OR34-4 The Association Between Testosterone Use and Major Adverse Cardiovascular Events (MACE): An Exploratory Retrospective Cohort Analysis of Two Large, Contemporary, Coronary Heart Disease Clinical Trials

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR34-Testosterone Replacement Therapy: Risks and Benefits
Clinical/Translational
Saturday, March 7, 2015: 11:30 AM-1:00 PM
Presentation Start Time: 12:15 PM
Room 6A (San Diego Convention Center)
Salim Janmohamed, BSc MBBS (Hons) FRCP1, Greg Cicconetti, PhD2, Carol E Koro, PhD3, Richard V Clark, MD, PhD4 and Elizabeth Tarka, MD2
1GSK R&D Ltd, Uxbridge, United Kingdom, 2GSK R&D Ltd, King of Prussia, PA, 3GSK R&D Ltd, Collegeville, PA, 4GSK R&D Ltd, Research Triangle Pk, NC
Background:  The cardiovascular (CV) safety profile of testosterone replacement therapy (TRT) in men is uncertain, particularly in older individuals with pre-existing coronary heart disease (CHD), and has been heightened by recent retrospective analyses of observational data.1  Prior studies, including relatively small prospective clinical trials of hypogonadal men, have yielded conflicting results.  Additional data are required to address this safety concern.

Objectives and Methods:  We utilized data from two large, international, double blind, placebo-controlled randomised clinical trials evaluating the potential effect of darapladib, a lipoprotein phospholipase A2 inhibitor, on ischemic events.  Subjects were men and women with documented stable coronary heart disease (N=15,828; STABILITY2) or recent acute coronary syndrome (N=13,026; SOLID3).  Cardiovascular risk factors were managed according to ‘standard of care’, and major adverse cardiovascular events (MACE - CV death, non-fatal MI, and non-fatal stroke) were prospectively ascertained and adjudicated.  These trials were recently completed and had median follow-up periods of 3.7 and 2.5 years, respectively.  Darapladib did not significantly reduce the risk of CV events.  Cox proportional hazards modelling was used to assess the risk of MACE in men who were exposed to testosterone (< 12 months and > 12 months) compared to those not exposed to testosterone using data from both trials combined.  The models were adjusted for treatment group, age, BMI, HDL/Total cholesterol ratio, Systolic BP, GFR, diabetes, aspirin use, statin use and smoking status. 

Results: TRT use amongst male trial subjects was low (N=217, 1%) and most (83%) was by US men.  The majority of MACE events (N=1412, 57%) were myocardial infarctions.  Men exposed to TRT for less than or equal to 12 months had a hazard ratio of 0.48 (95% CI: (0.15, 1.49), p=0.21) compared to those not exposed to TRT.  Men exposed to TRT for greater than 12 months had a hazard ratio of 0.47 (95% CI: (0.25, 0.87), p=0.02) compared to those not exposed to TRT.

Conclusions:  Pooled analyses of both studies, including adjustment for potential confounders, suggest that TRT is not associated with an increased risk of MACE in men with well characterised coronary heart disease.  Despite the limitations of this retrospective analysis, including small numbers of TRT exposed men and lack of ascertainment of gonadal status, these data do not corroborate recent observational reports that testosterone therapy is associated with increased CV risk.

(1) The Risk of Cardiovascular Events in Men Receiving Testosterone Therapy.  An Endocrine Society Statement. Feb. 7 2014. (2) Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease.  NEJM 2014; 370: 1702(3) Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. doi:10.1001/jama.2014.11061

Disclosure: SJ: Employee, GlaxoSmithKline, Employee, GlaxoSmithKline, Employee, GlaxoSmithKline. GC: Employee, GlaxoSmithKline, Employee, GlaxoSmithKline. CEK: Employee, GlaxoSmithKline, Employee, GlaxoSmithKline, Employee, GlaxoSmithKline. RVC: Employee, GlaxoSmithKline, Employee, GlaxoSmithKline, Employee, GlaxoSmithKline. ET: Employee, GlaxoSmithKline, Employee, GlaxoSmithKline, Employee, GlaxoSmithKline.

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting