testosterone increased VTE risk in men

a recent article tied testosterone therapy with increased risk of venous thromboembolism (VTE) in men, both those with and without hypogonadism (testosterone and VTE jamaintmed2019 in dropbox, or doi:10.1001/jamainternmed.2019.5135)

Details:

-- 39,622 men with documented VTE, from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database, from 2011-2018. These databases contain claims information from US employers, health plans, hospitals, and Medicare

-- these men had 12 months of continuous enrollment prior to VTE event, were followed at least 12 months, and were initially free of cancer at baseline

-- mean age 57, 75% <65 years old, testosterone route: intramuscular 28%/transdermal 68%

-- each man with VTE was matched with himself as his own control, assessing the times 6 months, 3 months, and one month prior to the VTE, and comparing that to similar time periods 6 months before each of  these, assessing the presence of testosterone prescriptions

-- 3110 men (7.8%) had evidence of hypogonadism, of whom 1330 (42.8%) were prescribed testosterone in the 12 months prior to their VTE event

-- 29,182 men (73.7%) were <65 years old

-- Main outcome: 1^st VTE event, stratified by the presence or absence of hypogonadism.

Results:

--testosterone therapy in the 6 months prior to VTE was associated with:

    -- men with hypogonadism: 1069 (34%) vs 697 (22%) of VTE cases; more than twofold VTE risk, adjusted OR 2.32 (1.97-2.74)

    -- men without hypogonadism: 294 (0.8%) vs 177 (0.5%) of  VTE cases; twofold VTE risk, adjusted OR 2.02 (1.47-2.77)

-- for men older than 65 with hypogonadism, in terms of timing of testosterone therapy comparing equal time periods before and after VTE, and adjusting for number of inpatient hospitalizations, outpatient encounters, and ED visits:

    -- 1 month after starting testosterone: there was a doubling of VTE risk, OR  1.32 (0.83-2.09)

    -- 3 months after starting: 2.5 times the VTE risk, OR 2.26 (1.54-3.32)

    -- 6 months after starting: twice the risk, OR 2.05 (1.44-2.93)

-- for men younger than 65 without hypogonadism:

    -- 1 month after starting testosterone: there was a doubling of VTE risk, OR  1.76 (1.38-2.23)

    -- 3 months after starting: more than twice the risk, OR 2.28 (1.87-2.79)

    -- 6 months after starting: more than twice the risk, OR 2.40 (1.99-2.88)

-- sensitivity analysis using the 2 different definitions of hypothyroidism (see below): similar estimates

-- the VTE risk was higher in men who filled more than one testosterone prescription

-- for men older than 65 without hypogonadism, in terms of timing of testosterone therapy comparing equal time periods before and after VTE, and adjusting for number of inpatient hospitalizations, outpatient encounters, and ED visits:

    -- 1 month after starting testosterone: OR  1.62 (0.74-3.51), not statistically significant

    -- 3 months after starting: OR 1.68 (0.90-3.14), not statistically significant

    -- 6 months after starting: OR 1.41 (0.77-2.56), not statistically significant

-- for men younger than 65 without hypogonadism:

    -- 1 month after starting testosterone: a doubling of VTE risk, OR  2.09 (1.18-3.69)

    -- 3 months after starting: 3x the risk, OR 2.99 (1.91-4.68)

    -- 6 months after starting: more than twice the risk, OR 2.33 (1.60-3.40)

    -- in terms of timing of testosterone therapy:

        -- 1 month after starting testosterone: 66% increased risk, OR 1.66 (1.34-2.04)

        -- 3 months after starting: 2.3x the risk, OR 2.28 (1.91-2.72)

        -- 6 months after: 2.3x the risk, or 2.32 (1.97-2.74)

    -- as with above, sensitivity analyses showed similar estimates with the 2 different definitions of hypogonadism,  and higher magnitude of the association with testosterone and those filling more than one prescription

-- No difference in VTE risk by route of testosterone therapy, transdermal vs intramuscular

Commentary:

-- testosterone prescriptions among men increased more than 300% from 2001 to 2013, thought to be from treating low libido and fat distribution associated with aging, obesity, and diabetes, though not necessarily with clinical hypogonadism. This increase in prescription rate was most pronounced in those 18 to 45 years old.

    -- In 2014 the FDA highlighted the potential risk of testosterone therapy for  heart attacks and strokes, and testosterone prescriptions have decreased and eventually plateaued

    -- by recent estimates, 2.3 million men >30 yo (3.2%) were prescribed testosterone therapy in 2013, decreasing to 1.15 million men (1.6%) in 2016

-- in this study, they did not have a very rigorous definition of hypogonadism, since they did not get access to specific laboratory values or information about patient symptoms. They tried 2 approaches: one was to assess an array of hypogonadism diagnoses, including post-irradiation and post-surgical diagnoses. And, a sensitivity analysis was performed defining hypogonadism by ICD codes spanning various testicular, pituitary, and hypothalamic disorders. Both of these approaches have been used in other studies

-- their basic conclusions was that there was approximately twice the testosterone-associated risk of VTE in the 1, 3, and 6 month periods prior to the VTE than in the equivalent control period 6 months earlier

    -- the magnitude of this association was stronger and those <65 yo

-- their conclusions were similar to some other studies, though not all. This study had the benefit of being very large, having lots of patients who had VTE’s, and had a higher quality control population (a case-crossover design, that being the patients themselves at an earlier period of time, which would minimize confounding by several variables that were unlikely to change much in the six-month period, such as obesity, lifestyle changes, family history of VTE)

--this study also complements prior studies suggesting increased risk of stroke and myocardial infarction associated with testosterone therapy

    -- another large data-mining study was just published from the UK Clinical Practice Research Datalink of 15,401 men >45 yo (71,541 person-years of follow-up); all had low testosterone levels but no evidence of hypogonadotropic or testicular disease. 850 patients had an ischemic stroke/TIA/MI, with a 21% increase in those on testosterone replacement therapy and a 35% increase in the 1^st 6 months to 2 years of continuous testosterone use. And, for those 45-59 yo, there was a 44% increased risk (see Loo SY, Am J Med 2019; 132: 1069)

    --see http://gmodestmedblogs.blogspot.com/2014/02/fda-testosterone-alert.html , for an FDA alert on increased stroke, heart attack and death in men on testosterone, and one of the studies finding a significant increase in MIs in men on testosterone, as compared with phosphodiesterase-5 inhibitors (Viagra, et al; an important comparison since it appears that many men take testosterone for improved sexual function)

-- the results of this current study parallel some of the findings of women on oral contraceptives, also finding increased VTE risk beginning shortly after starting the contraceptives

--limitations of the study: the basic one was that this was a large data-mining study, making assumptions on hypogonadism and VTE based on administrative data

So, this study does add to significant adverse effects of using testosterone therapy, adding a doubling of VTE risk to the already documented stroke and myocardial infarction risk. And, it reinforces the public health concern for using testosterone therapy especially in those who did not have hypogonadism (though their relative risk was lower, the absolute risk was higher), and those less than 65 years old

geoff​

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