion of the drug produced these outcomes based on measures of anti–factor Xa activity and clinical hemostasis: “The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (± SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8 ± 1.8 hours. After the bolus administration, the median anti–factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti–factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.” (S. J. Connolly, connostu@phri.ca)
“The advent of andexanet completes the story of direct oral anticoagulants, since there are now effective and relatively safe antidotes,” editorialists write (
pp. 1185–6). “The availability of effective reversing agents will probably accelerate the widespread introduction of direct oral anticoagulants in clinical practice. However, what we have not yet learned is how long it is necessary to cease anticoagulation after reversal for a major bleeding episode, such as intracranial hemorrhage. This highly relevant practical question needs urgent attention from clinical researchers.” (B. J. Hunt)
Romosozumab in Postmenopausal Osteoporosis: A sclerostin-binding monoclonal antibody, romosozumab, lowers the risk of vertebral fracture at 12 months, compared with placebo, according to a study of 7,180 postmenopausal women with low T scores at the total hip or femoral neck (10.1056/NEJMoa1607948). Participants received romosozumab or placebo for 12 months, followed by denosumab for 12 months. Results based on coprimary end points of cumulative incidences of new vertebral fractures at 12 and 24 months were as follows: “At 12 months, new vertebral fractures had occurred in 16 of 3,321 patients (0.5%) in the romosozumab group, as compared with 59 of 3,322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P <0.001). Clinical fractures had occurred in 58 of 3,589 patients (1.6%) in the romosozumab group, as compared with 90 of 3,591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P = 0.008). Nonvertebral fractures had occurred in 56 of 3,589 patients (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in the placebo group (P = 0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3,325 patients] in the romosozumab group vs. 2.5% [84 of 3,327] in the placebo group, a 75% lower risk with romosozumab; P <0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group.” (F. Cosman, cosmanf@helenhayeshosp.org)
Antimalarial Activity of KAF156: An agent in a new class of antimalarial drugs, the imidazolopiperazines, showed efficacy without safety concerns in a small study of adults in Thailand and Vietnam (pp. 1152–60). KAF156 reduced the clearance of both falciparum malaria and vivax malaria parasites in 10 patients on multiple doses and 21 patients receiving a single dose. (N. J. White, nickw@tropmedres.ac)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 23, 2016 * Vol. 23, No. 185
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Sept. issue of Health Affairs, a theme issue on Payment Reforms, Prescription Drugs & More (2016; 35).
Variability in MTM Eligibility Criteria: Medication therapy management (MTM) programs, required for Medicare Part D plans, “have considerable latitude in setting eligibility criteria,” researchers note (pp. 1572–80). Data on MTM programs for 2012 show variability in MTM use among plans, something recent changes in regulation may change: “Newly available data indicate that enrollment rates in medication therapy management among stand-alone prescription drug plans and Medicare Advantage drug plans averaged only 10 percent in 2012. The enrollment variation across plan sponsors—from less than 0.2 percent to more than 57.0 percent—was associated with the restrictiveness of their eligibility criteria. For example, enrollment was 16.4 percent in plans requiring two chronic conditions versus 9.2 percent in plans requiring three, and 12.7 percent in plans requiring the use of any Part D drug versus 4.4 percent in plans requiring the use of drugs in specific classes. This variation represents inequities in access to medication therapy management across plans and results in missed opportunities for interventions that might improve therapeutic outcomes and reduce spending. The new Part D Enhanced Medication Therapy Management model of the Centers for Medicare and Medicaid Services has the potential to significantly increase the impact of medication therapy management by aligning financial incentives with improvements in medication use and encouraging innovation.” (F. B. Hendrick, fhend001@umaryland.edu)
Anticancer Drugs, Costs & Life Expectancy: Comparing costs and mortality for the 1996–2000 and 2007–11 time periods, investigators find large increases in both medical costs and life expectancy (pp. 1581–7). Data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database show, for example, that patients with breast cancer who received physician-administered drugs incurred $72,000 more in outpatient and inpatient medical costs and lived an average of 13 months longer. (D. H. Howard, david.howard@emory.edu)
Out-Of-Pocket Burden For Specialty Drugs: Despite a shrinking “doughnut hole” in Medicare Part D benefits, patients on specialty drugs face a growing out-of-pocket burden when they reach the catastrophic coverage phase because of uncapped cost sharing, a study shows (pp. 1564–71): “Using 2008–12 pharmacy claims data from a 20 percent sample of Medicare beneficiaries, we analyzed trends in total and out-of-pocket spending among Medicare beneficiaries who take at least one high-cost specialty drug from the top eight specialty drug classes in terms of spending. Annual total drug spending per specialty drug user studied increased considerably during the study period, from $18,335 to $33,301, and the proportion of expenditures incurred while in the catastrophic coverage phase increased from 70 percent to 80 percent. We observed a 26 percent decrease in mean annual out-of-pocket expenditures incurred below the catastrophic coverage threshold, likely attributable to the ACA’s doughnut hole cost-sharing reductions, but increases in mean annual out-of-pocket expenditures incurred while in the catastrophic coverage phase offset these reductions almost entirely. Policy makers should consider implementing limits on patients’ out-of-pocket burden.” (E. Trish, etrish@healthpolicy.usc.edu)

>>>Medical Care Highlights
Source:
Oct. issue of Medical Care (2016; 54).
Potentially Inappropriate Medications in Older Adults: Greater health care service use and costs can result from use of potentially inappropriate medications (PIM) among older adults, according to a systematic review of 51 articles (pp. 950–64). “Most of the articles found that PIMs had a statistically significant effect on health care service use, especially on hospitalization, among older adults,” the authors write. “Five studies found statistically significant higher medical or total health care costs for PIM users compared [with] those who did not use any PIMs.” (V. Hyttinen)

>>>PNN NewsWatch
* Citing FDA sterility concerns, Wells Pharmacy Network is voluntarily recalling all sterile human and veterinary products prepared between Feb. 22 and Sept. 14 of this year and that remain within expiry.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 26, 2016 * Vol. 23, No. 186
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Erectile Dysfunction With 5-Alpha Reductase Inhibitors: Among patients using 5-alpha reductase inhibitors for benign prostatic hyperplasia (BPH) or alopecia, the risk of new-onset erectile dysfunction was not increased significantly, researchers report, but there was a risk of new cases during long-term of the drugs for BPH (i4823). In a cohort study with nested case–control analysis, the U.K. Clinical Practice Research Datalink provided these insights for men aged 40 years or more being treated with finasteride or dutasteride for BPH and those aged 40–59 years receiving finasteride for alopecia: “In the population with benign prostatic hyperplasia (n=71,849), the risk of erectile dysfunction was not increased with use of 5-alpha reductase inhibitors only (incidence rate ratio 0.92, 95% confidence interval 0.85 to 0.99; odds ratio 0.94, 95% confidence interval 0.85 to 1.03) or 5-alpha reductase inhibitors+alpha blocker (1.09, 0.99 to 1.21, 0.92; 0.80 to 1.06) compared with alpha blockers only, and remained null regardless of number of prescriptions or timing of use. The risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia, regardless of exposure. For the alopecia population (n = 12,346), the risk of erectile dysfunction was not increased for users of finasteride 1 mg compared with unexposed men with alopecia (1.03, 0.73 to 1.44; 0.95, 0.64 to 1.41).” (K. W. Hagberg, khagberg@bu.edu)
Beta-Blockers & Post-MI Mortality: In a prospective cohort study, early use of beta-blockers is supported by reduced 30-day mortality rates among patients with acute myocardial infarction and no heart failure or left ventricular dysfunction, but long-term findings question the utility of prolonging beta-blocker therapy past 1 year after the event (i4801). In the French registry of Acute ST- and non-ST-elevation Myocardial Infarction (FAST-MI), nationwide data from 223 centers showed these results for 2,679 consecutive patients: “Beta blockers were used early in 77% (2,050/2,679) of patients, were prescribed at discharge in 80% (1,783/2,217), and were still being used in 89% (1,230/1,383) of those alive at one year. Thirty day mortality was lower in patients taking early beta blockers (adjusted hazard ratio 0.46, 95% confidence interval 0.26 to 0.82), whereas the hazard ratio for one year mortality associated with beta blockers at discharge was 0.77 (0.46 to 1.30). Persistence of beta blockers at one year was not associated with lower five year mortality (hazard ratio 1.19, 0.65 to 2.18). In contrast, five year mortality was lower in patients continuing statins at one year (hazard ratio 0.42, 0.25 to 0.72) compared with those discontinuing statins. Propensity score and sensitivity analyses showed consistent results.” (E. Puymirat, etienne.puymirat@egp.aphp.fr)

>>>Lancet Highlights
Source:
Sept. 24 issue of Lancet (2016; 388).
Economic Burden of Physical Inactivity: Worldwide promotion of regular physical activity should be a priority, authors conclude, based on an analysis of the economic burden of inactivity (pp. 1311–24): “Conservatively estimated, physical inactivity cost health-care systems international $ (INT$) 53.8 billion worldwide in 2013, of which $31.2 billion was paid by the public sector, $12.9 billion by the private sector, and $9.7 billion by households.… High-income countries bear a larger proportion of economic burden (80.8% of health-care costs and 60.4% of indirect costs), whereas low-income and middle-income countries have a larger proportion of the disease burden (75.0% of disability-adjusted life–years).…” (D. Ding, melody.ding@sydney.edu.au)

>>>PNN NewsWatch
* FDA on Friday approved adalimumab-atto (Amjevita, Amgen) as a biosimilar to the innovator drug, Humira, with indications for multiple inflammatory diseases.
* Additional indications were also approved for
canakinumab (Ilaris, Novartis) use in three rare diseases in adult and pediatric patients.

>>>PNN JournalWatch
* Pathogenesis, Diagnosis, and Treatment of Venous Thromboembolism in Older Adults, in
Journal of the American Geriatrics Society, 2016; 64: 1869–78. (M. T. Rodina, matthew.rondina@hsc.utah.edu)
* Resolving the Etiology of Atopic Disorders by Using Genetic Analysis of Racial Ancestry, in
Journal of Allergy and Clinical Immunology, 2016; 138: 676–99. (T. B. Mersha, tesfaye.mersha@cchmc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 27, 2016 * Vol. 23, No. 187
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Sept. Journal of the American Geriatrics Society (2016; 64).
Long-Acting Opioids in Long-Stay Nursing Home Residents: The persistent use of long-term opioids, including the fentanyl patches that have safety problems, in long-stay nursing home (NH) residents is demonstrated in a cross-sectional analysis of Medicare data for 22,253 beneficiaries (pp. 1772–8). Information from the Minimum Data Set 3.0 for 2011 showed the following: “Of NH residents prescribed a long-acting opioid within 30 days of NH admission (n = 12,278), 9.4% (95% confidence interval = 8.9–9.9%) lacked a prescription drug claim for a short-acting opioid in the previous 60 days. The most common initial prescriptions of long-acting opioids were fentanyl patch (51.9% of opioid-naive NH residents), morphine sulfate (28.1%), and oxycodone (17.2%).” (K. L. Lapane, kate.lapane@umassmed.edu)
Proactive Primary Care Program & Daily Functioning of Older People: In 39 Dutch primary care practices, a nurse-led assessment and intervention program enabled less decline in in measures of daily functioning of older people than did usual care, researchers report (pp. 1779–88). At-risk community-dwelling people aged 60 years or older were identified through electronic medical records based on screening for frailty. Participants cluster-randomized to the intervention group received comprehensive geriatric assessment, evidence-based care planning, care coordination, and follow-up. Results showed: “The participants in both intervention arms had less decline in daily functioning than those in the usual care arm at 12 months (mean Katz-15 score: screening arm, 1.87, 95% confidence interval (CI) = 1.77–1.97; screening and nurse-led care arm, 1.88, 95% CI = 1.80–1.96; control group, 2.03, 95% CI = 1.92–2.13; P = .03). No differences in quality of life were observed.” (N. Bleijenberg, N.Bleijenberg@umcutrecht.nl)

Abuse Intervention Model: Authors present “the Abuse Intervention Model” in an effort to provide “a simple, coherent framework of known risk factors of the victim, perpetrator, and environment that applies to all types of abuse” of elders (pp.1879–83 ). “Theories of elder mistreatment, research on risk factors for elder mistreatment, and 10 years of experience of faculty and staff at an Elder Abuse Forensics Center who have investigated more than 1,000 cases of elder mistreatment inform this model,” the authors write. “It is hoped that this model … will be used to study and intervene in elder mistreatment.” (L. Mosqueda, Laura.Mosqueda@med.usc.edu)


>>>Allergy/Immunology Report
Source:
Sept. issue of the Journal of Allergy and Clinical Immunology (2016; 138).
Calcineurin inhibitors & Neutrophil Aspergillus Activity: In allogeneic hematopoietic stem cell transplant (HSCT) recipients, use of calcineurin inhibitors is associated with reduced neutrophil activity against the widely distributed mold Aspergillus fumigatus, a study shows (pp. 860–8). The effect occurs early in the posttransplantation period according to longitudinal data on 37 patients: “The ability of neutrophils to interfere with Aspergillus species hyphal growth was impaired after HSCT. The administration of calcineurin inhibitors appeared to play an important role in this impairment. We also observed that post-HSCT neutrophils produced less [neutrophil extracellular traps], which was correlated with increased fungal growth. Tapering immunosuppression led to the recuperation of inhibition capacity 10 months after HSCT.” (A. Fekkar, arnaud.fekkar@aphp.fr)
Helminth Parasites & Host Immunity: Immunomodulatory effects used by helminths to maintain host infections could be useful in management of human disease, according to a review article (pp. 666–75): “The host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research.” (R. M. Maizels, rick.maizels@glasgow.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 28, 2016 * Vol. 23, No. 188
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Sept. 27 issue of JAMA (2016; 316).
LDL Cholesterol & Cardiovascular Risk Reduction: Whether it’s done with statins or other approaches, lowering LDL cholesterol levels matters, a systematic review and meta-analysis of published studies July 2016 concludes (pp. 1289–97). “The use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar [relative risks (RRs)] of major vascular events per change in LDL-C.,” the authors write. “Lower achieved LDL-C levels were associated with lower rates of major coronary events.”
The analysis looked for reductions in the RR of a composite of cardiovascular death, acute myocardial infarction (MI) or other acute coronary syndrome, coronary revascularization, or stroke as related to absolute reductions in LDL-C. Five-year rates of major coronary events (coronary death or MI) was also considered. Results showed the following: “A total of 312,175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39,645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71–0.84; P <.001) for statins and 0.75 (95% CI, 0.66–0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75–0.79, P <.001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89–0.99) vs 0.91 (95% CI, 0.90–0.92) for niacin (P = .24); 0.88 (95% CI, 0.83–0.92) vs 0.94 (95% CI, 0.93–0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94–1.09) vs 0.90 (95% CI, 0.89–0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34–0.71) vs 0.61 (95% CI, 0.58–0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11,301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%–2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%–6.4%] per each 1-mmol/L lower LDL-C level; P <.001).” (M. S. Sabatine,
msabatine@partners.org)
Endovascular Thrombectomy in Ischemic Stroke: Compared with medical therapy alone, early endovascular thrombectomy plus medical therapy provides better outcomes in patients with ischemic stroke, authors of a meta-analysis report (pp. 1279–88): “Among all 1,287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, −6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, −5.2% [95% CI, −8.3% to −2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, −0.9% to 4.2%]).” (M. D. Hill, michael.hill@ucalgary.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 29, 2016 * Vol. 23, No. 189
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Early-release article and Sept. 29 issue of the New England Journal of Medicine (2016; 375).
Azithromycin Prophylaxis in Cesarean Delivery: The risks of postoperative infections were lower among women undergoing nonelective cesarean deliveries when adjunctive azithromycin was added to standard antimicrobial prophylaxis regimens, compared with placebo, researchers report (pp. 1231–41). The multicenter trial included 2,013 women with singleton pregnancies who had cesarean deliveries during labor or after membrane rupture. I.V. azithromycin 500 mg or placebo had these effects on a primary outcome of a composite of endometritis, wound infection, or other infection within 6 weeks of surgery: “The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; P <0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P = 0.02), wound infection (2.4% vs. 6.6%, P <0.001), and serious maternal adverse events (1.5% vs. 2.9%, P = 0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P = 0.63).” (A. T. N. Tita, atita@uabmc.edu)
After noting questions about the level of risk in this study population, the dose of cefazolin used in standard prophylactic regimens in the trial, and the need for prospective vaginal microbial collection, editorialists reach this conclusion (
pp. 1284–6): “Time will tell whether such findings result in changes in routine antibiotic prophylaxis before cesarean deliveries. However, on the basis of this well-designed, pragmatic, multicenter trial, it seems likely that a single adjunctive 500-mg dose of intravenous azithromycin would reduce a number of infectious complications for some women without established infections who are undergoing nonelective cesarean section.” (R. A. Weinstein)
Fluticasone Furoate–Vilanterol for COPD: Compared with usual care, once-daily fluticasone furoate plus vilanterol lowered exacerbations in a group of patients with difficult-to-treat chronic obstructive pulmonary disease (COPD) (pp. 1253–60). The 2,799 study participants at 75 general practices had these outcomes based on the rate of moderate or severe exacerbations among patients who had had an exacerbation within the prior year: “The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate–vilanterol therapy than with usual care (P = 0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate–vilanterol group. The numbers of other serious adverse events were similar in the two groups.” (J. Vestbo, jorgen.vestbo@manchester.ac.uk)
Clinton’s Vision for “Universal, Quality, Affordable Health Care”: Promising to “improve—not repeal—the Affordable Care Act,” the Democratic presidential nominee promises to “work tirelessly with anyone dedicated to improving our families’ health and ensuring that the promise of affordable, quality health care is achieved for all Americans” (10.1056/NEJMsb1612292). Prescription drugs were a primary emphasis in the candidate’s “affordability” section, calling for streamlining approval of generic drugs and biosimilar products and proposing a $250 per month limit on the copayments for covered prescription drugs. (H. Clinton; the Journal editors noted that the Republican nominee did not respond to an offer to answer the question, “What specific changes in policy do you support to improve access to care, improve quality of care, and control health care costs for our nation?&rdquoWinking

>>>PNN NewsWatch
* FDA yesterday approved Medtronic’s MiniMed 670G hybrid closed looped system, the first FDA-approved device for automatically monitoring glucose and providing appropriate basal insulin doses in people 14 years of age and older with type 1 diabetes.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2016, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Sept. 30, 2016 * Vol. 23, No. 190
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Oct. issue of Diabetes Care (2016; 89).
Pioglitazone & Diabetes Prevention: In the Insulin Resistance Intervention after Stroke (IRIS) trial, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events (pp. 1684–92). Pioglitazone is “the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial,” the authors noted. Participants (n = 3,876) had recent ischemic stroke or transient ischemic attack (TIA), no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0. Compared with placebo, pioglitazone produced these outcomes: “At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 µIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P <0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33–0.69]; P <0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30–0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34–0.62]).” (S. E. Inzucchi, silvio.inzucchi@yale.edu)
Liraglutide in the ADJUNCT Trials: Results of two Efficacy and Safety of Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes (ADJUNCT) trials are presented.
“Liraglutide added to insulin therapy reduced HbA
1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group,” conclude ADJUNCT ONE investigators (pp. 1702–10). Among 1,398 adults in the trial, three doses of liraglutide (1.8, 1.2, and 0.6 mg subcutaneously once daily) were compared with placebo over a 52-week period. (C. Mathieu, chantal.mathieu@med.kuleuven.be)
ADJUNCT TWO, a 26-week trial of patients with long-standing type 1 diabetes, showed that liraglutide added to capped insulin therapy “reduced HbA
1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg” (pp. 1693–701). Results for 835 study participants, randomized to placebo or the same three liraglutide doses as in the first trial, showed the following: “Mean baseline HbA1c (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: –0.33% [3.6 mmol/mol]; 1.2 mg: –0.22% [2.4 mmol/mol]; 0.6 mg: –0.23% [2.5 mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (–5.1, –4.0, and –2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (–0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.” Study investigators conclude, “The higher number of hypoglycemia and of hyperglycemia with ketosis in some of the liraglutide groups emphasizes the need for proper insulin titration and may ultimately limit the clinical utility of [glucagon-like peptide-1 receptor agonists] in a less well-supervised population with type 1 diabetes.” (B. Ahrén, bo.ahren@med.lu.se)

>>>PNN NewsWatch
* The 2016–17 influenza vaccination season kicked off yesterday at a media briefing in Washington, DC (video available on the National Foundation for Infectious Diseases website). CDC Director Tom Frieden, MD, MPH, received his annual flu shot, administered by a nurse. Representatives from pediatric, geriatric, nursing, and OB-GYN communities spoke. In the question-and-answer period, reporters asked several questions about the intranasal live attenuated influenza vaccine, which is not being used in the U.S. this year because of vaccine efficacy problems of uncertain origin.

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