PNN January–March 2018

PNN Pharmacotherapy Line
Jan. 2, 2018 * Vol. 25, No. 1
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Jan. 2 issue of and early-release articles from the Annals of Internal Medicine (2018; 168).
Statin Guidelines for Primary Prevention: Guidelines recommending that more persons use statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) should prevent more events than guidelines recommending use by fewer persons, according to findings of a systematic review and meta-analysis (10.7326/M17-0681). Researchers conducted an observational study of actual ASCVD events over 10 years followed by a modeling study to estimate the effectiveness of different guidelines in a contemporary cohort of 45,750 persons aged 40 to 75 years who did not use statins and did not have ASCVD at baseline between 2003 and 2009. The percentage of participants eligible for statins was 44% by the Canadian Cardiovascular Society (CCS) guideline, 42% by the American College of Cardiology/American Heart Association (ACC/AHA), 40% by the National Institute for Health and Care Excellence (NICE), 31% by the U.S. Preventive Services Task Force (USPSTF), and 15% by European Society of Cardiology/European Atherosclerosis Society (ESC/EAS). The estimated percentage of ASCVD events that could have been prevented by using statins for 10 years was 34% for CCS, 34% for ACC/AHA, 32% for NICE, 27% for USPSTF, and 13% for ESC/EAS. Guidelines from the ACC/AHA, CCS, or NICE should be followed rather than those from the USPSTF and ESC/EAS, the researchers concluded. (B. G. Nordestgaard, boerge.nordestgaard@regionh.dk)
Blood Pressure Control in Hypertensive Patients: “Multilevel, multicomponent strategies, followed by patient-level strategies, are most effective for [blood pressure (BP)] control in patients with hypertension and should be used to improve hypertension control,” conclude authors of a systematic review and meta-analysis (10.7326/M17-1805): “A total of 121 comparisons from 100 articles with 55,920 hypertensive patients were included. Multilevel, multicomponent strategies were most effective for systolic BP reduction, including team-based care with medication titration by a nonphysician (−7.1 mm Hg [95% CI, −8.9 to −5.2 mm Hg]), team-based care with medication titration by a physician (−6.2 mm Hg [CI, −8.1 to −4.2 mm Hg]), and multilevel strategies without team-based care (−5.0 mm Hg [CI, −8.0 to −2.0 mm Hg]). Patient-level strategies resulted in systolic BP changes of −3.9 mm Hg (CI, −5.4 to −2.3 mm Hg) for health coaching and −2.7 mm Hg (CI, −3.6 to −1.7 mm Hg) for home BP monitoring. Similar trends were seen for diastolic BP reduction.” (J. He, jhe@tulane.edu)
>>>Diabetes Care Report
Source:
Jan. issue of Diabetes Care (2018; 41).
Diabetes & Heart Failure: “The totality of evidence from randomized trials, which is supported by [three] observational analyses published in this issue of Diabetes Care, demonstrates that in patients with diabetes, heart failure is not only common and clinically important, but it can also be prevented and treated,” concludes a Commentary author (pp. 11–3). “This conclusion is particularly significant because physicians have long ignored heart failure in their focus on glycemic control and their concerns about the ischemic macrovascular complications of diabetes.” The author gives this perspective, “Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure.” (M. Packer, milton.packer@baylorhealth.edu)
>>>PNN JournalWatch
* Standards of Medical Care in Diabetes—2018, in Diabetes Care, 2018; 41 (suppl 1).
*
Disparities in Environmental Exposures to Endocrine-Disrupting Chemicals and Diabetes Risk in Vulnerable Populations, in Diabetes Care, 2018; 41: 193–205. (R. M. Sargis, rsargis@uic.edu)
*
Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-1811. (V. Sung)
*
Attention-Deficit/Hyperactivity Disorder and Very Preterm/Very Low Birth Weight: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-1645. (A. P. Franz)
*
Maternal Smoking and Attention-Deficit/Hyperactivity Disorder in Offspring: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-2465 (L. Huang)

PNN Pharmacotherapy Line
Jan. 3, 2018 * Vol. 25, No. 2
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 2 issue of JAMA (2018; 319).
Infant Formula & Type 1 Diabetes: During 11.5 years of follow-up, the cumulative incidence of type 1 diabetes was unchanged among infants who had been weaned to hydrolyzed versus conventional formula (pp. 38–48). Participants had human leukocyte antigen–conferred disease susceptibility and a first-degree relative with type 1 diabetes at 78 study centers in 15 countries when they were randomized to extensively hydrolyzed casein formula or conventional formula in 2002–07. Results showed the following when follow-up ended in early 2017: “Among 2,159 newborn infants (1,021 female [47.3%]) who were randomized, 1,744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1–Q3, 10.2–12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, −1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1–Q3, 3.1–8.9] vs 5.8 years [Q1–Q3, 2.6–9.1]; difference, 0.2 years [95% CI, −0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group).” (M. Knip, mikael.knip@helsinki.fi)
Recovering From Sepsis: Higher rates of survival among patients with sepsis has created a growing number of people who need posthospital care or recovery, authors of a review article write (pp. 62–75). Of the 19 million people worldwide who have sepsis in a given year, 14 million survive, but one third of them die during the following year and one sixth of them have severe persistent impairments. To provide the care needed by these patients, clinicians can consider these recommendations made in the conclusion of this article: “In the months after hospital discharge for sepsis, management should focus on (1) identifying new physical, mental, and cognitive problems and referring for appropriate treatment, (2) reviewing and adjusting long-term medications, and (3) evaluating for treatable conditions that commonly result in hospitalization, such as infection, heart failure, renal failure, and aspiration. For patients with poor or declining health prior to sepsis who experience further deterioration after sepsis, it may be appropriate to focus on palliation of symptoms.” (H. C. Prescott, hprescot@med.umich.edu)
Exploring Single Payer for U.S. Health Care: “A single-payer system could easily provide for universal coverage, but so could less-comprehensive reforms, if the public would support subsidies and compulsion,” writes a Viewpoint author in exploring options for addressing flaws in the U.S. health care system (pp. 15–6). “Single payer might improve health outcomes by providing more equal access to medical care, but attention to the social determinants of health might be a more effective way to improve health. The strongest case for single payer is its potential to control the cost of care. The current fragmented system of financing care precludes such control.” (V. R. Fuchs, vfuchs@stanford.edu)
A second Viewpoint explores Canadian single-payer experiences (
pp. 17–8). “Canada does offer important lessons for reform in the United States, not least in its relentless commitment to equitable access for some key services, its administrative efficiency, and its success in cost-containment. However, Canada’s health care arrangements are rooted in different values, facilitated by a different model of democratic governance, and reflect a different era, both in the conditions that fostered their creation and in an outmoded architecture that makes them a dubious exemplar for the United States. There is arguably much more for the United States to learn from the panoply of long-standing national experiments with universal coverage that can be found across the [Organisation for Economic Co-operation and Development]. Reinhardt, for one, suggested that Germany, the Netherlands, and Switzerland merited particularly close examination.” (C. D. Naylor, david.naylor@utoronto.ca)

PNN Pharmacotherapy Line
Jan. 4, 2018 * Vol. 25, No. 3
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 4 New England Journal of Medicine (2018; 378).
Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma: Among 75 participants in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression improved event-free and overall survival, compared with cyclophosphamide (pp. 35–47). At 54 months, patients with diffuse cutaneous systemic sclerosis (scleroderma) had these outcomes based on global rank composite scores: “In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1,404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan–Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.” (K. M. Sullivan, keith.sullivan@duke.edu)
Need for Universal Influenza Vaccine: “Even in years when influenza vaccines are well matched to circulating viruses, estimates of vaccine effectiveness range from 40 to 60%, which is lower than that for most licensed noninfluenza vaccines,” public health officials write in calling for renewed emphasis on development of an effective universal vaccine against this virus (pp. 7–9). Pointing to a 10% vaccine effectiveness figure in the 2016–17 Australian influenza season, the authors — including National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD — wrote the following: “Given that most of the U.S. influenza-vaccine supply is currently produced in eggs and the composition of the 2017–2018 Northern Hemisphere vaccine is identical to that used in Australia, it is possible that we will experience low vaccine effectiveness against influenza A (H3N2) viruses and a relatively severe influenza season if they predominate. This possibility underscores the need to strive toward a ‘universal’ influenza vaccine that will protect against seasonal influenza drift variants as well as potential pandemic strains, with better durability than current annual vaccines. Among other advantages, in all likelihood, such a vaccine would not be subject to the limitations of egg-based vaccine technology.” (C. I. Paules)
>>>PNN NewsWatch
* PharMEDium is voluntarily recalling 55 lots of different drug products involving a total of 25,327 units to the hospital/user level because of a lack of assurance of sterility. The recall results from “a commitment made during a recent inspection of the company’s facility,” PharMEDium said in a news release, adding that it “has not received any reports of complaints related to the products but is issuing this recall out of an abundance of caution.”
*
AuroMedics Pharma is voluntarily recalling lot AFO l 17001-A, expiry date Dec. 2018, of Ampicillin and Sulbactam for Injection, USP, 1.5 g in a single-dose vial, to the hospital level, because of presence of glass particles.
* Announcing “new steps to facilitate efficient
generic drug review to enhance competition, promote access, and lower drug prices,” FDA Commissioner Scott Gottlieb, MD, made these commitments to specific actions and initiatives in a statement released yesterday: “We’ll also continue to take steps aimed at making it harder for brand companies to sometimes adopt tactics that prevent generics from coming to market in the time frame that the law intended. This includes guidance development to address three important areas during the first quarter of 2018: potential abuses of the citizen petition process, companies that restrict access to testing samples of branded drugs, and abuses of the single, shared system REMS negotiation process.”

PNN Pharmacotherapy Line
Jan. 5, 2018 * Vol. 25, No. 4
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
Jan. issue of Pediatrics (2018; 141).
Persistent Opioid Use After Adolescent Surgery: Use of opioids by adolescents and young adults following surgery can persist, creating “an important pathway to prescription opioid misuse,” researchers report (10.1542/peds.2017-2439). Retrospective cohort analysis of the Truven Health Marketscan research databases for 2010–14 showed the following for opioid-naive patients ages 13–21 years who underwent 1 of 13 specified surgeries: “Among eligible patients, 60.5% filled a postoperative opioid prescription (88,637 patients). Persistent opioid use was found in 4.8% of patients (2.7%–15.2% across procedures) compared with 0.1% of those in the nonsurgical group. Cholecystectomy (adjusted odds ratio 1.13; 95% confidence interval, 1.00–1.26) and colectomy (adjusted odds ratio 2.33; 95% confidence interval, 1.01–5.34) were associated with the highest risk of persistent opioid use. Independent risk factors included older age, female sex, previous substance use disorder, chronic pain, and preoperative opioid fill.” (C. M. Harbaugh)
Parental Counseling Before Immunization Exemptions: In Washington State, provision of legally mandated parental counseling by a health care provider of parents requesting exemption from required school immunizations significantly reduced exemption rates, a study shows (10.1542/peds.2017-2364). Comparing exemption rates in 2013–14 with those of 1997–98, investigators found this impact of a 2011 law requiring counseling: “After SB5005 was implemented, there was a significant relative decrease of 40.2% (95% confidence interval: −43.6% to −36.6%) in exemption rates. This translates to a significant absolute reduction of 2.9 percentage points (95% confidence interval: −4.2% to −1.7%) in exemption rates.…” (S. B. Omer)
Timing of Inpatient Pentavalent Rotavirus Vaccination: Recommendations to delay administration of the pentavalent human-bovine reassortant rotavirus vaccine (RV5) until discharge from inpatient neonatal units may be misguided, according to data from an academic medical center (10.1542/peds.2017-1110). The recommendations are based on a theoretical risk of nosocomial transmission of vaccine-type rotavirus, but prospective cohort data show that some infants may be age-ineligible by discharge and that the precaution may be unnecessary: “Of 385 study infants, 127 were age-eligible for routine vaccinations during hospitalization. At discharge, 32.7% were up-to-date for rotavirus vaccination, compared with 82.7% for other vaccinations. Of rotavirus-unvaccinated infants, 42.6% were discharged at age >104 days and thus vaccination-ineligible. Of 1,192 stool specimens collected, rotavirus was detected in 13 (1.1%): 1 wild-type strain from an unvaccinated infant; 12 vaccine-type strains from 9 RV5-vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants (incidence rate: 0.0 [95% confidence interval: 0.0–1.5] cases per 1,000 patient days at risk).” (A. M. Hofstetter)
>>>Chest Highlights
Source:
Jan. issue of Chest (2018; 153).
Pharmaceutical Pricing: The 3 Cs of communication, continuity of care, and concordance of expectations (finding the common ground) should be used to address with patients the problems presented by higher-priced older pharmaceuticals, according to a summary of nine editorials based on an interprofessional session at CHEST 2016 (pp. 23–33). In a section on costs of epinephrine autoinjectors, a CVS Health physician writes that “pharmacists want to be part of the solution.… Because pharmacists interact with millions of people every day at the pharmacy counter and online, they understand the effect rising drug costs have on patients and their families.” (R. S. Irwin, Richard.Irwin@umassmemorial.org)
>>>PNN NewsWatch
* Vice President Mike Pence is among proponents pushing for federal right-to-try legislation in the U.S. Congress, Politco reports. As spelled out in H.R. 878, right-to-try allows terminally ill patients to use investigational drugs that have cleared phase 1 safety tests but not been approved for marketing by FDA. Politico has also posted a podcast in which FDA Commissioner Scott Gottlieb, MD, spells out the agency’s agenda for 2018.

PNN Pharmacotherapy Line
Jan. 8, 2018 * Vol. 25, No. 5
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Neoadjuvant Chemotherapy for Advanced Ovarian Cancer: Areas of the U.S. where cancer programs rapidly adopted neoadjuvant chemotherapy (NACT) in women with advanced epithelial ovarian cancer had significantly better mortality within 3 years, a quasi-experimental study shows (j5463): “In the rapidly adopting regions, patients treated in 2012 compared with 2011 had a mortality hazard ratio of 0.81 (95% confidence interval 0.71 to 0.94) after adjusting for mortality time trends, whereas no difference was observed in control regions (1.02, 0.93 to 1.12). Compared with control regions, larger declines in 90 day surgical mortality (7.0% to 4.0% v 5.0% to 4.3%, P = 0.01) and in the proportion of women not receiving surgery and chemotherapy (20.0% to 17.4% v 19.0 to 19.5%, P = 0.04) were observed in rapidly adopting regions. Cross sectional analysis confirmed that treatment in regions with greater use of NACT was associated was lower mortality (P = 0.001).” (A. Melamed, alexander.melamed@mgh.harvard.edu)
>>>Lancet Highlights
Source:
Jan. 6 issue of Lancet (2018; 391).
PCI in Stable Angina: Among 230 patients in the ORBITA trial who had stable angina and severe coronary stenosis, percutaneous coronary intervention (PCI) was no better than a placebo procedure in improving exercise time, researchers report (pp. 31–40). After 6 weeks of medication optimization, randomization to PCI or placebo procedure produced these outcomes: “Lesions had mean area stenosis of 84.4% (SD 10.2), fractional flow reserve of 0.69 (0.16), and instantaneous wave-free ratio of 0.76 (0.22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16.6 s, 95% CI −8.9 to 42.0, p = 0.200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group.” The authors conclude, “The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy.” (J. E. Davies, ORBITA.trial@gmail.com)
Stents & Double Antiplatelet Therapy in Older Adults: In the SENIOR trial, patients aged 75 years or older had better outcomes following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) plus a short period of double antiplatelet therapy (DAPT), compared with bare-metal stents (BMS) plus DAPT (pp. 41–50). Participants in nine countries had stable angina, silent ischemia, or an acute coronary syndrome and at least one coronary artery with 70% stenosis. After 1 or 6 months of DAPT in those with stable or unstable presentation, randomization to DES or BES produced these results: “Between May 21, 2014, and April 16, 2016, we randomly assigned 1,200 patients (596 [50%] to the DES group and 604 [50%] to the BMS group). The primary endpoint occurred in 68 (12%) patients in the DES group and 98 (16%) in the BMS group (relative risk [RR] 0.71 [95% CI 0.52–0.94]; p = 0.02). Bleeding complications (26 [5%] in the DES group vs 29 [5%] in the BMS group; RR 0.90 [0.51–1.54]; p=0.68) and stent thrombosis (three [1%] vs eight [1%]; RR 0.38 [0.00–1.48]; p = 0.13) at 1 year were infrequent in both groups.” (O. Varenne, livier.varenne@aphp.fr">olivier.varenne@aphp.fr)
>>>PNN JournalWatch
* Primary Prevention With Statins in the Elderly, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.10.080. (M. B. Mortensen)
*
Obesity: Pathophysiology and Management, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.11.011. (K. M. Gadde)
*
Cannabis Use and Risk of Prescription Opioid Use Disorder in the United States, in American Journal of Psychiatry, 2018; 175: 47–53. (M. Olfson)
*
Psychiatric Genomics: An Update and an Agenda, in American Journal of Psychiatry, 2018; 175: 15–27. (P. F. Sullivan)
*
Classification of Cough as a Symptom in Adults and Management Algorithms, in Chest, 2018; 153: 196–209. (R. S. Irwin, richard.irwin@umassmemorial.org)
*
Clinical Practice and Infrastructure Review of Fecal Microbiota Transplantation for Clostridium difficile Infection, in Chest, 2018; 153: 266–77. (B. J. Kelly, brendank@mail.med.upenn.edu)
*
Intraabdominal Hypertension, Abdominal Compartment Syndrome, and the Open Abdomen, in Chest, 2018; 153: 238–50. (W. K. Rogers, william-k-rogers@uiowa.edu)

PNN Pharmacotherapy Line
Jan. 9, 2018 * Vol. 25, No. 6
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Early-online articles from and Jan. issue of JAMA Internal Medicine (2018; 178).
Cost-effectiveness of New Shingles Vaccine in Older Adults: The adjuvanted herpes zoster subunit vaccine (HZ/su), already demonstrated to be highly efficacious in older adults, may also be more cost-effectiveness than the live attenuated herpes zoster vaccine (ZVL), if the new product is priced as expected (10.1001/jamainternmed.2017.7431). Total costs and quality-adjusted life-years (QALYs) were as follows in a Markov decision model cost-effectiveness evaluation: “Based on randomized clinical trial data, at a price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20,038 to $30,084 per QALY, depending on vaccination age. The finding was insensitive to variations in most model inputs other than the vaccine price and certain combinations of low adherence rate with a second dose and low efficacy of a single dose of HZ/su. At the current ZVL price ($213 per dose), HZ/su had lower overall costs than ZVL up to a price of $350 per 2-dose series. In probabilistic sensitivity analysis, HZ/su had 73% probability of being cost-effective for 60-year-olds at $50,000 per QALY.” (P. Le, lep@ccf.org)
“The HZ/su vaccine offers a substantial advantage over ZVL in terms of preventing HZ, while its efficacy appears to persist over a longer duration and in different age groups,” writes an editorialist (
10.1001/jamainternmed.2017.7442). “These clinical benefits directly translate into achieving high economic value as demonstrated by Le and Rothberg in their study. If priced at $280 per 2 required doses, HZ/su appears to be a cost-saving option compared with ZVL and a cost-effective option compared with no-vaccine strategies. However, the value of HZ/su vaccine would be even higher if it could be marketed at a price comparable to that of ZVL. A lower price would avoid additional budget implications for patients and payers and would allow wider use of this innovative product in the US elderly population.” (M. Najafzadeh, mnajafzadeh@bwh.harvard.edu)
Health Care Databases & Supplemental Indications: Could real-world databases be used to support supplemental indications of approved medications? Authors who analyzed longitudinal insurance claims from a national system think so (pp. 55–63). Using inclusion and exclusion criteria from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET), results for a primary composite outcome of myocardial infarction, stroke, or hospitalization for congestive heart failure were similar to those from the drug’s pivotal trial: “Of the 640,951 patients included in the study, 48,053 were newly prescribed ramipril (mean [SD] age, 68.29 [9.52] years; 31,940 male [66.5%]) and 4,665 were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2,413 male [51.7%]). After propensity score matching, a total of 4,665 patients were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2,413 [51.7%]), and 4,665 patients were newly prescribed ramipril (mean [SD] age, 69.36 [9.67] years; 2343 male [50.2%]). As seen in ONTARGET, the composite risk of stroke, myocardial infarction, and hospitalization for congestive heart failure was similar for the 2 medications (hazard ratio, 1.0; 95% CI, 0.9–1.1). In addition, the study found that telmisartan was associated with a substantially decreased risk of angioedema (hazard ratio, 0.1; 95% CI, 0.03–0.56) compared with ramipril.” (M. Fralick, mif823@mail.harvard.edu)
New, Unpronounceable Pharmaceuticals: “An agreed-on pronunciation for new drugs should help prevent errors in prescribing medications and save clinicians the embarrassment of correcting our colleagues,” an editorialist concludes after discussing lack of guidance in drug compendia (10.1001/jamainternmed.2017.7898). “It should make us more willing to communicate accurately using generic names as opposed to using trade names or pharmacologic classes of drugs. Wider adoption of the USAN pronunciation standards would help us as physicians and be better for patients.” (D. S. Frank, daniel.s.frank@gmail.com)

PNN Pharmacotherapy Line
Jan. 10, 2018 * Vol. 25, No. 7
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 9 issue of JAMA (2018; 319).
Idalopirdine in Alzheimer Disease: Trials of adjunctive idalopirdine in 2,525 patients with mild-to-moderate Alzheimer disease (AD) fail to support efficacy claims based on improved cognition over 24 weeks (pp. 130–42). The selective 5-hydroxytryptamine-6 receptor antagonist was used in three doses along with donepezil and in one trial, donepezil, rivastigmine, or galantamine, with these results: “In study 1, the mean change in [Alzheimer’s Disease Assessment Scale (ADAS-Cog)] total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, −0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, −0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, −0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, −0.55 [95% CI, −1.45 to 0.36]).” (A. Atri, atria@cpmcri.org)
“Given the series of failures in rigorous attempts to develop an effective treatment for Alzheimer disease, it may seem difficult to be optimistic, yet lessons from the past century paint a different picture,” an editorialist writes (
pp. 123–5). “For instance, President Nixon signed the National Cancer Act in January 1971 and asked Congress for an additional $100 million in funding (slightly >$600 million in today’s dollars). Since then, numerous treatments for cancer are now available that were unimaginable 45 years ago. President Obama signed the National Alzheimer Project Act in January 2011, directing an initial investment of $50 million in fiscal year 2012, and then asked Congress for an additional $80 million in fiscal year 2013. Since then, federal funding for Alzheimer disease research has increased to approximately $1.4 billion in fiscal year 2017.” (D. A. Bennett, david_a_bennett@rush.edu)
Real-World Hypertension & the 2017 ACC/AHA Guidelines: Writing about the recently released American College of Cardiology/American Heart Association (ACC/AHA) guidelines, a Viewpoint author brings the advice into the real world: “The greatest benefit of the guideline recommendations may be that they emphasize, most likely for young adults, lifestyle interventions, including weight loss, healthy diet, physical exercise, reduced sodium intake, increased potassium intake, and curtailed alcohol consumption,” (pp. 115–6). “In principle, shifting the health care system more toward prevention with lifestyle measures is a welcome move. In the long-term, this emphasis may add value for the current health care system that undervalues prevention, and primary prevention in particular. However, it is unclear whether patients and clinicians are ready for such a change and whether these tens of millions of individuals will be able to obtain appropriate counseling and endorse effective, sustainable lifestyle modifications. Resources, supporting personnel, and infrastructure are still lacking in most places to achieve this long-due change. If primary prevention efforts fail, the likely option will be to resort to medications even for patients who would have done well with lifestyle modification. Thus, an emphasis on lifestyle-based prevention may paradoxically promote further overmedicalization of US society.” (J. P. A. Ioannidis, jioannid@stanford.edu)
“Is the problem fundamentally with the guidelines or with the US lifestyle?” asks a second Viewpoint author (
pp. 117–8). “The problem is not the result of rigorously developed guidelines, but rather is inherent in the high prevalence of unfavorable cardiovascular risk factors. Patients and clinicians need to focus attention where it belongs: on promotion of healthy lifestyles; prevention of the risk factors in the first place; and only when needed, use drugs to reduce cardiovascular risk, following evidence-based recommendations.” (P. Greenland, p-greenland@northwestern.edu)

PNN Pharmacotherapy Line
Jan. 11, 2018 * Vol. 25, No. 8
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 11 New England Journal of Medicine (2018; 378).
Osimertinib in Non–Small-Cell Lung Cancer: Compared with a standard epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), the irreversible agent osimertinib was superior in efficacy and similar in safety in a phase 3 trial of 556 patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC) (pp. 113–25). Researchers report these results from the FLAURA trial: “The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P <0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P = 0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P = 0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).” (S. S. Ramalingam, ssramal@emory.edu)
While factors yet to be determined could affect osimertinib’s role in therapy, “the near doubling in median progression-free survival with first-line osimertinib is profoundly impressive,” writes an editorialist (
pp. 192–3). “It has activity in CNS disease that is superior to that of the other available TKIs, and it is less toxic. Osimertinib also makes detection of the T790M mutation unimportant. We cannot robustly predict in which patients T790M-mediated acquired resistance to first- or second-generation EGFR-TKIs will develop. Moreover, T790M is irrelevant to the 40% of patients who have disease progression by other mechanisms. These factors and the predictable and durable efficacy of first-line osimertinib make it the ideal first-line choice for EGFR-mutated NSCLC.” (S. Popat)
Long-Term Inhaled Budesonide in BPD: In surviving extremely premature neonates, 2-year survival rates were decreased among those receiving early inhaled budesonide for prevention of bronchopulmonary dysplasia, compared with placebo (pp. 148–57). Neurodevelopmental disabilities were similar, as noted in these results for 629 evaluable infants: “148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P = 0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P = 0.04).” (D. Bassler, dirk.bassler@usz.ch)
Massachusetts Medicaid Reforms: Discussing a shift of near-poor adults into private plans as proposed by the State of Massachusetts, Viewpoint authors discuss the potential impact and a related imposition of a closed drug formulary (pp. 109–11): “State attempts to prioritize coverage of expensive new hepatitis C drugs have been blocked by the courts, and supplemental rebates address only about 5% of total Medicaid drug spending. The Massachusetts waiver would depart from this long-standing approach by creating a closed formulary: the state would select which drugs to cover on the basis of clinical effectiveness, cost, and appropriateness, ensuring that at least one drug per therapeutic class was included. Closed formularies are used by most commercial and public payers; for example, pharmacy benefit managers CVS Health and Express Scripts reportedly exclude more than 170 and 150 drugs, respectively, from their formularies.” (B. D. Sommers)
>>>PNN NewsWatch
* International Laboratories is voluntarily recalling 30-count packages labeled as Clopidogrel Tablets, USP 75 mg, lot 117099A, to the consumer level, because they may contain Clopidogrel 75 mg or Simvastatin Tablets, USP 10 mg.

PNN Pharmacotherapy Line
Jan. 12, 2018 * Vol. 25, No. 9
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
Jan. issue of the American Journal of Psychiatry (2018; 175).
Smoking & ADHD in Female Adolescents: Initiation of smoking during adolescence is affected by specific subtypes of attention-deficit/hyperactivity disorder (ADHD) and gender, according to three population studies of 3,762 same-sex twins (pp. 63–70). “The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking,” the investigators conclude, adding these study results: “Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal.” (I. J. Elkins)
Asenapine Maintenance Therapy in Mania & Bipolar I Disorder: Compared with placebo, long-term asenapine treatment prevented recurrence of mood events in adults with bipolar I disorder, researchers report (pp. 71–9). During an initial open-label period of 12 to 16 weeks followed by a 26-week double-blind randomized withdrawal period, 549 patients were treated to a target asenapine dose of 10 mg twice daily in the open-label phase (with some patients titrated down to 5 mg twice daily). Those meeting stabilization/stable-responder criteria (n = 253) were randomized to asenapine or placebo treatment in the double-blind period, with these results: “Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period.” (A. Szegedi)
Cannabis Use & Risk of Prescription Opioid Use Disorder: Using data from the early 2000s, a study shows that cannabis use is associated with the initiation of nonmedical prescription opioid use and opioid use disorder among American adults (pp. 47–53). Odds ratios were in the 5.78 to 7.76 range for incident nonmedical prescription opioid use and opioid use disorder, respectively, in 2004–05 when cannabis use was documented during 2001–02. (M. Olfson)
>>>PNN NewsWatch
* CDC is encouraging use of antiviral agents for treating high-risk patients with influenza and those with more severe symptoms. The agency is working with manufacturers to resolve spot shortages that have developed in recent weeks as the influenza system has worsened in most states of the U.S.
*
FDA said yesterday it is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older because the risks of these medicines outweigh their benefits in children younger than 18. FDA is also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the boxed warning of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone. Some codeine cough medicines are available OTC in a few states, and FDA is also considering regulatory action for these products.
*
FDA has issued a warning letter to Becton Dickinson (BD) & Company that cited several violations of federal law, including marketing significantly modified versions of certain BD Vacutainer blood collection tubes without required FDA clearance or approval and failing to submit medical device reports to the FDA within the required timeframe.
*
PNN will not be published on Mon., Jan. 15, M. L. King Day.

PNN Pharmacotherapy Line
Jan. 16, 2018 * Vol. 25, No. 10
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 13 issue of Lancet (2018; 391).
Antifibrinolytic Delay in Acute Severe Hemorrhage: When treating patients with acute severe trauma or postpartum hemorrhage, tranexamic acid must be administered immediately to achieve its full benefit, researchers report, as “death from bleeding occurs soon after onset” (pp. 125–32). Individual patient-level data meta-analysis of randomized trials of more than 1,000 patients produced these findings: “We obtained data for 40,138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3,558 deaths, of which 1,408 (40%) were from bleeding. Most (884 [63%] of 1,408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2–3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1.20, 95% CI 1.08–1.33; p = 0.001), with no heterogeneity by site of bleeding (interaction p = 0.7243). Treatment delay reduced the treatment benefit (p <0.0001). Immediate treatment improved survival by more than 70% (OR 1.72, 95% CI 1.42–2.10; p <0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p = 0.5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events.” (I. Roberts, ian.roberts@lshtm.ac.uk)
Enteral v. Parenteral Early Nutrition in Shock With Ventilation: In the NUTRIREA-2 trial at 44 French intensive-care units, “early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition,” investigators conclude (pp. 133–43). The study, stopped early, produced these findings: “By day 28, 443 (37%) of 1,202 patients in the enteral group and 422 (35%) of 1,208 patients in the parenteral group had died (absolute difference estimate 2.0%; [95% CI −1.9 to 5.8]; p = 0.33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0.89 [95% CI 0.72–1.09]; p = 0.25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1.89 [1.62–2.20]; p <0.0001), diarrhoea (432 [36%] vs 393 [33%]; 1.20 [1.05–1.37]; p = 0.009), bowel ischaemia (19 [2%] vs five [<1%]; 3.84 [1.43–10.3]; p = 0.007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3.7 [1.03–13.2; p = 0.04).” (J. Reignier, jean.reignier@chu-nantes.fr)
>>>PNN NewsWatch
* FDA on Friday expanded the approved use of olaparib tablets (Lynparza, AstraZeneca) to include treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Olaparib becomes the first PARP inhibitor approved to treat metastatic breast cancer, and this is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a BRCA gene mutation. Patients are selected for treatment with olaparib based on an FDA-approved genetic test, the BRACAnalysis CDx (Myriad Genetic Laboratories).
*
Becton-Dickinson (BD) has informed FDA that it is no longer using the rubber stopper material associated with loss of drug potency in its general use syringes. BD has instead returned to a rubber stopper it used previously in the syringes, resolving a problem that applied to compounded or repackaged drugs first uncovered in 2015.
>>>PNN JournalWatch
* Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review, in Annals of Internal Medicine, 2018; 168: 121–30. (M. E. Suarez-Almazor, msalmazor@mdanderson.org)
*
Approach to the Investigation and Management of Patients With Candida auris, an Emerging Multidrug-Resistant Yeast, in Clinical Infectious Diseases, 2018; 66: 306–11. (S. Tsay, stsay@cdc.gov)

PNN Pharmacotherapy Line
Jan. 17, 2018 * Vol. 25, No. 11
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 16 issue of JAMA, a theme issue on obesity (2018; 319).
Bariatric Surgery in Obesity Management: Research studies examine the role of bariatric surgery and more conservative options in patients with obesity.
Compared with lifestyle and medical management, Roux-en-Y gastric bypass produced significantly improved measures of glucose, LDL cholesterol, and systolic blood pressure over a 5-year period, researchers report, but the differences waned over time (
pp. 266–78). At four U.S. and Taiwanese sites, 120 patients with obesity had these outcomes based on a composite measure of triple end point of hemoglobin A1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg at 5 years: “At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (difference, 19%; 95% CI, 4%–34%; P = .01). In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle–medical management group achieved an HbA1c level of less than 7.0% (difference, 41%; 95% CI, 19%–63%; P = .002). Gastric bypass had more serious adverse events than did the lifestyle–medical management intervention, 66 events vs 38 events, most frequently gastrointestinal events and surgical complications such as strictures, small bowel obstructions, and leaks. Gastric bypass had more parathyroid hormone elevation but no difference in B12 deficiency.” (C. Billington, billi005@umn.edu)
In a study from Israel of patients with obesity, investigators found that “bariatric surgery using laparoscopic banding, gastric bypass, or laparoscopic sleeve gastrectomy, compared with usual care nonsurgical obesity management, was associated with lower all-cause mortality over a median follow-up of approximately 4.5 years” (
pp. 279–90). “The evidence of this association adds to the limited literature describing beneficial outcomes of these 3 types of bariatric surgery compared with usual care obesity management alone.” (O. Reges, rnare@clalit.org.il">ornare@clalit.org.il)
A third study, which included 1,888 patients with severe obesity, also found benefits of bariatric surgery over a median of 6.5 years of follow-up (
pp. 291–301). Compared with specialized medical treatment at a tertiary care outpatient center in Norway, surgery showed these advantages: “Surgically treated patients had a greater likelihood of remission and lesser likelihood for new onset of hypertension (remission: absolute risk [AR], 31.9% vs 12.4%); risk difference [RD], 19.5% [95% CI, 15.8%–23.2%], relative risk [RR], 2.1 [95% CI, 2.0–2.2]; new onset: AR, 3.5% vs 12.2%, RD, 8.7% [95% CI, 6.7%–10.7%], RR, 0.4 [95% CI, 0.3–0.5]; greater likelihood of diabetes remission: AR, 57.5% vs 14.8%; RD, 42.7% [95% CI, 35.8%–49.7%], RR, 3.9 [95% CI, 2.8–5.4]; greater risk of new-onset depression: AR, 8.9% vs 6.5%; RD, 2.4% [95% CI, 1.3%–3.5%], RR, 1.5 [95% CI, 1.4–1.7]; and treatment with opioids: AR, 19.4% vs 15.8%, RD, 3.6% [95% CI, 2.3%–4.9%], RR, 1.3 [95% CI, 1.2–1.4]). Surgical patients had a greater risk for undergoing at least 1 additional gastrointestinal surgical procedure (AR, 31.3% vs 15.5%; RD, 15.8% [95% CI, 13.1%–18.5%]; RR, 2.0 [95% CI, 1.7–2.4]). The proportion of patients with low ferritin levels was significantly greater in the surgical group (26% vs 12%, P < .001).” (J. Hjelmesæth, joran.hjelmeseth@siv.no)
“The approach to the prevention and treatment of obesity needs to be reimagined,” a
JAMA editor writes in response to this and other material in this theme issue (pp. 238–40). “The relentless increase in the rate of obesity suggests that the strategies used to date for prevention are simply not working. The physical, emotional, and financial cost to society related to obesity is staggering. New approaches are needed, and these must include a realistic assessment of why the population has become obese and what needs to be done to reverse that trend. Hopefully, the next time JAMA publishes a theme issue on obesity, reports will document interventions that have succeeded in reducing the level of obesity in the population.” (E. H. Livingston, edward.livingston@jamanetwork.org)
>>>PNN NewsWatch
* Resolving the shortage of I.V. saline bags “remains one of my highest priorities,” FDA Commissioner Scott Gottlieb, MD, said in a statement released yesterday.

PNN Pharmacotherapy Line
Jan. 18, 2018 * Vol. 25, No. 12
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 18 issue of the New England Journal of Medicine (2018; 378).
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: In an open-label, phase 3 trial of patients with stage III epithelial ovarian cancer, addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery extended recurrence-free survival and overall survival, compared with surgery alone, without increasing adverse effects (pp. 230–40). The trial included 245 patients who had at least stable disease after three cycles of carboplatin and paclitaxel. Outcomes were as follows: “In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P = 0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P = 0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P = 0.76).” (W. J. van Driel, w.v.driel@nki.nl)
Editorialists conclude that “this randomized trial is a very important first step but should not drive changes in practice yet” (
pp. 293–4): “Primary cytoreductive surgery for certain patients with ovarian cancer remains the preferred approach over neoadjuvant treatment, and administration of HIPEC at the time of interval cytoreductive surgery does not change that. New confirmatory clinical investigations of HIPEC are needed to clarify some of the unanswered questions before HIPEC can become a common treatment strategy. These considerations will be important for clinical trial investigators as they focus on the positive effect of HIPEC as an intervention as compared with the effects of promising new agent combinations or immunotherapy treatments.” (D. R. Spriggs)
Managing Toxic Alcohol Poisonings: “Despite much progress in our understanding of the pathogenesis of reactions to … toxic alcohols and despite the development of effective treatments, much remains to be done to eliminate the severe clinical disturbances that result from exposure to these substances,” authors of a review article conclude (pp. 270–80). “Methanol, ethylene glycol, and diethylene glycol poisoning can cause severe cellular dysfunction and high mortality if not recognized and treated quickly. Isopropanol frequently causes medical complications but has a lower risk of death. A high anion-gap metabolic acidosis, an increased serum osmolal gap, or both can suggest that one of the toxic alcohols is present in the blood, but these abnormal laboratory results are not always present. One of the poisonings should be strongly suspected in persons with the clinical findings described previously, in all obtunded patients, or in those with an unexplained high osmolal gap, high anion-gap metabolic acidosis, or both. Definitive tests such as high-pressure liquid chromatography are not always available, even in developed countries but especially in undeveloped countries. Therefore, there is an unmet need for tests that are accurate and can be completed rapidly.”(J. A. Kraut, jkraut@ucla.edu)
>>>PNN NewsWatch
* FDA recalls: Levofloxacin in 5% Dextrose Injection 250 mg/50 mL in a single-use flexible container (AuroMedics Pharma LLC), lot CLF160003, exp. May 2018, to the hospital level, because of visible particulate matter tentatively identified as mold; Nexterone (amiodarone HCl) 150 mg/100 mL Premixed Injection (Baxter), lot NC109123, because of potential presence of particulate matter.
* Infusions of
rolapitant (Varubi, Tesaro) injectable emulsion have been associated with anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions, some requiring hospitalization. Reactions have occurred during or soon after infusion, most within the first few minutes of administration.

PNN Pharmacotherapy Line
Jan. 19, 2018 * Vol. 25, No. 13
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Feb. 1 issue of Clinical Infectious Diseases (2018; 66).
Penicillin Allergy & Surgical Site Infection Risk: Use of second-line perioperative antibiotics in patients who report penicillin allergies is linked to a 50% increase in surgical site infections (SSIs) in a study from Mass. Genl. Hosp. (pp. 329–36). Retrospective cohort analysis of those undergoing hip arthroplasty, knee arthroplasty, hysterectomy, colon surgery, or coronary artery bypass grafting in 2010–14 showed the following: “Of 8,385 patients who underwent 9,004 procedures, 922 (11%) reported a penicillin allergy, and 241 (2.7%) had an SSI. In multivariable logistic regression, patients reporting a penicillin allergy had increased odds (adjusted odds ratio, 1.51; 95% confidence interval, 1.02–2.22) of SSI. Penicillin allergy reporters were administered less cefazolin (12% vs 92%; P < .001) and more clindamycin (49% vs 3%; P < .001), vancomycin (35% vs 3%; P < .001), and gentamicin (24% vs 3%; P < .001) compared with those without a reported penicillin allergy. The increased SSI risk was entirely mediated by the patients’ receipt of an alternative perioperative antibiotic; between 112 and 124 patients with reported penicillin allergy would need allergy evaluation to prevent 1 SSI.” (K. G. Blumenthal, kblumenthal1@partners.org)
Long-Term Effectiveness of Quadrivalent HPV Vaccine: Women from Denmark, Iceland, Norway, and Sweden who received a three-dose regimen of quadrivalent human papillomavirus (qHPV) vaccine were protected through at least 10 years, a study shows, “with a trend for continued protection through 12 years of follow-up” (pp. 339–45). The combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18 was as follows in the FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease) study: “In the per-protocol population (2,084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9,437 person–years of follow-up. Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years. The number of person–years during the follow-up interval of 10–12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period.” (A. J. Saah, alfred_saah@merck.com)
>>>Oncology Highlights
Source:
Jan. 20 issue of the Journal of Clinical Oncology (2018; 36).
HPV Vaccination & Oral HPV Infections Among Young Adults: Vaccination against human papillomavirus (HPV) decreases oral infections of vaccine-type viruses among young Americans, a study shows, but low uptake of the vaccine is limiting its population-level effects (pp. 262–7). Using a cross-sectional study of men and women 18 to 33 years of age (N = 2,627) within the nationally representative National Health and Nutrition Examination Survey for 2011 to 2014, the investigators report: “Between 2011 and 2014, 18.3% of the US population 18 to 33 years of age reported receipt of at least one dose of the HPV vaccine before the age of 26 years (29.2% in women and 6.9% in men; P < .001). The prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated individuals (0.11% v 1.61%; Padj = .008), corresponding to an estimated 88.2% (95% CI, 5.7% to 98.5%) reduction in prevalence after model adjustment for age, sex, and race. Notably, the prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated men (0.0% v 2.13%; Padj = .007). Accounting for vaccine uptake, the population-level effect of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women, and 6.9% in men.” (A. K. Chaturvedi)
>>>PNN NewsWatch
* A draft guidance published yesterday by FDA outlines circumstances when a company should issue a public warning about a recall, describes the general timeline for companies to issue such a warning, discusses what information should be included in a public warning, and describes situations where the agency may take action to issue its own public warning should a company’s warning be deemed insufficient. This “is just the first in a series of policy steps we’ll take this year,” Commissioner Scott Gottlieb said in a related statement.

PNN Pharmacotherapy Line
Jan. 22, 2018 * Vol. 25, No. 14
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 20 issue of Lancet (2018; 391).
Rivaroxaban Therapy in Arterial Disorders: Two studies examine use of rivaroxaban with or without aspirin in patients with coronary, peripheral, or carotid artery disease.
In patients with stable coronary artery disease, addition of rivaroxaban to aspirin therapy had overall positive effects, with reduced morbidity and mortality despite an increase in major bleeding (
pp. 205–18). In the COMPASS trial, patients had these results based on a primary outcome of myocardial infarction, stroke, or cardiovascular death: “The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8,313 vs 460 [6%] of 8,261; hazard ratio [HR] 0.74, 95% CI 0.65–0.86, p <0.0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8,250 vs 460 [6%] of 8,261; HR 0.89, 95% CI 0.78–1.02, p = 0.094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8,313 vs 158 [2%] of 8,261; HR 1.66, 95% CI 1.37–2.03, p <0.0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8,250 vs 158 [2%] of 8,261; HR 1.51, 95% CI 1.23–1.84, p <0.0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8,313 vs 339 [4%] of 8,261; HR 0.77, 95% CI 0.65–0.90, p = 0.0012). (S. J Connolly, connostu@phri.ca)
Twice-daily, low-dose rivaroxaban combined with aspirin could be “an important advance in the management of patients with peripheral artery disease,” researchers conclude based on findings in 33 countries on six continents (
pp. 219–29). Results in patients with a history of peripheral artery disease of the lower extremities, of the carotid arteries, or coronary artery disease, showed the following: “The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2,492 vs 174 [7%] of 2,504; hazard ratio [HR] 0.72, 95% CI 0.57–0.90, p = 0.0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0.54 95% CI 0.35–0.82, p = 0.0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2,474 vs 174 [7%] of 2,504; HR 0.86, 95% CI 0.69–1.08, p = 0.19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0.67, 95% CI 0.45–1.00, p = 0.05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2,492 vs 48 [2%] of 2,504; HR 1.61, 95% CI 1.12–2.31, p = 0.0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2,474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2,504 in the aspirin alone group (HR 1.68, 95% CI 1.17–2.40; p = 0.0043).” (S. S Anand, anands@mcmaster.ca)
>>>PNN NewsWatch
* The shutdown of the federal government didn’t prevent FDA from posting these recall notices on Sunday for two products that are possibly contaminated with Salmonella: Arthri-D’s dietary supplement Arthri-D 120 count, lot 1701-092, and Break Ventures/California Basics’ dietary supplement Zero for Him 150 count, lot 1710-638.
>>>PNN JournalWatch
* Postsurgical Prescriptions for Opioid Naive Patients and Association With Overdose and Misuse: Retrospective Cohort Study, in BMJ, 2018; 360: j5790. (G. A. Brat, gbrat@bidmc.harvard.edu)
*
The Antiretroviral Agent Nelfinavir Mesylate: A Potential Therapy for Systemic Sclerosis, in Arthritis & Rheumatology, 2018; 70: 115–26. (J. A. Lasky, jlasky@tulane.edu)
*
Intrinsic and Extrinsic Causes of Malignancies in Patients With Primary Immunodeficiency Disorders, in Journal of Allergy and Clinical Immunology, 2018; 141: 59–68.e4. (M. G. Seidel, markus.seidel@medunigraz.at)
*
Dabigatran Reversal in a Patient With End-Stage Liver Disease and Acute Kidney Injury, in American Journal of Kidney Diseases, 2018; 71: 137–41. (J. E. Novak, jnovak2@hfhs.org)

PNN Pharmacotherapy Line
Jan. 23, 2018 * Vol. 25, No. 15
Providing news and information about medications and their proper use

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>>>Health Affairs Highlights
Source:
Jan. issue of Health Affairs (2018; 37).
Med Sync & Adherence: For patients with cardiovascular disease, pharmacy programs that synchronize medication refills increase adherence, a study shows, especially among those with low initial adherence (pp. 125–33). In 2011–14, Medicare beneficiaries with two or more chronic conditions — one of which was hypertension, hyperlipidemia, or diabetes — had these outcomes when receiving medication synchronization services: “Among nearly 23,000 patients matched by propensity score, the mean proportion of days covered (a measure of medication adherence) for the control group of patients without a synchronization program was 0.84 compared to 0.87 for synchronized patients—a gain of 3 percentage points. Adherence improvement in synchronized versus control patients was three times greater in patients with low baseline adherence, compared to those with higher baseline adherence. Rates of hospitalization and emergency department visits and rates of outpatient visits were 9 percent and 3 percent lower in the synchronized group compared to the control group, respectively, while cardiovascular event rates were similar.” (A. A. Krumme, akrumme@bwh.harvard.edu)
Rx Opioid Use & Parental Neglect: When considering the impact of the opioid epidemic, policymakers should factor “the ability of opioid-dependent parents to care for their children,” according to authors who looked at the association between rates of removal of children from homes and the opioid prescription rate in Florida in 2012–15 (pp. 134–9): “We performed a panel data analysis of opioid prescriptions that also controlled for the prescription rates of benzodiazepines and stimulants and for other risk factors for child removal. We found that a one-standard-deviation increase in the opioid prescription rate was associated with a 32 percent increase in the removal rate for parental neglect. When we obtained subset samples by percentage of white residents, the estimated relationships were approximately twice as large in the counties with the highest concentration of whites than in the counties with the lowest. Policy makers should consider the opioid epidemic’s effects on child welfare when determining the appropriate public health response.” (T. Quast, troyquast@health.usf.edu)
>>>Medical Care Report
Source:
Feb. issue of Medical Care (2018; 56).
Trends in Overactive Bladder Treatments: Over a 15-year period, dispensing patterns for medications for overactive bladder (OAB) changed as $4 generic programs and new medications became available (pp. 162–70). Data from the Truven Health Analytics’ Medicare Supplemental Database for 2000–15 showed the following for 9.5 million Medigap beneficiaries: “From 2000 to 2015, 771,609 individuals filled 13,863,998 OAB-related prescriptions. During 2000–2007, 3 new extended-release medications became available (tolterodine, darifenacin, solifenacin), leading to increases in overall OAB-related dispensing rates by 19.1 (99% confidence interval, 17.0–21.2), a 92% increase since 2000; overall rates remained stable during 2008–2015. By 2015, the most common medications were oxybutynin (38%), solifenacin (20%), tolterodine (19%), and mirabegron (12%). Dispensing rates peaked at age 90 (rate, 53.4; 99% confidence interval, 53.1–53.7). Women had higher rates than men at all ages (average ratewomen− ratemen, 22.0). The gap between upper and lower percentiles of medication payments widened between 2008–2015; by 2015, 25% of reimbursed dispensed prescriptions had total payments exceeding $250.” (A. C. Kinlaw, akinlaw@unc.edu)
Med Alerts for Opioid–Benzodiazepine Coprescribing: Among high-risk veteran patients, electronic medical record alerts “hold promise as a means of reducing opioid and benzodiazepine coprescribing,” researchers report (pp. 171–8). Over 12 months, alerts lowered rates of coprescribing among patients with substance use, sleep apnea, and suicide risk. (C. A. Malte, carol.malte@va.gov)
>>>PNN NewsWatch
* Magno-Humphries Laboratories is voluntarily recalling lot 352300 (exp. 01/19) of Basic Drugs Brand of Senna Laxative tablets, 8.6 mg Sennosides to the consumer level following discovery of one bottle that contained Basic Drugs Brand of naproxen sodium 220 mg.

PNN Pharmacotherapy Line
Jan. 24, 2018 * Vol. 25, No. 16
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 23/30 issue of JAMA (2018; 319).
Oral Treatment of Toenail Fungal Infection: Terbinafine and azole-based drugs are associated with higher clinical and mycological cure rates compared with placebo, according to authors of a JAMA Clinical Evidence Synopsis (pp. 397–8). “Terbinafine was associated with higher clinical cure rates vs placebo (370 vs 62 per 1,000 patients, respectively) and mycological cure rates (755 vs 167) (both P < .001),” the authors write of the 48 trials included in the analysis. “Similarly, treatment with azoles was associated with higher clinical cure rates vs placebo (309 vs 14 per 1,000 patients) and mycological cure rates (431 vs 74) (both P < .001).
“Azoles were associated with lower clinical cure rates vs terbinafine (471 vs 575 per 1,000 patients; P = .006) and mycological cure rates (525 vs 682; P < .001). Griseofulvin (a nonazole antifungal) was associated with (1) clinical and mycological cure rates that were not different than azoles and (2) lower cure rates compared with terbinafine. Terbinafine was associated with a lower recurrence rate vs placebo (33 vs 667 per 1,000 patients; P = .004) as were azoles (550 vs 1,000; P = .08). Recurrence rates were not different for azoles vs terbinafine.” (M. L. van Driel,
m.vandriel@uq.edu.au)
Applying Lessons From the Opioid Epidemic to Tobacco Control: “Perhaps public concern over the opioid epidemic can provide an opportunity to renew a sense of urgency around tobacco control,” Viewpoint authors conclude (pp. 339–40). “Indeed, the epidemics are not completely distinct. The communities most deeply affected by the opioid crisis also have some of the highest smoking rates, and individuals who use tobacco are also more likely to develop prescription opioid misuse. These overlapping epidemics suggest that common conditions may contribute to both and that common solutions may be useful. This moment, with attention focused intently on the opioid epidemic, may also provide the chance to address addiction to nicotine and thereby substantially reduce the harms caused by these 2 threats to health.” (I. Richman, ilana.richman@yale.edu)
Rise and Fall of Mandatory Cardiac Bundled Payments: Abandonment of a mandatory cardiac bundled payment plan by CMS in late 2017 is “a step in the wrong direction for several reasons,” writes a Viewpoint author (pp. 335–6). “Spending on high-cost health care continues to increase—high and rising health care costs cannot be ignored indefinitely. Absent a mandate, hospitals, clinicians, and postacute care facilities have little motivation to collaborate around innovative care redesign to improve coordination and efficiency. A voluntary program, at least a program in which fewer than 10% of hospitals participate and half of those end participation early, will neither invite meaningful changes in care delivery nor provide usable information about what works and what does not. Without testing a bundled payment model across a diverse, representative group of acute care hospitals, it will never be possible to gain actionable insights to inform iterative improvements in the design and implementation of novel payment models.” (K. E. Joynt Maddox, kjoyntmaddox@wustl.edu)
Three Decades of Peer Review Congresses: Reflecting on eight Peer Review Congresses conducted every 4 years since 1989, organizers recount the progress made over 30 years through research into peer review and the scope and diversity of Congress participants (pp. 350–3): “Despite the continued criticism of peer review, even if it were proved to cause harm, few would vote for its abolition, and most would advocate for its improvement, so more research is needed. That is what the congresses have shown. The eighth congress was once again full of discussion and argument, but, as one observer noted, it was remarkably good-humored. Plans for the Ninth International Congress on Peer Review and Scientific Publication are counting on the continued existence, use, and need for assessment of peer review and publication in all their evolving forms.” (A. Flanagin, annette.flanagin@jamanetwork.org)
>>>PNN NewsWatch
* Baxter International has expanded an earlier recall of Nexterone (amiodarone HCl) 150 mg/100 mL Premixed Injection to include lot NC109925, distributed between Aug. 23 and Oct. 2 of last year, because of potential particulate matter.

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

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>>>NEJM Report
Source:
Jan. 25 New England Journal of Medicine (2018; 378).
Solanezumab in Mild Alzheimer Disease: Yet another drug designed to clear amyloid-beta plaques and neurofibrillary tangles in patients with Alzheimer disease has failed in a phasae 3 trial (pp. 321–30). The humanized monoclonal antibody solanezumab 400 mg every 4 weeks produced these results in a placebo-controlled, double-blind study of 2,129 patients: “The mean change from baseline in the [cognitive subscale of the Alzheimer’s Disease Assessment Scale] score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the [Mini–Mental State Examination] score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.” (L. S. Honig, lh456@cumc.columbia.edu)
“Although it may not quite be time to give up on [amyloid-beta] immunotherapy for treating Alzheimer’s disease, it would be foolish to ignore the continued failures of antiamyloid approaches,” an editorialist writes (
pp. 391–2). “In spite of the mountain of evidence supporting the primacy of [amyloid-beta] in Alzheimer’s disease, many researchers are coming to the realization that our preclinical models of the disease may be missing the mark. Even if there is some future success in a primary prevention trial, there is still little headway being made in improving the treatment of Alzheimer’s disease. There is some hope that a combination of therapeutic approaches might help, since there is evidence that the different pathologic aspects of Alzheimer’s disease are interactive. Whether a multifaceted strategy or something entirely unforeseen is the answer, the field is clearly in need of innovative ideas. We may very well be nearing the end of the amyloid-hypothesis rope, at which point one or two more failures will cause us to loosen our grip and let go.” (M. P. Murphy)
Influenza & AMI: Confirming past studies that used nonspecific measures, a self-controlled case-series analysis shows a significant association between respiratory infections — influenza in particular — and acute myocardial infarction (pp. 345–53). With “risk interval” defined as the first 7 days after respiratory specimen collection and the “control interval” as 1 year before and 1 year after the risk interval, investigators found these connections in administrative claims data: “We identified 364 hospitalizations for acute myocardial infarction that occurred within 1 year before and 1 year after a positive test result for influenza. Of these, 20 (20.0 admissions per week) occurred during the risk interval and 344 (3.3 admissions per week) occurred during the control interval. The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05 (95% confidence interval [CI], 3.86 to 9.50). No increased incidence was observed after day 7. Incidence ratios for acute myocardial infarction within 7 days after detection of influenza B, influenza A, respiratory syncytial virus, and other viruses were 10.11 (95% CI, 4.37 to 23.38), 5.17 (95% CI, 3.02 to 8.84), 3.51 (95% CI, 1.11 to 11.12), and 2.77 (95% CI, 1.23 to 6.24), respectively.” (J. C. Kwong, jeff.kwong@utoronto.ca)
>>>PNN NewsWatch
* FDA and the Federal Trade Commission yesterday posted joint warning letters to the marketers and distributors of 12 opioid cessation products for illegally marketing unapproved products with claims about their ability to help in the treatment of opioid addiction and withdrawal. FDA said that it “is taking new steps to make safe and effective medication-assisted treatments available to those who suffer from opioid use disorder and to reduce the stigma that is sometimes associated with use of these therapies. Using products with unsubstantiated claims may prevent those addicted to opioids from seeking approved treatments that have been demonstrated to be safe and effective, delay their path to recovery, and put them at greater risk of death.”

PNN Pharmacotherapy Line
Jan. 26, 2018 * Vol. 25, No. 18
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
Jan. issue of the Journal of the American Geriatrics Society (2018; 66).
Opiate Prescribing in Older Adults: Long-term opioid prescribing is common for older adults in nursing homes and difficult to reduce, a cross-sectional analysis shows (pp. 48–55). Minimum Data Set 3.0 assessments at 13,522 U.S. nursing homes in the second quarter of 2012 and the following 120 days show these outcomes those receiving opioids and nonpharmacologic interventions that could reduce opioid use: “Of all long-stay residents, 32.4% were prescribed any opioid, and 15.5% were prescribed opioids long-term. Opioid users (versus nonusers) were more commonly prescribed pain adjuvants (32.9% vs 14.9%), other pain medications (25.5% vs 11.0%), and nonpharmacological pain management (24.5% vs 9.3%). Long-term opioid use was higher in women (aPR = 1.21, 95% CI = 1.18–1.23) and lower in racial and ethnic minorities (non-Hispanic blacks vs whites: APR = 0.93, 95% CI = 0.90–0.94) and those with severe cognitive impairment (vs no or mild impairment, aPR = 0.82, 95% CI = 0.79–0.83).” (J. N. Hunnicutt, jacob.hunnicutt@umassmed.edu)
“Opiate use is widespread during hospitalization and is associated with significant negative clinical outcomes and quality metrics,” conclude authors of a second study (
pp. 70–5). The retrospective cohort analysis was conducted at a tertiary acute care facility, where 9,245 older adults were treated as follows: “There was no difference in sex, race, ethnicity, or Charlson Comorbidity Index between opiate exposure groups. Participants who had never received opiates had a significantly shorter mean [length of stay (LOS)] than prior and new opiate users (5.2, 6.8, 7.7 days; P <.001) and were more likely to be discharged home (88.6%, 82.8%, 82.5%; P <.001) and significantly less likely to be readmitted within 30 days (19.6%, 25.0%, 22.3%; P <.001). Participants who had never been exposed to opiates had a significantly shorter mean LOS than those receiving short- and long-acting opiates (5.2, 7.3, 8.6 days; P < .001) and were more likely to be discharged home (88.6%, 82.6%, 82.4%; P < .001) and significantly less likely to be readmitted within 30 days (19.6%, 27.7%, 28.9%; P <.001).” (V. Patel, vpatel18@northwell.edu)
Prescription Shopping in America: “CMS [Medicare] Part D regulations are gaining clinical teeth, with [medication therapy management] requirements for certain beneficiaries with high drug expenditures and by incorporating quality measures for pharmacies geared at improving medication safety, adherence, and appropriateness,” conclude authors who assess “prescription shopping” and medication options among older adults in the U.S. (pp. 33–40). “However, much more can be done to lower medication costs and at the same time promote local relationships that maximize the benefits and reduce the risks of medications.” (G. Upchurch, gina@seniorpharmassist.org)
Commenting on this and a second article by two of the same authors (
pp. 25–32; G. Upchurch, gina@seniorpharmassist.org), an editorialist notes that both reports “draw on knowledge and understanding gained by Senior PharmAssist from decades of counseling older adults who seek assistance with medication management and access” (p. 18). “These primers are an excellent starting point for enriching our understanding of these programs and helping us advocate for the older adults we serve.” (D. Saliba)
>>>PNN NewsWatch
* Recommendations of the CDC Advisory Committee on Immunization Practices on use of the recently approved shingles vaccine are summarized in this week’s MMWR. Recombinant zoster vaccine (RZV), adjuvanted (Shingrix, GlaxoSmithKline) is recommended for use in immunocompetent adults aged 50 years or older, including those who previously received the older product, zoster vaccine live (ZVL). ACIP recommended use of RZV over ZVL. Because of a lack of data, ACIP has made no recommendations for use of RZV in immunocompromised patients. The RZV product, which requires reconstitution before administration, differs from ZVL in two practical ways: It is stored under refrigeration rather than in the freezer, and it is administered intramuscularly rather than subcutaneously. RZV can be given concomitantly (at different sites) with other adult vaccines, including most influenza vaccines, but data are not available for coadministration with the adjuvanted influenza vaccine Fluad.

PNN Pharmacotherapy Line
Jan. 29, 2018 * Vol. 25, No. 19
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 27 issue of Lancet (2018; 391).
Meds for Opioid Relapse Prevention: A 24-week trial provides insights into clinical use of the extended-release opioid antagonist naltrexone (XR-NTX) and sublingual doses of the partial opioid agonist buprenorphine–naloxone (BUP-NX) (pp. 309–18). At 8 U.S. community-based inpatient units and during outpatient follow-up, investigators found XR-NTX more difficult to use for induction but the two approaches similar once initatied. “Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications,” the group concludes after reporting these open-label results: “Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n = 283) or BUP-NX (n = 287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p <0.0001). Among all participants who were randomly assigned (intention-to-treat population, n = 570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1.36, 95% CI 1.10–1.68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n = 474), 24 week relapse events were similar across study groups (p = 0.44). Opioid-negative urine samples (p <0.0001) and opioid-abstinent days (p <0.0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p = 0.0012), then converged by week 24 (p = 0.20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).” (J. D. Lee, joshua.lee@nyumc.org)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
“No Safe Level of Smoking”: Smoking just one cigarette per day significantly increases a person’s risk of stroke and coronary heart disease [CHD], a study shows, with risks going up to about one-half of those associated with smoking 20 cigarettes per day (j5855). “Men who smoked one cigarette per day had 46% of the excess relative risk [of CHD] for smoking 20 cigarettes per day (53% using relative risks adjusted for multiple factors), and women had 31% of the excess risk (38% using relative risks adjusted for multiple factors),” the authors report. “The excess risk for stroke associated with one cigarette per day (in relation to 20 cigarettes per day) was 41% for men and 34% for women (or 64% and 36% using relative risks adjusted for multiple factors).” (A. Hackshaw, a.hackshaw@ucl.ac.uk)
>>>PNN NewsWatch
* FDA on Friday approved lutetium Lu 177 dotatate (Lutathera, Advanced Accelerator Applications) for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. This is the first time a radiopharmaceutical has been approved for the treatment of GEP-NETs. The product received orphan drug designation from the FDA, is a first-in-class drug, and is the first available FDA-approved peptide receptor radionuclide therapy, a form of targeted treatment comprising a targeting molecule that carries a radioactive component.
>>>PNN JournalWatch
* Medications That Cause Dry Mouth As an Adverse Effect in Older People: A Systematic Review and Metaanalysis, in Journal of the American Geriatrics Society, 2018; 66: 76–84. (E Tan, edwin.tan@monash.edu)
*
The Age-Friendly Health System Imperative, in Journal of the American Geriatrics Society, 2018; 66: 22–4. (T. Fulmer, terry.fulmer@johnahartford.org)
*
Mortality Reduction in EMPA-REG OUTCOME Trial: Beyond the Antidiabetes Effect, in Diabetes Care, 2018; 41: 219–23. (S. Suissa, samy.suissa@mcgill.ca)
*
Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis, in Diabetes Care, 2018; 41: 372–82. (G. Targher, giovanni.targher@univr.it)

PNN Pharmacotherapy Line
Jan. 30, 2018 * Vol. 25, No. 20
Providing news and information about medications and their proper use

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>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (2018; 41).
Incretin-Based Therapies & Pancreatic Cancer: An increased short-term risk of pancreatic cancer associated with the start of incretin-based therapies could be the result of “an occult pancreatic cancer that provokes or aggravates diabetes,” investigators conclude based on data from Belgium and the Lombardy region of Italy (pp. 286–92). During 5- or 6-year time periods, the risk of pancreatic cancer among those started on incretin drugs or another noninsulin antidiabetic drug (NIAD) were as follows: “The cohorts included 525,733 patients with diabetes treated with NIADs and 33,292 with incretin drugs. Results in both cohorts were similar. Eighty-five and 1,589 subjects who developed pancreatic cancer were registered among the incretin and NIAD new users, respectively, which represented an aHR of pancreatic cancer of 2.14 (95% CI 1.71–2.67) among those prescribed an incretin compared with an NIAD. The aHR with a drug use lag exposure of 6 months was 1.69 (1.24–2.32). The aHR decreased from 3.35 (2.32–4.84) in the first 3 months after the first incretin prescription to 2.12 (1.22–3.66) in months 3–5.9, 1.95 (1.20–3.16) in months 6–11.9, and 1.69 (1.12–2.55) after 12 months. Among those prescribed an NIAD, pancreatic cancer occurred mostly within the year after the first prescription. The risk of pancreatic cancer among patients subsequently prescribed insulin was 6.89 (6.05–7.85).” (P. Autier, philippe.autier@i-pri.org)
TCF7L2 Variants & Phenotypic Heterogeneity of Type 1 Diabetes: “While many of the type 2 diabetes loci uncovered to date have a clear and unequivocal primary role in the islet beta-cell, this is less clear for the TCF7L2 locus,” authors write (pp. 224–6) in response to a research study showing “a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis” in carriers of this type 2–linked variant (pp. 311–7; M. J. Redondo, redondo@bcm.edu). “Applying a genetic risk score approach with the remaining established type 2 diabetes loci is warranted to investigate whether the effect Redondo et al. have identified can be extended to other key loci. Such an effect could be important as we seek to define type 1 diabetes, which at one end of a spectrum is associated with a potent immunogenetic mix that leads to severe diabetic ketoacidosis and, at the other end, with modest immunogenetic features and limited metabolic damage not requiring insulin treatment.” (R. D. Leslie, r.d.g.leslie@qmul.ac.uk)
>>>Nephrology Report
Source:
Feb. American Journal of Kidney Diseases (2018; 71).
Phosphate-Binder Use in Dialysis: Considering the rapidly increasing costs of phosphate binders in U.S. patients on dialysis ($1.5 billion in 2015), CMS should consider funding a study of the clinical need for these agents using hard outcomes, authors of a review article conclude (pp. 246–53). If higher phosphate concentrations are associated with improved clinical outcomes, such a study could assess “whether particular phosphate binders are superior to placebo or other binders in improving these outcomes,” the authors add. (W. L. St. Peter, stpet002@umn.edu)
“Hyperphosphatemia is presumed to cause disease by promoting vascular calcification and altering key mineral metabolism hormones that contribute to cardiac hypertrophy and bone disease,” notes an associated article (
pp. 254–6). “One expected clinical benefit of lowering phosphate concentrations is a reduction in heart failure, which is among the most common causes of morbidity and hospitalization in dialysis patients and those with [chronic kidney disease]. Although the clinical entity of ‘heart failure’ for patients with kidney disease encompasses heterogeneous causes, including diastolic and systolic dysfunction, vessel stiffness, and impaired responses to volume overload, many of these pathways are suspected to be influenced by phosphate toxicity. Moreover, even a modest impact of phosphate-binder treatment on heart failure would be clinically relevant, given the burden of this disease in the dialysis population.” (B. Kestenbaum, brk@u.washington.edu)
>>>PNN NewsWatch
* All unexpired lots of the prescription medical food Limbrel are being recalled to the patient level at FDA’s request because of a link with elevated liver-function tests or acute hypersensitivity pneumonitis, Primus Pharmaceuticals announced.

PNN Pharmacotherapy Line
Jan. 31, 2018 * Vol. 25, No. 21
Providing news and information about medications and their proper use

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>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (2018; 38).
Philosophy of Practice for Comprehensive Medication Management: Among 30 lead pharmacists participating in a large comprehensive medication management (CMM) study, philosphies of practice varied significantly, a study shows (pp. 69–79). Responses to an instrument with open- and closed-ended items led investigators to propose five core tenets that should be embraced by pharmacists providing CMM: “Twelve codes emerged that participants used to describe their philosophy of practice. These codes were mapped to five predefined tenets of a philosophy of practice. Only 3 (10%) participants included all five tenets in their philosophy of practice, 8 (26.7%) included four, 8 (26.7%) included three, 6 (20%) included two, and 5 (16.7%) included one tenet. Overall, participants rated their alignment with the five tenets highly. ‘Embracing a patient-centered approach’ received the highest mean score of 9.17/10; ‘Meeting a societal need’ had the lowest mean score of 8.37/10.” The other tenets were assuming responsibility for optimizing medication use, caring through an ongoing patient–pharmacist relationship, and working as a collaborative member of the health care team. (D. L. Pestka, pestk003@umn.edu)
>>>AJHP Highlights
Source:
Feb. 1 issue of the American Journal of Health-System Pharmacy (2018; 75).
Managing G6PD Deficiency: In a review of the most common enzyme deficiency in people, authors conclude that glucose-6-phosphate dehydrogenase (G6PD) deficiency “should be considered in patients who experience acute hemolysis after exposure to known oxidative medications, infection, or ingestion of fava beans” (pp. 97–104): “A diagnosis of G6PD deficiency is most often made through enzymatic activity detection, but molecular analysis may be required in females heterozygous for the disorder. When clinically feasible, rasburicase, primaquine, dapsone, pegloticase, and methylene blue should not be used until a G6PD diagnostic test has been performed.” (K. D. Belfield, kristendbelfield@gmail.com)
Minimizing Opioid Use After Acute Major Trauma: At a tertiary medical center, a pain management strategy successfully lowered milligram morphine equivalents (MMEs) of opioids prescribed on discharge following acute major traumatic injuries, researchers report (pp. 105–10). Retrospective analysis of patients admitted with acute trauma before and after implementation of a targeted provider and patient education strategy showed these results: “Compared with the preintervention cohort, the postintervention cohort had a lower median daily discharge MME overall (45 MME versus 90 MME, p < 0.001); after stratification of MME data by baseline opioid use, this finding held true only for patients with no opioid prescription at admission. Although utilization of gabapentinoids, skeletal muscle relaxants, and clonidine increased during the postintervention period, inpatient opioid use did not differ significantly in the 2 cohorts. Utilization of both nonsteroidal antiinflammatory drugs and acetaminophen was lower in the postintervention cohort versus the preintervention cohort.” (D. Oyler, doug.oyler@uky.edu)
>>>PNN NewsWatch
* FDA is working with manufacturers of OTC loperamide to use blister packs or other single-dose packaging and to limit the number of doses in a package, the agency said yesterday. FDA said it continues to receive reports of serious heart problems and deaths with much higher than the recommended doses of loperamide, primarily among people who are intentionally misusing or abusing the product, despite the addition of a warning to the medicine label and a previous communication. Loperamide is a safe drug when used as directed, FDA added.
* Citing the agency’s action on OTC loperamide,
Commissioner of Food and Drugs Scott Gottlieb, MD, yesterday said, “Appropriate prescribing practices, better packaging, and education are important steps within our statutory authority to help address the human and financial toll of opioid addiction. They can reduce harm while still providing effective pain management protocols. Today’s Part 15 hearing, and [these] new actions … are indicative of the kinds of steps we need to take as we confront this epidemic.”

PNN Pharmacotherapy Line
Feb. 1, 2018 * Vol. 25, No. 22
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 1 issue of the New England Journal of Medicine (2018; 378).
Tisagenlecleucel in B-Cell Lymphoblastic Leukemia: Confirming the results of a single-center phase 1–2a study, investigators show in a global study that a single infusion of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (pp. 439–48). The phase 2 trial was conducted at 25 centers and used a primary end point of overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.
Results showed: “For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.” (S. L. Maude,
maude@email.chop.edu)
CD19 CAR Therapy in Acute Lymphoblastic Leukemia: Median overall survival was 12.9 months —and 20.1 months among those with low disease burden — among 53 adults (23–74 years of age) with relapsed B-cell acute lymphoblastic leukemia who received infusions of autologous T cells expressing the 19-28z CD19-specific chimeric antigen receptor (CAR), a phase 1 trial shows (pp. 448–59). At the Memorial Sloan Kettering Cancer Center, CAR T cells were manufactured and administered, with these results: “After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.” (M. Sadelain, m-sadelain@ski.mskcc.org)
Paradigm Shift in Managing Atrial Fibrillation in HF: Compared with rate or rhythm control using medical therapy, catheter ablation significantly lowered incidence of a composite end point of death from any cause or hospitalization for worsening heart failure in patients with symptomatic paroxysmal or persistent atrial fibrillation, researchers report (pp. 417–27). The CASTLE-AF trial showed the end point occurred in 28.5% of 51 patients undergoing ablation therapy compared with 44.6% of 82 patients on medical therapy. (N. F. Marrouche, nassir.marrouche@carma.utah.edu)
In response to these findings, an editorialist writes (
pp. 468–9). “Where to now? Can we increase the success of the ablative procedure, and would that increase translate into further improvement in reverse remodeling and further reductions in rates of heart failure and mortality? If a reduction in the density of atrial fibrillation to 25% improves outcomes in this trial, what could be accomplished with reductions to 5% or even with elimination? All that is for the future. For the present, it seems reasonable to be more aggressive in offering ablation for atrial fibrillation in patients who also have congestive heart failure.” (M. S. Link)

PNN Pharmacotherapy Line
Feb. 2, 2018 * Vol. 25, No. 23
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
Feb. issue of Pediatrics (2018; 141).
Rhinovirus & Risk of Bacterial Infection in Febrile Infants: While febrile infants with viral respiratory infections are known to have a reduced risk of bacterial infections, a study uncovers a complicated relationship that limits utility of screening for for human rhinovirus (HRV) with polymerase chain reaction (PCR) to infants in the 29–90-day-old range (10.1542/peds.2017-2384). Screening of infants at 22 hospitals from 2007 to 2016 showed these results: “Of 10,964 febrile infants identified, 4,037 (37%) had RVPCR. Of these, 2,212 (55%) were positive for a respiratory virus; 1,392 (35%) for HRV alone. Bacterial infection was identified in 9.5%. Febrile infants with HRV detected were more likely to have bacterial infection than those with non-HRV viruses (7.8% vs 3.7%; P < .001; RR 2.12 [95% CI 1.43–3.15]). Risk of urinary tract infection was not significantly different for HRV-positive infants at any age, nor was risk of invasive bacterial infection (IBI; bacteremia and/or meningitis) meaningfully different for infants 1–28 day olds. Infants 29–90 days old with HRV had a decreased likelihood of IBI (RR 0.52 [95% CI 0.34–0.80]).” (A. J. Blaschke)
Acid-Suppressive Drug Use During Pregnancy & Childhood Asthma: The odds that a child will develop asthma are increased when the mother takes acid-suppressing drugs during pregnancy, according to a meta-analysis of eight population-based studies (10.1542/peds.2017-0889): “When all the studies were pooled, acid-suppressive drug use in pregnancy was associated with an increased risk of asthma in childhood (relative risk [RR] = 1.45; 95% confidence interval [CI] 1.35–1.56; I2 = 0%; P < .00001). The overall risk of asthma in childhood increased among proton pump inhibitor users (RR = 1.34; 95% CI 1.18–1.52; I2 = 46%; P < .00001) and histamine-2 receptor antagonist users (RR = 1.57; 95% CI 1.46–1.69; I2 = 0%; P < .00001).” (T. Lai)
Prophylactic Hydrocortisone in Extremely Preterm Infants: Early low-dose hydrocortisone treatment for preventing bronchopulmonary dysplasia (BPD) in extremely preterm infants is beneficial overall, with a higher treatment effect in those born after placental vascular disease, researchers report (10.1542/peds.2017-1788). In an exploratory analysis of data from the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, “The strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06).” (A. Héneau)
>>>PNN NewsWatch
* FDA is adding a boxed warning and Medication Guide to labeling for obeticholic acid (Ocaliva, Intercept Pharmaceutical) about incorrect dosing of the hepatic medication on a daily instead of weekly basis in patients with moderate-to-severe primary biliary cholangitis (PBC), increasing the risk of serious liver injury. To ensure correct dosing and reduce the risk of liver problems, FDA is clarifying the current recommendations for screening, dosing, monitoring, and managing PBC patients with moderate-to-severe liver disease taking obeticholic acid.
* Efforts to secure sufficient quantities of saline bags, antiviral agents, and other products needed for the
challenging influenza season are recounted by FDA Commissioner Scott Gottlieb, MD, in a statement released yesterday: “The products include large volume saline bags typically used to hydrate patients; small volume IV saline bags (generally in 50 and 100 ml sizes) that are often used to deliver other medicines; as well as empty IV containers of varying sizes that are being used by many health care providers to compound their own IV saline solutions by filling these empty containers. As such, we’re actively working to improve the large and small IV bag shortage and tracking potential shortages of critical medical products, such as the empty IV containers.
“We are also hearing from some health care providers that there are spot shortages of some antivirals used to treat the flu and flu tests; however, at this time, there is no nationwide shortage of these products. The FDA is carefully monitoring the situation and we will provide updates as needed.”

PNN Pharmacotherapy Line
Feb. 5, 2018 * Vol. 25, No. 24
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 360).
Cancer Risk, Chronic Diseases & Disease Markers: Major lifestyle factors are associated with cancer risks, a prospective cohort study indicates, with physical activity is especially important in cancer prevention (k134). Results of standard medical screenings in Taiwan show these relationships among various disease markers and incident cancers for 405,878 participants: “A statistically significantly increased risk of incident cancer was observed for the eight diseases and markers individually (except blood pressure and pulmonary disease), with adjusted hazard ratios ranging from 1.07 to 1.44. All eight diseases and markers were statistically significantly associated with risk of cancer death, with adjusted hazard ratios ranging from 1.12 to 1.70. Chronic disease risk scores summarizing the eight diseases and markers were positively associated with cancer risk in a dose-response manner, with the highest scores associated with a 2.21-fold (95% confidence interval 1.77-fold to 2.75-fold) and 4.00-fold (2.84-fold to 5.63-fold) higher cancer incidence and cancer mortality, respectively. High chronic disease risk scores were associated with substantial years of life lost, and the highest scores were associated with 13.3 years of life lost in men and 15.9 years of life lost in women. The population attributable fractions of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors combined (cancer incidence: 20.5% v 24.8%; cancer mortality: 38.9% v 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was attenuated by 48% for cancer incidence and 27% for cancer mortality.” (X. Wu, xwu@mdanderson.org)
Migraine & Cardiovascular Risks: In a population-based cohort study from Denmark, patients with migraine were significantly more likely to develop several cardiovascular diseases (k96). Concluding that “migraine may be an important risk factor for most cardiovascular diseases,” investigators show increased risks of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter in patients with migraine over 19 years of follow-up of 51,032 patients with migraine and 510,320 matched controls. (K. Adelborg, kade@clin.au.dk)
>>>Lancet Highlights
Source:
Feb. 3 issue of Lancet (2018; 391).
Long-Term Glucocorticoids in Duchenne Muscular Dystrophy: Cumulative glucocorticoid therapy of 1 year or more is beneficial in patients with Duchenne muscular dystrophy, researchers report, with “reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death” (pp. 451–61). In 440 boys and men aged 2 to 28 years in nine countries, these outcomes were recorded in a prospective cohort study: “Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2.1–4.4 years and upper limb milestones by 2.8–8.0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2.1–2.7 years in comparison with prednisone or prednisolone (log-rank p <0.012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0.47, 95% CI 0.22–1.00; p = 0.0501).” (C. M. McDonald, cmmcdonald@ucdavis.edu)
>>>PNN NewsWatch
* Kareway Products is voluntarily recalling 60,000 lots of Gericare Eye Wash, Sterile Eye Irrigation Solution, 4 fluid ounces to the hospital, retail, or consumer level because of potential microbial contamination.
>>>PNN JournalWatch
* Late-Onset ADHD Reconsidered With Comprehensive Repeated Assessments Between Ages 10 and 25, in American Journal of Psychiatry, 2018; 175: 140–9. (M. H. Sibley)
*
Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health, in Pediatrics, 2018; 141: 10.1542/peds.2017-3716. (S. J. Schwarzenberg)

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

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>>>Internal Medicine Report
Source:
Feb. 6 issue of Annals of Internal Medicine (2018; 168).
CEA of Individualized Glycemic Control in Type 2 Diabetes: Lower medication costs are an important factor in making individualized approaches to glycemic control cost-effective for U.S. adults with type 2 diabetes, researchers report (pp. 170–8). Using a lifetime horizon and health care sector perspective, a cost-effectiveness analysis produced these outcomes for individualized versus uniform intensive glycemic control for patients aged 30 years or older: “Individualized control saved $13,547 per patient compared with uniform intensive control ($105,307 vs. $118,854), primarily due to lower medication costs ($34,521 vs. $48,763). Individualized control decreased life expectancy (20.63 vs. 20.73 years) due to an increase in complications but produced more [quality-adjusted life-years (QALYs)] (16.68 vs. 16.58) due to fewer hypoglycemic events and fewer medications.” The sensitivity analysis showed that “individualized control was cost-saving and generated more QALYs compared with uniform intensive control, except in analyses where the disutility associated with receiving diabetes medications was decreased by at least 60%.” (N. Laiteerapong, nlaiteer@medicine.bsd.uchicago.edu)
Marijuana Use & Cardiovascular Risk Factors: Evidence is insufficient to assess the effects of marijuana on cardiovascular risk factors and outcomes, according to authors of a systematic review (pp. 187–94). Vascular risk factors (hyperglycemia, diabetes, dyslipidemia, and obesity) and cardiovascular outcomes (stroke, myocardial infarction, cardiovascular mortality, and all-cause mortality in cardiovascular cohorts) were considered in the analysis of published observational studies: “13 and 11 studies examined associations between marijuana use and cardiovascular risk factors and clinical outcomes, respectively. Although 6 studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and were not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, dyslipidemia, acute myocardial infarction, stroke, or cardiovascular and all-cause mortality was insufficient. Although the current literature includes several long-term prospective studies, they are limited by recall bias, inadequate exposure assessment, minimal marijuana exposure, and a predominance of low-risk cohorts.” (D. Ravi, divyaravi.88@gmail.com)
Genomic Sequencing for Precision Cancer Care: “Recent advances in next-generation sequencing technology, coupled with decreasing costs, present a transformative opportunity to improve patient outcomes through implementation of routine, prospective tumor and germline genomic profiling,” authors write in an Ideas and Opinion article (pp. 221–2). “Cancer is a genomic disease defined by diverse somatic and germline alterations that promote aberrant cell growth. Tumor genomic profiling of single genes or limited gene panels to guide therapy selection is now part of standard management of several solid tumor types, including melanoma, lung cancer, colorectal cancer, and ovarian cancer. However, treatment of many solid tumors is still based on the site of origin rather than being personalized to the molecular alterations specific to an individual patient’s cancer.” (D. B. Solit, solitd@mskcc.org)
Provider Types & Obstructive Sleep Apnea: In patients with known or suspected obstructive sleep apnea (OSA), outcomes were similar when care was provided by sleep specialist physicians (SSPs) and non–sleep specialists (NSSs), according to a systematic review of provider types and outcomes (pp. 195–202). While limited by extensive training or experience in sleep medicine for NSSs, review of study outcomes showed the following: “Four observational studies (n = 580; mean age, 52 years; 77% male) reported good agreement between NSSs and SSPs on appropriate diagnostic testing and classification of OSA severity (low-strength evidence). Five randomized trials and 3 observational studies (n = 1515; mean age, 52 years; 68% male) found that care provided by NSSs and SSPs resulted in similar quality of life, adherence, and symptom scores (low-strength evidence). Evidence was insufficient for access to care and adverse events.” (T. J. Wilt, tim.wilt@va.gov)

PNN Pharmacotherapy Line
Feb. 7, 2018 * Vol. 25, No. 26
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Feb. 6 issue of JAMA (2018; 319).
Oral Anticoagulants, Intracerebral Hemorrhage & Mortality: Among patients with intracerebral hemorrhage (ICH) who had received oral anticoagulants (OACs), risk of in-hospital mortality was lower with use of non-warfarin OACs (NOACs) than with warfarin, a study shows (pp. 463–73). The lowest risk of in-hospital mortality was in patients who had received no prior OACs in the retrospective cohort study of 141,311 patients with ICH admitted to 1,662 Get With The Guidelines–Stroke hospitals, which reports these results: “The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant.” (G. C. Fonarow, gfonarow@mednet.ucla.edu)
Fetal Alcohol Spectrum Prevalence: In four U.S. communities, the prevalence of fetal alcohol spectrum disorders was conservatively estimated at 1.1% to 5.0% in a cross-sectional study of first graders (pp. 474–82). The communities, in four different regions of the country, had these numbers of students with the disorder: “A total of 6,639 children were selected for participation from a population of 13,146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8–15.8) to 50.0 (95% CI, 39.9–61.7) per 1,000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1–54.0) to 98.5 (95% CI, 57.5–139.5) per 1,000 children.” (C. D. Chambers, chchambers@ucsd.edu)
“The message about alcohol use during pregnancy to the public should be clear and consistent: there is no safe amount, time, or type of alcohol to drink during pregnancy or when trying to get pregnant,” editorialists write in reinforcing advice of the American Academy of Pediatrics (
pp. 448–9). “Special attention should be paid to young women who may engage in binge drinking because it can lead to unprotected sex and unplanned pregnancies. Prepregnancy drinking behavior is known to affect the likelihood of prenatal drinking to a great extent. Primary care clinicians should routinely include appropriate screening for alcohol use among all women of childbearing age, preconceptual health promotion, contraceptive counseling, and referral to substance abuse programs for those identified to have an alcohol use disorder. For women for whom it is not possible to ascertain prepregnancy drinking habits, identification of prenatal alcohol use should be a priority because reducing or eliminating alcohol use during pregnancy can potentially reduce the severity of the effects on the fetus. In addition, fetal alcohol spectrum disorders are an intergenerational issue with a high rate of recurrence within families; as such, families of affected children should be provided with ongoing support to reduce the likelihood of bearing additional children with fetal alcohol spectrum disorders.” (S. Lange, shannon.lange@camh.ca)
>>>PNN NewsWatch
* “Compounds in kratom make it so it isn’t just a plant – it’s an opioid,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “And it’s an opioid that’s associated with novel risks because of the variability in how it’s being formulated, sold, and used recreationally” and for self-medication.

PNN Pharmacotherapy Line
Feb. 8, 2018 * Vol. 25, No. 27
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 8 issue of the New England Journal of Medicine (2018; 378).
340B Drug Pricing Program: Availability of 340B-priced drugs “has been associated with hospital–physician consolidation in hematology–oncology and with more hospital-based administration of parenteral drugs in hematology–oncology and ophthalmology,” a study shows (pp. 539–48). The program has not met some of its original objectives, including expanded care or lower mortality for low-income patients, the authors add, based on these findings from Medicare claims data: “Hospital eligibility for the 340B Program was associated with 2.3 more hematologist–oncologists practicing in facilities owned by the hospital, or 230% more hematologist–oncologists than expected in the absence of the program (P = 0.02), and with 0.9 (or 900%) more ophthalmologists per hospital (P = 0.08) and 0.1 (or 33%) more rheumatologists per hospital (P = 0.84). Program eligibility was associated with significantly higher numbers of parenteral drug claims billed by hospitals for Medicare patients in hematology–oncology (90% higher, P = 0.001) and ophthalmology (177% higher, P=0.03) but not rheumatology (77% higher, P = 0.12). Program eligibility was associated with lower proportions of low-income patients in hematology–oncology and ophthalmology and with no significant differences in hospital provision of safety-net or inpatient care for low-income groups or in mortality among low-income residents of the hospitals’ local service areas.” In discussing their results, these researchers note: “The finding that patients served by eligible hospitals were less likely to have Medicaid, which reimburses hospitals less generously than other forms of supplemental coverage, is consistent with the financial incentives of hospitals and with evidence that 340B-participating hospitals have increasingly affiliated with hematology–oncology practices serving affluent communities.” (S. Desai, sunita.desai@nyu.edu)
“The controversy surrounding 340B is an archetypal problem in modern U.S. health care policy,” authors of a Perspective article write (
pp. 501–3). “The legislation was passed because of private industry’s reaction to a prior law mandating discounts. After its passage, the new policy, though well intentioned, was expanded beyond its planned scope as health care organizations figured out how to use it to maximize their revenue. The program became so large and convoluted that it requires scaling back, inevitably causing pain for hospitals that have spent years relying on the revenue it brought in and building businesses around it. The stakeholder groups each argue that their particular point of view is the one that will help patients the most, but no one can be sure who is right. Predictably, stakeholders complain loudly about the effects of changes and Congress delays or alters the implementation. In this case, the American Hospital Association sued to halt the 340B cuts, and members of Congress have introduced legislation to prevent them from happening. As the current debate about 340B plays out and the policy changes are enacted in 2018, stay tuned for the next act in this long-playing drama.” (W. F. Gellad)
Prazosin for PTSD: Among 304 military veterans with posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin proved similar to placebo for alleviating “distressing dreams” and improving sleep quality, researchers report (pp. 507–17). Participants recruited from 13 VA medical centers randomly received prazosin or placeob for 5 weeks in daily maximum doses of 5 or 20 mg. Based on three primary outcome measures, the investigators found: “At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the [Clinician-Administered PTSD Scale] item B2 score (between-group difference, 0.2; 95% confidence interval [CI], −0.3 to 0.8; P = 0.38), in the mean change in [Pittsburgh Sleep Quality Index] score (between-group difference, 0.1; 95% CI, −0.9 to 1.1; P = 0.80), or in the [Clinical Global Impression of Change] score (between-group difference, 0; 95% CI, −0.3 to 0.3; P = 0.96).… At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.” (M. A. Raskind, murray.raskind@va.gov)

PNN Pharmacotherapy Line
Feb. 9, 2018 * Vol. 25, No. 28
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
Feb. issue of Chest (2018; 153).
Inhaled Corticosteroids & Fracture Risk in COPD: In both men and women, long-term use of inhaled corticosteroids (ICSs) for chronic obstructive pulmonary disorder (COPD) is associated with a modest risk hip and upper extremity fracture, according to Quebec health data (pp. 321–8). Nested case-control analysis showed these patterns when each case of fracture was matched with 20 controls: “In the cohort of 240,110 subjects, 19,396 sustained a fracture during a mean 5.3 years (rate, 15.2 per 1,000 per year). Any use of ICSs was not associated with an increased rate of fracture (RR, 1.00; 95% CI, 0.97–1.03). The fracture rate was increased with >4 years of ICS use at daily doses ≥1,000 μg in fluticasone equivalents (RR, 1.10; 95% CI, 1.02–1.19). This risk increase did not differ between men and women.” (S. Suissa, samy.suissa@mcgill.ca)
“Can we finally put this to bed?” ask editorialists with regard to continued widespread use of long-term ICSs in patients with COPD despite a campaign targeting prescribers (
pp. 293–4). “ICS therapy is useful in patients who experience frequent exacerbations,” the writers conclude. “However, they are fraught with significant side effects, which may be dose-dependent. It is now well established that ICSs have deleterious effects on bone that increase the risk of fractures, a side effect that is largely avoidable and can be mitigated by careful monitoring and most importantly by reducing (and in most cases eliminating) the use of ICSs for patients with COPD in the community.” (D. D. Sin, on.Sin@hli.ubc.ca">Don.Sin@hli.ubc.ca)
>>>Circulation Report
Source:
Feb. 6 issue of Circulation (2018; 137).
Validating DAPT Scores in a Japanese PCI Patients: The dual antiplatelet therapy (DAPT) score was useful for predicting ischemic and bleeding risks in a pooled cohort of participants in three Japanese studies of percutaneous coronary interventions, researchers report (pp. 551–62). At 13 to 36 months after percutaneous coronary interventions in those with DAPT scores of 2 or more (high DS) or less than 1 (low DS), outcomes were as follows: “Among 12,223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3,944 patients had high DS and 8,279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, P = 0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, P = 0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, P = 0.03; 1.5% versus 0.8%, P = 0.002; 0.7% versus 0.3%, P <0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%, P <0.001; 1.0% versus 1.6%, P = 0.03, respectively).” (T. Kimura, taketaka@kuhp.kyoto-u.ac.jp)
>>>PNN NewsWatch
* Proper use of inhaled corticosteroids and other control medicines in children with asthma is emphasized in a new Vital Signs report from the CDC. Asthma attacks decreased in number among children of all races and ethnicities between 2001 and 2016, but 50% of children with asthma had exacerbations in 2016. “Asthma can’t be cured – but most of the time, we can control asthma symptoms and prevent asthma attacks,” Acting CDC Director Anne Schuchat, M.D., said during a media briefing.
*
FDA yesterday approved the RadioGenix System (NorthStar Medical Radioisotopes) for producing technetium-99m (Tc-99m), the most widely used radioisotope in medical imaging. The Nuclear Regulatory Commission is issuing guidance and will license the RadioGenix System to enable the Tc-99m it produces to be used for its medical purpose. “The system we’ve approved today will not only help save and improve the lives of patients, but will reduce the risk of drug shortages and strengthen our national security by creating a U.S.-based manufacturing capacity that is less vulnerable to supply disruptions,” said FDA Commissioner Scott Gottlieb, M.D.

PNN Pharmacotherapy Line
Feb. 12, 2018 * Vol. 25, No. 29
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Feb. 10 issue of Lancet (2018; 391).
Weight Management & Remission of Type 2 Diabetes: Over a 12-month period, nearly one-half of 306 individuals with type 2 diabetes achieved remission through primary care–delivered intensive weight management interventions (pp. 541–51). The open-label, cluster-randomized DiRECT trial included 49 primary care practices in Scotland and the Tyneside region of England and patients with a type 2 diagnosis within 6 years who had body mass indices of 27–45 kg/sq m and were not receiving insulin. All antidiabetic and antihypertensive drugs were withdrawn and participant diets were totally replaced by formula for 3 to 5 months. Foods were reintroduced in stepped fashion, and structured support was provided for long-term weight loss management.
Results showed: “At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p <0.0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19.7, 95% CI 7.8–49.8; p <0.0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0–5 kg weight loss, 19 (34%) of 56 participants with 5–10 kg loss, 16 (57%) of 28 participants with 10–15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10.0 kg (SD 8.0) in the intervention group and 1.0 kg (3.7) in the control group (adjusted difference −8.8 kg, 95% CI −10.3 to −7.3; p <0.0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7.2 points (SD 21.3) in the intervention group, and decreased by 2.9 points (15.5) in the control group (adjusted difference 6.4 points, 95% CI 2.5–10.3; p = 0.0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study.” (R. Taylor,
roy.taylor@newcastle.ac.uk)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Adverse Effects of Trimethoprim for UTI in Older Adults: Increased risks of kidney injury and hyperkalemia were evident among older patients treated with trimethoprim for urinary tract infections in an analysis of the U.K. Clinical Practice Research Datalink and Hospital Episode Statistics database (k341). Among more than 1.1 million patients aged 65 or older, these outcomes were noted for 178,238 people treated at least once for UTI with antibiotics: “The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57).…” (K. Mansfield, kathryn.mansfield@lshtm.ac.uk)
>>>PNN JournalWatch
* Global Impact of 2017 American Heart Association/American College of Cardiology Hypertension Guidelines: A Perspective From Japan, in Circulation, 2018; 137: 543–5. (K. Kario, kkario@jichi.ac.jp)
*
Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report, in Chest, 2018; 153: 467–97. (S. K. Field, sfield@ucalgary.ca)
*
Extending the Reach of Evidence-Based Medicine: A Proposed Categorization of Lower-Level Evidence, in Chest, 2018; 153: 498–506. (F. C. Detterbeck, frank.detterbeck@yale.edu)
*
Addressing the Unknowns of Antimicrobial Resistance: Quantifying and Mapping the Drivers of Burden, in Clinical Infectious Diseases, 2018; 66: 612–6. (G. M. Knight, gmknight@imperial.ac.uk)

PNN Pharmacotherapy Line
Feb. 13, 2018 * Vol. 25, No. 30
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Feb. issue of JAMA Internal Medicine (2018; 178).
LABAs/LAMAs & Cardiovascular Risk in COPD: Initiation of inhaled long-acting bronchodilators in people with chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular events, a nested case–control study from Taiwan shows, “irrespective of prior [cardiovascular disease (CVD)] status and history of exacerbations” (pp. 229–38). Treatment with inhaled long-acting beta-2 agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in 284,220 patients aged 40 years or older with no use in the prior year (new users) or use within the prior year (prevalent users) produced these outcomes for inpatient or emergency care visits for coronary artery disease, heart failure, ischemic stroke, or arrhythmia, according to the Taiwan National Health Insurance Research Database for 2007–11: “During a mean follow-up of 2.0 years, 37,719 patients with CVD (mean age, 75.6 years; 71.6% men) and 146,139 matched controls (mean age, 75.2 years; 70.1% men) were identified. New LABA and LAMA use in COPD was associated with a 1.50-fold (95% CI, 1.35–1.67; P < .001) and a 1.52-fold (95% CI, 1.28–1.80; P < .001) increased cardiovascular risk within 30 days of initiation, respectively, whereas the risk was absent, or even reduced with prevalent use. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not differ in the CVD risks. The risk persisted in an alternative case–crossover study and remained across subgroups without CVD history or prior exacerbations.” (M-T Wang, wmt@mail.ndmctsgh.edu.tw)
Promotional & Legal Maneuvers to Protect Restasis Sales: Thinking about alternative uses for the billions of dollars spent in the U.S. for Allergan’s Restasis product (cyclosporine ophthalmic emulsion, 0.05%) “should bring tears to your eyes,” Viewpoint authors write (pp. 181–2). “Which is what Restasis is supposed to do—just not like this.” The authors note that annual sales of the product have been about $2 billion in the U.S., with demand driven by $645 million in direct-to-consumer advertising over a 10-year period and payments of $9.1 million to 24,152 physicians in 2013–15. “In the case of Restasis, even evidence-based clinical resources may be misleading,” the authors add. “For example, the ‘Dry Eyes’ chapter in UpToDate, a point-of-care resource, summarized a systematic review as follows: ‘All nine [Restasis] trials that evaluated symptoms ... found improvement.’ But 4 of these 9 trials only demonstrated within-group—not between-group—improvements. The other 5 trials found that only 1 or 2 of the 4 to 8 symptoms tested improved. For the symptom score (a primary outcome in drug approval trials), Restasis was superior to artificial tears or placebo in just 1 of the 9 trials of initial treatment. Although the UpToDate authors note that they ‘have not seen such a degree of beneficial results in their practice,’ the chapter does not mention that, as disclosed in the systematic review, the senior author was an Allergan consultant. Moreover, neither the UpToDate chapter nor the systematic review discusses the tenuous evidence of efficacy found in the treasure trove of regulatory documents.” (S. Woloshin, steven.woloshin@dartmouth.edu)
Congressional, regulatory, or judicial actions may stop a novel legal maneuver Allergan is using to extend patent life of Restasis, a Viewpoint article explains (
pp. 179–80): “In September 2017, Allergan Plc announced that it had transferred the 6 patents for cyclosporine ophthalmic emulsion (Restasis), its blockbuster drug for chronic dry eye, to the Saint Regis Mohawk Tribe, a federally recognized Indian tribe of about 15,000 members in rural upstate New York with a $50 million annual budget,” the author writes. “The Tribe received $13.75 million initially and is eligible for $15 million in annual royalties—a small fraction of the roughly $1.5 billion in annual U.S. revenues for Restasis. The deal allows the Tribe, as the patents’ legal owner, to assert what is known as sovereign immunity in a proceeding at the US Patent and Trademark Office (USPTO) where Mylan Pharmaceuticals … is challenging the patents.…
“Whether selling patents to Indian tribes or other sovereigns to protect them from inter partes review is a viable strategy remains highly unsettled, and the situation could shift markedly depending on what Congress, the USPTO, and the Federal Circuit decide in the months ahead.” (G. Ablavsky,
ablavsky@law.stanford.edu)

PNN Pharmacotherapy Line
Feb. 14, 2018 * Vol. 25, No. 31
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Oncology Highlights
Source:
Feb. 10 issue of the Journal of Clinical Oncology (2018; 36).
Out-of-Pocket Costs & Abandonment of Oral Anticancer Agents: Across cancers of all types, higher out-of-pocket (OOP) costs were associated with higher rates of abandonment of oral anticancer drugs, a study shows (pp. 476–82). Retrospective claims data for adjudicated prescriptions from 2014 and 2015 were used to assess rates of claim reversal (failure to purchase approved prescription), delayed initiation (reversal with subsequent fill of same agent within 90 days after adjudication), and abandonment (reversal with no fill of same agent within 90 days) for an index oral anticancer agent. Results showed the following: “Among the final sample (N = 38,111), risk-adjusted rates of claim reversal ranged from 13% to 67%, increasing with higher OOP costs. Although the abandonment rate was 18% overall, risk-adjusted rates were higher in greater OOP cost categories (10.0% for ≤$10 group v 13.5% for $50.01 to $100 group, 31.7% for $100.01 to $500 group, 41.0% for $500.01 to $2,000 group, and 49.4% for > $2,000 group; P < .001 compared with ≤$10 group). Rates remained similar after accounting for use of alternate oral, injectable, or infusible anticancer agents. Delayed initiation was also more frequent for higher OOP cost categories (3% in ≤ $10 group v 18% in > $2,000 group; P < .001). Sensitivity and subgroup analyses by insurance type, pharmacy type, sex, and indication identified similar associations.” (J. A. Doshi, jdoshi@pennmedicine.upenn.edu)
>>>Infectious Diseases Report
Source:
Feb. 15 issue of Clinical Infectious Diseases (2018; 66).
Low CDI Risk With Tetracyclines: Compared with other antibiotics for treating systemic diseases, tetracyclines may be associated with a decreased risk of Clostridium difficile infection (CDI), according to a systematic review and meta-analysis of four case–control and two cohort studies (pp. 514–22): “Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47–0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40–0.75; P < .001).” (S. Khanna, khanna.sahil@mayo.edu)
Pneumococcal Vaccination & Pneumonia Hospitalizations: Public funding of conjugated pneumococcal vaccine (PCV) for infants reduced disease and associated costs in Ontario, researchers report (pp. 541–7). During five intervals with differing policies and vaccine availability [prevaccine period, availability of 7-valent PCV (PCV7) for private purchase, public funding for PCV7, replacement of PCV7 with 10-valent PCV (PCV10), and replacement of PCV10 with 13-valent PCV (PCV13)], population-based health administrative data for vaccine-eligible groups show a 34% to 45% decline in pneumonia hospitalizations and a 38% to 46% decline in hospitalization-related costs, and less disease and lower costs in PCV-ineligible older children and older adults. (D. L. Luca, dleeluca@mathematica-mpr.com)
>>>PNN NewsWatch
* Apace Packaging is voluntarily recalling one lot of Acyclovir Tablet, USP, 400 mg, 50 ct unit dose, NDC 50268-061-15, lot no. 19900, to the retail level, because a small number of blister cards may also include torsemide 20 mg tablets.
* Initiatives included in the Administration’s proposed
fiscal year 2019 budget for FDA include advancing pharmacy outsourcing as a domestic industry and promoting competition through generic drug development and substitution, writes Commissioner Scott Gottlieb, MD, in a statement released yesterday. “These initiatives are aimed at supporting new and ongoing efforts to foster more investment and innovation in the development of therapeutics and diagnostics that target unmet medical needs; advance drug and device competition; stand up new domestic industries – such as pharmacy outsourcing facilities; and create more modern, domestically based manufacturing, including continuous manufacturing of drugs and biological products, including vaccines. These manufacturing platforms can bring more businesses back to the U.S., help lower drug and device development costs, and reduce the risk of shortages.”

PNN Pharmacotherapy Line
Feb. 15, 2018 * Vol. 25, No. 32
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Feb. 15 issue of the New England Journal of Medicine (2018; 378).
Edoxaban for Cancer-Associated VTE: In an open-label comparison with subcutaneous dalteparin in patients with cancer who had acute symptomatic or incidental venous thromboembolism, oral edoxaban was noninferior with respect to a composite primary outcome of recurrent venous thromboembolism or major bleeding, researchers report (pp. 615–24). Edoxaban, a direct anticoagulant, produced a lower rate of venous thromboembolism but a higher rate of major bleeding, as shown in these results for 6–12 months of prophylaxis: “A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P = 0.006 for noninferiority; P = 0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, −3.4 percentage points; 95% CI, −7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).” (G. E. Raskob, gary-raskob@ouhsc.edu)
“Not all patients with cancer and venous thromboembolism are candidates for edoxaban therapy,” editorialists write (
pp. 673–4). “The use of direct oral anticoagulants should be avoided in patients with a creatinine clearance of less than 30 ml per minute, and their use in patients with gastrointestinal cancer should be based on patient preference. Some patients may choose the convenience of an oral agent despite an increased risk of gastrointestinal bleeding.” (J. Hirsh)
Nusinersen in Later-Onset Spinal Muscular Atrophy: The antisense oligonucleotide agent nusinersen produced “significant and clinically meaningful improvement in motor function” in a phase 3 trial of 126 children with later-onset spinal muscular atrophy (pp. 625–35). Compared with a sham procedure, nusinersen produced these changes based on a primary end point of the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment: “In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P <0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P <0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).” (E. Mercuri, eugeniomaria.mercuri@unicatt.it)
Metastatic Prostate Cancer: The “increasingly complex” management of metastatic prostate cancer is reviewed (pp. 645–57): “Although we celebrate the life-prolonging effects of the new hormonal therapies, the diagnosis of metastatic prostate cancer currently leads to lifelong androgen-deprivation therapy. Despite progress on multiple research fronts, we have imperfect tools to identify patients who need therapy in the first place, and once the disease spreads beyond the control of local therapies, we do not know how best to sequence or combine the expanding number of active therapies.” (O. Sartor, sartor@tulane.edu">osartor@tulane.edu)
>>>PNN NewsWatch
* Following a priority review, FDA yesterday approved apalutamide (Erleada, Janssen) for treatment of patients with nonmetastatic, castration-resistant prostate cancer. The first agent approved for this indication, apalutamide is a next-generation androgen receptor inhibitor that decreased the risk of distant metastasis or death by 72% and improved median metastasis-free survival by more than 2 years in phase 3 trials.
* The
Banyan Brain Trauma Indicator is the first marketed blood test for detecting concussions in adults, FDA reports.

PNN Pharmacotherapy Line
Feb. 16, 2018 * Vol. 25, No. 33
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Highlights
Source:
Feb. Journal of the American Geriatrics Society (2018; 66).
PPIs & Dementia Risk: Concerns that long-term PPI use could be associated with increased dementia risk are not supported by results of a prospective population-based cohort study of 3,484 older adults in Kaiser Permanente Washington (pp. 247–53). Among those 65 or older without baseline dementia, these results were identified in every-2-year dementia screens: “Over a mean follow-up of 7.5 years, 827 participants (23.7%) developed dementia (670 with possible or probable AD). PPI exposure was not associated with risk of dementia (P = .66) or AD (P = .77). For dementia, the risk for specific levels of cumulative exposure compared to no use was: 365 [total standardized daily doses (TSDDs)] (HR 0.87, 95% CI 0.65–1.18), 1,095 TSDDs (HR 0.99, CI 0.75–1.30) and 1,825 TSDDs (HR 1.13, CI 0.82–1.56). These TSDD levels represent approximately 1, 3 and 5 years of daily use respectively. Duration of PPI use was not associated with dementia outcomes either.” (S. Gray, slgray@u.washington.edu)
UTI Antibiotics & Confusion: Antibiotic use for suspected urinary-tract infections (UTIs) raises nursing home residents’ risk of developing confusion by 9-fold, a cross-sectional study shows (pp. 274–81). At five Australian facilities, 450 residents had these nonspecific symptoms documented during antibiotic use: “UTI accounted for 33% of all current infections treated with antibiotics and 40% of all infections treated with antibiotics within the last 30 days. One in 5 NH residents had received antibiotics within the last 30 days, of which 45% were for UTI. The most significant factors independently associated with antibiotics for UTI were urinary catheter (OR = 13, 95% CI = 2.4–67, P = .003), urinary frequency (OR = 10, 95% CI = 2.2–47, P = .003), fever (OR = 10, 95% CI = 1.3–85, P = .028), new-onset hypotension (OR = 10, 95% CI = 1.4–73, P = .024), and confusion (OR = 8.9, 95% CI = 3.1–26, P < .001). Of these, confusion was the most prevalent factor in the population.” (S. Mayne, sean.mayne@my.jcu.edu.au)
>>>Allergy/Immunology Report
Source:
Feb. J. Allergy and Clinical Immunology (2018; 141).
Vaccine-Associated Hypersensitivity: Advances in vaccinology create a need to watch for new or different adverse events emerging, authors of a review article write (pp. 463–72): “Postvaccination acute-onset hypersensitivity reactions include self-limited localized adverse events and, rarely, systemic reactions ranging from urticaria/angioedema to full-blown anaphylaxis with multisystem involvement. Risk of anaphylaxis after all vaccines is estimated to be 1.31 (95% CI, 0.90–1.84) per million vaccine doses, respectively. Serious hypersensitivity reactions after influenza vaccines are particularly important because of the large number of persons vaccinated annually. Influenza vaccines are unique in requiring annual changes in the vaccines’ antigenic composition to match the predicted circulating influenza strains. Recently, novel influenza vaccine types were introduced in the United States (recombinant vaccines, some with higher antigen content, and a new adjuvanted vaccine). Providers should be aware of changing recommendations on the basis of recent published evidence for persons with a history of egg allergy to receive annual influenza vaccination. Further research is needed to elucidate the pathophysiology and risk factors for reported vaccine-associated adverse events. Further research is also needed to determine whether repeated annual inactivated influenza vaccination, the number of vaccine antigens administered at the same time, and the current timing of routine infant vaccinations are optimal for overall population well-being.” (M. M. McNeil, mmm2@cdc.gov)
>>>PNN NewsWatch
* Cases of influenza-like illness continue unabated in most of the U.S., government officials said yesterday. Figures for the 2017–18 influenza season are updated in a report in this week’s MMWR, and hospitalizations and physician visits are already approaching the record levels of recent severe seasons — with several weeks remaining. In addition, the proportion of cases caused by influenza B virus is unusually large, which could portend a severe period ahead, since B strains tend to predominate late in the season. Overall vaccine effectiveness is pegged at 36%, according to a second MMWR article.
*
PNN will not be published on Mon., Feb. 19, Presidents Day.

PNN Pharmacotherapy Line
Feb. 20, 2018 * Vol. 25, No. 34
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Feb. 20 issue of the Annals of Internal Medicine (2018; 168).
Perioperative Aspirin in Patients With Prior PCI: A multicenter trial conducted in 23 countries shows that perioperative aspirin may be more beneficial than harmful when used perioperatively in patients who have had percutaneous coronary intervention (PCI) (pp. 237–44). Among more than 10,000 participants aged 45 years or older undergoing noncardiac surgery, these results were recorded for aspirin or placebo therapy initiated within 4 hours before surgery and continued perioperatively: “In patients with prior PCI, aspirin reduced the risk for the primary outcome [of death or nonfatal myocardial infarction within 30 days] (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, −2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50).” (P. J. Devereaux, philipj@mcmaster.ca)
Hepatitis B Vaccination in Patients With HIV: Missed opportunities to vaccinate patients with HIV infection against hepatitis B virus are common, a study shows, with more than one-third of those living with HIV in the U.S. sample not starting the series while receiving medical care in 2009–12 (pp. 245–54). Among 18,089 adult participants with HIV in the Medical Monitoring Project, results indicated a need for vaccination in alternative sites: “At the beginning of the surveillance period, 44.2% (95% CI, 42.2% to 46.2%) of U.S. HIV patients were candidates to initiate vaccination. By the end of the surveillance period, 9.6% (CI, 8.4% to 10.8%) of candidates were vaccinated, 7.5% (CI, 6.4% to 8.6%) had no documented vaccination but had documented infection or immunity, and 82.9% (CI, 81.1% to 84.7%) remained candidates. Among patients at facilities funded by the Ryan White HIV/AIDS Program (RWHAP), 12.5% (CI, 11.1% to 13.9%) were vaccinated during the surveillance period versus 3.7% (CI, 2.6% to 4.7%) at facilities not funded by RWHAP. At the end of surveillance, 36.7% (CI, 34.4% to 38.9%) of HIV patients were candidates to initiate vaccination.” (J. Weiser, jweiser@cdc.gov)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Paradoxical Effects of Anticoagulation in CKD: “Giving anticoagulants to older people with concomitant atrial fibrillation and chronic kidney disease was associated with an increased rate of ischaemic stroke and haemorrhage but a paradoxical lowered rate of all cause mortality,” conclude authors of a retrospective cohort analysis of Royal College of General Practitioners Research and Surveillance Centre data from 2006 to 2016 (k342). “Careful consideration should be given before starting anticoagulants in older people with chronic kidney disease who develop atrial fibrillation. There remains an urgent need for adequately powered randomised trials in this population to explore these findings and to provide clarity on correct clinical management.” (J. Camm, jcamm@sgul.ac.uk)
>>>PNN NewsWatch
* FDA on Friday expanded the approved indications of durvalumab (Imfinzi, AstraZeneca) to include treatment of patients with unresectable stage III non-small cell lung cancer whose cancer has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
>>>PNN JournalWatch
* Adjunctive Rifampicin for Staphylococcus aureus Bacteraemia (ARREST): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial, in Lancet, 2018; 391: 668–78. (G. E. Thwaites, gthwaites@oucru.org)
*
Individualizing Prevention for Older Adults, in Journal of the American Geriatrics Society, 2018; 66: 229–34. (S. J. Lee, sei.lee@ucsf.edu)
*
Novel Therapies for Alopecia Areata: The Era of Rational Drug Development, in Journal of Allergy and Clinical Immunology, 2018; 141: 499–504. (A. M. Christiano, amc65@cumc.columbia.edu)
*
Intravenous Thrombolysis and Platelet Count, in Neurology, 2018; 90: e690–7. (H. Gensicke)

PNN Pharmacotherapy Line
Feb. 21, 2018 * Vol. 25, No. 35
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Feb. 20 issue of JAMA (2018; 319).
Haloperidol, Delirium & Survival in Critically Ill Adults: In the REDUCE trial, use of haloperidol for prevention of delirium in high-risk patients in intensive-care units (ICUs) did not improve 28-day survival rates, researchers report (pp. 680–90). Among 1,789 critically ill adults in 21 ICUs in the Netherlands — where nonpharmacological measures are used routinely for delirium prevention — randomization to intravenous haloperidol 1 mg or 2 mg or to placebo had these effects on a primary outcome of number of days survived over a 28-day period: “The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0–0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78–1.30, P = .82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0–0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0–0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group).” (M. van den Boogaard, mark.vandenBoogaard@radboudumc.nl)
“Delirium is a common accompaniment of critical illness, but it need not be so,” editorialists write (
pp. 659–60). “The REDUCE study has demonstrated that in critically ill patients currently receiving best-practice nonpharmacological interventions to prevent delirium, the addition of haloperidol does not improve survival nor reduce the incidence of delirium or the harms associated with delirium. The REDUCE study has demonstrated that the plausible and simple administration of prophylactic haloperidol is not the solution for the complex problem of delirium in critically ill patients.” (A. Delaney, adelaney@med.usyd.edu.au)
Acute Respiratory Distress Syndrome: Pharmacotherapy is not the answer in management of patients with acute respiratory distress syndrome (ARDS), according to results of a narrative review (pp. 698–710): “The cornerstone of management remains mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Aspirin was not effective in preventing ARDS in patients at high-risk for the syndrome. Adjunctive interventions to further minimize VILI, such as prone positioning in patients with a Pao2/Fio2 ratio less than 150 mm Hg, were associated with a significant mortality benefit whereas others (eg, extracorporeal carbon dioxide removal) remain experimental. Pharmacologic therapies such as beta-2 agonists, statins, and keratinocyte growth factor, which targeted pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm. Recent guidelines on mechanical ventilation in ARDS provide evidence-based recommendations related to 6 interventions, including low tidal volume and inspiratory pressure ventilation, prone positioning, high-frequency oscillatory ventilation, higher vs lower positive end-expiratory pressure, lung recruitment maneuvers, and extracorporeal membrane oxygenation.” (E. Fan, eddy.fan@uhn.ca)
“Matching intervention to pathophysiology is essential,” editorialists add (
pp. 664–6). “Physiological studies that better characterize the factors causing ventilator-induced lung injury are indicated prior to undertaking [a randomized controlled trial] aimed at avoiding it. When a damaging threshold is determined, the indication for the most adequate therapy will immediately follow.” (L. Gattinoni, gattinoniluciano@gmail.com)
>>>PNN NewsWatch
* The Advisory Committee on Immunization Practices convenes at the CDC in Atlanta today for a 2-day meeting. On this morning’s agenda, which is streamed live, are discussions and votes on influenza vaccines, including Fluarix Quadrivalent (GlaxoSmithKline) and a reformulated intranasal vaccine from Medimmune/AstraZeneca (FluMist) that uses a new strain of a live attenuated influenza virus (LAIV). Efficacy of LAIV in children aged 2 to 17 years will also be discussed.

PNN Pharmacotherapy Line
Feb. 22, 2018 * Vol. 25, No. 36
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 22 New England Journal of Medicine (2018; 378).
Larotrectinib in TRK Fusion–Positive Cancers: In adults and children with tropomyosin receptor kinase (TRK) fusion–positive cancers, the highly selective TRK inhibitor larotrectinib produced marked and durable antitumor activity, researchers report (pp. 731–9). Using three protocols based on patient age, the study showed: “A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.” (D. M. Hyman, hymand@mskcc.org)
Calling this study “an illustration of what is likely to be the future of drug development in rare genomic entities,” an editorialist concludes (
pp. 763–5): “To address the challenge of orphan molecular segments such as NTRK fusions, the oncology community must pursue innovative trial designs, implement new biotechnologies for diagnosis, and radically change the current pathways of care. The major unknown factor in this field is how many other orphan molecular entities will meet the same therapeutic success as the one observed with larotrectinib. Finally, since these alterations are rare, there is a need for a global effort. This implies harmonization among regulatory agencies across the world and an expansion of global trials.” (F. AndréWinking
VTE Prophylaxis After Hip or Knee Arthroplasty: Following rivaroxaban prophylaxis for 5 postoperative days following total hip or total knee arthroplasty, extended prophylaxis with aspirin is not significantly different from rivaroxaban for prevention of symptomatic venous thromboembolism, a study shows (pp. 699–707). Randomization on postoperative day 5 to continuation of the direct oral anticoagulant in a 10-mg dose or to aspirin 81 mg daily for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty, 90-day outcomes were as follows: “A total of 3,424 patients (1,804 undergoing total hip arthroplasty and 1,620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1,707 patients (0.64%) in the aspirin group and in 12 of 1,717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], −0.55 to 0.66; P <0.001 for noninferiority and P = 0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, −0.65 to 0.29; P = 0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, −1.07 to 0.47; P = 0.43).” (D. R. Anderson, david.anderson@dal.ca)
>>>PNN NewsWatch
* Facing a lack of clinical data on a reformulated live attenuated influenza vaccine (LAIV) but no way of generating the data without widespread use of the product, the Advisory Committee on Immunization Practices yesterday voted 12–2 to reinstate FluMist (MedImmune/AstraZeneca) to its immunization schedule for the coming season. The decision “may have come too late for the vaccine to play a major role in next winter’s vaccination program,” StatNews reports, since “many doctor’s offices will have already ordered their flu vaccine stocks for next season and the contracts for the publicly funded Vaccines for Children program have already been let.” The ACIP meeting continues today with discussions of pneumococcal vaccines in older adults, use of vaccines and other biologics in health care–associated infections, meningococcal disease, and Japanese encephalitis vaccine.

PNN Pharmacotherapy Line
Feb. 23, 2018 * Vol. 25, No. 37
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Health Affairs Highlights
Source:
Feb. issue of Health Affairs, a theme issue on diffusion of innovations (2018; 37).
Vaccines & Health Equity in Developing Countries: In 41 low- and middle-income countries, vaccines yielded health and economic benefits by averting both deaths and medical impoverishment, a study shows (pp. 316–24). The impact of 10 antigens and their corresponding vaccines were assessed across income quintiles for differential health impact (number of deaths averted) and household economic impact (cases of medical impoverishment averted): “Our analysis indicated that benefits across these vaccines would accrue predominantly in the lowest income quintiles. Policy makers should be informed about the large health and economic distributional impact that vaccines could have, and they should view vaccination policies as potentially important channels for improving health equity. Our results provide insight into the distribution of vaccine-preventable diseases and the health benefits associated with their prevention.” (A. Y. Chang, angela.chang@mail.harvard.edu)
Medicaid v. Marketplace Economics in Near-Poor Adults: In states that did not expand Medicaid eligibility under the Affordable Care Act, nonelderly adults with incomes in the 100% to 138% federal poverty range have lower coverage rates and increased out-of-pocket expenses for enrollees, researchers report (pp. 299–307). Data from 2010 to 2015 show these patterns in the impact of Medicaid expansion versus Marketplace availability: “For adults with family incomes of 100–138 percent of poverty, living in a Medicaid expansion state was associated with a 4.5-percentage-point reduction in the probability of being uninsured, a $344 decline in average total out-of-pocket spending, a 4.1-percentage-point decline in high out-of-pocket spending burden (that is, spending more than 10 percent of income), and a 7.7-percentage-point decline in the probability of having any out-of-pocket spending relative to living in a nonexpansion state. These findings suggest that policies that substitute Marketplace for Medicaid eligibility could lower coverage rates and increase out-of-pocket expenses for enrollees.” (F. Blavin, fblavin@urban.org)
Medicare’s Annual Wellness Visit: Practices that are providing annual wellness visits to at least one-fourth of their Medicare patients have more stable patient assignment and a slightly healthier patient mix, Medicare data for 2008–15 indicate (pp. 283–91). Practices serving racial minorities, dual eligibles, and other underserved populations had lower visit rates, which could worsen inequities, the group reports. (I. Ganguli, iganguli@bwh.harvard.edu)
>>>Medical Care Report
Source:
Mar. issue of Medical Care (2018; 56).
Medication Adherence & Medicaid Utilization: Among more than 1.3 million Medicaid beneficiaries, improvements in medication adherence were associated with substantial reductions in health services utilization, a study shows (pp. 266–73). Benefits were evident even at adherence rates below the commonly used threshold of 0.8 proportion of days covered, the investigators report, adding these details for 2008–10 in 10 states: “Full adherence was associated with 8%–26% fewer hospitalizations and 3%–12% fewer emergency department visits among those with congestive heart failure, hypertension, diabetes, and schizophrenia/bipolar. In all analyses, full adherence was associated with up to 15% fewer outpatient physician/clinic visits. Moreover, low and moderate levels of adherence were also related to less health care use.” The authors conclude, “Interventions should focus not just on perfecting moderate adherers, but also on encouraging Medicaid patients with chronic conditions to initiate pharmacotherapy.” (M. C. Roebuck, cr@rxeconomics.com)
>>>PNN NewsWatch
* Based on findings from the 10-year CLARICOR trial, FDA advises caution before prescribing clarithromycin to patients with heart disease because of a potential increased risk of heart problems or death that can occur years later. The large clinical trial showed an unexpected increase in deaths among patients with coronary heart disease who received a 2-week course of clarithromycin that became apparent after patients had been followed for 1 year or longer. There is no clear explanation for how clarithromycin would lead to more deaths than placebo in these patients.

PNN Pharmacotherapy Line
Feb. 26, 2018 * Vol. 25, No. 38
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Feb. 24 issue of Lancet (2018; 391).
Atezolizumab in Platinum-Refractory Urothelial Carcinoma: Among patients with metastatic urothelial carcinoma overexpressing programmed death–ligand 1 (PD-L1) that had progressed after platinum-based chemotherapy, the anti-PD-L1 atezolizumab was safer than standard chemotherapy, with similar efficacy outcomes, researchers report (pp. 748–57). In an open-label, phase 3 trial at 217 centers, random assignment of 931 patients to platinum-based chemotherapy or atezolizumab produced these results: “In the [population with more PD-L1 expression in tumor-infiltrating immune cells] (n = 234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11.1 months [95% CI 8.6–15.5; n = 116] vs 10.6 months [8.4–12.2; n = 118]; stratified hazard ratio [HR] 0.87, 95% CI 0.63–1.21; p = 0.41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in [this] population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15.9 months [95% CI 10.4 to not estimable] vs 8.3 months [5.6–13.2]; HR 0.57, 95% CI 0.26–1.26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).” (T. Powles, thomas.powles@bartshealth.nhs.uk)
Gonadotrophins, Intrauterine Insemination for Anovulation in Clomifene Failure: Among normogonadotropic women who were not pregnant after six cycles of clomifene citrate, a switch of treatment to gonadotrophins increased the chance of livebirth over continued treatment with clomifene citrate, a study shows (pp. 758–65). At 48 Dutch hospitals, 666 participants were assigned to six cycles of gonadotrophins plus intrauterine insemination, gonadotrophins plus intercourse, clomifene citrate plus intrauterine insemination, or clomifene citrate plus intercourse, with these results: “Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1.24 [95% CI 1.05–1.46]; p = 0.0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1.14 [95% CI 0.97–1.35]; p = 0.1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins.” (M. van Wely, m.vanwely@amc.uva.nl)
>>>PNN NewsWatch
* Reviewing the new adjuvanted recombinant hepatitis B vaccine (Heplisav-B, Dynavax), the Medical Letter notes the increased immunogenicity of the product’s two-dose series, compared with three doses of the older Engerix-B product. Long-term data are lacking, though. The CDC’s Advisory Committee on Immunization Practices last week recommended addition of Heplisav-B to its adult immunization schedule.
* Hospira is voluntarily recalling 3 lots of
Labetalol Hydrochloride Injection, USP, 100 mg/20 mL vial (NDC 0409-2267-20), and one lot of Labetalol Hydrochloride Injection, USP, Novaplus (NDC 0409-2267-25) to the hospital/institution level because of cracks on the rim surface of vials underneath the stopper and crimp seal.
>>>PNN JournalWatch
* Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management, in Diabetes Care, 2018; 41: 627–37. (M. Horowitz, michael.horowitz@adelaide.edu.au)
*
Review: Defining a Unified Vascular Phenotype in Systemic Sclerosis, in Arthritis & Rheumatology, 2018; 70: 162–70. (Y. Allanore, yannick.allanore@aphp.fr)
*
Intranasal Ketamine and Its Potential Role in Cancer-Related Pain, in Pharmacotherapy, 2018; 38: 10.1002/phar.2090. (R. D. Harvey, donald.harvey@emory.edu)

PNN Pharmacotherapy Line
Feb. 27, 2018 * Vol. 25, No. 39
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
Mar. issue of Diabetes Care (2018; 41).
Niacin Effects on Gut Microbiome: For patients with prediabetes or type 2 diabetes, a delayed-release niacin intervention that improves the gut microbiome is worth exploring, according to a 500-participant study (pp. 398–405). Metabolic phenotypes were identified based on niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and the gut microbiome. Microcapsules that release NA and NAM in the colon were formulated and tested in two additional human intervention studies, with these results: “We found a reduced alpha-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.” (M. Laudes, matthias.laudes@uksh.de)
Gut Microbiota–Related Metabolites & Weight Loss: Patients with overweight and obesity and decreases in circulating choline or l-carnitine levels while on a low-calorie weight-loss diet had significantly greater weight loss and improved gut microbiota–related metabolites, researchers report (pp. 413–9). Trimethylamine N-oxide (TMAO), its precursors (choline and l-carnitine), body weight (BW), waist circumference (WC), body fat composition, fat distribution, and resting energy expenditure (REE) showed these changes during dieting in the POUNDS Lost trial: “Individuals with a greater reduction of choline (P <0.0001) and l-carnitine (P <0.01) rather than TMAO showed significant losses of BW and WC at 6 months. The reduction of choline was significantly predictive of decreases in body fat composition, fat distribution, and REE. Results of sensitivity analysis showed that the baseline diabetes risk status, such as the presence of hyperglycemia (31% of the total participants) and fasting glucose levels, did not modify the associations. Early changes in choline and l-carnitine were significantly predictive of weight loss over 2 years (P <0.05 for all). Individuals with increases in choline or l-carnitine were 2.35-times (95% CI 1.38, 4.00) or 1.77-times (1.06, 2.95) more likely to fail to lose weight (–5% or more loss) at 2 years.” (L. Qi, lqi1@tulane.edu)
Smoking Cessation in Diabetes Education: Long-term abstinence among smokers with diabetes or prediabetes was increased significantly through use of the Ottawa Model for Smoking Cessation (OMSC) in the cluster-randomized Tobacco Intervention in Diabetes Education study conducted in Ontario (pp.406–12). Compared with 7 sites using a wait-list control (WLC) condition, 7 sites using the OMSC intervention showed these outcomes: “A total of 313 smokers (OMSC group n = 199, WLC group n = 114) with diabetes or prediabetes were enrolled. The [carbon monoxide]-confirmed abstinence rate at 6 months was 11.1% in the OMSC group versus 2.6% in the WLC group (odds ratio 3.73 [95% CI 1.20, 11.58]; P = 0.02).” (R. D. Reid, breid@ottawaheart.ca)
Online ‘Standards of Care’: Instead of a single annual update, the Standards for Medical Care in Diabetes will now be updated online and revised continuously, the American Diabetes Association (ADA) announced (pp. 387–8). “The living Standards of Care represent a paradigm shift that reflects the ADA’s goal and desire to get the latest information into the hands of providers as soon as possible to meet our mission objective to ‘improve the lives of all people living with diabetes,’” authors wrote. Examples of “update worthy” events might be FDA approval of metformin for prevention in prediabetes, major clinical trial results that affect practice, new drug approvals, and new or updated ADA consensus definitions or positions. (W. T. Cefalu, wcefalu@diabetes.org)

PNN Pharmacotherapy Line
Feb. 28, 2018 * Vol. 25, No. 40
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Feb. 27 issue of JAMA (2018; 319).
Meropenem-Vaborbactam in Complicated UTIs: In the phase 3, multicenter, multinational, randomized TANGO I trial of patients with complicated urinary tract infection (UTI), meropenem-vaborbactam was noninferior to piperacillin-tazobactam with respect to a composite outcome of complete resolution or improvement of symptoms along with microbial eradication (pp. 788–99). The primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population; the European Medicines Agency (EMA) end point was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations.
Results showed: “Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, −0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, −4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam.” (K. S. Kaye,
keithka@med.umich.edu)
Gabapentin for Chronic Neuropathic Pain: With 1 in 14 adults having neuropathic pain and few effective remedies available, gabapentin is an important therapeutic option, according to a JAMA Clinical Evidence Synopsis (pp. 818–9). “In people with moderate or severe neuropathic pain, oral gabapentin (1200-3600 mg/d) was associated with greater achievement of substantial (pain intensity reduction of ≥50% or very much improved on Patient Global Impression of Change [PGIC] scale) or moderate (pain intensity reduction of ≥25% or much or very much improved on PGIC scale) benefit than placebo,” the authors write. “In patients with [postherpetic neuralgia], gabapentin was associated with higher rates of substantial benefit (32% for gabapentin vs 17% for placebo) and moderate benefit (46% for gabapentin vs 25% for placebo).” (A. Moore, andrew.moore@ndcn.ox.ac.uk)
“Twenty-five years after the initial FDA approval of gabapentin, there is still limited evidence to support its widespread use for the majority of indications for which it is prescribed, many of which are off-label,” editorialists write (
pp. 776–8). “With hundreds of clinical trials and dozens of Cochrane reviews evaluating different FDA-approved and off-label indications, the history of gabapentin’s availability illustrates how additional regulatory requirements and postmarketing surveillance initiatives might have led to better coordination of evaluation efforts, and could have provided an evidence base that was more expeditiously and rigorously developed, that was reliably reported to patients and clinicians, and that served to improve clinical care.” (J. S. Ross, joseph.ross@yale.edu)
Varicose Veins & Venous Thromboembolism: Adults with varicose veins have a higher risk of incident deep vein thrombosis (DVT) but perhaps not pulmonary embolism or peripheral arterial disease, a retrospective analysis of national health data from Taiwan indicates (pp. 807–17). “Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research.,” conclude the investigators. (P-C Chen, peichun@mail.cmu.edu.tw)
>>>PNN NewsWatch
* Bella All Natural is voluntarily recalling its Diet Capsules labeled as Bella, lot number MFD:10.15.2017 EXP: 10.14.2019, to the consumer level because of the presence of sibutramine, FDA said.

PNN Pharmacotherapy Line
Mar. 1, 2018 * Vol. 25, No. 41
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Mar. 1 issue of the New England Journal of Medicine (2018; 378).
Hydrocortisone Therapy in Septic Shock: The uncertainty over the role of hydrocortisone support in critically ill patients with septic shock continues with differing results from two large clinical trials.
Continuous hydrocortisone infusion at 200 mg/d for up to 7 days in 3,658 patients with septic shock who were on ventilation produced no significant benefits in a primary end point of all-cause death at 90 days (27.9% versus 28.8% with placebo), the ADRENAL trial shows (
pp. 797–808). Those on hydrocortisone had faster resolution of shock (median of 3 days versus 4 days with placebo) and a shorter duration of ventilation (median of 6 days versus 7 days with placebo). (B. Venkatesh, bvenkatesh@georgeinstitute.org.au)
In the APROCCHSS trial of 1,241 patients with septic shock, the 90-day all-cause mortality rate was significantly lower with hydrocortisone plus fludrocortisone than placebo (43.0% versus 49.1%) (
pp. 809–18). This trial, which began as a three-drug comparison that included drotrecogin alfa (activated) before that agent’s market withdrawal, also showed benefits in a number of secondary outcomes. (D. Annane, djillali.annane@aphp.fr)
“Will these two trials change clinical practice?” asks an editorialist (
pp. 860–1). “Although 90-day survival differed between the studies, both showed the beneficial effects of hydrocortisone on secondary outcomes of shock reversal and the duration of mechanical ventilation. It is unlikely that in the near future sufficiently powered trials will provide us with better data. Thus, clinicians will have to use these data and subsequent meta-analyses to decide how best to treat patients with septic shock. Estimating 90-day mortality at the bedside is not practical. It is likely that some practitioners caring for a patient with a deteriorating condition who is receiving escalating doses of vasopressors, in whom other core interventions have been instituted (i.e., appropriate antibiotics and adequate volume resuscitation and source control), will consider that the short-term benefits of low-dose hydrocortisone may exceed any risks (e.g., antiinflammatory effects) as an added therapy in selected patients.” (A. F. Suffredini)
Balanced Crystalloids versus Saline: In trials at Vanderbilt U. that compared clinical effects of balanced crystalloids with those of saline infusions, benefits are demonstrated in critically ill but not noncritically ill patients.
Comparing lactated Ringer’s solution or Plasma-Lyte A with saline in 13,347 noncritically ill patients in the emergency department, SALT-ED investigators found no difference in the number of days alive after discharge before day 28 (median of 25 days in each group) (
pp. 819–28). Major adverse kidney events within 30 days were lower with balanced crystalloids than with saline. (T. W. Rice, todd.rice@vanderbilt.edu)
SMART investigators showed a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction with balanced crystalloids in 7,942 critically ill patients, compared with saline (
pp. 829–39). Lactated Ringer’s solution or Plasma-Lyte A significantly lowered the rate of major kidney adverse events (14.3% versus 15.45 with saline); differences in in-hospital mortality at 30 days, new renal-replacement therapy, and incidence of persistent renal dysfunction showed statistical trends (0.05 < P < 0.1). (T. W. Rice, todd.rice@vanderbilt.edu)
“What clinicians need to consider is whether the results of an open-label trial conducted in a single, major U.S. medical center can be generalized to the ways in which their own patients survive, feel, and function,” an editorialist writes (
pp. 862–3). “None of the currently used resuscitation fluids are ‘physiological,’ and questions regarding their safety and efficacy will remain, despite the results of these two trials and any randomized, controlled trials that are currently recruiting participants. Considerations remain regarding the effects of different types of resuscitation fluids and the ways they are used in specific, high-risk patient populations. Assessments of longer-term, patient-centered outcomes and health economics are fundamental to informing clinicians about their choice of resuscitation fluids in critically ill patients. The trials presented here inform that thinking but do not provide unequivocal clinical direction.” (J. Myburgh)

PNN Pharmacotherapy Line
Mar. 2, 2018 * Vol. 25, No. 42
Providing news and information about medications and their proper use

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>>>Psychiatry Report
Source:
Mar. issue of the American Journal of Psychiatry (2018; 175).
Adjunctive Cannabidiol in Schizophrenia: In an exploratory study of 88 patients with schizophrenia, cannabidiol (CBD) had beneficial effects mediated through a mechanism other than dopamine antagonism (pp. 225–31). The results could indicate the possibility of a new class of drugs for this disorder, the investigators conclude. Results based on responses on the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S) were as follows: “After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=−1.4, 95% CI=−2.5, −0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=−0.5, 95% CI=−0.8, −0.1) and as not severely unwell (CGI-S: treatment difference=−0.3, 95% CI=−0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=−0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=−0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.” (P. McGuire)
SSRIs in Mild Cognitive Impairment: In the longitudinal Alzheimer’s Disease Neuroimaging Initiative, long-term SSRI treatment was associated with a slower progression from mild cognitive impairment (MCI) to Alzheimer’s dementia (pp. 232–41). Results for 755 currently nondepressed participants showed these results: “In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with a delayed progression to Alzheimer’s dementia by approximately 3 years, compared with short-term SSRI treatment, treatment with other antidepressants, or no treatment and compared with MCI patients without a history of depression. No differences in CSF biomarker levels were observed between treatment groups.” (C. Bartels)
Antidepressant Outcomes Predicted by Genetic Variation: A single-nucleotide polymorphism (SNP) affecting the hypothalamic-pituitary-adrenal (HPA) axis function “may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective,” researchers report (pp. 251–61). Complete genotyping data for 636 patients in the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits showed these associations and outcomes for 16 candidate SNPs during treatment with escitalopram, sertraline, or extended-release venlafaxine: “The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.” (C. P. O’Connell)
>>>PNN NewsWatch
* FDA said yesterday it is alerting health care professionals and patients not to use drug products from Cantrell Drug Company of Little Rock, AR, including opioid products and other drugs intended for sterile injection, that were produced by the company and distributed nationwide. The agency cited concerns “about serious deficiencies in Cantrell’s compounding operations, including its processes to ensure quality and sterility assurance that put patient safety at risk.”

PNN Pharmacotherapy Line
Mar. 5, 2018 * Vol. 25, No. 43
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Mar. 3 issue of Lancet (2018; 391).
Dolutegravir–Rilpivirine for HIV-1 Suppression: In the phase 3 SWORD-1 and SWORD-2 trials, the combination of dolutegravir and rilpivirine was noninferior to patients’ current antiretroviral therapy (ART) regimens (CARs), researchers report (pp. 839–49). Based on a primary endpoint of proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication, investigators found these results in 1,028 participants with HIV-1 in 12 countries: “At week 48 (last patient visit was Nov. 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir–rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0.2% (95% CI −3.0 to 2.5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir–rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir–rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir–rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]).” (L. P. Kahl, lesley.p.kahl@viivhealthcare.com)
Triple Antiplatelet Therapy in Acute Cerebral Ischemia: In an international, prospective, randomized, open-label, blinded-endpoint trial in 3,096 adult participants with ischemic stroke or transient ischemic attack (TIA) within 48 hours of onset, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA but did significantly increase the risk of major bleeding (pp. 850–9). Intensive antiplatelet therapy consisted of aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily; this regimen was compared with guideline-based therapy with clopidogrel alone or combined aspirin and dipyridamole. Results showed: “The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0.90, 95% CI 0.67–1.20, p = 0.47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2.54, 95% CI 2.05–3.16, p <0.0001).” (P. M. Bath, philip.bath@nottingham.ac.uk)
>>>PNN NewsWatch
* Biogen and AbbVie on Friday announced a voluntary worldwide withdrawal of their daclizumab product (Zinbryta) for relapsing multiple sclerosis. The companies said they believe that characterizing the complex and evolving benefit/risk profile of the drug will not be possible going forward given the limited number of patients being treated. The action followed announcement of an urgent review after eight patients in Germany and Spain who have multiple sclerosis developed encephalitis and other serious inflammatory brain disorders after taking the injectable agent, the Wall Street Journal reported.
*
FDA is warning consumers to be wary of promotions of products claiming to prevent, treat, or cure influenza. “Consumers should be aware that there are no legally marketed over-the-counter (OTC) drugs to prevent or cure the flu,” the agency said. “However, there are legal OTC products to reduce fever and to relieve muscle aches, congestion and other symptoms typically associated with the flu. Products sold online are fraudulent if they claim to prevent, treat or cure the flu, and have not been evaluated by the FDA for that intended use.”
>>>PNN JournalWatch
* 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.12.048. (K. A. Hicks)
*
Pediatric Medication Safety in the Emergency Department, in Pediatrics, 2018; 141: 10.1542/peds.2017-4066. (L. Benjamin)
* Guidelines for Adolescent Depression in Primary Care (GLAD-PC):
Part I. Practice Preparation, Identification, Assessment, and Initial Management, and Part II. Treatment and Ongoing Management, in Pediatrics, 2018; 141: 10.1542/peds.2017-4081 and 10.1542/peds.2017-4082. (GLAD-PC Steering Group)

PNN Pharmacotherapy Line
Mar. 6, 2018 * Vol. 25, No. 44
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-release articles from and the Mar. 6 issue of Annals of Internal Medicine (2018; 168).
Glycemic Control in Type 2 Diabetes Mellitus: In an updated guidance statement, the American College of Physicians recommends relaxed glycemic targets for pharmacologic treatment of nonpregnant adults with type 2 diabetes (10.7326/M17-0939). Based on review of conflicting guidelines, the College formulated these guidance statements (A. Qaseem, aqaseem@acponline.org):
* Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients’ preferences, patients’ general health and life expectancy, treatment burden, and costs of care.
* Clinicians should aim to achieve an HbA
1c level between 7% and 8% in most patients with type 2 diabetes.
* Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA
1c levels less than 6.5%.
* Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA
1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.
Direct-Acting Antivirals in Kidney Transplantation: Used as prophylaxis before and after kidney transplantation from donors infected with hepatitis C virus (HCV) to noninfected recipients, direct-acting antivirals (DAAs) were safe and effective in a small study (10.7326/M17-2871). The transplant kidneys came from deceased donors aged 13 to 50 years with confirmed HCV infection. All recipients received grazoprevir 100 mg and elbasvir 50 mg immediately before transplant and continued receiving this combination for 12 weeks after transplant. Recipients who received organs from donors with HCV genotype 2 or 3 infection had sofosbuvir 400 mg added to their regimen. Among the 10 organ recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. “If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection,” the authors conclude. (C. M. Durand, christinedurand@jhmi.edu)
Vaccination in Infants Born to Mothers Taking Adalimumab: Because of persistence of adalimumab in some infants born to mothers being treated for active inflammatory bowel disease during gestation, administration of live vaccinations should be delayed until the agent is not detectable, authors of a letter recommend (10.7326/L17-0629). Researchers report the case of a 34-year-old woman who took adalimumab for Crohn disease during her pregnancy. Once her Crohn disease was under control, the mother continued to take a maintenance dose until her baby was born at 39 weeks. While the birth was uneventful, the infant has had persistent serum presence of adalimumab up to its last test at 19 months. The persistence of this agent remains unexplained, but the researchers caution that clinicians should be aware of this possibility and delay vaccines in children born to mothers treated for inflammatory bowel disease with infliximab or adalimumab. (R. Labetoulle)
Physical Activity & Frailty: In a study of 1,635 community-dwelling adults aged 70–89 years, a structured, moderate-intensity physical activity program failed to reduce risks for frailty during a 2-year period (pp. 309–16). Compared with a health education program consisting of workshops and stretching exercises, the physical activity intervention was associated only with significant improvement in inability to rise from a chair, one of three criteria in the Study of Osteoporotic Fractures. (A. Trombetti, Andrea.Trombetti@hcuge.ch)
>>>PNN NewsWatch
* Hospira is voluntarily recalling three lots of Hydromorphone HCl Injection, USP CII 10 mg/mL, 1 mL in 2 mL single dose vials, lot numbers 71330DD (NDC 0409-2634-01), and 691853F and 700753F (NDC 0703-0110-01 – Teva lots) to the hospital/institution level because some units may be empty or cracked at the bottom of the glass vial.

PNN Pharmacotherapy Line
Mar. 7, 2018 * Vol. 25, No. 45
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 6 issue of JAMA (2018; 319).
Meds for Chronic Back Pain or Osteoarthritis Pain: Opioids were not superior nonopioids in a 12-month study of pain-related function in 240 patients with moderate-to-severe chronic back pain or hip or knee osteoarthritis pain (pp. 872–82). At VA primary care clinics, these results were generated for immediate-release morphine, oxycodone, or hydrocodone/acetaminophen or acetaminophen/NSAIDs: “Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month {Brief Pain Inventory (BPI)] interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, −0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]).” (E. E. Krebs, erin.krebs@va.gov)
Vaccine Antigen Exposure in Young Children: Concerns that multiple vaccines in young children can weaken the immune system are unfounded, according to an case–control study of patients seen at institutions participating in the Vaccine Safety Datalink (VSD) (pp. 906–13). Emergency department and inpatient visits for nonvaccine-targeted infections showed these patterns based on cumulative vaccine antigen exposure: in 193 cases and 751 controls: “Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was −2.3 (95% CI, −10.1 to 5.4; P = .55). Among children with vs without non–vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07).” (J. M. Glanz, jason.m.glanz@kp.org)
“The present study provides further reassurance to parents that the U.S. childhood vaccination schedule is safe in terms of not being associated with an increased risk of non–vaccine-targeted infections, yet the small but vocal minority of antivaccine groups may not be satisfied by the evidence provided through VSD and other vaccine safety surveillance,” editorialists write (
pp. 870–1). “For example, insistence by such groups that vaccines cause autism persists, despite overwhelming science to the contrary. Although the VSD and other mechanisms, such as the Post-Licensure Immunization Safety Monitoring system, must continue to study the scientific questions, closer attention must also be paid to fulfilling the VSD’s second purpose of strengthening the public’s confidence in vaccines.” (S. T. O’Leary, sean.oleary@ucdenver.edu)
Vitamin & Mineral Supplements: “When reviewing medications with patients, clinicians should ask about use of micronutrient (and botanical or other dietary) supplements in counseling about potential interactions,” write authors of a Viewpoint article (pp. 859–60). “For example, supplemental vitamin K can decrease the effectiveness of warfarin, and biotin (vitamin B7) can interfere with the accuracy of cardiac troponin and other laboratory tests. Patient-friendly interaction checkers are available free of charge online (search for interaction checkers on drugs.com, WebMD, or pharmacy websites).” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
>>>PNN NewsWatch
* FDA yesterday granted fast-track approval to ibalizumab-uiyk (Trogarzo, TaiMed Biologics USA Corp.) for treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen. The first agent in a new class of HIV drugs in a decade, ibalizumab-uiyk is a CD4-directed post-attachment HIV-1 inhibitor that blocks HIV by binding to CD4+ receptors on host cells.
*
Sagent Pharmaceuticals has recalled 10 lots of Methylprednisolone Sodium Succinate for Injection, USP, 40 mg, 125 mg, and 1 g to the user level because of unknown impurities.

PNN Pharmacotherapy Line
Mar. 8, 2018 * Vol. 25, No. 46
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Mar. 8 issue of the New England Journal of Medicine (2018; 378).
Increasing Glucocorticoid Doses in Asthma Exacerbations: Two studies yield conflicting results concerning management of asthma exacerbations with sharply increased doses of inhaled glucocorticoids.
In 254 children ages 5–11 years with mild-to-moderate persistent asthma, quintupling maintenance fluticasone propionate doses at early signs of loss of asthma control failed to reduce the rate of severe asthma exacerbations or improve other asthma outcomes, and may have been associated with diminished linear growth, researchers report (
pp. 891–901). Participants treated for 48 weeks had these outcomes during the double-blind study: “The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P = 0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was −0.23 cm per year (P = 0.06).” (D. J. Jackson, djj@medicine.wisc.edu)
A similar study of adults and adolescents showed fewer severe asthma exacerbations when inhaled glucocorticoid doses were increased 4-fold as part of a personalized self-management plan (
pp. 902–10): “A total of 1,922 participants underwent randomization, of whom 1,871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P = 0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group.” (T. Harrison, tim.harrison@nottingham.ac.uk)
“Currently, clinicians are challenged to prevent and treat asthma exacerbations and to implement self-management plans,” concludes an editorialist (
pp. 950–2). “Evidence indicates that substantial escalation of regularly used inhaled glucocorticoids, even by a factor of 4 or 5, fails to prevent most asthma exacerbations. A small subgroup of adults and adolescents with asthma may have a response to an escalation strategy; however, their baseline and exacerbation characteristics remain to be defined.” (P. G. Bardin)
Tenofovir for Preventing Perinatal Hepatitis B Transmission: Reacting to a negative study of tenofovir disoproxil fumarate (TDF) for preventing perinatal hepatitis B virus (HBV) transmission from hepatitis B e antigen (HBeAg)–positive mothers to children (pp. 911–23, G. Jourdain, gonzague.jourdain@ird.fr), an editorialist reaches this conclusion (pp. 952–3): “Vaccination, particularly if delayed, may fail to protect infants born to mothers with high serum levels of HBV DNA or HBeAg; the current levels of evidence supporting antiviral therapy with TDF (or possibly lamivudine or telbivudine) to reduce levels of maternal HBV DNA during pregnancy have been accepted by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver. Preventing the residuum of chronic neonatal infections requires testing for [hepatitis B surface antigen] and HBV DNA and antiviral treatment or, alternatively, simple measures that bypass additional testing and treatment.… HBV vaccination at birth, despite the challenges for poverty-affected countries to deliver vaccination in rural and isolated locales, is feasible. A conjoint mobilization of HIV services to serve persons with chronic HBV infection is required. [This statistically “negative”] trial … puts down an intriguing marker attesting to the possibility that rapidly phasing in the timely administration of a safe monovalent HBV vaccine within a few hours after birth could contribute to the interruption of mother-to-child transmission and avert preventable HBV infections in childhood.” (G. Dusheiko)

PNN Pharmacotherapy Line
Mar. 9, 2018 * Vol. 25, No. 47
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Cardiology Report
Source:
Mar. issue of the Journal of the American College of Cardiology (2018; 71).
Digoxin & Mortality in AF: Use of digoxin is an independent risk factor for mortality in patients with atrial fibrillation (AF), a study shows, regardless of whether they have heart failure (10.1016/j.jacc.2017.12.060). Showing that those with the highest serum digoxin levels are at greatest risk, the authors report these findings from 17,897 patients with AF using a propensity score–adjusted analysis: “At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score–matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users.” (R. D. Lopes)
Resource Use & Costs of Cardiovascular Care: The immense resource and financial cost of cardiovascular disease (CVD) is quantified based on 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis) (10.1016/j.jacc.2017.12.064). Concluding that “maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals,” the investigators report these findings: “Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78%). Approximately $2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level >3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from <$7,700 for low-risk (Framingham risk score <6%, 0 CACS, and normal glucose measurements at baseline) to >$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20%, or CACS ≥400) subgroups. Among high-risk enrollees, CVD costs accounted for $74 million of the $155 million consumed by MESA participants.” (L. J. Shaw)
NOACs & Risk of Serious Liver Injury: Non–vitamin K antagonist oral anticoagulants (NOACs) are not associated with increased risk of hepatic injury, compared with vitamin K antagonists (VKAs), according to data from Quebec health insurance administrative databases (10.1016/j.jacc.2018.01.009). In a cohort analysis of patients with or without prior liver disease who were newly diagnosed with nonvalvular atrial fibrillation, these associations of medication use and hepatic risks were made: “The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person–years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively).” (A. Douros)
>>>PNN NewsWatch
* Testifying yesterday before a House Committee on Energy and Committee subcommittee, FDA Commissioner Scott Gottlieb, MD, said the agency is using CMS data to study the difference in efficacy between cell- and egg-based influenza vaccines. FDA is also “looking at how we develop a more robust recombinant vaccine manufacturing process to increase yield, while reducing cost,” Gottlieb said.

PNN Pharmacotherapy Line
Mar. 12, 2018 * Vol. 25, No. 48
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Mar. 10 issue of Lancet (2018; 391).
Need for Self-monitored Blood Pressure: Patient self-monitoring of blood pressure “could become the cornerstone of hypertension management in primary care,” TASMINH4 investigators conclude based on findings of significantly lower blood pressures among those titrated based on patient readings than on clinic determinations (pp. 949–59). The study compared self-monitoring blood pressure (self-monitoring group), self-monitoring blood pressure with telemonitoring (telemonitoring group), and usual care (clinic blood pressure; usual care group) at 152 U.K. general practices, with these results: “1,182 participants were randomly assigned to the self-monitoring group (n = 395), the telemonitoring group (n = 393), or the usual care group (n = 394), of whom 1,003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137.0 [SD 16.7] mm Hg and telemonitoring, 136.0 [16.1] mm Hg vs usual care, 140.4 [16.5]; adjusted mean differences vs usual care: self-monitoring alone, −3.5 mm Hg [95% CI −5.8 to −1.2]; telemonitoring, −4.7 mm Hg [–7.0 to −2.4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference −1.2 mm Hg [95% CI −3.5 to 1.2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups.” (R. J McManus, richard.mcmanus@phc.ox.ac.uk)
>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 360).
Fluoroquinolones & Aortic Integrity: In a nationwide study conducted in Sweden in 2006–18, patients taking oral fluoroquinolones had significantly higher risk of aortic aneurysm or dissection, researchers report (k678). Based on 360,088 treatment episodes, 78% of them with ciprofloxacin, these 60-day risk levels were identified in comparison with people taking amoxicillin: “Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1,000 person years among fluoroquinolone users and 0.7 cases per 1,000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection.” (B. Pasternak, bjorn.pasternak@ki.se)
Vitamin D & Cancer Risk: In Japan, a prospective case–cohort study indicates lower overall cancer risks among people with higher plasma levels of 25-hydroxyvitamin D (k671). The study, conducted at nine public health centers across the country, compared 3,301 people with incident cancers with 4,044 randomly selected cohorts. Vitamin D quartile results showed: “Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend = 0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend = 0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios.” (T. Yamaji, tyamaji@ncc.go.jp)
>>>PNN JournalWatch
* Designing Surveillance of Healthcare-Associated Infections in the Era of Automation and Reporting Mandates, Clinical Infectious Diseases, 2018: 66: 970–6. (M. S. M. van Mourik, M.S.M.vanMourik-2@umcutrecht.nl)
*
Efficacy of Acupuncture Is Noninferior to Nicotine Replacement Therapy for Tobacco Cessation, Chest, 2018: 153: 680–8. (J-s Yang, zml@ibucm.com)
*
Targeting HER2 by Combination Therapies, Journal of Clinical Oncology, 2018: 36: 808–11. (M. M. Moasser, mark.moasser@ucsf.edu)

PNN Pharmacotherapy Line
Mar. 13, 2018 * Vol. 25, No. 49
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-online articles from and Mar. issue of JAMA Internal Medicine (2018; 178).
In-Hospital Multifaceted Clinical Pharmacist Intervention: In Denmark, a multifaceted pharmacist intervention based on medication review, patient interview, and follow-up may have reduced the number of readmissions and emergency department (ED) visits (pp. 375–82). In the Odense Pharmacist Trial Investigating Medication Interventions at Sector Transfer (OPTIMIST), participants were randomized into 3 groups: usual care (no intervention), a basic intervention (medication review), and an extended intervention (medication review, 3 motivational interviews, and follow-up with the primary care physician, pharmacy, and nursing home). Results showed: “A total of 1,467 patients (679 men [46.3%] and 788 women [53.7%]; median age, 72 years; interquartile range, 63–80 years) were part of the primary analysis, including 498 randomized to usual care, 493 randomized to the basic intervention, and 476 randomized to the extended intervention. The extended intervention had a significant effect on the numbers of patients who were readmitted within 30 days (hazard ratio [HR], 0.62; 95% CI, 0.46–0.84) or within 180 days (HR, 0.75; 95% CI, 0.62–0.90) after inclusion and on the number of patients who experienced the primary composite end point (HR, 0.77; 95% CI, 0.64–0.93). The study showed a nonsignificant reduction in drug-related readmissions within 30 days (HR, 0.65; 95% CI, 0.39–1.09) and within 180 days (HR, 0.80; 95% CI, 0.59–1.08) after inclusion and in deaths (HR, 0.83; 95% CI, 0.22–3.11). The number needed to treat to achieve the primary composite outcome for the extended intervention (vs usual care) was 12.” (L. Vestergaard Ravn-Nielsen, leneravn.nielsen@gmail.com)
Atorvastatin Usage After Patent Expiration: In the 2 years following marketing of generic atorvastatin in 2012, costs fell by 28% while usage rose by 20%, according to a study of the nationally representative, longitudinal Medical Expenditure Panel Survey (MEPS) database (doi: 10.1001/jamainternmed.2018.0990). The authors report: “From 2012 to 2014, of 110,789 MEPS participants, 75,174 were eligible for the study (age, mean [standard error], 47.0 [0.2] years; 52% were female). From 2012 to 2014, overall atorvastatin users increased 20%, from 12.5 million adults (5.3% of U.S. adults) to 15.0 million adults (6.2% of U.S. adults), and prescriptions increased from 50.3 million to 74.0 million. Lipitor use decreased from 3.9 million adults in 2012 to 0.7 million adults in 2014, with a concomitant increase in uptake of generic statin from 8.6 million in 2012 to 14.3 million in 2014.
“In this time period, total atorvastatin-associated expenditures decreased from $7.0 billion to $5.4 billion. Total national expenditures associated with Lipitor were $3.5 billion (50% of total atorvastatin cost) in 2012 vs $357 million (7% of total cost) in 2014. Excess expenditure associated with continued Lipitor use totaled $2.1 billion from 2012 to 2014. More than half (57%) of excessive spending ($1.2 billion) was noted among patients with Medicare or Medicaid, who accounted for 58% of Lipitor users. We found that per-user total expenditure for Lipitor were higher compared with generic throughout 2012 to 2014. However, in 2014, Lipitor per-user [out-of-pocket] cost was lower than generic atorvastatin ($27 vs $49).” (K. Nasir,
khurram.nasir@yale.edu)
Menthol Cigarette Ban & Smoking Behavior: Planned behaviors of smokers did not match what they actually did following a total ban of menthol cigarettes in Ontario at the start of 2017 (doi: 10.1001/jamainternmed.2017.8650). Most participants (59.7% of 325 smokers) recruited by telephone indicated they planned to switch to nonmenthol cigarettes, but only 28.2% did so the first month of the ban. Instead, the authors report that “a larger proportion (60 [29.1%) attempted to quit compared with only 30 (14.5%) who said they would do so.” Another third of smokers switched to other flavored tobacco or e-cigarette products. more than the 5.8% of respondents who had planned to do so. (M. Chaiton, michael.chaiton@utoronto.ca)
>>>PNN NewsWatch
* PDX Aromatics, doing business as Kraken Kratom, Phytoextractum, and Soul Speciosa, has initiated a recall of certain kratom-containing powder products because it has the potential to be contaminated with Salmonella.

PNN Pharmacotherapy Line
Mar. 14, 2018 * Vol. 25, No. 50
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 13 issue of JAMA (2018; 319).
Copayments Exceeding Prescription Drug Costs: Prescription copayments exceed the drug costs in more than one-third of claims, according to data from the first half of 2013, with an average overpayment of $6.94 and 12 of the 20 most commonly prescribed drugs having overpayments of more than 33% (pp. 1045–7): “Among 9.5 million claims, 2.2 million (22.94% [95% CI, 22.91%–22.97%]) involved overpayments. The 28.17% rate (95% CI, 28.14%–28.20%) for generic drugs was significantly greater than for brand drugs (5.95% [95% CI, 5.92%–5.98%]); difference, 22.22% (95% CI, 22.17%–22.26%), P < .001. The mean overpayment was $7.69 (SD, $8.59); 17.15% (95% CI, 17.10%–17.20%) exceeded $10. Although less common, overpayments were significantly larger on brand drugs (mean, $13.46 [SD, $18.01]) than on generic drugs (mean, $7.32 [SD, $7.43]); difference, $6.14 (95% CI, $6.09–$6.19), P < .001. Aggregate overpayments totaled $135 million for 2013 or $10.51 per covered member.” (K. Van Nuys, vannuys@usc.edu)
Acetylcysteine/Salbutamol During Invasive Ventilation: For patients on invasive ventilation in intensive-care units (ICUs), on-demand nebulized acetylcysteine with salbutamol may be “a reasonable alternative” to routine nebulization, researchers report (pp. 933–1001). Adult patients who needed invasive ventilation for more 24 hours in seven Dutch ICUs had these outcomes: “Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54–75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0–26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0–26) ventilator-free days (1-sided 95% CI, −0.00003 to &infinWinking. There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, −15.5% [95% CI, −20.7% to −10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, −13.4% [95% CI, −18.4% to −8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, −4.1% [95% CI, −5.9% to −2.2%]; P < .001).” (M. J. Schultz, marcus.j.schultz@gmail.com)
U.S. Health Care Spending: Expenditures for health care in the U.S. is nearly twice that of 10 high-income countries, despite similar utilization levels, a study shows (pp. 1024–39). “In 2016, the U.S. spent 17.8% of its gross domestic product on health care, and spending in the other countries ranged from 9.6% (Australia) to 12.4% (Switzerland),” investigators write. “The proportion of the population with health insurance was 90% in the U.S., lower than the other countries (range, 99%–100%), and the U.S. had the highest proportion of private health insurance (55.3%). For some determinants of health such as smoking, the U.S. ranked second lowest of the countries (11.4% of the U.S. population ≥15 years smokes daily; mean of all 11 countries, 16.6%), but the U.S. had the highest percentage of adults who were overweight or obese at 70.1% (range for other countries, 23.8%–63.4%; mean of all 11 countries, 55.6%). Life expectancy in the U.S. was the lowest of the 11 countries at 78.8 years (range for other countries, 80.7–83.9 years; mean of all 11 countries, 81.7 years), and infant mortality was the highest (5.8 deaths per 1,000 live births in the U.S.; 3.6 per 1,000 for all 11 countries). The U.S. did not differ substantially from the other countries in physician workforce (2.6 physicians per 1,000; 43% primary care physicians), or nursing workforce (11.1 nurses per 1,000).… For pharmaceutical costs, spending per capita was $1,443 in the U.S. vs a range of $466 to $939 in other countries. Salaries of physicians and nurses were higher in the U.S.; for example, generalist physicians salaries were $218,173 in the U.S. compared with a range of $86,607 to $154,126 in the other countries.” (I. Papanicolas, i.n.papanicolas@lse.ac.uk)
Even limited reductions in health care costs could save billions, an author writes in one of four editorials (
pp. 983–5): “Can the United States reduce the cost of health care? Yes. But will the country do it? Answering that question is up to the medical profession, health systems, payers, and policy makers. The future of the U.S. health care system is in their hands.” (E. J. Emanuel, MEHPchair@upenn.edu)

PNN Pharmacotherapy Line
Mar. 15, 2018 * Vol. 25, No. 51
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Mar. 15 New England Journal of Medicine (2018; 378).
Cultured Cells/ROCK Inhibitor for Bullous Keratopathy: Administered with a rho-associated protein kinase (ROCK) inhibitor into the anterior chamber of the eye, human corneal endothelial cells (CECs) increased CEC density after 24 weeks in 11 persons with bullous keratopathy, researchers report (pp. 995–1003). The uncontrolled, single-group study included patients with no detectable CECs. Results showed the following: “At 24 weeks after cell injection, we recorded a CEC density of more than 500 cells per square millimeter (range, 947 to 2833) in 11 of the 11 treated eyes (100%; 95% confidence interval [CI], 72 to 100), of which 10 had a CEC density exceeding 1,000 cells per square millimeter. A corneal thickness of less than 630 μm (range, 489 to 640) was attained in 10 of the 11 treated eyes (91%; 95% CI, 59 to 100), and an improvement in best corrected visual acuity of two lines or more was recorded in 9 of the 11 treated eyes (82%; 95% CI, 48 to 98).” (S. Kinoshita, shigeruk@koto.kpu-m.ac.jp)
“These outcomes are encouraging; however, as the authors acknowledge, there are questions that must be addressed before introduction of this approach into wider clinical practice can be considered,” an editorialist writes (
pp. 1057–8). “What is the acceptable age range of the donor (a factor that can influence cell number, viability, and proliferation potential)? What is the acceptable density of the cells used for seeding? What is the maximum number of culture passages that would permit the production of high-quality homogeneous endothelial cell populations for transplantation purposes?” (R. Dana)
Treating Cryptococcal Meningitis in Africa: As induction therapy for cryptococcal meningitis in resource-limited settings, amphotericin B plus flucytosine for 1 week and fluconazole plus flucytosine for 2 weeks proved effective and safe in 721 patients living with HIV (pp. 1004–17). This or other induction regimens followed by fluconazole consolidation therapy for 10 weeks yielded these results: “Mortality in [an] oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.” (T. S. Harrison, tharriso@sgul.ac.uk)
HIV-Associated Cancers: Reviewing cancers and other conditions that occur in patients with HIV, authors provide these insights (pp. 1029–41): “Although the development of [antiretroviral therapy (ART)] has done much to improve overall survival and reduce the incidence of AIDS-defining cancers, other cancers have come to the forefront and have become common causes of complications and death among persons with HIV infection. As the HIV-infected population ages, a wide variety of HIV-associated cancers have become increasingly important. These cancers pose both challenges and opportunities. The National Cancer Institute sponsors a range of clinical studies in the United States and globally to prevent and treat HIV-associated cancers through the AIDS Malignancy Consortium, the Intramural Program, the Cancer Immunotherapy Trials Network, and the Bone and Marrow Transplant Clinical Trials Network. Results from previous studies support evidence-based guidelines for the treatment of several HIV-associated cancers. However, many questions remain. Addressing these questions will open new approaches for the prevention, diagnosis, and treatment of cancer among the more than 35 million people globally who are infected with HIV.” (R. Yarchoan, robert.yarchoan@nih.gov)

PNN Pharmacotherapy Line
Mar. 16, 2018 * Vol. 25, No. 52
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Mar. 15 issue of Clinical Infectious Diseases (2018; 66).
Twice-Annual Influenza Vaccination in Older Adults: In Hong Kong, twice-annual administration of influenza vaccine to older adults may have improved protection against continued circulation of an A/H3N2 strain in the summer and autumn, researchers report (pp. 904–12). However, later immune responses to the vaccine were lower among twice-annual recipients, which could complicate efforts to extend protection in tropical and subtropical areas with more prolonged influenza seasons. Among older adults aged 75 years or older, receipt of the mismatched 2014–15 vaccine with or without a follow-up vaccination with the 2015 southern hemisphere influenza vaccine produced these results: “We enrolled 978 older adults with 470 vaccinations for summer 2015 and 827 vaccinations for winter 2015–2016. Recipients of southern hemisphere vaccination had higher geometric mean titers (GMTs) by the hemagglutination inhibition assay against all 3 vaccine strains. When receiving influenza vaccination for the subsequent winter, the southern hemisphere vaccine recipients had higher prevaccination GMTs but lower postvaccination GMTs, compared to those who had not received the southern hemisphere vaccine. Furthermore, cellular immunity was impacted by biannual vaccination, with reduced influenza-specific CD4 T-cell responses in the second season of vaccination.” (B. J. Cowling, bcowling@hku.hk)
TB & AMI: Latent tuberculosis infection (LTBI) is independently associated with acute myocardial infarction (AMI), according to a case–control study from Peru (pp. 886–92). In 2015–17, 105 case patients with first-time diagnosis of type 1 (spontaneous) AMI had these outcomes compared with 110 controls without a history of AMI: “Overall, the median age was 62 years (interquartile range, 56–70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08–3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05–3.45).” (M. A. Huaman, moises.huaman@uc.edu)
>>>Oncology Highlights
Source:
Mar. 20 issue of the Journal of Clinical Oncology (2018; 36).
Osimertinib As First-Line Treatment of NSCLC: Osimertinib proved useful as first-line treatment of EGFR-mutated advanced non–small-cell lung cancer (NSCLC), according to these results from the AURA study (pp. 841–9): “Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median [progression-free survival] time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected.” (S. S. Ramalingam, suresh.ramalingam@emory.edu)
>>>PNN NewsWatch
* FDA yesterday issued an advance notice of proposed rulemaking to explore a product standard to lower nicotine in cigarettes to minimally or nonaddictive levels, FDA Commissioner Scott Gottlieb, MD, said in a statement posted to the agency website. “This new regulatory step advances a comprehensive policy framework that we believe could help avoid millions of tobacco-related deaths across the country,” Gottlieb wrote. “We believe this unprecedented approach to nicotine and tobacco regulation not only makes sense, but also offers us the best opportunity for achieving significant, meaningful public health gain.”

PNN Pharmacotherapy Line
Mar. 19, 2018 * Vol. 25, No. 53
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Mar. 17 issue of Lancet (2018; 391).
Cannabidiol in Lennox–Gastaut Seizures: In the GWPCARE4 trial, addition of cannabidiol to anticonvulsant therapy reduced the frequency of drop seizures in 171 children and adults with Lennox–Gastaut syndrome while producing tolerable adverse events, researchers report (pp. 1085–96). At 24 clinical sites in the U.S. and Europe, oral cannabidiol or matched placebo for 14 weeks produced these results: “14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR −69.6 to −1.9) in the cannabidiol group and 21.8% (IQR −45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was −17.21 (95% CI −30.32 to −4.09; p=0.0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.” (E. A. Thiele, ethiele@mgh.harvard.edu)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Immunologic Adverse Events & Anti-PD-1 Drugs: A small but increased risk of organ-specific immune-related adverse events is associated with use of anti-programmed cell death 1 (PD-1) drugs, according to authors who conducted a systematic review and meta-analysis of 13 studies (k793): “Studies compared nivolumab (n = 6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.” (D. Korenstein, korenstd@mskcc.org)
>>>PNN NewsWatch
* Bayer is voluntarily recalling Alka-Seltzer Plus packages that were sold only in the U.S. at Walmart, CVS, Walgreens, and Kroger (including subsidiary units) after Feb. 9, 2018, because the ingredients on the front sticker may not match the actual product in the carton. The affected packages can be identified by checking the Bayer logo located on the lower left corner of the front of the carton. If the logo has an orange or green background, the product is included in the recall.
* Based on tests conducted of United Pharmacy products that were recalled in November 2017,
FDA is advising compounders to perform stability studies for solutions containing glutamine to confirm that the glutamine is not degrading before the product’s specified beyond-use date.
>>>PNN JournalWatch
* Extrafine Inhaled Triple Therapy Versus Dual Bronchodilator Therapy in Chronic Obstructive Pulmonary Disease (TRIBUTE): A Double-Blind, Parallel Group, Randomised Controlled Trial, Lancet, 2018: 391: 1076–84. (A. Papi, ppa@unife.it)
*
Delirium—A Framework to Improve Acute Care for Older Persons, Journal of the American Geriatrics Society, 2018: 66: 446–51. (S. K. Inouye, AgingBrainCenter@hsl.harvard.edu)
*
IL-31: A New Key Player in Dermatology and Beyond, Journal of Allergy and Clinical Immunology, 2018: 141: 858–66. (I. S. Bağci, Bagci.Isin_Sinem@med.uni-muenchen.de)
*
Cancer in Primary Immunodeficiency Diseases: Cancer Incidence in the United States Immune Deficiency Network Registry, Journal of Allergy and Clinical Immunology, 2018: 141: 1028–35. (B. H. Segal, Brahm.Segal@RoswellPark.org)

PNN Pharmacotherapy Line
Mar. 20, 2018 * Vol. 25, No. 54
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Mar. 20 issue of Annals of Internal Medicine (2018; 168).
Hydroxychloroquine in Hand Osteoarthritis: Hydroxychloroquine is no more effective than placebo for relieving moderate to severe hand pain and radiographic osteoarthritis, according to a 248-participant study (pp. 385–95). Conducted at 13 English centers, the study produced these results based on a primary end point of average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]): “At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of −0.16 point (95% CI, −0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group).” (S. Kingsbury, s.r.kingsbury@leeds.ac.uk)
Opioid Analgesic Use & Invasive Pneumococcal Diseases: Records from the Tennessee Medicaid database link opioid use with increased risk of invasive pneumococcal disease (IPD), researchers report (pp. 396–404). Nested case–control analysis of 1,233 children aged 5 years or older and adults with IPD and 24,399 matched controls yielded these findings: “Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately.” (A. D. Wiese, andrew.d.wiese.1@vanderbilt.edu)
Antithyroid Drugs & Congenital Malformations: A nationwide cohort study conducted using the Korean National Health Insurance database shows an increased risk of congenital malformations following exposure to antithyroid drugs (ATDs) during the first trimester of pregnancy (pp. 405–13). The risk was particularly high when methimazole (MMI) was used alone or in combination with propylthiouracil, the investigators found. Results for 2.9 million completed pregnancies with live-born infants born to 2.2 million women in 2008–14: “12,891 pregnancies (0.45%) were exposed to ATDs during the first trimester. The prevalence of malformations in exposed offspring was 7.27%, compared with 5.94% in offspring of women who were not prescribed ATDs during pregnancy (P < 0.001) (adjusted odds ratio, 1.19 [95% CI, 1.12 to 1.28]). Absolute increases in the prevalence of congenital malformations per 1,000 live births were 8.81 cases (CI, 3.92 to 13.70 cases) for propylthiouracil alone, 17.05 cases (CI, 1.94 to 32.15 cases) for [MMI] alone, and 16.53 cases (CI, 4.73 to 28.32 cases) for propylthiouracil and MMI, compared with pregnancies without ATD prescriptions. In the MMI group, a high cumulative dose (>495 mg) during the first trimester was associated with an increased risk for malformations compared with a low dose (1 to 126 mg) (adjusted odds ratio, 1.87 [CI, 1.06 to 3.30]).” (J. H. Chung, thyroid@skku.edu)
>>>PNN NewsWatch
* The case count for Salmonella-contaminated kratom products is up to 87, CDC said in an update last week. People in 35 states have developed illnesses, including 27 who were hospitalized. Symptoms of diarrhea, fever, and abdominal cramps last for 4 to 7 days. Kratom — also known as Thang, Kakuam, Thom, Ketom, and Biak — is a plant consumed for its stimulant effects and as an opioid substitute.
*
“Global Introduction of New Vaccines: Delivering More to More” is a live continuing education webinar being broadcast from the CDC today at 1 pm Eastern time. Speakers will address regional and global outbreaks of new and emerging vaccine-preventable diseases.

PNN Pharmacotherapy Line
Mar. 21, 2018 * Vol. 25, No. 55
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>>>JAMA Report
Source:
Mar. 20 issue of JAMA (2018; 319).
Home-Based HIV Testing & Same-Day ART: In sub-Saharan Africa, offering home-based HIV testing and immediate initiation of antiretroviral therapy (ART) enhanced patient linkage to services at 3 months and produced higher viral suppression rates at 12 months, researchers report (pp. 1103–12). Conducted in northern Lesotho in 2016–17, the study compared usual care with clinic referral with same-day, home-based ART following home-based HIV testing, with these results: “Among 278 randomized individuals (median age, 39 years [interquartile range, 28.0–52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P < .001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P = .007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.” (N. D. Labhardt, n.labhardt@unibas.ch)
Editorialists write that this approach offers advantages in areas with continued high rates of HIV infections (
pp. 1094–5): “Household-based HIV testing [is] a pathway to identifying HIV-negative individuals at risk of HIV acquisition, and linking them to HIV prevention services such as voluntary medical male circumcision and pre-exposure prophylaxis while providing access to condoms and reproductive health services. Home-based testing should be part of a package of testing and outreach services to be determined based on the testing needs, preferences, and constraints of a given population. Large-scale studies are ongoing that aim to utilize such diverse strategies to enhance HIV prevention and treatment outcomes in communities. Although much has been achieved in confronting the HIV epidemic, more remains to be done to achieve global targets for treatment and prevention. Innovative, patient-centered, effective, and scalable innovations are needed to get to the finish line.” (I. T. Katz, ikatz2@bwh.harvard.edu)
USPSTF Statement on Skin Cancer Prevention: In an update to previous recommendations on behavioral counseling for the primary prevention of skin cancer and skin self-examination for prevention of skin cancer, the U.S. Preventive Services Task Force (USPSTF) emphasizes sun-protection behaviors in infants, children, and young adults through age 24 with fair skin types (pp. 1134–42). For older people, behavioral counseling interventions yielded “a small increase in sun protection behaviors,” and the task force said evidence was inadequate to recommend counseling all adults about prevention or about skin self-examination as a means of preventing skin cancer. (D. C. Grossman, chair@uspstf.net)
“Promoting skin cancer knowledge and awareness more broadly may have a greater effect,” writes a
JAMA Oncology editorialist (doi: 10.1001/jamaoncol.2018.0469). “Using a photograph of melanoma during skin examination was shown to be associated with thinner melanomas, and having an atypical-appearing melanoma, such as one that is predominately pink in color, is associated with having a thicker melanoma. Thus, better educating patients on what is concerning is likely an important component to improving early self-detection. Such educational initiatives are difficult to validate, but using newer technologies such as web and text-based interventions that have proven effective in promoting sun-protective behaviors could potentially be used to improve self-detection as well. An [insufficient evidence] statement is not a recommendation against, but rather a call for more research to better determine how to improve patient self-detection of early melanoma and its effect on outcomes.” (L. K. Ferris, ferrislk@upmc.edu)
>>>PNN NewsWatch
* FDA yesterday approved brentuximab vedotin (Adcetris, Seattle Genetics) to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. This is the fifth FDA-approved indication for this product.

PNN Pharmacotherapy Line
Mar. 22, 2018 * Vol. 25, No. 56
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>>>NEJM Report
Source:
Mar. 22 issue of the New England Journal of Medicine (2018; 378).
H. pylori Therapy for Prevention of Metachronous Gastric Cancer: Positive outcomes followed use of Helicobacter pylori eradication therapy in patients with early gastric cancer or high-grade adenoma, researchers report (pp. 1085–95). In 396 patients included in a modified intention-to-treat analysis, antibiotics or placebo produced these outcomes with respect to subsequent (metachronous) development of new gastric cancer at 1-year follow-up: “During a median follow-up of 5.9 years, metachronous gastric cancer developed in 14 patients (7.2%) in the treatment group and in 27 patients (13.4%) in the placebo group (hazard ratio in the treatment group, 0.50; 95% confidence interval, 0.26 to 0.94; P = 0.03). Among the 327 patients in the subgroup that underwent histologic analysis, improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% of the patients in the treatment group and in 15.0% of those in the placebo group (P <0.001). There were no serious adverse events; mild adverse events were more common in the treatment group (42.0% vs. 10.2%, P <0.001).” (I. J. Choi, cij1224@ncc.re.kr)
H. pylori eradication is still effective in patients with advanced preneoplastic lesions,” writes an editorialist (pp. 1154–6). “The intervention prevents later gastric cancer in only a subgroup of patients, so endoscopic or histologic surveillance remains mandatory. This requirement extends to all patients with severe atrophic gastritis with or without intestinal metaplasia even after successful eradication. Since the selection of eradication therapy is aimed at minimizing the development of antimicrobial resistance, bismuth-based regimens should be given preference.” (P. Malfertheiner)
Venetoclax–Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: In a phase III trial of patients with relapsed or refractory chronic lymphocytic leukemia, progression-free survival was significantly higher with venetoclax plus rituximab than with bendamustine plus rituximab (pp. 1107–20). The open-label study included 389 participants and reports these results: “After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax–rituximab group (32 events of progression or death in 194 patients) than in the bendamustine–rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P <0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax–rituximab group versus 27.8% in the bendamustine–rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax–rituximab group than in the bendamustine–rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax–rituximab group was 3.1% (6 of 194 patients).” (J. F. Seymour, john.seymour@petermac.org)
Genetic Variant and Protection from Chronic Liver Disease: A protein-truncating variant of an allele associated with serum hepatic enzymes appears to be protective against nonalcoholic steatohepatitis and fibrosis as well as progression to advanced liver disease, according to the DiscovEHR cohort study (pp. 1096–106). Identification of the loss-of-function variant in HSD17B13 could lead to identification of subpopulations who could benefit from agents that inhibit the production or action of the gene product coded by this allele. (F. E. Dewey, frederick.dewey@regeneron.com)

PNN Pharmacotherapy Line
Mar. 23, 2018 * Vol. 25, No. 57
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Highlights
Source:
Mar. Journal of the American Geriatrics Society (2018; 66).
Drug-Related Hospital Readmissions: Hospital readmissions caused by medications are common, especially in older adults, according to a systematic review of 19 published studies, researchers report (pp. 602–8). Concluding that further research into specific causes and possible interventions are needed, the authors report these findings: “Nine [studies] measured readmissions due to drug-related problems, seven due to adverse drug reactions, two due to adverse drug events, and one due to drug–drug interactions. Rates of readmissions due to drugs varied from 3% to 64% (median 21%, interquartile range (IQR) 14–23%). Readmissions were deemed preventable in 5% to 87% of cases (median 69%, IQR 19–84%). Evidence regarding the risk factors for drug-related readmissions and drugs causing these readmissions was inconsistent.” (F. Karapinar-Çarkıt, f.karapinar@olvg.nl)
Influenza Underdiagnosis in Hospitalized Older Adults: Among hospitalized patients with fever or respiratory symptoms, older individuals are less likely to have provider-ordered influenza tests, a study shows (pp. 467–72). A total of 1,422 participants at four Tennessee hospitals were examined, with these results for laboratory surveillance using reverse-transcriptase polymerase chain reaction (RT-PCR): “Twenty-eight percent (399/1,422) of participants had provider-ordered influenza testing. Participants who were tested were younger than those not tested (58 ± 18 vs 66 ± 15, p <.001) and more likely to have influenza-like illness (ILI) (71% vs 49%, p <.001). ILI decreased with increasing age (aged 18–49, 63%; aged 50–64, 60%; aged ≥65, 48%). ILI and younger age were independent predictors of provider-ordered testing. Of the 136 participants with influenza confirmed using RT-PCR, ILI was the only significant predictor of provider-ordered testing (adjusted odds ratio = 3.43, 95% confidence interval = 1.22–9.70).” (L. M. Hartman, lauren.hartman@vanderbilt.edu)
Academic Detailing & Prescribing Quality for Older Veterans: Prescribing of potentially inappropriate medications (PIMs) was reduced through academic detailing and tools provided to primary care providers (PCPs) and pharmacists at four rural outpatient clinics in Georgia (pp. 621–7). Audits and prescribing feedback were also a part of the intervention, which was based on the Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE) model and yielded these findings: “More than 7,000 older veterans were seen in more than 20,000 PCP encounters during the 14-month intervention period. Implementation of the IMPROVE intervention reduced PIM prescribing incidence from 9.6 new medications per 100 encounters during baseline to 8.7 after the intervention (P = .009). IMPROVE reduced PIM prevalence (proportion of encounters involving veterans who were taking at least 1 PIM) from 22.6% to 16.7% (P < .001). These approaches were effective in reducing PIMs prescribed to older veterans in a rural setting and constitute a feasible model for disseminating geriatric best practices to the primary care setting.” (A. Mirk, anna.mirk@va.gov)
Oral Health & Physical Frailty: Oral health problems increase older men’s risks of being frail and developing frailty, according to a cross-sectional and longitudinal study of 1,622 community-dwelling men (pp. 473–9). Data from the British Regional Health Study show these results based on objective assessments of tooth count and periodontal disease: “Three hundred three (19%) men were frail at baseline (aged 71–92). Having fewer than 21 teeth, complete tooth loss, fair to poor self-rated oral health, difficulty eating, dry mouth, and more oral health problems were associated with greater likelihood of being frail. Of 1,284 men followed for 3 years, 107 (10%) became frail. The risk of incident frailty was higher in participants who were edentulous (odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.03–3.52); had 3 or more dry mouth symptoms (OR = 2.03, 95% CI = 1.18–3.48); and had 1 (OR = 2.34, 95% CI = 1.18–4.64), 2 (OR = 2.30, 95% CI = 1.09–4.84), or 3 or more (OR = 2.72, 95% CI = 1.11–6.64) oral health problems after adjustment for age, smoking, social class, history of cardiovascular disease or diabetes mellitus, and medications related to dry mouth.” (S. E. Ramsay, sheena.ramsay@newcastle.ac.uk)

PNN Pharmacotherapy Line
Mar. 26, 2018 * Vol. 25, No. 58
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Mar. 24 issue of Lancet (2018; 391).
Sirolimus for SLE: In an open-label, phase 1/2 trial, sirolimus therapy is linked to “progressive improvement in disease activity … associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus,” researchers report (pp. 1186–96). The 12-month, single-arm trial started oral sirolimus at doses of 2 mg/d and titrated to serum sirolimus levels of 6–15 ng/mL, with these effects on the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): “Mean SLEDAI score decreased from 10.2 (SD 5.6) at enrolment to 4.8 (4.5) after 12 months of treatment (p <0.001) and the mean total BILAG index score decreased from 28.4 (12.4) at enrolment to 17.4 (10.7) after 12 months of treatment (p <0.001). The mean daily dose of prednisone required to control disease activity decreased from 23.7 mg (SD 9.6) to 7.2 mg (2.3; p <0.001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4−CD8− double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z = –2.50, p = 0.012), neutrophil counts (Z = –1.92, p = 0.054), and haemoglobin (Z = –2.83, p = 0.005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z = 2.06, p = 0.0400).” (A. Perl, perla@upstate.edu)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
DPP-4 Inhibitors & IBD: “The use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease” in a population-based study, investigators after following experiences of 141,170 patients at 700 general practices in the U.K. Clinical Practice Research Datalink (k872). In 2007–16, adjusted hazard ratios for incident inflammatory bowel disease associated with new use of the agents showed these patterns: “During 552,413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100,000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 v 34.5 per 100,000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses.” (L. Azoulay, laurent.azoulay@mcgill.ca)
>>>PNN NewsWatch
* FDA on Friday issued a draft guidance limiting the bulk drug substances that can be used in compounding by outsourcing facilities. The guidance interprets the “clinical need” provision of the Drug Quality and Security Act and outlines factors the agency proposes to evaluate bulk drug substances.
>>>PNN JournalWatch
* Lenvatinib Versus Sorafenib in First-Line Treatment of Patients With Unresectable Hepatocellular Carcinoma: A Randomised Phase 3 Non-inferiority Trial, Lancet, 2018; 391: 1163–73. (M. Kudo, m-kudo@med.kindai.ac.jp)
*
NGM282 for Treatment of Non-Alcoholic Steatohepatitis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial, Lancet, 2018; 391: 1174–85. (S. A Harrison, sharrison@pinnacleresearch.com)
*
Cardiovascular Complications in Pregnancy: It Is Time for Action, Circulation, 2018; 137: 1213–5. (C. R. Graves, cgraves@tnmfm.com)
*
Antibiotic-Resistant Infection Treatment Costs Have Doubled Since 2002, Now Exceeding $2 Billion Annually, Health Affairs, 2018: doi.org/10.1377/hlthaff.2017.1153. (K. E. Thorpe, kthorpe@emory.edu)
*
Explicit Disability Bias in Peer Review, Medical Care, 2018; 56: 277–8. (L. I. Iezzoni, liezzoni@mgh.harvard.edu)
*
Personal Bias in Scientific Review: We Can Do Better, Medical Care, 2018; 56: 279–80. (J. J. Allison, jeroan.allison@umassmed.edu)

PNN Pharmacotherapy Line
Mar. 27, 2018 * Vol. 25, No. 59
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
Apr. issue of Diabetes Care (2018; 41).
Insulin Resistance Markers & DPP-4 Inhibitor Responses: As a starting point to charting a path to “a precision diabetes approach to DPP-4 inhibitor therapy,” researchers report that “markers of higher insulin resistance are consistently associated with reduced glycemic response” to these drugs (pp. 705–12). The Predicting Response to Incretin Based Agents (PRIBA) study included 254 noninsulin-treated participants who were starting DPP-4 inhibitor therapy and looked at 6-month responses. Laboratory results on markers available in the Clinical Practice Research Datalink (CPRD) were used as comparators that considered baseline markers and 3-year durability of response: “In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [P = 0.03], HOMA2 insulin resistance [P = 0.01], and triglycerides [P < 0.01]) were associated with reduced 6-month HbA1c response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA1c response (both P < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m2) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA1c reduction 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and normal triglycerides]; P = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; P < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists.” (A. G. Jones, angus.jones@exeter.ac.uk)
Sulfonylureas & Risk of Serious Cardiovascular Events: Based on retrospective cohort analysis of 1999–2010 U.S. Medicaid claims from five large states, use of glyburide is associated with lower risks of sudden cardiac arrest and ventricular arrhythmia (SCA/VA) than treatment with glipizide (pp. 713–22). These findings are consistent with those of “a very small clinical trial suggesting that glyburide may reduce ventricular tachycardia and isolated ventricular premature complexes,” the authors write. “This potential benefit must be contextualized by considering putative effects of different sulfonylureas on other cardiovascular end points, cerebrovascular end points, all-cause death, and hypoglycemia.” The analysis used a validated ICD-9–based algorithm with a positive predictive value of ~85% to show the following: “Of sulfonylurea users under study (N = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person–years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude incidence rate of 3.6 per 1,000 person–years. Compared with glipizide, propensity score–adjusted hazard ratios for SCA/VA were 0.82 (95% CI 0.69–0.98) for glyburide and 1.10 (0.89–1.36) for glimepiride. Numerous secondary analyses showed a very similar effect estimate for glyburide; yet, not all CIs excluded the null.” (C. E. Leonard, celeonar@pennmedicine.upenn.edu)
Disease-Modifying Therapy in Type 1 Diabetes: “What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes?” ask authors of a Perspectives in Care article (pp. 653–61). “Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health–funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial–Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium’s plans for the future.” (C. J. Greenbaum, cjgreen@benaroyaresearch.org)

PNN Pharmacotherapy Line
Mar. 28, 2018 * Vol. 25, No. 60
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 27 issue of JAMA (2018; 319).
High-Dose Oral Ibuprofen for Preterm PDA: In a systematic review and network meta-analysis of 68 randomized trials with 4,802 infants, high doses of oral ibuprofen were associated with higher likelihood of hemodynamically significant patent ductus arteriosus (PDA) closure, a study shows, compared with placebo or intravenous ibuprofen or indomethacin (pp. 1221–38). Trials included preterm infants with a gestational age younger than 37 weeks. Results of the meta-analysis showed the following: “The overall PDA closure rate was 67.4% (2,867 of 4,256 infants). A high dose of oral ibuprofen was associated with significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64–8.17; absolute risk difference, 199 [95% CrI, 95–258] more per 1,000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08–5.31]; absolute risk difference, 124 [95% CrI, 14–188] more per 1,000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.” (S. Mitra, souvik.mitra@iwk.nshealth.ca)
County-Level Trends in Infectious Disease Mortality: Lower respiratory infections were the most common cause of death from infectious diseases in a county-level analysis of mortality rates from 1980 to 2014 (pp. 1248–60). Notable in the death records were large differences among counties, especially for lower respiratory infections and HIV/AIDS, and an increase in deaths from diarrheal infections in 2000–14: “Between 1980 and 2014, there were 4,081,546 deaths due to infectious diseases recorded in the United States. In 2014, a total of 113,650 (95% uncertainty interval [UI], 108,764–117,942) deaths or a rate of 34.10 (95% UI, 32.63–35.38) deaths per 100,000 persons were due to infectious diseases in the United States compared to a total of 72,220 (95% UI, 69,887–74,712) deaths or a rate of 41.95 (95% UI, 40.52–43.42) deaths per 100,000 persons in 1980, an overall decrease of 18.73% (95% UI, 14.95%–23.33%). Lower respiratory infections were the leading cause of infectious diseases mortality in 2014 accounting for 26.87 (95% UI, 25.79–28.05) deaths per 100,000 persons (78.80% of total infectious diseases deaths). There were substantial differences among counties in death rates from all infectious diseases. Lower respiratory infection had the largest absolute mortality inequality among counties (difference between the 10th and 90th percentile of the distribution, 24.5 deaths per 100,000 persons). However, HIV/AIDS had the highest relative mortality inequality between counties (10.0 as the ratio of mortality rate in the 90th and 10th percentile of the distribution). Mortality from meningitis and tuberculosis decreased over the study period in all U.S. counties. However, diarrheal diseases were the only cause of infectious diseases mortality to increase from 2000 to 2014, reaching a rate of 2.41 (95% UI, 0.86–2.67) deaths per 100,000 persons, with many counties of high mortality extending from Missouri to the northeastern region of the United States.” (C. J. L. Murray, cjlm@uw.edu)
“Despite the substantial progress in reducing infectious disease–related mortality, important challenges remain, including the increasing threat of antimicrobial resistance and the ongoing risk of new and emerging pathogens,” editorialists write (
pp. 1205–6; P. N. Malani, pmalani@umich.edu).
>>>PNN NewsWatch
* FDA yesterday permitted marketing of the Dexcom G6 integrated continuous glucose monitoring system for determining blood glucose levels in children aged 2 and older and adults with diabetes. The agency said this is the first type of continuous glucose monitoring system it has permitted to be used as part of an integrated system with other compatible medical devices and electronic interfaces, including automated insulin dosing systems, insulin pumps, blood glucose meters, or other electronic devices used for diabetes management.

PNN Pharmacotherapy Line
Mar. 29, 2018 * Vol. 25, No. 61
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Mar. 29 issue of the New England Journal of Medicine (2018; 378).
Adjuvant Chemotherapy for Stage III Colon Cancer: In six phase 3 trials of adjuvant therapy in patients with stage III colon cancer, overall results did not show noninferiority for shorter regimens of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin), the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration reports (pp. 1177–88). In lower-risk patients, CAPOX for 3 months was as effective as 6 months, the investigators conclude. Based on a primary end point of disease-free survival at 3 years, the 3- and 6-month regimens produced these results: “After 3,263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P = 0.01 for superiority).” (A. Grothey, grothey.axel@mayo.edu)
“To truly optimize the application of adjuvant chemotherapy, we need two things: better markers to assess the risk of recurrence and the likelihood of benefit and more effective, less toxic treatments,” editorialists conclude (
pp. 1242–4). “Until we see improvements in these two important areas, the findings of the IDEA collaboration provide useful information in helping oncologists discuss the duration of adjuvant therapy that best suits the goals, preferences, and tolerances of their patients.” (R. L. Schilsky)
Cardiovascular Safety of Gout Medications: While febuxostat and allopurinol had similar rates of adverse cardiovascular events in patients with concomitant gout and cardiovascular disease, the risks of all-cause mortality and cardiovascular mortality were slightly but significantly higher with febuxostat, researchers report (pp. 1200–10). A double-blind noninferiority trial produced these findings based on a primary composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization: “In total, 6,190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P = 0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis.” (W. B. White, wwhite@uchc.edu)
>>>PNN NewsWatch
* FDA said yesterday that a federal court has ordered Florida-based MyNicNaxs, LLC, and two company officers to stop selling drugs and dietary supplements until the company complies with the Federal Food, Drug, and Cosmetic Act and other requirements in a consent decree. MyNicNaxs distributed weight loss and sexual enhancement products, which the company marketed as dietary supplements, directly to consumers online. Some products tested positive for undeclared active pharmaceutical ingredients, FDA said.

PNN Pharmacotherapy Line
Mar. 30, 2018 * Vol. 25, No. 62
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Nephrology Report
Source:
Apr. issue of the American Journal of Kidney Diseases (2018; 71).
Health Insurance & Peritoneal Dialysis: Americans continue to encounter insurance-coverage problems during the initiation of peritoneal dialysis (PD), despite a Medicare policy of coverage of the intervention as patients develop end-stage renal disease (ESRD), researchers report (pp. 479–87). Retrospective analysis of patients in the U.S. Renal Data System for 2006–12 showed these results for those aged 60–64 years with “limited insurance” (Medicaid or no insurance) at ESRD onset and patients 66–70 years who were dually eligible for Medicare and Medicaid at ESRD onset: “After adjusting for observable patient and geographic differences, patients with limited insurance had an absolute 2.4% (95% CI, 1.1%–3.7%) lower probability of PD use by dialysis month 4 compared with patients with Medicare at ESRD onset. The association between insurance and PD use reversed when patients became Medicare eligible; patients with limited insurance had a 3-fold higher rate of switching to PD therapy between months 4 and 12 of dialysis (HR, 2.9; 95% CI, 1.8–4.6) compared with patients with Medicare at ESRD onset.” (K. F. Erickson, kevin.erickson@bcm.edu)
The above authors conclude that “educating providers about Medicare reimbursement policy and expanding access to pre-ESRD education and training may help overcome these barriers,” and an editorialist points to these additional options for improving provision of PD (
pp. 455–7): “As Perez et al acknowledge, they are unable to rule out the possibility of factors other than insurance delaying the start of PD therapy despite an analytic approach that attempts to compare like populations (eg, Medicaid or uninsured ages 60–64 vs dual-eligible ages 66–70 years). This is because, as Perez et al note, there may be unmeasured patient factors correlated with health insurance that predispose patients to a later PD therapy initiation. Such factors include lack of education, social support, patient activation, and knowledge about treatment options. In some cases, there may be a lack of nephrologist training or experience with PD that may make it difficult to share information about treatment options with patients in a timely manner.” (M. Turenne, marc.turenne@arborresearch.org)
>>>PNN NewsWatch
* FDA yesterday granted accelerated approval to blinatumomab (Blincyto, Amgen) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse. This product is the first-and-only approved bispecific CD19-directed CD3 T cell engager immunotherapy, Amgen noted in a news release, and it is now also the first-and-only therapy to be FDA-approved for MRD.
* Deaths of Americans from
overdoses of opioids, cocaine, and psychostimulants continued to climb in 2016, the CDC reported in an MMWR article released yesterday (pp. 349–58). Drug overdoses killed 63,632 Americans. Nearly two-thirds of these deaths (66%) involved a prescription or illicit opioid. Overdose deaths increased in all categories of drugs examined for men and women, people ages 15 and older, all races and ethnicities, and across all levels of urbanization. CDC said that its new analysis confirms that recent increases in drug overdose deaths are driven by continued sharp increases in deaths involving synthetic opioids other than methadone, such as illicitly manufactured fentanyl (IMF). IMF is mixed into counterfeit opioid and benzodiazepine pills, heroin, and cocaine, likely contributing to increases in overdoses involving these other substances. Data from 31 states and the District of Columbia showed that across demographic categories, the largest increase in opioid overdose death rates was in men aged 25–44. Death rates from overdoses involving synthetic opioids increased in 21 states, with 10 states doubling their rates from 2015 to 2016. New Hampshire, West Virginia, and Massachusetts had the highest death rates from synthetic opioids. Eight states had significant increases in death rates involving prescription opioids. West Virginia, Maryland, Maine, and Utah had the highest rates.


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