Men taking testosterone therapy face a significantly increased risk of blood clots in the first 6 months after starting treatment, warn researchers who say that previous studies may have missed the risk due to methodological issues.
The research, which was published online in the BMJ on November 30, shows that the risk of venous thromboembolism (VTE) is increased by 63% in the first 6 months after starting testosterone therapy, corresponding to an additional 10 cases per 10,000 person-years.
The team notes that, although the increase in VTE risk is transient and "still relatively low in absolute terms," the results "support the addition of the general warning for risk of venous thromboembolism with testosterone products required by the US Food and Drug Administration [in 2014]."
Lead author Carlos Martinez, MD, Institute for Epidemiology, Statistics and Informatics, Frankfurt, Germany told Medscape Medical News that the "benefits of testosterone treatment must be weighed against the risks," the evaluation of which is "best handled by the treating physician and in particular the endocrinologist, together with the patient."
He continued: "It is important to understand the potential risks of testosterone treatment in order to be able to make informed decisions about the best treatment for any particular patient, and it is also important to increase awareness of the risks in order to have more rapid diagnosis and treatment of any venous thromboembolism.
"Patients should be informed of the symptoms and signs of deep vein thrombosis [DVT] and pulmonary embolism [PE] — for example, leg pain, leg swelling, or shortness of breath, and be told that, if such symptoms occur, they should bring these to the attention of a doctor," he added.
Large Increase in Prescribing of Testosterone in Men
There has been a large increase in the prescribing of testosterone therapy in men, primarily for sexual dysfunction and/or decreased energy, since the turn of the century, with a 10-fold increase in prescriptions per capita in the United States and a 40-fold increase in Canada, a figure that includes internet sales.
While previous studies have reported contradictory results in terms of whether testosterone use is associated with an increased risk of VTE, the current researchers note that none of those studies "investigated the timing and duration of testosterone use, which could have masked a risk of venous thromboembolism soon after the start of treatment, as seen with oral contraceptives."
To investigate this further, the team examined data on 19,215 males with confirmed VTE and 909,530 age-matched controls from a source population of 2.92 million individuals registered at 370 UK general practices. Their records were linked to hospital-discharge diagnosis and in-hospital procedures, as well as information on all-cause mortality.
The VTE cases included 8394 DVTs, 10,787 PEs, and 65 unspecified VTEs. The incidence rate for VTE in the source population was 15.8 per 10,000 person-years.
Current testosterone use was identified in 0.36% of VTE patients and 0.14% of controls, while recent use was reported in 0.11% and 0.09% of patients and controls, respectively.
The most common testosterone preparations for currently treated individuals were intramuscular preparations (54.2%), transdermal preparations (36.2%), and oral preparations (7.8%).
Logistic regression analysis taking into account comorbidities and all matching factors indicated that the overall adjusted rate ratio of VTE for current vs no testosterone treatment was 1.25, suggesting an additional excess VTE incidence rate of 3.9 per 10,000 person-years over the base rate of 15.8 per 10,000 person years.
Confining the analysis to a treatment duration of up to 6 months, the team found that the adjusted rate ratio of VTE for current vs no treatment was 1.63, indicating an additional excess VTE incidence rate of 10.0 per 10,000 person-years over the base rate.
The adjusted rate ratio of VTE after 6 months of treatment for current vs no treatment was 1.00, while that for recent testosterone treatment vs no treatment was 0.68, which was not significant.
The increased risk of VTE seen with up to 6 months of testosterone treatment was observed in patients with and without pathological hypogonadism, at rate ratios of 1.52 and 1.88, respectively, and in those with and without known VTE risk factors, at rate ratios of 1.41 and 1.91, respectively.
Previous Studies Could Have Missed Peak VTE Risk at Start of Testosterone Therapy
The researchers point out that, having failed to examine the timing and duration of testosterone use, previous studies could have missed the transient peak in VTE risk at the start of treatment due to "a phenomenon known as depletion of susceptibles."
While the mechanism underlying the transient increased risk is not known, the team suggests that it may involve an initial decrease in fibrinolysis, associated with previously undiagnosed thrombophilia-hypofibrinolysis and/or increased cardiovascular risk due to erectile dysfunction, followed by a secondary response to increase fibrinolysis, which then neutralizes the increased risk.
Nevertheless, Dr Martinez emphasized that "measuring the timing and duration of treatment is a crucial element in drug safety and highly pertinent in the context of hormonal therapy and venous thromboembolism."
He added: "The dates of treatment and of events are always collected in clinical trials, and one would hope that the duration of treatment is included in the analysis, where appropriate."
The authors declare no relevant financial relationships for the submitted work. Dr Martinez has received personal fees from Boehringer Ingelheim and grants from CSL Behring, Bayer, and Bristol-Myers Squibb. Other disclosures for the coauthors are listed in the paper.
BMJ. Published online November 30, 2016. Article
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Cite this: Blood Clot Risk Highest in First 6 Months of Testosterone Therapy - Medscape - Dec 01, 2016.