Eleanor Lucas

National Trends in Ambulatory Oral Anticoagulant Use

BACKGROUND Four direct oral anticoagulants (DOACs) have been brought to market for the treatment of nonvalvular atrial fibrillation and venous thromboembolism. Many forces, including numerous positive trial results, emerging safety concerns, marketing, and promotion, may shape DOAC adoption by providers. However, relatively little is known regarding their ambulatory utilization compared with warfarin, as well as the degree to which they have decreased under-treatment of atrial fibrillation. METHODS We used the IMS Health National Disease and Therapeutic Index, a nationally representative audit of outpatient office visits, to estimate the use of warfarin and DOACs between 2009 and 2014. RESULTS Overall, visits with anticoagulation use increased from 2.05 (95% confidence interval [CI], 1.82-2.27) to 2.83 (95% CI, 2.49-3.17) million (M) quarterly visits (P < .001). Of these, DOAC use has grown to 4.21M (95% CI, 3.63M-4.79M; 38.2% of total) treatment visits in 2014 since their introduction in 2010. Use of all oral anticoagulants in treatment visits for atrial fibrillation has increased from 0.88M (95% CI, 0.74M-1.02M) to 1.72M (95% CI, 1.47M-1.97M; P < .001), with similar DOAC and warfarin use in 2014. Atrial fibrillation visits with anticoagulant use increased from 51.9% (95% CI, 50.4%-53.8%) to 66.9% (95% CI, 65.0%-69.3%) between 2009 and 2014 (P < .001). In 2014, rivaroxaban was the most commonly prescribed DOAC for atrial fibrillation (47.9% of office visits), followed by apixaban (26.5%) and dabigatran (25.5%). CONCLUSIONS Direct oral anticoagulants have been adopted rapidly, matching the use of warfarin, and are associated with increased use of oral anticoagulation for patients with atrial fibrillation.

Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews

Given the conflicting evidence regarding the association between exogenous testosterone and cardiovascular events, we systematically assessed published systematic reviews for evidence of the association between exogenous testosterone and cardiovascular events. We searched PubMed, MEDLINE, Embase, Cochrane Collaboration Clinical Trials, ClinicalTrials.gov, and the US Food and Drug Administration website for systematic reviews of randomised controlled trials published up to July 19, 2016. Two independent reviewers screened 954 full texts from 29 335 abstracts to identify systematic reviews of randomised controlled trials in which the cardiovascular effects of exogenous testosterone on men aged 18 years or older were examined. We extracted data for study characteristics, analytic methods, and key findings, and applied the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist to assess methodological quality of each review. Our primary outcome measure was the direction and magnitude of association between exogenous testosterone and cardiovascular events. We identified seven reviews and meta-analyses, which had substantial clinical heterogeneity, differing statistical methods, and variable methodological quality and quality of data abstraction. AMSTAR scores ranged from 3 to 9 out of 11. Six systematic reviews that each included a meta-analysis showed no significant association between exogenous testosterone and cardiovascular events, with summary estimates ranging from 1·07 to 1·82 and imprecise confidence intervals. Two of these six meta-analyses showed increased risk in subgroup analyses of oral testosterone and men aged 65 years or older during their first treatment year. One meta-analysis showed a significant association between exogenous testosterone and cardiovascular events, in men aged 18 years or older generally, with a summary estimate of 1·54 (95% CI 1·09-2·18). Our optimal information size analysis showed that any randomised controlled trial aiming to detect a true difference in cardiovascular risk between treatment groups receiving exogenous testosterone and their controls (with a two-sided p value of 0·05 and a power of 80%) would require at least 17 664 participants in each trial group. Therefore, given the challenge of adequately powering clinical trials for rare outcomes, rigorous observational studies are needed to clarify the association between testosterone-replacement therapy and major adverse cardiovascular outcomes.

Cardiovascular Risks of Exogenous Testosterone Use Among Men: A Systematic Review and Meta-Analysis

PURPOSE We sought to evaluate whether exogenous testosterone therapy is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo. METHODS Study selection included randomized controlled trials (RCTs) and observational studies that enrolled men aged 18 years or older receiving exogenous testosterone for 3 or more days. The primary outcomes were death due to all causes, myocardial infarction, and stroke. Secondary outcomes were other hard clinical outcomes such as heart failure, arrhythmia, and cardiac procedures. Peto odds ratio was used to pool data from RCTs. Risk of bias was assessed using Cochrane Collaboration tool and Newcastle and Ottawa scale, respectively. The strength of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation Working Group approach. RESULTS A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs). Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision, and inconsistency. CONCLUSIONS We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone.

Financial Conflicts of Interest and the Centers for Disease Control and Prevention’s 2016 Guideline for Prescribing Opioids for Chronic Pain

HEALTH CARE POLICY AND LAW Financial Conflicts of Interest and the Centers for Disease Control and Prevention’s 2016 Guideline for Prescribing Opioids for Chronic Pain An increase in opioid prescribing for chronic, noncancer pain has been associated with large increases in addiction and overdose deaths in the United States. In response, the US Centers for Disease Control and Prevention (CDC) developed guidelines for prescribing opioids for chronic pain.1 When the draft guidelines were released, there was criticism. Some organizations argued that the development of the guidelines was not transparent and the recommendations were based on weak evidence.2,3 Subsequently, the CDC postponed the release of the guidelines and opened them to public comment for a 30-day period. More than 150 organizations formally submitted comments. We analyzed these comments to identify levels of support for the guidelines and whether financial relationships with opioid manufacturers were associated with opposition to the guidelines. The final guidelines were released in Marrch 2016.4 Methods | We extracted data from publicly available comments that 158 organizations submitted to the CDC’s docket.1 Two reviewers independently classified each comment into 1 of 4 mutually exclusive levels of support: supportive, generally supportive with recommendations, generally not supportive with recommendations, and not supportive. Comments from 9 organizations (5.7%) were coded as supportive by 1 reviewer and not supportive by the other; a third reviewer adjudicated these cases. Blinded to level of support, we classified each organization’s financial relationship to opioid manufacturers using their self-reported relationships and public websites, annual reports, and federal tax returns. We used the Wilcoxon rank sum test to assess the association between organizations’ final relationship to opioid manufacturers and their level of support for the proposed guidelines.

Efficacy and safety of biosimilar insulins compared to their reference products: A systematic review

Importance For nearly a century, no generic form of insulin has been available in the United States. However, the first biosimilar insulin, Basaglar, was approved by the U.S. Food and Drug Administration in 2015, and subsequently Admelog and Lusduna in 2017. Objective To summarize the scientific evidence comparing the safety, efficacy, pharmacokinetics, and pharmacodynamics of biosimilar and reference insulin products. Data sources We conducted a systematic review using PubMed, Cochrane, Embase, Latin America and Caribbean Health Sciences, South Asian Database of Controlled Clinical Trials, and IndiaMED from their inception through January 14, 2018. Study selection We included randomized controlled trials (RCTs) comparing safety, clinical efficacy, pharmacokinetics and pharmacodynamics of any biosimilar insulin with a reference product in adults regardless of sample size and location. Data extraction and synthesis Two researchers independently reviewed all titles, abstracts and text; extracted data; and performed quality assessments. Main outcomes and measures Efficacy, safety, pharmacokinetics, and pharmacodynamics of biosimilar and reference insulin products Results Of 6945 articles screened, 11 studies were included in the data synthesis. LY2963016, Basalog, Basalin, and MK-1293 were compared to Lantus while SAR342434 was compared to Humalog. Three trials enrolled healthy volunteers, five enrolled type 1 diabetics, and two enrolled type 2 diabetics. One study enrolled both healthy and type 1 diabetics. Of the eleven studies, six examined pharmacokinetic and/or pharmacodynamic parameters and five examined clinical efficacy and immunogenicity. All studies included adverse events. All PK and/or PD studies showed that comparable parameters of biosimilar and reference products were within the pre-specified equivalence margins. Clinical studies suggested similar clinical efficacy and immunogenicity. Adverse events were similar between the groups across all studies. Conclusions and relevance Few published studies have compared biosimilar and reference insulins, though those that did suggest that the biosimilars have comparable safety and clinical efficacy as its reference product.