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Testosterone treatment and risk of venous thromboembolism: population based case-control study

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5968 (Published 30 November 2016) Cite this as: BMJ 2016;355:i5968
  1. Carlos Martinez, consultant epidemiologist1,
  2. Samy Suissa, James McGill professor of epidemiology, biostatistics and medicine2,
  3. Stephan Rietbrock, statistician/epidemiologist1,
  4. Anja Katholing, statistician/epidemiologist1,
  5. Ben Freedman, deputy director HRI and professor of cardiology3 4 5,
  6. Alexander T Cohen, consultant physician6,
  7. David J Handelsman, professor/director3
  1. 1Institute for Epidemiology, Statistics and Informatics GmbH, 60388 Frankfurt, Germany
  2. 2Centre For Clinical Epidemiology, Lady Davis Research Institute - Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada
  3. 3ANZAC Research Institute, University of Sydney, Concord Hospital, Concord NSW 2139, Australia
  4. 4Heart Research Institute, Charles Perkins Centre, University of Sydney, NSW 2006 Australia
  5. 5Concord Hospital Dept of Cardiology, Sydney Medical School, University of Sydney, Sidney NSW 2006, Australia
  6. 6Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, King’s College London, London, UK
  1. Correspondence to: C Martinez carlos.martinez{at}pharmaepi.com
  • Accepted 28 October 2016

Abstract

Objective To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

Design Population based case-control study

Setting 370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality.

Participants 19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013.

Exposure of interest Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months.

Main outcome measure Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors.

Results The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months’ treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one.

Conclusions Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.

Footnotes

  • Contributors: CM, DJH, and SS were responsible for conception/design of the study. AK, SR, and CM were responsible for data acquisition and analysis. All authors were involved in interpretation of data. CM and DJH were involved in drafting the manuscript, and all authors critically revised it for important intellectual content. CM is the guarantor.

  • Funding: No external funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; CM has received personal fees from Boehringer Ingelheim and grants from CSL Behring, Bayer Pharma AG, and Bristol-Myers Squibb; SS has received speaking fees from Novartis, Boehringer-Ingelheim, and AstraZeneca and research grants from Bayer Pharma AG, Boehringer-Ingelheim, Bristol-Myers Squibb, and Novartis; BF has received grants, personal fees, and non-financial support from Bayer Pharma AG, grants and non-financial support from Aspen, Boehringer Ingelheim, grants and personal fees from BMS/Pfizer, and personal fees from Servier, Astra-Zeneca, and Gilead. ATC has received grants and personal fees from Bayer HealthCare, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer and personal fees from Boehringer Ingelheim, Johnson and Johnson, Ono Pharmaceuticals, Portola, Sanofi, X01, and Jannsen; DJH’s institution received part funding from two companies (Besins, Lawley) in 2015 for investigator initiated clinical testosterone pharmacology research on which he is principal investigator, but he receives no personal funding; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study was approved by the Independent Scientific Advisory Committee for CPRD for Clinical Practice Research Datalink research (research No 14_154). No further ethics approval was required for the analysis of the data. The CPRD Group has obtained ethical approval from a multi-centre research ethics committee for all purely observational research using CPRD data; namely, studies that do not include patient involvement (the vast majority of CPRD studies). Data that could directly identify the patient were not collected in this study.

  • Data sharing: Clinical Practice Research Datalink data cannot be shared because of licensing restrictions.

  • Transparency: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant) have been explained.

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