Geetha Iyer

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.

An Algorithm to Identify Generic Drugs in the FDA Adverse Event Reporting System

IntroductionAlthough generic drugs constitute approximately 88% of drugs prescribed in the US, there are no reliable methods to identify generic drugs in the US FDA Adverse Event Reporting System (FAERS).ObjectiveThe aim of this study was to develop an algorithm for identifying generic drugs in the FAERS.Data SourceWe used 1237 adverse event reports for tamsulosin, levothyroxine, and amphetamine/dextroamphetamine from the publicly available FAERS from 2011–2013, and 277 source case narratives obtained from the FDA.MethodsTwo reviewers independently and in duplicate used a three-item algorithm including the following criteria: manufacturer name, New Drug Application (NDA) number/abbreviated NDA (ANDA), and specific use of the term ‘generic’ or ‘brand’ to classify the focal drug of each case report as definitely generic (two of three criteria), probably generic (one of three criteria), brand, and cannot be assessed. Inter-rater reliability was estimated using kappa coefficients, and internal consistency was estimated using Cronbach’s alpha. We compared the classification of the drugs as generic versus non-generic in publicly available FAERS compared with the original case reports (reference).ResultsThe focal drug was classified as generic (definite or probable) in 15.8% (39/234), 9% (67/742), and 16.7% (42/261) of tamsulosin, levothyroxine and amphetamine/dextroamphetamine cases, respectively (overall kappa 0.89, 95% confidence interval 0.85–0.93), while 37% of reports could not be classified due to incomplete information. Among the drugs classified as generics using the publicly available FAERS, we categorized 95.3% as generic drugs using the original case reports. Among those drugs that did not meet the algorithm-based definition of generic in the publicly available data, 20.9% were reclassified as generics using the original case reports.ConclusionsThe algorithm demonstrated high inter-rater reliability with moderate internal consistency for identifying generic drugs in the FAERS, in our sample. Future efforts should focus on improving the reliability and validity of identifying generics through improving the completeness of reporting in the FAERS.

The effect of vitamin D supplementation on glucose metabolism in type 2 diabetes mellitus: A systematic review and meta-analysis of intervention studies

AIMS We aimed to assess whether vitamin D supplementation improves glucose metabolism in adults with type 2 diabetes. METHODS PubMed and Cochrane database were searched up to July 1st 2016 for randomized controlled trials that assessed the relationship between vitamin D supplementation and glucose metabolism (change in hemoglobin A1C (HbA1C) and fasting blood glucose (FBG)) among adults with type 2 diabetes. RESULTS Twenty nine trials (3324 participants) were included in the systematic review. Among 22 studies included in the meta-analysis, 19 reported HbA1C, 16 reported FBG outcomes and 15 were deemed poor quality. There was a modest reduction in HbA1C (-0.32% [-0.53 to -0.10], I2=91.9%) compared to placebo after vitamin D supplementation but no effect on FBG (-2.33mg/dl [-6.62 to 1.95], I2=59.2%). In studies achieving repletion of vitamin D deficiency (n=7), there were greater mean reductions in HbA1C (-0.45%, [-1.09 to 0.20]) and FBG (-7.64mg/dl [-16.25 to 0.97]) although not significant. CONCLUSIONS We found a modest reduction of HbA1C after vitamin D treatment in adults with type 2 diabetes albeit with substantial heterogeneity between studies and no difference in FBG. Larger studies are needed to further evaluate the glycemic effects of vitamin D treatment especially in patients with vitamin D deficiency.

Patient-relevant outcomes associated with generic tamsulosin, levothyroxine and amphetamine in the FDA Adverse Event Reporting System: a pilot study

AIM Patient-reported outcomes associated with adverse events (AEs) reported with generics have not been evaluated. To map AEs associated with generics to the NIH Patient-reported Outcomes Measurement Information System. METHODS We mapped 381 AEs from 148 case reports of generic tamsulosin, levothyroxine and amphetamine/dextroamphetamine to the physical, mental and social domain of the NIH Patient-Reported Outcomes Measurement Information System after reviewing 1237 case reports in the US FDAs Adverse Event Reporting System (FAERS; 2011-2013). RESULTS 75%, 76% and 71% reports were classified under the physical domain for tamsulosin, levothyroxine and amphetamine/dextroamphetamine, while 9%, 9% and 18% reports were classified under the mental domain, respectively. CONCLUSION FAERS reveals several domains of patient-relevant concerns associated with generic drugs.

Cardiovascular risks associated with clarithromycin

A growing literature suggests these risks are not negligible

Post-stroke social networks, depressive symptoms, and disability in Tanzania: A prospective study

Background Evidence suggests that social networks improve functional recovery after stroke, but this work has not been extended to low- and middle-income countries (LMICs). Post-stroke depression interferes with functional outcome but is understudied in LMICs. Aims To determine the relationships between social networks, disability, and depressive symptoms in patients surviving 90-days post-stroke in Dar es Salaam, Tanzania. Methods Participants ≥ 18 years, admitted ≤ 14 days of stroke onset, were enrolled. Disability was measured using the modified Rankin Scale, social networks by the Berkman-Syme social network index, and depressive symptoms by the Patient Health Questionnaire-9 (PHQ-9) by telephone interview at 90 days. A Kruskal-Wallis test or Spearmans correlation coefficient was used to assess the associations between social networks, depressive symptoms, and disability. Results Of 176 participants, 43% (n = 75) died, with an additional 11% (n = 20) lost to follow-up by 90 days. Among 81 survivors, 94% (n = 76, 57% male, average age 54 years) had complete information on all scales (mean and median follow-up time of 101 and 88 days). Thirty percent (n = 23, 41.9%, 95% confidence interval 20.2) had at least mild depressive symptoms (PHQ-9 ≥ 5 points). Nearly two-thirds (n = 46, 61%) reported ≥ 3 close friends. A higher social network index score was associated with fewer depressive symptoms (p < 0.0001) and showed a trend towards significance with lower disability (p = 0.061). Higher depressive symptom burden was correlated with higher disability (r = 0.52, p < 0.0001). Conclusion Post-stroke social isolation is associated with more depressive symptoms in Tanzania. Understanding social networks and the associated mechanisms of recovery in stroke is especially relevant in the context of limited resources.

Challenges to Diagnosis and Management of Infections in Older Adults

Infectious diseases continue to be a major cause of morbidity and mortality among adults aged 65 and older despite improvements in antibiotic therapy and vaccinations. Older adults are at increased risk for developing infections compared to younger adults because of age-associated changes in immune function, comorbidities, and repeated exposures to healthcare settings. Diagnosing infections can be challenging in older adults because common signs and symptoms of infection (e.g., fever, leukocytosis) can be absent, especially in frail adults with cognitive impairment. Pneumonia, urinary tract infection, cellulitis, and Clostridium difficile diarrheal illness are among the most common causes of infection in this age group. This chapter reviews the challenges associated with diagnosis and management of the most frequently encountered infections in older adults.

Evaluation of impact of teaching clinical pharmacology and rational therapeutics to medical undergraduates and interns

Objectives: To find out the impact of teaching clinical pharmacology and rational therapeutics (CPT) to medical undergraduates (UGs) and interns. Materials and Methods: This cross-sectional, prospective study was conducted on three UGs batches and interns using two pretested validated structured questionnaires, modified from the work of Tobaiqy et al. The study was approved by the Institutional Ethics Committee. ANOVA and Chi-square test were used for statistical analysis. The value of P< 0.05 was considered statistically significant. Results: A total of 379 UGs and 96 interns participated in this study. Mean knowledge score of interns was significantly reduced as compared to UGs (P < 0.0001). A significant increase in confidence for unsupervised prescribing of nonsteroidal anti-inflammatory drugs (99%), oral rehydration salt, iron salts was perceived among interns as compared to UGs (P < 0.05). However, 63.5% confessed problems in selection of drugs, drug–drug interactions, prescribing in special patient population. Although they were confident prescribing fixed dose combination for adult patients (89.5%), majority were hesitant to prescribe opioids (77%), steroids (76%), vaccines (75%), and antihypertensives (62%). Conclusion: The theoretical CPT teaching transfers knowledge to UGs; however, it is not retained in internship and does not adequately prepare interns to prescribe safe and rational drugs.

Editorialists’ reply to Blake

Blake reminds readers that, in one of their investigations, Wong and colleagues used a Helicobacter pylori eradication regimen consisting of three products as their exposure of interest.1 2 3 We are not aware of evidence indicating that the …