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Providing news and information about medications and their proper use
PNN July–September 2019
PNN Pharmacotherapy Line
July 1, 2019 * Vol. 26, No. 126
Click here for a PDF of this issue.
>>>Lancet Report
Source: June 29 issue of Lancet (2019; 393).
Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: In patients who have had a bleed-related stroke during antithrombotic therapy, the "risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention," authors conclude (pp. 2613–23; RESTART Collaboration).
PICO: Prospective, randomized, open-label, blinded endpoint, parallel-group trial at 122 U.K. hospitals of adults who were taking antithrombotic (antiplatelet or anticoagulant) therapy for prevention of occlusive vascular disease when they developed intracerebral hemorrhage; randomization to start or avoid antiplatelet therapy; primary outcome of recurrent symptomatic intracerebral hemorrhage over 5 years.
Results: "Participants were followed for a median of 2.0 years (IQR [1.0–3.0]; completeness 99.3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0.51 [95% CI 0.25–1.03]; p = 0.060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0.71 [0.39–1.30]; p = 0.27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1.02 [0.65–1.60]; p = 0.92)."
>>>BMJ Highlights
Source: Early-release article from BMJ (2019; 365).
Dual Antiplatelet Therapy After PCI With Drug-Eluting Stent: Considering patients with all clinical presentations who have undergone percutaneous coronary intervention (PCI) with drug-eluting stent (DES), short-term dual antiplatelet therapy (DAPT) with clopidogrel could be considered based on both direct and indirect effects, authors of review article conclude (l2222; H. Yuan, yuanhong01@csu.edu.cn).
PICO: Systematic review and network meta-analysis of 17 randomized controlled trials of two of the three durations of DAPT (short term, standard term, and long term) after PCI with DES; primary study outcomes of cardiac or noncardiac death, all-cause mortality, myocardial infarction, stent thrombosis, and all bleeding events.
Results: "Compared with short term DAPT, network meta-analysis showed that long term DAPT resulted in higher rates of major bleeding (odds ratio 1.78, 95% confidence interval 1.27 to 2.49) and non-cardiac death (1.63, 1.03 to 2.59); standard term DAPT was associated with higher rates of any bleeding (1.39, 1.01 to 1.92). No noticeable difference was observed in other primary endpoints. The sensitivity analysis revealed that the risks of non-cardiac death and bleeding were further increased for ≥18 months of DAPT compared with short term or standard term DAPT. In the subgroup analysis, long term DAPT led to higher all cause mortality than short term DAPT in patients implanted with newer-generation DES (1.99, 1.04 to 3.81); short term DAPT presented similar efficacy and safety to standard term DAPT with acute coronary syndrome presentation and newer-generation DES placement. The heterogeneity of pooled trials was low, providing more confidence in the interpretation of results."
>>>PNN JournalWatch
* Spread of Measles in Europe and Implications for US Travelers, in Pediatrics, 2019; 144: 10.1542/peds.2019-0414. (K. M. Angelo)
* Omega-3 Long-Chain Polyunsaturated Fatty Acids for Bronchopulmonary Dysplasia: A Meta-analysis, in Pediatrics, 2019; 144: 10.1542/peds.2019-0181. (Q. Wang)
* Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec, in Children and Adolescents With Type 1 Diabetes: The onset 7 Trial, in Diabetes Care, 2019; 42: 1255–62. (B. W. Bode, bbode001@gmail.com)
* Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples, in American Journal of Psychiatry, 2019; 176: 531–42. (M. Hoogman)
* Hospital Readmission Rates in Medicare Advantage and Traditional Medicare: A Retrospective Population-Based Analysis, in Annals of Internal Medicine, 2019; 10.7326/M18-1795. (O. A. Panagiotou, restis_panagiotou@brown.edu">orestis_panagiotou@brown.edu)
>>>Internal Medicine Report
Source: Early-online articles from and July 2 issue of Annals of Internal Medicine (2019; 171).
Self-management of Epilepsy: Self-management of epilepsy modestly improves some patient outcomes, authors conclude based on a systematic review of 13 randomized and 2 nonrandomized trials of 2,514 patients (10.7326/M19-0458; M. W. Luedke, matthew.luedke@duke.edu).
PICO: Six components and efficacy of self-management interventions in the treatment of epilepsy in community-dwelling persons.
Results: "Interventions were delivered primarily in group settings, used a median of 4 components, and followed 2 general strategies: 1 based on education and the other on psychosocial therapy. Education-based approaches improved self-management behaviors (standardized mean difference, 0.52 [95% CI, 0.0 to 1.04]), and psychosocial therapy–based approaches improved quality of life (mean difference, 6.64 [CI, 2.51 to 10.77]). Overall, self-management interventions did not reduce seizure rates, but 1 educational intervention decreased a composite of seizures, emergency department visits, and hospitalizations."
Long-Term Osteoporosis Fracture Prevention: For long-term prevention of osteoporotic fractures in men or postmenopausal women, alendronate and zoledronic acid provide an optimal balance between efficacy and safety, according to results of a systematic review (pp. 37–50; H. A. Fink, Howard.fink@va.gov).
PICO: 48 studies of men or postmenopausal women aged 50 years or older with low or medium risk of bias and comparing long-term osteoporosis drug treatment (ODT) (>3 years) versus control or ODT continuation versus discontinuation; outcomes of reported incident fractures (for trials) or harms (for trials and observational studies).
Results: "In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate [strength of evidence (SOE)]), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE)."
Editorial: Research gaps are identified in an accompanying position paper from an NIH workshop (pp. 51–7; A. Siu, albert.siu@mssm.edu): "Aging of the population increases the prevalence of osteoporosis and its consequences. Although ODTs may have played a part in more recent reductions in fracture incidence, uncommon but potentially serious side effects have been associated with these treatments. Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients' values and preferences. The research outlined … is urgently needed to advance prevention of osteoporosis-related mortality and morbidity."
>>>PNN NewsWatch
* A new draft guidance, Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products — Content and Format, is now available, FDA said yesterday. Commissioner Norman E. "Ned" Sharpless, M.D., wrote in a statement, "The recommendations in this draft guidance, when finalized, will represent our current thinking on the content and format of this section for prescription medications that are scheduled under the Controlled Substances Act (CSA) as well as for prescription medications not scheduled under the CSA for which there is important information to convey to health care professionals related to abuse and dependence."
>>>JAMA Report
Source: July 2 issue of JAMA (2019; 322).
State Laws & Kindergartners' Vaccination Status: Statewide legislative and educational interventions are associated with lower annual rates of kindergartners without up-to-date vaccination status and decreased numbers of schools inside clusters with high rates of kindergartners without up-to-date vaccination status, researchers report(pp. 49–56; S. C. Pingali, cassandra.lukemire@alumni.emory.edu).
PICO: Observational study using cross-sectional California school-entry data in 2000–17; changes in laws in 2014 and 2016, and a conditional admission education program in 2015; primary outcome of yearly rate of kindergartners without up-to-date vaccination status and secondary outcomes related to geographic clusters with higher rates of incompletely vaccinated kindergartners.
Results: "In California between 2000 and 2017, 9,323,315 children started attending kindergarten and 721,593 were not up to date on required vaccinations. Prior to the interventions, the statewide rate of kindergartners without up-to-date status for required vaccinations increased from 7.80% during 2000 to 9.84% during 2013 and then decreased after the interventions to 4.87% during 2017. The percentage chance for within-school contact among kindergartners without up-to-date vaccination status decreased from 26.02% during 2014 to 4.56% (95% CI, 4.21%–4.99%) during 2017. During 2012–2013, there were 124 clusters that contained 3,026 schools with high rates of kindergartners without up-to-date vaccination status. During 2014–2015, there were 93 clusters that contained 2,290 schools with high rates of kindergartners without up-to-date vaccination status. During 2016–2017, there were 110 clusters that contained 1613 (95% CI, 1565–1691) schools."
Editorial: "Perhaps the most compelling evidence for a unified national approach to limit nonmedical exemptions to childhood vaccination is that the United States has previously achieved virtual eradication of measles (ie, no endemic spread), as recently as the year 2000," editorialists write (pp. 33–4; M. M. Davis, mmdavis@luriechildrens.org). "Following that achievement, state-level policy changes relaxed immunization requirements and set the stage for progressively larger outbreaks in the United States in recent years. Such system failures result when the products, processes, and people (including the public) that comprise systems do not function or behave in ways that protect health optimally. The best way to remedy the current system failure regarding measles vaccination may be to adopt a unified national approach to prohibit nonmedical exemptions, and thereby regain the degree of nationwide protection against vaccine-preventable disease from which children and other community members will benefit."
Durable Control of HIV Infection Without ART: "Achieving a sustained, durable [antiretroviral therapy (ART)]–free HIV remission by a variety of minimally toxic approaches that are potentially scalable remains an overarching priority in HIV research," write authors of a Viewpoint article (pp. 27–8; A. S. Fauci, afauci@niaid.nih.gov). "Success of such an effort has important implications for the economic costs of lifelong ART in large numbers of patients, medical issues such as drug resistance and/or drug toxicities that are associated with lifelong ART, and the personal and societal stigma associated with the indefinite requirement of ART. Such approaches will require novel and innovative strategies to take advantage of the opportunities and overcome the numerous obstacles currently faced in removing or controlling the persistent replication-competent HIV reservoirs in the absence of ART. Building on the extensive foundation of research in this field and the unprecedented success of combination ART, it is important to continue to explore new pathways to successfully attain an ART-free remission for persons with HIV."
* FDA has issued warning letters to three repackers of active pharmaceutical ingredients: B&B Pharmaceuticals, Inc., Asclemed USA, Inc., doing business as Enovachem, and Spectrum Laboratory Products, Inc., for significant violations of current good manufacturing practice requirements.
* PNN will not be published on Thurs. and Fri., July 4–5, Independence Day.
Source: July 6 Lancet (2019; 394).
Oral Semaglutide in Type 2 Diabetes: In a comparative trial of patients with type 2 diabetes, oral semaglutide was noninferior to liraglutide and superior to placebo for decreasing glycosylated hemoglobin, and superior in decreasing body weight compared with both liraglutide and placebo at week 26, researchers report (pp. 39–50; R. Praley, richard.pratley@flhosp.org). "Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care," the authors conclude.
PICO: Adult patients with HbA1c of 7.0–9.5% on a stable dose of metformin with or without a sodium-glucose co-transporter-2 inhibitor; once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1.8 mg), or placebo for 52 weeks; primary endpoint of change from baseline to week 26 in HbA1c.
Results: "Mean change from baseline in HbA1c at week 26 was −1.2% (SE 0.1) with oral semaglutide, −1.1% (SE 0.1) with subcutaneous liraglutide, and −0.2% (SE 0.1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] −0.1%, 95% CI −0.3 to 0.0; p<0.0001) and superior to placebo (ETD −1.1%, −1.2 to −0.9; p <0.0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD −0.2%, 95% CI −0.3 to −0.1; p = 0.0056) and placebo (ETD −1.2%, −1.4 to −1.0; p <0.0001) at week 26. Oral semaglutide resulted in superior weight loss (−4.4 kg [SE 0.2]) compared with liraglutide (−3.1 kg [SE 0.2]; ETD −1.2 kg, 95% CI −1.9 to −0.6; p=0.0003) and placebo (−0.5 kg [SE 0.3]; ETD −3.8 kg, −4.7 to −3.0; p <0.0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (−1.5 kg, 95% CI −2.2 to −0.9; p <0.0001) and placebo (ETD −4.0 kg, −4.8 to −3.2; p <0.0001). Adverse events were more frequent with oral semaglutide (n = 229 [80%]) and subcutaneous liraglutide (n = 211 [74%]) than with placebo (n = 95 [67%])."
* FDA on Wednesday granted accelerated approval to selinexor (Xpovio, Karyopharm Therapeutics) tablets in combination with dexamethasone for treatment of adults with relapsed refractory multiple myeloma who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
* Altaire Pharmaceuticals said last week that it is voluntarily recalling to the retail level numerous lots of several ophthalmic drug products and lots within expiry sold at Walgreens and Wal-Mart because of management concerns regarding the sufficiency of quality assurance controls over critical systems in the manufacturing facility.
* Esketamine for Treatment-Resistant Depression—First FDA-Approved Antidepressant in a New Class, in New England Journal of Medicine, 2019; 381: 1–4. (J. Kim)
* Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer, in New England Journal of Medicine, 2019; 381: 13–24. (K. M. Chi, kchi@bccancer.bc.ca)
* Chronic Rhinosinusitis with Nasal Polyps, in New England Journal of Medicine, 2019; 381: 55–63. (C. Hopkins, claire.hopkins@gstt.nhs.uk)
* Genetic Variation, Comparative Genomics, and the Diagnosis of Disease, in New England Journal of Medicine, 2019; 381: 64–74. (E.E. Eichler, eee@gs.washington.edu)
* Changes in Hospital Safety Following Penalties in the US Hospital Acquired Condition Reduction Program: Retrospective Cohort Study, in BMJ, 2019; 366: l4109. (A. M. Ryan, amryan@umich.edu)
* Role of Diet in Type 2 Diabetes Incidence: Umbrella Review of Meta-Analyses of Prospective Observational Studies, in BMJ, 2019; 366: l2368. (S. Schlesinger, sabrina.schlesinger@ddz.de)
* Dietary Fats and Mortality Among Patients With Type 2 Diabetes: Analysis in Two Population Based Cohort Studies, in BMJ, 2019; 366: l2368. (S. Schlesinger, sabrina.schlesinger@ddz.de)
Source: Early-online articles from and July issue of JAMA Internal Medicine (2019; 179).
Promoting Sleep/Reducing Hypnotic Agents in Inpatients: "Promoting sleep while reducing sedative-hypnotic initiation for insomnia among inpatient settings can benefit patients through avoidable harm reduction," conclude authors of a Review article (pp. 965–72; C. Soong, christine.soong@utoronto.ca). "Several strategies have demonstrated efficacy in reducing sedative-hypnotic use and intervention selection should be based on local drivers of inappropriate prescribing. Creating a sleep-friendly inpatient environment is an important enabler of sedative-hypnotic reduction efforts. This guide can aid quality improvement teams, administrators, and clinicians toward achieving a safer hospital environment for inpatients."
Bundled Hospital CAP Intervention With Corticosteroids: More gastrointestinal bleeds and no improvement in efficacy outcomes resulted from use of a bundle of evidence-supported treatments in patients hospitalized with community-acquired pneumonia, researchers report (10.1001/jamainternmed.2019.1438; H. Karunajeewa, harin.karunajeewa@wh.org.au).
PICO: Double-blind, stepped-wedge, cluster-randomized clinical trial at two Australian hospitals in 2016–17; consecutive sample of 816 patients with community-acquired pneumonia; prednisolone acetate 50 mg/d for 7 days and de-escalation from parenteral to oral antibiotics; outcomes of changes in hospital length of stay, mortality, readmission, and intervention-associated adverse events.
Results: "An unadjusted geometric mean ratio of 0.95 (95% CI, 0.78–1.16) was observed for the difference in length of stay (days) between the intervention and control groups. Similarly, no significant differences were observed for the secondary outcomes of mortality and readmission, and the results remained unchanged after further adjustment for sex and age. The study reported higher proportions of gastrointestinal bleeding in the intervention group (9 [2.2%]) compared with the controls (3 [0.7%]), with an unadjusted estimated difference in mean proportions of 0.008 (95% CI, 0.005–0.010)."
12-Month Dispensing of Oral Contraceptives in the VA: In the Veterans Affairs (VA) health care system, use of a 12-month dispensing option for oral contractive pills (OCPs) could "produce substantial cost savings … while better supporting reproductive autonomy and reducing unintended pregnancy among women veterans," a study shows (10.1001/jamainternmed.2019.1678; C. Judge-Golden, cpj6@pitt.edu).
PICO: Decision model from the VA payer perspective that estimated incremental costs to the health care system of allowing the option to receive a 12-month supply of OCPs up front, compared with the standard 3-month maximum, during a 1-year time horizon; assumed a model cohort of 24,309 reproductive-aged, heterosexually active, female VA enrollees who wished to avoid pregnancy for at least 1 year; outcomes of incremental per-woman and total costs to the VA.
Results: "The 12-month OCP dispensing option … resulted in anticipated VA annual cost savings of $87.12 per woman compared with the cost of 3-month dispensing, or an estimated total savings of $2,117,800 annually. Cost savings resulted from an absolute reduction of 24 unintended pregnancies per 1,000 women per year with 12-month dispensing, or 583 unintended pregnancies averted annually. Expected cost savings with 12-month dispensing were sensitive to changes in the probability of OCP coverage gaps with 3-month dispensing, the probability of pregnancy during coverage gaps, and the proportion of pregnancies paid for by the VA. When simultaneously varying all variables across plausible ranges, the 12-month strategy was cost saving in 95.4% of model iterations."
Editorial: "Particularly in this environment where access to traditional clinic-based family planning services may be increasingly difficult, it is critical that we expand all these new models of contraceptive provision that rely less on a physician or advanced practice clinician in a brick-and-mortar facility," an editorialist writes (10.1001/jamainternmed.2019.1676; D. Grossman, daniel.grossman@ucsf.edu). "Our patients need these options now more than ever."
July 10, 2019 * Vol. 26, No. 131
Zoster Vaccine After Stem Cell Transplantation: The incidence of herpes zoster was reduced by the 2-dose course of recombinant zoster vaccine when given to adults after autologous hematopoietic stem cell transplantation (HSCT), researchers report (pp. 123–33; K. M. Sullivan, keith.sullivan@duke.edu).
PICO: Phase 3, randomized, observer-blinded study of 1,846 patients aged 18 years or older who had undergone recent autologous HSCT in 28 countries in 2012–17; recombinant zoster vaccine or placebo at 50 to 70 days after transplantation and 1–2 months thereafter; primary end point of occurrence of confirmed herpes zoster cases.
Results: "Among 1,846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1,735 (94%) received a second dose and 1,366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1,000 person–years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22–0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n = 1; placebo, n = 9; IRR, 0.1; 95% CI, 0.00–0.78; P = .02) and of other prespecified herpes zoster–related complications (vaccine, n = 3; placebo, n = 13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster–associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42–0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points."
Cannabis Use in Pregnancy: In studies from Canada and the U.S., use of marijuana during pregnancy was common, and the Canadian analysis shows increased risks of preterm birth and other perinatal problems with cannabis use.
PICO—Study 1: Population-based retrospective cohort study of live births and stillbirths in Ontario, in 2012–17; primary outcome of preterm birth before 37 weeks' gestation (pp. 145–52; D. J. Corsi, dcorsi@ohri.ca).
Results—Study 1: "Mothers had a mean age of 30.4 years and 9,427 (1.4%) reported cannabis use during pregnancy.… The crude rate of preterm birth less than 37 weeks' gestation was 6.1% among women who did not report cannabis use and 12.0% among those reporting use in the unmatched cohort (risk difference, 5.88% [95% CI, 5.22%–6.54%]).…"
PICO—Study 2: National Survey on Drug Use and Health for U.S. in 2012–17; cannabis use by pregnancy status (pp. 167–9; B. Han, beth.han@samhsa.hhs.gov).
Results—Study 2: Adjusted prevalence of past-month daily/near daily cannabis use in 2002–03 compared with 2016–17 increased from 0.9% to 3.4% among pregnant women overall, from 1.8% to 5.3% during the first trimester, from 0.6% to 2.5% during the second trimester, and from 0.5% to 2.5% during the third trimester.
Editorial: "These 2 studies send a straightforward message: cannabis use in pregnancy is likely unsafe; with an increasing prevalence of use (presumably related to growing social acceptability and legalization in many states), its potential for harm may represent a public health problem," editorialists write (pp. 121–2; M. Silverstein, michael.silverstein@bmc.org). "This message is based on the sound, if imperfect, epidemiology of these 2 studies and is heightened by a misperception that marijuana is safe, as evidenced by its direct marketing to pregnant women for morning sickness despite accumulating evidence of harm. However, there is an additional series of equally legitimate concerns, rooted more in history than epidemiology. These historical concerns relate to past and ongoing discourses on alcohol use in pregnancy and to the cocaine 'epidemic that wasn't' of the 1980s. Both of these histories, although imperfect comparators with the emerging data on cannabis, illustrate points that provide important context to the 2 present studies.…"
>>>NEJM Report
Source: July 11 issue of the New England Journal of Medicine (2019; 381).
CRP for Guiding Antibiotic Prescribing in COPD: Point-of-care testing of C-reactive protein (CRP) reduced antibiotic use in patients with chronic obstructive pulmonary disease (COPD) without evidence of harm, researchers report (pp. 111–20; C. C. Butler, christopher.butler@phc.ox.ac.uk).
PICO: Multicenter, open-label, randomized, controlled trial of 653 patients with COPD in England and Wales; acute exacerbations were managed with usual care guided by CRP point-of-care testing (CRP-guided group) or usual care alone (usual-care group); primary outcomes of patient-reported use of antibiotics for acute exacerbations of COPD within 4 weeks after randomization (to show superiority) and COPD-related health status at 2 weeks after randomization, as measured by the Clinical COPD Questionnaire (to show noninferiority).
Results: "Fewer patients in the CRP-guided group reported antibiotic use than in the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31; 95% confidence interval [CI], 0.20 to 0.47). The adjusted mean difference in the total score on the Clinical COPD Questionnaire at 2 weeks was −0.19 points (two-sided 90% CI, −0.33 to −0.05) in favor of the CRP-guided group. The antibiotic prescribing decisions made by clinicians at the initial consultation were ascertained for all but 1 patient, and antibiotic prescriptions issued over the first 4 weeks of follow-up were ascertained for 96.9% of the patients. A lower percentage of patients in the CRP-guided group than in the usual-care group received an antibiotic prescription at the initial consultation (47.7% vs. 69.7%, for a difference of 22.0 percentage points; adjusted odds ratio, 0.31; 95% CI, 0.21 to 0.45) and during the first 4 weeks of follow-up (59.1% vs. 79.7%, for a difference of 20.6 percentage points; adjusted odds ratio, 0.30; 95% CI, 0.20 to 0.46). Two patients in the usual-care group died within 4 weeks after randomization from causes considered by the investigators to be unrelated to trial participation."
Editorial: "Reducing the use of antibiotics probably confers both immediate and delayed benefits in this patient population," editorialists write in support of greater stewardship efforts in patients with COPD (pp. 174–5; A. S. Brett). "Antibiotic use is associated with risks of adverse events such as Clostridioides difficile colitis. Moreover, antibiotic exposure confers a predisposition to airway colonization by multidrug-resistant bacteria, which may subsequently cause pneumonia in vulnerable patients with COPD. Notably, in the current study, a narrow-spectrum agent (amoxicillin) was the most commonly prescribed antibiotic, and no patients received fluoroquinolones."
Reforming the Orphan Drug Act: "It is time to tackle [the problems discussed here] through sensible, patient-centered reform of the Orphan Drug Act," authors of a Perspective article conclude after analyzing the impact of this 1983 law (pp. 106–8; A. Sarpatwari). "The status quo increasingly threatens public health, as rising drug prices present growing access challenges for patients and indication slicing hampers collection of critical preapproval information on the safety and efficacy of drugs when used in ways that will reflect their most common use in the market. "
Adolescent Vaccination Over Parental Objection: Addressing the problem faced when adolescents have not been vaccinated because of parental objections, Commentary authors write, "Parental involvement in vaccination decisions remains important," (pp. 104–6; R. D. Silverman). "Many vaccine-hesitant parents ultimately agree to vaccination. Yet adolescents need not be harmed by parental decisions that are based on misinformation or disinformation. Allowing adolescents to consent to vaccination despite persistent parental resistance facilitates access to a medically recommended and evidence-based treatment. It promotes the minor's health, poses minimal personal risk, and offers substantial prosocial benefits, including reinforcement of the norm of vaccination and enhancement of community protection against the spread of dangerous and costly yet preventable diseases. Given such benefits, we believe that states should enact laws that expand both access to vaccines and the rights of minors who are at least 12 to 14 years of age to consent to vaccination."
>>>Cardiology Report
Source: July 16 issue of the Journal of the American College of Cardiology (2019; 74).
Edoxaban in AF & Liver Disease: Bleeding was increased in patients with liver disease who were receiving oral anticoagulants for atrial fibrillation (AF), a study shows, while thromboembolic events were not unchanged (pp. 179 ff; ).
PICO: Randomized, double-blind ENGAGE AF-TIMI 48 compared edoxaban with warfarin in patients with AF; follow-up of 2.8 years; primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding stratified by history of liver disease.
Results: "Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in [pharmacokinetics/pharmacodynamics] assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups."
Editorial: "Considering the growing number of patients with both AF and liver disease, there is an unmet need for evidence supporting the use of DOAC in these specific populations," editorialists write (pp. 190 ff; E-K Choi). "There have been no consensus statements for patients with relatively mild liver disease or abnormalities on liver function tests."
>>>Chest Highlights
Source: July issue of Chest (2019; 156).
Antibiotic Stewardship in ICUs: Principles and practices of antibiotic stewardship in the intensive care unit (ICU) are reviewed (pp. 163–71; R. G. Wunderink, r-wunderink@northwestern.edu): "In the face of emerging drug-resistant pathogens and a decrease in the development of new antimicrobial agents, antibiotic stewardship should be practiced in all critical care units. Antibiotic stewardship should be a core competency of all critical care practitioners in conjunction with a formal antibiotic stewardship program (ASP). Prospective audit and feedback, and antibiotic time-outs, are effective components of an ASP in the ICU. As rapid diagnostics are introduced in the ICU, assessment of performance and effect on outcomes will clearly be needed. Disease-specific stewardship for community-acquired pneumonia that relies on clinical pathways may be particularly high-yield. Computerized decision support has the potential to individualize stewardship for specific patients. Finally, infection control and prevention is the cornerstone of every ASP."
Chronic Cough & GERD in Children: The CHEST Expert Cough Panel recommends no treatment for gastroesophageal reflux disease (GERD) in pediatric patients when clinical features are absent and use of pediatric GERD guidelines to guide both treatment and investigations (pp. 131–40; A. B. Chang, annechang@ausdoctors.net).
PICO: Consensus regarding 4 questions was obtained using CHEST Expert Cough Panel's protocol and American College of Chest Physicians (CHEST) methodological guidelines and GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework along with Delphi methodology.
Results: "Few randomized controlled trials addressed … two questions and none addressed the other two. The single meta-analysis (two randomized controlled trials) showed no significant difference between the groups (any intervention for GERD vs placebo for cough resolution; OR, 1.14; 95% CI, 0.45–2.93; P = .78). Proton pump inhibitors (vs placebo) caused increased serious adverse events. Qualitative data from existing CHEST cough systematic reviews were consistent with two international GERD guidelines."
* Altaire Pharmaceuticals has expanded its recall of specific, unexpired OTC ophthalmic drug products and lots to include those sold at CVS Health during certain time periods (see PNN, July 8).
Health Outcomes of Children After Maternal Pandemic H1N1 Influenza Vaccination: Most 5-year health outcomes were normal in children exposed to 2009 pandemic H1N1 (pH1N1) influenza vaccination during pregnancy, researchers report, and small associations with increased asthma and reduced gastrointestinal infections may have resulted from residual confounding (l4151; D. Fell, dfell@cheo.on.ca).
PICO: Retrospective cohort study using population-based birth registry of all 104,249 live births in Ontario from Nov. 2009 through Oct. 2010; rates of immune-related (infectious diseases, asthma), nonimmune-related (neoplasms, sensory disorders), and nonspecific morbidity outcomes (urgent or inpatient health services use, pediatric complex chronic conditions) evaluated from birth to 5 years of age.
Results: "Of 104,249 live births, 31,295 (30%) were exposed to pH1N1 influenza vaccination in utero. No significant associations were found with upper or lower respiratory infections, otitis media, any infectious diseases, neoplasms, sensory disorders, urgent and inpatient health services use, pediatric complex chronic conditions, or mortality. A weak association was observed between prenatal pH1N1 vaccination and increased risk of asthma (adjusted hazard ratio 1.05, 95% confidence interval 1.02 to 1.09) and decreased rates of gastrointestinal infections (adjusted incidence rate ratio 0.94, 0.91 to 0.98). These results were unchanged in sensitivity analyses accounting for any potential differential healthcare seeking behavior or access between exposure groups."
3- Versus 4-Drug First-Line Antiretroviral HIV Regimens: Used in treatment-naive people with HIV infections, quadruple-drug regimens held no advantage over triple antiretroviral therapy, a review shows (l4179; Z. Yang, zyang@cuhk.edu.hk). "This finding lends support to current guidelines recommending the triple regimen as first-line treatment," the authors conclude.
PICO: Systematic review and meta-analysis of 12 randomized controlled trials of 4,251 treatment-naive people with HIV infection; outcomes of undetectable HIV-1 RNA, CD4 T cell count, virological failure, new AIDS-defining events, death, and severe adverse effects.
Results: "Quadruple and triple combination antiretroviral therapies had similar effects on all relevant effectiveness and safety outcomes, with no point estimates favouring quadruple therapy. With the triple therapy as the reference group, the risk ratio was 0.99 (95% confidence interval 0.93 to 1.05) for undetectable HIV-1 RNA, 1.00 (0.90 to 1.11) for virological failure, 1.17 (0.84 to 1.63) for new AIDS defining events, 1.23 (0.74 to 2.05) for death, and 1.09 (0.89 to 1.33) for severe adverse effects. The mean difference in CD4 T cell count increase between the two groups was −19.55 cells/μL (−43.02 to 3.92). In general, the results were similar, regardless of the specific regimens of combination antiretroviral therapies, and were robust in all subgroup and sensitivity analyses."
* Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association, in Circulation, 2019; 140: e98–e124. (https://professional.heart.org/statements; kelle.ramsay@wolterskluwer.com)
* 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons, in Circulation, 2019; 140: e125–e151. (https://professional.heart.org/statements; kelle.ramsay@wolterskluwer.com)
* The Clinical Impact and Cost-effectiveness of Measles-Mumps-Rubella Vaccination to Prevent Measles Importations Among International Travelers From the United States, in Clinical Infectious Diseases, 2019; 69: 306–15. (E. P. Hyle, ehyle@mgh.harvard.edu)
* The Juncture Between Clostridioides difficile Infection and Inflammatory Bowel Diseases, in Clinical Infectious Diseases, 2019; 69: 366–72. (L. S. Munoz-Price, smunozprice@mcw.edu)
* Comparative Efficacy of Therapeutics for Chronic Cancer Pain: A Bayesian Network Meta-Analysis, in Journal of Clinical Oncology, 2019; 20: 1742–52. (X. Wang, wangxiaojing8888@163.com)
* Pharmacologic Treatments for Chronic Cancer-Related Pain: Does Anything Work? [editorial], in Journal of Clinical Oncology, 2019; 20: 1686–9. (E. M. Lavoie Smith, ellenls@umich.edu)
Source: Early-online articles from Annals of Internal Medicine (2019; 171).
Oral Anticoagulant Therapy in Chronic Kidney Disease: In patients with early-stage chronic kidney disease (CKD), non–vitamin K oral anticoagulants (NOACs) have a superior benefit–risk profile compared with vitamin K antagonists (VKAs), a review shows, but evidence is insufficient to extend this finding to patients with more advanced CKD (10.7326/M19-0087; S. V. Badve, sbadve@georgeinstitute.org.au).
PICO: Systematic review and meta-analysis of randomized controlled trials of VKAs or NOACs for any indication in patients with CKD that reported efficacy or bleeding outcomes.
Results: "Forty-five trials involving 34,082 participants who received anticoagulation for atrial fibrillation (AF) (11 trials), venous thromboembolism (VTE) (11 trials), thromboprophylaxis (6 trials), prevention of dialysis access thrombosis (8 trials), and cardiovascular disease other than AF (9 trials) were included. All but the 8 trials involving patients with [dialysis-dependent end-stage kidney disease (ESKD)] excluded participants with creatinine clearance less than 20 mL/min or estimated glomerular filtration rate less than 15 mL/min/1.73 m2. In AF, compared with VKAs, NOACs reduced risks for stroke or systemic embolism (risk ratio [RR], 0.79 [95% CI, 0.66 to 0.93]; high-certainty evidence) and hemorrhagic stroke (RR, 0.48 [CI, 0.30 to 0.76]; moderate-certainty evidence). Compared with VKAs, the effects of NOACs on recurrent VTE or VTE-related death were uncertain (RR, 0.72 [CI, 0.44 to 1.17]; low-certainty evidence). In all trials combined, NOACs seemingly reduced major bleeding risk compared with VKAs (RR, 0.75 [CI, 0.56 to 1.01]; low-certainty evidence)."
Editorial: "The reduced risk observed for hemorrhagic stroke with NOACs compared with VKAs in the general population and now in patients with early CKD suggests a potential benefit in ESKD," editorialists write (10.7326/M19-1504; D. Zimmerman, dzimmerman@ottawahospital.on.ca). "However, a recent retrospective cohort study of patients who have ESKD with AF observed no difference in the risks for stroke or systemic embolism between the NOAC (apixaban) or the VKA (warfarin), raising concerns that these medications might be all risk and no benefit, at least for prophylaxis."
Anticoagulants & Snare Polypectomy: Continuous administration of anticoagulants (CA) with cold snare polypectomy (CSP) produced outcomes similar to periprocedural heparin bridging (HB) with hot snare polypectomy (HSP) while reducing length of hospitalizations (10.7326/M19-0026; Y. Takeuchi, takeuti-yo@mc.pref.osaka.jp).
PICO: At 30 Japanese institutions, the incidence of polypectomy-related major bleeding was assessed for those undergoing HB+HSP or CA+CSP.
Results: "The incidence of polypectomy-related major bleeding in the HB+HSP and CA+CSP groups was 12.0% (95% CI, 5.0% to 19.1%) and 4.7% (CI, 0.2% to 9.2%), respectively. The intergroup difference for the primary end point was +7.3% (CI, −1.0% to 15.7%), with a 0.4% lower limit of 2-sided 90% CI, demonstrating the noninferiority of CA+CSP. The mean procedure time for each polyp and the hospitalization period were longer in the HB+HSP than in the CA+CSP group."
* Reflecting on a federal court decision requiring makers and importers of e-cigarettes and other electronic nicotine delivery systems (ENDS) to file for FDA approval within 10 months, Acting Commissioner Norman E. "Ned" Sharpless, M.D., wrote in a statement released yesterday: "While certain ENDS products may hold some promise in helping addicted adult smokers transition away from combustible tobacco to a potentially less harmful form of nicotine delivery, these products – like all tobacco products – pose risk, and should not be used by kids. Years of progress to combat youth use of tobacco – to prevent lifetimes of addiction to nicotine – is now threatened by an epidemic of e-cigarette use by kids. We must also keep our nation's youth from using dangerous combusted tobacco products like cigars. As part of our Youth Tobacco Prevention Plan, we will maintain our energy and focus on using our authorities forcefully to prevent kids from getting their hands on tobacco products, with a particular emphasis on the threat of youth vaping."
Source: Early-release article from and July 16 issue of JAMA (2019; 322).
Lifestyle Overcomes Genetics in Dementia Risk: A healthy lifestyle is associated with lower risk of dementia in older adults with both low and high genetic risks, researchers report (10.1001/jama.2019.9879; D. J. Llewellyn, david.llewellyn@exeter.ac.uk).
PICO: Retrospective cohort study of adults of European ancestry aged 60 years or more without cognitive impairment or dementia at baseline in 2006–10, with follow-up until 2016 or 2017; polygenic risk score for dementia with low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) risk categories and a weighted healthy lifestyle score based on smoking, physical activity, diet, and alcohol use.
Results: "A total of 196,383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1,545,433 person–years (median [interquartile range] follow-up, 8.0 [7.4–-8.6] years). Overall, 68.1% of participants followed a favorable lifestyle, 23.6% followed an intermediate lifestyle, and 8.2% followed an unfavorable lifestyle. Twenty percent had high polygenic risk scores, 60% had intermediate risk scores, and 20% had low risk scores. Of the participants with high genetic risk, 1.23% (95% CI, 1.13%–1.35%) developed dementia compared with 0.63% (95% CI, 0.56%–0.71%) of the participants with low genetic risk (adjusted hazard ratio, 1.91 [95% CI, 1.64–2.23]). Of the participants with a high genetic risk and unfavorable lifestyle, 1.78% (95% CI, 1.38%–2.28%) developed dementia compared with 0.56% (95% CI, 0.48%–0.66%) of participants with low genetic risk and favorable lifestyle (hazard ratio, 2.83 [95% CI, 2.09–3.83]). There was no significant interaction between genetic risk and lifestyle factors (P = .99). Among participants with high genetic risk, 1.13% (95% CI, 1.01%–1.26%) of those with a favorable lifestyle developed dementia compared with 1.78% (95% CI, 1.38%–2.28%) with an unfavorable lifestyle (hazard ratio, 0.68 [95% CI, 0.51–0.90])."
Mortality & State-Mandated Protocolized Sepsis Care: Regulations in New York State requiring hospitals to use evidence-based protocols for sepsis were associated with lower in-hospital mortality rates, a study shows (pp. 240–50; J. M. Kahn, jeremykahn@pitt.edu).
PICO: Retrospective cohort study of adult inpatients with sepsis in New York State and in 4 control states using all-payer hospital discharge data before and after implementation of the 2013 New York State sepsis regulations; primary outcome of 30-day in-hospital mortality.
Results: "In this retrospective cohort study of 1,012,410 hospitalized adults with sepsis, mandated protocolized sepsis care in New York State was associated with a significantly greater decline in risk-adjusted mortality in New York compared with a group of control states that did not implement mandated protocolized sepsis care. By the 10th quarter after implementation of the regulations, the adjusted absolute mortality was 3.2% lower than expected in New York State relative to the control states." Hospital length of stay was significantly lower in New York State, and the rates of Clostridium difficile infections were significantly lower with the state-mandated sepsis care.
Editorial: "The approach of the New York State government to improve overall sepsis care and outcomes is an experiment," editorialists write (pp. 250–1; D. N. Kyriacou, demetrios.kyriacou@jamanetwork.org). "Because major public health interventions cannot be based on a single observational study … further assessments of the association, potential effects (both intended and unintended), and costs are warranted before implementation of similar sepsis care regulations in other states. In addition, future research should focus on the identification of specific elements of sepsis care that provide rigorous scientific evidence of clinical effectiveness. Because demands on nurses and physicians to provide rapid intensive care to patients in critical settings can affect patient treatment, any strategy aimed toward reducing sepsis-related morbidity and mortality must be based on convincing evidence before being mandated by governmental regulations."
* Altaire Pharmaceuticals has expanded its recall of specific unexpired prescription and OTC ophthalmic drug products sold by OCuSOFT (see PNN, July 8 and 12).
Drug-Induced Liver Injury: "Drug-induced liver injury is an uncommon but clinically important form of liver disease, its frequency driven by how often drugs are taken and the likelihood that they cause injury," authors of a review article conclude (pp. 264–73; J. H. Hoofnagle, hoofnaglej@nih.gov). "The multiple types and phenotypes of injury vary according to the agent, presenting a diagnostic challenge. Recognizing phenotypes of drug-induced liver injury is helpful in establishing the diagnosis, identifying the responsible agent, and providing insights into pathogenesis. A better understanding of the pathogenesis of drug-induced liver injury should allow for better diagnostics and, ultimately, improved approaches to prevention and treatment."
Systolic/Diastolic Blood Pressure & CV Outcomes: Elevated systolic and diastolic blood pressures are both associated with increased risk of adverse cardiovascular events, a study shows, regardless of the cutpoint used to define "elevated" (pp. 243–51; A. C. Flint, alexander.c.flint@kp.org). Higher systolic blood pressures had greater effects on outcomes than diastolic blood pressures.
PICO: 1.3 million adults in a general outpatient population; effect of the burden of systolic and diastolic hypertension on a composite outcome of myocardial infarction, ischemic stroke, or hemorrhagic stroke over a period of 8 years, with controls for demographic characteristics and coexisting conditions.
Results: "The burdens of systolic and diastolic hypertension each independently predicted adverse outcomes. In survival models, a continuous burden of systolic hypertension (≥140 mm Hg; hazard ratio per unit increase in z score, 1.18; 95% confidence interval [CI], 1.17 to 1.18) and diastolic hypertension (≥90 mm Hg; hazard ratio per unit increase in z score, 1.06; 95% CI, 1.06 to 1.07) independently predicted the composite outcome. Similar results were observed with the lower threshold of hypertension (≥130/80 mm Hg) and with systolic and diastolic blood pressures used as predictors without hypertension thresholds. A J-curve relation between diastolic blood pressure and outcomes was seen that was explained at least in part by age and other covariates and by a higher effect of systolic hypertension among persons in the lowest quartile of diastolic blood pressure."
Insights from Test-and-Treat HIV Trials: Reacting to findings of three trials of universal HIV testing and treatment that showed modest or no reductions in HIV incidence (pp. 207–18, R. J. Hayes, richard.hayes@lshtm.ac.uk; pp. 219–29, D. V. Havlir, diane.havlir@ucsf.edu; pp. 230–42, S. Lockman, slockman@hsph.harvard.edu), an editorialist writes (pp. 286–8; S. S. Abdool Karim): "The three trials collectively signal a way forward. They indicate that increasing viral suppression is achievable, even by routinely available care, but also that reaching universal coverage is very difficult, even with substantial effort. Viral suppression approximating or exceeding 73% (Joint United Nations Program on HIV/AIDS [UNAIDS] 90–90–90 target) in the three current trials had some evidence of clinical and survival benefit but was not enough to reduce HIV incidence or to meet the 2030 UNAIDS goal of epidemic control. In these settings, programs need to consider going beyond universal testing and treatment to universal testing, treatment, and prophylaxis to achieve HIV epidemic control."
Sodium Reduction & Processed, Restaurant Foods: After detailing results of major reports and their recommendations regarding the need to restrict daily sodium intake of Americans to 2,300 mg, Perspective authors conclude (pp. 201–3; J. E. Henney): "The goal isn't to blindly regulate sodium out of foods, nor for federal or state agencies to take a heavy-handed approach to a complicated challenge. Should the food industry continue to resist voluntary action and collaboration with the FDA on achieving a healthier food supply, however, it should expect to face lawsuits in state and federal courts, petitions to the FDA to force reductions in added sodium, and increased regulation — actions that we believe are more than justified by the law and the public health consequences of adding excess sodium to food."
>>>Infectious Diseases Report
Source: Aug. 1 issue of Clinical Infectious Diseases (2019; 69).
Risk Factors for Unnecessary Antibiotic Therapy: Ordering of unnecessary antibiotic therapy (UAT) is associated with unspecified diagnoses and absence of microbial testing, researchers report, and antimicrobial stewardship programs should focus on these factors (pp. 466–72; P-M Roger, roger@elsan.care).
PICO: Prospective, multicenter evaluation of curative antibiotics prescribed over 2 consecutive days; UAT defined as recognition of noninfectious syndromes (NIS), nonbacterial infections, use of redundant antimicrobials, and continuation of empirical broad-spectrum antimicrobials.
Results: "Four hundred fifty-three antibiotic therapies were analyzed at 17 institutions. An infectious disease was the reason for hospitalization in 201 cases (44%). An unspecified diagnosis of infection was observed in 104 cases (23%). Microbial samples were taken in 296 cases (65%), allowing isolation of a pathogen in 156 cases (53%). Unspecified diagnosis was associated with the absence of a microbial sample compared to patients with a diagnosis: (56/104 [54%] vs 240/349 [69%]; P = .005). A total of 158 NIS were observed (35%). UAT was observed in 169 cases (37%), due to NIS in 106 cases. In multivariate analysis, the modifiable risk factors for UAT were unspecified diagnosis (adjusted odds ratio [AOR], 1.83; 95% confidence interval [CI], 1.04–3.20) and absence of a blood culture (AOR, 5.26; 95% CI, 2.56–10.00)."
CDI & Early De-escalation of Antimicrobial Therapy: De-escalation from antipseudomonal beta-lactam (APBL) therapy within 48 hours of Enterobacteriaceae bloodstream infections (BSIs) could reduce patients' 90-day risk of Clostridioides difficile infection (CDI), a study shows (pp. 414–20; M. N. Al-Hasan, majdi.alhasan@uscmed.sc.edu). Authors recommend use of clinical risk assessment tools or rapid diagnostic testing.
PICO: Hospitalized with Enterobacteriaceae BSI in 2011–15; time to CDI in patients who received >48 hours or ≤48 hours of empirical APBL.
Results: "Among 808 patients with Enterobacteriaceae BSI, 414 and 394 received >48 and ≤48 hours of APBL, respectively. Incidence of CDI was higher in patients who received >48 hours than those who received ≤48 hours of APBL (7.0% vs 1.8%; log-rank P = .002). After adjustment for propensity to receive >48 hours of APBL and other variables in the multivariable model, receipt of >48 hours of APBL (hazard ratio [HR], 3.56 [95% confidence interval {CI}, 1.48–9.92]; P = .004) and end-stage renal disease (HR, 4.27 [95% CI, 1.89–9.11]; P = .001) were independently associated with higher risk of CDI."
>>>Geriatrics Highlights
Source: Early-online article from the Journal of the American Geriatrics Society (2019; 67).
Antibiotic Stewardship in 27 Community Nursing Homes: Involvement of the medical director can be important in success of antibiotic stewardship programs in community nursing homes (NHs), according to a 2-year study (10.1111/jgs.16059; P. D. Sloane, philip_sloane@med.unc.edu).
PICO: Standardized antibiotic stewardship quality improvement program; antibiotic prescribing rates per 1,000 resident days; rate of urine test ordering; and incidence of Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA) infections.
Results: "Systemic antibiotic prescription rates decreased from baseline by 18% at 12 months (incident rate ratio [IRR] = 0.82; 95% confidence interval [CI] = 0.69–0.98) and 23% at 24 months (IRR = 0.77; 95% CI = 0.65–0.90). A 10% increase in the proportion of residents with the medical director as primary physician was associated with a 4% reduction in prescribing (IRR = 0.96; 95% CI = 0.92–0.99). Incidence of C. difficile and MRSA infections, hospitalizations, and hospital readmissions did not change significantly. No adverse events from antibiotic nonprescription were reported. Estimated 2-year implementation costs per NH, exclusive of medical provider time, ranged from $354 to $3,653."
* FDA has approved imipenem/cilastatin/relebactam (Recarbrio, Merck) for treating adults with complicated urinary tract infections or complicated intra-abdominal infections who have limited or no alternative treatment options.
Source: Early-release articles from BMJ (2019; 365).
Preventable Patient Harm Across Medical Care Settings: Quality improvement practices in medical care should be focused on preventable rather than overall patient harm, authors of a review article conclude (l4185; M. Panagioti, maria.panagioti@manchester.ac.uk).
PICO: Systematic review and meta-analysis of 70 observational studies of 337,025 participants reporting preventable patient harm.
Results: "The pooled prevalence for preventable patient harm was 6% (95% confidence interval 5% to 7%). A pooled proportion of 12% (9% to 15%) of preventable patient harm was severe or led to death. Incidents related to drugs (25%, 95% confidence interval 16% to 34%) and other treatments (24%, 21% to 30%) accounted for the largest proportion of preventable patient harm. Compared with general hospitals (where most evidence originated), preventable patient harm was more prevalent in advanced specialties (intensive care or surgery; regression coefficient b = 0.07, 95% confidence interval 0.04 to 0.10)."
Medicare Part D Spending on Essential Medicines: In the Medicare Part D program, spending for essential medicines as defined by the World Health Organization (WHO) grew substantially in the 2011–15 timeframe, largely because of use of two expensive drugs for hepatitis C virus, researchers report (l4257; A. Mostaghimi, amostaghimi@bwh.harvard.edu).
PICO: Retrospective cost analysis of the U.S. Medicare Part D files for 2011–15 for WHO essential medicines; total and per beneficiary Medicare spending, total and per beneficiary out-of-pocket patient spending, cumulative beneficiary count, claim count, and per unit drug cost, adjusted for 2015 U.S. dollars.
Results: "Medicare Part D expenditures on 265 WHO essential medicines between 2011 and 2015 was $87.2 bn (£68.4 bn; 76.5 bn euros), with annual spending increasing from $11.9 bn in 2011 to $25.8 bn in 2015 (116%). Patients' out-of-pocket spending for essential medicines over the same period was $12.1 bn. Total annual out-of-pocket spending increased from $2.0 bn to $2.9 bn (47%), and annual per beneficiary out-of-pocket spending on these drugs increased from $20.42 to $21.17 (4%). Total prescription count increased from 376.1 m to 498.9 m (33%), and cumulative beneficiary count grew from 95.9 m to 135.8 m (42%). Of the essential medicines included in the study, the per unit cost of 133 (50%) agents increased faster than the average inflation rate during this period. Overall, approximately 58% of the increase in total spending during this period can be attributed to the introduction of novel agents."
Source: July 20 issue of Lancet (2019; 394).
Drug-Coated PCI Balloons in Patients With High Bleeding Risk: In the DEBUT trial, percutaneous coronary intervention with drug-coated balloons was superior to bare-metal stents in patients at high bleeding risk who had new ischemic lesions in a coronary artery or bypass graft (pp. 230–9; T. Rissanen, tuomas.rissanen@siunsote.fi).
PICO: Noninferiority trial of 208 patients at five sites in Finland; percutaneous coronary intervention with a balloon coated with paclitaxel and iopromide or a bare-metal stent; primary outcome of major adverse cardiac events at 9 months.
Results: "At 9 months, major adverse cardiac events had occurred in one patient (1%) in the drug-coated balloon group and in 15 patients (14%) in the bare-metal stent group (absolute risk difference −13.2 percentage points [95% CI −6.2 to −21.1], risk ratio 0.07 [95% CI 0.01 to 0.52]; p <0.00001 for non-inferiority and p = 0.00034 for superiority). Two definitive stent thrombosis events occurred in the bare metal stent group but no acute vessel closures in the drug-coated balloon group."
* Oral Diseases: A Global Public Health Challenge, in Lancet, 2019; 394: 249–60. (R. G. Watt, r.watt@ucl.ac.uk)
* The Impact of Antibiotic Stewardship Program Resources on Infection Prevention Programs, in Clinical Infectious Diseases, 2019; 69: 552–3. (S. C. Bleasdale, bleasdal@uic.edu)
* Immunotherapy for Urothelial Cancer: Where Are the Randomized Trials?, in Journal of Clinical Oncology, 2019; 37: 10.1200/JCO.18.02257. (F. E. Vera-Badillo, francisco.verabadillo@kingstonhsc.ca)
>>>Nephrology Report
Source: Aug. issue of the American Journal of Kidney Diseases (2019; 74).
Aldosterone Antagonism in Early Polycystic Kidney Disease: While aldosterone antagonism reduced systolic blood pressure in patients with early autosomal dominant polycystic kidney disease (ADPKD), vascular function was not improved, researchers report (pp. 213–23; K. L. Nowak, kristen.nowak@ucdenver.edu).
PICO: Prospective, randomized, controlled, double-blind, clinical trial of 60 participants with early autosomal dominant polycystic kidney disease (ADPKD); spironolactone in doses up to 50 mg/d or placebo for 24 weeks; primary end point of change in brachial artery flow-mediated dilation (FMDBA).
Results: "Participants had a mean age of 34 ± 10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P = 0.9 for comparison of change between groups) or [change in carotid-femoral pulse-wave velocity] (640 ± 127 and 603 ± 101 cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659 ± 138 and 658 ± 131 cm/s; P = 0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, −6 [IQR, −15, 1] vs −2 [IQR, −7, 10] mm Hg in the placebo group; P = 0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress."
Repository Corticotropin v. Glucocorticoid in Nephrotic Syndrome: Advantages for repository corticotropin (rACTH) are not likely to emerge from studies being cited by the product manufacturer as reasons for price increases, authors conclude (pp. 256–62; D. M. Cohen, cohend@ohsu.edu): "Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for [rACTH] injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications."
* FDA yesterday approved the first generics of Lyrica (pregabalin) for management of neuropathic pain associated with diabetic peripheral neuropathy, for management of postherpetic neuralgia, as an adjunctive therapy for the treatment of partial onset seizures in patients 17 years of age and older, for management of fibromyalgia, and for management of neuropathic pain associated with spinal cord injury. The approvals were granted to Alembic Pharmaceuticals, Alkem Laboratories, Amneal Pharmaceuticals, Dr. Reddy's Laboratories, InvaGen Pharmaceuticals, MSN Laboratories Ltd., Rising Pharmaceuticals, Inc., Sciegen Pharmaceuticals Inc., and Teva Pharmaceuticals.
* Following up on a public education effort first that began in Sept. 2018, FDA yesterday announced the launch of its first e-cigarette prevention TV ads educating kids about the dangers of e-cigarette use. The agency also plans to provide new posters for high schools and educational materials for middle schools across the U.S. as part of "The Real Cost" Youth E-Cigarette Prevention Campaign.
Source: July 23/30 issue of JAMA (2019; 322).
Filgotinib in Refractory Moderate-to-Severe RA: Compared with placebo in the FINCH 2 trial, filgotinib produced significantly greater clinical responses at 12 weeks in patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy (pp. 315–25; M. C. Genovese, genovese@stanford.edu).
PICO: Multinational, 24-week phase 3 trial conducted in 2016–18 of 448 patients with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs; filgotinib 100 or 200 mg or placebo; primary end point of the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12.
Results: "At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%–46.3%] and 26.4% [95% CI, 15.0%–37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%–75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%–65.0%] for filgotinib, 100 mg; both P < .001).…"
Editorial: "To help promote use, these oral JAK inhibitor therapies will need to be priced at levels comparable with the conventional synthetic DMARDs rather than the biologics," editorialists write (pp. 309–11; J. A. Singh, Jasvinder.md@gmail.com). "Patients and clinicians express frustration over the high pricing of new RA therapies because a portion of the cost is often passed on to the patients by the health insurance plan, which limits access to these therapies. Head-to-head comparison of filgotinib with other JAK inhibitors, biologic DMARDs, and triple conventional DMARD therapy will further define the most appropriate use of filgotinib for patients with RA by examining the comparative efficacy and safety."
Hyperglycemia Management in Ischemic Stroke: No differences in 90-day functional outcomes were identified in a comparison of intensive versus standard glucose control in patients with acute ischemic stroke (pp. 326–35; K. C. Johnston, kj4v@virginia.edu).
PICO: Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial of 1,151 adult patients with hyperglycemia and recent-onset acute ischemic stroke; continuous intravenous insulin or subcutaneous sliding-scale insulin; primary efficacy outcome of the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score.
Results: "During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, −0.83% [95% CI, −5.72% to 4.06%]).…"
Pharmacy Benefit Manager Reform in Ohio: Business practices of pharmacy benefit managers (PBMs) are exposed in results of an Ohio audit conducted in June 2018, Viewpoint authors write (pp. 299–300; T. J. Royce, Trevor_royce@med.unc.edu): "The audit incorporated 39 million drug transactions between March 1, 2017, and March 30, 2018. It reported that PBMs reimbursed independent pharmacies at a higher rate than their own proprietary pharmacies (eg, CVS Caremark PBM to CVS pharmacies). The audit also reported an 8.8% spread between the amount PBMs billed to Medicaid managed care plans and the amount paid to pharmacies; this spread amounted to $223.7 million in the audit year. A subsequent report from the office of the Ohio Auditor of State found substantially higher spread pricing (31%) and associated revenue (93%) among generic drugs, which accounted for the highest volume dispensed (86% of claims), compared with branded drugs (13% of claims; spread pricing at 0.8%) and specialty drugs (0.5% of claims and spread pricing at 1%)."
* FDA says it has issued a warning letter to Curaleaf for illegally selling unapproved products containing cannabidiol online with unsubstantiated claims.
Source: July 25 New England Journal of Medicine (2019; 381).
Ribociclib + Endocrine Therapy in Breast Cancer: In the MONALEESA-7 trial, patients with advanced hormone-receptor–positive, HER2-negative breast cancer had significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone, researchers report (pp. 307–16; D. Tripathy, dtripathy@mdanderson.org).
PICO: Ribociclib or placebo in addition to endocrine therapy; overall survival evaluated using a stratified log-rank test and summarized with the use of Kaplan–Meier methods.
Results: "A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87)."
Editorial: "On the basis of the MONALEESA-7 trial and other trials in the first-line setting, the standard of care should now include a CDK4/6 inhibitor as first-line treatment," writes an editorialist (pp. 371–2; H. S. Rugo). "We are redefining the standards and outcomes in metastatic disease; the treatment of early-stage disease is the next frontier."
Maintenance Olaparib for Metastatic Pancreatic Cancer: Patients with a germline BRCA mutation and metastatic pancreatic cancer had significantly longer progression-free survival with maintenance olaparib than with placebo, according to the POLO study (pp. 317–27; T. Golan, talia.golan@sheba.health.gov.il).
PICO: Phase 3 trial of olaparib as maintenance therapy in 154 patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy; primary end point of progression-free survival.
Results: "The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, −2.47 points; 95% CI, −7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, −0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event."
* FDA yesterday approved an intranasal formulation of glucagon, Baqsimi nasal powder (Lilly), the first glucagon therapy approved for the emergency treatment of severe hypoglycemia that can be administered without an injection. The product will be available in a single-use dispenser that can be administered to someone having a severe hypoglycemic episode.
>>>Health Affairs Report
Source: Early-online articles from and July issue of Health Affairs (2019; 38).
Economics of 20 Years of Antiretroviral Therapy: While expenditures for medications for HIV infections provide a positive return, countries have several obstacles to achieving the potential gains possible with better care, according to authors of a global policy research article (10.1377/hlthaff.2018.05391; S. S. Forsythe).
PICO: Relevant demographic and epidemiological impacts calculated using the Spectrum package of models, which includes the AIDS Impact Model.
Results: "Since the introduction of azidothymidine in 1987, significant improvements in treatment for people living with HIV have yielded substantial improvements in global health as a result of the unique benefits of antiretroviral therapy (ART). ART averted 9.5 million deaths worldwide in 1995–2015, with global economic benefits of $1.05 trillion. For every $1 spent on ART, $3.50 in benefits accrued globally. If treatment scale-up achieves the global 90-90-90 targets of the Joint United Nations Programme on HIV/AIDS, a total of 34.9 million deaths are projected to be averted between 1995 and 2030. Approximately 40.2 million new HIV infections could also be averted by ART, and economic gains could reach $4.02 trillion in 2030. Having provided ART to 19.5 million people represents a major human achievement. However, 15.2 million infected people are currently not receiving treatment, which represents a significant lost opportunity. Further treatment scale-up could yield even greater health and economic benefits."
Part D Anomalies in Brand-Name Versus Generic Costs to the Patient: Medicare Part D beneficiaries receive the "wrong price signal" when they must pay more for generic drugs than for brand-name products, authors conclude after studying spending patterns (10.1377/hlthaff.2018.05476; S. B. Dusetzina): "The current Medicare Part D benefit may require greater out-of-pocket spending for beneficiaries filling prescriptions for higher-price generic drugs, compared to those filling brand-name counterparts. This can occur among patients who reach the catastrophic coverage phase under the Part D benefit, when differences between the prices for generic and brand-name drugs are not large. This scenario may be common with specialty drugs (typically high-price products used to treat rare or complex conditions), when the number of generic manufacturers or clinical alternatives are limited. In this study we demonstrated that patients would pay more out of pocket for generic medications than for brand-name drugs in these cases, driven by manufacturer discounts provided in the Medicare Part D coverage gap. Overpayments for specialty generic drugs relative to brand-name drugs ranged from $869 to $1,072 in 2019, despite lower point-of-sale prices for these drugs. Policy makers should consider modifying the Part D benefit to increase incentives for generic drug use."
Time To Limit Drug Price Increases: A recent blog reviews the content and need for a Senate Finance Committee proposal that would limit drug price increases in the U.S. (10.1377/hblog20190715.557473; G. F. Anderson). Noting that for "every price reduction for brand-name drugs in 2018, there were 96 increases," the author provides this background and perspective: "A proposal announced Tuesday by Senate Finance Committee Chair Chuck Grassley (R–IA) and ranking member Ron Wyden (D–OR) and scheduled for mark-up on Thursday would set a cap on list price increases for drugs covered under Medicare's outpatient drug benefit. If a drug company raised the list price above the limit, then the company would give back some or all of the increase above the cap to Medicare and/or Medicare beneficiaries. The cap would be set using an inflation factor such as the Consumer Price Index for All Urban Consumers (CPI-U) and would be calculated for each outpatient drug covered by Medicare. The proposal would specify a 'base year.' That base year would be the point from which excessive manufacturer price increases would be penalized.…
"A major limitation of this proposal is that it does not address high launch prices. Pharmaceutical companies could set even higher launch prices of new drugs in response to a cap on price increases. A separate approach should be explored to address this issue."
Recurrent VTE After Anticoagulant Discontinuation: A systematic review and meta-analysis quantifies long-term risk of symptomatic recurrent venous thromboembolism (VTE) after discontinuation of anticoagulant treatment (l4363; M. A. Rodger, mrodger@ohri.ca).
PICO: 18 randomized controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in 7,515 patients with a first unprovoked VTE event who had been treated for at least 3 months.
Results: "The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3–5, and 3.1 events/year (1.7 to 4.9) in years 6–10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%)."
HIV Incidence & Contraception Options: Any of three contraceptive options can be recommended in African women at high risk of HIV transmission, a study shows (pp. 303–13; Evidence for Contraceptive Options and HIV Outcomes [ECHO] Trial Consortium).
PICO: Open-label trial of intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant.
Results: "397 HIV infections occurred (incidence 3.81 per 100 woman-years [95% CI 3.45–4.21]): 143 (36%; 4.19 per 100 woman-years [3.54–4.94]) in the DMPA-IM group, 138 (35%: 3.94 per 100 woman-years [3.31–4.66]) in the copper IUD group, and 116 (29%; 3.31 per 100 woman-years [2.74–3.98]) in the LNG implant group. In the modified intention-to-treat analysis, the hazard ratios for HIV acquisition were 1.04 (96% CI 0.82–1.33, p = 0.72) for DMPA-IM compared with copper IUD, 1.23 (0.95–1.59, p = 0.097) for DMPA-IM compared with LNG implant, and 1.18 (0.91–1.53, p = 0.19) for copper IUD compared with LNG implant. 12 women died during the study: six in the DMPA-IM group, five in the copper IUD group, and one in the LNG implant group. Serious adverse events occurred in 49 (2%) of 2,609 participants in the DMPA-IM group, 92 (4%) of 2607 participants in the copper IUD group, and 78 (3%) of 2,613 participants in the LNG implant group. Adverse events resulting in discontinuation of the randomly assigned method occurred in 109 (4%) women in the DMPA-IM group, 218 (8%) women in the copper IUD group, and 226 (9%) women in the LNG implant group (p <0.0001 for DMPA-IM vs copper IUD and for DMPA-IM vs LNG implant). 255 pregnancies occurred: 61 (24%) in the DMPA-IM group, 116 (45%) in the copper IUD group, and 78 (31%) in the LNG implant group. 181 (71%) pregnancies occurred after discontinuation of randomly assigned method."
* FDA on Friday issued a guidance is to assist sponsors in the clinical development of drugs for the prevention of delayed graft function in kidney transplantation.
* The Influence of Type 2 Diabetes–Associated Factors on Type 1 Diabetes, in Diabetes Care, 2019; 42: 1357–64. (M. J. Redondo, redondo@bcm.edu)
* Metabolic Acidosis in CKD: Core Curriculum 2019, in American Journal of Kidney Diseases, 2019; 74: 263–75. (K. L. Raphael, kalani.raphael@hsc.utah.edu)
Source: Online articles from Annals of Internal Medicine (2019; 171).
SGLT-2 Inhibitors & Severe UTIs: Despite previous concerns about severe urinary tract infections (UTIs) associated with use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors, the agents may not produce any higher risk than other second-line antidiabetic agents, researchers report (10.7326/M18-3136; C. V. Dave, chintandave19@gmail.com).
PICO: Population-based cohort study using two large, U.S.-based databases of commercial claims in 2013–15; cohorts of patients with type 2 diabetes and initiating use of SGLT-2 inhibitors or the nonglifozin classes dipeptidyl peptidase-4 (DPP-4) inhibitors (cohort 1) or glucagon-like peptide-1 receptor (GLP-1) agonists (cohort 2); primary outcome of a severe UTI event.
Results: "After 1:1 matching on propensity score, 123,752 patients were identified in cohort 1 and 111,978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99])."
Editorial: "Although concerns emerged about a potentially increased risk for genitourinary tract infections with use of SGLT-2 inhibitors, accumulating evidence suggests that harms are restricted to genital tract infections," editorialists write (10.7326/M19-1950; K. B. Filion, kristian.filion@mcgill.ca). "Some limitations are noted, but this study is methodologically rigorous and provides reassuring, real-world evidence regarding this potential safety issue. Reassurance, however, comes with some caveats. First, the study excluded high-risk patients and those with a history of UTI, key subgroups for which further evidence is needed. Second, some analyses of secondary outcomes (such as urosepsis) and specific molecules had more modest statistical power, and safety data from RCTs suggest that risk may vary by molecule. Safety assessments by large networks, such as the Sentinel System or the Canadian Network for Observational Drug Effect Studies may be needed to conclusively address these issues. Ultimately, although some uncertainty remains, the study by Dave and colleagues provides encouraging evidence of the real-world safety of SGLT-2 inhibitors, allowing patients to benefit from their use with greater confidence in their safety with respect to severe UTI."
Emergence of Resistant Candida: Since its isolation in 2009, the multidrug-resistant yeast Candida auris has emerged as a cause of invasive infections on all inhabited continents, review authors report (10.7326/M19-2205; S. Vallabhaneni, fco6@cdc.gov): "Prevention of invasive Candida infections requires antibiotic stewardship, improved maintenance practices for central venous catheters, and targeted antifungal prophylaxis. Prevention of colonization and infection with C auris includes some of these interventions, although azole-based antifungal prophylaxis is probably less effective for many strains because of resistance. The key difference for C auris prevention is the need for strict adherence to infection control measures, including hand hygiene; contact precautions for colonized and infected patients, such as use of single rooms or patient cohorts; and thorough cleaning and disinfecting of the patient environment and shared medical equipment with an agent active against C auris.
"We need to learn much more about C auris. Where did it come from? What characteristics enable its high resistance and rapid spread? What is its environmental niche, and what factors in the environment potentiate its rapid emergence? Rapid diagnostic tests and effective decolonization methods are urgently needed. We do know that preventing the spread of this organism is a priority that requires bolstering laboratory detection capacity; strengthening public health surveillance; and improving infection control practices, especially in postacute care settings."
>>>Diabetes Report
Source: Early-online articles from and Aug. issue of Diabetes Care (2019; 42).
GI Hormonal Therapy Benefits: A cocktail of three gastrointestinal hormones — glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) (GOP) — produces some of the beneficial effects of bariatric surgery in patients with diabetes and obesity, a study shows (pp. 1446–53; T. M. Tan, t.tan@imperial.ac.uk).
PICO: Single-blinded mechanistic study of 26 obese patients with prediabetes/diabetes randomized to subcutaneous GOP or saline infusion for 4 weeks compared with 21 patients who had undergone Roux-en-Y gastric bypass (RYGB), or 22 patients who followed a very low-calorie diet (VLCD); outcomes of body weight, fructosamine levels, glucose and insulin during a mixed meal test (MMT), energy expenditure (EE), energy intake (EI), and mean glucose and measures of glucose variability during continuous glucose monitoring.
Results: "GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change −4.4 [95% CI −5.3, −3.5] kg) versus saline (−2.5 [−4.1, −0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (−44.1 [−62.7, −25.5] µmol/L) versus saline (−11.7 [−18.9, −4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD."
Oral Semaglutide Monotherapy in Type 2 Diabetes: Compared with placebo in patients with type 2 diabetes, the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, semaglutide, produced "superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) … with a safety profile consistent with other GLP-1 receptor agonists," researchers report (10.2337/dc19-0749; PIONEER 1 Investigators).
PICO: Multicenter, international, 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial of 703 adults with type 2 diabetes insufficiently controlled with diet and exercise; randomized once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo; primary end point of change from baseline to week 26 in HbA1c.
Results: "In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg, P < 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, P = 0.01], and −2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and 2.2% with placebo."
Once-Weekly Efpeglenatide in Type 2 Diabetes: In patients with early type 2 diabetes, the long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA) efpeglenatide significantly lowered HbA1c and weight with a reasonable safety profile (10.2337/dc18-2648; J. Rosenstock).
PICO: 12-week dose-ranging study of efpeglenatide once weekly compared with open-label liraglutide 1.8 mg; >90% of participants on metformin monotherapy; primary efficacy end point of change in HbA1c from baseline to week 13.
Results: "From a baseline HbA1c of 7.7–8.0% (61.0–63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6–1.2%, P < 0.05 for all) to a final HbA1c of 6.3–6.8% (45.4–50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA1c <7% (61–72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences −1.4 and −2.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide."
Aug. 1, 2019 * Vol. 26, No. 147
Source: Aug. 1 New England Journal of Medicine (2019; 381).
Ibrutinib–Rituximab or Chemoimmunotherapy for CLL: In patients with previously untreated chronic lymphocytic leukemia (CLL), ibrutinib–rituximab increased progression-free survival and overall survival compared with a standard chemoimmunotherapy regimen, researchers report (pp. 432–43; T. D. Shanafelt, tshana@stanford.edu).
PICO: Phase 3 trial of 529 patients 70 years of age or younger with previously untreated CLL; ibrutinib/rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine/cyclophosphamide/rituximab; primary end point of progression-free survival.
Results: "At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib–rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P <0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib–rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P <0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib–rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib–rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib–rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib–rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P <0.001)."
Fractional-Dose Yellow Vaccine During Outbreak: In the final report of use of a fractional dose of the 17DD yellow fever vaccine during a shortage, the dose was effective at inducing seroconversion in participants who were seronegative at baseline (pp. 444–54; R. M. Casey, rcasey@cdc.gov).
PICO: Neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination with one-fifth the standard dose of 17DD vaccine; plaque reduction neutralization test with a 50% cutoff.
Results: "Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P <0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P <0.001 for both comparisons)."
Gene Therapy: Review authors write: "For ex vivo gene therapy, future goals include better lentiviral vector design to further improve safety and transgene control, efficient large-scale production and analytical characterization of vectors, and the development of less toxic conditioning regimens that permit robust engraftment of gene-corrected stem cells, including replacement of chemotherapy conditioning with antibody-based methods to reduce complications" (pp. 455–64; K. A. High, kathy.high@sparktx.com). "For in vivo gene therapy with adeno-associated viral (AAV) vectors, efforts in the next decade will focus on the elucidation and management of the human immune response to the vector and continued improvements in AAV vector design and development to improve targeting and permit lower [effective] doses."
>>>Pediatrics Highlights
Source: Aug. issue of Pediatrics (2019; 144).
Neuropsychiatric Effects & Synthetic Cannabinoid Toxicity: Risks of neuropsychiatric morbidity in adolescents are higher with synthetic cannabinoid (SC) than cannabis exposure, researchers report, and a distinct neurospychiatric profile of acute SC toxicity can be identified in adolescents (10.1542/peds.2018-2690; S. A. R. Anderson).
PICO: Records of adolescents presenting to emergency departments (ED) as recorded in the Toxicology Investigators Consortium Case Registry in 2010–18; exposures classified as SC-only exposure, SC-polydrug exposures, cannabis-only exposure, and cannabis-polydrug exposures.
Results: "Adolescents presenting to the ED with SC-only exposure (n = 107) had higher odds of coma and/or central nervous system depression (odds ratio [OR] 3.42; 95% confidence interval [CI] 1.51–7.75) and seizures (OR 3.89; 95% CI 1.39–10.94) than those with cannabis-only exposure (n = 86). SC-only drug exposure was associated with lower odds of agitation than cannabis-only exposure (OR 0.18; 95% CI 0.10–0.34). In contrast, the group with SC-polydrug exposures (n = 38) had higher odds of agitation (OR 3.11; 95% CI 1.56–7.44) and seizures (OR 4.8; 95% CI 1.80–12.74) than the cannabis-polydrug exposures group (n = 117)."
Toxicity of Bupropion v. SSRI Overdoses: Off-label use of bupropion for depression should take into consideration its overdose risk as compared with those of selective serotonin reuptake inhibitors (SSRIs), a study shows (10.1542/peds.2018-3295; A. Overberg).
PICO: Analysis of cases coded as "suspected suicide" in the National Poison Data System in 2013–17 for adolescent (ages 10–19) exposures to SSRIs or bupropion; factors analyzed were demographics, clinical effects, therapies, and medical outcome.
Results: "There were 30,026 cases during the study period. Sertraline and fluoxetine accounted for nearly 60%, whereas bupropion was reported in 11.7%. Bupropion exposure was significantly associated with death (0.23% vs 0%; P < .001) or serious outcome (58.1% vs 19%; P < .001) as well as the 10 most common clinical effects, including seizures (27.0% vs 8.5%; P < .001) and hallucinations (28.6% vs 4.3%; P < .001). Bupropion exposure was significantly associated with the need for cardiopulmonary resuscitation (0.51% vs 0.01%; P < .001), intubation (4.9% vs 0.3%; P < .001), vasopressors (1.1% vs 0.2%; P < .001), and benzodiazepines (34.2% vs 5.5%; P < .001). There was a significant increase in all exposures and in proportion of serious outcomes over time."
CRAFFT Tool for Predicting Substance Use Disorder: The CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble) tool "has good concurrent validity for problematic substance use and [substance use disorders (SUDs)] in [pediatric emergency department (PED)] patients and is useful in predicting SUDs at up to 3 years follow-up but with limited sensitivity," investigators conclude (10.1542/peds.2018-3415; R. P. Shenoi).
PICO: 4,753 participants aged 12–17 years who completed an assessment battery (CRAFFT and other measures of alcohol, drug use, and risk behaviors); battery of tests readministered to a subsample at 1-, 2-, and 3-year follow-up to investigate future SUDs.
Results: "Of 2,175 participants assigned to follow-up, 1,493 (68.6%) completed 1-year, 1,451 (66.7%) completed 2-year, and 1,265 (58.1%) completed the 3-year follow-up. A baseline CRAFFT value of ≥2 was significantly associated with problematic substance use or mild or moderate to severe SUD diagnosis on the Diagnostic Interview Schedule for Children at baseline (P < .001). The results persisted after 1, 2, and 3 years (P < .001). The best combined sensitivity and specificity was achieved with a baseline CRAFFT value of ≥1 as a cutoff for predicting problematic substance use and a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of mild SUD at 1, 2, and 3 years. The baseline CRAFFT score that best predicted a moderate to severe SUD at 1 year was ≥2; but at 2 and 3 years, the cutoff score was ≥1."
Source: Aug. 3 issue of Lancet (2019; 394).
Veverimer in CKD Metabolic Acidosis: In a study of 217 patients with chronic kidney disease and metabolic acidosis, long-term veverimer effectively and safely reversed metabolic acidosis, researchers report, and subjective and objective measures of physical function were improved (pp. 396–406; D. E. Wesson, donald.wesson@bswhealth.org).
PICO: Randomized, blinded, placebo-controlled, 40-week extension of a 12-week parent study of patients with estimated glomerular filtration rates of 20–40 mL/min per 1.73 m2) and metabolic acidosis (serum bicarbonate 12–20 mmol/L); participants continued on the same treatment as in the parent study; primary endpoint of safety.
Results: "Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p = 0.0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p <0.001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life–Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12.1 points (SE 3.3; p <0.0001). Time to do the repeat chair stand test improved by 4.3 s (1.2) on veverimer versus 1.4 s (1.2) on placebo (p <0.0001)."
Hospital Volume & Outcomes for Acute Pulmonary Embolism: Death from pulmonary embolism is reduced when care is provided at high-volume hospitals, according to a study of patients with acute symptomatic pulmonary embolism (l4416; D Jiménez, djimenez.hrc@gmail.com).
PICO: Multinational population-based cohort study using 2001–18 data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry; 39,257 consecutive patients with confirmed diagnosis of acute symptomatic pulmonary embolism at 353 hospitals in 16 countries; primary outcome of pulmonary embolism–related mortality within 30 days after diagnosis.
Results: "Patients with acute symptomatic pulmonary embolism admitted to high volume hospitals (>40 pulmonary embolisms per year) had a higher burden of comorbidities. A significant inverse association was seen between annual hospital volume and pulmonary embolism related mortality. Admission to hospitals in the highest quarter (that is, >40 pulmonary embolisms per year) was associated with a 44% reduction in the adjusted odds of pulmonary embolism related mortality at 30 days compared with admission to hospitals in the lowest quarter (<15 pulmonary embolisms per year; adjusted risk 1.3% v 2.3%; adjusted odds ratio 0.56 (95% confidence interval 0.33 to 0.95); P = 0.03). Results were consistent in all sensitivity analyses. All cause mortality at 30 days was not significantly reduced between the two quarters (adjusted odds ratio 0.78 (0.50 to 1.22); P = 0.28). Survivors showed little change in the odds of recurrent venous thromboembolism (odds ratio 0.76 (0.49 to 1.19)) or major bleeding (1.07 (0.77 to 1.47)) between the low and high volume hospitals."
* FDA has approved pexidartinib (Turalio, Daiichi Sankyo) capsules for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not responsive to improvement with surgery.
* Psychiatric Genetics Begins to Find Its Footing, in American Journal of Psychiatry, 2019; 176: 609–14. (J. W. Smoller)
* Management of Infants at Risk for Group B Streptococcal Disease, in Pediatrics, 2019; 144: 10.1542/peds.2019-1881. (K. M. Puopolo et al. for the American Academy of Pediatrics Committees on Fetus and Newborn and on Infectious Diseases)
Source: Aug. 6 issue of Annals of Internal Medicine (2019; 171).
Antibiotics in Hospitalized Patients With Pneumonia: Excess antibiotic therapy is common among patients hospitalized for pneumonia, particularly at discharge, and is associated with increased numbers of patient-reported adverse events, researchers report (pp. 153–63; V. M. Vaughn, valmv@med.umich.edu). "Future interventions should focus on whether reducing excess treatment and improving documentation at discharge improves outcomes," the authors conclude.
PICO: Retrospective cohort study of 43 hospitals in the Michigan Hospital Medicine Safety Consortium and 6,481 general care medical patients with pneumonia; primary outcome of the rate of excess antibiotic treatment duration.
Results: "Two thirds (67.8% [4,391 of 6,481]) of patients received excess antibiotic therapy. Antibiotics prescribed at discharge accounted for 93.2% of excess duration. Patients who had respiratory cultures or nonculture diagnostic testing, had a longer stay, received a high-risk antibiotic in the prior 90 days, had community-acquired pneumonia, or did not have a total antibiotic treatment duration documented at discharge were more likely to receive excess treatment. Excess treatment was not associated with lower rates of any adverse outcomes, including death, readmission, emergency department visit, or Clostridioides difficile infection. Each excess day of treatment was associated with a 5% increase in the odds of antibiotic-associated adverse events reported by patients after discharge."
Editorial: "Change is scary, and medicine is a conservative profession," editorialists write (pp. 210–1; B. Spellberg, bspellberg@dhs.lacounty.gov). "The core ethos of our profession is based on an oath that is 3 millennia old. Nevertheless, to live up to the expectations that our patients have for us and that we have for one another, we must overcome inertia and tradition and change practice when compelling evidence becomes available. After dozens of [randomized controlled trials] and more than a decade since the initial clarion call to move to short-course therapy, it is time to adapt clinical practice for diseases that have been studied and adopt the mantra 'shorter is better.'"
Supplements, Diet & Cardiovascular Outcomes: While use of calcium plus vitamin D may increase risk of stroke, other nutritional supplements and dietary interventions are associated with improved cardiovascular outcomes in adults, a study shows, including reduced salt intake, use of omega-3 long-chain polyunsaturated fatty acid, and folate supplementation (pp. 190–8; S. U. Khan, safinmc@gmail.com).
PICO: 105 meta-analyses using data from 277 trials, 24 interventions, and 992,129 participants.
Results: "There was moderate-certainty evidence that reduced salt intake decreased the risk for all-cause mortality in normotensive participants (risk ratio [RR], 0.90 [95% CI, 0.85 to 0.95]) and cardiovascular mortality in hypertensive participants (RR, 0.67 [CI, 0.46 to 0.99]). Low-certainty evidence showed that omega-3 long-chain polyunsaturated fatty acid was associated with reduced risk for myocardial infarction (RR, 0.92 [CI, 0.85 to 0.99]) and coronary heart disease (RR, 0.93 [CI, 0.89 to 0.98]). Folic acid was associated with lower risk for stroke (RR, 0.80 [CI, 0.67 to 0.96]; low certainty), whereas calcium plus vitamin D increased the risk for stroke (RR, 1.17 [CI, 1.05 to 1.30]; moderate certainty). Other nutritional supplements, such as vitamin B6, vitamin A, multivitamins, antioxidants, and iron and dietary interventions, such as reduced fat intake, had no significant effect on mortality or cardiovascular disease outcomes (very low– to moderate-certainty evidence)."
Editorial: "Fish oils are the most widely used supplements, and recent randomized trials add to the contradictory findings," editorialists write (pp. 216–7; E. J. Topol, etopol@scripps.edu). "Although the analysis by Khan and colleagues found low-certainty evidence for omega-3 long-chain polyunsaturated fatty acid, recent randomized trials in the general population and in patients with diabetes have failed to confirm any benefit in cardiovascular outcomes. The results of these trials would tend to downgrade the low-certainty rating of omega-3 fatty acid supplements to uncertain at best."
Source: Aug. 6 issue of JAMA (2019; 322).
Naloxone Co-prescribing With Part D Opioids: Naloxone co-prescribing increased in 2017 compared with 2016 for patients in the Medicare Part D program who were receiving opioids, a study shows, but only a minority of patients received the reversal agent (pp. 462–4; C. M. Jones, fjr0@cdc.gov). "Clinicians, pharmacists, and patients should be educated about the circumstances necessitating naloxone co-prescribing," the authors conclude.
PICO: Patients filling an opioid prescription in 2016 or 2017 and having Part D coverage the entire year in which the opioid was filled; co-prescribing defined as receiving a prescription for naloxone within 7 days of any prescription opioid claim.
Results: "Nationally, in 2016 and 2017, a total of 12,778,098 and 12,569,263 Medicare Part D beneficiaries, respectively, received at least 1 opioid prescription and 19,758 and 58,092 received naloxone within 7 days of an opioid prescription. Rates for naloxone co-prescription with any opioid increased from 1.5 per 1,000 patients in 2016 to 4.6 per 1,000 in 2017. Rates increased across all categories. Patients receiving opioids and benzodiazepines for 300 days per year or longer with a maximum of 90 morphine milligram equivalents per day or greater had the highest rates (38.5 per 1,000 in 2017).
"In 2017, state rates of naloxone co-prescribing with any opioid ranged from 0.7 per 1,000 in Nebraska to 33.0 per 1,000 in Virginia. Virginia and Vermont had the highest rates across all categories in 2017 and experienced the largest absolute and percentage increases between 2016 and 2017. The rate for Virginia increased from 1.2 to 33.0 per 1,000, an absolute increase of 31.8 per 1,000 (2650% increase). The rate for Vermont increased from 2.0 to 32.3 per 1,000, an absolute increase of 30.3 per 1,000 (1515% increase)."
Blood Pressure Measurements & Mortality: Higher 24-hour and nighttime blood pressure readings were significantly associated with greater risks of death and a composite of cardiovascular outcomes in a longitudinal population-based cohort study of 11,135 adults (pp. 409–20; J. A. Staessen, jan.staessen@med.kuleuven.be).
* Pharmacists and other health care providers play a critical role in ensuring that patients receive naloxone, CDC said yesterday in commenting on a new Vital Signs study, Life-Saving Naloxone From Pharmacies. "It is clear from the data that there is still much needed education around the important role naloxone plays in reducing overdose deaths," said CDC Director Robert R. Redfield, MD. "The time is now to ensure all individuals who are prescribed high-dose opioids also receive naloxone as a potential life-saving intervention. As we aggressively confront what is the public health crisis of our time, CDC will continue to stress with health care providers the benefit of making this overdose-reversing medicine available to patients."
* "FDA oversight of compounding continues to remain essential, because compounded drugs, while important to patients who need them, pose ongoing and serious risks if they are not manufactured properly," FDA Acting Commissioner Norman E. "Ned" Sharpless, MD, said yesterday in reaction to a federal district court decision upholding the agency's interpretation of clinical need regarding the bulk substances that may be used by outsourcing facilities in drug compounding. "Every year, the FDA learns of cases of patient illnesses and deaths due to improperly compounded drugs and caused by issues like contamination in drugs that need to be sterile because they are entering the bloodstream, the eye, or the spine or because the drugs are not made at the right strength and are superpotent."
* Despite a "data manipulation issue that impacts the accuracy of certain data from product testing performed in animals," FDA said yesterday it will allow the gene therapy product Zolgensma to remain on the market. FDA approved the product on May 24 for treatment of children younger than 2 years of age with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 gene. About a month later, the product's manufacturer, AveXis, informed the agency about the problem with data submitted for FDA review as part of the biologics license application.
Source: Aug. 8 issue of the New England Journal of Medicine (2019; 381).
Voxelotor in Sickle Cell Disease: In a trial of 274 people with sickle cell disease, the deoxygenated sickle hemoglobin (HbS) polymerization inhibitor voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis, report researchers with the Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization (HOPE) trial (pp. 509–19; E. Vichinsky, evichinsky@mail.cho.org).
PICO: Multicenter, phase 3, double-blind, randomized, placebo-controlled trial of voxelotor 1500 mg and 900 mg administered orally once daily; primary end point of the percentage of participants who had a hemoglobin response.
Results: "In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators."
Editorial: "The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the FDA," writes an editorialist (pp. 579–80; A. Thompson).
Vitamin D for Prevention of Type 2 Diabetes: Compared with placebo in participants with prediabetes in the Vitamin D and Type 2 Diabetes (D2d) trial, vitamin D3 supplementation at doses of 4000 IU/d failed to significantly reduce the risk of progression to diabetes (pp. 520–30; A. G. Pittas, apittas@tuftsmedicalcenter.org).
PICO: Adults who met at least two of three glycemic criteria for prediabetes (elevated fasting plasma glucose level; elevated glucose in 2-hour challenge tests; glycated hemoglobin levels of 5.7% to 6.4%); 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level; primary outcome of time-to-new-onset diabetes.
Results: "By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups."
Editorial: "The D2d trial was a well-conducted randomized, controlled trial that addresses an important hypothesis in diabetes prevention," (pp. 581–2; D. J. Wexler). "Any benefit of vitamin D for diabetes prevention, if present, is modest and clearly does not pertain to a vitamin D–sufficient population. Whether targeting populations with vitamin D levels below 12 ng per milliliter, many of whom have additional risk factors for diabetes, would have an effect on beta-cell function and progression to type 2 diabetes remains unresolved."
* CMS said yesterday that Medicare will cover CAR T-cell therapies when they are provided in health care facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) for FDA-approved indications (according to the FDA-approved label). Medicare will also cover approved CAR T-cell therapies for off-label uses recommended in CMS-approved compendia.
>>>Circulation Report
Source: Early-online articles from Circulation (2019; 140).
Metformin in Diabetes With or Without HF, CKD: In patients with type 2 diabetes mellitus (T2DM) and high risk of cardiovascular (CV) complications, metformin use was associated with lower rates of all-cause mortality in a post hoc analysis of the SAVOR-TIMI 53 trial (10.1161/CIRCULATIONAHA.119.040144; B. A. Bergmark, bbergmark@bwh.harvard.edu).
PICO: Participants classified as ever or never users of metformin and presence of prior heart failure (HF) or chronic kidney disease (CKD); inverse probability of treatment weighting (IPTW) used to estimate effects of metformin exposure on a composite end point of CV death, myocardial infarction (MI), or ischemic stroke as well as CV death and all-cause mortality.
Results: "Of the 12,156 patients with baseline biomarker samples, 8,971 (74%) had metformin exposure, 1,611 (13%) had prior HF, and 1,332 (11%) had at least moderate CKD (eGFR ≤45 mL/min/1.73 m2). Metformin use was associated with no difference in risk for the composite end point (HRIPTW 0.92; 95% CI 0.76–1.11), but lower risk of all-cause mortality (HRIPTW 0.75; 95% CI 0.59–0.95). There was no significant relationship between metformin use and these end points in patients with prior HF or moderate to severe CKD."
Donor Simvastatin in Heart Transplantation: "Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and — also considering its documented general safety profile — may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation," investigators conclude (10.1161/CIRCULATIONAHA.119.039932; K. B. Lemström; karl.lemstrom@helsinki.fi).
PICO: After declaration of brain death and upon acceptance as a cardiac donor, 84 multiorgan donors randomly received simvastatin 80 mg via nasogastric tube or no simvastatin; primary efficacy end point of heart recipient plasma troponin T and I levels during the first 24 hours after heart transplantation.
Results: "Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14,900 ± 12,100 ng/L to 9,800 ± 7,900 ng/L, P = 0.047), and troponin I by 40% (171,000 ± 151,000 ng/L to 103,000 ± 109,000 ng/L, P=0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32,800 ± 24,300 ng/L to 20,900 ± 15,900 ng/L; P = 0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days (P = 0.046).…"
>>>Cardiology Highlights
Source: Aug. 13 issue of the Journal of the American College of Cardiology (2019; 74).
Antithrombotic Therapy for Stroke Prevention: A JACC scientific expert panel provides these insights into use of antithrombotic therapy for prevention of recurrent strokes in patients with ischemic cerebrovascular disease (pp. 786 ff.; V. J. Del Brutto): "Stroke survivors carry a high risk of recurrence. Antithrombotic medications are paramount for secondary prevention and thus crucial to reduce the overall stroke burden. Appropriate antithrombotic agent selection should be based on the best understanding of the physiopathological mechanism that led to the initial ischemic injury. Antiplatelet therapy is preferred for lesions characterized by atherosclerosis and endothelial injury, whereas anticoagulant agents are favored for cardiogenic embolism and highly thrombophilic conditions. Large randomized controlled trials have provided new data to support recommendations for the evidence-based use of antiplatelet agents and anticoagulant agents after stroke. In this review, the authors cover recent trials that have altered clinical practice, cite systematic reviews and meta-analyses, review evidence-based recommendations based on older landmark trials, and indicate where there are still evidence-gaps and new trials being conducted."
* Ridge Properties d/b/a Pain Relief Naturally is voluntarily recalling several lots of 4% lidocaine topical cream and liquid gel products sold at the consumer level. FDA analysis has found these pre-tattoo products to have microbiological contamination and higher-than-labeled lidocaine potency.
Aug. 12, 2019 * Vol. 26, No. 154
Source: Aug. 10 issue of Lancet (2019; 394).
Population & Herd Effects With HPV Vaccine: Based on 10 years since the human papillomavirus (HPV) vaccine became available, studies have accumulated showing compelling evidence of its substantial impact on infections and anogenital warts and cervical intraepithelial neoplasia grade 2+ (CIN2+) (pp. 497–509; M. Brisson, marc.brisson@crchudequebec.ulaval.ca).
PICO: Updated systematic review and meta-analysis of 65 articles from 14 high-income countries; primary assessment of relative risk of HPV-related outcomes.
Results: "After 5–8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0.17, 95% CI 0.11–0.25) among girls aged 13–19 years, and decreased significantly by 66% (RR 0.34, 95% CI 0.23–0.49) among women aged 20–24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0.46, 95% CI 0.33–0.66) among girls aged 13–19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0.33, 95% CI 0.24–0.46) among girls aged 15–19 years, decreased significantly by 54% (RR 0.46, 95% CI 0.36–0.60) among women aged 20–24 years, and decreased significantly by 31% (RR 0.69, 95% CI 0.53–0.89) among women aged 25–29 years. Among boys aged 15–19 years anogenital wart diagnoses decreased significantly by 48% (RR 0.52, 95% CI 0.37–0.75) and among men aged 20–24 years they decreased significantly by 32% (RR 0.68, 95% CI 0.47–0.98). After 5–9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0.49, 95% CI 0.42–0.58) among screened girls aged 15–19 years and decreased significantly by 31% (RR 0.69, 95% CI 0.57–0.84) among women aged 20–24 years."
25-Year Whitehall II Cohort Follow-up: In two articles, researchers report that participants in the Whitehall II study had lower incidence of dementia when adhered to Life Simple 7 cardiovascular health recommendations at midlife (l4414; S. Sabia, severine.sabia@inserm.fr) and worse cognitive trajectories following major surgery (l4466; R. D. Sanders, robert.sanders@wisc.edu).
PICO: Prospective longitudinal cohort study of participants in civil service departments in London at study inception in 1985–88; cardiovascular health score included adherence to the Life Simple 7 recommendations (four behavioral [smoking, diet, physical activity, body mass index] and three biological [fasting glucose, blood cholesterol, blood pressure]); surgeries and hospitalizations; primary outcomes of incident dementia in the cardiovascular analysis and global cognitive scores in the surgery analysis.
Results — Cardiovascular Health: "347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were −1.5 (95% confidence interval −2.3 to −0.7) for the group with intermediate cardiovascular health and −1.9 (−2.8 to −1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score)."
Conclusion — Surgery & Cognition: "Major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. The odds of substantial cognitive decline after surgery was about doubled, though lower than for medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery."
* Pharmacogenomics, in Lancet, 2019; 394: 521–32. (D. M. Roden, dan.roden@vumc.org)
* Pexidartinib Versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN), in Lancet, 2019; 394: 478–87. (W. D. Tap, tapw@mskcc.org)
* Disparities in Geographic Access to Hospital Outpatient Pulmonary Rehabilitation Programs in the United States, in Chest, 2019; 156: 308–15. (I. S. Moscovice, mosco001@umn.edu)
* Past, Present, and Future Research on the Lung Microbiome in Inflammatory Airway Disease, in Chest, 2019; 156: 376–82. (M. A. Sze, marc.sze@merck.com)
Source: Early-online articles from and Aug. issue of JAMA Internal Medicine (2019; 179).
Population-Based Trends in U.S. Diabetes Care: Gaps in diabetes care present in 2005 still persist in the U.S., researchers report, particularly among younger adults, women, and nonwhite individuals (10.1001/jamainternmed.2019.2396; P. Kazemian, pooyan.kazemian@mgh.harvard.edu).
PICO: Nationally representative, serial cross-sectional 2005–16 National Health and Nutrition Examination Surveys of individuals with fasting blood glucose levels; outcomes of overall and stratified proportions of participants who met care goals based on age, gender, race/ethnicity.
Results: "In 2013–2016, of 1,742 US adults with diagnosed diabetes, 94% (95% CI, 92%–96%) were linked to diabetes care; 64% (95% CI, 58%–69%) met hemoglobin A1c level, 70% (95% CI, 64%–75%) met blood pressure level, and 57% (95% CI, 51%–62%) met cholesterol level targets; 85% were nonsmokers (95% CI, 82%–88%); and 23% (95% CI, 17%–29%) achieved the composite goal. Results were similar in 2005–2008 (composite 23%) and in 2009–2012 (composite 25%). There was no significant improvement in diagnosis or target achievement during the study period. Compared with middle-aged adults (45–64 years) with diagnosed diabetes, older patients (≥65 years) had higher odds (adjusted odds ratio [aOR], 1.70; 95% CI, 1.17–2.48) and younger adults (18–44 years) had lower odds (aOR, 0.53; 95% CI, 0.29–0.97) of meeting the composite target. Women had lower odds of achieving the composite target than men (aOR, 0.60; 95% CI, 0.45–0.80). Non–Hispanic black individuals vs non–Hispanic white individuals had lower odds of achieving the composite target (aOR, 0.57; 95% CI, 0.39–0.83). Having health insurance was the strongest predictor of linkage to diabetes care (aOR, 3.96; 95% CI, 2.34–6.69)."
Editorial: These results "depict a plateau in diabetes care quality nationally," writes an editorialist (10.1001/jamainternmed.2019.2392; M. K. Ali, mkali@emory.edu). "The marginal costs and efforts to close the remaining 20% to 30% of gaps are likely to be high. Given this report's clear message of persistent and deep disparities in diabetes care, local-level innovations alone will likely be insufficient. In our view, without policy-level initiatives to address socioeconomic disparities, we will not be able to move the needle on diabetes care nationally. Much like the tax code, small amendments will worsen the situation. We need to boldly find ways to align the economic and health motivations of the key stakeholders in our society to revolutionize care for chronic conditions in America. The message of this report is clear: people are still getting left behind; we need to act now or they will slip (further) through the cracks."
Anticholinergic Drugs & Risk of Dementia: Exposure to strong anticholinergic drugs is associated with an increased risk of dementia, a study shows (pp. 1084–93; C. A. C. Coupland, carol.coupland@nottingham.ac.uk).
PICO: Nested case–control study of 58,769 patients with dementia in English general practices; total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the prior 1–11 years; adjusted odds ratios for dementia.
Results: "The adjusted OR for dementia increased from 1.06 (95% CI, 1.03–1.09) in the lowest overall anticholinergic exposure category (total exposure of 1–90 TSDDs) to 1.49 (95% CI, 1.44–1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24–1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16–2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53–1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56–1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22–1.57) all for more than 1095 TSDDs."
* FDA is warning consumers not to purchase or drink Miracle or Master Mineral Solution and similar products sold online as medical treatments for autism, cancer, HIV/AIDS, and other serious conditions. The solution, when mixed, develops into a dangerous bleach that has caused severe and potentially life-threatening side effects.
Source: Aug. 13 issue of JAMA (2019; 322).
Emergency Buprenorphine Without a Prescription: "Buprenorphine could be offered without a prescription, available behind the counter at pharmacies, in a model similar to that used for other medications," write authors who note that emergency use of buprenorphine meets the conditions of other agents in this category (relatively safe and effective, and the public understands indications for use) (pp. 501–2; P. J. Roy, MD, payel.roy@bmc.org). "Buprenorphine could be available for those in need similar to emergency contraception, while limiting unrestricted access by setting age and quantity limitations similar to those used for pseudoephedrine. Limiting quantities (eg, 3-day supply) could encourage patients to seek long-term treatment from a clinician with a DEA waiver for their medical and psychosocial needs.
"In addition, a behind-the-counter model could provide uninsured patients, who have the least access to clinicians, with needed treatment. Out-of-pocket costs may remain a barrier to access, but could serve as another incentive for patients to seek prescriptions, which would be more likely to be covered by insurers. In addition, pharmacists could observe the initial dose to ensure that opioid withdrawal symptoms are not precipitated by buprenorphine.
"Emergency circumstances that would justify providing buprenorphine without a prescription would need to be clearly defined. Potential situations may include (1) when a person with [opioid use disorder (OUD)] is waiting for an office-based treatment intake assessment or is having severe withdrawal symptoms, or (2) when a person who has successfully tapered off buprenorphine perceives that he or she is at imminent risk for relapse. This model could potentially enable many persons with OUD to access and benefit from buprenorphine."
Blood Pressures, Brain Changes & Dementia Risk: Commenting on studies of intensive versus standard blood pressure control (target systolic blood pressures of 120 versus 140 mm Hg) and change in total white matter lesion volume and total brain volume (pp. 524–34; R. N. Bryan, nick.bryan@austin.utexas.edu) and blood pressures in mid- to late life and cognitive function (pp. 535–45; K. A. Walker, kwalke26@jhmi.edu), an editorialist writes, "The compelling, albeit not definitive, findings from these 2 studies are encouraging for several reasons" (pp. 512–3; S. Prabhakaran, shyam1@uchicago.edu). "First, blood pressure lowering to targets used in SPRINT, especially if applied in midlife, may provide greater benefits than observed in SPRINT MIND, which enrolled participants with mean age of nearly 68 years. This type of primary prevention strategy, if proven, would have major public health implications. Second, future dementia prevention trial designs would benefit from using imaging biomarkers to increase statistical power and decrease sample sizes, duration of follow-up, and consequently costs. Third, multimodal approaches that include modification of other vascular risk factors through pharmacologic and lifestyle interventions may have effects additive to blood pressure lowering alone. Indeed, a Finnish trial of diet, exercise, and cognitive training in elderly patients resulted in less cognitive decline than standard management. Another study of lipid management reported that statins could slow the progression of [white matter hyperintensity (WMH)]. Future trials should consider multimodal interventions in the prevention of dementia. Fourth, vascular risk factor intervention trials might target individuals with midlife hypertension and evidence of at least mild WMH on brain MRI, a group that would be predicted to have the greatest risks of late-life dementia but that is in the earliest stages of disease development."
* FDA has issued a guidance document detailing requirements for child-resistant packaging (CRP) statements in drug product labeling. The document discusses what information firms should include to support CRP statements in labeling of drug and biologic product applications, including nonprescription drug products approved under new drug or abbreviated new drug applications and those that are marketed under the Over-the-Counter (OTC) Drug Review.
Source: Aug. 15 issue of the New England Journal of Medicine (2019; 381).
Teplizumab in Relatives at Risk for Type 1 Diabetes: Teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, delayed progression to clinical type 1 diabetes in relatives of patients with type 1 diabetes, researchers report (pp. 603–13; K. C. Herold, kevan.herold@yale.edu).
PICO: Phase 2, randomized, placebo-controlled, double-blind trial of a 14-day course of teplizumab in relatives of 76 patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease; follow-up for progression to clinical type 1 diabetes based on oral glucose-tolerance tests at 6-month intervals.
Results: "The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo."
Editorial: "Although [this] trial showed a marked delay in the onset of overt diabetes, the results should not be taken to imply that immune modulation constitutes a potential curative approach," editorialists write (pp. 666–7; C. J. Rosen). "Rather, these data provide strong albeit indirect evidence about the pathogenesis of beta-cell destruction and the potential to modify the course of type 1 diabetes with newer biologic agents. This trial will probably prompt the development of more refined screening criteria for treatment of persons at highest risk, although challenges in using immune modulators for type 1 diabetes remain. This trial was small (76 participants) and involved only one 2-week treatment course. The duration and frequency of treatments, the long-term side effects of those therapies, the identification of subgroups of persons who do not have a response to the treatment, and the clinical course of persons who initially do have a response still need to be determined. Nevertheless, we can finally say, 40 years after [publication of an article by] Eisenbarth, that there has been substantial progress in modulating the early course of type 1 diabetes."
Liraglutide in Pediatric Type 2 Diabetes: Added to metformin and with or without basal insulin, liraglutide improved glycemic control in children and adolescents with type 2 diabetes, a study shows, but the drug produced more frequent gastrointestinal events (pp. 637–46; W. V. Tamborlane, william.tamborlane@yale.edu).
PICO: Patients 10 to less than 17 years of age early in the course of with type 2 diabetes randomly received subcutaneous liraglutide or placebo during a 26-week double-blind period, followed by a 26-week open-label extension period; primary end point of change from baseline in the glycated hemoglobin level after 26 weeks.
Results: "Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P <0.001); the difference increased to −1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide."
* FDA yesterday approved the nitroimidazole pretomanid (The Global Alliance for TB Drug Development) tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs. The new drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs as part of a three-drug, 6-month, all-oral regimen for the treatment of people with extensively drug-resistant TB or multidrug-resistant TB who are treatment-intolerant or nonresponsive.
Source: Aug. 15 issue of Clinical Infectious Diseases (2019; 69).
Principal Controversies in Vaccine Safety: "Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases," write authors of an invited article (pp. 726–31; F. DeStefano, FDestefano@cdc.gov). "We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including (1) measles, mumps, and rubella vaccine and autism; (2) thimerosal, a mercury-based vaccine preservative and the risk of neurodevelopmental disorders; (3) vaccine-induced Guillain-Barré syndrome (GBS); (4) vaccine-induced autoimmune diseases; (5) safety of human papillomavirus vaccine; (6) aluminum adjuvant-induced autoimmune diseases and other disorders; and (7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns."
Screening and Prevention of Group B Streptococcus Disease: At an autumn 2016 U.K. Dept. of Health meeting, participants discussed how to address research evidence gaps to minimize the impact of infant group B streptococcus (GBS) disease in the United Kingdom (pp. 720–5; K. Le Doare, k.ledoare@nhs.net): "A number of research priorities were highlighted, including improving the screening for GBS colonization in pregnant women, offering intrapartum antibiotic prophylaxis and point-of-care testing, and understanding the effect of widespread intrapartum antibiotic use on long-term infant health.…"
>>>Clinical Oncology Report
Source: Early-online article from the Journal of Clinical Oncology (2019; 37).
VTE Prophylaxis in Cancer: The American Society of Clinical Oncology updates its recommendations for prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer (10.1200/JCO.19.01461; N. S. Key): "Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or [low-molecular-weight heparin (LMWH)] to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE."
* FDA yesterday granted accelerated approval to entrectinib (Rozlytrek, Genentech) for treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or for whom surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. The agency also approved the product for treatment of adults with ROS1-positive, metastatic non-small cell lung cancer.
* FDA has issued a proposed rule to require new health warnings on cigarette packages and in advertisements to promote greater public understanding of the negative health consequences of smoking. The proposed warnings feature photorealistic color images depicting some of the lesser-known, but serious health risks of cigarette smoking.
* Pfizer is voluntarily recalling eletriptan hydrobromide (Relpax) 40 mg tablets, lots AR5407 and CD4565, to the patient level because these product lots may not meet in-house microbiological specification for the potential presence of Pseudomonas and Burkholderia.
Vitamin D Supplementation & Mortality: Despite a 16% reduction in cancer deaths, authors of a meta-analysis report that vitamin D supplementation alone was not associated with all-cause mortality in adults compared with placebo or no treatment (l4673; F. Fang, fangfang1057@outlook.com).
PICO: Systematic review and meta-analysis of randomized controlled trials of 52 trials with 75,454 participants.
Results: "Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2 = 0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.84, 0.74 to 0.95, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction = 0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality."
30-Day Hospital Revisits for Targeted Conditions: In the U.S., emergency department visits and observation stays within 30 days of hospital discharge for patients with three conditions targeted by the Hospital Readmissions Reduction Program (HRRP) exceeded the decline in 30-day readmissions, a study shows (l4563; R. K. Wadhera, rwadhera@bidmc.harvard.edu). The authors conclude, "Although reductions in readmissions have been attributed to improvements in discharge planning and care transitions, our findings suggest that these declines could instead be because hospitals and clinicians have intensified efforts to treat patients who return to a hospital within 30 days of discharge in emergency departments and as observation stays."
PICO: Retrospective cohort study of hospital stays for Medicare patients for heart failure, acute myocardial infarction, or pneumonia in 2012–15; outcome of total hospital revisits within 30 days of discharge after hospital stays.
Results: "Our study cohort included 3,038,740 total index hospital stays from January 2012 to September 2015: 1,357,620 for heart failure, 634,795 for acute myocardial infarction, and 1,046,325 for pneumonia. Counting all revisits after discharge, the total number of hospital revisits per 100 patient discharges for target conditions increased across the study period (monthly increase 0.023 visits per 100 patient discharges (95% confidence interval 0.010 to 0.035)). This change was due to monthly increases in treat-and-discharge visits to an emergency department (0.023 (0.015 to 0.032) and observation stays (0.022 (0.020 to 0.025)), which were only partly offset by declines in readmissions (−0.023 (−0.035 to −0.012)). Increases in observation stay use were more pronounced among non-white patients than white patients. No significant change was seen in mortality within 30 days of discharge for target conditions (−0.0034 (−0.012 to 0.0054))."
* FDA on Friday approved the orphan drug fedratinib (Inrebic, Impact Biomedicines/Celgene) for oral treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.
* Also on Friday, FDA approved the Barostim Neo System (CVRx) for the improvement of symptoms in patients with advanced heart failure who are not suited for treatment with other heart failure devices, such as cardiac resynchronization therapy.
* Risankizumab Compared With Adalimumab in Patients With Moderate-To-Severe Plaque Psoriasis (Immvent): A Randomised, Double-Blind, Active-Comparator-Controlled Phase 3 Trial, in Lancet, 2019; 394: 576–86. (K. Reich, kreich@jerucon.com)
* Omadacycline: A New Option in an Era of Increasing Antibiotic Resistance, supplement to Clinical Infectious Diseases, 2019; 69 (suppl 1).
* Special Series: Advances in the Management of Invasive Cervical Carcinoma, in Journal of Clinical Oncology, 2019; 37.
* Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma, in Journal of Clinical Oncology, 2019; 37: 2105–19. (J. K. Lin, johnklin@stanford.edu)
Source: Early-online article from and Aug. 20 issue of Annals of Internal Medicine (2019; 171).
Lipophilic Statins & Cancer Outcomes in Chronic Viral Hepatitis: A Swedish study associates use of lipophilic statins with significantly reduced incidence and mortality of hepatocellular carcinoma (HCC) in patients with viral hepatitis (10.7326/M18-2753; J. F. Ludvigsson, jonasludvigsson@yahoo.com).
PICO: Prospective propensity score (PS)–matched cohort using registers for Swedes with viral hepatitis in 2005–13; outcome of time-to-incident HCC; filled statin prescriptions for ≥30 cumulative defined daily doses (cDDDs).
Results: "Compared with matched nonusers, 10-year HCC risk was significantly lower among lipophilic statin users (8.1% vs. 3.3%; absolute risk difference [RD], −4.8 percentage points [95% CI, −6.2 to −3.3 percentage points]; adjusted subdistribution hazard ratio [aHR], 0.56 [CI, 0.41 to 0.79]) but not hydrophilic statin users (8.0% vs. 6.8%; RD, −1.2 percentage points [CI, −2.6 to 0.4 percentage points]; aHR, 0.95 [CI, 0.86 to 1.08). The inverse association between lipophilic statins and HCC risk seemed to be dose-dependent. Compared with nonusers, 10-year HCC risk was lowest with 600 or more lipophilic statin cDDDs (8.4% vs. 2.5%; RD, −5.9 percentage points [CI, −7.6 to −4.2 percentage points]; aHR, 0.41 [CI, 0.32 to 0.61]), and 10-year mortality was significantly lower among both lipophilic (15.2% vs. 7.3%; RD, −7.9 percentage points [CI, −9.6 to −6.2 percentage points]) and hydrophilic (16.0% vs. 11.5%; RD, −4.5 percentage points [CI, −6.0 to −3.0 percentage points]) statin users."
Antibiotic Use Without a Prescription: Increased understanding of Americans' use of antibiotics without a prescription is needed, investigators conclude based on a review of the "seemingly prevalent" practice (pp. 257–63; L. Grigoryan, grigorya@bcm.edu).
PICO: Scoping review of research on the prevalence of and factors influencing nonprescription antibiotic use in the United States; 31 articles reporting studies of nonprescription antibiotic use.
Results: "Depending on population characteristics, prevalence of nonprescription antibiotic use varied from 1% to 66%, storage of antibiotics for future use varied from 14% to 48%, and prevalence of intention to use antibiotics without a prescription was 25%. Antibiotics were obtained without a prescription from various sources, including previously prescribed courses, local markets or stores, and family or friends. Reported factors contributing to nonprescription use included easy access through markets or stores that obtain antibiotics internationally for under-the-counter sales, difficulty accessing the health care system, costs of physician visits, long waiting periods in clinics, and transportation problems."
Source: Aug. Journal of the American Geriatrics Society (2019; 67).
Oral Anticoagulants in AF: In a subgroup of the ARISTOPHANES study, patients aged 80 years or older with nonvalvular atrial fibrillation (NVAF) had better outcomes with non–vitamin K antagonist oral anticoagulants (NOACs) than with warfarin (pp. 1662–71; S. Deitelzweig, sdeitelzweig@ochsner.org).
PICO: Retrospective observational study based on 88,582 very old (aged ≥80 y) NVAF patients newly initiating apixaban, dabigatran, rivaroxaban, or warfarin in 2013–15.
Results: "The patients in the six matched cohorts had a mean follow-up time of 7 to 9 months. Compared with warfarin, apixaban (HR = .58; 95% confidence interval [CI] = .49–.69), dabigatran (HR = .77; 95% CI = .60–.99), and rivaroxaban (HR = .74; 95% CI = .65–.85) were associated with lower risks of stroke/[systemic embolism (SE)]. For [major bleeding (MB)], apixaban (HR = .60; 95% CI = .54–.67) was associated with a lower risk; dabigatran (HR = .92; 95% CI = .78–1.07) was associated with a similar risk, and rivaroxaban (HR = 1.16; 95% CI = 1.07–1.24) was associated with a higher risk compared with warfarin. Apixaban was associated with a lower risk of stroke/SE and MB compared with dabigatran (stroke/SE: HR = .65; 95% CI = .47–.89; MB: HR = .60; 95% CI = .49–.73) and rivaroxaban (stroke/SE: HR = .72; 95% CI = .59–.86; MB: HR = .50; 95% CI = .45–.55). Dabigatran was associated with a lower risk of MB (HR = .77; 95% CI = .67–.90) compared with rivaroxaban."
Continuing Olanzapine in Remission of Psychotic Depression: Compared with sertraline plus placebo, sertraline plus olanzapine reduced the risk of relapse in patients with psychotic depression that was in remission, researchers report (pp. 622–31; A. J. Flint, alastair.flint@uhn.ca). Investigators in the STOP-PD II randomized clinical trial concluded that "this benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain."
PICO: 126 adults with an episode of psychotic depression that was in remission following treatment with sertraline plus olanzapine for up to 12 weeks in 2011–17; randomization to continued olanzapine or switch to placebo (all participants continued sertraline); primary outcome of risk of relapse.
Results: "At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150–200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10–20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, −0.01 to 0.10), high-density lipoprotein cholesterol (−0.01 mg/dL; 95% CI, −0.03 to 0.01), triglyceride (−0.153 mg/dL; 95% CI, −0.306 to 0.004), glucose (−0.02 mg/dL; 95% CI, −0.12 to 0.08), or HbA1c levels (−0.0002 mg/dL; 95% CI, −0.0021 to 0.0016)."
Editorial: "Psychotic depression presents clinicians with the challenge of treating an illness with high potential morbidity, both from acute and lifetime perspectives," editorialists write (pp. 615–7; W. H. Coryell, william-coryell@uiowa.edu). "However, psychotic depression can be highly responsive to well-chosen treatment. In the STOP-PD II trial, 42% of patients in the combination group met criteria for remission in the acute phase, a rate that compares favorably with 12-week remission rate of 28% described for the 'very severe' [major depressive disorder] group in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial of 4 alternative antidepressants. It seems likely then that judicious discontinuation of antipsychotic agents followed by close vigilance over the subsequent several months is likely to be an effective strategy. For those patients who tolerate antipsychotic medications well, longer periods taking combined treatment may be preferable."
Smoking Cessation & CVD Risk Reduction: Commenting on a study that quantifies the effects of smoking cessation on risk of cardiovascular disease (CVD) (pp. 642–50; M. S. Duncan, meredith.s.duncan@vumc.org), editorialists write (p. 651; T. B. Cole, tbcole@bellsouth.net): "According to these new analyses, a former smoker's risk of CVD does not approximate the risk of a never smoker until 10 to 15 years have elapsed since cessation. The risk of CVD does appear to decline substantially within the first 5 years, and smokers who are contemplating quitting may take some encouragement from this finding. On a population level, the implications of this study are sobering: reductions in CVD associated with declining smoking rates in countries such as Japan and the United States can be expected to lag quit rates by 10 to 15 years, and in countries where smoking rates appear to be increasing, such as China and Indonesia, rates of CVD are likely to increase for decades into the future. To counter these trends, all countries, particularly those most vulnerable to tobacco marketing, should implement tobacco control strategies to prevent smoking initiation and motivate current smokers to quit."
* FDA has approved oral and I.V. formulations of lefamulin (Xenleta, Nabriva Therapeutics) for treatment of community-acquired bacterial pneumonia (CABP) in adults. As the first I.V. and oral antibiotic with a novel mechanism of action approved by FDA in nearly two decades, lefamulin represents an important new empiric monotherapy treatment option for adults with CABP, the company said in a news release.
PDMPs—Friend or Folly? After reviewing the impact of prescription drug monitoring programs (PDMPs) on the opioid-overdose crisis, a Perspective author concludes that "PDMPs could be more carefully calibrated to maximize clinician, patient, and population interests" (pp. 699–701; R. L. Haffajee). Concerns about the programs include whether they leave pain untreated, infringe on medical practice, allow trolling of databases by law-enforcement officials, and present an incomplete picture since illicit drug use is not included. "So what role should PDMPs play moving forward?" the author asks. "I believe that concerns about PDMPs, although substantial and credible, don't justify wholesale abandonment of these rich tools from which we derive considerable clinical and law-enforcement benefit. PDMPs, along with other policy levers, have contributed to continuous reductions in opioid prescriptions in the United States since 2011, and further reductions may be warranted. Policies that require prescribers to check PDMP data but permit some clinical discretion regarding what to do with such information may be preferable to blunt policies that restrict the amount of prescription opioids supplied regardless of individual patient characteristics."
Serelaxin in Patients with Acute Heart Failure: Compared with placebo in patients hospitalized for acute heart failure, the vasodilator serelaxin did not lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days, RELAX-AHF-2 investigators report (pp. 716–26; J. R. Teerlink, john.teerlink@ucsf.edu).
PICO: Multicenter, double-blind, placebo-controlled, event-driven trial of 6,545 patients hospitalized for acute heart failure and having dyspnea and other signs/symptoms; 48-hour intravenous infusion of serelaxin or placebo in addition to standard care; primary end points of death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
Results: "At day 180, death from cardiovascular causes had occurred in 285 of the 3,274 patients (8.7%) in the serelaxin group and in 290 of the 3,271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups."
Editorial: "Hospitalization for worsening symptoms is an important event in chronic heart failure; it identifies patients with particularly rapid advancement of the underlying disorder," writes an editorialist (pp. 776–7; M. Packer). "However, decompensation is not an acute illness or an indicator of subclinical myocardial injury that requires emergency intervention with a novel treatment; the acute elevation of troponin level may subside, but the troponin level remains elevated after hospital discharge. Although it is important to achieve clinical stabilization, it is more critical to ensure that patients are treated vigorously between hospitalizations to decrease the risk of readmission and death. A focus on intensive outpatient care (rather than an obsession with inpatient therapy) is needed to reduce the burden of heart failure."
Selinexor/Dexamethasone for Multiple Myeloma: With dexamethasone, the selective inhibitor of nuclear export compound selinexor improved objective treatment responses in patients with multiple myeloma refractory to currently available therapies (pp. 727–38; S. Jagannath, sundar.jagannath@mountsinai.org).
PICO: 122 patients with triple-class refractory multiple myeloma; oral selinexor plus dexamethasone twice weekly; primary end point of overall response.
Results: "A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months.…"
>>>Medical Care Report
Source: Sept. issue of Medical Care (2019; 57).
Long-Term Medication Adherence After Buprenorphine: Initiation of buprenorphine for opioid use disorder (OUD) increased adherence to medications for unrelated chronic conditions in an observational study (pp. 667–72; H-Y Chang).
PICO: Retrospective cohort study of 12,719 commercially ensured individuals with a diagnosis of OUD and buprenorphine initiation in 2011–15 using Truven Health's MarketScan data; individuals using any of 5 therapeutic classes (antilipids, antipsychotics, antiepileptics, antidiabetics, antidepressants) were included; outcome of having buprenorphine and a long-term medication on hand for each therapeutic class of interest.
Results: "Across the 5 therapeutic classes, the probability with a given treatment on hand was always higher on days when buprenorphine was on hand. After adjustment for demographics, morbidity, and baseline adherence, buprenorphine was associated with a greater odds of adherence to antilipids [odds ratio (OR), 1.27; 95% confidence interval (CI), 1.04–1.54], antiepileptics (OR, 1.22; CI, 1.10–1.36) and antidepressants (OR, 1.42; CI, 1.32–1.60)."
Predicting Outcomes in Geriatric Type 2 Diabetes: For managing therapy in older adults with type 2 diabetes, "pharmacists and other health care providers can use models with prior history of adverse event, number of medicines, chronic kidney disease, depression and retinopathy to prioritize interventions," researchers report (pp. 702–9; S. Kabue).
PICO: Observational retrospective cohort study of 120,256 adults aged 65 years or older with type 2 diabetes from a large integrated health system; risk factors associated with 7 adverse outcomes (hypoglycemia, hip fractures, syncope, emergency department visit or hospital admission, death, and 2 combined outcomes) were identified.
Results: "The most significant predictors [were] age, number of medicines, prior history of outcome within the past 2 years, chronic kidney disease, depression, and retinopathy. Experiencing an adverse outcome within the prior 2 years was the strongest predictor of future adverse outcomes (odds ratio range: 4.15–7.42). The best performing models across all outcomes included: prior history of outcome, physiological characteristics, comorbidities and pharmacy-specific factors (c-statistic range: 0.71–0.80)."
>>>Health Affairs Highlights
Source: Aug. issue of Health Affairs, a special issue on military health systems (2019; 38).
Opioid Epidemic in Homeless/Unstably Housed Veterans: The challenges of homelessness and unstable housing are evident in a study of veterans with opioid use disorder (OUD) (pp. 1289–97; A. M. Midboe, Amanda.Midboe@va.gov).
PICO: Retrospective observational study of OUD in a national sample of veterans who accessed specialized homeless programs in the Veterans Health Administration; subgroup of veterans with a history of OUD provided insights into opioid dose, concomitant opioid–benzodiazepine prescribing, and receipt of medication for addiction treatment (MAT) and overdose prevention medication (naloxone).
Results: "Rates of OUD history varied significantly across age, gender, and program type. Among the subgroup of homeless veterans with an OUD history, prescribing practices and rates of MAT and naloxone receipt varied significantly by age and specialized homeless program. Rates of receipt of MAT and naloxone were moderate and low, respectively, indicating opportunities for program-specific interventions."
TRICARE — Quality And Access: Quality of and access to care are compared for families with TRICARE, other insurance, or no health coverage (pp. 1377–85; D. M. Rubin, rubin@email.chop.edu).
PICO: Medical Expenditure Panel Survey data.
Results: "TRICARE-insured families were less likely to report accessible or responsive care compared to civilian peers, whether commercially or publicly insured or uninsured. Military families whose children had complex health or behavioral health care needs reported worse health care access and quality than similar nonmilitary families. Addressing these gaps may require military leaders to examine barriers to achieving acceptable health care access across military treatment facilities and off-base nonmilitary specialty providers, particularly for children with complex health or behavioral health needs."
Polypill for Primary, Secondary CVD Prevention: In the PolyIran study, a fixed-dose combination therapy (polypill strategy) was effective in preventing major cardiovascular events, with medication adherence high and adverse event numbers low (pp. 672–83; R. Malekzadeh, malek@tums.ac.ir).
PICO: A two-group, pragmatic, cluster-randomized trial nested within the Golestan Cohort Study (GCS) allocated villages to receive a package of nonpharmacologic preventive interventions alone (minimal care group; educational training about healthy lifestyle such as healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) or together with a once-daily, four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan.
Results: "Median adherence to polypill tablets was 80.5% (IQR 48.5–92.2). During follow-up, 301 (8.8%) of 3,417 participants in the minimal care group had major cardiovascular events compared with 202 (5.9%) of 3,421 participants in the polypill group (adjusted hazard ratio [HR] 0.66, 95% CI 0.55–0.80). We found no statistically significant interaction with the presence (HR 0.61, 95% CI 0.49–0.75) or absence of pre-existing cardiovascular disease (0.80; 0.51–1.12; p interaction = 0.19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0.43, 95% CI 0.33–0.55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up—ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group."
Fatty Acids & T2D: An extensive review of trials of omega-3, omega-6, and total polyunsaturated fatty acids (PUFA) shows that the intervention "has little or no effect on prevention and treatment of type 2 diabetes mellitus," the authors conclude (l4697; L. Hooper, L. Hooper@uea.ac.uk).
PICO: Systematic review and meta-analyses of 83 randomized controlled trials of PUFA for preventing type 2 diabetes and improving glucose metabolism.
Results: "Long chain omega-3 had little or no effect on likelihood of diagnosis of diabetes (relative risk 1.00, 95% confidence interval 0.85 to 1.17; 58,643 participants, 3.7% developed diabetes) or measures of glucose metabolism (HbA1c mean difference −0.02%, 95% confidence interval −0.07% to 0.04%; plasma glucose 0.04, 0.02 to 0.07, mmol/L; fasting insulin 1.02, −4.34 to 6.37, pmol/L; [homoeostatic model assessment for insulin resistance] 0.06, −0.21 to 0.33). A suggestion of negative outcomes was observed when dose of supplemental long chain omega-3 was above 4.4 g/d. Effects of alpha-linolenic acid, omega-6, and total PUFA on diagnosis of diabetes were unclear (as the evidence was of very low quality), but little or no effect on measures of glucose metabolism was seen, except that increasing alpha-linolenic acid may increase fasting insulin (by about 7%). No evidence was found that the omega-3/omega-6 ratio is important for diabetes or glucose metabolism."
* With reports of vaping-related pulmonary disease growing and the first death related to this condition in the news over the weekend, a CDC website on e-cigarettes provides tips for talking to youth about the risk of nicotine in all forms and the dangers of vaping.
* Impact on Patient Outcomes of Pharmacist Participation in Multidisciplinary Critical Care Teams: A Systematic Review and Meta-Analysis, in Critical Care Medicine, 2019; 47: 1243–50. (H. Lee)
* The Bedside Critical Care Pharmacist: A Mandatory ICU Team Member Essential for Patient Care, in Critical Care Medicine, 2019; 47: 1276–8. (R. MacLaren)
* Military Telehealth: A Model For Delivering Expertise To The Point Of Need In Austere And Operational Environments, in Health Affairs, 2019; 38: 1386–92. (J. C. Pamplin, jeremy.c.pamplin.mil@mail.mil)
Rethinking Rx Opioids & Buprenorphine: Ideas and Opinions authors advocate "rethinking opioid dose tapering, prescription opioid dependence, and indications for buprenorphine" (10.7326/M19-1488; R. Chou, chour@ohsu.edu): "We propose consideration of sublingual or buccal buprenorphine as a treatment option for patients with prescription opioid dependence. Buprenorphine is a partial opioid agonist that carries lower risk for respiratory compromise than pure opioid agonists while providing analgesic benefits. Higher-dose sublingual and buccal formulations are approved by the U.S. Food and Drug Administration for [opioid use disorder] treatment in office-based settings by clinicians who undergo training and obtain a Drug Enforcement Administration waiver. Patients with prescription opioid dependence should also have access to higher-dose buprenorphine formulations for maintenance therapy or to facilitate tapering."
Coagulopathy After Synthetic Cannabinoid Use: In a letter, authors describe the clinical course of a young woman who developed coagulopathies after smoking synthetic cannabinoid contaminated with second-generation vitamin K antagonist rodenticides (superwarfarins) (10.7326/L19-0321; A. Rasin). "The patient was empirically treated for rodenticide poisoning because the consulting medical toxicology team was aware of [a] local outbreak," the group writes. "She initially received 2 units of fresh frozen plasma and 10 mg of phytonadione (VK1) intravenously, followed by 50 mg of VK1 orally every 8 hours. The bleeding resolved within 24 hours. The patient's oral VK1 dose was titrated downward using international normalized ratio (INR) as a guide. Outpatient treatment was difficult to arrange because she required a high dose of VK1 that was prohibitively expensive and in insufficient supply at local outpatient pharmacies. Thus, she remained hospitalized until the hospital pharmacy and family medicine clinic could arrange access to VK1. The patient was discharged on hospital day 6, receiving twice-daily doses of 50 mg of VK1 orally. She was managed in the clinic for the next 2 months. Coagulopathy persisted for at least 62 days, because on day 62, after 1 week of VK1 nonadherence, her INR increased to 2.0. She was lost to follow-up after moving out of state."
Midlife Infarctions & Cognitive Decline: Data from two ARIC (Atherosclerosis Risk in Communities) study sites show that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons (10.7326/M18-0295; B. G. Windham, gwindham@umc.edu).
PICO: Longitudinal cohort study of stroke-free participants aged 50 years or older; magnetic resonance imaging data (1993–95) and up to 5 cognitive assessments over 20 years; infarctions categorized as none, smaller only, larger only (3–20 mm), or both smaller and larger.
Results: "Among 1,884 participants…, 1,611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, −0.57 SD [95% CI, −0.89 to −0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions."
Suicide Prevention/Management: Algorithms and use of cognitive and dialectical behavior therapy are presented in a systematic review (10.7326/M19-0869; K. E. D'Anci, kdanci@ecri.org) and a synopsis of VA and DOD Clinical Practice Guidelines (10.7326/M19-0687; J. Sall, james.sall@va.gov). Comparing the U.S. and other countries, an editorialist cautions (10.7326/M19-2347; E. D. Caine, eric_caine@urmc.rochester.edu). "Approaches in the United States depend largely on engaging symptomatic persons when they seek care, as we see in these guidelines. However, most suicides apparently happen on the first attempt, and the bulk of them occur among middle-aged men, a group not known for seeking care or asking for help. Experiences in other countries invite us to look beyond narrowly defined forms of evidence to ask questions and conduct research that we in the United States have avoided thus far."
High-Dose Vitamin D & Bone Health: In a study of volumetric bone mineral density (BMD) and strength, high-dose vitamin D supplements produced worse outcomes than lower doses, leading investigators to conclude, "These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful." (pp. 736–45; S. K. Boyd, skboyd@ucalgary.ca).
PICO: Three-year, double-blind, randomized clinical trial of 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L; vitamin D3 400, 4000, or 10,000 IU/d, with calcium supplements provided to those with dietary intake of less than 1200 mg per day; coprimary outcomes of total volumetric BMD at radius and tibia and bone strength (failure load) at radius and tibia.
Results: "Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10,000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (−3.9 mg HA/cm3 [95% CI, −6.5 to −1.3]) and 10,000 IU group (−7.5 mg HA/cm3 [95% CI, −10.1 to −5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of −1.2% (400 IU group), −2.4% (4000 IU group), and −3.5% (10,000 IU group). Tibial volumetric BMD differences from the 400 IU group were −1.8 mg HA/cm3 (95% CI, −3.7 to 0.1) in the 4000 IU group and −4.1 mg HA/cm3 in the 10,000 IU group (95% CI, −6.0 to −2.2), with mean percent change values of −0.4% (400 IU), −1.0% (4000 IU), and −1.7% (10,000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12)."
Tandem Autologous Stem Cell Transplant in Neuroblastoma: Event-free survival (EFS) was improved in patients with high-risk neuroblastoma by treatment with tandem rather than single autologous stem cell transplant, researchers report (pp. 746–55; J. R. Park, julie.park@seattlechildrens.org).
PICO: 355 patients aged 30 years or younger with protocol-defined high-risk neuroblastoma in 2007–12 at 142 Children's Oncology Group centers in five countries; randomized to tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan or single transplant with carboplatin/etoposide/melphalan; primary outcome of EFS from randomization to occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause).
Results: "Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%–68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%–55.7%) in the single transplant group (1-sided log-rank P = .006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6–8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%)."
U.S. Cardiometabolic Mortality Trends: CDC Wide-Ranging Online Data for Epidemiologic Research (WONDER) data for 1999–2017 show a "continued but slower decline in [age-adjusted mortality rates (AAMR)] for heart disease, a plateau in mortality rates from stroke and diabetes, and an increasing AAMR for hypertension (although hypertension as underlying cause of death remained relatively infrequent) between 2010 and 2017," a study shows (pp. 780–2; S. S. Khan, s-khan-1@northwestern.edu).
* FDA yesterday approved istradefylline (Nourianz, Kyowa Kirin) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson disease experiencing "off" episodes.
* FDA is reminding patients and health professionals not to use drug products intended to be sterile made by Pacifico National Inc., an outsourcing facility doing business as AmEx Pharmacy, in Melbourne, FL. The drugs—which include compounded ophthalmic products among other drug products — pose unnecessary risks due to significant quality and sterility concerns, FDA said.
Dolutegravir + Tenofovir Prodrugs for HIV: Dolutegravir (DTG) plus either of two prodrugs of tenofovir were noninferior to standard therapy in a phase 3 trial, researchers report (pp. 803–15; W. D. F. Venter, fventer@wrhi.ac.za).
PICO: Interim, 48-week report of a 96-week, investigator-led, open-label, randomized trial in South Africa comparing emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — tenofovir alafenamide fumarate (TAF) (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group); primary end point of the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter.
Results: "At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens."
Editorial: Editorialists, reflecting on this and other articles in this issue — including a report of neural tube defects in neonates (pp. 827–40; R. Zash, rzash@bidmc.harvard.edu) — examine "cracks in the plan" for solving the world's HIV problem with dolutegravir-based antiretroviral therapy (pp. 873–4; D. V. Havlir): "This recent headwind caused by the imperfections of dolutegravir should not slow down the urgency to deliver livesaving therapy to millions still in need. We need to accelerate (not slow) the transition to dolutegravir-based regimens for initial therapy, offer treatment as early as possible, make use of the best currently available treatment options, shore up pharmacovigilance, and continue research at the same time. Indeed, the new World Health Organization guidelines embrace these principles and provide a tailwind for countries to sail ahead in the face of risk and unknowns."
Semaglutide & Cardiovascular Outcomes: In a cardiovascular outcomes trial conducted in 3,183 patients with type 2 diabetes with cardiovascular disease or at high risk, oral semaglutide was noninferior to placebo, confirming that the drug has a safety profile similar to other GLP-1 receptor agonists (pp. 841–51; M. Husain, mansoor.husain@uhn.ca). "The present trial showed noninferiority of oral semaglutide to placebo (hazard ratio, 0.79; 95% CI, 0.57 to 1.11), ruling out an 80% excess cardiovascular risk," the authors conclude. "Gastrointestinal adverse events were the major reason for discontinuation of oral semaglutide."
* "We have known that certain drug manufacturing processes pose a risk for forming genotoxic impurities, and this is an issue the FDA and other regulators have been working on for a number of years – well before the nitrosamine impurities were discovered in angiotensin II receptor blockers (ARBs) last summer," writes Janet Woodcock, MD, of the agency's Center for Drug Evaluation and Research, in a statement posted yesterday. "Ultimately, our goal is to be certain that no ARBs with unacceptable impurity levels reach patients. Based on our current assessments, including lab testing, the agency has identified 43 ARB medications that have been determined not to contain any nitrosamine impurities. As we continue our assessments and as companies continue to manufacture ARBs without nitrosamine impurities to replenish the U.S. supply, we expect this figure to rise. We know that ARBs can be produced without nitrosamine impurities, and we are working with manufacturers to reach that point."
Source: Sept. issue of Diabetes Care (2019; 42).
Antidiabetic Agents & Mortality in Pancreatic CA, Postpancreatitis Diabetes: In patients with postpancreatitis diabetes mellitus (PPDM), metformin promotes a survival benefit, but the drug has no effect in those with pancreatic cancer–related diabetes (PCRD) (pp. 1675–83; M. S. Petrov, max.petrov@gmail.com).
PICO: Nationwide pharmaceutical dispensing data (2006–15) linked to hospital discharge data for 1,862 individuals with PCRD or PPDM; 6-month lag used to minimize reverse causality.
Results: "In individuals with PCRD, ever users of metformin (adjusted hazard ratio 0.54; 95% CI 0.46–0.63) and ever users of insulin (adjusted hazard ratio 0.46; 95% CI 0.39–0.55) had significantly lower risks of mortality compared with never users of antidiabetic medications. These associations attenuated toward the null with the use of a 6-month lag. In individuals with PPDM, ever users of metformin had a significantly lower risk of mortality (adjusted hazard ratio 0.51; 95% CI 0.36–0.70), whereas ever-users of insulin did not have a significantly changed risk of mortality (adjusted hazard ratio 0.75; 95% CI 0.49–1.14) compared with never users of antidiabetic medications. The former association remained significant with the use of a 6-month lag."
Glucose Control Targets in Type 2 Diabetes: Glycated hemoglobin target levels have remained static for three decades, an author writes, and recent evidence indicates that higher targets may be preferable and lower targets should be avoided (pp. 1615–23; P. Home, philip.home@newcastle.ac.uk): "Prospective data from randomized and observational studies, in people with type 2 diabetes and indeed those without diabetes, find cardiovascular and mortality risk are uniformly lowest at lower levels including into the normal range. In some studies with large populations, a high proportion of people are found to attain such levels, and the UK Prospective Diabetes Study and more recent studies appear to confirm the importance of starting low and continuing long. Studies of cardiovascular events and mortality in people with diabetes will already factor in any effect of hypoglycemia, which therefore should not be double-counted in setting targets. Nevertheless, some factors should lead to modification of target levels, and these will include experience of hypoglycemia where therapy change and glucose monitoring cannot ameliorate it and sometimes prospectively in those at social or occupational risk."
Anxiety With High-Cost Health Care in Type 2 Diabetes: Using electronic health records, researchers associate anxiety with depression in people with type 2 diabetes and also with use of high-cost health care resources (pp. 1669–74; E. Iturralde, estibaliz.m.iturralde@kp.org): "After adjustment for covariates including depression, anxiety was positively related to the number of [emergency department (ED)] visits in 2012 (incidence rate ratio 1.27; 95% CI 1.21, 1.34), the likelihood of visiting the ED on a chronic, frequent basis during 2010–2012 (odds ratio 2.55; 95% CI 1.90, 3.44), and high-cost status in 2012 (odds ratio 1.29; 95% CI 1.23, 1.36), but anxiety was not related to total hospitalization costs in 2012 (relative cost ratio 1.06; 95% CI 0.94, 1.21; P = 0.33)."
* In the latter half of 2017 and the first half of 2018 in 25 states, "opioid deaths decreased 5% overall and decreased for prescription opioids and illicit synthetic opioids excluding illicitly manufactured fentanyl (IMF)," CDC authors write in this week's MMWR (pp. 737–44; R. Matt Gladden, mgladden@cdc.gov). "However, IMF deaths increased 11%. Benzodiazepines, cocaine, or methamphetamine were present in 63% of opioid deaths." The group concludes, "Continued increases in IMF deaths highlight the need to broaden outreach to persons at high risk for IMF overdoses and improve linkage to risk-reduction services and evidence-based treatment. Prevention and treatment efforts should attend to broad polysubstance use/misuse."
* Saturday is International Overdose Awareness Day, a global event that aims to raise awareness that overdose death is preventable and to reduce the stigma associated with drug-related death.
* PNN will not be published on Mon., Sept. 2, Labor Day.
Sept. 3, 2019 * Vol. 26, No. 169
Source: Early-online articles from the Annals of Internal Medicine (2019; 171).
Antipsychotics for Delirium in Hospitalized Adults: "Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients," conclude authors of a systematic review (10.7326/M19-1860; D. M. Needham, dale.needham@jhmi.edu).
PICO: Systematic review of 16 randomized controlled trials of antipsychotic versus placebo or another antipsychotic, and 10 prospective observational studies reporting harms.
Results: "There was no difference in sedation status (low and moderate [strength of evidence (SOE)]), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating delirium in adult inpatients, but potentially harmful cardiac effects tended to occur more frequently."
Editorial: An editorialist, commenting on this and a second review that assessed use of antipsychotic agents for prevention of delirium (10.7326/M19-1859; K. J. Neufeld, kneufel2@jhmi.edu), concludes: "There is a much bigger research priority that has eluded us for 30 years: How do we manage delirium to improve short- and long-term outcomes?" (10.7326/M19-2624; E. R. Marcantonio). "This includes the many patients with 'quiet delirium' currently not recognized, who have equally poor outcomes as the agitated patients. In my opinion, a patient-centered bundled approach that 1) identifies delirium early, 2) evaluates and addresses underlying causes, 3) prevents complications, and 4) promotes functional recovery is most likely to succeed. Identifying which practices belong in this bundle, and how to deliver it in a standardized, high-quality, and sustainable way, should be a major focus of the next generation of delirium treatment research."
* Reviewing what is known about respiratory illnesses reported after use of e-cigarette products, Acting FDA Commissioner Ned Sharpless, MD, and CDC Director Robert R. Redfield, MD, write this in a joint statement: "More information is needed to better understand whether there's a relationship between any specific products or substances and the reported illnesses. At this time, there does not appear to be one product involved in all of the cases, although THC and cannabinoids use has been reported in many cases. At this time, the specific substances within the e-cigarette products that cause illness are not known and could involve a variety of substances. We continue to gather information about the names of the products used, where they were purchased, and how the products were used. That information is critical to help determine whether patterns emerge on which we can take additional action. While we continue to gather more information about these incidents and any specific products or substances involved, we also believe it's important to provide the public with useful information to help protect themselves and their loved ones, as well as continue to notify health care professionals about the illnesses, what to watch for, and how to collect and report information on these cases. As part of that commitment, CDC [has] issued a Health Alert Network Health Advisory. The advisory includes the recommendation that while this investigation is ongoing, if you are concerned about these specific health risks, consider refraining from the use of e-cigarette products."
* Alcohol Use Disorders, in Lancet, 2019; 394: 781–92. (J. Rehm, jtrehm@gmail.com)
* Antibody–Drug Conjugates for Cancer, in Lancet, 2019; 394: 793–804. (W. D. Figg, figgw@mail.nih.gov)
* Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review, in Pediatrics, 2019; 144: e20191305. (M. Marin)
Source: Sept. 3 issue of JAMA (2019; 322).
Medications for Reducing Risk of Primary Breast Cancer: A systematic review shows that "tamoxifen, raloxifene, and aromatase inhibitors [are] associated with lower risk of primary invasive breast cancer in women but also [are] associated with adverse effects that differed between medications" (pp. 868–86; H. D. Nelson, nelsonh@ohsu.edu).
PICO: Systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Outcomes of probability of breast cancer in individuals; incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality.
Results: "A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55–0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59–0.84]; 4 trials [n = 28,421]), raloxifene (RR, 0.44 [95% CI, 0.24–0.80]; 2 trials [n = 17,806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26–0.70]; 2 trials [n = 8,424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05–1.47]; n = 19,747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53–0.73]; 2 trials [n = 16,929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45–0.98]; 1 trial [n = 13,388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication."
Task Force Recommendations: Based on this evidence, the U.S. Preventive Services Task Force (USPSTF) made these updates to its recommendations on medications for risk reduction of primary breast cancer (pp. 857–67; D. K. Owens, chair@uspstf.net):
* The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation)
* The USPSTF recommends against the routine use of risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, in women who are not at increased risk for breast cancer. (D recommendation)
Editorial 1: "High-quality evidence demonstrates consistent moderate reductions in the risk of developing breast cancer with tamoxifen, raloxifene, and aromatase inhibitors, although these medications do not reduce breast cancer mortality," editorialists write (pp. 821–3; L. E. Pace, lpace@bwh.harvard.edu). "Given the barriers to use, including the harms associated with a preventive treatment with moderate benefit, more accurate identification of women most likely to benefit or experience harm could help to focus preventive efforts on the clinical situations in which these medications will have most effect.…"
Editorial 2: In JAMA Oncology, editorialists add this perspective on the role of personalized medicine (10.1001/jamaoncol.2019.3785; M. B. Daly, mary.daly@fccc.org): "In the new era of precision medicine, there is a realization that one size fits all is no longer acceptable for most treatments. The new USPSTF statement mirrors this trend by making a strong case for the need to consider the unique risk profiles of potential chemoprevention candidates and incorporate this complex information into risk models for individualized decision-making. More efficient and sophisticated tools to more precisely quantify each individual's benefit/risk for a variety of chemoprevention drugs may ultimately translate into precision medicine for breast cancer prevention."
* A federal judge has entered a consent decree against Tennessee-based Basic Reset and Biogenyx for drug, device and dietary supplement violations, FDA said yesterday.
Source: Sept. 5 New England Journal of Medicine (2019; 381).
SAGE-217 in Major Depressive Disorder: SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, reduced depressive symptoms by day 15 of therapy, but with adverse events, researchers report (pp. 903–11; H. Gunduz-Bruce, handan.gunduz-bruce@sagerx.com).
PICO: Double-blind, phase 2 trial of 89 patients with major depression; SAGE-217 30 mg or placebo once daily; primary end point of change from baseline to day 15 on the 17-item Hamilton Depression Rating Scale (HAM-D).
Results: "The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (± SE) change in the HAM-D score from baseline to day 15 was −17.4 ± 1.3 points in the SAGE-217 group and −10.3 ± 1.3 points in the placebo group (least-squares mean difference in change, −7.0 points; 95% confidence interval, −10.2 to −3.9; P <0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence."
Editorial: "Even if SAGE-217 is not found to be helpful in treatment-resistant depression, the availability of an agent that targets a central neurotransmitter system not previously targeted and that may produce a rapid antidepressant response is provocative," an editorialist writes (pp. 980–1; E. F. Coccaro). Noting that antidepressants that target nonmonoamine neurotransmitters have sometimes failed after promising early results, the writer adds, "Although SAGE-217 represents an exciting conceptual development in new agents for major depressive disorder, only time will tell whether positive allosteric modulators of GABAA receptors will enter the pharmacopeia of agents that are effective for major depressive disorder."
Inhaled GM-CSF for Pulmonary Alveolar Proteinosis: In patients with severe pulmonary alveolar proteinosis, inhaled human recombinant granulocyte–macrophage colony-stimulating factor (GM-CSF) produced limited improvements in laboratory outcomes and no clinical benefits (pp. 923–32; K. Nakata, radical@med.niigata-u.ac.jp).
PICO: Double-blind, placebo-controlled trial of daily inhaled GM-CSF (sargramostim) 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen while breathing ambient air of <70 mm Hg (or <75 mm Hg in symptomatic patients); primary end point of change in the alveolar–arterial oxygen gradient between baseline and week 25.
Results: "The change in the mean (± SD) alveolar–arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, −4.50 ± 9.03 mm Hg vs. 0.17 ± 10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, −36.08 Hounsfield units; 95% confidence interval, −61.58 to −6.99, calculated with the use of the Mann–Whitney U test and the Hodges–Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group."
Mitapivat in Pyruvate Kinase Deficiency: An oral, small-molecule allosteric pyruvate kinase activator in red cells, mitapivat increased hemoglobin levels in half of patients with deficiency of this enzyme (pp. 933–44; R. F. Grace, rachael.grace@childrens.harvard.edu).
PICO: Uncontrolled, phase 2 study of 52 adults with pyruvate kinase deficiency; mitapivat 50 or 300 mg twice daily for 24 weeks.
Results: "A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis.…"
>>>Psychiatry Report
Source: Sept. issue of the American Journal of Psychiatry (2019; 176).
Treatment Continuation in ADHD: Individuals with attention-deficit/hyperactivity disorder (ADHD) continue benefiting from methylphenidate therapy after more than 2 years of treatment, a study shows (pp. 754–62; A-F M. Matthijssen). Some individuals can be withdrawn from the drug, supporting guideline recommendations for periodic assessment.
PICO: 94 children and adolescents treated with methylphenidate for more than 2 years; double-blind assignment to continuation of treatment for 7 weeks (extended-release methylphenidate 36 or 54 mg/d) or gradual withdrawal over 3 weeks, to 4 weeks of placebo; primary outcome measure of investigator-rated ADHD Rating Scale (ADHD-RS); secondary outcome measures of investigator-rated Clinical Global Impressions improvement scale (CGI-I) and the Conners' Teacher Rating Scale–Revised: Short Form (CTRS-R:S).
Results: "The mean ADHD-RS scores at baseline for the continuation and discontinuation groups, respectively, were 21.4 (SD = 9.7) and 19.6 (SD = 8.9); after 7 weeks, the mean scores were 21.9 (SD = 10.8) and 24.7 (SD = 11.4), with a significant between-group difference in change over time of −4.6 (95% CI = −8.7, −0.56) in favor of the group that continued methylphenidate treatment. The ADHD-RS inattention subscale and the CTRS-R:S ADHD index and hyperactivity subscale also deteriorated significantly more in the discontinuation group. The CGI-I indicated worsening in 40.4% of the discontinuation group, compared with 15.9% of the continuation group."
Editorial: "Clearly, this study demonstrates that stimulant administration remains generally effective over 2 years of treatment; but what about the fact that 60% of those who were transitioned to placebo 'did not worsen,'" asks an editorialist (pp. 685–6; S. R. Pliszka, pliszka@uthscsa.edu). "Will this finding result in headlines announcing that '60% of children with ADHD can be taken off medication after 2 years?' This conclusion would be premature, to say the least. All clinicians have had the experience of parents who have not restarted stimulant medication at the start of the school year, only to be called after the first 6-week grading period to restart medication because their child was failing several classes. The authors are correct in their conclusion that patients with ADHD should be assessed at least annually to see if discontinuation is possible, particularly for adolescents who seem to be functioning well when off medication. The medication should be restarted at the first sign of relapse."
Substance-Induced Psychotic Disorders/Schizophrenia: "Schizophrenia following substance-induced psychosis is likely a drug-precipitated disorder in highly vulnerable individuals, not a syndrome predominantly caused by drug exposure," conclude investigators who studied the Swedish medical registries from 1997 to 2015 (pp. 711–9; K. S. Kendler). "Substance-induced psychotic disorder appears to result from substantial drug exposure in individuals at high familial risk for substance abuse and moderately elevated familial risk for psychosis. Familial risk for psychosis, but not substance abuse, predicts progression from substance-induced psychosis to schizophrenia."
"These findings provide a data basis for psychoeducation and close follow-up of individuals with substance-induced psychotic disorders," editorialists write (pp. 683–4; R. Tandon, rajiv.tandon@med.wmich.edu). "Furthermore, they reinforce the need for effective treatment of substance-induced psychotic disorder with appropriately selected antipsychotic agents. They also rekindle the controversy about whether cannabis use causes schizophrenia or merely precipitates the onset of schizophrenia in individuals predisposed to developing the condition. An answer to that question is of high significance in the context of increasing availability of medical and recreational cannabis in the United States and across the world "
* An acetate derivative of vitamin E has been identified in most of the marijuana products used by people with vaping-related pulmonary disease, the Washington Post reports. The derivative is an oil, which could account for the cough and shortness of breath symptoms seen with the syndrome. The CDC has scheduled a media briefing for later today on this topic.
Source: Sept. 7 issue of Lancet (2019; 394).
Guselkumab in Moderate-to-Severe Psoriasis: Compared with the interleukin (IL)-17A inhibitor secukinumab in patients with moderate-to-severe psoriasis, the IL-23p19 inhibitor guselkumab showed superior long-term efficacy in a 48-week trial (pp. 831–9; K. Reich, k.reich@uke.de).
PICO: Phase 3, double-blind, randomized trial of 1,048 adults with moderate-to-severe plaque-type psoriasis; guselkumab 100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab 300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks; primary endpoint of proportion of patients achieving 90% reduction in Psoriasis Area and Severity Index (PASI 90 response) at week 48.
Results: "The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p <0.0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p = 0.0616).… Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations."
Treatment of Hypothyroidism: While some adverse health outcomes were evident among patients with elevated thyroid stimulating hormone (TSH) levels, maintenance within recommended limits made no "clinically meaningful difference" to long-term health outcomes in a study of 162,369 patients with hypothyroidism (l4892; K. Nirantharakumar, K.Nirantharan@bham.ac.uk).
PICO: Adults with incident hypothyroidism in 1995–2017; longitudinal TSH concentrations; disease risk and mortality.
Results: "We found no difference in mortality rates within the recommended normal TSH range of 0.4–4 mIU/L; however, mortality was higher in the lowest TSH category (<0.1 mIU/L) and for concentrations above 4 mIU/L. Similarly, we observed no increase in risk of ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, and fractures in patients with hypothyroidism across TSH concentrations within the specified normal range. The risk of heart failure was elevated when TSH was above 10 mIU/L and lower when TSH was below 0.4 mIU/L. Interestingly, we found a higher risk of fragility fractures for TSH above 10 mIU/L, driven predominantly by women and patients aged over 65 years."
* Based on available information regarding lung illness associated with use of e-cigarette products, the CDC recommends that youth, young adults, and pregnant women not use e-cigarette products, and that adults who do not already use tobacco products not start e-cig use.
* Nintedanib (Ofev, Boehringer Ingelheim) capsules were approved on Friday by FDA to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with systemic sclerosis or scleroderma.
* Hospira is voluntarily recalling lot W20308 of Bacteriostatic Water for Injection, USP, 30 mL, multidose vials to the hospital/retail level because of lack of confirmation of sterilization for some vials.
* Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin— Preliminary Report, in New England Journal of Medicine, 2019: 10.1056/NEJMoa1911614. (J. E. Layden, jennifer.layden@illinois.gov)
* Vaping-Induced Lung Injury [editorial], in New England Journal of Medicine, 2019: 10.1056/NEJMe1912032. (D. C. Christiani)
* Fluid Management in Acute Kidney Injury, in Chest, 2019; 156: 594–603. (M. Ostermann, marlies.ostermann@gstt.nhs.uk)
* Direct-Acting Oral Anticoagulants in Critically Ill Patients, in Chest, 2019; 156: 604–18. (L. Moores, lisa.moores@usuhs.edu)
* 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, in Journal of the American College of Cardiology, 2019; 74: 10.1016/j.jacc.2019.03.010. (D. K. Arnett)
Sept. 10, 2019 * Vol. 26, No. 174
Source: Early-online articles from and Sept. issue of JAMA Internal Medicine (2019; 179).
Electronic Cigarette Use & Smoking Reduction: In France in the CONSTANCES (Consultants des Centres d'Examens de Santé study, use of electronic cigarettes (ECs) was "associated with a decrease in smoking level and an increase in smoking cessation attempts but also with an increase in the level of smoking relapse in the general population after approximately 2 years of follow-up" (pp. 1193–200; R. Gomajee, ramchandar.gomajee@inserm.fr).
PICO: Cohort study of 5,400 smokers and 2,025 former smokers at baseline who quit smoking since ECs were introduced in France in 2010 and were followed for nearly 2 years; main outcome measure of association between EC use and the number of cigarettes smoked during follow-up.
Results: "Among the 5,400 daily smokers (2,906 women and 2,494 men; mean [SD] age, 44.9 [12.4] years), regular EC use was associated with a significantly higher decrease in the number of cigarettes smoked per day compared with daily smokers who did not use ECs (–4.4 [95% CI, –4.8 to –3.9] vs –2.7 [95% CI, –3.1 to –2.4]), as well as a higher adjusted relative risk of smoking cessation (1.67; 95% CI, 1.51–1.84]). At the same time, among the 2,025 former smokers (1,004 women and 1,021 men; mean [SD] age, 43.6 [12.1] years), EC use was associated with an increase in the rate of smoking relapse among former smokers (adjusted hazard ratio, 1.70; 95% CI, 1.25–2.30)."
Improving Adverse Event Reporting for Compounded Drugs: Commenting on problems with unreported adverse events involving compounded drugs (see related statement below in PNN NewsWatch), FDA officials write, "In view of the lower regulatory standard for compounded products and increased risk that such unapproved products present, the FDA plans to take concerted steps to improve adverse event reporting and analyses" (10.1001/jamainternmed.2019.3830; J. Kim, jenny.kim@fda.hhs.gov). "As part of this initiative, the FDA has contracted with the National Academy of Sciences, Engineering, and Medicine to conduct a study on the risks associated with compounded hormones. This study, expected in 2020, will inform the FDA's regulatory decision-making, including its review of labeling and marketing materials. Dissemination of the study findings may increase public awareness about such products, including any safety risks that clinicians and patients should consider. The FDA also plans to work with outsourcing facilities to improve mechanisms for obtaining reports of adverse events associated with their products and for subsequent adverse event reporting to the agency. The FDA is also prioritizing its statutory obligation to make available a memorandum of understanding under which states would investigate complaints of adverse events associated with certain compounded drug products and report them to the agency"
* Seeking to help protect patients from poor-quality compounded drugs while preserving access to lawfully marketed compounded drugs for patients who have a medical need for them, FDA yesterday issued a statement on adverse event reporting of compounded drugs focused on hormones prepared in the form of pellets. "Compounded bioidentical hormone replacement therapy (BHRT) products such as progesterone and testosterone, are used at times instead of FDA-approved drugs for hormone replacement therapy," the agency said. "Some compounders market BHRT products as superior to FDA-approved drugs by making assertions that they are more natural, safer, or better for patients than FDA-approved drug products."
* FDA said yesterday that it has issued a warning letter to JUUL Labs for marketing unauthorized modified risk tobacco products by engaging in labeling, advertising, and/or other activities directed to consumers, including a presentation given to youth at a school. The agency also sent a letter to the company expressing concern and requesting more information about several issues raised in a recent Congressional hearing regarding JUUL's outreach and marketing practices, including those targeted at students, tribes, health insurers, and employers.
Source: Sept. 10 issue of JAMA (2019; 322).
Treating Inflammation in Uveitis: In the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial, first-line corticosteroid-sparing treatment with mycophenolate mofetil was not more effective than with methotrexate, researchers report (pp. 936–45; N. R. Acharya, Nisha.Acharya@ucsf.edu).
PICO: Adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy in five countries in 2013–17, with follow-up to 2018; oral methotrexate 25 mg weekly or oral mycophenolate mofetil 3 g daily; primary outcome of treatment success at 6 months (control of inflammation in both eyes, no more than prednisone 7.5 mg daily and 2 or fewer drops of prednisolone acetate 1%, and no treatment failure due to safety or intolerability).
Results: "Among 216 patients who were randomized (median age, 38 years; 135 (62.5%) women), 194 (89.8%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7%) patients in the methotrexate group vs 56 (57.1%) in the mycophenolate group (difference, 9.5% [95% CI, −5.3% to 21.8%]; odds ratio [OR], 1.50 [95% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4%) in the methotrexate group vs 42 (55.3%) in the mycophenolate group (difference, 19.1% [95% CI, 3.6% to 30.6%]; OR, 2.35 [95% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3%) in the methotrexate group vs 14 (63.6%) in the mycophenolate group (difference, −30.3% [95% CI, −51.6% to 1.1%]; OR, 0.29 [95% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0%) in the methotrexate group and 8 patients (7.4%) in the mycophenolate group."
Oral HPV Herd Protection in Unvaccinated Americans: "Vaccine-type oral HPV prevalence declined by 37% between 2009–2010 and 2015–2016 in a sample of unvaccinated U.S. men aged 18 to 59 years, suggesting herd protection against oral HPV infections," a study concludes (pp. 977–9; M. L. Gillison, mgillison@mdanderson.org).
PICO: Oral HPV infections in unvaccinated U.S. men and women aged 18 to 59 years via temporal (2009–16) comparisons of oral HPV prevalence for 4 vaccine types (HPV-16/-18/-6/-11) and 33 nonvaccine types in 4 cycles of the National Health and Nutrition Examination Survey (NHANES).
Results: "HPV vaccination rates increased from 0% to 5.8% in men and from 7.3% to 15.1% in women.… Vaccine-type oral HPV prevalence declined from 2.7% during 2009–2010 to 1.6% during 2015–2016 in unvaccinated men aged 18 to 59 years (adjusted prevalence ratio [PR], 0.63 [95% CI, 0.44–0.90]; P= .009 for trend). This decline was not heterogeneous by age (P = .41 for interaction). Prevalence of nonvaccine-type oral HPV infections remained unchanged in unvaccinated men aged 18 to 59 years (8.6% in 2009–2010 vs 8.4% in 2015–2016; adjusted PR, 1.02 [95% CI, 0.79–1.33]; P = .66 for trend).
"In unvaccinated women aged 18 to 59 years, oral HPV prevalence remained unchanged for vaccine types (0.6% in 2009–2010 vs 0.5% in 2015–2016; adjusted PR, 0.96 [95% CI, 0.23–3.98]; P = .79 for trend) and for nonvaccine types (2.6% in 2009–2010 vs 3.3% in 2015–2016; adjusted PR, 1.29 [95% CI, 0.71–2.35]; P = .58 for trend) "
Direct-to-Consumer Telemedicine: "The activities of [direct-to-consumer (DTC) telemedicine] companies have [thus far] been limited to a relatively short list of conditions or medications," authors write (pp. 925–6; A. Mehrotra, Mehrotra@hcp.med.harvard.edu). "However, it is clear that the companies want to expand to more complex acute care and disease management; for example, Lemonaid Health has expanded to include laboratory testing. Some companies envision a transformation of their platforms into 1-stop shops for comprehensive care. For example, the Hims founder stated his intention for the company to become a holistic source of health care not only for prescriptions, but also for 'information, advice, and comfort.' As DTC telemedicine companies continue to expand, it will be imperative for physicians, other health care professionals, and policy makers to monitor these new treatment options to ensure convenience does not come at the expense of quality."
Source: Sept. 12 issue of the New England Journal of Medicine (2019; 381).
Roxadustat Treatment for Anemia: In two studies, the oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase roxadustat (FG-4592) was effective for treating anemia in patients with chronic kidney disease who were off or on dialysis, researchers report.
PICO—Study 1: Phase 3 trial in China of 154 patients with chronic kidney disease who were not undergoing dialysis; randomized to double-blind roxadustat or placebo three times a week for 8 weeks followed by 18-week open-label phase; hemoglobin 7.0–10.0 g/dL at baseline; primary end point of mean change from baseline in hemoglobin level, averaged over weeks 7 through 9 (pp. 1001–10; N. Chen, nanchenmd@hotmail.com).
Results—Study 1: "During the primary-analysis period, the mean (± SD) change from baseline in the hemoglobin level was an increase of 1.9 ± 1.2 g per deciliter in the roxadustat group and a decrease of 0.4 ± 0.8 g per deciliter in the placebo group (P <0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14 ± 63.40 ng per milliliter in the roxadustat group and 15.10 ± 48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period."
PICO—Study 2: Trial of 305 patients in China who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks; randomized to roxadustat or epoetin alfa three times per week for 26 weeks; primary end point of mean change in hemoglobin level from baseline to the average level during weeks 23 through 27 (pp. 1011–22; N. Chen, nanchenmd@hotmail.com).
Results—Study 2: "Roxadustat led to a numerically greater mean (± SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7 ± 1.1 g per deciliter) than epoetin alfa (0.5 ± 1.0 g per deciliter) and was statistically noninferior (difference, 0.2 ± 1.2 g per deciliter; 95% confidence interval [CI], −0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, −22 mg per deciliter; 95% CI, −29 to −16), as was the decrease in low-density lipoprotein cholesterol (difference, −18 mg per deciliter; 95% CI, −23 to −13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, −64.8 to −13.6), as compared with 2.3 ng per milliliter (95% CI, −51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group."
Editorial: "Although the present trials indicate that roxadustat effectively treated anemia while reducing hepcidin levels and maintaining lower levels of erythropoietin, adverse events may yet appear when larger, longer trials are completed," writes an editorialist (pp. 1070–2; J. Kaplan). "Accordingly, it is reasonable to await in-progress trials (ClinicalTrials.gov numbers, NCT02273726. and NCT01750190) and to proceed with additional studies reexamining the risks and benefits of normalization of the hemoglobin level in patients with anemia of chronic kidney disease and carefully monitoring for as yet unappreciated problems with HIF prolyl hydroxylase inhibitors. If HIF prolyl hydroxylase inhibitors fulfill their promise and facilitate normalization of hemoglobin levels in patients with chronic kidney disease and reduce cardiovascular morbidity related to anemia without the increased risks that have been seen in trials of erythropoietin-stimulating agents, there might ultimately be a revolution in the treatment of anemia of chronic kidney disease."
>>>Circulation Highlights
Source: Sept. 10 issue of Circulation (2019; 140).
CETP Inhibitor Genotypes: Seeking to determine whether cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 genotype, the REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) "provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of … anacetrapib" (pp. 891–8; J. C. Hopewell, jemma.hopewell@ndph.ox.ac.uk). "The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib," the authors note.
PICO: Individuals with stable atherosclerotic vascular disease being treated with intensive atorvastatin therapy were randomized to anacetrapib 100 mg daily or matching placebo; primary outcome of major vascular events (composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype.
Results: "Among 19,210 genotyped individuals of European ancestry, 2,504 (13.0%) had a first major vascular event during 4 years median follow-up: 1,216 (12.6%) among anacetrapib-allocated participants and 1,288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: hazard ratio (HR) = 0.92 (95% CI, 0.81–1.05) for GG; HR = 0.94 (95% CI, 0.84–1.06) for AG; and HR = 0.93 (95% CI, 0.76–1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib."
Source: Sept. 17 issue of the Journal of the American College of Cardiology (2019; 74).
LDL Cholesterol & Risks of PAD, CKD: Elevated levels of LDL cholesterol (LDL-C) are causally involved in pathogenesis of chronic kidney disease (CKD) and peripheral arterial disease (PAD) researchers report, but not with development of retinopathy and neuropathy (pp. 1465–76; M. Benn; marianne.benn@regionh.dk).
PICO: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the U.K. Biobank (n = 408,455); meta-analysis of randomized statin trials (n = 64,134).
Results: "Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy."
Oral Fluoroquinolones & Mitral/Aortic Regurgitation: In addition to other adverse cardiac effects, fluoroquinolones (FQs) are linked to increased risk of aortic and mitral regurgitation during current or recent use (pp. 1444–50; M. Etminan, etminanm@mail.ubc.ca).
PICO: Disproportionality analysis using a random sample of FDA adverse reporting system database.
Results: "[Among] 12,505 cases and 125,020 control subjects … the adjusted RRs for current users of FQ compared with amoxicillin and azithromycin users were 2.40 (95% CI: 1.82 to 3.16) and 1.75 (95% CI: 1.34 to 2.29), respectively. The adjusted RRs for recent and past FQ users when compared with amoxicillin were 1.47 (95% CI: 1.03 to 2.09) and 1.06 (95% CI: 0.91 to 1.21), respectively."
H. pylori Treatment, Vitamin/Garlic Supplements & Gastric Cancer: A statistically significant reduction in risk of mortality from gastric cancer for more than 22 years is associated with Helicobacter pylori treatment for 2 weeks and vitamin or garlic supplementation for 7 years, researchers report (l5016; K.-F. Pan, pankaifeng2002@yahoo.com).
PICO: In a Chinese province with a high incidence of gastric cancer, a blinded randomized placebo-controlled trial, 2,258 residents positive for H. pylori received treatment (amoxicillin plus omeprazole), vitamin (C, E, and selenium) supplements, garlic supplements, or their placebos for 7.3 years in 1995–2003; 1,107 H. pylori–negative participants received vitamin or garlic supplements or their placebos during those years; primary outcomes of cumulative incidence of gastric cancer through 2017.
Results: "151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995–2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease."
Total or Type 2 Diabetes Incidence: The proportions of people diagnosed with clinical diabetes has plateaued or fallen in most populations since 2006, according to findings of a systematic review (l5003; D. J. Magliano, dianna.magliano@baker.edu.au).
PICO: Studies reporting trends of diabetes incidence in adults from 1980 to 2017 conducted according to PRISMA guidelines and using open population based cohorts, diabetes registries, and administrative/health insurance databases; secular trends in incidence of total diabetes or type 2 diabetes in adults.
Results: "Among the 22,833 screened abstracts, 47 studies were included, providing data on 121 separate sex specific or ethnicity specific populations; 42 (89%) of the included studies reported on diagnosed diabetes. In 1960–89, 36% (8/22) of the populations studied had increasing trends in incidence of diabetes, 55% (12/22) had stable trends, and 9% (2/22) had decreasing trends. In 1990–2005, diabetes incidence increased in 66% (33/50) of populations, was stable in 32% (16/50), and decreased in 2% (1/50). In 2006–14, increasing trends were reported in only 33% (11/33) of populations, whereas 30% (10/33) and 36% (12/33) had stable or declining incidence, respectively."
* Low levels of the carcinogen N-nitrosodimethylamine have been detected in ranitidine products, FDA said on Friday, including some marketed under the brand name Zantac.
* Comparative Efficacy and Tolerability of 32 Oral Antipsychotics for the Acute Treatment of Adults With Multi-Episode Schizophrenia: A Systematic Review and Network Meta-analysis, in Lancet, 2019; 394: 939–51. (M. Huhn, maximilian.huhn@tum.de)
* Clinical Practice Guidelines and Consensus Statements About Pain Management in Critically Ill End-of-Life Patients: A Systematic Review, in Critical Care Medicine, 10.1097/CCM.0000000000003975. (A. Durán-Crane)
* Pathophysiology and Management of Hyperammonemia in Organ Transplant Patients, in American Journal of Kidney Diseases, 2019; 74: 390–8. (H. Seethapathy, hseethapathy@bwh.harvard.edu)
* The Use of Erythropoiesis-Stimulating Agents in Patients With CKD and Cancer: A Clinical Approach, in American Journal of Kidney Diseases, 10.1053/j.ajkd.2019.04.022. (M. J. Choi, michael.choi@gunet.georgetown.edu)
Blood Cultures in Severe Sepsis & Timing of Antimicrobial Administration: Sensitivity of blood cultures is reduced during the time period shortly after administration of antimicrobial agents in patients with severe manifestations of sepsis, researchers report (10.7326/M19-1696; M. P. Cheng, mcheng@bwh.harvard.edu).
PICO: Patient-level, single-group, diagnostic study conducted at 7 emergency departments in North America in 325 adults with severe manifestations of sepsis (systolic blood pressure <90 mm Hg or serum lactate level ≥4 mmol/L); outcome of results of blood cultures before and within 120 minutes after initiation of antimicrobial treatment.
Results: "Preantimicrobial blood cultures were positive for 1 or more microbial pathogens in 102 of 325 (31.4%) patients. Postantimicrobial blood cultures were positive for 1 or more microbial pathogens in 63 of 325 (19.4%) patients. The absolute difference in the proportion of positive blood cultures between pre- and postantimicrobial testing was 12.0% (95% CI, 5.4% to 18.6%; P <0.001). Sensitivity of postantimicrobial culture was 52.9% (CI, 42.8% to 62.9%). When the results of other microbiological cultures were included, microbial pathogens were found in 69 of 102 (67.6% [CI, 57.7% to 76.6%]) patients."
Editorial: "While acknowledging the diagnostic value of obtaining blood cultures before antimicrobial agents are administered, it is crucial to prevent unintentional treatment delays, particularly given the increased risk for death associated with delaying anti-infective treatment," editorialists write (10.7326/M19-2489; M. D. Siegel, mark.siegel@yale.edu). "In contrast to other, more time-consuming procedures done to obtain cultures, such as lumbar puncture, blood cultures can generally be obtained in a few minutes, assuming standard equipment and qualified personnel are available.… In the future, one can imagine new molecular techniques that would be more sensitive than traditional blood cultures, which may yield sufficient information, even after antimicrobial agents are administered. If more sensitive techniques do come into widespread use, we will likely be prompted to ask again if it is necessary to withhold antibiotics until testing is done. Until then, we would advise clinicians to quickly obtain blood cultures and, immediately after that, to give patients the crucial antimicrobial agents they need to achieve the best possible hope of survival."
Personalized Predictions for Aspirin in Primary Prevention: Individualized benefit–harm analysis shows that personalized predictions can identify some people without cardiovascular disease (CVD) who will benefit from aspirin therapy (10.7326/M19-1132; V. Selak, v.selak@auckland.ac.nz).
PICO: Individualized benefit–harm analysis based on sex-specific risk scores and estimates of the proportional effect of aspirin on CVD and major bleeding from a 2019 meta-analysis; 245,028 persons (43.6% women) aged 30 to 79 years without established CVD who had their CVD risk assessed between 2012 and 2016 at New Zealand primary care sites.
Results: "2.5% of women and 12.1% of men were likely to have a net benefit from aspirin treatment for 5 years if 1 CVD event was assumed to be equivalent in severity to 1 major bleed, increasing to 21.4% of women and 40.7% of men if 1 CVD event was assumed to be equivalent to 2 major bleeds. Net benefit subgroups had higher baseline CVD risk, higher levels of most established CVD risk factors, and lower levels of bleeding-specific risk factors than net harm subgroups."
Editorial: "Given [the] diversity of findings and recommendations, establishing firm, evidence-based recommendations for aspirin use in primary prevention is difficult," (10.7326/M19-2475; J. B. Kostis, kostis@rwjms.rutgers.edu). "It seems reasonable to recommend aspirin for the primary prevention of CVD in select patients, including those who are at high risk for CVD, provided that the bleeding risk is low, as evidenced by a history of bleeding and comorbid conditions."
* Fitoterapia USA is voluntarily recalling 19,000 bottles of Macho Artificial Passion Fruit Flavored Vitamin C Liquid Supplement to the consumer level because of presence of tadalafil, FDA said.
ARNI Therapy in HF With Reduced Ejection Fraction: Angiotensin receptor–neprilysin inhibition (ARNI) therapy in patients with heart failure with reduced ejection fraction (HFrEF) is assessed in two trials — the EVALUATE-HF trial (pp. 1077–84; S. D. Solomon, ssolomon@bwh.harvard.edu) and the PROVE-HF study (pp. 1085–95; J. L. Januzzi Jr., JJanuzzi@partners.org).
EVALUATE-HF PICO: Randomized, double-blind clinical trial of 464 U.S. participants with heart failure and ejection fraction of 40% or less in 2016–18; follow-up through early 2019; sacubitril-valsartan (target dosage, 97/103 mg twice daily) or enalapril (target dosage, 10 mg twice daily) for 12 weeks; primary outcome of change from baseline in aortic characteristic impedance (Zc), a measure of central aortic stiffness.
EVALUATE-HF Results: "There was no significant difference in the change in aortic characteristic impedance at 12 weeks among patients treated with sacubitril-valsartan vs enalapril (−2.9 vs −0.7 dyne × s/cm5)."
PROVE-HF PICO: Prospective, 12-month, single-group, open-label study of U.S. patients with HFrEF; dose-adjusted sacubitril-valsartan in 2016–18; primary outcome of the correlation between changes in log2–NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e-prime) at 12 months.
PROVE-HF Results: "Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332–1822) and 455 pg/mL (IQR, 153–1090) at 12 months (difference, P < .001). At 12 months, the change in log2–NT-proBNP concentration was correlated with changes in LVEF (r = −0.381 [IQR, −0.448 to −0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e-prime (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, −12.25 mL/m2 [IQR, −12.92 to −11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, −15.29 mL/m2 [95% CI, −16.03 to −14.55]; P < .001). LAVI and E/e-prime ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%)."
Editorial: "The PROVE-HF study and the EVALUATE-HF trial reported in this issue of JAMA together strongly suggest that ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF," writes an editorialist (pp. 1051–3; M. H. Drazner, mark.drazner@utsouthwestern.edu). "Although neither investigation assessed this question as its primary end point, and one study was observational in nature, the replication of the reduction in left ventricular volumes, left atrial volumes, and E/e-prime ratio in these 2 reports, as well as the large, progressive increase in left ventricular ejection fraction in PROVE-HF, are important. As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes this condition."
* FDA yesterday announced Project Orbis, an initiative that provides a framework for concurrent submission and review of oncology drugs among several international partners. FDA, the Australian Therapeutic Goods Administration, and Health Canada collaboratively reviewed applications for two oncology drugs, allowing for simultaneous approvals for lenvatinib (Lenvima) in combination with pembrolizumab (Keytruda; Eisai and Merck Sharp & Dohme) for treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
Antithrombotic Therapy in Patients With AF/Stable Coronary Disease: Compared with combination therapy in patients with atrial fibrillation and stable coronary artery disease, rivaroxaban monotherapy was noninferior for efficacy and superior for safety, report AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) investigators (pp. 1103–13; S. Yasuda, yasuda.satoshi.hp@ncvc.go.jp).
PICO: Multicenter, open-label Japanese trial of 2,236 patients with atrial fibrillation who had undergone percutaneous coronary intervention or coronary-artery bypass grafting more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization; randomized to monotherapy with rivaroxaban or combination therapy with rivaroxaban plus a single antiplatelet agent; primary efficacy end point of composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; primary safety end point of major bleeding.
Results: "The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P <0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority)."
Editorial: "[Current] recommendations apply only to patients who have a combination of atrial fibrillation and active coronary disease," an editorialist writes (pp. 1169–70; R. C. Becker). "They do not address the question of how to treat patients with atrial fibrillation who have stable coronary disease. Do the collective data from the AFIRE and OAC-ALONE trials provide definitive guidance for clinicians who are treating patients in this population? In my judgment, they do add an element of support for current guidelines and underscore the potential effect of direct oral anticoagulants on the pathobiology of coronary artery disease and cardioembolic events in patients with atrial fibrillation, but they fall short of securing level 1 and class A evidence. Further investigation will be required."
Polypill for Cardiovascular Disease Prevention: Compared with usual care, a polypill strategy significantly reduced systolic blood pressure and LDL cholesterol level in a socioeconomically vulnerable minority population (pp. 1114–23; T. J. Wang, thomas.j.wang@vumc.org).
PICO: Randomized, controlled trial of adults without cardiovascular disease; assigned to polypill (atorvastatin 10 mg, amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg) or usual-care group at a federally qualified community health center in Alabama; two primary outcomes of the changes from baseline in systolic blood pressure and low-density lipoprotein (LDL) cholesterol level at 12 months.
Results: "The trial enrolled 303 adults, of whom 96% were black. Three quarters of the participants had an annual income below $15,000. The mean estimated 10-year cardiovascular risk was 12.7%, the baseline blood pressure was 140/83 mm Hg, and the baseline LDL cholesterol level was 113 mg per deciliter. The monthly cost of the polypill was $26. At 12 months, adherence to the polypill regimen, as assessed on the basis of pill counts, was 86%. The mean systolic blood pressure decreased by 9 mm Hg in the polypill group, as compared with 2 mm Hg in the usual-care group (difference, −7 mm Hg; 95% confidence interval [CI], −12 to −2; P = 0.003). The mean LDL cholesterol level decreased by 15 mg per deciliter in the polypill group, as compared with 4 mg per deciliter in the usual-care group (difference, −11 mg per deciliter; 95% CI, −18 to −5; P <0.001)."
* Distribution of generic formulations of ranitidine has been halted worldwide by Sandoz, according to media reports. FDA reported last week that some ranitidine products have trace amounts of the carcinogen NDMA (see PNN, Sept. 16).
Source: Oct. 1 issue of Clinical Infectious Diseases (2019; 69).
Antibiotic Treatment Length for Uncomplicated Gram-Negative Bacteremia: "Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention," conclude authors who compared 7- and 14-day regimens (pp. 1091–8; D. Yahav, dafna.yahav@gmail.com).
PICO: Randomized, multicenter, open-label, noninferiority trial of 604 inpatients in Israel and Italy with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours; randomized to 7 (intervention) or 14 days (control) of covering antibiotic therapy; primary outcome of 90-day composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days).
Results: "The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, –2.6% [95% confidence interval, –10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm."
>>>Vaccine Highlights
Source: Sept. 30 issue of Vaccine (2019; 37).
Clinical Trials of GMO-Containing Vaccines in Europe: "Regulatory requirements associated with the development of genetically-modified organism (GMO)–containing vaccines in Europe add an additional burden to the clinical trial application procedure and to the preparation and initiation of a clinical trial of such vaccines," write authors of a review article (pp. 6144–53; S. Mali, Stephanie.Mali@fagg-afmps.be). "Recombinant technology has revolutionised the way novel vaccines are developed and manufactured. The possibility to genetically modify micro-organisms to bring immunogenic material (antigens/epitopes) to the human (or animal) immune system to provoke an immune response, provides new hope to producing prophylactic vaccines against HIV, malaria and tuberculosis and emerging diseases.… The GMO regulatory framework is complex and only partially harmonised across Europe, which may hamper multi-country clinical trials with GMO-containing vaccines. This paper provides an overview of clinical trial applications with GMO-containing vaccines in Europe and reviews the regulatory framework in countries where GMO-containing vaccine clinical trial authorisation applications were submitted between 2004 and 2017."
Profitability of Adult Vaccines in American Private Practices: Analysis of adult vaccinations offered in 13 private physician practices showed that 10 had a positive annual income, but the median annual incomes varied from less than $3,000 in obstetrics/gynecology to $90,000 in family medicine (pp. 6180–5; B. Yarnoff, byarnoff@rti.org).
PICO: Convenience sample of 13 practices in 2017; cost and payment data, time-motion study, and survey of practice managers.
Results: "Median annual total income from vaccination services was $90,343 at family medicine practices (range: $3,968–$249,628), $28,267 at internal medicine practices (−$32,659–$141,034) and $2,886 at obstetrics and gynecology practices (−$73,451–$23,820). Adult vaccination was profitable at the median of our sample, but there is wide variation in profitability due to differences in costs and payment rates across practices."
* Stepping up its response to the growing number of people with lung injury associated with use of e-cigarettes, the CDC yesterday held a telebriefing on the topic. "CDC, FDA and its state partners are engaged in a complex investigation that spans many states, involves hundreds of cases, and involves a wide variety of substances and products," CDC Director Robert R. Redfield, MD, said in a statement. "What we do know is that all cases have one thing in common: the use of e-cigarettes or vaping devices. Most of the cases reported using THC or both THC and nicotine. Some of the cases have reported using only nicotine."
Source: Sept. 21 issue of Lancet (2019; 394).
Oral Antihypertensives for Severe Hypertension in Pregnancy: Three oral antihypertensive drugs are viable initial options for treating severe hypertension of pregnancy in low-resource settings, researchers report (pp. 1011–21; H. Bracken, hbracken@gynuity.org).
PICO: Multicenter, parallel-group, open-label, randomized controlled trial of hourly oral nifedipine 10 mg, hourly oral labetalol 200 mg, or a single dose of methyldopa 1000 mg in adult pregnant women at two Indian hospitals; primary outcome of blood pressure control (120–150 mm Hg systolic blood pressure and 70–100 mm Hg diastolic blood pressure) within 6 h with no adverse outcomes.
Results: "The primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p = 0.03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p = 0.05) or the labetalol and methyldopa groups (p = 0.80). Seven serious adverse events (1% of births) were reported during the study: one (<1%) woman in the labetalol group had an intrapartum seizure and six (1%) neonates (one [<1%] neonate in the nifedipine group, two [1%] neonates in the labetalol group, and three [1%] neonates in the methyldopa group) were stillborn. No birth had more than one adverse event."
Cardiovascular Risks in Adult Cancer Survivors: Survivors of 20 adult cancers have increased risk of cardiovascular diseases over a medium to long time period, a study shows (pp. 1041–54; K. Bhaskaran, krishnan.bhaskaran@lshtm.ac.uk).
PICO: Population-based cohort study using the U.K. Clinical Practice Research Datalink to identify risks for cardiovascular disease outcomes in adults who were alive 12 months after diagnosis with any of 20 site-specific cancers.
Results: "Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1.72 (95% CI 1.57–1.89) in patients after prostate cancer to 9.72 (5.50–17.18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological (adjusted HR 1.94, 1.66–2.25, with non-Hodgkin lymphoma; 1.77, 1.50–2.09, with leukaemia; and 3.29, 2.59–4.18, with multiple myeloma), oesophageal (1.96, 1.46–2.64), lung (1.82, 1.52–2.17) kidney (1.73, 1.38–2.17) and ovarian (1.59, 1.19–2.12). Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy."
* Semaglutide (Rybelsus, Novo Nordisk), the first oral glucagon-like peptide-1, has been approved by FDA for use in adults with type 2 diabetes with diet and exercise to improve control of blood glucose. The company said FDA is still reviewing an NDA for semaglutide for an additional indication to reduce the risk of major adverse cardiovascular events such as heart attack, stroke, or cardiovascular death in adults with type 2 diabetes and established cardiovascular disease; a decision is expected in the first quarter of 2020.
* Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial, in Annals of Internal Medicine, 2019; 171: 406–14. (J. E. Manson, jmanson@rics.bwh.harvard.edu)
* Sodium–Glucose Cotransporter-2 Inhibitors: Lack of a Complete History Delays Diagnosis, in Annals of Internal Medicine, 2019; 171: 421–6. (B. R. Leslie, seventhdoctor@gmail.com)
* The Prevention of Infections in Older Adults: Oral Health, in Journal of the American Geriatrics Society, 2019; 10.1111/jgs.16154. (P. Coll, coll@uchc.edu)
Source: Early-online articles from the Journal of the American Geriatrics Society (2019; 67).
Physician Perspectives on Deprescribing in Older Adults: Those implementing deprescribing programs for cardiovascular medications in older adults need to address physician attitudes and related barriers, a study shows, particularly in settings of limited life expectancy (10.1111/jgs.16157; T. S. Anderson, tsander1@bidmc.harvard.edu).
PICO: National cross-sectional survey using a random sample of geriatricians, general internists, and cardiologists from the American College of Physicians that assesses clinical practice of deprescribing cardiovascular medications, reasons and barriers to deprescribing, and choice of medications to deprescribe in hypothetical clinical cases.
Results: "In each specialty, 750 physicians were surveyed, with a response rate of 26% for geriatricians, 26% for general internists, and 12% for cardiologists. Over 80% of respondents within each specialty reported that they had recently considered deprescribing a cardiovascular medication. Adverse drug reactions were the most common reason for deprescribing for all specialties. Geriatricians also commonly reported deprescribing in the setting of limited life expectancy. Barriers to deprescribing were shared across specialties and included concerns about interfering with other physicians' treatment plans and patient reluctance. In hypothetical cases, over 90% of physicians in each specialty chose to deprescribe when patients experienced adverse drug reactions. Geriatricians were most likely and cardiologists were least likely to consider deprescribing cardiovascular medications in cases of limited life expectancy (all P < .001), such as recurrent metastatic cancer (84% of geriatricians, 68% of general internists, and 45% of cardiologists), Alzheimer dementia (92% of geriatricians, 81% of general internists, and 59% of cardiologists), or significant functional impairment (83% of geriatricians, 68% of general internists, and 45% of cardiologists)."
Cognitive Performance Among Older Adults in Japan, U.S.: "Even with large differences in educational attainment and a strong effect of education on cognitive functioning, the overall differences in cognitive functioning between the United States and Japan are modest," investigators conclude (10.1111/jgs.16163; E. M. Crimmins, crimmin@usc.edu). "Differences in health appear to have little effect on national differences in cognition."
PICO: Data on 1,953 Japanese adults and 2,959 U.S. adults, aged 68 years or older, taken from the Nihon University Japanese Longitudinal Study of Aging and the U.S. Health and Retirement Study; episodic memory and arithmetic working memory were measured using immediate and delayed word recall and serial 7s.
Results: "Americans have higher scores on episodic memory than Japanese people (0.72 points on a 20-point scale); however, when education is controlled, American and Japanese people did not differ. Level of working memory was higher in Japan (0.36 on a 5-point scale) than in the United States, and the effect of education on working memory was stronger among Americans than Japanese people. There are no differences over the age of 85 years."
* FDA yesterday issued a final guidance for industry, Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment. "The final guidance includes up-to-date information on our recommendations to help advance the development of products for ALS patients, including recommendations on clinical trial design and ways to measure effectiveness," the agency wrote in an accompanying statement. "We know that an important element of product development is working early and often with researchers and companies to help facilitate their clinical development programs. That's why our final guidance recommends that researchers and companies interact with the FDA early in product development so that we can best advise on proposed development programs and the efficient design of trials to produce the data needed for FDA approval in order to get effective therapies to patients as efficiently as possible. Because this guidance presents nonbinding recommendations for the FDA and sponsors, the FDA is open to considering alternative approaches to meeting our requirements for approval."
Linagliptin & CV Outcomes in Type 2 Diabetes: The dipeptidyl peptidase-4 inhibitor linagliptin, previously shown to be noninferior to placebo in cardiovascular safety trials, was noninferior to the active comparator glimepiride in a trial of adults with relatively early type 2 diabetes (pp. 1155–66; N. Marx, nmarx@ukaachen.de).
PICO: Randomized, double-blind, active-controlled, noninferiority trial of adults with type 2 diabetes who received linagliptin 5 mg or glimepiride 1–4 mg once daily in addition to usual care; primary outcome of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Results: "Of 6,042 participants randomized, 6,033 (mean age, 64.0 years; 2,414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3,023 participants (11.8%) in the linagliptin group and 362 of 3,010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84–1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2,822 participants (93.4%) in the linagliptin group and 2,856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1,132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21–0.26])."
Editorial: "In practice, the risk of hypoglycemia and weight gain with sulfonylureas may be mitigated with individualized glycemic targets and flexible dose adjustment for changes in meal size and physical activity, although these strategies have not been rigorously evaluated," writes an editorialist (pp. 1147–9; D. J. Wexler, dwexler@mgh.harvard.edu). "Further evidence on the comparative effectiveness of glimepiride and a DPP-4 inhibitor, a GLP-1 receptor agonist, and basal insulin, each added to metformin, is expected with the publication of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study in 2022. In the meantime, clinicians can continue to use low-cost sulfonylureas added to metformin for management of hyperglycemia in type 2 diabetes with confidence in their effectiveness for reduction of microvascular complications as well as their cardiovascular safety. The adverse effect profile of sulfonylureas and their very low cost must be balanced against characteristics of other glucose-lowering medications as clinicians consider the best approach for an individual patient."
Metformin & MACE in Diabetes/Reduced Kidney Function: Commenting on a study that shows a lower risk of major adverse cardiovascular events among patients with diabetes and reduced kidney function treated with metformin compared with a sulfonylurea (pp. 1167–77; C. L. Roumie, christianne.roumie@vanderbilt.edu), editorialists advocate for decisions to be made by "informed patients" (pp. 911–2; L. M. Pogach, leonard.pogach@va.gov): "We believe that when presented with a balanced risk-benefit discussion of all 3 agents [metformin, empagliflozin, liraglutide], many if not most patients will choose metformin as the first-line drug in the setting of CKD. However, there is clearly a role for the newer agents, particularly for those patients who need more than 1 agent to treat their diabetes, or for those who are unable to tolerate metformin, or who are no longer appropriate candidates for the medication. The challenge is for clinicians to present clear information to guide patient decisions, based on each patient's clinical circumstances and preferences."
* FDA yesterday announced approval of Smallpox and Monkeypox Vaccine, Live, Non-Replicating (Jynneos, Bavarian Nordic A/S), for prevention of smallpox and monkeypox disease in adults at high risk for infections with these viruses. This vaccine is part of the Strategic National Stockpile (SNS), the nation's largest supply of potentially life-saving pharmaceuticals and medical supplies for use in a public health emergency that is severe enough to cause local supplies to be depleted. The availability of this vaccine in the SNS will help ensure that the vaccine is accessible in the U.S. if needed.
Biologics for Ulcerative Colitis: Studies show effectiveness of ustekinumab in patients with moderate-to-severe ulcerative colitis (pp. 1201–14; B. E. Sands, bruce.sands@mssm.edu) and vedolizumab in moderately to severely active ulcerative colitis (pp. 1215–26; B. E. Sands, bruce.sands@mssm.edu), and an editorial examines use of biologic agents in management of ulcerative colitis.
Study 1 PICO: Placebo-controlled trial of ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis; primary end point of clinical remission in the induction trial (week 8) and the maintenance trial (week 44).
Study 1 Results: "The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P <0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P <0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo."
Study 2 PICO: Phase 3b, double-blind, double-dummy, randomized trial of vedolizumab or adalimumab in adults with moderately to severely active ulcerative colitis; primary outcome of clinical remission at week 52.
Study 2 Results: "At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P <0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, −9.3 percentage points; 95% CI, −18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient–years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient–years."
Editorial: "The findings in both these trials by Sands et al. highlight the importance of alternative biologic treatments and regimens for ulcerative colitis in patients who are not able to receive anti-TNF therapies because of unacceptable side effects or who have disease that is refractory to anti-TNF therapies," (pp. 1279–81; R. J. Farrell). "The cost-effectiveness of all biologics will have to come into sharper focus in future trials and longitudinal studies of biologics to help determine not only their eventual place in the treatment algorithm for moderate-to-severe ulcerative colitis but also the true effect of existing and newer biologics on disease course and rates of colectomy."
* Speaking before the U.S. House of Representatives Energy and Commerce Subcommittee, Acting FDA Commissioner Norman E. "Ned" Sharpless, M.D., made these points about electronic nicotine delivery systems and the outbreak of vaping-related illness: "If we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act. Because many of the products associated with cases contain THC oils, we have engaged the DEA to help with our investigation."
>>>Diabetes Care Report
Source: Oct. issue of Diabetes Care (2019; 42).
Liraglutide & Acute Gallbladder, Biliary Disease: An increased risk of gallbladder- or biliary tract–related events was evident among participants with type 2 diabetes and high risks for cardiovascular (CV) events in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, researchers report (pp. 1912–20; M. A. Nauck, michael.nauck@rub.de).
PICO: International, randomized, double-blind, controlled trial of 9,340 participants with type 2 diabetes at high risk for CV events; randomized to liraglutide or placebo with standard care for 3.5–5 years; post-hoc analysis of time to first event of uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction.
Results: "There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P <0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract–related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract–related events (57% with liraglutide vs. 59% with placebo)."
Sotagliflozin in Type 1 Diabetes: Use of the sodium–glucose cotransporter 1/2 inhibitor (SGLT1i/SGLT2i) sotagliflozin (SOTA) by patients with type 2 diabetes was associated with short- and long-term renal hemodynamic changes similar to those seen with SGLT2i, studies show (pp. 1921–9; D. Cherney, david.cherney@uhn.ca).
PICO: 52-week pooled analysis of 1,575 adults in the inTandem1 and inTandem2 trials who were randomized to SOTA 200 mg, SOTA 400 mg, or placebo in addition to optimized insulin therapy; outcomes of changes in cardiorenal biomarkers.
Results: "At 52 weeks, in response to SOTA 200 and 400 mg, the placebo-corrected least squares mean change from baseline in estimated glomerular filtration rate was −2.0 mL/min/1.73 m2 (P = 0.010) and −0.5 mL/min/1.73 m2 (P = 0.52), respectively. Systolic blood pressure difference was −2.9 and −3.6 mm Hg (P < 0.0001 for both); diastolic blood pressure changed by −1.4 (P = 0.0033) and −1.6 mm Hg (P = 0.0008). In participants with baseline urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, UACR decreased by 23.7% (P = 0.054) and 18.3% (P = 0.18) for SOTA 200 and SOTA 400 mg, respectively, versus placebo. Increases in serum albumin and hematocrit and reductions in uric acid were observed throughout 52 weeks with both SOTA doses."
Linagliptin & Cognitive Performance: In the CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy of patients with type 2 diabetes and cardiorenal disease, linagliptin therapy failed to mitigate decline in cognitive function over 2.5 years (pp. 1930–8; G. J. Biessels, g.j.biessels@umcutrecht.nl).
PICO: Study participants with cardiorenal disease randomized to linagliptin 5 mg or placebo once daily, in addition to standard of care; primary cognitive outcome of occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24.
Results: "Of the 6,979 participants in CARMELINA, CARMELINA-COG included 1,545 (mean ± SD age, 68 ± 8 years; MMSE, 28.3 ± 1.7; estimated glomerular filtration rate, 52 ± 23 mL/min/1.73 m2; and HbA1c, 7.8 ± 0.9% [61.4 ± 10.1 mmol/mol]). Over a median treatment duration of 2.5 years, accelerated cognitive decline occurred in 28.4% (linagliptin) vs. 29.3% (placebo) (odds ratio 0.96 [95% CI 0.77, 1.19]). Consistent effects were observed across subgroups by baseline characteristics. Absolute cognitive performance changes were also similar between treatment groups."
* FDA has expanded the approval of glecaprevir/pibrentasvir (Mavyret, AbbVie) tablets for an 8-week duration for the treatment of treatment-naive adults and certain children with chronic hepatitis C virus genotypes 1–6.
Ticagrelor in Diabetes & Stable Coronary Artery Disease: The risks of cardiovascular death, myocardial infarction, and stroke were reduced by addition of ticagrelor to aspirin in patients with diabetes, stable coronary artery disease, and previous percutaneous coronary intervention (PCI), report Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) investigators (pp. 1169–80; D. L. Bhatt. dlbhattmd@post.harvard.edu).
PICO: Phase 3, randomized, double-blinded, placebo-controlled trial of patients aged 50 years or older, with type 2 diabetes, receiving antihyperglycemic drugs for at least 6 months, with stable coronary artery disease, and other mutually nonexclusive criteria; primary efficacy outcome of a composite of cardiovascular death, myocardial infarction, or stroke.
Results: "In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7.3%] of 5,558 vs 480 [8.6%] of 5,596; HR 0.85 [95% CI 0.74–0.97], p = 0.013). The same effect was not observed in patients without PCI (p = 0.76, p interaction = 0.16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3.1%] with ticagrelor vs 183 (3.3%) with placebo; HR 0.96 [95% CI 0.78–1.18], p = 0.68), as well as all-cause death (282 [5.1%] vs 323 [5.8%]; 0.88 [0.75–1.03], p = 0.11). TIMI major bleeding occurred in 111 (2.0%) of 5,536 patients receiving ticagrelor and 62 (1.1%) of 5,564 patients receiving placebo (HR 2.03 [95% CI 1.48–2.76], p <0.0001), and fatal bleeding in 6 (0.1%) of 5,536 patients with ticagrelor and 6 (0.1%) of 5,564 with placebo (1.13 [0.36–3.50], p = 0.83). Intracranial haemorrhage occurred in 33 (0.6%) and 31 (0.6%) patients (1.21 [0.74–1.97], p = 0.45). Ticagrelor improved net clinical benefit: 519/5,558 (9.3%) versus 617/5,596 (11.0%), HR= 0.85, 95% CI 0.75–0.95, p = 0.005, in contrast to patients without PCI where it did not, p interaction = 0.012. Benefit was present irrespective of time from most recent PCI."
Fenofibrate & Cardiovascular Outcomes in Statin Users: Among patients with metabolic syndrome, the risk of major cardiovascular events was significantly lower with fenofibrate as an add-on to statin treatment than with statin treatment alone, researchers report (l5125; S. G. Kim, k50367@korea.ac.kr).
PICO: Adults in Korea with metabolic syndrome and age ≥40 years receiving statin treatment, including 2,156 participants receiving statin plus fenofibrate and 8,549 on statins only; primary outcome of a composite of cardiovascular events (incident coronary heart disease, ischemic stroke, and death from cardiovascular causes).
Results: "The incidence rate per 1,000 person years of composite cardiovascular events was 17.7 (95% confidence interval 14.4 to 21.8) in the combined treatment group and 22.0 (20.1 to 24.1) in the statin group. The risk of composite cardiovascular events was significantly reduced in the combined treatment group compared with statin group (adjusted hazard ratio 0.74, 95% confidence interval 0.58 to 0.93; P = 0.01). The significance was maintained in the on-treatment analysis (hazard ratio 0.63, 95% confidence interval 0.44 to 0.92; P = 0.02). The risk of incident coronary heart disease, ischaemic stroke, and cardiovascular death was lower in the combined treatment group than statin group but was not significant. Participant characteristics did not appear to be associated with the low risk of composite cardiovascular events with combined treatment."
* FDA on Friday approved rituximab (Rituxan, Genentech) injection, in combination with glucocorticoids, for the treatment of pediatric patients 2 years of age and older with either of two rare blood vessel disorders, granulomatosis with polyangiitis and microscopic polyangiitis.
* A Diet Rich in Vegetables and Fruit and Incident CKD: A Community-Based Prospective Cohort Study, in American Journal of Kidney Diseases, 2019; 74: 491–500. (S. H. Han, hansh@yuhs.ac)
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