Dec 2018

PNN October–December 2018

PNN Pharmacotherapy Line
Oct. 1, 2018 * Vol. 25, No. 189
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Sept. 29 issue of Lancet (2018; 392).
Long-Term Outcomes With BP/Lipid Therapy in Hypertension: After 16 years of follow-up in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study, researchers report “long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin” among patients initially diagnosed with hypertension and total cholesterol levels below 6.5 mmol/L (250.97 mg/dL) (pp. 1127–37). “Patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure,” the authors conclude. “Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes.” (P. Sever, p.sever@imperial.ac.uk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Hormonal Contraception & Ovarian Cancer: Use of contemporary combined hormonal contraception — but not progestin-only products — may have prevented 21% of cases of ovarian cancer among younger women over a 20-year period, a study estimates (k3609). A cohort analysis of nationwide data from Denmark shows these patterns of contraception use and ovarian cancer for women aged 15–49 years in 1995–2014: “During 21.4 million person years, 1,249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13,344,531 person years. Never users had 771 ovarian cancers during 8,150,250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (relative risk 0.58 (95% confidence interval 0.49 to 0.68) and 0.77 (0.66 to 0.91), respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82 (0.59 to 1.12) with ≤1 year use to 0.26 (0.16 to 0.43) with >10 years’ use; P <0.001 for trend). Similar results were achieved among women followed up to their first switch in contraceptive type. Little evidence of major differences in risk estimates by tumour type or progestogen content of combined oral contraceptives was seen. Use of progestogen-only products were not associated with ovarian cancer risk. Among ever users of hormonal contraception, the reduction in the age standardised absolute rate of ovarian cancer was 3.2 per 100,000 person years. Based on the relative risk for the never use versus ever use categories of hormonal contraception (0.66), the population prevented fraction was estimated to be 21%—that is, use of hormonal contraception prevented 21% of ovarian cancers in the study population.” (L. Iversen, l.iversen@abdn.ac.uk)
>>>PNN NewsWatch
FDA on Friday approved cemiplimab-rwlc (Libtayo, Regeneron Pharmaceuticals) injection for treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Approval of this intravenous agent is the first of a drug specifically for advanced CSCC.
Amikacin liposome inhalation suspension (Arikayce, Insmed) was approved by FDA on Friday for treatment of refractory pulmonary infections of Mycobacterium avium complex.
* Two lots of Endo’s 
Robaxin (methocarbamol tablets, USP) 750 mg tablets in 100-count bottle packs are being recalled to the consumer level because of incorrect daily dosing information on the label.
>>>PNN JournalWatch
Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation, in Annals of Internal Medicine, 2018; 10.7326/M17-2762. (S. J. Shah, sachin.shah@ucsf.edu)
CKD and Sedentary Time: Results From the Canadian Health Measures Survey, in American Journal of Kidney Diseases, 2018; 72: 529–37. (C. Bohm, cbohm@hsc.mb.ca)
Social Determinants of Health: Addressing Unmet Needs in Nephrology, in American Journal of Kidney Diseases, 2018; 72: 582–91. (Y. N. Hall, ynhall@kri.washington.edu)
Alcohol Use in Patients with Chronic Liver Disease, in New England Journal of Medicine, 2018; 379: 1251–61. (J. H. Samet, jsamet@bu.edu)

PNN Pharmacotherapy Line
Oct. 2, 2018 * Vol. 25, No. 190
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online article from and Oct. 2 issue of Annals of Internal Medicine (2018; 169).
Cost Drivers Among Dual Eligibles: The high cost of care of dual-eligible Medicare and Medicaid beneficiaries comes primarily from long-term care and not preventable hospitalizations and other ambulatory care–sensitive conditions, according to results of an observational study (10.7326/M18-0085). Medicare–Medicaid Linked Enrollee Analytic Data Source data for 2008 to 2010 show these patterns among 1.9 million dual-eligible beneficiaries who were alive all 3 years: “In the first year, 192,835 patients were high-cost. More than half (54.8%) remained high-cost across all 3 years. These patients were younger than transiently high-cost patients, with fewer medical comorbidities and greater intellectual impairment. Persistently high-cost patients spent $161,224 per year compared with $86,333 per year for transiently high-cost patients and $22,352 per year for non–high-cost patients. Most of the spending among persistently high-cost patients (68.8%) was related to long-term care, and very little (<1%) was related to potentially preventable hospitalizations for ambulatory care–sensitive conditions.” (A. K. Jha, ajha@hsph.harvard.edu)
Chronic Pain Among Suicide Decedents: Chronic pain may be an important contributor to suicide, authors of a retrospective analysis conclude based on data from 18 states participating in the National Violent Death Reporting System (NVDRS) in the U.S. (pp. 448–55). “Access to quality, comprehensive pain care and adherence to clinical guidelines may help improve pain management and patient safety,” the investigators conclude based on these data from 2003 through 2014: “Of 123,181 suicide decedents included in the study, 10,789 (8.8%) had evidence of chronic pain, and the percentage increased from 7.4% in 2003 to 10.2% in 2014. More than half (53.6%) of suicide decedents with chronic pain died of firearm-related injuries and 16.2% by opioid overdose.” (E. Petrosky, xfq7@cdc.gov)
E-Cigarette Use Among U.S. Adults: A 2016 survey shows that 4.5% of adults in the U.S. were using e-cigarettes, with higher numbers in some states and among younger adults, LGBT persons, current cigarette smokers, and persons with comorbid conditions (pp. 429–38). Data from the Behavioral Risk Factor Surveillance System show that 10.8 million adults used e-cigarettes during that year: “The prevalence of current e-cigarette use was highest among persons aged 18 to 24 years (9.2% [95% CI, 8.6% to 9.8%]), translating to approximately 2.8 million users in this age range. More than half the current e-cigarette users (51.2%) were younger than 35 years. In addition, the age-standardized prevalence of e-cigarette use was high among men; lesbian, gay, bisexual, and transgender (LGBT) persons; current combustible cigarette smokers; and those with chronic health conditions. The prevalence of e-cigarette use varied widely among states, with estimates ranging from 3.1% (CI, 2.3% to 4.1%) in South Dakota to 7.0% (CI, 6.0% to 8.2%) in Oklahoma.” (M. J. Blaha, mblaha1@jhmi.edu)
Effectiveness of Fecal Immunochemical Test Screening Programs: Comparing detection rates for proximal versus distal colorectal neoplasia with the fecal immunochemical test (FIT), researchers report that a “multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round” (10.7326/M18-0855). The retrospective study of a screening program in the Venato region of Italy produced these results for 123,347 people with 441,647 FITs: “Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1,000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed.” (M. Zorzi, manuel.zorzi@azero.veneto.it)
>>>PNN NewsWatch
* October is American Pharmacists Month! Resources and ideas for celebrating are available online from APhA.

PNN Pharmacotherapy Line
Oct. 3, 2018 * Vol. 25, No. 191
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Oct. 2 issue of JAMA (2018; 320).
Diagnosis and Management of Rheumatoid Arthritis: “Scientific advances have improved therapies that prevent progression of irreversible joint damage in up to 90% of patients with [rheumatoid arthritis (RA)],” conclude authors of a review article that summarizes recent studies of HLA-DRB1 haplotypes in RA and use of non-TNF and anti-TNF treatments (pp. 1360–72). “The development of novel instruments to measure disease activity and identify the presence or absence of remission have facilitated new treatment strategies to arrest RA before joints are damaged irreversibly. Outcomes have been improved by recognizing the benefits of early diagnosis and early therapy with disease-modifying antirheumatic drugs (DMARDs). The treatment target is remission or a state of at least low disease activity, which should be attained within 6 months. Methotrexate is first-line therapy and should be prescribed at an optimal dose of 25 mg weekly and in combination with glucocorticoids; 40% to 50% of patients reach remission or at least low disease activity with this regimen. If this treatment fails, sequential application of targeted therapies, such as biologic agents (eg, [TNF] inhibitors) or Janus kinase inhibitors in combination with methotrexate, have allowed up to 75% of these patients to reach the treatment target over time. New therapies have been developed in response to new pathogenetic findings. The costs of some therapies are considerable, but these costs are decreasing with the advent of biosimilar drugs (drugs essentially identical to the original biologic drugs but usually available at lower cost).” (D. Aletaha, daniel.aletaha@meduniwien.ac.at)
“Although [such] findings … may not have immediate clinical implications, identification of the precise HLA variants that influence disease course is of great interest,” editorialists write (pp. 1623–4). “These observations open the door to further research, including replication for this haplotype and discovery related to its combination with other determinants of disease development and progression. Such discoveries will prove helpful both to understand and predict the variable disease course and response to therapy that occurs in patients with rheumatoid arthritis.” (D. T. Felson, 
dfelson@bu.edu)
Aging, Cell Senescence, Disease & the Healthspan: Use of medications for altering the aging process is reviewed in the first of three related Viewpoint articles (pp. 1319–20): “If senolytic drugs are effective across a range of disorders, provided they are safe, clinical trials of senolytics might move toward studies in presymptomatic individuals to delay or prevent age-related conditions.” (J. L. Kirkland, kirkland.james@mayo.edu)
“One major challenge for improving human health by treating aging processes is that from a regulatory perspective (eg, the US Food and Drug Administration) there is no indication that is similar to targeting aging,” authors write (
pp. 1321–2). “Even if safe and effective drugs are available, health care payers will be reluctant to pay for such treatment without regulatory approval. Consequently, for now, drug companies are reluctant to invest in treatments targeting aging.” (N. Barzilai, nir.barzilai@einstein.yu.edu)
“The longer people live, the more important aging biology becomes as a primary risk factor in determining both length and quality of life,” Viewpoint authors write in discussing the lifespan versus the healthspan (
pp. 1323–4). “In long-lived populations, a substantial part of life, and certainly most deaths, now occur in a period in the life-span when the risk for frailty and disability increases exponentially. In this period, which could be called the red zone, it becomes increasingly more difficult to intervene using conventional disease-oriented approaches; the further into this period that humans venture, the more resistant diseases become.” (S. J. Olshansky, sjayo@uic.edu)
>>>PNN NewsWatch
* FDA yesterday issued a revised draft guidance on use of 505(q) petitions, which can be misused by companies to block or delay marketing of generic drugs. “We know there’s no easy or single solution to the challenges posed by high drug development costs and the high prices,” Commissioner Scott Gottlieb, MD, writes. But “we can make additional, new headway in helping to promote competition, reduce prices, and enable more patients to have access to medicines.”

PNN Pharmacotherapy Line
Oct. 4, 2018 * Vol. 25, No. 192
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Oct. 4 New England Journal of Medicine (2018; 379).
Rivaroxaban in Heart Failure & Coronary Disease: In the COMMANDER-HF trial, rivaroxaban did not improve outcomes in 5,022 patients with chronic heart failure, left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation (pp. 1332–42). The study concept was based on activation of thrombin-related pathways in heart failure, the researchers report, noting that “treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.” Compared with placebo in patients who also received standard care after treatment of episodes of worsening heart failure, the study showed: “Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2,507 patients assigned to rivaroxaban and in 658 (26.2%) of 2,515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P = 0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P = 0.48).” (F. Zannad, f.zannad@chru-nancy.fr)
“Clinical trials in heart failure must strive for a better match of the patient to the therapy,” editorialists write (
pp. 1372–4). “Future trials testing this ‘precision’ approach will require greater specificity of phenotyping, genotyping, or both, with more screening hurdles for the trialists and a smaller target population for the sponsors. In the meantime, the results of COMMANDER HF support the position that oral anticoagulation is not indicated for patients with heart failure and reduced ejection fraction in the absence of atrial fibrillation.” (M. A. Pfeffer)
Tyrosine Kinase 2 Inhibition in Psoriasis: A phase 2 trial of the oral agent BMS-986165 demonstrates greater clearing of psoriasis over a 12-week period with 3 mg or higher doses of the tyrosine kinase 2 inhibitor, compared with placebo (pp. 1313–21). Study participants were adults with moderate-to-severe psoriasis; exclusion criteria included lack of prior response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Based on a primary end point of 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12, results were as follows: “A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P <0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P <0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P <0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P <0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment.” (K. Papp, kapapp@probitymedical.com)
Next-Generation Sequencing for Genetic Testing: “Genomic data are a potential component of precision medicine, and exome and genome sequences have been described as a lifelong clinical resource,” write authors of a review of genetic testing with next-generation sequencing (pp. 1353–62). “These data can potentially produce refinement of risk estimates for common diseases, pharmacogenomic data, and diagnoses for late-onset disorders. Exome-sequencing studies detect one to seven carrier variants on average, and one trial showed that 2% of studies produce potentially actionable pathogenic or likely pathogenic variants in at least one [gene]. Approximately 130 pharmacogenomic biomarkers are included in current drug labeling, but the literature regarding the usefulness of pharmacogenomic data for individual variants has been mixed. Most persons have one or more such variants…. However, studies of genotype-guided warfarin dosing — arguably one of the best-known pharmacogenomic examples — have not yielded clear guidance.” (D. R. Adams, david.adams@nih.gov)

PNN Pharmacotherapy Line
Oct. 5, 2018 * Vol. 25, No. 193
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
 Oct. issue of the American Journal of Psychiatry (2018; 175).
Medications for Alcohol and Opioid Use Disorders: Suicidality and crime were reduced during pharmacotherapy of patients with alcohol and opioid use disorders, researchers report (pp. 970–8). Among a population cohort of 21,281 individuals with records in Swedish registries, rates of suicidal behaviors, accidental overdoses, and crime were compared during periods of medication treatment and no treatment, with these results: “No significant associations with any of the primary outcomes were found for acamprosate. For naltrexone, there was a reduction in the hazard ratio for accidental overdoses during periods when individuals received treatment compared with periods when they did not (hazard ratio = 0.82, 95% CI = 0.70, 0.96). Buprenorphine was associated with reduced arrest rates for all crime categories (i.e., violent, nonviolent, and substance-related) as well as reduction in accidental overdoses (hazard ratio = 0.75, 95% CI = 0.60, 0.93). For methadone, there were significant reductions in the rate of suicidal behaviors (hazard ratio = 0.60, 95% CI = 0.40–0.88) as well as reductions in all crime categories. However, there was an increased risk for accidental overdoses among individuals taking methadone (hazard ratio = 1.25, 95% CI = 1.13, 1.38).” (Y. Molero)
Molecular Genetics & New Strategies for Opioid Addiction: Molecular-based genetics could provide direction for new medication strategies for management of opioid addiction, write authors of a review article (pp. 935–42): “The opioid epidemic is at the epicenter of the drug crisis, resulting in an inconceivable number of overdose deaths and exorbitant associated medical costs that have crippled many communities across the socioeconomic spectrum in the United States. Classic medications for the treatment of opioid use disorder predominantly target the opioid system and thus have been underutilized, in part due to their own potential for abuse and heavy regulatory burden for patients and clinicians. Opioid antagonists are now evolving in their use, not only to prevent acute overdoses but as extended-use treatment options. Strategies that target specific genetic and epigenetic factors, along with novel nonopioid medications, hold promise as future therapeutic interventions for opioid abuse. Success in increasing the treatment options in the clinical toolbox will, hopefully, help to end the historical pattern of recurring opioid epidemics.” (Y. L. Hurd)
>>>Pediatrics Highlights
Source:
 Oct. issue of Pediatrics (2018; 142).
Alcohol Use & Interactions Among Medically Vulnerable Youth: Many youth with chronic medical conditions use alcohol at rates similar to other young people, a study shows, making it important to counsel them on the risks of alcohol in general and its interactions with other medications (10.1542/peds.2017-4026). An electronic survey of adolescents with type 1 diabetes, juvenile idiopathic arthritis, moderate persistent asthma, cystic fibrosis, attention-deficit/hyperactivity disorder, or inflammatory bowel disease showed the following: “Of 396 youth, 86.4% were on [alcohol-interactive (AI)] medications, of whom, 35.4% reported past-year alcohol use (46.3% among those who were not on AI medications). AI medication use was associated with 43% lower odds of past-year alcohol use (adjusted odds ratio: 0.57; 95% confidence interval: 0.39–0.85) and lower total consumption (beta = −.43; SE = 0.11; P < .001). Perceptions of alcohol-medication interference partially mediated the relationship between AI medication exposure and past-year alcohol use (Sobel test P = .05).” (E. R. Weitzman)
>>>PNN NewsWatch
* In New York City in 2010–16, congenital syphilis occurred mostly in babies of women whose infections were detected too late during pregnancy, a study in this week’s Morbidity and Mortality Weekly Report shows (2018; 67: 1088–93). “Provider and public health systems play a critical role in preventing congenital syphilis through screening and treating pregnant women for syphilis; these systems need to be maintained and strengthened,” the authors write.
Silver Star Brands is voluntarily recalling four Native Remedies, two Healthful Naturals, and two PetAlive products.
PNN will not be published on Mon., Oct. 8, Columbus Day.

PNN Pharmacotherapy Line
Oct. 9, 2018 * Vol. 25, No. 194
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 JAMA Internal Medicine (2018; 178). 
Drug Safety in Real-World Studies: Articles examine safety indicators of NSAIDs and allopurinol in large-scale studies of real-world data. 
Among 814,049 older adults with 2.4 million primary care visits for musculoskeletal conditions, NSAID use was frequent among those at high risk for chronic kidney disease (CKD) but not linked to adverse, short-term outcomes, researchers report (
10.1001/jamainternmed.2018.4273). Administrative claims databases in Ontario yielded these insights into prescription NSAID dispensing within 7 days of a primary care visit: “The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%–16.7%) among 7,365 primary care physicians. Within a sample of 35,552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, −0.001 to 0.002; P = .74).” (R. S. Bhatia, sacha.bhatia@wchospital.ca)
Similarly, concerns about drug-associated renal function decline in patients taking allopurinol for gout may be unfounded, an analysis shows (
10.1001/jamainternmed.2018.4463). In a large cohort of patients newly diagnosed with gout who had records in a U.K. general practitioner database, “allopurinol initiation of at least 300 mg/d was associated with a lower risk of renal function deterioration,” the authors write. “Because allopurinol does not appear to be associated with renal function decline, clinicians should consider evaluating other potential causes when patients with gout experience renal function decline.” (T. Neogi, tneogi@bu.edu)
“The bigger issue is how these studies should influence practice, if at all,” editorialists write (
10.1001/jamainternmed.2018.5766). “Clinicians already recognize that many patients with heart failure, kidney disease, or hypertension tolerate a short course of NSAIDs without obvious harm, and that in many patients with gout, higher doses of allopurinol can be prescribed without concerns about progression of CKD. On balance, these studies help soften our stance on the use of NSAIDs and allopurinol in patients with relative contraindications.
“Done well, observational studies can provide valuable information about the real-world safety of drugs. Moving forward, detailed real-world data will be increasingly available in electronic health records and registries. In response to initiatives such as the 21st Century Cures Act, the National Evaluation System for Health Technology, and the US Food and Drug Administration’s Sentinel Initiative, we can expect to see more observational studies testing longstanding assumptions about treatments, along with new uses for old therapies. Yes, the findings will need to be contextualized and viewed with more skepticism than [randomized controlled trials], but in some instances, they can be thoughtfully integrated into our treatment decisions.” (D. N. Juurlink, 
dnj@ices.on.ca)
>>>PNN NewsWatch
* Two FDA decisions announced on Friday have implications for vaccine-administering pharmacists and those in community settings. Gardasil 9 (Human Papillomavirus (HPV) 9-valent Vaccine, Recombinant) is now licensed for use in women and men aged 27 through 45 years, and the Bose Hearing Aid will be available for self-use in adults with perceived mild-to-moderate hearing impairment.
>>>PNN JournalWatch
Amoxicillin–Clavulanate Versus Azithromycin for Respiratory Exacerbations in Children with Bronchiectasis (BEST-2): A Multicentre, Double-Blind, Non-Inferiority, Randomised Controlled Trial, in Lancet, 2018; 392: 1197–206. (V. Goyal, drvikasgoyal@gmail.com)
Long Term Adjuvant Endocrine Therapy and Risk of Cardiovascular Disease in Female Breast Cancer Survivors: Systematic Review, in BMJ, 2018; 363: k3845. (A. Matthews, anthony.matthews@lshtm.ac.uk)
Discoveries on the Genetics of ADHD in the 21st Century: New Findings and Their Implications, in the American Journal of Psychiatry, 2018; 175: 943–50. (A. Thapar)

PNN Pharmacotherapy Line
Oct. 10, 2018 * Vol. 25, No. 195
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Oct. 9 issue of JAMA (2018; 320).
Targeted Polymyxin B Hemoperfusion in Septic Shock: In the EUPHRATES trial, patients with septic shock and high endotoxin activity had similar mortality outcomes after randomization to polymyxin B therapy or sham treatments, researchers report (pp. 1455–63). A total of 450 adult critically ill patients participated in the study at 55 North American tertiary hospitals; all had septic shock and an endotoxin activity assay level of 0.60 or higher when they were enrolled in 2010–16. Standard therapy plus two polymyxin B hemoperfusion treatments or sham therapy completed within the first 24 hours of enrollment produced these results: “Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0–71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a [multiple organ dysfunction score] of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, −10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).” (R. P. Dellinger, dellinger-phil@cooperhealth.edu)
Antibiotics for Sepsis: Responding to recommendations made previously as part of the Surviving Sepsis Campaign, authors write, “The time has come to balance the recommendation for early and aggressive antibiotics for all patients with possible sepsis with the diagnostic uncertainty regarding sepsis and the possible harm associated with unnecessary antibiotics” (pp. 1433–4). “The Surviving Sepsis Campaign and similar quality improvement initiatives have helped improve quality of care by focusing much-needed attention on sepsis and emphasizing the importance of early diagnosis and optimal management. The good that these initiatives have done could be further enhanced by encouraging and permitting clinicians to gather more data to confirm infection in patients without shock before prescribing antibiotics when the evidence for infection is equivocal.” (M. Klompas, mklompas@bwh.harvard.edu)
Chronic Wound Management: “Effective care for chronic wounds requires a multimodal approach, including wound bed optimization, management of chronic medical conditions, and consistent follow-up,” conclude authors of an update article that includes an analysis of wound bed preparation and adjunctive therapies such as antimicrobial dressings and bariatric therapy (pp. 1481–2). “Advanced wound therapies, such as [negative-pressure wound therapy (NPWT)], can benefit some patients, but evidence to support the use of one specific advanced dressing type over another is limited. Cost-effectiveness is a key consideration given the expense of many advanced dressings. However, some of these products decrease dressing change frequency and may improve healing, which can lead to overall cost reductions. Dressing selection can generally be based on wound assessment, physician and patient familiarity with the products, availability, and affordability.” (M. T. Longaker, longaker@stanford.edu)
>>>PNN NewsWatch
* FDA yesterday released revised draft “guidance documents that will advance the development of generic transdermal and topical delivery systems (TDS),” FDA Commissioner Scott Gottlieb, MD, wrote on the agency website. “Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs” provides updated advice for the design and conduct of studies evaluating the adhesive performance of a proposed generic TDS. “Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs” provides recommendations for the design and conduct of studies to evaluate the in vivo skin irritation and sensitization potential of a proposed generic TDS.

PNN Pharmacotherapy Line
Oct. 11, 2018 * Vol. 25, No. 196
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Oct. 11 New England Journal of Medicine (2018; 379).
DNA Sequencing to Determine TB Drug Susceptibility: Testing the feasibility of predicting susceptibility of Mycobacterium tuberculosis isolates to first-line drugs using DNA sequencing, investigators find that genotypic results correlate well with phenotypic sensitivities (pp. 1403–15). Whole-genome sequences and associated phenotypes of resistance or susceptibility to isoniazid, rifampin, ethambutol, and pyrazinamide showed these associations for 10,209 isolates from 16 countries on six continents: “The largest proportion of phenotypes was predicted for rifampin (9,660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8,794 [89.8%] of 9,794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7,516 isolates with complete phenotypic drug-susceptibility profiles, 5,865 (78.0%) had complete genotypic predictions, among which 5,250 profiles (89.5%) were correctly predicted. Among the 4,037 phenotypic profiles that were predicted to be pansusceptible, 3,952 (97.9%) were correctly predicted.” (T. Walker, timothy.walker@ndm.ox.ac.uk)
Using this approach to bring individualized therapy “to patients in high-burden, resource-limited settings will be challenging, to say the least,” editorialists write (
pp. 1474–5). “Globally, only 22% of the 6.3 million people with newly diagnosed tuberculosis in 2016 had access to rifampin drug-susceptibility testing. However, previous programmatic failures, while underscoring the challenges, should not preclude us from aiming to provide the same standard of care for all patients with tuberculosis regardless of where they reside. Our goals should include the provision of universal drug-susceptibility testing as a key requirement for meeting the WHO End TB targets. At the time of the first-ever United Nations General Assembly High-Level Meeting on the Fight to End Tuberculosis, there is hope that renewed political will for mobilizing the resources needed to capitalize on advances such as that reported [in this study] will be brought to bear on this formidable global health challenge.” (H. Cox)
Personalized Prognosis in Myeloproliferative Neoplasms: Genomic classification of myeloproliferative neoplasms — including polycythemia vera, essential thrombocythemia, and myelofibrosis— could enable “personalized predictions of patients’ outcomes and … treatment,” conclude authors of a study of 69 myeloid cancer genes (pp. 1416–30). Genomic classification of myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients showed these results: “A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy.” (A. R. Green, arg1000@cam.ac.uk)
>>>PNN NewsWatch
Pregnant women who received influenza vaccinations were 40% less likely to be hospitalized for laboratory-confirmed influenza, according to a large CDC-coauthored study released today by Clinical Infectious Diseases. Data for more than 2 million pregnant women from four countries showed that 80% of pregnancies overlapped with the influenza season and the vaccine was equally protective across comorbidities and all trimesters.

PNN Pharmacotherapy Line
Oct. 12, 2018 * Vol. 25, No. 197
Providing news and information about medications and their proper use

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>>>Circulation Highlights
Source:
 Oct. 9 issue of Circulation (2018; 138).
Sacubitril/Valsartan v. Irbesartan in Chronic Kidney Disease: In the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial, 12 months of sacubitril/valsartan showed similar effects on kidney function and albuminuria as irbesartan but with additional beneficial effects on blood pressure and cardiac biomarkers in 414 people with chronic kidney disease (pp. 1505–14). Participants had glomerular filtration rates (GFRs) of 20–60 mL/min/1.73 sq m at study entry. Sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily had these effects on GFR: “At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 sq m among those assigned irbesartan; difference, –0.1 (0.7) mL/min/1.73 sq m. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, –9%; 95% CI, –18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4–7.4) and 2.1 (95% CI, 1.0–3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8–23) and 18% (95% CI, 11–25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75–1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96–1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P = 0.10) was not significantly different between randomized groups.” (R. Haynes, harp3@ndph.ox.ac.uk)
“For the majority of patients with CKD who do not have reduced ejection fraction and yet remain at high cardiovascular risk, a larger clinical trial designed to examine the effect of sacubitril/valsartan on clinical end points of cardiovascular mortality and events will be required to determine whether this therapy is effective for reducing cardiovascular risk and improving patient outcomes in the broader CKD population,” editorialists write (
pp. 1515–8). “When one considers that the price of sacubitril/valsartan is >15-fold higher than generic valsartan, understanding whether this new therapy is effective and offers value for money (ie, that higher medication costs are offset by reductions in the cost of hospitalizations for heart disease) in the current setting of constrained healthcare resources seems particularly important.” (B. Manns, Braden.Manns@albertahealthservices.ca)
Apixaban Use in End-Stage Kidney Disease & Atrial Fibrillation: Effectiveness and safety measures were better with apixaban than warfarin in 25,523 Medicare beneficiaries with end-stage kidney disease and atrial fibrillation (AF) who received one of the drugs in 2010–15 (pp. 1519–29). In the dataset, too few patients received dabigatran or rivaroxaban for inclusion of those drugs in the analysis. Based outcomes of survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death, results for apixaban or warfarin were as follows among this older population: “An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P = 0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P <0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n = 1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n = 1317; HR, 0.61; 95% CI, 0.37–0.98; P = 0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45–0.92; P = 0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42–0.97; P = 0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46–0.85; P = 0.003 for death).” (K. C. Siontis, siontis.konstantinos@mayo.edu)
If these results are confirmed, “standard dose apixaban will be the preferred anticoagulant for stroke prevention in AF among patients dependent on dialysis,” an editorialist concludes (
pp. 1534–6; E. M. Hylek, ehylek@bu.edu).

PNN Pharmacotherapy Line
Oct. 15, 2018 * Vol. 25, No. 198
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Oct. 13 issue of Lancet (2018; 392).
Predictive Value of Baseline/On-Statin Lipoprotein(a) Levels: Support for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials comes from a meta-analysis of individual-patient data from seven statin studies of 26,069 people (pp. 1311–20). Hazard ratios (HRs) for cardiovascular events within each trial were estimated using predefined lipoprotein(a) levels in four ranges, as follows: “Initiation of statin therapy reduced LDL cholesterol (mean change −39% [95% CI −43 to −35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex ( vs <15 mg/dL) were 1.04 (95% CI 0.91–1.18) for 15 mg/dL to less than 30 mg/dL, 1.11 (1.00–1.22) for 30 mg/dL to less than 50 mg/dL, and 1.31 (1.08–1.58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0.94 (0.81–1.10), 1.06 (0.94–1.21), and 1.43 (1.15–1.76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p = 0.010) and was more pronounced at younger ages (interaction p = 0.008) without effect-modification by any other patient-level or study-level characteristics.” (P. Willeit, peter.willeit@i-med.ac.at)
Ustekinumab in SLE: The interleukin (IL)-12 and IL-23–targeting monoclonal antibody ustekinumab was effective and safe in a phase 2, placebo-controlled trial of 102 patients with systemic lupus erythematosus, researchers report (pp. 1330–9): “The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus.” (R. F. van Vollenhoven, r.vanvollenhoven@vumc.nl)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Standing More at Work: In the multicomponent intervention Stand More AT (SMArT) Work trial, provision of a height-adjustable work station with educational and motivational sessions reduced sitting times of desk-based workers in the U.K. National Health Service trust over 3, 6, and 12 months (k3870). A primary outcome of occupational sitting time measured with a thigh-worn accelerometer showed the following: “A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (−83.28 min/workday, 95% confidence interval −116.57 to −49.98, P = 0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (−50.62 min/workday, −78.71 to −22.54, P <0.001) and six months (−64.40 min/workday, −97.31 to −31.50, P <0.001) and daily sitting time at six months (−59.32 min/day, −88.40 to −30.25, P <0.001) and 12 months (−82.39 min/day, −114.54 to −50.26, P = 0.001).” (C. L. Edwardson, ce95@le.ac.uk)
>>>PNN JournalWatch
Evaluation of the Diet Wide Contribution to Serum Urate Levels: Meta-Analysis of Population Based Cohorts, in BMJ, 2018; 363: k3951. (T. R. Merriman, tony.merriman@otago.ac.nz)
Classification, Ontology, and Precision Medicine, in New England Journal of Medicine, 2018; 379: 1452–62. (P. N. Robinson, peter.robinson@jax.org)
Provider Specialty, Anticoagulation, and Stroke Risk in Patients With Atrial Fibrillation and Cancer, in the Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.07.077. (W. T. O’Neal)
Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention, in the Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.07.079. (M. Inouye)
P2Y12-ADP Receptor Blockade in Chronic Kidney Disease Patients With Acute Coronary Syndromes: Review of the Current Evidence, in Circulation, 2018; 138: 1582–96. (L. Bonello, laurent.bonello@ap-hm.fr)

PNN Pharmacotherapy Line
Oct. 16, 2018 * Vol. 25, No. 199
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Oct. 16 issue of Annals of Internal Medicine (2018; 169).
Beta-Blockers During Pregnancy: Beyond known effects of underlying chronic hypertension and associated conditions, use of beta-blockers during the first trimester of pregnancy “is not associated with a large increase in the risk for overall malformations or cardiac malformations,” conclude authors who analyzed health registries of five Nordic countries and the U.S. Medicaid database (10.7326/M18-0338). “Of 3,577 women with hypertensive pregnancies in the Nordic cohort and 14,900 in the U.S. cohort, 682 (19.1%) and 1,668 (11.2%), respectively, were exposed to beta-blockers in the first trimester,” the investigators report. “The pooled adjusted relative risk (RR) and risk difference per 1,000 persons exposed (RD1000) associated with beta-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, −6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, −4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, −0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, −2.0 to 4.0) (based on U.S. cohort data only).” (B. T. Bateman, bbateman@bwh.harvard.edu)
“There is little reason to believe that daily use of an oral beta-antagonist in the first trimester of pregnancy heightens risk for congenital malformations,” writes an editorialist (
10.7326/M18-2500). “There is reason, however, why the fetus of a woman prescribed this class of medication might be at higher risk for a structural birth defect: Women with chronic hypertension are more likely than women without hypertension to have higher body mass index, older age, and prepregnancy diabetes mellitus, factors which are themselves risk factors for birth defects. In fact, chronic hypertension itself, whether treated or not, is associated with slightly higher odds of fetal cardiac malformation. The study by Bateman and colleagues reinforces these observations, which some of the same authors have previously described.” (J. G. Ray, rayj@smh.ca)
Statins & Noncardiovascular Outcomes: Available observational and controlled trials do not support broad use of statins for noncardiovascular outcomes, a review article concludes (pp. 543–53). This supports “leaving the current recommendations unchanged,” the authors write. The umbrella review considered 278 unique noncardiovascular outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of randomized controlled trials (RCTs). Two observational trials provided highly suggestive (class II) evidence of benefits in cancer mortality and COPD, while RCTs showed decreased all-cause mortality in chronic kidney disease. (E. Theodoratou, E.Theodoratou@ed.ac.uk)
>>>PNN NewsWatch
* In remarks to the National Academy of Medicine yesterday, HHS Secretary Alex Azar proposed requiring pharmaceutical companies to provide drug costs in television advertising. “Patient empowerment and transparency are at the core of the President’s drug-pricing blueprint that was released five months ago,” Azar said in a statement released in response to an industry proposal for creating websites providing pricing information. “Our vision for a new, more transparent drug-pricing system does not rely on voluntary action. The drug industry remains resistant to providing real transparency around their prices, including the sky-high list prices that many patients pay. So while the pharmaceutical industry’s action today is a small step in the right direction, we will go further and continue to implement the President’s blueprint to deliver new transparency and put American patients first.” 
* FDA yesterday issued 
new guidance documents providing “drug developers greater clarity and direction as they pursue the next generation of therapies and treatments for patients” in the areas of hematologic malignancies and targeted therapies for rare genetic variants of diseases. “Using more sophisticated approaches to learn about the safety and efficacy of treatments, we can reduce the barriers to bringing new science forward and make sure more patients can benefit sooner from improved treatments,” FDA Commissioner Scott Gottlieb, MD, said in announcing the actions.
* Fat Burners Zone is voluntarily recalling a lot of 
Zero Xtreme capsules to the consumer level. FDA said it has found Zero Xtreme to be tainted with sibutramine.

PNN Pharmacotherapy Line
Oct. 17, 2018 * Vol. 25, No. 200
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>>>JAMA Report
Source:
 Oct. 16 issue of JAMA (2018; 320).
Adjunctive Theophylline in COPD: In a 1-year study of high-risk adults with COPD, addition of low-dose theophylline to an inhaled corticosteroid regimen produced no additional reductions in exacerbations, researchers report (pp. 1548–59). The TWICS (theophylline with inhaled corticosteroids) trial included 1,567 participants with reduced pulmonary function (FEV1/FVC <0.7) and at least two exacerbations over the prior year. For 1 year following randomization in 2014–16, participants in the theophylline 200 mg once or twice daily group had a mean of 2.24 exacerbations compared with 2.23 in the placebo group. “Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%),” the authors write. (D. Price, dprice@opri.sg)
“It is somewhat disappointing that low-dose theophylline did not result in a reduction in exacerbation risk because the drug is relatively inexpensive, and its rationale was based on sound preclinical and human mechanistic studies,” write editorialists (
pp. 1541–2). “Perhaps future formulations that can deliver theophylline to the airway via the inhaled route or pharmacological analogues that can mimic its effect on increasing [histone deacetylase] levels with a better safety profile are possible approaches that can help in the development of targeted therapies for patients with COPD who are at increased risk for exacerbation despite use of current best inhaled agents.” (G. J. Criner, gerard.criner@tuhs.temple.edu)
Bariatric Surgery & Macro-vascular Disease Outcomes: “Even though there appears to be relatively weak evidence supporting aggressive medical management of type 2 diabetes for reducing CV events and mortality, evidence for the benefits of bariatric surgery for improving these outcomes is increasing,” write editorialists responding to a retrospective cohort study (pp. 1570–82; D. Arterburn, david.e.arterburn@kp.org) of macrovascular (coronary artery disease and cerebrovascular diseases) events in 5,301 patients with severe obesity and type 2 diabetes who underwent bariatric surgery (pp. 1545–7). “Yet, access to bariatric surgery is limited by stringent private insurance requirements, lack of Medicaid coverage in some states, and high out-of-pocket costs. [These authors] provide additional evidence that bariatric surgery is associated with lower rates of macrovascular events. Given the benefits of bariatric surgery for patients with type 2 diabetes, including potentially greater long-term benefits than most pharmaceuticals, insurance coverage for weight loss operations should be expanded for appropriate patients.” (S. Ikramuddin, ikram001@umn.edu)
Influenza Pandemic Vulnerability: “I think people believe that because you can go on the internet and order something from Amazon and it’s here tomorrow, that anything we need in the medical care field will be available in equal speed,” says Michael Osterholm, PhD, MPH, of U. Minn. in a JAMA interview on the threat of an influenza pandemic (pp. 1523–5). “We don’t have stockpiles of anything beyond a limited supply the U.S. government has of some medical products, which would be quickly exhausted if we are in a real pandemic. We have to anticipate these things, and we have to have plans. Right now, anticipation is the word that probably applies to the next 12 hours. What we need to understand is that it has to apply to the next 10 to 15 years.” 
Asked to rank influenza in terms of all the microbes that could cause widespread harm, Osterholm says, “There really are only 2 disease categories today that really have the ability to wreak havoc on the global society, both in terms of number of severe cases and deaths as well as economic disruption. That’s influenza and pandemic influenza and its antimicrobial resistance, which is coming too.…” (R. Voelker)
>>>PNN NewsWatch
Cybersecurity of medical devices is the focus of a new framework between FDA and the Dept. of Homeland Security (DHS). DHS continues to serve as the central medical device vulnerability coordination center, and FDA continues to engage in regular, ad hoc, and emergency coordination calls with DHS and advise DHS regarding the risk to patient health and potential harms of identified threats and vulnerabilities.

PNN Pharmacotherapy Line
Oct. 18, 2018 * Vol. 25, No. 201
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Oct. 18 issue of the New England Journal of Medicine (2018; 379).
Aspirin for Prevention in the Poststatin Era: In four research articles and an editorial, the contemporary place of prophylactic aspirin is examined. 
Compared with placebo in older adults, enteric-coated aspirin 100 mg used for primary prevention failed to prolong disability-free survival over 5 years but produced a significantly higher rate of major hemorrhage, report investigators in the Aspirin in Reducing Events in the Elderly (ASPREE) trial (
pp. 1499–508). Participants (n = 19,114) in Australia and the U.S. were age 70 years or older (65 for blacks and Hispanics in the U.S.) and did not have cardiovascular disease, dementia, or physical disability when randomized in 2010–14. Before early termination of the study for futility, results showed: “The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person–years in the aspirin group and 21.2 per 1000 person–years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P = 0.79).… The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P <0.001).” (J. J. McNeil, john.mcneil@monash.edu)
In two additional analyses of this group of “healthy elderly,” the ASPREE investigators find no benefits of aspirin on primary prevention of cardiovascular disease (
pp. 1509–18) and an unexpected increase in all-cause mortality among those on the drug (pp. 1519–28). Rates of fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure during a median of 4.7 years of aspirin or placebo produced rates of 10.7 and 11.3 events per 1,000 person–years for aspirin and placebo, respectively (not significantly different), but rates of major hemorrhage of 8.6 and 6.2 events per 1,000 person–years for the respective drugs (P <.0.001). In the all-cause mortality analysis, “cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1,000 person–years,” the authors write. “Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).” (J. J. McNeil, john.mcneil@monash.edu)
Patients with diabetes and no evident cardiovascular diseases at entry into the ASCEND (A Study of Cardiovascular Events in Diabetes) randomized trial had significantly fewer serious vascular events with enteric-coated aspirin, but major bleeding events “largely counterbalanced” benefits of the drug, investigators conclude (
pp. 1529–39). During a mean of 7.4 years of follow-up in 15,480 participants, enteric-coated aspirin 100 mg produced rates of serious vascular events in 8.5% versus 9.6% (P = 0.01), major bleeding events of 4.1% versus 3.2% (P = 0.003), gastrointestinal tract cancers of 2.0% versus 2.0%, and all cancers of 11.6% versus 11.5%. (J. Armitage, ascend@ndph.ox.ac.uk)
“What can we conclude about the use of aspirin for prophylaxis 150 years after its chemical synthesis?” asks an editorialist (
pp. 1572–4). “For secondary prevention, in which risk is determined largely by the extent of atherosclerotic disease, the benefits of aspirin outweigh the risks of bleeding. In contrast, for primary prevention, in which risk is determined largely by age and the presence or absence of diabetes, the benefit–risk ratio for prophylactic aspirin in current practice is exceptionally small. Thus, beyond diet maintenance, exercise, and smoking cessation, the best strategy for the use of aspirin in the primary prevention of cardiovascular disease may simply be to prescribe a statin instead.” (P. M. Ridker)
Fatty Acid Supplements in Diabetes: ASCEND investigators also looked at effects on n-3 fatty acids in their population of 15,480 participants with diabetes and no evident cardiovascular disease, finding no significant difference in serious vascular events with use of the supplement (pp. 1540–50). Capsules containing 1 g of n-3 fatty acids or olive oil produced no significant differences in rates of nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death (excluding confirmed intracranial hemorrhage), all-cause mortality, or rates of nonfatal serious events during a mean follow-up period of 7.4 years. (L. Bowman, ascend@ndph.ox.ac.uk)

PNN Pharmacotherapy Line
Oct. 19, 2018 * Vol. 25, No. 202
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>>>Infectious Diseases Report
Source:
 Nov. 1 issue of Clinical Infectious Diseases (2018; 67).
HPV Vaccine in HIV-Infected Adults Older Than 26 Years: In a phase 3 study, use of the quadrivalent human papillomavirus (HPV) vaccine in patients living with HIV who are aged 27 years or older is not supported for prevention of new anal HPV infections or improving outcomes with biopsied anal high-grade squamous intraepithelial lesions (bHSIL) (pp. 1339–46). A role for the vaccine in preventing oral HPV infections is suggested by the trial, as noted in these results: “A total of 575 participants were randomized. The Data and Safety Monitoring Board stopped the study early due to futility. Vaccine efficacy was 22% (95.1% confidence interval [CI], −31%, 53%) for prevention of persistent anal infection or single detection at the final visit, 0% (95% CI −44%, 31%) for improving bHSIL outcomes and 88% (95.1% CI 2%, 98%) for preventing persistent oral HPV infection, but was 32% (95.1% CI −80%, 74%) for 6-month persistent oral HPV infection or single detection at the final visit.” The 9-valent HPV vaccine was recently approved by FDA for use in patients aged 27–45 years, but the CDC’s Advisory Committee on Immunization Practices has not addressed use of the vaccine in patients living with HIV. (T. J. Wilkin, w2001@med.cornell.edu)
Influenza Infection in Transplant Recipients: Influenza vaccination and early antiviral therapy are important interventions in patients with transplants, according to a study of 616 participants with confirmed influenza infections (pp. 1322–9). The multicountry study found these results for recipients of solid organ grafts and hematopoietic stem cells: “Antiviral therapy was given to 94.1% for a median of 5 days (range, 1–42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21–.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26–.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively).” (D. Kumar, deepali.kumar@uhn.ca)
>>>Vaccine Highlights
Source:
 Oct. 1, 8, 15, and 22 issues of Vaccine (2018; 36); the Oct. 22 issue has a vaccine hesitancy theme.
Statins & Influenza Vaccine: In Taiwan, influenza-vaccinated older adults had higher risks of medically attended acute respiratory illness (MAARI) when they were taking statins — particularly simvastatin and lovastatin (pp. 6133–7). A retrospective cohort study of 440,180 adults aged 66 years or older showed the following for the 2007–08 through 2012–13 influenza seasons: “In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02–1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02–1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (ORsimvastatin: 1.14, 95% CI: 1.10–1.18; ORlovastatin: 1.18, 95% CI: 1.12–1.25).” (H-T Chiu, r04451001@ntu.edu.tw)
Using Motivational Interviewing to Address Vaccine Hesitancy: Using motivational interviewing with new mothers is a “promising tool to address vaccine hesitancy,” according to authors of a Commentary article (pp. 6553–5): “PromoVac is delivered to parents during their postpartum stay at the maternity ward by research nurses who are trained in MI theory and techniques. This educational intervention lasts approximately 15–20 min and is carried out in simple and understandable language in order to allow discussion and questions from parents rather than to provide prescriptive and direct information. The MI intervention is oriented according to Prochaska’s stages of change, a model proposing that people pass through several stages when they want to change a behavior. Thus, each MI intervention is adapted to the parents’ readiness to vaccinate their child.” (A. Gagneur, Arnaud.Gagneur@USherbrooke.ca)

PNN Pharmacotherapy Line
Oct. 22, 2018 * Vol. 25, No. 203
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Oct. 20 issue of Lancet (2018; 392).
Nurse-Led Gout Care: Compared with usual care provided by general practitioners in the U.K., nurse-led care of patients with gout was efficacious and cost-effective over a 2-year period, researchers report (pp. 1403–12). “Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes,” the authors conclude, based on a primary outcome of percentage of participants who achieved serum urate concentrations less than 360 μmol/L (6 mg/dL) at 2 years: “517 patients were enrolled, of whom 255 were assigned nurse-led care and 262 usual care. Nurse-led care was associated with high uptake of and adherence to urate-lowering therapy. More patients receiving nurse-led care had serum urate concentrations less than 360 μmol/L at 2 years than those receiving usual care (95% vs 30%, RR 3.18, 95% CI 2.42–4.18, p <0.0001). At 2 years all secondary outcomes favoured the nurse-led group. The cost per [quality-adjusted life–year] gained for the nurse-led intervention was £5066 at 2 years.” (M. Doherty, michael.doherty@nottingham.ac.uk)
Corticosteroid Injections for Carpal Tunnel Syndrome: In primary care patients with mild or moderate carpal tunnel syndrome, a single corticosteroid injection should be the treatment of choice for rapid symptom response, a study concludes, based on evidence of superior clinical effectiveness compared with night-resting splints (pp. 1423–33). In this randomized, open-label, pragmatic trial of adults with this condition, methylprednisolone acetate 20 mg injections or night-resting splints showed these results based on a primary outcome of overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks: “Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2.02 [SD 0.81]) than the night splint group (2.29 [0.75]; adjusted mean difference −0.32; 95% CI −0.48 to −0.16; p = 0.0001). No adverse events were reported.” (E. Roddy, e.roddy@keele.ac.uk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
n3-PUFA Levels & Healthy Ageing: In the Cardiovascular Health Study, increased dietary consumption of n-3 polyunsaturated fatty acids (n3-PUFAs) from seafood but not plants was associated with better outcomes regarded as indicators of healthy ageing (k4067). The study defined healthy ageing as survival without chronic diseases (cancer or cardiovascular, lung, and severe chronic kidney disease), absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Findings were as follows: “Higher levels of long chain n3-PUFAs were associated with an 18% lower risk (95% confidence interval 7% to 28%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15% (6% to 23%) and 16% (6% to 25%), respectively. Alpha-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95% confidence interval 0.83 to 1.02).” (H Lai, Heidi.Lai@tufts.edu)
>>>PNN JournalWatch
Acinetobacter Pneumonia: Improving Outcomes With Early Identification and Appropriate Therapy, in Clinical Infectious Diseases, 2018; 67: 1455–62. (M. H. Kollef, kollefm@wustl.edu)
Pneumococcal Vaccination in Adult Solid Organ Transplant Recipients: A Review of Current Evidence, in Vaccine, 2018; 42: 6253–61. (C. Dendle, claire.dendle@monash.edu)
Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2018; 36: 3043–54. (R. A. Taplitz)
Medical Marijuana in the United States: Historical Perspectives, Legal Considerations, and Professional Obligations of the Pharmacist, in Journal of the American College of Clinical Pharmacy, 2018; 1: 10.1002/jac5.1014. (J. S. Wheeler, jwheele4@uthsc.edu)

PNN Pharmacotherapy Line
Oct. 23, 2018 * Vol. 25, No. 204
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Early-release articles from the New England Journal of Medicine (2018; 379).
Antipsychotic Management of ICU Delirium: Compared with placebo, neither haloperidol nor ziprasidone significantly altered the duration of delirium in 1,183 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in ICU, researchers report (10.1056/NEJMoa1808217). In the MIND-USA trial, the Confusion Assessment Method for the ICU was used to detect the presence or absence of delirium at 12-hour intervals; drug doses were then halved or doubled up to haloperidol 20 mg daily or ziprasidone 40 mg daily. Based on a primary end point of the number of days alive without delirium or coma during the 14-day intervention period, the investigators found: “The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P = 0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.” (E. W. Ely, wes.ely@vumc.org)
“Why did [this] trial fail to show benefit?” asks an editorialist (
10.1056/NEJMe1813382). “It is likely that our concept of delirium is flawed. The neurochemistry of sudden alteration in mentation is complex and involves several neurotransmitters as well as structural, immunologic, and network alterations and possible brain infection that is not clinically evident. The investigators deserve credit for conducting a difficult trial, but it would have been astounding if there were a single magic bullet for the restitution of normal brain function in ICU patients with delirium.” (T. P. Bleck)
>>>Internal Medicine Report
Source:
 Early-online articles from Annals of Internal Medicine (2018; 169).
Rethinking Buprenorphine in Opioid Use Disorder: Clinicians may need to rethink the way they treat opioid use disorder with buprenorphine, according to a review showing that many current practices are too restrictive and in conflict with science (10.7326/M18-1652). The research focused on the following seven areas: location of buprenorphine induction; combining buprenorphine with a benzodiazepine; relapse during buprenorphine treatment; requirements for counseling; uses of drug testing; use of other substances during buprenorphine treatment; and duration of buprenorphine treatment. Results suggest a more progressive approach to treating opioid use disorder that minimizes barriers in the Opioid Treatment Cascade of Care, including linkage, initiation, and maintenance of buprenorphine therapy. In addition to allowing home induction of buprenorphine, the researchers suggest that the old practice of requiring counseling with buprenorphine use may do more harm than good. The authors also challenge previous practices of discharging patients for relapse or use of other substances. They note that nearly all evidence guiding current practice was found before the lethality of heroin and illicitly produced fentanyl appeared at scale, making updated, evidence-based treatment all the more critical. (S. Martin, stmartin@gmail.com)
Editorialists strongly agree that the magnitude of the opioid epidemic calls for a reexamination of the conservative approaches to buprenorphine use (
10.7326/M18-2722): “The influx of fentanyl and fentanyl analogues has changed the way we calculate the risk of withholding access to this life-saving medication because of concomitant use of benzodiazepines or other drugs or opioid-positive results on urine tests during treatment. A reduction in opioid use should be viewed as a step forward rather than treatment failure.” (G. D’Onofrio, gail.donofrio@yale.edu)
>>>PNN NewsWatch
Promise Pharmacy is voluntarily recalling one lot of Prednisolone and Gatifloxacin Ophthalmic Solution 1%/0.5% sterile, 3-ml vials, to the patient level because of unidentified small particulate matter.

PNN Pharmacotherapy Line
Oct. 24, 2018 * Vol. 25, No. 205
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Oct. 23/30 issue of JAMA (2018; 320).
SNPs & Bleeding in Blacks Taking Warfarin: A preliminary case–control, genomewide association study of patients of African descent taking warfarin identifies four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium on chromosome 6 that are associated with an increased risk of major bleeding at INRs of less than 4 (pp. 1670–7). While requiring confirmation in a prospective cohort, the study demonstrates in those of African descent these significantly increased risks of bleeding in discovery (31 cases) and replication (40 cases) cohorts associated with the SNPs rs115112393, rs16871327, rs78132896, and rs114504854: “Four SNPs in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding in a discovery cohort of 215 patients (odds ratio [OR], 8.3) and a replication cohort of 188 patients (OR, 8.2), and reached genome-wide significance when the cohorts were combined using meta-analysis (OR, 8.3).” (M. A. Perera, minoli.perera@northwestern.edu)
Myo-inositol on Type 1 Retinopathy of Prematurity: In a study of 638 infants of less than 28 weeks’ gestational age, treatment of myo-inositol for up to 10 weeks failed to improve rates of type 1 retinopathy of prematurity (ROP) or mortality (pp. 1649–58). Prior research had suggested a benefit of the compound, which is present in breast milk but not some formulas. The study was terminated early because of increased mortality among infants receiving myo-inositol. Results for myo-inositol 40 mg/kg intravenous or enteral doses or placebo every 12 hours were as follows: “Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%–11%]; adjusted relative risk, 1.66 [95% CI, 1.14–2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).” (D. L. Phelps, dale_phelps@urmc.rochester.edu)
Immune Checkpoint Inhibitor Toxicity: Used in treatment of metastatic cancer, immune checkpoint inhibitors (ICIs) “frequently cause immunologic toxicity with variable clinical manifestations and severity,” authors of a JAMA Insights article conclude (pp. 1702–3). By altering the actions of T cells, ICIs “may expose preexisting organ-specific inflammation, a genetic propensity for autoimmunity, or shared antigens between self and malignant cells,” the authors write, adding that the increasingly used drugs have been linked with colitis, pneumonitis, skin adverse effects, endocrine dysfunction, hepatitis, myocarditis, and neurotoxicities. “Prompt initiation of steroids in collaboration with the treating oncologist is essential for managing toxicity,” conclude the authors. “Rigorous studies are needed to better understand the pathophysiology of [adverse effects] associated with ICIs, to identify patients at highest risk of severe outcomes, and to develop evidence-based therapies to manage toxicity.” (J. A. Sosman, jeffrey.sosman@nm.org)
>>>PNN NewsWatch
FDA will hold a 2-day advisory committee meeting on Dec. 17–18 to solicit input and advice on strategies to increase the availability of naloxone products intended for use in the community. Comments filed by Dec. 3 will be provided to the committee.
* A 
federal court has ordered Tennessee-based Keystone Laboratories to stop selling OTC drug products until the company complies with the Federal Food, Drug, and Cosmetic Act and other requirements listed in a consent decree.
* As part of the 11th annual International Internet Week of Action (IIWA), 
FDA acted yesterday in partnership with international agencies to target 465 websites that illegally sell potentially dangerous, unapproved versions of opioid, oncology, and antiviral prescription drugs to U.S. consumers.

PNN Pharmacotherapy Line
Oct. 25, 2018 * Vol. 25, No. 206
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Oct. 25 issue of the New England Journal of Medicine (2018; 379).
Triple CFTR Modulation in Cystic Fibrosis: In two research articles, investigators provide evidence supporting use of the next-generation cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-659 and VX-445, in triple combination with tezacaftor and ivacaftor, in patients with cystic fibrosis and one or two specific CFTR mutations.
In vitro and clinical activity of VX-659 is demonstrated in the first trial, which combined the agent with tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype) (
pp. 1599–611). Pulmonary, sweat chloride, and Cystic Fibrosis Questionnaire–Revised respiratory domain scores improved in both genotypic populations. (S. M. Rowe, smrowe@uab.edu)
A similar corrector, VX-445, also yielded positive results in patients with one or both of these mutations (
pp. 1612–20). As with the first study, authors conclude that “this approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients.” (J. L. Taylor-Cousar, taylor-cousarj@njhealth.org)
These promising results could be a “major breakthrough” if confirmed in larger clinical trials, an editorialist writes (pp. 1671–2): “[These trials] show that triple-combination therapy in patients with a Phe508del–Phe508del CFTR mutation improved the percentage of predicted FEV
1 more than double-combination therapy. Both trials also reported efficacy in patients with a Phe508del–MF CFTR mutation, and neither reported dose-limiting side effects or toxicity. Only three patients in the VX-445 trial discontinued treatment owing to severe adverse events. These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common CFTR mutation. It is unclear whether the effects on lung function can be sustained for longer periods of treatment or whether these compounds will effectively reduce exacerbation rates and address other meaningful outcomes, such as weight gain. These questions should soon be answered in the ongoing phase 3 trials of these regimens.” (F. Holguin)
M72/AS01E Vaccine to Prevent Tuberculosis: In a phase 2b trial of a new tuberculosis vaccine, safety and efficacy were demonstrated in a cohort of infected adults with active pulmonary disease and those meeting a primary case definition (pp. 1621–34): “The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P = 0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P = 0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.” (O. Van Der Meeren, livier.x.van-der-meeren@gsk.com">olivier.x.van-der-meeren@gsk.com)
Noting that “all vaccine development has been an iterative process,” an editorialist concludes (
pp. 1672–4): “The work presented represents an important step forward toward developing an effective immunization against tuberculosis; it is probably not the final iteration. The results reinforce the importance of international collaborations, set the stage for testing additional candidates, and offer renewed hope that effective new vaccines can be developed for tuberculosis.” (B. R. Bloom)
>>>PNN NewsWatch
* Commenting on yesterday’s signing of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities ActFDA Commissioner Scott Gottlieb, MD, said that the law provides the agency with “important new tools to work more effectively across all four broad domains”: interdiction and enforcement, mandatory recall orders for controlled substances, requiring packaging, such as unit dose blister packs, for opioids and other drugs that pose a risk of abuse or overdose, and supporting development of nonaddictive drugs.

PNN Pharmacotherapy Line
Oct. 26, 2018 * Vol. 25, No. 207
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
 Early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Cognition & Vitamin D: Monitored over a 3-year period, older black women had no changes in rates of cognitive decline during a placebo-controlled trial of vitamin D supplements, researchers report (10.1111/jgs.15607). Participants were healthy postmenopausal women age 65 years or older (mean, 68.2 years; 46% had college education or higher) when they were randomized to vitamin D in doses adjusted to achieve a serum concentration above 30 ng/mL. Results showed: “The average dose of vitamin D3 was 3,490 ± 1,465 IU per day, and average serum 25(OH)D at 3 years was 46.8 ± 1.2 ng/mL in the active group and 20.7 ± 1.1 ng/mL in the placebo group. Serum 25(OH)D concentration was maintained at greater than 30 ng/mL in 90% of the active group. Over the 3-year period, [Mini-Mental State Examination] scores increased in both groups (p < .001), although change over time was not significantly different between the groups. No adverse events associated with vitamin D were observed.” (J. F. Aloia, jaloia@nyumc.org)
Addressing Prescribing Cascades: Prescribing cascades — misrecognition of adverse drug effects as new conditions requiring additional medications — are the topic of a scoping review (10.1111/jgs.15543): “Of 369 resources identified, 58 met inclusion criteria; 29 of these were categorized as preventing, 20 as detecting, and 9 as reversing prescribing cascades. Resources originated from 14 countries and mostly focused on older adults. The goal of preventing resources was to educate and increase general awareness of the concept of prescribing cascades as a way to prevent inappropriate prescribing and to illustrate application of the concept to specific drugs (e.g., anticholinergics) and conditions (e.g., inflammatory bowel disease). Detecting resources included original investigations or case reports that identified prescribing cascades using health administrative data, patient cohorts, and novel sources such as social media. Reversing prescribing cascade resources focused on the medication review process and deprescribing initiatives.” (P. A. Rochon, paula.rochon@wchospital.ca)
>>>Health Affairs Report
Source:
 Oct. issue of Health Affairs (2018; 37).
Generic Drug Price Hikes: Relevant to yesterday’s announcement of an HHS initiative to lower drug costs under Medicare Part B, a study changes in patient spending caused by sudden Part D price increases for generics (pp. 1578–86): “The fraction of drugs that at least doubled in price increased from 1.00 percent of generic products in 2007 to 4.39 percent in 2013. Almost all were initially low- or medium-price medications and not among the most widely used generics. Changes in out-of-pocket spending for these drugs were modest. However, the elevated prices persisted for two to five years. Data for 2011–15 showed similar trends. Potential steps to ensure that generic markets remain strong include fast-tracking new generic drug applications when competition is limited, allowing temporary importation of off-patent drugs, and implementing greater oversight of drug company mergers and takeovers.” (G. Joyce, gjoyce@usc.edu)
>>>PNN NewsWatch
Influenza vaccination in the U.S. remains low at about 4 in 10 adults, the CDC reports in a FluVaxView article posted yesterday. With a national average of 37.1% during the 2017–18 season, the 6.2 percentage point decline in vaccination rates may have contributed to the season’s severity, the Washington Post adds. “That’s huge. It’s a striking inflection down from the previous year,” influenza expert William Schaffner says in the Post article. On a state-by-state basis, vaccination rates ranged from 29.2% in Louisiana to 46.3% in West Virginia; populous states Texas (30.7%), Florida (33.1%), New York (33.9%), Georgia (34.8%), and California (35.0%) all fell below the national average. CDC authors called on “healthcare providers … to strongly recommend and offer flu vaccination to all of their patients” to prevent a repeat of the morbidity and mortality in the 2018–19 season.
FDA earlier this week approved the first-in-class polymerase acidic endonuclease inhibitor baloxavir marboxil (Xofluza, Shionogi & Co.; Genentech/Roche) for treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

PNN Pharmacotherapy Line
Oct. 29, 2018 * Vol. 25, No. 208
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 362).
ACE Inhibitors & Lung Cancer: Compared with angiotensin receptor blockers, use of ACE inhibitors (ACEIs) — particularly among those treated for 5 years or more — is associated with an increased risk of lung cancer, researchers report (k4209). Data from the U.K. Clinical Practice Research Datalink show these relationships in a cohort of 992,061 patients newly treated with antihypertensive medications in 1995–2015 who were followed until the end of 2016: “The cohort was followed for a mean of 6.4 (SD 4.7) years, generating 7,952 incident lung cancer events (crude incidence 1.3 (95% confidence interval 1.2 to 1.3) per 1,000 person years). Overall, use of ACEIs was associated with an increased risk of lung cancer (incidence rate 1.6 v 1.2 per 1,000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29), compared with use of angiotensin receptor blockers. Hazard ratios gradually increased with longer durations of use, with an association evident after five years of use (hazard ratio 1.22, 1.06 to 1.40) and peaking after more than 10 years of use (1.31, 1.08 to 1.59). Similar findings were observed with time since initiation.” (L. Azoulay, laurent.azoulay@mcgill.ca)
“Although a 14% relative increase in lung cancer incidence might not translate to a large absolute risk, the findings are important given the considerable use of ACEIs worldwide,” an editorialist writes. “Nonetheless, in an individual patient, concerns about the long term risk of lung cancer should be balanced against gains in life expectancy associated with use of ACEIs. As Hicks and colleagues point out, further studies with long term follow-up are now needed to enhance the scientific evidence on the long term safety of these drugs.” (D. Cronin-Fenton, 
dc@clin.au.dk)
Safety of Zoster Vaccines in Older Adults: Compared with the older live attenuated zoster vaccine, the adjuvant recombinant subunit product has a greater risk of injection site reactions in adults aged 50 years or older, concludes a systematic review with bayesian/network meta-analyses of 2 million patients in 27 studies (k4029): “Network meta-analysis of 11 randomised controlled trials showed the adjuvant recombinant subunit vaccine to be associated with statistically more adverse events at injection sites than the live attenuated vaccine (relative risk 1.79, 95% credible interval 1.05 to 2.34; risk difference 30%, 95% credible interval 2% to 51%) and placebo (5.63, 3.57 to 7.29 and 53%, 30% to 73%, respectively). Network meta-analysis of nine randomised controlled trials showed the adjuvant recombinant subunit vaccine to be associated with statistically more systemic adverse events than placebo (2.28, 1.45 to 3.65 and 20%, 6% to 40%, respectively).” (A. C. Tricco, triccoa@smh.ca)
>>>Lancet Highlights
Source:
 Oct. 27 issue of Lancet (2018; 392).
Albiglutide & CVD Prevention: Compared with placebo for prevention of major cardiovascular events (death, myocardial infarction, or stroke), the glucagon-like peptide 1 receptor agonist albiglutide proved significantly effective, according to Harmony Outcomes investigators (pp. 1519–29). “Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes,” the group concludes. (J. J. V. McMurray, john.mcmurray@glasgow.ac.uk)
>>>PNN JournalWatch
Sleep Apnea Morbidity: A Consequence of Microbial-Immune Cross-Talk?, in Chest, 2018; 154: 754–9. (D. Gozal, dgozal@uchicago.edu)
Sleep Disorders and Atopic Dermatitis: A 2-Way Street?, in Journal of Allergy and Clinical Immunology, 2018; 142: 1033–40. (B-L Chiang, gicmbor@ntu.edu.tw)
Clockwork Allergy: How the Circadian Clock Underpins Allergic Reactions, in Journal of Allergy and Clinical Immunology, 2018; 142: 1021–31. (A. Nakao, anakao@yamanashi.ac.jp)
“Planting the Seed”: Perceived Benefits of and Strategies for Discussing Long-Term Prognosis with Older Adults, in Journal of the American Geriatrics Society, 2018; 66: 10.1111/jgs.15524. (A. K. Smith, aksmith@ucsf.edu)
An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity, in Arthritis & Rheumatism, 2018; 70: 1557–64. (M. G. Moghadam, m.ghiti@hotmail.com)
New Medicare Diabetes Prevention Coverage May Limit Beneficiary Access and Widen Health Disparities, in Medical Care, 2018; 56: 908–11. (N. D. Ritchie)

PNN Pharmacotherapy Line
Oct. 30, 2018 * Vol. 25, No. 209
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
 Nov. issue of Diabetes Care (2018; 41).
GMI: New Tool for Estimating A1C During CGM: A Perspective article describes the need for and use of a glucose control term in patients with diabetes on continuous glucose monitoring (CGM) (pp. 2275–80): “Estimated A1C (eA1C) is a measure converting the mean glucose from CGM or self-monitored blood glucose readings, using a formula derived from glucose readings from a population of individuals, into an estimate of a simultaneously measured laboratory A1C. Many patients and clinicians find the eA1C to be a helpful educational tool, but others are often confused or even frustrated if the eA1C and laboratory-measured A1C do not agree. In the U.S., the Food and Drug Administration determined that the nomenclature of eA1C needed to change. This led the authors to work toward a multipart solution to facilitate the retention of such a metric, which includes renaming the eA1C the glucose management indicator (GMI) and generating a new formula for converting CGM-derived mean glucose to GMI based on recent clinical trials using the most accurate CGM systems available. The final aspect of ensuring a smooth transition from the old eA1C to the new GMI is providing new CGM analyses and explanations to further understand how to interpret GMI and use it most effectively in clinical practice. This Perspective will address why a new name for eA1C was needed, why GMI was selected as the new name, how GMI is calculated, and how to understand and explain GMI if one chooses to use GMI as a tool in diabetes education or management.” (R. M. Bergenstal, richard.bergenstal@parknicollet.com)
Comparing Hypertension Guidelines: High percentages of Americans with diabetes are categorized and treated similarly based on 2017 blood pressure (BP) guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) and American Diabetes Association (ADA), researchers report (pp. 2322–9). Using the U.S. National Health and Nutrition Examination Survey (NHANES) for 2011–16, the group found these diagnostic and treatment results for 2,266 individuals with diabetes: “The prevalence (95% CI) of hypertension among U.S. adults with diabetes was 77.1% (73.9, 80.0) and 66.3% (63.4, 69.1) according to the ACC/AHA and ADA definitions, respectively. Also, 22.9% (20.0, 26.1) did not have hypertension according to either definition, and the concordance in hypertension status was 89.2% (87.2, 91.0). Among U.S. adults with diabetes not taking antihypertensive medication, 52.8% (47.7, 57.8) were not recommended to initiate antihypertensive medication by either the ACC/AHA or the ADA document and 22.4% (19.2, 25.9) were recommended to initiate it by both documents (overall concordance 75.2% [70.4, 79.4]). Among those taking antihypertensive medication, 45.3% (41.3, 49.4) and 50.4% (46.5, 54.2) had BP above the goal in neither and both documents, respectively (overall concordance 95.7% [93.4, 97.2]).” (P. Muntner, pmuntner@uab.edu)
Gut Microbiota in Type 1 Diabetes: Modulation of gut microbiota should be studied further in patients at high risk of type 1 diabetes, conclude authors who found taxonomic and functional differences in healthy participants and those with nonautoimmune diabetes or type 1 diabetes (pp. 2385–95). The case–control study showed that 15 children with maturity-onset diabetes of the young 2 (MODY2) had “significantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance,” and 15 children with type 1 diabetes had “lower microbiota diversity” and “significantly higher relative abundance of BacteroidesRuminococcusVeillonellaBlautia, and Streptococcus genera,” compared with healthy participants. (J. Carlos Fernández-García, josecarlosfdezgarcia@hotmail.com)
Emerging Drugs & Regimens: In 24-hour study, fixed-ratio pramlintide and regular human insulin improved postprandial hyperglycemia and glycemic variability among patients with type 1 diabetes (pp. 2346–52; R. Nahra, rajaa.nahra@astrazeneca.com).
In a cohort study of patients with confirmed insulin receptor autoantibodies, combined immunosuppression using rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine, changed the natural course of the disease (
pp. 2353–60; J. Klubo-Gwiezdzinska, joanna.klubo-gwiezdzinska@nih.gov).

PNN Pharmacotherapy Line
Oct. 31, 2018 * Vol. 25, No. 210
Providing news and information about medications and their proper use

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>>>Nephrology Report
Source:
 Nov. issue of the American Journal of Kidney Diseases (2018; 72).
Oral Anticoagulants for Nonvalvular AF in CKD: Because of the complexities of managing nonvalvular atrial fibrillation (AF) in patients with advanced chronic kidney diseases (CKD), nephrologists should be “active members of the multidisciplinary [care] team,” according to authors presenting pragmatic considerations for the clinician (pp. 717–27): “During the past few years, 4 non–vitamin K–dependent oral anticoagulant (NOAC) agents have supplemented warfarin in the therapeutic armamentarium for the prevention of systemic thromboembolism in nonvalvular AF. However, the use of NOACs in CKD specifically mandates a nuanced understanding due to their varying dependence on renal clearance, with resultant safety implications related to either underdosing (thromboembolism) or excessive drug exposure (bleeding). This pragmatic review highlights unique considerations pertaining to accurate estimation and temporal monitoring of kidney function in the context of NOAC use with specific clinical deliberations and variables when determining whether an NOAC is appropriate for a patient with CKD. The dependence of NOACs on renal clearance and several troubling safety signals in the published literature suggest that it is vital for nephrologists to be active members of a multidisciplinary team caring for these high-risk patients with CKD and AF.” (G. R. Shroff, shrof010@umn.edu)
Immunosuppressives in Proliferative Lupus Nephritis: Authors summarize findings of a Cochrane review on use of mycophenolate mofetil (MMF) and intravenous cyclophosphamide in the management of systemic lupus erythematosus (pp. 756–7). “MMF provides equivalent disease remission and probably avoids drug-related toxicity compared to intravenous cyclophosphamide, supporting the use of MMF in addition to corticosteroids as first-line induction therapy for proliferative lupus nephritis. MMF is appropriate as first-line maintenance therapy, providing the greatest efficacy for prevention of disease relapse after induction with fewer adverse events.
“Lower dose MMF combined with tacrolimus may induce complete remission to a greater extent than intravenous cyclophosphamide. However, the generalizability of these findings may be limited. The safety and effectiveness of biologics is uncertain.” (D. J. Tunnicliffe, 
david.tunnicliffe@health.nsw.gov.au)
“Improving the evidence base is an obvious first step in addressing all the deficits highlighted in this updated Cochrane Review,” an editorialist concludes (
pp. 758–60). “Unfortunately, some of the largest ongoing clinical trials in lupus nephritis still rely on a proteinuria-based remission end point, exemplified by the current studies of voclosporin, a novel [calcineurin inhibitor], and belimumab, a monoclonal antibody directed against B lymphocyte stimulator (BLyS; ClinicalTrials.gov identifiers NCT03021499 and NCT01639339, respectively). Lupus nephritis trials should be designed to be large enough and with sufficient duration of follow-up to evaluate non–proteinuria-based outcomes, such as doubling of serum creatinine level, progression to [end-stage kidney disease], and all-cause mortality. Also, these trials should be designed to specifically address questions about doses and duration of therapy, requirements for concomitant corticosteroid use, and toxicity profiles that our patients continue to ask and that, unfortunately, we continue to answer with low-certainty evidence (to borrow a phrase from these Cochrane authors).” (A. S. Bomback, asb68@cumc.columbia.edu)
Smoking & Hemodialysis: Mortality and hospitalization risks are elevated among patients on hemodialysis when they also smoke, a study shows (pp. 673–81). The relationship was especially strong for younger patients and those with diabetes. Second-hand smoke had no effect. (N. J. Ofsthun, norma.ofsthun@fmc-na.com)
CVD Risk Factors in CKD: A review article details management of traditional cardiovascular risk factors in patients with chronic kidney diseases (pp. 728–44; L. P. Gregg, lucile.gregg@utsouthwestern.edu).
>>>PNN NewsWatch
FDA yesterday issued a final rule repealing the regulation that allows use of lead acetate as a color additive in hair coloring products. FDA took the action in response to a color additive petition. citing potential lead exposure.

PNN Pharmacotherapy Line
Nov. 1, 2018 * Vol. 25, No. 211
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 1 issue of the New England Journal of Medicine (2018; 379).
Health Care–Associated Infections in U.S. Hospitals: Prevention strategies against Clostridioides difficile and pneumonia are needed to continue progress in prevention of health care–associated infections in U.S. hospitals, point-prevalence surveys from 2011 and 2015 show (pp. 1732–44). Through the Emerging Infections Program sites in 10 sites, up to 25 hospitals in each area provided data on a random sample of health care–associated infections on a self-selected day, with these results: “In 2015, a total of 12,299 patients in 199 hospitals were surveyed, as compared with 11,282 patients in 183 hospitals in 2011. Fewer patients had health care–associated infections in 2015 (394 patients [3.2%; 95% confidence interval {CI}, 2.9 to 3.5]) than in 2011 (452 [4.0%; 95% CI, 3.7 to 4.4]) (P <0.001), largely owing to reductions in the prevalence of surgical-site and urinary tract infections. Pneumonia, gastrointestinal infections (most of which were due to Clostridium difficile [now Clostridioides difficile]), and surgical-site infections were the most common health care–associated infections. Patients’ risk of having a health care–associated infection was 16% lower in 2015 than in 2011 (risk ratio, 0.84; 95% CI, 0.74 to 0.95; P = 0.005), after adjustment for age, presence of devices, days from admission to survey, and status of being in a large hospital.” (S. S. Magill, smagill@cdc.gov)
CD47 Blockade in Non-Hodgkin’s Lymphoma: In a phase 1b trial of 22 patients who also received rituximab, Hu5F9-G4 CD-47 blocking antibody showed “promising activity in patients with aggressive and indolent lymphoma” with no clinically significant safety events (pp. 1711–21). “Adverse events were predominantly of grade 1 or 2,” researchers report. “The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with [diffuse large B-cell lymphoma (DLBCL)] and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.” (R. Advani, radvani@stanford.edu)
“If confirmed and extended, the results reported by Advani et al. pave the way to macrophage checkpoint blockade as a new immunotherapy strategy,” editorialists write (
pp. 1777–9). “The development of macrophage checkpoint strategies goes back to the very roots of cancer immunology and immunotherapy. In applying macrophage activation in cancer treatment, we are in a sense going back to the future.” (A. Mantovani)
Sildenafil in Idiopathic Pulmonary Fibrosis: Addition of sildenafil to nintedanib treatment of idiopathic pulmonary fibrosis (IPF) yielded no further benefit, researchers report (pp. 1722–31). Among 274 patients with IPF and low lung diffusion capacity, “nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone,” the authors conclude. “No new safety signals were identified with either treatment regimen in this population of patients.” (G. Raghu, graghu@uw.edu)
>>>PNN NewsWatch
FDA yesterday permitted marketing, with special controls, of the 23andme Personal Genome Service Pharmacogenetic Reports test as a direct-to-consumer test. FDA is authorizing the test to detect 33 variants for multiple genes affecting patient responses to more than 50 prescription and OTC medications. This is the first authorization of a direct-to-consumer report on pharmacogenetics; itcame through the FDA’s de novo classification process. With this authorization, the FDA has classified these direct-to-consumer pharmacogenetic reports as moderate risk that have special controls to ensure safety, effectiveness, and accuracy. The tests are available without a prescription.

PNN Pharmacotherapy Line
Nov. 2, 2018 * Vol. 25, No. 212
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
 Nov. issue of Pediatrics (2018; 142).
Medical Exemptions & Vaccine Exemption Policy: Experiences with medical exemptions in California following passage of that state’s Senate Bill 227 (SB277) — which eliminated nonmedical vaccine exemptions for school entry — are documented through semistructured telephone interviews of health officers and immunization staff at local health jurisdictions (e20181051): “Four main themes emerged related to experiences with medical exemptions: (1) the role of stakeholders, (2) reviewing medical exemptions received by schools, (3) medical exemptions that were perceived as problematic, and (4) frustration and concern over medical exemptions. Generally, local health jurisdictions described a narrow role in providing support and technical assistance to schools. Only 5 jurisdictions actively tracked medical exemptions received by schools, with 1 jurisdiction facing a lawsuit as a result. Examples were provided of medical exemptions that listed family history of allergies and autoimmune diseases as contraindications for immunization and of physicians charging steep fees for medical exemptions. Participants also reported concerns about the increase in medical exemptions after the implementation of SB277.” (S. Mohanty)
“Vaccines are safe, >1000 times safer than the diseases they prevent,” editorialists remind readers (
e20182009). “Protection from vaccines extends beyond individuals when vaccination rates are high enough to confer community immunity.…
“Vaccines are one of the greatest public health successes in history. Mandating vaccination for school is an effective strategy to prevent outbreaks. This protection is undermined when unscrupulous physicians monetize their license and abuse the authority delegated to them from the state by granting unwarranted [medical exemptions (MEs)]. Public health officers need the information to identify these physicians and the authority to withdraw their ability to grant MEs and to invalidate unwarranted MEs to protect children and public health. Pediatricians can partner with public health advocates and proscience parents to pass laws that empower public health officers to protect our children and community. Every child needs community immunity.” (R. J. Pan)
>>>Psychiatry Highlights
Source:
 Nov. issue of the American Journal of Psychiatry (2018; 175).
White Matter & Antipsychotics: “Long-term antipsychotic treatment does not adversely affect white matter tracts over the longer-term course of illness and may confer benefits,” conclude authors who looked at white matter deficits in schizophrenia (pp. 1129–36). In 31 never-treated and 46 antipsychotic-treated patients with long-term schizophrenia and 58 healthy comparison participants, the authors found: “Fractional anisotropy significantly differed among the three groups in 14 of 20 white matter tracts defined in the Johns Hopkins University white matter template. Never-treated patients displayed greater reduction of fractional anisotropy than antipsychotic-treated patients in the left anterior thalamic radiation, the left cingulum-hippocampus pathway, the splenium and genu of the corpus callosum, and the left superior longitudinal fasciculus, and greater fractional anisotropy in the right uncinate fasciculus. Both patient groups showed multiple reductions relative to healthy comparison subjects. Never-treated patients showed an accelerated and clinically relevant age-related reduction of fractional anisotropy in the genu of the corpus callosum.” (Y. Xiao)
“While the results of this study present additional pieces of the larger puzzle, they still should be interpreted with caution,” editorialists write, citing the study size and possible type I and II errors (
pp. 1056–7). “Drug-naive patients are more likely (although not explicitly measured) to have lower socioeconomic status, less family support, lack of physical activity, and a possible substance abuse disorder, as well as a higher likelihood of malnutrition. Nonetheless, the findings are still very intriguing and will no doubt provide renewed energy to the debate about the impact of antipsychotic medications.” (M. Kubicki)
>>>PNN NewsWatch
Roche Diagnostics is recalling certain test strip lots used with its CoaguChek test meter by providers and patients to monitor warfarin.

PNN Pharmacotherapy Line
Nov. 5, 2018 * Vol. 25, No. 213
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 362).
Mirtazapine in Treatment-Resistant Depression: Added to a serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressant for treatment-resistant depression in primary care settings, mirtazapine was of no added clinically important benefit, researchers report (k4218). The assessment included 480 adults who were randomized to mirtazapine or placebo after depression symptoms remained despite 6 weeks of SNRI or SSRI treatment. Results for 431 participants included in the 12-week analysis were as follows: “Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P = 0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.” (D. S. Kessler, david.kessler@bristol.ac.uk)
Maternal–Fetal Zika Virus Transmission & Outcomes: The frequencies of congenital Zika virus transmission and resulting severe perinatal complications are quantified in a study from French Guiana, with investigators concluding, “The burden of [congenital Zika syndrome (CZS)] might be lower than initially described in South America and may not differ from other congenital infections” (k4431). Prospective enrollment of 300 pregnant women and their 305 fetuses/newborns showed these patterns of infection and outcomes: “Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed.” (D. Baud, david.baud@chuv.ch)
>>>PNN NewsWatch
* Despite concerns expressed by an FDA advisory committee chair and U.S. Senators, FDA on Friday approved AcelRx’s formulation of sufentanil sublingual tablet 30 mcg, Dsuvia. “To address concerns about the potential risks associated with Dsuvia, this product will have strong limitations on its use,” FDA Commission Scott Gottlieb, MD, said in a statement. “It can’t be dispensed to patients for home use and should not be used for more than 72 hours. And it should only be administered by a health care provider using a single-dose applicator. That means it won’t be available at retail pharmacies for patients to take home. These measures to restrict the use of this product only within a supervised health care setting, and not for home use, are important steps to help prevent misuse and abuse of Dsuvia.…”
Janssen Pharmaceuticals is recalling three lots of its norethindrone/ethinyl estradiol product to the pharmacy level because they do not include the appropriate instructions for the Veridate® dispenser: one lot of Ortho-Novum Tablets and two lots of Ortho-Novum 7/7/7.
>>>PNN JournalWatch
Antibiotic Shortages in Pediatrics, in Pediatrics, 2018; 142: e20180858. (R. Banerjee)
Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective, in American Journal of Psychiatry, 2018; 175: 1073–83. (A. S. Brown)
Ejection Fraction Pros and Cons: JACC State-of-the-Art Review, in Journal of the American College of Cardiology, 2018; 72: 2360 ff. (T. H. Marwick)
Management of Pharyngitis: Should America Fall in Line With the Rest of the Developed World?, in Circulation, 2018; 138: 1920–2. (J. Berkley, berkley_j@meuhedet.co.il)

PNN Pharmacotherapy Line
Nov. 6, 2018 * Vol. 25, No. 214
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Nov. 6 issue of Annals of Internal Medicine (2018; 169).
Overlapping Opioid & Benzodiazepines in Veterans: Dual-eligible veterans receiving prescriptions from both the VA system and Medicare Part D were significantly more likely to have overlapping medication orders for benzodiazepines and opioids in 2013, researchers report (pp. 593–601). Simultaneous use of drugs in the two categories is associated with increased risk for overdose. In a cross-sectional analysis of data for 2013 from the VA and Medicare systems, the authors found these outcomes based on the Pharmacy Quality Alliance (PQA) measure of opioid–benzodiazepine overlap (≥2 filled prescriptions for benzodiazepines with ≥30 days of overlap with opioids) and the proportion of patients with high-dose opioid–benzodiazepine overlap (≥30 days of overlap with a daily opioid dose >120 morphine milligram equivalents): “Of 368,891 eligible veterans, 18.3% received prescriptions from the VA only, 30.3% from Medicare only, and 51.4% from both VA and Medicare. The proportion with PQA opioid–benzodiazepine overlap was larger for the dual-use group than the VA-only group (23.1% vs. 17.3%; adjusted risk ratio [aRR], 1.27 [95% CI, 1.24 to 1.30]) and Medicare-only group (23.1% vs. 16.5%; aRR, 1.12 [CI, 1.10 to 1.14]). The proportion with high-dose overlap was also larger for the dual-use group than the VA-only group (4.7% vs. 2.3%; aRR, 2.23 [CI, 2.10 to 2.36]) and Medicare-only group (4.7% vs. 2.9%; aRR, 1.06 [CI, 1.02 to 1.11]).” (W. F. Gellad, walid.gellad@va.gov)
Medicine & Marijuana: “Regardless of whether individual practitioners are for or against [medical marijuana (MM)], we must acknowledge that it has become a clinical reality,” authors write in an attempt to reconcile “the discrepancies in medicine’s relationship to MM” (pp. 646–7). “Individual providers and professional organizations should unite in advocating reclassification of cannabis from Schedule I, defined by federal drug enforcement authorities as drugs with no currently accepted medical use and a high potential for abuse, to Schedule II, defined as drugs with a high potential for abuse (including cocaine). This rescheduling would loosen restrictions on biomedical research; without it, daunting administrative hurdles to the study of MM will likely persist. Our team, for instance, has labored a year to obtain a Schedule I license enabling MM clinical trials. Once this license is in hand, our study drug will likely come from a federally authorized field in Mississippi whose typically low-tetrahydrocannabinol crop approximates neither products available on the street nor those found at registered MM dispensaries.” (I. Braun, ibraun@partners.org)
Public Health Response to Opioid Crisis: Authors propose a six-element response of the U.S. public health system to the ongoing opioid crisis (10.7326/M18-1757). “The comprehensive approach presented here builds on successful efforts by states and territories,” the authors write. “It incorporates national ‘roadmaps’ and ‘frameworks’ that have been developed individually to guide government responses to the opioid crisis but have not fully addressed all of the tactical approaches to ending it.” Elements of the proposed response are as follows (M. Levine, Mark.Levine@vermont.gov):
Leadership, with key leaders in government and nongovernment agencies and in communities statewide, establishes a shared vision for comprehensively addressing opioid use disorder throughout the jurisdiction.
Partnership and collaboration promote the cross-cutting, multisector work needed to comprehensively address opioid use disorder. 
Epidemiology and surveillance [are used] to improve prevention, treatment, and recovery response by using real-time public health data for decision making and to inform the development and implementation of programs and policies.
Education and prevention include building individual and community resilience, addressing health-related social needs, implementing evidence-based campaigns to educate and build awareness, and engaging communities in addressing the root causes of addiction.
Treatment and recovery may or may not be part of a public health agency’s purview. 
Harm reduction and overdose prevention efforts (such as syringe services programs) provide opportunities to intervene and refer individuals to treatment.

PNN Pharmacotherapy Line
Nov. 7, 2018 * Vol. 25, No. 215
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 6 issue of JAMA, a theme issue on global hypertension (2018; 320).
High Blood Pressure in Young Adults: In four studies and related commentaries, guideline-defined blood pressure (BP) elevations are young adults is examined. 
Young adults with high BPs as defined in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines have significantly higher risk for subsequent cardiovascular disease (CVD) events, a study shows (
pp. 1774–82). In 4,851 adults in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, those with elevated BP, stage 1 hypertension, or stage 2 hypertension before age 40 had these outcomes: “Over a median follow-up of 18.8 years, 228 incident CVD events occurred ([coronary heart disease (CHD)], 109; stroke, 63; heart failure, 48; [peripheral artery disease], 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07–1.75), 2.74 (95% CI, 1.78–4.20), 3.15 (95% CI, 2.47–4.02), and 8.04 (95% CI, 6.45–10.03) per 1,000 person–years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01–2.77), 1.75 (95% CI, 1.22–2.53), and 3.49 (95% CI, 2.42–5.05), respectively.” (Y. Yano, yyano@jichi.jp)
A similar analysis of young adults covered by the Korean National Insurance Service reaches the same conclusion for those with stage 1 or stage 2 hypertension (
pp. 1783–92).Among nearly 2.5 million people, risks of CVD events were increased among both men and women with stage 1 or 2 hypertension as defined in the 2017 ACC/AHA criteria. (S. M. Park, smpark.snuh@gmail.com)
“Studies are needed to elucidate the developmental origins of higher blood pressure levels in children and the impact of social determinants of health, acculturation, and allostatic load on blood pressure trajectories in youth,” writes an editorialist (
pp. 1760–3). “Greater clarity is needed regarding the potential use of individual characteristics (eg, geographic residence in the stroke belt, black race with apolipoprotein L1 risk alleles, or a positive family history of CVD), long-term CVD risk, and blood pressure–mediated target organ damage to guide treatment decisions for high blood pressure levels in young adults. Optimal blood pressure targets in relation to plausible clinical benefit vs possible harm due to long-term blood pressure–lowering treatments need to be clearly delineated for young adults with nonnormal blood pressure levels according to the ACC/AHA classification. Bridging these critical knowledge gaps may help define how, when, and what measures could be implemented to maintain an optimal blood pressure profile from childhood through young adulthood and beyond. Answers to these questions will be a public health legacy to the current generation of children and young adults and to their future offspring.” (R. S. Vasan, vasan@bu.edu)
Focusing on hypertension as a “public health challenge of global proportions,” authors of a second editorial make these recommendations (
pp. 1757–9): “The traditional health care model of office visits for the control of blood pressure must be replaced. The control rate of hypertension in the United States has been hovering at a disconcerting 50%. Innovative systems of health care delivery are needed to improve quality of care and reduce costs. Inventive solutions will involve new technologies and models like algorithmic, non–physician-based treatment plans that rely on the automatic transmission of home blood pressure measurements, or hypertensive care delivered in unconventional settings. The management of hypertension on the population level must continue to strengthen as a team effort. More ambitious, innovative thinking should mobilize the international health care community to create sustainable solutions for controlling the problem of high blood pressure, one of the most deleterious health risk factors in nearly every country around the world.” (G. Curfman, gregory.curfman@jamanetwork.org)
Nitrites in Heart Failure: Compared with placebo in 105 patients with heart failure with preserved ejection fraction, inhaled inorganic nitrite failed to improve exercise capacity in a 4-week trial (pp. 1764–73; B. A. Borlaug, borlaug.barry@mayo.edu).

PNN Pharmacotherapy Line
Nov. 8, 2018 * Vol. 25, No. 216
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 8 New England Journal of Medicine (2018; 379).
Triple-Drug Treatment for Lymphatic Filariasis: Compared with single or three annual doses of a two-drug regimen, a three-drug combination proved superior for clearing microfilariae in participants in Papua New Guinea with lymphatic filariasis, researchers report (pp. 1801–10). The World Health Organization has a 2020 goal of eliminating this condition through mass drug administration. In this study of the optimal regimen for clearing Wuchereria bancrofti microfilaremia, ivermectin plus diethylcarbamazine plus albendazole produced rates of 96% at 1, 2, and 3 years, compared with rates ranging from 32% to 83% for a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and 34% to 98% for three annual doses of the two-drug regimen. (C. L. King, cxk21@case.edu)
“The widespread use of the triple-drug treatment will further facilitate the public health success of the global filariasis elimination efforts, accelerating the reduction of transmission, particularly in what have previously been residual hotspots,” writes an editorialist (
pp. 1871–2). “It will bring additional health benefits with the incorporation of ivermectin into national programs, thus reducing the transmission of scabies as well as intestinal helminths.” (D. H. Molyneux)
Elotuzumab in Multiple Myeloma: The immunostimulatory monoclonal antibody elotuzumab plus pomalidomide and dexamethasone produced significantly lower rates of progression or death among 117 patients with multiple myeloma, compared with pomalidomide plus dexamethasone alone, a study shows (pp. 1811–22). Patients had refractory or relapsed multiple myeloma that was refractory to lenalidomide and a proteasome inhibitor. “After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group,” the investigators write. “The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P = 0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11).” (M. A. Dimopoulos, mdimop@med.uoa.gr)
Energy-Dense Enteral Nutrition in Critically Ill Patients: Among 3,957 patients undergoing mechanical ventilation, use of energy-dense enteral nutrition provided no benefits over routine products, according to authors at 46 intensive care units in Australia and New Zealand (pp. 1823–34). In addition to lack of improvement in a primary outcome of all-cause mortality at 90 days, the authors report, “Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events.” (S. L. Peake, sandra.peake@sa.gov.au)
Single-Dose Zoliflodacin for Urogenital Gonorrhea: While effective for treating most uncomplicated cases of urogenital and rectal gonococcal infections, oral zoliflodacin was less useful in patients with pharyngeal infections in a phase 2 trial of the DNA biosynthesis inhibitor (pp. 1835–45). Participants were men or women with signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea, or who were untreated after potentially infectious sexual contact within 14 days. “Among the 141 participants in the [microbiologic intention-to-treat] population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone,” results show. “All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively.” (S. N. Taylor, staylo2@lsuhsc.edu)
>>>PNN NewsWatch
Kadesh, Inc. is voluntarily recalling all lots of the OTC product Puriton Eye Relief Drops, 15-mL bottle, to the consumer level because of a lack of sterility assurance.

PNN Pharmacotherapy Line
Nov. 9, 2018 * Vol. 25, No. 217
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
 Nov. issue of Chest (2018; 154).
Lower Glucose Target in Critically Ill Patients: Tight glycemic control in critically ill patients is supported by mortality data from a cohort of 1,809 patients, most of them in cardiac units, researchers report (pp. 1044–51). Patients receiving intravenous insulin were treated to target glucose levels of 80–110 or 90–140 mg/dL, with these results: “Median glucose was lower in the 80–110 mg/dL group (104 vs 122 mg/dL, P < .001). Severe hypoglycemia occurred at very low rates in both groups (1.16% vs 0.35%, P = .051). Unadjusted 30-day mortality was lower in the 80–110 mg/dL group (4.3% vs 9.2%, P < .001). This remained after propensity score-adjusted regression (OR, 0.65; 95% CI, 0.43–0.98; P = .04).” (A. M. Hersh, Andrew.m.hersh.mil@mail.mil)
Reflecting on the current practice of using higher blood glucose (BG) targets in critical care, an editorialist writes, “The widespread adoption of the ‘moderate’ BG target of 140 to 180 mg/dL in the critically ill reflected the principle of ‘first, do no harm’” (
pp. 1004–5). “However, the study by Hersh et al. has shown that dedicated clinical teams using standardized protocols that include high frequency of BG measurement can safely achieve ‘tight’ and ‘moderately tight’ levels of mean ICU glycemia. Optimal glucose control includes safety (low rates of hypoglycemia) and efficacy (appropriate BG targets based on patient characteristics). These principles are achievable and should prompt reassessment of BG targets in the critically ill.” (J. S. Krinsley, jkrinsley@stamhealth.org)
>>>Cardiology Report
Source:
 Nov. 6 issue of the Journal of the American College of Cardiology (2018; 72).
sST2 Biomarker in HF: The soluble suppression of tumorigenesis-2 (sST2) biomarker provides strong predictive value in patients with chronic heart failure (HF), a study reports (10.1016/j.jacc.2018.08.2165). Used with N-terminal pro−B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT), sST2 “deserves consideration to be part of a multimarker panel,” the authors conclude, based on these individual-level data from prior studies: “Among the 4,118 patients (96%) with available data, 1,029 (24%) were hospitalized at least once for worsening HF over 2.2 years. The best sST2 cutoff for the prediction of all-cause and cardiovascular death and HF hospitalization was 28 ng/ml, with good performance at Kaplan–Meier analysis (log-rank: 117.6, 61.0, and 88.6, respectively; all p <0.001). In a model that included age, sex, body mass index, ischemic etiology, LVEF, New York Heart Association functional class, glomerular filtration rate, HF medical therapy, NT-proBNP, and hs-TnT, the risk of all-cause death, cardiovascular death, and HF hospitalization increased by 26%, 25%, and 30%, respectively, per each doubling of sST2. sST2 retained its independent prognostic value across most population subgroups.” (M. Emdin)
Ejection Fraction in “Modern Cardiology”: In a review article, the continued place in cardiology of ejection fraction (EF) is assessed based on availability of new ly available biomarkers (10.1016/j.jacc.2018.08.2162): “EF reflects both cardiac function and remodeling, and is widely recognized as a valuable diagnostic and prognostic tool. Its use in a variety of settings, ranging from heart failure and myocardial infarction to valvular heart disease, has made it a cornerstone of modern cardiology, pervading guidelines and practice. However, the development of the test was in another era, with younger patients and a lower prevalence of heart failure with preserved EF. The performance expectations of EF in the current era are also demanding—in relation to detection of subclinical LV dysfunction, and especially relating to recognition of changes in LV function on sequential testing—for example in patients taking cardiotoxic drugs. This review discusses whether the impressive evidence base for EF justifies its ongoing use in the context of newer markers of LV function, and the sophisticated questions posed by modern cardiology.” (T. H. Marwick)
>>>PNN NewsWatch
FDA yesterday allowed remarketing of OTC Primatene Mist inhaler, still containing the problematic agent epinephrine.
CDC is reporting the lowest level of use of cigarette/nicotine/tobacco products ever recorded among Americans — 14% in 2017, a decline from 15.5% in 2016.

PNN Pharmacotherapy Line
Nov. 12, 2018 * Vol. 25, No. 218
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Nov. 10 issue of Lancet (2018; 392).
Global Burden of Disease — The Past: “Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health,” conclude collaborators in the Global Burden of Diseases 2017 project (pp. 1736–88). “Improvements in global health have been unevenly distributed among populations,” the authors add, based on cause-specific mortality data from 195 countries and territories for 1980 through 2017. “For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for [noncommunicable diseases], and the death rate for selected causes has increased in the past decade.” (GBD 2017 Causes of Death Collaborators)
Predictions for Future Causes of Global Mortality: Forecasting mortality causes for 2016 to 2040 in 195 countries and territories, investigators predict “global life expectancy [will] increase by 4.4 years (95% UI 2.2 to 6.4) for men and 4.4 years (2.1 to 6.4) for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7.8 years (5.9 to 9.8) to a non-significant loss of 0.4 years (–2.8 to 2.2) for men, and an increase of 7.2 years (5.3 to 9.1) to essentially no change (0.1 years [–2.7 to 2.5]) for women” (pp. 2052–90). “Our reference forecast points to overall improvements through 2040 in most countries, yet the range found across better and worse health scenarios renders a precarious vision of the future—a world with accelerating progress from technical innovation but with the potential for worsening health outcomes in the absence of deliberate policy action. For some causes of [years of life lost], large differences between the reference forecast and alternative scenarios reflect the opportunity to accelerate gains if countries move their trajectories toward better health scenarios—or alarming challenges if countries fall behind their reference forecasts. Generally, decision makers should plan for the likely continued shift toward [noncommunicable diseases] and target resources toward the modifiable risks that drive substantial premature mortality. If such modifiable risks are prioritised today, there is opportunity to reduce avoidable mortality in the future. However, [communicable, maternal, neonatal, and nutritional] causes and related risks will remain the predominant health priority among lower-income countries. Based on our 2040 worse health scenario, there is a real risk of HIV mortality rebounding if countries lose momentum against the HIV epidemic, jeopardising decades of progress against the disease.…” (C. J. L. Murray, cjlm@uw.edu)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 363) report:
* Comparative safety data for immune checkpoint inhibitors used for treating cancers (
k4226; J. Ma, majun2@mail.sysu.edu.cn).
* Gender-specific risk factors for myocardial infarction, including several more common in women (
k4247; S. A. E. Peters, sanne.peters@georgeinstitute.ox.ac.uk).
* Better outcomes with triple therapy for COPD, compared with one- or two-drug regimens (
k4388; W Yao, yaoweimin2014@yeah.net).
>>>PNN NewsWatch
* FDA’s New Inspection Protocol Project uses standardized electronic inspection protocols to collect data in a structured manner for more consistent oversight of aseptic manufacturing facilities, FDA Commissioner Scott Gottlieb says in a statement posted on Friday.
>>>PNN JournalWatch
* Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis, in Chest, 2018; 154: 1108–14. (L. T. Hong, lhong@llu.edu)
*
Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report, in Chest, 2018; 154: 1121–201. (G. Y. H. Lip, gregory.lip@liverpool.ac.uk)
*
Antimicrobial Resistance and Respiratory Infections, in Chest, 2018; 154: 1202–12. (G. D. Wright, wrightge@mcmaster.ca)
*
Evaluation of Community Pharmacy Tech-Check-Tech as a Strategy for Practice Advancement, in Journal of the American Pharmacists Assoc., 2018; 58: 652–8. (R. Fleagle Miller, rachael.fleaglemiller@nm.org)

PNN Pharmacotherapy Line
Nov. 13, 2018 * Vol. 25, No. 219
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Nov. issue of JAMA Internal Medicine (2018; 178).
Low-Dose Amitriptyline for Chronic Low Back Pain: When the only alternative is an opioid, low-dose amitriptyline “may be worth considering” in patients with chronic low back pain, authors conclude based on results of a 146-patient, 6-month trial (pp. 1474–81). Compared with benztropine mesylate 1 mg/d, amitriptyline 25 mg/d reduced disability at 3 months, improved pain intensity nonsignificantly at 6 months, and produced minimal adverse effects. (D. M. Urquhart, donna.urquhart@monash.edu)
NSAIDs & HTN, HF or CKD: Short-term use of prescription NSAIDs was not associated with increased risk of adverse safety outcomes in older adults with hypertension, heart failure, or chronic kidney disease in a retrospective cohort study from Ontario (pp. 1516–25). Administrative claims data analysis showed these results for patients aged 65 years or older and histories of these conditions: “The study identified 2,415,291 musculoskeletal-related primary care visits by 814,049 older adults (mean [SD] age, 75.3 [4.0] years; 61.1% female) with hypertension, heart failure, or CKD, of which 224,825 (9.3%) were followed by prescription NSAID use. The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%–16.7%) among 7,365 primary care physicians. Within a sample of 35,552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, −0.001 to 0.002; P = .74).” (R. S. Bhatia, sacha.bhatia@wchospital.ca)
Commenting on this and another real-world study of allopurinol use in patients with gout (
pp. 1526–33; T. Neogi, tneogi@bu.edu), editorialists point to the importance of adding information available in large databases on patient experiences to findings from randomized controlled trials (RCTs) (pp. 1533–4): “Done well, observational studies can provide valuable information about the real-world safety of drugs. Moving forward, detailed real-world data will be increasingly available in electronic health records and registries. In response to initiatives such as the 21st Century Cures Act, the National Evaluation System for Health Technology, and the US Food and Drug Administration’s Sentinel Initiative, we can expect to see more observational studies testing longstanding assumptions about treatments, along with new uses for old therapies. Yes, the findings will need to be contextualized and viewed with more skepticism than RCTs, but in some instances, they can be thoughtfully integrated into our treatment decisions.” (D. N. Juurlink, dnj@ices.on.ca)
Long-Term Benzodiazepine Use Among Older Adults: Among older adults covered by Pennsylvania’s prescription assistance program, transitions of new prescriptions for benzodiazepines to long-term use were associated with white race, provision of refills, and higher number of days supplied (pp. 1560–2), as shown in these results: “The mean (SD) age of adults newly prescribed a benzodiazepine was 78.4 (7.0) years. One year after the index prescription, 152 (26.4%) met the definition of long-term use; this group was prescribed a mean (SD) of 232.7 (82.6) benzodiazepine days. In adjusted analyses, white race (odds ratio [OR], 4.19; 95% CI, 1.51–11.59), days supplied in the index prescription (OR, 1.94; 95% CI, 1.52–2.47), and poor sleep quality (OR, 4.05; 95% CI, 1.44–11.43) were associated with increased long-term benzodiazepine use. High anxiety and depression did not predict long-term benzodiazepine use in either unadjusted or adjusted analyses.” (L. B. Gerlach, glauren@med.umich.edu)
>>>PNN NewsWatch
* FDA has approved revefenacin (Yupelri, Theravance Biopharma and Mylan) inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease. The drug, a long-acting muscarinic antagonist, is the first and only once-daily, nebulized bronchodilator approved for the treatment of COPD in the U.S.

PNN Pharmacotherapy Line
Nov. 14, 2018 * Vol. 25, No. 220
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Nov. 13 issue of JAMA (2018; 320).
Pharmacist Interventions: Three studies and an editorial examine the extent and impact of pharmacists’ interventions. 
In the D-PRESCRIBE (Developing Pharmacist-Led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly) trial, community pharmacists decreased use of inappropriate medications at 6 months through interventions with older adults (
pp. 1889–98). Compared with usual care, education of older adults in Quebec who were on one of four Beers criteria medications produced these results: “Among 489 patients (mean age, 75 years; 66% women), 437 (89%) completed the trial (219 [88%] in the intervention group vs 218 [91%] in the control group). At 6 months, 106 of 248 patients (43%) in the intervention group no longer filled prescriptions for inappropriate medication compared with 29 of 241 (12%) in the control group (risk difference, 31% [95% CI, 23% to 38%]). In the intervention vs control group, discontinuation of inappropriate medication occurred among 63 of 146 sedative–hypnotic drug users (43.2%) vs 14 of 155 (9.0%), respectively (risk difference, 34% [95% CI, 25% to 43%]); 19 of 62 glyburide users (30.6%) vs 8 of 58 (13.8%), respectively (risk difference, 17% [95% CI, 2% to 31%]); and 19 of 33 nonsteroidal anti-inflammatory drug users (57.6%) vs 5 of 23 (21.7%), respectively (risk difference, 35% [95% CI, 10% to 55%]) (P for interaction = .09). Analysis of the antihistamine drug class was not possible because of the small sample size (n = 12). No adverse events requiring hospitalization were reported, although 29 of 77 patients (38%) who attempted to taper sedative–hypnotics reported withdrawal symptoms.” (C. Tannenbaum, cara.tannenbaum@umontreal.ca)
Two years after a state law permitted trained pharmacists to furnish naloxone without a physician’s prescription, only a quarter of California pharmacies were were doing so, a study shows (
pp. 1933–4). An anonymous 20% random sample of community pharmacies in the state showed these results in early 2018: “Pharmacist-furnished naloxone was available at 23.5% (95% CI, 21.0%–26.0%) of pharmacies.… There was a significant difference by pharmacy type, with 31.6% (95% CI, 28.3%–35.1%) of chain pharmacies compared with 7.5% (95% CI, 5.1%–10.6%) of independent pharmacies furnishing naloxone (P < .001).
“Among pharmacies furnishing naloxone (n = 269), 225 (83.6%) offered a nasal formulation. Fourteen (5.2%) offered combination buprenorphine–naloxone tablets used for treatment of opioid use disorder, not opioid overdose. Of pharmacies furnishing naloxone, 50.6% had nasal naloxone in stock. Chain pharmacies were significantly more likely to have nasal naloxone in stock (52.3%; 95% CI, 46.3%–59.4%) compared with independents (31.0%; 95% CI, 15.3%–50.8%) (P = .03). Regarding insurance billing, 59.9% of pharmacies replied correctly that pharmacist-furnished naloxone could be billed, with no significant difference by pharmacy type. The median cash price of nasal naloxone (pack of 2) at chain pharmacies was $136 (IQR, $120–$143.50) compared with $150 (IQR, $138.50–$170) (P = .04) at independents.” (T. Puzantian, 
talia_puzantian@kgi.edu)
In mid-2018, naloxone was generally available at Texas chain pharmacies, researchers report (
pp. 1934–7). Interviews of one pharmacist at each of 2,317 major chain units in the state showed that 83.7% of respondents would dispense naloxone without a prescription, 76.4% currently stocked naloxone, 79.9% would allow naloxone purchase for someone else, and 49.7% would bill the purchaser’s insurance. (K. E. Evoy, evoy@uthscsa.edu)
“Once started, medications can be difficult to stop,” editorialists write in response to the three studies (
pp. 1867–9). “Older adults often take too many medications. More naloxone in the hands of friends and family can save lives. Change, or overcoming inertia in health care, is difficult but essential to deprescribing harmful medications and making effective medications available to individuals who need them. Involving groups that are less often the target of interventions to overcome inertia, such as patients and pharmacists, will likely be necessary for medicine to achieve such changes. These changes are more likely to be achieved if patients, pharmacists, nurses, and organizations all push and pull in the same direction.” (C. S. Landefeld, sethlandefeld@uabmc.edu)

PNN Pharmacotherapy Line
Nov. 15, 2018 * Vol. 25, No. 221
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 15 issue of and early-release articles from New England Journal of Medicine (2018; 379).
Prednisone for Preventing Paradoxical TB-Associated IRIS: For preventing paradoxical tuberculosis (TB)–associated immune reconstitution inflammatory syndrome (IRIS) in patients with HIV and TB, prednisone provides protection during the early initiation of antiretroviral therapy (ART), researchers report (pp. 1915–25). Compared with placebo, prednisone 40 mg/d for 14 days and then 20 mg/d for 14 days yielded these results: “Among the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P = 0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P = 1.00). Severe infections (acquired immunodeficiency syndrome–defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P = 0.23). One case of Kaposi’s sarcoma occurred in the placebo group.” (G. Meintjes, graemein@mweb.co.za)
Palbociclib/Fulvestrant in Advanced Breast Cancer: Among women with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, addition of palbociclib to fulvestrant therapy extended overall survival in a placebo-controlled trial (pp. 1926–36). Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, produced significant changes in this subgroup but no significant benefits in the overall population: “Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P = 0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P <0.001). No new safety signals were observed with 44.8 months of follow-up.” (N. C. Turner, nick.turner@icr.ac.uk)
Disclosing Prescription-Drug Prices in Advertisements: Aspects of a recent CMS rule proposing disclosure of prescription-drug prices in direct-to-consumer advertising “undercut the government’s ability to argue that it will materially improve patient decision making and reduce drug spending,” according to authors of a Perspective article (10.1056/NEJMp1814065). (S. B. Dusetzina)
>>>PNN NewsWatch
FDA yesterday warned of serious complications when medications are delivered into spinal fluid with implanted pumps not approved for that use. Complications may include dosing errors, pump failure, opioid withdrawal, infection, and other complications such as pain, fever, vomiting, muscle spasms, cognitive changes, weakness, and cardiac or respiratory distress. FDA recommends that health professionals review the implanted pump labeling to identify the medicines and medicine concentrations approved for use with that device.

PNN Pharmacotherapy Line
Nov. 16, 2018 * Vol. 25, No. 222
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 Dec. 1 issue of Clinical Infectious Diseases (2018; 67).
Benchmarking Inpatient Antimicrobial Use: In 2.7 million inpatient admissions, a simplified antimicrobial stewardship program (ASP) ratio showed promise for improving the comparison of antibiotic use between health care facilities, researchers report (pp. 1677–85). The model — which included common facility and encounter factors in a single-level parsimonious model — yielded these results in comparison with a complex ratio based on all available factors and a facility ratio using only broad hospital characteristics: “Diagnosis-related groups, infection present on admission, patient class, and unit type were the major predictors of expected antibiotic use. Aside from a history of gram-positive resistance in the prior 12 months for anti–methicillin-resistant Staphylococcus aureus drugs, additional clinical and comorbid history information did not improve the model. The simplified ASP ratio demonstrated higher Pearson correlation (R2 = 0.97–0.99) to the complex ratio than the facility ratio (R2 = 0.57–0.85) and provided clinical explanations when discordant.” (K. C. Yu, kalvin.c.yu@kp.org)
Zoster Vaccine Live in HIV-Infected Adults with High CD4 Counts: In a study of adult patients with HIV on antiretroviral therapy (ART) whose CD4+ counts were 200 cells/µL or more, live attenuated zoster vaccine (ZV) was safe and efficacious (pp. 1712–9). Two vaccine doses were studied, with these results based on a primary endpoint of serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose: “Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%–8.2%] vs 2.1% [95% CI, .3%–7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%–47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%–20.6%) (P < .001). Week 12 median natural log [varicella zoster virus (VZV)] antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction–confirmed [herpes zoster] occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related.” (C. A. Benson, cbenson@ucsd.edu)
>>>Vaccine Highlights
Source:
 Nov. 26 issue of Vaccine (2018; 36).
Acute Otitis Media & Antimicrobial Rx’s Declining: During the 2011–16 period, the incidence of acute otitis media (AOM), antimicrobial prescriptions for AOM, and associated medical expenses declined in the U.S., a study shows, with authors concluding that further research is needed to see if the results correlate with the 2007 change in pneumococcal vaccine in the pediatric vaccination schedule (pp. 7479–86). For children 9 years of age or younger, these findings were obtained from national data on AOM cases, medical expenditures, and population: “In 2011, there were an estimated 11.5 million AOM episodes in children aged 0–9 years in the U.S. with AOM incidence rates (IR) of 476, 204, and 284 episodes per 1,000 children aged 0–2, 3–9, and 0–9 years, respectively. All subsequent years had lower IRs, and by 2016, IR was 25.1% lower than in 2011 in children 0–9 years. In addition, there were estimates of 10.8 million and 9.2 million fewer cumulative AOM episodes and antimicrobial prescriptions for AOM nationwide between 2012 and 2016, compared to annual 2011 estimates, representing a ~$5.6 billion decrease in direct medical expenditures. The average number of antibiotic prescriptions per AOM visit remained stable with 0.89 and 0.86 prescriptions per visit in 2011 and 2016, respectively.” (J. A. Suaya, Jose.suaya@pfizer.com)
Pneumococcal Vaccination Among Older Adults: Completion rates of the two-vaccine series for pneumococcal disease is low among adults age 65 years or older, according to data on 224,132 people with records in the Clinformatics DataMart database (pp. 7574–9; X. Yang, xiaoqin.yang@merck.com).
>>>PNN NewsWatch
* In statements released yesterday, FDA detailed its rationale on reducing the use of flavors in e-cigarettes and results of the 2018 National Youth Tobacco Survey showing a “dramatic increase in e-cigarette use among youth over past year.”

PNN Pharmacotherapy Line
Nov. 19, 2018 * Vol. 25, No. 223
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 362).
Inappropriate Prescribing in Older People & Hospital Admission: Medications considered potentially inappropriate in older adults were associated with increased risk of hospital admissions in a longitudinal study of 44 general practices in Ireland in 2012–15 (k4524). Using 45 criteria from the Screening Tool for Older Persons’ Prescription (STOPP) version 2, the investigators found these results among 38,229 patients with an average age of 76.8 years in 2012: “Each year, 10.4–15.0% (3,015/29,077 in 2015 to 4,537/30,231 in 2014) of patients had at least one hospital admission. The overall prevalence of potentially inappropriate prescribing ranged from 45.3% (13,940/30,789) of patients in 2012 to 51.0% (14,823/29,077) in 2015. Independently of age, sex, number of prescription items, comorbidity, and health cover, hospital admission was associated with a higher rate of distinct potentially inappropriate prescribing criteria met; the adjusted hazard ratio for hospital admission was 1.24 (95% confidence interval 1.20 to 1.28).” (F. Moriarty, frankmoriarty@rcsi.ie)
SGLT2 Inhibitors & Serious Adverse Events: Lower limb amputation and diabetic ketoacidosis were significantly more common with use of SGLT2 inhibitors than GLP1 agonists, according to an analysis of nationwide registries of Sweden and Denmark (k4365). The frequencies of seven serious adverse events were analyzed: lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis. Comparing use of SGLT2 inhibitors versus GLP1 agonists, significant increases in hazard ratios were found for lower limb amputation (2.7 vs. 1.1 events per 1,000 person–years; hazard ratio 2.32) and diabetic ketoacidosis (1.3 vs. 0.6 events per 1,000 person–years; hazard ratio, 2.14). (P. Ueda, peter.ueda@ki.se)
>>>Lancet Highlights
Source:
 Nov. 17 issue of Lancet (2018; 392).
LY3298176 in Type 2 Diabetes: The novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist LY3298176 showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile, in patients with type 2 diabetes, researchers report (pp. 2180–93). Among 316 participants in the phase 2 trial, comparison of LY3298176 with placebo or selected GLP01 agonists showed significant improvements in the primary outcome, A1C levels, at 26 weeks. Secondary outcomes were also improved significantly, including change in A1C levels from baseline to 12 weeks; change in body weight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the A1C target (≤6.5% and <7.0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% body weight loss from baseline to 26 weeks. (A. Haupt, haupt_axel@lilly.com)
>>>PNN NewsWatch
FDA on Friday approved the antibacterial drug rifamycin (Aemcolo, Cosmo Technologies), with an indication for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli not complicated by fever or blood in the stool.
* “The timely completion of 
postmarketing studies remains a critical part of our regulatory responsibility,” FDA Commissioner Scott Gottlieb, MD, said on Friday in a statement reviewing FDA’s efforts to hold industry accountable for fulfilling such studies on the benefits and safety of new drugs.
>>>PNN JournalWatch
Early Clindamycin for Bacterial Vaginosis in Pregnancy (PREMEVA): A Multicentre, Double-Blind, Randomised Controlled Trial, in Lancet, 2018; 392: 2171–9. (R. Dessein, rodrigue.dessein@chru-lille.fr)
The Effect of Antibiotic Selection Pressure on the Nasopharyngeal Macrolide Resistome: A Cluster-Randomized Trial, in Clinical Infectious Diseases, 2018; 67: 1736–42. (J. D. Keenan, jeremy.keenan@ucsf.edu)
Understanding Barriers and Predictors of Maternal Immunization: Identifying Gaps Through an Exploratory Literature Review, in Vaccine, 2018; 36: 7445–55. (C. S. Lutz, nfi5@cdc.gov)
Personalizing Medicine, in Journal of Clinical Oncology, 2018; 10.1200/JCO.18.01240. (T. Gilligan, Gilligt@ccf.org)

PNN Pharmacotherapy Line
Nov. 20, 2018 * Vol. 25, No. 224
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from the Annals of Internal Medicine (2018; 169).
Diabetes Outcomes With Nonphysician Care: At 568 VA facilities, diabetic outcomes were similar among 368,481 adult patients whose care was managed by physicians, nurse practitioners (NPs), and physician assistants (PAs), a study shows (10.7326/M17-1987). The results suggest that “similar chronic illness outcomes may be achieved by physicians, NPs, and PAs,” the authors conclude based on these findings for primary care provider (PCP) type and disease outcomes (hemoglobin A1c [HbA1c], systolic blood pressure [SBP], and low-density lipoprotein cholesterol [LDL-C]): “The PCPs were physicians (n = 3487), NPs (n = 1445), and PAs (n = 443) for 74.9%, 18.2%, and 6.9% of patients, respectively. The difference in HbA1c values compared with physicians was −0.05% (95% CI, −0.07% to −0.02%) for NPs and 0.01% (CI, −0.02% to 0.04%) for PAs. For SBP, the difference was −0.08 mm Hg (CI, −0.34 to 0.18 mm Hg) for NPs and 0.02 mm Hg (CI, −0.42 to 0.38 mm Hg) for PAs. For LDL-C, the difference was 0.01 mmol/L (CI, 0.00 to 0.03 mmol/L) (0.57 mg/dL [CI, 0.03 to 1.11 mg/dL]) for NPs and 0.03 mmol/L (CI, 0.01 to 0.05 mmol/L) (1.08 mg/dL [CI, 0.25 to 1.91 mg/dL]) for PAs. None of these differences were clinically significant.” (G. L. Jackson, george.l.jackson@duke.edu)
“The time has come to embrace many different approaches to providing primary care, particularly for persons with a chronic disease, such as diabetes,” writes an editorialist (
10.7326/M18-2941). “To this end, we have certified diabetes educators (including providers from registered nurses to physicians), pharmacists, registered dietitians, therapists (of all sorts), physical and occupational therapists, exercise physiologists, and podiatrists, among others, who are part of the diabetes treatment team,” the writer adds. “Given the right system—with resources to provide education and support, along with referral to an endocrinologist or a diabetes team if needed, and including more innovative programs, such as telehealth, online programs, and device-based data transfer and support—persons with diabetes can achieve their goals. Moreover, it is time to stop calling NPs and PAs ‘midlevel’ providers, as is common in certain systems. Nurse practitioners and PAs are competent PCPs in their own right and should be fully accepted as such.” (A. L. Peters)
Delays in Diabetes Care With High-Deductible Plans: Patients with diabetes had delays in care for first symptoms of macrovascular disease, the first diagnostic test, and the first procedure-based treatment following employer-mandated transitions to high-deductible insurance plans, researchers report (10.7326/M17-3365). Compared with control patients in low-deductible plans, 33,957 people with diabetes whose care was transitioned from low- to high-deductible plans had these outcomes: “The delay for the high-deductible group was 1.5 months (95% CI, 0.8 to 2.3 months) for seeking care for the first major symptom, 1.9 months (CI, 1.4 to 2.3 months) for the first diagnostic test, and 3.1 months (CI, 0.5 to 5.8 months) for the first procedure-based treatment.” (J. F. Wharam, jwharam@post.harvard.edu)
“[This] natural experiment provides an important piece (but only 1 piece) of the puzzle of whether or when high-deductible health plans are a good idea for patients,” an editorialist writes (
10.7326/M18-2825). “Confidence that they are not for patients with known diabetes is enhanced by this research. High cost sharing is a powerful tool; the authors prudently recommend caution to employers and policymakers considering high-deductible plans. One thing is certain: The switch is going to be a bumpy ride.” (M. V. Pauly)
>>>PNN NewsWatch
* Manufacturers of edible oils containing high levels of oleic acid can now make qualified health claims for cardiovascular benefits, FDA Commissioner Scott Gottlieb, MD, writes in a statement. Labeling must state that “supportive but not conclusive scientific evidence suggests that daily consumption of about 1.5 tablespoons (20 grams) of oils containing high levels of oleic acid may reduce the risk of coronary heart disease.” The claim will also need to make it clear that to achieve this benefit, these oils “should replace fats and oils higher in saturated fat and not increase the total number of calories you eat in a day.”

PNN Pharmacotherapy Line
Nov. 21, 2018 * Vol. 25, No. 225
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Nov. 20 issue of JAMA (2018; 320).
Recombinant Alkaline Phosphatase in Acute Kidney Injury: In a dose-finding adaptive phase 2a/2b trial of 301 critically ill adults with sepsis and associated acute kidney injury (AKI), human recombinant alkaline phosphatase had no significant effect on 7-day creatinine clearances, compared with placebo, researchers report (pp. 1998–2009). Results from the STOP-AKI trial showed “the optimal therapeutic dose of recombinant alkaline phosphatase was 1.6 mg/kg,” the authors write. “Treatment with this dose for 3 days when added to standard care resulted in a median increase in endogenous creatinine clearance of 27.6 mL/min vs 14.7 mL/min for placebo in the first 7 days, a difference that was not statistically significant.” (P. Pickkers, peter.pickkers@radboudumc.nl)
Lanreotide in Autosomal Dominant Polycystic Kidney Disease: The somatostatin analogue lanreotide failed to slow the decline in renal function in 305 adult patients with autosomal dominant polycystic kidney disease (ADPKD) in a study conducted at four Dutch nephrology clinics (pp. 2010–9). Compared with standard care in the open-label trial, lanreotide had these effects on annual rates of change of estimated glomerular filtration rate (eGFR): “Annual rate of eGFR decline for the lanreotide vs the control group was −3.53 vs −3.46 mL/min/1.73 m2 per year (difference, −0.08 [95% CI, −0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (−3.58 vs −3.45; difference, −0.13 mL/min/1.73 m2 per year [95% CI, −1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, −0.03 units per year [95% CI, −0.13 to 0.08]; P = .67).…” (R. T. Gansevoort, R.T.Gansevoort@umcg.nl)
Physical Activity Guidelines for Americans: “With so many health benefits, why is it so difficult to get people moving?” ask the HHS Assistant and Deputy Assistant Secretaries for Health in a Viewpoint article (pp. 1971–2). Responding to publication of Physical Activity Guidelines for Americans, 2nd edition (pp. 2020–8; R P. Troiano, troianor@mail.nih.gov) and its information and guidance on the types and amounts of physical activity that provide substantial health benefits, and an accompanying editorial (pp. 1983–4; P. D. Thompson, Paul.Thompson@hhchealth.org), the Viewpoint authors write: “Numerous factors influence physical activity behavior. Although some of the benefits of physical activity begin immediately, benefits related to the reduction of disease risk require regular physical activity over time and thus may not be immediately evident. In addition, making physical activity a habit requires overcoming personal barriers such as lack of time, fatigue, disability, perceived lack of enjoyment, and finding ways to make activity a routine part of the day despite other responsibilities. Family, friends, and peers can significantly influence this lifestyle choice, as do environmental factors such as climate, weather, personal safety, and access to parks, sidewalks, playgrounds, and organized sports.” (B. P. Giroir, Brett.Giroir@hhs.gov)
>>>PNN NewsWatch
FDA yesterday approved emapalumab-lzsg (Gamifant, Novimmune SA) for treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. FDA said this is the first approval of a drug specifically for HLH. Emapalumab-lzsg has been designated an orphan drug, and the application was handled through FDA priority review and breakthrough therapy processes.
FDA has posted warning letters issued to two companies for illegal marketing of products labeled as dietary supplements that contain tianeptine, a chemical compound that FDA says the “companies are illegally claiming treats opioid use disorder, pain, and anxiety, and [making] other unlawful and unproven claims.”
Dayna Less, PharmD, a PGY1 pharmacy resident, was among those killed on Monday in the shootings at Mercy Hospital in Chicago, writes Thomas E. Menighan in an APhA CEO blog
PNN will not be published on Thurs. and Fri., Nov. 22 and 23, Thanksgiving Day.

PNN Pharmacotherapy Line
Nov. 26, 2018 * Vol. 25, No. 226
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 26 New England Journal of Medicine (2018; 379).
Oral Peanut Desensitization: A clinical trial of 12% defatted peanut flour (AR101) (pp. 1991–2001; PALISADE Group of Clinical Investigators) opens the door for more specific oral immunotherapies for peanut allergy, an editorialist writes (pp. 2074–5): “The clinical value of AR101 will be to allow the initiation of peanut immunotherapy with a product that reliably contains the tiny initial quantities of peanut that are required to safely launch oral desensitization. The lowest-dose capsules of AR101 contain 0.5 mg and 1 mg of peanut protein. In the absence of a product such as AR101, it is extremely difficult to administer such a small amount of allergen to a patient on a consistent basis. The Cambridge group used microscales and issued the doses of peanut flour in vials. However, errors regarding the initial doses during the increasing-dose phase would seem to be a more likely occurrence if allergy treatment centers all measured their own doses of peanut flour rather than using a carefully manufactured product. Furthermore, the issuing of peanut flour to a patient with peanut allergy may result in the peanut being deemed an unlicensed medicinal product by regulatory organizations in some countries. Once a product such as AR101 appears, such regulators will insist that a licensed product be used when it is available, thus preventing the ongoing use of peanut flour itself.” (M. R. Perkin)
Probiotics in Children With Gastroenteritis: Commenting on a negative trial of Lactobacillus rhamnosus GG for acute gastroenteritis in children (pp. 2002–14; D. Schnadower, david.schnadower@cchmc.org) an editorialist concludes (pp. 2076–7). “These negative trial data will be valuable to clinicians and professional bodies in making decisions regarding the use of either of these probiotic formulations in children with diarrhea. However, given the large number of probiotic agents now available and considering their various mechanisms of action, abilities to colonize the bowel, and probably narrow potential efficacy for specific diseases, the possibility remains that probiotics other than L. rhamnosus might be effective in infectious diarrhea in children. For example, a recent large, placebo-controlled trial in rural India showed that prophylaxis with a probiotic formula containing L. plantarum in healthy newborns in the first 5 days of life led to a significant reduction in the rate of sepsis and lower respiratory tract infections in the first 2 months of life. This particular probiotic strain, as compared with other probiotics, including L. rhamnosus, can colonize the intestinal tract for a prolonged period.…” (J. T. LaMont)
>>>Lancet Highlights
Source:
 Nov. 24 issue of Lancet (2018; 392).
Lorcaserin & Type 2 Diabetes in Overweight and Obesity: A selective serotonin 2C receptor agonist, lorcaserin reduces risk of incident diabetes and microvascular complications and induces remission of hyperglycemia in patients with obesity and overweight, researchers report (pp. 2269–79). Results of the CAMELLIA-TIMI 61 trial support use of the agent “as an adjunct to lifestyle modification for chronic management of weight and metabolic health,” the authors conclude based on these placebo-controlled results in 12,000 patients in 8 countries: “At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2.6 kg (95% CI 2.3–2.9) for those with diabetes, 2.8 kg (2.5–3.2) for those with prediabetes, and 3.3 kg (2.6–4.0) for those with normoglycaemia (p <0.0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8.5%] of 2,015 vs 204 [10.3%] of 1,976; hazard ratio 0.81, 95% CI 0.66–0.99; p = 0.038) and by 23% in patients without diabetes (174 [6.7%] of 2,615 vs 215 [8.4%] of 2,569; 0.77, 0.63–0.94; p = 0.012).…” (E. A. Bohula, ebohula11@bwh.harvard.edu)
>>>PNN NewsWatch
Glasdegib (Daurismo, Pfizer) was approved last week by FDA for use with low-dose cytarabine for treatment of newly diagnosed acute myeloid leukemia in adults aged 75 years or older or with comorbidities that may preclude use of intensive chemotherapy.
>>>PNN JournalWatch
Efficacy and Tolerability of Erenumab in Patients With Episodic Migraine in Whom Two-to-Four Previous Preventive Treatments Were Unsuccessful: A Randomised, Double-Blind, Placebo-Controlled, Phase 3b Study, in Lancet, 2018; 392: 2280–7. (U. Reuter, uwe.reuter@charite.de)

PNN Pharmacotherapy Line
Nov. 27, 2018 * Vol. 25, No. 227
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
 Nov. issue of and early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Marijuana Use in Community-Dwelling Older Adults: In one of the states where marijuana has been legalized for medical and recreational use, community-dwelling older adults report use of Cannabis for a variety of common geriatric conditions (pp. 2167–71). In an anonymous survey conducted at two academic geriatric primary care clinics, English-speaking respondents report the following: “Three hundred forty-five individuals completed the survey (55% response rate); 113 (32%) had used marijuana in the past, of whom 55 (16%) had used since legalization. More than half of current users were aged 75 and older, and one-quarter were aged 85 and older. Most current users were white women. Of current users, 44% used marijuana products at least weekly for common conditions including chronic pain, depression, anxiety, and insomnia, and most found marijuana helpful for these conditions. Most respondents reported obtaining marijuana recreationally (67%) without a prescription. Nine respondents reported negative side effects attributable to marijuana use.” (G. Orosz, Gretchen.Orosz@ucdenver.edu)
Trauma with Glucose-Lowering Drugs: Use of hypoglycemic glucose-lowering drugs (GLDs) in adults aged 65 years or older is associated with an increased risk of serious trauma, report authors of an observational, nested case–control study conduced in France (pp. 2086–91). Patients with first hospitalizations for trauma in 2009–15 were assessed based on records in the Echantillon Généraliste de Bénéficiaires claims database, with these results: “Risk of hospitalization for trauma was significantly higher with use of GLDs (HR = 1.15, 95% CI = 1.08–1.22). Greater risk was found only in individuals treated with hypoglycemic GLDs alone (HR = 1.26, 95% CI = 1.15–1.38), particularly insulin (HR = 1.49, 95% CI = 1.32–1.68) and glinides (HR = 1.34, 95% CI = 1.12–1.61).” (F. Salvo, francesco.salvo@u-bordeaux.fr)
Nonspecific Symptoms & Infection in Older Patients: In the emergency department (ED), “altered mental status or malaise/lethargy does not substantially increase the probability of bacterial infection in older adults … and should not be used alone to indicate infection in this population,” authors of a 424-patient study conclude (10.1111/jgs.15679). Fever of 38° C is associated with higher risk of infection, the group adds based on these positive and negative likelihood ratios (PLR and NLR) from a prospective, observational study: “Fever of 38° C or higher either before or during the ED visit had moderate to large increases in probability of infection (PLR, 5.15–18.10), with initial fever in the ED perfectly predictive, but absence of fever did not rule out infection (NLR, 0.79–0.92). Results were similar when analyzing lower respiratory, gastrointestinal, and urinary tract infections (UTIs) individually. Of older adults diagnosed as having UTIs, 47% did not complain of UTI symptoms.” (J. M. Caterino, jeffrey.caterino@osumc.edu)
>>>PNN NewsWatch
* Moving toward “a new paradigm in the development of cancer drugs that are ‘tissue agnostic,’” FDA announced yesterday that it has granted accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology) for treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. NTRK genes, encoding for TRK proteins, can become fused to other genes abnormally, resulting in growth signals that support the growth of tumors. NTRK fusions, while rare, occur in cancers arising in many sites. Before this approval, no treatment had been approved for cancers frequently expressing this mutation, including mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma, and infantile fibrosarcoma. This is the second time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the anatomic location or source of the tumor. The approval follows policies that FDA developed in a guidance document released earlier this year.

PNN Pharmacotherapy Line
Nov. 28, 2018 * Vol. 25, No. 228
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Nov. 27 issue of JAMA (2018; 320).
Decontamination Strategies in Ventilated Patients: Interventions to reduce the risk of septicemia in ventilated patients were all ineffective in comparison with standard care in a study conducted in 13 European intensive-care units (pp. 2087–98). In a 6-month study, use of chlorhexidine 2% mouthwash, selective oropharyngeal decontamination (SOD) using antibiotic (colistin, tobramycin, and nystatin) toothpaste, and selective digestive tract decontamination (SDD) using the toothpaste and a gastrointestinal suspension with the same antibiotics all yielded similar rates of ICU-acquired bloodstream infections with multidrug-resistant gram-negative bacteria and 28-day mortality in ICUs with moderate-to-high levels of antibiotic resistance as chlorhexidine body washes with a hand-hygiene improvement program. (B. H. Wittekamp, b.h.j.wittekamp@umcutrecht.nl)
Given the challenges of conducting this study in several countries with varying ICU practices, “it is … somewhat unfortunate that the authors used an historical baseline period to compare the outcomes associated with the different regimens,” editorialists write (
pp. 2081–3). “Trials with historical control groups have become less common because of the possible bias and uncertainty about differences in care practices and patient populations between baseline and study periods. Such studies tend to favor the experimental treatment; even so, the decontamination regimens failed to show a positive association with reductions in bloodstream infections or mortality. One possibility is that in this trial, SDD failed because the 4-day course of intravenous third-generation cephalosporins that is always used with SDD in the Netherlands was omitted, but, as stated by the authors, SOD also failed, which worked in the Netherlands, but never includes prophylaxis with intravenous cephalosporins.” (C. M. J. E. Vandenbroucke-Grauls, vandenbrouckegrauls@vumc.nl)
Prevention of Hereditary Angioedema With Lanadelumab: A fully human monoclonal antibody that selectively inhibits active plasma kallikrein, lanadelumab administered subcutaneously to patients with hereditary angioedema type I or II for 26 weeks significantly reduced the attack rate compared with placebo, researchers report (pp. 2108–21). “These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema,” the Hereditary Angioedema Long-term Prophylaxis (HELP) study group concludes. “Further research is needed to determine long-term safety and efficacy.” (A. Banerji, abanerji@mgh.harvard.edu)
Gabapentinoid Prescribing Patterns in the U.K.: Between 2007 and 2017, the rate of prescribing by U.K. primary care physicians of the gabapentinoids gabapentin and pregabalin tripled, according to a research letter (pp. 2149–51). With 50% of the prescriptions for off-label indications and 20% with a coprescription for opioids, “caution is necessary when prescribing gabapentinoids, especially among patients also prescribed opioids,” the investigators conclude. (C. Renoux, christel.renoux@mcgill.ca)
Influenza Vaccine for 2018–19: A summary of the influenza vaccines for the current season is reprinted from a recent issue of the Medical Letter (pp. 2143–4). In addition to information on seasonal trivalent and quadrivalent products presented in tabular form, details are included in a separate table on the vaccines licensed for use in older adults: recombinant vaccine (Flublok Quadrivalent), high-dose vaccine (Fluzone High-Dose), and adjuvanted vaccine (Fluad). “[These] vaccines elicit greater antibody responses than standard-dose unadjuvanted vaccines among persons aged 65 years or older, and the high-dose and recombinant vaccines have been shown in randomized clinical trials to be more effective among older patients in preventing laboratory-confirmed influenza,” the article concludes. (www.medicalletter.org/tmlj)
>>>PNN NewsWatch
Teva Pharmaceuticals has initiated a voluntary recall to the patient level of all lots of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide tablets because of an impurity in a source ingredient.
FDA is warning consumers not to purchase or use Rhino male enhancement products because of recent reports of associated chest pain, severe headaches, and prolonged erections.

PNN Pharmacotherapy Line
Nov. 29, 2018 * Vol. 25, No. 229
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 29 issue of the New England Journal of Medicine (2018; 379).
Alirocumab & Cardiovascular Outcomes After ACS: In a placebo-controlled trial, fatal and nonfatal ischemic cardiovascular events were significantly reduced in patients with prior acute coronary syndromes during treatment with the PCSK9 inhibitor alirocumab plus high-intensity statin therapy, researchers report (pp. 2097–107). The ODYSSEY OUTCOMES study included 18,924 patients at sites worldwide with high LDL cholesterol, non–HDL cholesterol, or apolipoprotein B levels despite statin therapy at a high-intensity dose or at the maximum tolerated dose. Randomized therapy with added alirocumab or placebo produced these outcomes based on a primary end point of composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization: “The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1,052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P <0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).” (G. G. Schwartz, gregory.schwartz@ucdenver.edu)
These results “will change clinical practice,” editorialists conclude (
pp. 2161–2). “The use of alirocumab to target an LDL cholesterol level of 25 to 50 mg per deciliter after an acute coronary syndrome resulted in a lower risk of major adverse cardiac events than placebo. Patients who had a baseline LDL cholesterol level of 100 mg per deciliter (2.6 mmol per liter) or more seemed to derive more benefit. However, the high cost of monoclonal antibodies to PCSK9 (even after recent substantial price reductions in the United States) obligates careful consideration of the type of high-risk patient who would most benefit from their clinical use.” (J. R. Burnett)
Atezolizumab in Advanced Triple-Negative Breast Cancer: Compared with nanoparticle albumin-bound (nab)–paclitaxel, atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in a phase 3 trial (pp. 2108–21; P. Schmid, p.schmid@qmul.ac.uk).
>>>PNN NewsWatch
* One of three FDA product approvals announced yesterday, the breakthrough therapy and orphan drug amifampridine (Firdapse, Catalyst Pharmaceuticals) tablets became the first marketed U.S. product for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults following a priority review. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles, producing weakness and other symptoms.
* Following a fast-track, priority review, 
FDA approved the orphan drug gilteritinib (Xospata, Astellas) tablets for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. The FDA also approved an expanded indication for a companion diagnostic to include use with gilteritinib — the LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, which is used to detect the FLT3 mutation in patients with AML.
FDA approved its 15th biosimilar productrituximab-abbs (Truxima, Celltrion and Teva) as the first biosimilar to rituximab (Rituxan). The product is approved for the treatment of adult patients with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL) to be used as a single agent or in combination with chemotherapy. This is the first biosimilar to be approved in the U.S. for the treatment of NHL. In the past month, FDA has also approved adalimumab-adaz (Hyrimoz, Sandoz) as a biosimilar to adalimumab (Humira) and pegfilgrastim-cbqv (Udenyca, Coherus) as a biosimilar to pegfilgrastim (Neulasta).

PNN Pharmacotherapy Line
Nov. 30, 2018 * Vol. 25, No. 230
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
 Dec. issue of Diabetes Care (2018; 41).
SGLT Inhibitors in Type 1 Diabetes: Research reports and an editorial examine utility of SGLT-1 inhibitors in type 1 diabetes (T1D).
In the DEPICT-1 trial, dapagliflozin improved glycemic control and weight loss in 708 patients with T1D but also increased the risk of diabetic ketoacidosis (DKA; 
pp. 2552–9). The phase 3 trial used a placebo control and produced these results: “Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA1c (difference vs. placebo [95% CI] −0.33% [−0.49, −0.17] [−3.6 mmol/mol (−5.4, −1.9)] and −0.36% [−0.53, −0.20] [−3.9 mmol/mol (−5.8, −2.2)], respectively) and body weight (difference vs. placebo [95% CI] −2.95% [−3.83, −2.06] and −4.54% [−5.40, −3.66], respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite DKA (4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively).” (P. Dandona, pdandona@kaleidahealth.org)
Ketoacidosis rates were elevated with higher doses of empagliflozin in the EASE trial, which also showed improvements in glycemic control and weight (
pp. 2560–9). In 1,707 patients with T1D, outcomes with empagliflozin or placebo were as follows: “The observed largest mean placebo-subtracted glycated hemoglobin reductions were −0.28% (95% CI −0.42, −0.15) for 2.5 mg, −0.54% (−0.65, −0.42) for 10 mg, and −0.53% (−0.65, −0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by −1.8/−3.0/−3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by −6.4/−13.3/−12.7% (all P < 0.0001); and decreased systolic blood pressure by −2.1/−3.9/−3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated [DKA] occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
“These observations … have important clinical implications,” editorialists write (
pp. 2444–7). “Balancing benefits versus risks of SGLTi will require thoughtful decisions by regulatory and professional groups, care providers, and also people with diabetes. The most obvious responsibility falls upon regulators and groups creating guidance for clinical care. Does the evidence provided by these short-term studies justify approval of these agents for use in T1D? If so, what tactics for mitigation of risks are needed? Are we at a stage where we can stratify individual patients according to benefits versus risks so as to allow appropriate use of these new drugs by selected cohorts? We can expect a vigorous discussion of these questions. To support such decisions, we need more information. Of particular interest is whether a direct renal effect limiting progression of nephropathy—beyond that provided by improved control of A1C and blood pressure—can be demonstrated in T1D, and the present studies do not address this question. Also, confirmation of the short-term risk of DKA in T1D reminds us that long-term risks also need further evaluation in both T1D and T2D. As suggested in earlier commentaries, drugs in this class should be prescribed cautiously until longer-term, prospectively collected experience with them is available.” (M. C. Riddle, riddlem@ohsu.edu)
>>>PNN NewsWatch
National Influenza Vaccination Week begins Sunday. Resources are available on the CDC website for health professionals, employers and other vaccine advocates. Data in this week’s MMWR show that 46.7% of adult women in the U.S. received an influenza vaccination in the past 12 months, as did 39.9% of men. Figures increase with age, reaching 67.1% of older adults.
World AIDS Day is observed each year on Dec. 1. Worldwide, 36.9 million people are living with HIV/AIDS, CDC says in an MMWR article published this week, and 940,000 people died from AIDS-related illnesses in 2017. Spread of the virus continues; 1.8 million persons were newly infected in 2017.

PNN Pharmacotherapy Line
Dec. 3, 2018 * Vol. 25, No. 231
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Dec. 1 issue of Lancet (2018; 392).
Kinase Inhibition in Immune Diseases: In the first of two studies of filgotinib, the selective Janus kinase 1 (JAK1) inhibitor was effective without new safety signals in patients with active psoriatic arthritis (pp. 2367–77). In Europe, the phase 2 EQUATOR trial randomized patients with moderate-to-severe psoriatic arthritis to filgotinib 200 mg or placebo orally once daily for 16 weeks while they continued one or more conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Results based on 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 were as follows: “Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30.2–59.6], p <0.0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group.” (P. Mease, pmease@philipmease.com)
In the TORTUGA trial, adults filgotinib was efficacious and safe for treatment of active ankylosing spondylitis in adult patients from the same seven European countries as in the EQUATOR trial (
pp. 2378–87). Investigators in the phase 2 trial included patients with active disease with inadequate response or intolerance to two or more NSAIDs. Filgotinib 200 mg or placebo once daily was added to current use of csDMARDs and evaluated based on change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12: “Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n = 58) or placebo (n = 58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was −1.47 (SD 1.04) in the filgotinib group and −0.57 (0.82) in the placebo group, with a least squares mean difference between groups of −0.85 (95% CI −1.17 to −0.53; p <0.0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study.” (D. van der Heijde, mail@dvanderheijde.nl)
>>>PNN JournalWatch
Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association, in Diabetes Care, 2018; 41: 2648–687. (S. Arslanian, silva.arslanian@chp.edu)
Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), in Diabetes Care, 2018; 41: 2669–701. (J. B. Buse, jbuse@med.unc.edu)
Clinical Practice Guideline: Maintenance Intravenous Fluids in Children, in Pediatrics, 2018; 142: 10.1542/peds.2018-3083. (L. G. Feld, feldllc@gmail.com)
Pediatric Considerations Before, During, and After Radiological or Nuclear Emergencies, in Pediatrics, 2018; 142: 10.1542/peds.2018-3000. (J. A. Paulson; AAP Council on Environmental Health)
Improving Depression Outcome by Patient-Centered Medical Management, in American Journal of Psychiatry, 2018; 175: 1187–98. (A. J. Rush)
Perspectives on the Management of Vascular Depression, in American Journal of Psychiatry, 2018; 175: 1169–75. (W. D. Taylor)
Stakeholder Perspectives on the Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) Project, in Gerontologist, 2018; 58: 1177–87. (M. Ersek, ersekm@upenn.edu)

PNN Pharmacotherapy Line
Dec. 4, 2018 * Vol. 25, No. 232
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Dec. 4 issue of Annals of Internal Medicine (2018; 169).
Drug Use–Associated Infective Endocarditis & Valve Surgeries: In North Carolina from 2007 to 2017, drug use–associated infective endocarditis (DUA-IE) and heart valve surgeries increased by 12-fold, according state hospital data, a likely outcome of the opioid epidemic (10.7326/M18-2124). By the end of the study period, more than half of all IE valve surgeries were in those with DUA-IE, as shown in these results: “Of 22,825 IE hospitalizations, 2,602 (11%) were for DUA-IE. Valve surgery was performed in 1,655 IE hospitalizations (7%), including 285 (17%) for DUA-IE. Annual DUA-IE hospitalizations increased from 0.92 to 10.95 and DUA-IE hospitalizations with surgery from 0.10 to 1.38 per 100,000 persons. In the final year, 42% of IE valve surgeries were performed in patients with DUA-IE. Compared with other surgical patients with IE, those with DUA-IE were younger (median age, 33 vs. 56 years), were more commonly female (47% vs. 33%) and white (89% vs. 63%), and were primarily insured by Medicaid (38%) or uninsured (35%). Hospital stays for DUA-IE were longer (median, 27 vs. 17 days), with higher median charges ($250,994 vs. $198,764). Charges for 282 DUA-IE hospitalizations exceeded $78 million.” (A. J. Schranz, aschranz@med.unc.edu)
“In the midst of the 1930s malaria outbreak [in New York City among people injecting heroin], the population at risk started to cut heroin with quinine to prevent malaria infection,” writes an editorialist (
10.7326/M18-3026). “They saw a threat and developed a strategy to effectively reduce it. The field is open for innovative patient-centered research on how to prevent endocarditis and provide equitable, evidence-based treatment focusing not only on the microbe but on the underlying substance use disorder. Action is urgently needed to understand and improve the cascade of care for persons with DUA-IE.” (A. G. Wurcel, awurcel@tuftsmedicalcenter.org)
Managing Gout: In a patient-focused beyond-the-guidelines review article, authors offer this assessment of gout management (pp. 788–95). “Gout is the most common form of inflammatory arthritis. In 2012, the American College of Rheumatology (ACR) issued a guideline, which was followed in 2017 by one from the American College of Physicians (ACP). The guidelines agree on treating acute gout with a corticosteroid, nonsteroidal anti-inflammatory drug, or colchicine and on not initiating long-term urate-lowering therapy (ULT) for most patients after a first gout attack and in those whose attacks are infrequent (<2 per year). However, they differ on treatment of both recurrent gout and problematic gout. The ACR advocates a ‘treat-to-target’ approach, and the ACP did not find enough evidence to support this approach and offered an alternative strategy that bases intensity of ULT on the goal of avoiding recurrent gout attacks (‘treat-to-avoid-symptoms&rsquoWinking with no monitoring of urate levels. They also disagree on the role of a gout-specific diet. [In this aricle], a general internist and a rheumatologist discuss these guidelines; they debate how they would manage an acute attack of gout, if and when to initiate ULT, and the goals for ULT. Lastly, they offer specific advice for a patient who is uncertain about whether to begin this therapy.” (R. B. Burns, rburns@bidmc.harvard.edu)
Fractional-Dose Yellow Fever Vaccination: A study of fractional doses of yellow fever vaccination shows that people receiving one-fifth the usual dose of the vaccine require no booster shots for 10 years (pp. 761–5). Because of vaccine shortages, fractional doses of 17D yellow fever virus (17D-YFV) vaccine have been used as a vaccine-sparing strategy. Among 155 participants in an original trial showing noninferiority of this approach over 1 year after vaccination, 75 patients participated in a 10-year follow-up study, with these results: “Thirty-nine of 40 (98% [95% CI, 89% to 100%]) participants had protective levels of yellow fever–neutralizing antibodies more than 10 years after receiving a fractional dose of 17D-YFV vaccine compared with 34 of 35 (97% [CI, 87% to 100%]) in the standard-dose group.” (A. H. E. Roukens)
>>>PNN NewsWatch
* At ASHP’s 53rd Midyear Clinical Meeting and Exhibition in Anaheim, Abdul Latif Sheikh, BSPharm, MS, FFIP, President and CEO of the Pakistan Society of Health-System Pharmacists, received the 2018 Donald E. Francke Medal.

PNN Pharmacotherapy Line
Dec. 5, 2018 * Vol. 25, No. 233
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Dec. 4 issue of JAMA (2018; 320).
Vaccines as Integral Components of Cancer Immunotherapy: The “renaissance in immuno-oncology came with the use of [checkpoint inhibitor monoclonal antibody (CIMA) therapy],” write authors of a Viewpoint, the first in a series (pp. 2195–6). “Evidence is emerging demonstrating synergy in the use of cancer vaccines plus CIMAs. Advances in basic immunology and translational immunotherapy are rapidly unravelling the complexity of the immune system and, consequently, agents and strategies are being developed that can be and are being used to increase the efficacy of therapeutic cancer vaccines. As such, the use of vaccines could be considered a necessary, albeit insufficient, component of an effective anticancer therapeutic regimen among patients with low T-cell count tumors.” (J. Schlom, js141c@nih.gov)
“With regulatory approval last year of the first tumor site agnostic drug (immunotherapy for tumors with high microsatellite instability expression), the era in which therapies are dictated by the anatomic site of origin is coming to an end,” editorialists write in describing the “changes, challenges, and opportunities” of “oncology in transition” (
pp. 2203–4). “For the next year, a series of commissioned Viewpoints will explore facets of oncology to help readers understand how the field has arrived at this exciting moment, delineate the challenges ahead, and prioritize what needs to happen to continue progress and ensure that recent discoveries achieve their full potential. Some thought leaders argue that medicine is on a path of drug discovery toward cure or prolonged stability of most cancers, emblemized by substantial progress in immunotherapy; others contend that this is exaggerated or that the cost of this development and resulting care delivery will be untenable.” (E. Basch, ebasch@med.unc.edu)
Anticoagulants, PPIs & Upper GI Bleeds: In patients at high risk of hospitalization for upper gastrointestinal bleeds, selection of anticoagulants and use of PPI cotherapy are important factors. (pp. 2221–30). A study of Medicare beneficiaries showed the following: “During 754,389 person-years of anticoagulation treatment with apixaban, dabigatran, rivaroxaban, and warfarin, the risk of hospitalization for upper gastrointestinal tract bleeding was highest for rivaroxaban [and lowest for apixaban]. The use of PPI cotherapy (264,447 person–years) was associated with a significantly lower overall risk of gastrointestinal bleeding for all anticoagulants (incidence rate ratio, 0.66).” (W. A. Ray, wayne.ray@vanderbilt.edu)
>>>PNN NewsWatch
* Patients in Idaho who are long-term users of opioids commonly have concomitant prescriptions for benzodiazepines, often written by the same prescriber, according to a presentation yesterday at the ASHP Midyear Clinical Meeting in Anaheim. Idaho State researchers (Berain et al.) examined all prescriptions of controlled substances for 301,975 patients reported to the Idaho Prescription Drug Monitoring Program in 2017. One-third of the patients receiving a controlled substance were identified as long-term users, meaning they had taken the drugs for more than 90 days without a break of at least 7 days. Nearly one-quarter of those chronic users were also prescribed a benzodiazepine or other CNS depressants, with 56% of the overlapping prescriptions coming from the same prescriber.
Mylan Pharmaceuticals is expanding its consumer-level voluntary nationwide recall to include all lots of valsartan-containing products within expiry. The 104 additional lots include 26 lots of Amlodipine and Valsartan Tablets, USP, 51 lots of Valsartan Tablets, USP, and 27 lots of Valsartan and Hydrochlorothiazide Tablets, USP. These products are being recalled due to detected trace amounts of the N-nitrosodiethylamine carcinogen contained in Mylan’s API Valsartan, USP.
FDA yesterday recognized the genetic variant information in the Clinical Genome Resource (ClinGen) consortium’s ClinGen Expert Curated Human Genetic Data, funded by NIH to support clinical validity in premarket submissions. The information contained in this open database has been collected and studied by researchers across the world. FDA said this is first time the agency has formally recognized a public database that contains information about genes, genetic variants, and their relationship to disease.

PNN Pharmacotherapy Line
Dec. 6, 2018 * Vol. 25, No. 234
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Dec. 6 New England Journal of Medicine (2018; 379).
Pantoprazole for GI Bleeding Prophylaxis in Critical Care: The utility of PPIs in the ICU is questioned in a 3,282-patient study showing no mortality difference between placebo and pantoprazole for prevention of gastrointestinal bleeding (pp. 2199–208). The European study provides these results for I.V. pantoprazole 40 mg daily using a primary outcome of 90-day mortality: “At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P = 0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.” (A. Perner, anders.perner@regionh.dk)
“The take-home message from this trial is that, given the low incidence of clinically important upper gastrointestinal bleeding in the ICU, prophylaxis with a PPI, if initiated, should be reserved for seriously ill patients who are at high risk for this complication,” editorialists conclude (
pp. 2263–4). “Although 90-day mortality was not affected by pantoprazole administration in the current trial, the between-group difference in the rate of important upper gastrointestinal bleeding may still support the recommendation of using a prophylactic PPI, particularly given the absence of a difference in the rate of adverse events between the pantoprazole group and the placebo group. We base this view mainly on the admittedly small (1.7-percentage-point) difference in bleeding rates between the groups. Additional data are needed to determine the clinical effects of prophylaxis for gastrointestinal bleeding in the ICU, especially in groups of patients who are at very high risk for this complication, and to quantify any protective or harmful effects attributable to the coadministration of enteral nutrition.” (A. Barkun)
Interstitial Lung Disease in Rheumatoid Arthritis: Reacting to a study showing a strong genetic association between rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) and a gain-of-function promoter variant seen in patients with idiopathic pulmonary fibrosis (pp. 2209–19; D. A. Schwartz, david.schwartz@ucdenver.edu), editorialists provide these insights (pp. 2265–6). “The strong association of the MUC5B promoter variant with ILD in patients with RA raises the question of whether all patients with RA should be evaluated for MUC5B carrier status. This will be most appropriate when early detection can mandate preventive or effective therapies. On the other hand, once clinical disease is present, MUC5B genotyping might provide information on prognosis and, as understanding of pathogenesis improves, may guide management. Overall, [these results] support the concept that genetics really can add to our understanding of disease heterogeneity, and the results provide hope that this approach will lead to further insights in the future.” (P. K. Gregersen)
Politics & Pandemics: Marking the 100th anniversary of the influenza pandemic of 1918, the Obama administration Ebola czar notes that Spanish flu “killed more Americans than World Wars I and II combined” (pp. 2191–3). Reviewing current trends that pose threats to an effective response to pandemics (isolationism and xenophobia, antiscientific thinking and resistance to evidence-based medicine, disease-related dangers of climate change), the Viewpoint author suggests a health professional response: “Now, we need the medical community to take on the criticism and controversy, the unpleasantness and attacks, and to step into the halls of Congress, the offices of the executive branch, and the public arena in order to win passage of key policies and to confront the social and political trends that are making global health less secure. The men and women of this community are in a position to help make us all safer by wading into difficult and divisive issues that are undermining our global capacity to face down a future pandemic.” (R. Klain)

PNN Pharmacotherapy Line
Dec. 7, 2018 * Vol. 25, No. 235
Providing news and information about medications and their proper use

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>>>Psychiatry Report
Source:
 Dec. issue of the American Journal of Psychiatry (2018; 175).
Opioid Effects in Antidepressant Effects of Ketamine: In a study terminated at the interim analysis, researchers show that the rapid antidepressant effects of ketamine require opioid system activation but that the dissociative effects of the drug are not mediated by the opioid system (pp. 1205–15). The planned study of 30 adults with treatment-resistant depression had treated 12 participants in crossover fashion with both placebo and naltrexone 50 mg preceding an intravenous infusion of ketamine 0.5 mg/kg at termination. Results showed: “In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item [Hamilton Depression Rating Scale] scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.” (N. R. Williams)
“Clearly, more work is needed to understand ketamine’s antidepressant effects and its mechanisms,” writes an editorialist (
pp. 1157–8). Referring to the three current “epidemics” of opioid dependence, depression, and suicide, the author concludes: “In Greek mythology, several monsters had multiple heads. If you cut off one of the Hydra’s heads, it grew back, and sometimes more than one. We would hate to treat the depression and suicide epidemics by overusing ketamine, which might perhaps unintentionally grow the third head of opioid dependence. With these new findings, we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form. If ketamine does indirectly activate opioid receptors, it could even have positive effects in approaching the opioid as well as the other epidemics. In any case, we need to better understand ketamine’s mode of action and how it should best be used and administered.” (M. S. George, georgem@musc.edu)
Prazosin for Alcohol Use Disorder: Seeking to confirm positive results of a preliminary study, investigators show that “prazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups” (pp. 1216–24). Among 80 participants with alcohol use disorder and without posttraumatic stress disorder, titrated doses of prazosin or placebo had these effects in a 12-week trial: “There was a significant interaction between condition and week for both number of drinks and number of heavy drinking days, such that the rate of drinking and the probability of heavy drinking showed a greater decrease over time for participants in the prazosin condition compared with those in the placebo condition. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition.” (T. L. Simpson)
While prior work has shown prazosin and other alpha-1 adrenergic agents to be possibly beneficial in management of alcohol use disoder, the moderate effect size and some mixed findings indicate a need to identify and test “key moderators of the positive effect,” an editorialist writes (
pp. 1159–60): “It appears that individuals with alcohol use disorder who have withdrawal-related alcohol intake may be those likely to benefit the most from prazosin treatment. Further testing and development of this key moderator could enhance personalized-medicine approaches in the treatment of alcohol use disorders.” (R. Sinha)
>>>PNN NewsWatch
* Despite improvements, one in four nonsmokers in the U.S. continues to be exposed to secondhand smoke, an MMWR article reports (pp. 1342–6; J.Tsai, jxt9@cdc.gov). Disparities are also evident, with 14.0 million children aged 3–11 years exposed, including about two-thirds of non-Hispanic black children, 40% of non-Hispanic white kids, and 20% of Hispanic children.

PNN Pharmacotherapy Line
Dec. 10, 2018 * Vol. 25, No. 236
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Dec. 8 issue of Lancet (2018; 392).
Ixekizumab in Ankylosing Spondylitis: In 341 patients with ankylosing spondylitis not previously treated with biological disease-modifying anti-rheumatic drugs (bDMARDs), the high-affinity interleukin-17A (IL-17A) monoclonal antibody ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms, researchers report (pp. 2441–51). The phase 3 superiority study of patients with inadequate response to or intolerance of NSAIDs produced these results using every 2- or 4-week doses of ixekizumab, active comparator (adalimumab every 2 weeks), or placebo: “At week 16, compared with placebo (16 [18%] of 87), more patients achieved [40% improvement in Assessment of SpondyloArthritis international Society (ASAS) criteria] with ixekizumab Q2W (43 [52%] of 83; p <0.0001), ixekizumab Q4W (39 [48%] of 81; p <0.0001), and adalimumab (32 [36%] of 90; p = 0.0053). One serious infection occurred in each of the ixekizumab Q2W (1%), ixekizumab Q4W (1%), and adalimumab (1%) groups; none were reported with placebo. One (1%) Candida infection occurred in the adalimumab group and one (1%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn’s disease. No treatment-emergent opportunistic infections, malignancies, or deaths occurred.” (D. van der Heijde, mail@dvanderheijde.nl)
Health & Climate Change: As the United Nations’ Katowice Climate Change Conference opens in Poland, Lancet publishes in print form its 2018 health and climate change countdown report (pp. 2479–514). Assessment of effects of climate change on health-related factors such as extreme weather events and vector- and water-borne diseases led to these key messages (N. Watts, nicholas.watts@ucl.ac.uk):
* “Present day changes in heat waves, labour capacity, vector-borne disease, and food security provide early warning of the compounded and overwhelming impact on public health that are expected if temperatures continue to rise. Trends in climate change impacts, exposures, and vulnerabilities show an unacceptably high level of risk….”
* “A lack of progress in reducing emissions and building adaptive capacity threatens both human lives and the viability of the national health systems they depend on, with the potential to disrupt core public health infrastructure and overwhelm health services.”
* “Despite these delays, a number of sectors have seen the beginning of a low-carbon transition, and it is clear that the nature and scale of the response to climate change will be the determining factor in shaping the health of nations for centuries to come.”
* “Ensuring a widespread understanding of climate change as a central public health issue will be crucial in delivering an accelerated response, with the health profession beginning to rise to this challenge.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Incretin-Based Drugs & Cholangiocarcinoma: Increased risk of cholangiocarcinoma in adults with type 2 diabetes taking incretin-based drugs is evident in a population-based cohort study from the U.K. (k4880): “During 614,274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100,000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).” (L. Azoulay, laurent.azoulay@mcgill.ca)
>>>PNN JournalWatch
Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine, in American Journal of Psychiatry, 2018; 175: 1225–31. (L. S. Cohen )
Bacterial Vaginosis and Desquamative Inflammatory Vaginitis, in New England Journal of Medicine, 2018; 379: 2246–54. (J. Paavonen, jorma.paavonen@hus.fi)
Mapping Symptoms to Brain Networks with the Human Connectome, in New England Journal of Medicine, 2018; 379: 2237–45. (M. D. Fox, foxmdphd@gmail.com)

PNN Pharmacotherapy Line
Dec. 11, 2018 * Vol. 25, No. 237
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from and Dec. issue of JAMA Internal Medicine (2018; 178).
Opioid Prescriptions From Dental Clinicians: Substantial numbers of adolescents and young adults are exposed to opioids through prescriptions from dental clinicians, a study shows, and “use of these prescriptions may be associated with an increased risk of subsequent opioid use and abuse” (10.1001/jamainternmed.2018.5419). Records for patients aged 16–25 years in the Optum Research Database were examined for outpatient opioid prescriptions in 2015, with these results: “Among 754,002 individuals with continuous enrollment in 2015, 97,462 patients (12.9%) received 1 or more opioid prescriptions, of whom 29,791 (30.6%) received prescriptions supplied by a dental clinician. The opioid-exposed cohort included 14,888 participants (7,882 women [52.9%], 11,273 white [75.7%], with mean [SD] age, 21.8 [2.4] years), and the randomly selected opioid-nonexposed cohort included 29,776 participants (15,764 women [52.9%], 20,078 [67.4%] white, with mean [SD] age, 21.8 [2.4] years). Among the 14,888 individuals in the index dental opioid cohort, 1,021 (6.9%) received another opioid prescription 90 to 365 days later compared with 30 of 29,776 (0.1%) opioid-nonexposed controls (adjusted absolute risk difference, 6.8%; 95% CI, 6.3%–7.2%), and 866 opioid-exposed individuals (5.8%) experienced 1 or more subsequent health care encounters with an opioid abuse–related diagnosis compared with 115 opioid-nonexposed controls (0.4%) (adjusted absolute risk difference, 5.3%; 95% CI, 5.0%–5.7%). There was only 1 death in each cohort.” (A. R. Schroeder, aschroe@stanford.edu)
Cost-Related Insulin Underuse: In an urban diabetes clinic, cost-related insulin underuse was common among those with types 1 or 2 diabetes, according to a research letter (10.1001/jamainternmed.2018.5008). A survey of 354 patients identified 51 (25.5%) who reported this problem. “Patients with cost-related underuse were more likely to report lower incomes; 31 [60.8%] of these patients discussed the cost of insulin with their clinician and 15 [29.4%] changed insulin type owing to cost,” the authors write. “Patients who reported cost-related underuse (vs those who did not) were more likely to have poor glycemic control in the multivariable analysis (22 [43.1%] vs 41 [28.1%]; odds ratio = 2.96; 95% CI, 1.14–8.16; P = .03).” (K. J. Lipska, kasia.lipska@yale.edu)
Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension: “Physicians should be cautious when initiating treatment in low-risk patients with mild hypertension,” investigators conclude, “particularly because such an approach may affect millions of individuals with little evidence of benefit” (pp. 1626–34). Data from the Clinical Practice Research Datalink in 1998 through 2015 for adults aged 18–75 years were used to assess rates of mortality, cardiovascular disease (CVD), and adverse events in this longitudinal cohort study: “During a median follow-up period of 5.8 years (interquartile range, 2.6–9.0 years), no evidence of an association was found between antihypertensive treatment and mortality (hazard ratio [HR], 1.02; 95% CI, 0.88–1.17) or between antihypertensive treatment and CVD (HR, 1.09; 95% CI, 0.95–1.25). Treatment was associated with an increased risk of adverse events, including hypotension (HR, 1.69; 95% CI, 1.30–2.20; number needed to harm at 10 years [NNH10], 41), syncope (HR, 1.28; 95% CI, 1.10–1.50; NNH10, 35), electrolyte abnormalities (HR, 1.72; 95% CI, 1.12–2.65; NNH10, 111), and acute kidney injury (HR, 1.37; 95% CI, 1.00–1.88; NNH10, 91).” (J. P. Sheppard, james.sheppard@phc.ox.ac.uk)
RAS Blockade After Acute Kidney Injury: Commenting on a study of ACE inhibitors and ARBs after acute kidney injury (pp. 1681–90; N. Pannu, npannu@ualberta.ca), an editorialist concludes (pp. 1690–2) that “prompt addition or resumption of [renin angiotensin system] blockers seems to be judiciously indicated” but also that patients need close monitoring pending answers to key questions. (R. J. Alpern, robert.alpern@yale.edu)
>>>PNN NewsWatch
* FDA has cleared the reSET-O app, which uses prescription cognitive behavioral therapy to increase retention in outpatient treatment of opioid use disorder, and released a draft guidance for compounding outsourcing facilities.

PNN Pharmacotherapy Line
Dec. 12, 2018 * Vol. 25, No. 238
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Dec. 11 issue of JAMA (2018; 320).
Alfacalcidol in Maintenance Hemodialysis: The vitamin D receptor activator alfacalcidol failed to improve a composite of cardiovascular outcomes in the J-DAVID trial of patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, researchers report (pp. 2325–34). Oral daily 0.5 mcg doses were compared with placebo using a composite measure of fatal and nonfatal cardiovascular events over a median of 4 years, with these results in 964 intention-to-treat patients: “The primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, −1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94–1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83–1.52]; P = .46).” Serious adverse events classified as cardiovascular, infections, or oncologic disorders were similar between the groups. (T. Shoji, t-shoji@med.osaka-cu.ac.jp)
“The J-DAVID trial sends researchers and clinicians back to the drawing board to rethink the current approaches to treatment of 1,25[OH]2D deficiency in patients with [end-stage kidney disease (ESKD)],” editorialists write (
pp. 2319–21). “In the case of [vitamin D receptor agonists (VDRAs)] for patients with ESKD undergoing hemodialysis, were observational treatment effect estimates of the reported mortality benefits incorrect, or were they simply not focused on precise clinical scenarios characterized by the combination of calcium loading, phosphate retention, and secondary hyperparathyroidism that affects patients? It is unlikely that there are simple, one-size-fits-all answers to the complexity of mineral metabolism in ESKD. Future studies are needed, both observational and randomized, to understand who should be treated with VDRAs, to what biochemical target levels patients should be treated, and what therapeutic combinations of VDRAs and mineral metabolism cointerventions should be used to prevent CVD in patients with ESKD undergoing hemodialysis.” (J. J. Scialla, julia.scialla@duke.edu)
Mexiletine in Nondystrophic Myotonia: Findings from a series of N-of-one trials support efficacy of mexiletine in reducing muscle stiffness among patients with nondystrophic myotonia, adding to results of a prior randomized trial (pp. 2344–53). The analysis included results from 27 Dutch patients with genetically confirmed nondystrophic myotonia; doses of mexiletine 600 mg daily were significantly more effective than placebo based on changes in daily-reported muscle stiffness. (B. C. Stunnenberg, Bas.Stunnenberg@Radboudumc.nl)
Expansion of Medicare 340B: “The growth of the 340B program has also distorted prescribing patterns of physicians,” Viewpoint authors write in describing the battle over CMS changes pitting the pharmaceutical industry against hospitals (pp. 2311–2). “The system of pharmaceutical pricing and reimbursement in the United States has inherent problematic incentives, with wholesalers and pharmacy benefit managers commonly criticized for the needless complexity of the system. But prescriber incentives are also concerning. When expensive drugs bring practitioners more profits than less expensive drugs, the more expensive drugs tend to be favored. The Government Accountability Office found that when hospitals enter the 340B program, wherein their profits from expensive drugs increase more than their profits from less expensive drugs, hospital prescribing also shifts to more expensive drugs. Patients do not directly benefit because many 340B hospitals do not discount the drugs they dispense to poorer individuals.” (P. B. Bach, bachp@mskcc.org)
>>>PNN NewsWatch
* FDA yesterday released a warning letter to the Chinese facility that produced the contaminated valsartan active pharmaceutical ingredient responsible for recent product recalls. Separately, a statement by FDA Commissioner Scott Gottlieb, MD, describes actions planned for increasing competition among biosimilar products during 2019. A particular point of emphasis involved the “deceptions” involved in companies abusing REMS and other limited distribution systems to “hide anticompetitive behavior.”

PNN Pharmacotherapy Line
Dec. 13, 2018 * Vol. 25, No. 239
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 13 issue of the New England Journal of Medicine (2018; 379).
Substance-Use Disorders in Later Life: “Alcohol-use disorder, prescription-drug misuse, and illicit-drug use are growing health problems in later life yet may be overlooked by health care providers,” conclude authors of a review article (pp. 2351–60). Changes in the functional status of older adults can be clues to “problematic substance use,” and the group writes of the emergence of marijuana use as state laws have been relaxed or rescinded: “All clinicians who care for older adults must be alert for possible signs and symptoms of substance-use disorders in their patients. Use of prescription-drug monitoring programs will help identify persons who obtain multiple prescriptions for medications with high misuse potential. Although opioid abuse is growing among older adults, marijuana is currently the most frequently used illicit substance in this age group. However, alcohol-use disorder remains the most prevalent substance-use disorder in later life. The fact that rates of alcohol-use disorder are increasing among older adults is cause for alarm. Research is needed to develop targeted screening methods and to identify the best treatment models for substance-use disorders in older adults. Treatment plans must encompass care for older patients with coexisting medical and psychiatric illnesses. New models of care may need to be created that allow for both coordination of services in integrated health care settings and treatment programs tailored for older patients.” (S. W. Lehmann, slehman@jhmi.edu)
Durvalumab After Chemoradiotherapy in Stage III NSCLC: Compared with placebo in patients with stage III, unresectable non–small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy, durvalumab produced significantly longer overall survival, researchers report (pp. 2342–50). A phase 3 trial of durvalumab — a selective, high-affinity, engineered, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 and thereby allows T cells to recognize and kill tumor cells — was previously reported; it showed significantly prolonged progression-free survival. The current report looks at a second primary end point, with these results for 709 patients with a median follow-up of 25.2 months: “The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P = 0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P = 0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.” (S. J. Antonia, scott.antonia@moffitt.org)
>>>PNN NewsWatch
* In a new guidance, FDA updates the 2016 advice on “Data Integrity and Compliance With Drug CGMP: Questions and Answers.” The agency’s goal is improving “drug quality through vigilant oversight of data integrity and good manufacturing practice,” FDA Commissioner Scott Gottlieb, MD, writes, adding: “This new guidance is one part of our multilayered approach to ensuring the integrity of data. We also use inspections to uncover data integrity problems. For example, our preapproval inspection process is used to help ensure the integrity of data by evaluating, among other factors, its proper storage and handling. In tandem with preapproval inspections, we also conduct thorough assessments of applications prior to approval and when companies submit information about changes to their manufacturing processes.”

PNN Pharmacotherapy Line
Dec. 14, 2018 * Vol. 25, No. 240
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Chest Highlights
Source:
 Dec. issue of Chest (2018; 154).
Costs of Rivaroxaban in Preventing Recurrent VTE: In the Reduced-Dose Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism (EINSTEIN-CHOICE) trial, continuation of therapy with rivaroxaban 10 and 20 mg instead of aspirin was associated with lower clinical event costs but higher total health-care costs, researchers report (pp. 1371–8). When the cost of rivaroxaban was discounted by 15%, rivaroxaban 10 mg had lower total health-care costs than aspirin, as shown in these calculations of the sum of clinical event costs and drug costs from a U.S. managed care perspective: “Rivaroxaban users had lower per patient per month (PPPM) clinical event costs compared with aspirin users ($123, $243, and $381 for rivaroxaban 10 mg, rivaroxaban 20 mg, and aspirin, respectively). However, vs aspirin, PPPM total health-care costs were $24 higher for patients treated with rivaroxaban 10 mg ($143 higher for rivaroxaban 20 mg) due to higher cost of rivaroxaban. With a 15% discount for rivaroxaban 10 mg, the lower cost of clinical events for the rivaroxaban-treated patients more than fully offset the higher drug costs, and yielded a $19 lower total health-care cost.” (D. Lejeune, dominique.lejeune@analysisgroup.com)
Inhaled Tranexamic Acid for Hemoptysis: Nebulized tranexamic acid (TA) “can be used safely and effectively to control bleeding in patients with nonmassive hemoptysis,” conclude authors of a 48-patient, double-blind, randomized controlled trial (pp. 1379–84). Mortality and hemoptysis recurrence rate at 30 days and 1 year were as follows for TA 500 mg three times daily and a saline placebo: “TA was associated with a significantly reduced expectorated blood volume starting from day 2 of admission. Resolution of hemoptysis within 5 days of admission was observed in more TA-treated patients than in those receiving placebo (96% vs 50%; P < .0005). Mean hospital length of stay was shorter for the TA group (5.7 ± 2.5 days vs 7.8 ± 4.6 days; P = .046), with fewer patients requiring invasive procedures such as interventional bronchoscopy or angiographic embolization to control the bleeding (0% vs 18.2%; P = .041). No side effects were noted in either group throughout the follow-up period. In addition, a reduced recurrence rate was noted at the 1-year follow-up (P = .009).” (D. Shitrit, davids3@clalit.org.il)
>>>Infectious Diseases Report
Source:
 Jan. 1 issue of Clinical Infectious Diseases (2019; 68).
MRSA v. MSSA Costs in U.S. Hospitalizations: While hospitalizations for methicillin-resistant Staphylococcus aureus (MRSA) infections have previously been associated with worse patient outcomes and higher costs of care, methicillin-susceptible (MSSA) infection hospitalizations now may produce greater costs, a study shows (pp. 22–8). Data from the National Inpatient Sample from the Agency for Healthcare Research and Quality for the years 2010–2014 show these cost patterns: “Propensity score–adjusted costs were significantly higher for MSSA-related pneumonia ($40,725 vs $38,561; P = .045) and other hospitalizations ($15,578 vs $14,792; P <.001) than for MRSA-related hospitalizations. Similar patterns were observed from 2010 to 2013, although crude cost differences between MSSA- and MRSA-related pneumonia hospitalizations rose from 25.8% in 2010 to 31.0% in 2014. Compared with MSSA-related hospitalizations, MRSA-related hospitalizations had a higher adjusted mortality rate.” (E. Y. Klein, eklein@jhu.edu, klein@cddep.org)
Treatment Failure & Mortality With Complicated UTIs: No mortality benefit was found among hospitalized patients with early appropriate empiric treatment of complicated urinary tract infections (cUTIs) in a multinational retrospective cohort analysis, as shown in these results for 2013–14 (pp. 29–36): “Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were [ICU admission, corticosteroid treatment, bedridden, older age, metastatic cancer, and CaUTI]. Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics, were not associated with treatment failure or 30-day mortality.…” (N. Eliakim-Raz, noaeliakim@gmail.com)

PNN Pharmacotherapy Line
Dec. 17, 2018 * Vol. 25, No. 241
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Dec. 15 issue of Lancet (2018; 392).
Eicosapentaenoic acid & Aspirin in Colorectal Adenoma Prevention: Optimal use of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin for prevention of colorectal adenomas “might require a precision medicine approach,” conclude authors of placebo-controlled, 2 x 2 factorial trial of 709 participants (pp. 2583–94). The seAFOod Polyp Prevention trial tested daily doses of EPA–free fatty acid (FFA) 3 g and aspirin 300 mg separately and in combination, with these results in comparison with placebo: “The [adenoma detection rate (ADR)] was 61% (100 of 163) in the placebo group, 63% (97 of 153) in the EPA group, 61% (100 of 163) in the aspirin group, and 61% (98 of 161) in the EPA plus aspirin group, with no evidence of any effect for EPA (risk ratio [RR] 0.98, 95% CI 0.87 to 1.12; risk difference −0.9%, −8.8 to 6.9; p = 0.81) or aspirin (RR 0.99 (0.87 to 1.12; risk difference −0.6%, −8.5 to 7.2; p = 0.88). EPA and aspirin were well tolerated (78 [44%] of 176 had ≥1 adverse event in the placebo group compared with 82 [46%] in the EPA group, 68 [39%] in the aspirin group, and 76 [45%] in the EPA plus aspirin group), although the number of gastrointestinal adverse events was increased in the EPA alone group at 146 events.… Six upper-gastrointestinal bleeding events were reported across the treatment groups….” (M. A. Hull, m.a.hull@leeds.ac.uk)
Morphine in Premature Neonates: In nonventilated premature infants undergoing screening for premature retinopathy or heel sticks, pretreatment with oral morphine 100 mcg/kg provided little analgesic effect in comparison with placebo (pp. 2595–605). Based on results of the 31-participant Procedural Pain in Premature Infants (Poppi) study, investigators conclude, “We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants.” (R. Slater, rebeccah.slater@paediatrics.ox.ac.uk)
>>>BMJ Highlights
Source:
 Early-release articles from the annual Christmas issue of BMJ (2018; 362).
Holidays, Time Patterns & MIs: With Christmas Eve falling on a Monday this year, the results of a study of timing of myocardial infarction in Sweden should be reason for caution (k4811). Higher risks of myocardial infarction were found at these times of the day, week, or year: “Christmas and Midsummer holidays were associated with a higher risk of myocardial infarction (incidence rate ratio 1.15, 95% confidence interval 1.12 to 1.19, P <0.001, and 1.12, 1.07 to 1.18, P <0.001, respectively). The highest associated risk was observed for Christmas Eve (1.37, 1.29 to 1.46, P <0.001). No increased risk was observed during Easter holiday or sports events. A circaseptan and circadian variation in the risk of myocardial infarction was observed, with higher risk during early mornings and on Mondays. Results were more pronounced in patients aged over 75 and those with diabetes and a history of coronary artery disease.” (D. Erlinge, david.erlinge@med.lu.se)
Hospital Discharge During December Holidays: Outpatient follow-up are less likely and 30-day mortality and readmissions higher for patients discharged from hospitals in Ontario around the holidays, researchers report (k4481). Compared with control periods, those discharged in 2002–16 during a 2-week December holiday period had fewer prompt follow-up visits and 9% greater risk of dying within 30 days. (L. Lapointe-Shaw, lauren.lapointe.shaw@mail.utoronto.ca)
>>>PNN JournalWatch
New Approaches to the Management of Adult Acute Lymphoblastic Leukemia, in Journal of Clinical Oncology, 2018; 36: 3504–19. (R. Bassan, Renato.bassan@aulss3.veneto.it)
Use of Renin-Angiotensin System Blockade in Advanced CKD: An NKF-KDOQI Controversies Report, in American Journal of Kidney Diseases, 2018; 72: 873–84. (M. R. Weir, mweir@som.umaryland.edu)
Emerging Concepts in Hematopoietic Stem Cell Transplantation–Associated Renal Thrombotic Microangiopathy and Prospects for New Treatments, in American Journal of Kidney Diseases, 2018; 72: 857–65. (R. Wanchoo, rwanchoo1@northwell.edu)
Predictive Markers for Humoral Influenza Vaccine Response in Patients With Common Variable Immunodeficiency, in Journal of Allergy and Clinical Immunology, 2018; 142: 1922–31.e2. (A. Gardulf, ann.gardulf@ki.se)

PNN Pharmacotherapy Line
Dec. 18, 2018 * Vol. 25, No. 242
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 the Annals of Internal Medicine (2018; 169).
Reference Infliximab & Biosimilar in Crohn Disease: Effectiveness and safety were similar for the biosimilar CT-P13 and reference product (RP) infliximab in a comparative equivalence cohort study of infliximab-naive patients with Crohn disease (CD) (10.7326/M18-1512). Using the French nationwide Système National des Données de Santé database, researchers identified 5,050 infliximab-naive patients with CD. Based on a composite primary outcome of death, CD-related surgery, all-cause hospitalization, and reimbursement of another biologic therapy, results showed: “Overall, 1,147 patients in the RP group and 952 patients in the CT-P13 group met the composite end point (including 838 and 719 hospitalizations, respectively). In multivariable analysis of the primary outcome, CT-P13 was equivalent to RP (HR, 0.92 [95% CI, 0.85 to 0.99]). No differences in safety outcomes were observed between the 2 groups: serious infections (HR, 0.82 [CI, 0.61 to 1.11]), tuberculosis (HR, 1.10 [CI, 0.36 to 3.34]), and solid or hematologic cancer (HR, 0.66 [CI, 0.33 to 1.32]).” (A. Meyer, antoinemeyer@gmail.com)
“The introduction of biosimilars has resulted in cost savings, and further economic benefits are anticipated as use of these products increases,” editorialists write (
10.7326/M18-3060). “This will improve patient access to biosimilars, which, in turn, is expected to decrease work absenteeism and increase productivity. Nevertheless, the challenges of increased use of biosimilars must not be underestimated. Regardless of the aforementioned strict and comprehensive requirements for documentation of similarity, pharmacovigilance systems must be able to distinguish between the original product and the biosimilar to allow rapid identification of any signal of impaired safety and efficacy. Furthermore, when a patient is switching to a biosimilar or a treatment-naive patient is starting therapy with a biosimilar, communication must be open and clear and patient concerns must be considered. Most important, to alleviate concerns, health care professionals must be proactive in increasing patients’ confidence by providing evidence-based information from the growing experience with biosimilars.” (O. Haagen Nielsen, le.haagen.nielsen@regionh.dk">ole.haagen.nielsen@regionh.dk)
CEA of Buprenorphine–Naloxone v. Extended-Release Naltrexone: In a cost-effectiveness analysis, “buprenorphine–naloxone is preferred to extended-release naltrexone for first-line treatment when both options are clinically appropriate and patients require detoxification before initiating extended-release naltrexone,” investigators conclude (10.7326/M18-0227). The study, consisting of 24 weeks of intervention and 12 weeks of observation, showed these results for 470 adults in 8 U.S. programs based on incremental costs combined with incremental quality-adjusted life–years (QALYs) and incremental time abstinent from opioids: “Use of the health care sector perspective and a willingness-to-pay threshold of $100,000 per QALY showed buprenorphine–naloxone to be preferable to extended-release naltrexone in 97% of bootstrap replications at 24 weeks and in 85% at 36 weeks. Similar results were obtained with incremental time abstinent from opioids as an outcome and with use of the societal perspective.” (S. M. Murphy, smm2010@med.cornell.edu)
Long-Term Outcomes With Moderate Anemia: Conservative management of hospitalized patients with moderate anemia is supported by a retrospective cohort study conducted in an integrated health system with 4 million members (10.7326/M17-3253). At 21 hospitals from 2010 to 2014, the prevalence of moderate anemia increased from 20% to 25% at hospital discharge, and rehospitalizations increased in parallel with decreased red blood cell (RBC) transfusion. “This increase was not accompanied by a rise in subsequent RBC use, rehospitalization, or mortality within 6 months of hospital discharge,” the authors conclude. “Longitudinal analyses support the safety of practice recommendations to limit RBC transfusion and tolerate anemia during and after hospitalization.” (N. H. Roubinian, Nareg.H.Roubinian@kp.org)
>>>PNN NewsWatch
* Asclemed USA is voluntarily recalling 20 lots of Dyural-40 and 61 lots of Dyural-80 (Sodium Chloride, USP, 0.9%) because of undeclared latex in stoppers.

PNN Pharmacotherapy Line
Dec. 20, 2018 * Vol. 25, No. 244
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 20 New England Journal of Medicine (2018; 379).
Adjuvant FOLFIRINOX for Pancreatic Cancer: As adjuvant therapy in 493 patients with resected pancreatic ductal adenocarcinoma, a modified adjuvant FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) increased survival in comparison with gemcitabine, but with increased adverse effects, researchers report in these findings (pp. 2395–406): “At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P <0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P = 0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).” (T. Conroy, t.conroy@nancy.unicancer.fr)
“This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer,” an editorialist writes (
pp. 2463–4). “The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease.…” (H. L. Kindler)
Zoledronate in Older Women with Osteopenia: Fragility fractures were reduced in older women with osteopenia by zoledronate therapy, a placebo-controlled study shows (pp. 2407–16). In a 6-year trial in 2,000 women age 65 years or older, “A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P <0.001),” the authors report. “The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P = 0.001), symptomatic fractures (hazard ratio, 0.73; P = 0.003), vertebral fractures (odds ratio, 0.45; P = 0.002), and height loss (P <0.001).” (I. R. Reid, i.reid@auckland.ac.nz)
“The results of the trial by Reid et al. should have an effect on clinical practice,” an editorialist concludes (pp. 2465–6). “Given the effectiveness of infrequent administration of zoledronate in reducing the risk of fragility fracture, this treatment can certainly be added to our armamentarium for treating osteoporosis, and it would represent an approach that would not be hindered by adherence issues.…” (C. J. Rosen)
Sorafenib for Advanced and Refractory Desmoid Tumors: In a phase 3 placebo-controlled, crossover-permitted trial, 87 sorafenib-treated patients with progressive, refractory, or symptomatic desmoid tumors had significantly prolonged progression-free survival and durable responses (pp. 2417–28): “The 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P <0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%).” (M. M. Gounder, gounderm@mskcc.org)

PNN Pharmacotherapy Line
Dec. 21, 2018 * Vol. 25, No. 245
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
 Early-online articles from and Dec. issue of the Journal of the American Geriatrics Society (2018; 66).
Pharmacotherapy in Older Adults with CVD: “The needs and circumstances of older adults with [cardiovascular disease (CVD)] differ from those that the current medical system has been designed to meet,” concludes a report of a workshop sponsored by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society (10.1111/jgs.15634). “Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person-centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices.” (J. B. Schwartz, janice.schwartz@ucsf.edu)
Polypharmacy & Outcomes With Vitamin K Antagonists: Among 2,011 individuals receiving vitamin K antagonists in the prospective multicenter thrombEVAL study, the risk of adverse events is increased in those on polypharmacy, defined as five or more medications (10.1111/jgs.15712). Over a 3-year follow-up period, these outcomes were identified: “Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all-cause mortality, but not for thromboembolic events, increased across groups of medication.… Per additional drug, bleeding risk was increased by 4%.” (P. S. Wild, philipp.wild@unimedizin-mainz.de)
Patient Willingness to Replace Fall-Associated Meds: Made aware of the fall risks associated with medications for pain, difficulty sleeping, mood or sadness, and anxiety- or nervousness-related health issues, most consumers expressed willingness to make recommended changes in responses to the summer 2016 wave of the ConsumerStyles survey (10.1111/jgs.15696): “About one-fifth of all respondents reported using at least one class of medication that increases fall risk. Older adults were less likely to report using medications for mood or sadness, less likely to report knowing the side effects of pain medications, and more willing to change their sleep medications compared with their younger counterparts. Among all respondents using these medication classes, less than one-third knew the potential fall-related side effects. However, most of them expressed willingness to change their medication if advised by their healthcare provider.” (Y. K. Haddad, yhaddad@cdc.gov)
Medication Use Quality & Safety in Older Adults: “Improving the quality of medication use and medication safety in older adults is an important public health priority and is of paramount importance for clinicians who care for them,” advise authors of a narrative review of four diverse articles of drug use in various clinical and residential settings (pp. 2254–8;  S. L. Gray, slgray@uw.edu).
>>>PNN NewsWatch
* FDA yesterday announced recalls of two lots of losartan potassium tablets, USP, by Torrant Pharmaceuticals to the consumer level because of presence of the impurity N-nitrosodiethylamine and of Roche CoaguChek test strips distributed directly to U.S. consumers by Terrific Care/Medex Supply Dist. because of inaccurately high INR test results. FDA also said it has warned Genetech of San Diego and its president for marketing stem cell products without FDA approval and for significant deviations from current good tissue practice and current good manufacturing practice requirements, including some violations that may have led to microbial contamination.
* In two statements, FDA Commissioner Scott Gottlieb, MD, provided insights into new steps to strengthen the long-term safety oversight of the 
Essure device following discontinuation of its U.S. sales and new regulations governing production and marketing of hemp.
PNN will not be published on Mon. and Tues., Dec. 24 and 25, Christmas Eve and Day.

PNN Pharmacotherapy Line
Dec. 26, 2018 * Vol. 25, No. 246
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Dec. 22 issue of Lancet (2018; 392).
Pegbelfermin in Nonalcoholic Steatohepatitis: The pegylated human fibroblast growth factor 21 (FGF21) analogue pegbelfermin (BMS-986036) was well tolerated and effective in a phase 2a trial of 80 patients with nonalcoholic steatohepatitis (pp. 2705–17). The trial was stopped at 8 weeks when an interim analysis indicated benefits as follows: “We observed a significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (−6.8% vs −1.3%; p = 0.0004) and in the group receiving 20 mg pegbelfermin weekly (−5.2% vs −1.3%; p = 0.008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events.” (E. D. Charles, edgar.charles@bms.com)
>>>JAMA Highlights
Source:
 Dec. 25 issue of JAMA (2018; 320).
Long-term Pain Control in Knee Osteoarthritis: Celecoxib and glucosamine sulfate were the only agents associated with a decrease in pain in patients with knee osteoarthritis in a systematic review and Bayesian random-effects network meta-analysis (pp. 2564–79). In 47 randomized controlled trials of 33 pharmacological interventions in 22,037 patients with knee osteoarthritis, results showed uncertainty around estimates of effect size for change in pain for all comparisons with placebo, including for those for celecoxib and glucosamine. Associations with improvement in joint space narrowing were found only for glucosamine sulfate, chondroitin sulfate, and strontium ranelate. (L. C. Rovati, lucio.rovati@unimib.it)
Increased Mortality With Hospital Readmissions Reduction Program: Reacting to a cohort study showing a significant association between initiation of the Hospital Readmissions Reduction Program (HRRP) and increased postdischarge mortality for patients with pneumonia or heart failure (pp. 2542–52; R. W. Yeh, ryeh@bidmc.harvard.edu), an editorialist writes (pp. 2539–41): “Irrespective of the intent of the policy, there is no evidence that patients have benefited from the HRRP. Yet, taken together with previous studies there is now independently corroborated evidence that the HRRP was associated with increased postdischarge mortality among patients with heart failure and new evidence that the HRRP was associated with increased mortality among patients hospitalized for pneumonia. In light of these findings, it is incumbent upon Congress and CMS to initiate an expeditious reconsideration and revision of this policy. Alternative strategies can be deployed to more effectively achieve the goal of reducing avoidable readmissions, improve patient-prioritized outcomes like health status, while better protecting patients from unintentional harms, including preventable deaths.” (G C. Fonarow, gfonarow@mednet.ucla.edu)
>>>PNN NewsWatch
FDA on Friday approved the breakthrough agent tagraxofusp-erzs (Elzonris, Stemline Therapeutics) infusion for treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years of age and older. An aggressive and rare disease of the bone marrow and blood, BPDCN can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. Tagraxofusp-erzs was designated an orphan drug and approved on a priority basis.
* Also on Friday, 
FDA approved on a priority basis the orphan drug ravulizumab (Ultomiris, Alexion Pharmaceuticals) injection for treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). The long-acting complement inhibitor prevents hemolysis in patients with PNH, a rare acquired disorder that can be life-threatening.
>>>PNN JournalWatch
The Major Causes of Death in Children and Adolescents in the United States, in New England Journal of Medicine, 2018; 379: 2468–75. (R. M. Cunningham, stroh@med.umich.edu)
Osteoporosis in Older Persons: Old and New Players, in Journal of the American Geriatrics Society, 2018; 66: 10.1111/jgs.15716. (G. Duque, gustavo.duque@unimelb.edu.au)

PNN Pharmacotherapy Line
Dec. 27, 2018 * Vol. 25, No. 247
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 27 New England Journal of Medicine (2018; 379).
Maintenance Olaparib in Advanced Ovarian Cancer: The risk of disease progression or death was reduced by 70% by treatment with the oral poly(adenosine diphosphate–ribose) polymerase inhibitor olaparib in women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, researchers report (pp. 2495–505). As detailed in a Quick Take video, 391 patients in a phase 3 trial were randomized to oral olaparib as maintenance therapy or placebo; 388 of them had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. Based on a primary end point of progression-free survival, results showed: “After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P <0.001). Adverse events were consistent with the known toxic effects of olaparib.” (K. Moore, kathleen-moore@ouhsc.edu)
Editorialists note that since nearly all of the patients in this SOLO1 study had germline BRCA1/2 mutations, these “results may not be generalizable to patients with either somatic BRCA mutations or wild-type BRCA genes” (
pp. 2567–8). However, since the company (Myriad) that conducted the genetic sequencing in this trial has declined to provide the identity and distribution of the genetic variants detected in these patients, the trial results could be misapplied in in practice: “The trial treatment might be incorrectly excluded from or included in regimens for patients with those and other rare variants. Given that the knowledge of genetic variants is dynamic and additional specific adverse variants will certainly be discovered, full transparency by reporting to ClinGen or similar sources would be a helpful requirement in the future, so that patients with BRCA1/2 mutations can fully benefit from the sacrifices of the participants in the trial.” (D. R. Spriggs)
Ibrutinib in Older Patients with Untreated CLL: Compared with chemoimmunotherapy, ibrutinib significantly increased rates of progression-free survival in a phase 3 trial of older adults with untreated chronic lymphocytic leukemia (CLL) (pp. 2517–28). Participants aged 65 years or older were randomized to bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab, with these results: “The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P <0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P <0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P = 0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).” (J. A. Woyach, jennifer.woyach@osumc.edu)
Tofacitinib in Cutaneous Sarcoidosis: In a patient whose sarcoidosis was not responsive to medications and had not been treated with systemic glucocorticoids, tofacitinib produced clinical remission of cutaneous disease at 10 months, a case report shows (pp.2540–6). After two treatment periods during which tofacitinib improved symptoms but was stopped because of insurance issues, a third cycle provided an opportunity to assess responses of skin-lesion samples to the JAK1/3 inhibitor. “Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis,” the authors conclude. (B. King, brett.king@yale.edu)

PNN Pharmacotherapy Line
Dec. 28, 2018 * Vol. 25, No. 248
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
 Jan. issue of and supplement to Diabetes Care (2019; 42).
Standards of Medical Care in Diabetes—2019: Eat better. Get more exercise. Maintain flexibility and balance. And when an injectable agent is needed, start with a GLP-1 agonist rather than insulin. Those are some of the big takeaways in the Standards of Medical Care document just released by the American Diabetes Association (S4–S6). The annual update also includes a new section on older adults, with simplified insulin regimens designed to “match individual’s self-management abilities” (pp. S139–S147). A dedicated section on Diabetes Technology consolidates material previously in other sections, including use on continuous glucose monitors and insulin infusion devices, and makes new recommendations (pp. S71–S80).
Among the drug-related recommendations (
pp. S90–S102) in the 2019 update are the following:
* Most people with type 1 diabetes should be treated with multiple daily injections of prandial and basal insulin, or continuous subcutaneous insulin infusion. A (evidence level on an A [high] to E [limited] scale)
* Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E
* For type 2 diabetes, a patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include comorbidities (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease), hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences. E
* Metformin is the preferred initial pharmacologic agent for the treatment of type 2 diabetes (
Fig. 9.2). A
* Once initiated, metformin should be continued as long as it is tolerated and not contraindicated; other agents, including insulin, should be added to metformin. A
* The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (>10% [86 mmol/mol]) or blood glucose levels (≥300 mg/dL [16.7 mmol/L]) are very high. E
* Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease, sodium–glucose cotransporter 2 inhibitors, or glucagon-like peptide 1 receptor agonists with demonstrated cardiovascular disease benefit (
Table 9.1) are recommended as part of the antihyperglycemic regimen. A
* In most patients who need the greater glucose-lowering effect of an injectable medication, glucagon-like peptide 1 receptor agonists are preferred to insulin. B
* For patients with type 2 diabetes and chronic kidney disease, consider use of a sodium–glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist shown to reduce risk of chronic kidney disease progression, cardiovascular events, or both. C
Medical Costs Before, After Diabetes Diagnosis: Excess medical expenditures, known to be evident after a diabetes diagnosis, are also higher in the prior decade, a study shows (pp. 62–8). The 2001–13 MarketScan data for American adults aged 25–64 years showed these expenditures for two cohorts up to 10 years before and after diabetes diagnosis: “The per capita annual total excess medical expenditure for the diabetes cohort was higher for the entire 10 years prior to their index date, ranging between $1,043 in year −10 and $4,492 in year −1. Excess expenditure spiked in year 1 ($8,109), declined in year 2, and then increased steadily, ranging from $4,261 to $6,162 in years 2–10. The cumulative excess expenditure for the diabetes cohort during the entire 20 years of follow-up was $69,177 ($18,732 before and $50,445 after diagnosis).” (S. S. Shrestha, gqm2@cdc.gov)
>>>PNN NewsWatch
* As PNN closes out 2018, biosimilars come to mind as one of the more prominent pharmacy-focused developments during the past 12 months. FDA has approved some 68 new chemical or biological entities since Jan. 1, a record number fueled by the emphasis on FDA’s Biosimilars Action Plan, released in July 2018. Of the 15 biosimilars approved since the first one in Mar. 2015 (filgrastim-sndz, Zarxio), 8 were approved this year or in Dec. 2017.
PNN will not be published on Mon. and Tues., Dec. 31 and Jan. 1, New Year’s Eve and Day.