In 2011, 2.9 percent of men older than 40 years in the United States were taking some form of testosterone replacement therapy, either as intramuscular, intradermal, subcutaneous implantable, or oral preparations.1 In 2017, that number is likely higher, given aggressive advertising about “low T” as a lifestyle impairment and the availability of testosterone preparations to increase the “spring in your feet” (as advertising materials promise). In 2015, a superb New England Journal of Medicine “Perspective” article concluded that “to date there is no definite evidence that increasing serum testosterone concentrations in men (with age-related hypogonadism) is beneficial and safe.”2 Due to the lack of conclusive data, it has not been known whether testosterone is prothrombotic, and, if it is, whether it is prothrombotic per se and, thus, in all patients on testosterone replacement therapy, or only in patients who develop testosterone-induced erythrocytosis. These issues are relevant for decision making in two clinical scenarios:
The patient who develops a venous thromboembolic event (VTE) on testosterone replacement therapy: Did the testosterone contribute to the VTE development? Should testosterone in this situation be viewed as a transient VTE risk factor and the patient, therefore, be treated only short-term (such as 3 months) with anticoagulation if testosterone is discontinued?
The patient who has a history of VTE and is no longer on anticoagulation: Can testosterone replacement therapy safely be given?
A recent article reports the results of a well-done, very large population-based case-control study from the United Kingdom that investigated a) whether testosterone is a risk factor for VTE, and b) how the risk changes depending on how long a man has been taking testosterone. Patients with a first VTE event (deep vein thrombosis and pulmonary embolism) were identified via a comprehensive validated algorithm by use of hospital discharge diagnoses, causes of death, and medical records. Testosterone exposure was identified by prescriptions written. Individuals were defined as being either unexposed or currently exposed to testosterone, and the latter group was stratified into two groups in respect to time since start of therapy before VTE diagnosis: up to six months before the VTE or more than six months before event. Fifty matched controls without VTE in the source population were identified for every VTE patient. The study population consisted of 19,215 patients with VTE and 909,530 controls.
The main findings include: 1) The adjusted rate ratio of VTE for current versus no testosterone treatment was 1.25 (95% CI, 0.94-1.66). 2) In the first six months of testosterone therapy, the rate ratio of VTE was 1.63 (95% CI, 1.12-2.37); after more testosterone treatment, it was 1.00 (95% CI, 0.68-1.47). 3) Stratification by route of administration yielded similar rate ratios for intramuscular, transdermal, and oral testosterone use. The authors appropriately conclude that “starting testosterone treatment was associated with an increased risk of VTE, which peaked within six months and declined thereafter.” An additional conclusion is that the VTE risk in the first six months is only small.
In Brief
How do these findings influence my medical practice? Firstly, in the patient diagnosed with VTE who started testosterone therapy within six months of the VTE, I now list testosterone as a contributing, albeit only mild, VTE risk factor. In the patient who had been on testosterone for more than six months prior to the VTE, however, I conclude that the testosterone did not contribute to the VTE. Secondly, with respect to duration of anticoagulation decisions, 1) I would view the patient with testosterone-associated, but otherwise unprovoked VTE who had been on testosterone for more than six months as having a truly unprovoked event, and thus recommend long-term anticoagulation; and 2) it is unclear how long the man who developed a VTE within six months of having started testosterone should be treated with anticoagulation. Recent discussion with several of my academic colleagues has not yielded a consensus — management suggestions range from short-term anticoagulation, as the transient VTE risk factor testosterone has been removed; to empiric use of a D-dimer with discontinuation of anticoagulation if a patient is D-dimer negative on anticoagulation and still negative four weeks later, but continuation or restarting of anticoagulation if the D-dimer is initially positive or turns positive at four weeks; to long-term anticoagulation. I favor the D-dimer approach. Given the lack of data on how such a patient is best managed, treatment decisions are not evidence-based. They also need to take the patient’s preference into consideration.
Finally, unfortunately it remains unknown whether testosterone therapy leads to VTE only in patients who develop erythrocytosis, or whether the drug is prothrombotic per se, independent of the hematocrit. This important question was not addressed in this study.
References
Competing Interests
Dr. Moll indicated no relevant conflicts of interest.
