Nelson Vergel
Founder, ExcelMale.com
Negative studies on TRT and cardiovascular safety- Were they done properly?
Randomized controlled studies
Theoretical concerns around testosterone are associated with rise in hematocrit, a decrease in HDL cholesterol and a possible risk in fibrinogen. Two groups have reported an association of TRT with adverse cardiovascular outcomes. A trial of 209 older frail men [Basaria et al. 2010] over 65 randomized to receive either placebo or 100 g of topical testosterone gel was terminated early as there were 23 cardiac events (two deaths) in the 106 men in the testosterone group versus five in the placebo group, despite positive results in study endpoints. These events included MI and dysrhythmias and hypertension. The authors conceded that there were more cardiovascular comorbidities in the active treatment group and that the starting dose and escalation were outside the product license. The active treatment group had more severe cardiovascular disease. recommended dose and many of the events were reported with inadequate validation.
Retrospective studies
Vigen and colleagues retrospectively reported a composite outcome of all-cause mortality, MI and stroke rates in a cohort of men with low testosterone levels who had undergone coronary angiography and subsequently received TRT [Vigen et al. 2013]. The actual reported rate of events was 10.1% for the testosterone-treated group and 21.2% in controls, showing a reduced event rate in the treated group by more than half. However, after statistical adjustment for over 50 variables, the outcome was reversed! The use of TRT was associated with increased risk of adverse outcomes (19.9% in no treatment group versus 25.7% in treated group) 3 years after the angiography. The study has been criticized for its statistical techniques, lack of adjustment for baseline testosterone concentrations, the inadequacy of testosterone treatment in study subjects, and some corrections in actual data have been published by the authors. They also inappropriately excluded 128 men who had events in the untreated group but subsequently took testosterone. These would have made a huge difference if included. Sixty-three percent had testosterone patches, which were withdrawn because of high rates of skin irritation which would have been expected to contribute to high discontinuation rates [Schoenfeld et al. 2013]. The authors also conceded that they wrongly included 104 women. However, the likely explanation for the stark difference between adjusted and actual event rates is probably that the actual effect size of TRT on study points is much smaller than the effect of comorbidities that needed adjustment amongst mismatched groups.
In another study, Finkle and colleagues retrospectively examined 55,593 insurance claims and compared the incidence of rate of MI in the 1-year prior and 90 days after initial prescription of TRT [Finkle et al. 2014]. They reported an increased rate of nonfatal MIs, especially with men aged 65 or older. In men younger than 65 the risk was confined to those with preexisting heart disease. There was no control group and there was no information available on testosterone concentrations (pre or post treatment) or of cardiovascular risk factors in subjects who were treated. Furthermore, the treatment duration of 3 months is wholly inadequate for a trial looking at nonfatal cardiac events, especially in the light of studies showing long-term reduction in all-cause mortality.
Meta-analyses
A meta-analysis of placebo-controlled trials of testosterone therapy lasting more than 12 weeks by Xu and colleagues concluded that testosterone therapy may increase the risk of cardiovascular-related events but most studies involved small cohorts with a small number of events [Xu et al. 2013]. The authors concluded that Pharma sponsored studies tended to find benefit from TRT whereas independent studies did not [Xu et al. 2013]. The authors were criticized for their selection and inclusion of studies. Findings from the TOM study [Basariaet al. 2010] heavily skewed their findings and the inclusion of a study involving an unlicensed oral formulation in men with advanced liver cirrhosis suggested selection bias. The authors failed to consider that Pharma supported studies frequently involve no influence in design or analysis and may provide adequate resources for proper conduct of the study. A recent meta-analysis by Corona and colleagues was critical of the selection criteria and inappropriate use of statistics for lower powered studies in the Xu paper and concluded that there was no increased risk associated with TRT [Corona et al. 2013a]. The conclusion was that there was no evidence of long-term risk and a suggestion of benefit in men with metabolic syndrome or T2DM. Both papers called for a well powered long-term study but this is unlikely based on cost, especially if industry funding is considered a likely confounder. Rather surprisingly, in March 2015, the US Food and Drug Administration called for future studies of TRT to include assessment of cardiovascular disease and stroke risk [US Food and Drug Administration, 2014]
Source: An update on the role of testosterone replacement therapy in the management of hypogonadism
Randomized controlled studies
Theoretical concerns around testosterone are associated with rise in hematocrit, a decrease in HDL cholesterol and a possible risk in fibrinogen. Two groups have reported an association of TRT with adverse cardiovascular outcomes. A trial of 209 older frail men [Basaria et al. 2010] over 65 randomized to receive either placebo or 100 g of topical testosterone gel was terminated early as there were 23 cardiac events (two deaths) in the 106 men in the testosterone group versus five in the placebo group, despite positive results in study endpoints. These events included MI and dysrhythmias and hypertension. The authors conceded that there were more cardiovascular comorbidities in the active treatment group and that the starting dose and escalation were outside the product license. The active treatment group had more severe cardiovascular disease. recommended dose and many of the events were reported with inadequate validation.
Retrospective studies
Vigen and colleagues retrospectively reported a composite outcome of all-cause mortality, MI and stroke rates in a cohort of men with low testosterone levels who had undergone coronary angiography and subsequently received TRT [Vigen et al. 2013]. The actual reported rate of events was 10.1% for the testosterone-treated group and 21.2% in controls, showing a reduced event rate in the treated group by more than half. However, after statistical adjustment for over 50 variables, the outcome was reversed! The use of TRT was associated with increased risk of adverse outcomes (19.9% in no treatment group versus 25.7% in treated group) 3 years after the angiography. The study has been criticized for its statistical techniques, lack of adjustment for baseline testosterone concentrations, the inadequacy of testosterone treatment in study subjects, and some corrections in actual data have been published by the authors. They also inappropriately excluded 128 men who had events in the untreated group but subsequently took testosterone. These would have made a huge difference if included. Sixty-three percent had testosterone patches, which were withdrawn because of high rates of skin irritation which would have been expected to contribute to high discontinuation rates [Schoenfeld et al. 2013]. The authors also conceded that they wrongly included 104 women. However, the likely explanation for the stark difference between adjusted and actual event rates is probably that the actual effect size of TRT on study points is much smaller than the effect of comorbidities that needed adjustment amongst mismatched groups.
In another study, Finkle and colleagues retrospectively examined 55,593 insurance claims and compared the incidence of rate of MI in the 1-year prior and 90 days after initial prescription of TRT [Finkle et al. 2014]. They reported an increased rate of nonfatal MIs, especially with men aged 65 or older. In men younger than 65 the risk was confined to those with preexisting heart disease. There was no control group and there was no information available on testosterone concentrations (pre or post treatment) or of cardiovascular risk factors in subjects who were treated. Furthermore, the treatment duration of 3 months is wholly inadequate for a trial looking at nonfatal cardiac events, especially in the light of studies showing long-term reduction in all-cause mortality.
Meta-analyses
A meta-analysis of placebo-controlled trials of testosterone therapy lasting more than 12 weeks by Xu and colleagues concluded that testosterone therapy may increase the risk of cardiovascular-related events but most studies involved small cohorts with a small number of events [Xu et al. 2013]. The authors concluded that Pharma sponsored studies tended to find benefit from TRT whereas independent studies did not [Xu et al. 2013]. The authors were criticized for their selection and inclusion of studies. Findings from the TOM study [Basariaet al. 2010] heavily skewed their findings and the inclusion of a study involving an unlicensed oral formulation in men with advanced liver cirrhosis suggested selection bias. The authors failed to consider that Pharma supported studies frequently involve no influence in design or analysis and may provide adequate resources for proper conduct of the study. A recent meta-analysis by Corona and colleagues was critical of the selection criteria and inappropriate use of statistics for lower powered studies in the Xu paper and concluded that there was no increased risk associated with TRT [Corona et al. 2013a]. The conclusion was that there was no evidence of long-term risk and a suggestion of benefit in men with metabolic syndrome or T2DM. Both papers called for a well powered long-term study but this is unlikely based on cost, especially if industry funding is considered a likely confounder. Rather surprisingly, in March 2015, the US Food and Drug Administration called for future studies of TRT to include assessment of cardiovascular disease and stroke risk [US Food and Drug Administration, 2014]
Source: An update on the role of testosterone replacement therapy in the management of hypogonadism
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