Does Testosterone Therapy Increase Risk of Cardiovascular Events among Men? A Meta-analysis

Importance: There has been increasing interest in use of testosterone therapy (TT) beyond patients with hypogonadism to include younger men without documented hormone measurements for the purpose of improving libido, sexual function, bone density, and body mass. However, there is no conclusive data about safety of TT due to lack of adequately powered randomized clinical trials (RCTs) specifically designed for this purpose. Objective: To examine the overall risk of cardiovascular events associated with TT via meta-analysis of published randomized and observational studies. Data Sources: We searched MEDLINE, EMBASE, CINAHL, the Cochrane Controlled Trials Register and the National Institute of Health Clinical Trials.gov database from 1966 to 2014. Study Selection: Out of the initial 2,800 studies identified, we obtained a total of 34 studies for detailed analysis after applying our inclusion/exclusion criteria. Two reviewers used eligibility criteria to assess all titles, abstracts, and full texts and resolved disagreements by discussion. Data Extraction and Synthesis: One reviewer did data abstractions and quality assessments, which were confirmed by a second reviewer. Data were then collected and analyzed using random and fixed effect model, as appropriate. Risk estimates were extracted as adjusted hazard ratios (HRs) from included studies. Main Outcome and Measures: Association of TT with cardiovascular events as a primary endpoint and association of TT with ischemic heart disease, all-cause mortality and cerebrovascular events as secondary endpoints. Results: TT was associated with increased incidence of cardiovascular events (adjusted hazard ratio (HR) = 1.41, 95% CI = 1.19-1.67, p = 0.0004), all-cause mortality (adjusted HR = 1.29, 95% CI = 1.03-1.62, p = 0.02), and ischemic heart disease (adjusted HR=1.51, 95% CI = 1.05-2.18, p = 0.02) but there was no clear association with cerebrovascular events (adjusted HR=0.91, 95% CI = 0.66-1.25, p=0.54). Subgroup analyses of our primary endpoint by study type (randomized versus observational studies) did not change our results (adjusted HR=1.40, 95% CI = 1.05-1.87, p = 0.02 and adjusted HR=1.54, 95% CI = 1.09-2.17, p = 0.01 respectively). Additional analysis using meta-regression and sensitivity analyses to account for factors such as history of prior CV events, indication for TT and duration of follow up did not change our results. However, we did notice lack of association between CV events and Intramuscular testosterone. Conclusions and Relevance: TT may be associated with an increased risk of all-cause mortality, cardiovascular events, and ischemic heart disease. These findings support the need for an adequately powered randomized study.

Heart Failure with Preserved Ejection Fraction and Therapeutic Approaches: A Systematic Review and Meta-analysis.

Aims: Evidence is still lacking regarding optimal treatment for patients with heart failure with preserved ejection fraction (HfPEF). Our objective is to present an individual evaluation for each of the current available heart failure medications using a metaanalytical model. Methods and Results: Using meta-analytical techniques we assessed the impact of standard systolic heart failure medications on the combined endpoint of all-cause mortality and/or hospitalization for heart failure as a primary endpoint and on mortality and heart failure hospitalization as separate secondary endpoints for patients with HfPEF. Studies were heterogeneous (Q test, p=0.01) and a random effect model was adopted for analysis. A total of 22 randomized and prospective observational studies of 16,802 patients were included; mean follow up duration was 27 months. Only angiotensin converting enzyme inhibitors (ACEIs) significantly reduced the composite end point of allcause mortality and /or hospitalization for heart failure (HR 0.74 & 95% CI [0.61-0.89], p=0.01). As for all-cause mortality, only ACEIs (HR 0.57 & 95% CI [0.45-0.71], p=0.005), beta blockers (HR 0.63 & 95% CI [0.41-0.98], p=0.03) and statins (HR 0.41 & 95% CI [0.23-0.72], p=0.001) offered a survival benefit. As for hospitalization for heart failure, only digoxin had a significant effect (HR 0.77 & 95% CI [0.61-0.98], p=0.02). Conclusions: Our analysis suggests that ACEI, beta blockers, statin and digoxin as potential medications that can improve outcomes in patients with HfPEF. However, prospective randomized studies are needed to better assess response to these medications.

A Meta-analysis of Ostial and Trunk versus Distal Lesions in Unprotected Left Main Coronary Artery Stenting.

Aims: To assess outcomes for percutaneous coronary intervention (PCI) in ostial and trunk versus distal unprotected left main coronary artery (LMCA) lesions in the drugeluted stent (DES) era. Study Design: A meta-analysis and systematic review. Methods: With the help of a librarian, we searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and the Clinical Trials Registry from 2001 to July 2012. We included studies that enrolled ≥ 50 patients and had ≥6 months of follow-up. Our co-primary endpoints were the incidence of major adverse cardiac events (MACE) and target lesion/vessel revascularization (TLR/TVR). Data was abstracted and analyzed by two independent reviewers and differences were resolved by consensus. We assessed the results for heterogeneity in our analysis by examining the forest plots and then calculating a Q statistic, which we compared with the I2 index. If there was no evidence of statistical heterogeneity and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model; otherwise the random-effects model was used. Results: We identified 11studies involving 3,718 patients. Mean duration of follow-up was 29 months (range 12-62months). Compared with ostial and trunk stenting, distal LMCA PCI was associated with increased MACE (OR 1.95, 95% CI 1.43-2.66) and TLR/TVR (OR 3.13, 95% CI 1.90-5.16).No significant differences were detected for cardiac death (OR 1.06, 95% CI 0.72-1.58, p=0.58), MI (OR 1.15, 95% CI 0.74-1.77, p=0.80) or stent thrombosis (OR 1.57, 95% CI 0.90-2.77, p=0.41). Conclusion: Patients with ostial and trunk LMCA lesions treated with DES have better outcomes than patients with distal lesions. Our findings may support unprotected nondistal LMCA stenting as a primary approach in selected patient subsets.