Nelson Vergel
Founder, ExcelMale.com
We have been waiting for this study for a while. Done with Androgel. Dr Bhasin el al.
Here are the main learning points of this study:
We conducted this randomized, placebo-controlled trial to address uncertainty as to whether testosterone-replacement therapy in middle-aged and older men with hypogonadism increases the risk of cardiovascular events. We included men with established cardiovascular disease or multiple cardiac risk factors who would be most vulnerable to an increased risk of adverse cardiovascular outcomes. Among 5198 patients who received testosterone or placebo for a mean duration of 22 months, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. The hazard ratio for a primary end-point event was 0.96 (95% CI, 0.78 to 1.17), a noninferiority finding that was confirmed in sensitivity analyses with adjustment for the influence of interruptions or discontinuations of testosterone or placebo.
The FDA initiated a review of the cardiovascular safety of testosterone products in 2010 after a small placebo-controlled trial was prematurely discontinued because of an increased incidence of cardiovascular events among patients who received testosterone therapy.14 However, subsequent meta-analyses showed variable results and most, including a recent patient-level meta-analysis,15 did not confirm these findings. Cardiac events in those trials were not uniformly adjudicated, definitions were broad and inconsistent, and the trials were not adequately powered for cardiovascular outcomes. Retrospective observational studies, which were limited by potential confounding and selection bias, also showed conflicting findings,1-5 although one analysis from a large health care database suggested that an age of 65 years or older or preexisting cardiovascular disease might be important modifiers of increased risk with testosterone-replacement therapy.2 Nearly half the patients enrolled in the current trial were 65 years of age or older, and more than half had preexisting cardiovascular disease. The 372 adjudicated primary end-point events that occurred in this trial were greater in number than those in all previous randomized trials of testosterone combined.
The incidence of pulmonary embolism was higher with testosterone than with placebo. Although most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia,16 a meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations.15 Our findings support current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events.17There were more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury among patients who received testosterone than among those who received placebo; these adverse events were not expected. A cohort study suggested that normalization of low testosterone levels by testosterone-replacement therapy was associated with a decrease in the incidence of atrial fibrillation.18 In the current trial, the small increase in blood pressure observed in the testosterone group was similar to that reported previously with other testosterone formulations.19
Our trial design specified that noninferiority testing for cardiovascular safety be performed in the population of all patients who had undergone randomization and who had received at least one dose of testosterone or placebo. This modified intention-to-treat analysis preserves the integrity of randomization but may attenuate differences between trial groups and bias toward noninferiority when patients are not adherent to or discontinue their assigned testosterone or placebo. We therefore planned three on-treatment sensitivity analyses and specified that the trial would not conclude until accrual of at least 256 primary end-point events that met the criteria for the principal sensitivity analysis. By considering only those end-point events that occurred while patients were receiving testosterone or placebo or within a time frame of physiologic effect after discontinuation of testosterone or placebo, on-treatment analyses can strengthen safety signals by providing a more specific accounting of outcomes related to testosterone therapy. These sensitivity analyses provided support for the noninferiority conclusions.
The incidence of adherence and of retention was lower in this trial than in most cardiovascular outcome studies. Similar levels of adherence and retention have been reported in other trials of testosterone20,21 as well as other therapies for symptomatic conditions such as menopause,22,23obesity,24,25 and chronic pain.26 These findings reflect the challenge of retaining patients who have persistent symptoms and choose to switch medications or discontinue trial participation. The consistency of the results from the intention-to-treat and on-treatment sensitivity analyses suggests that nonadherence was unlikely to have had an impact on the noninferiority conclusions. The effect of nonretention, however, is more difficult to quantify, and the possibility of bias due to informative censoring cannot be ruled out despite a similar incidence of nonretention in the two trial groups. It is somewhat reassuring that of the patients who discontinued trial participation, nearly half did so after end-of-trial visits began, and outcome data were available for more than 80% of the potential person-time follow-up.
Controlled trials have shown that the use of testosterone in older men improves sexual function,27-29 increases volumetric and areal bone mineral density,30 corrects unexplained anemia,31,32 and moderately reduces depressive symptoms.33 However, because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has weighed on treatment decisions by clinicians and patients.17 Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism.
Among men with hypogonadism and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone-replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low.
Here are the main learning points of this study:
- The trial was conducted to ascertain if testosterone-replacement therapy in middle-aged and older men with hypogonadism increases the risk of cardiovascular events.
- The participants were men with established cardiovascular disease or multiple cardiac risk factors.
- Over a mean duration of 22 months, testosterone-replacement therapy was found to be noninferior to placebo with regards to the incidence of major adverse cardiac events. The hazard ratio was 0.96 (95% CI, 0.78 to 1.17), indicating noninferiority.
- The study's findings challenge previous uncertainties around testosterone therapy's cardiovascular safety, some of which stemmed from inconsistent results in previous trials and retrospective observational studies.
- While the incidence of pulmonary embolism was higher in the testosterone group, the study found that adverse events such as nonfatal arrhythmias, atrial fibrillation, and acute kidney injury were unexpected.
- The study advised caution when using testosterone therapy for men who have had previous thromboembolic events.
- It was observed that adherence and retention rates were lower in this trial compared to most cardiovascular outcome studies, which might have influenced the results. However, the consistency between the intention-to-treat and on-treatment sensitivity analyses suggests that nonadherence likely didn't significantly bias the noninferiority conclusions.
- The trial confirmed known benefits of testosterone therapy in older men, such as improved sexual function, increased bone mineral density, correction of unexplained anemia, and reduced depressive symptoms.
- While the study provides some assurance regarding the cardiovascular safety of testosterone therapy, it encourages careful consideration of the potential benefits and risks of this treatment in middle-aged and older men with hypogonadism.
- Men with hypogonadism who already had heart disease or who had multiple risk factors for heart disease were followed for an average of 22 months. During that time, there were no major bad cardiac events that were worse with testosterone replacement therapy than with a placebo. The overall incidence of adverse events was low.
We conducted this randomized, placebo-controlled trial to address uncertainty as to whether testosterone-replacement therapy in middle-aged and older men with hypogonadism increases the risk of cardiovascular events. We included men with established cardiovascular disease or multiple cardiac risk factors who would be most vulnerable to an increased risk of adverse cardiovascular outcomes. Among 5198 patients who received testosterone or placebo for a mean duration of 22 months, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. The hazard ratio for a primary end-point event was 0.96 (95% CI, 0.78 to 1.17), a noninferiority finding that was confirmed in sensitivity analyses with adjustment for the influence of interruptions or discontinuations of testosterone or placebo.
The FDA initiated a review of the cardiovascular safety of testosterone products in 2010 after a small placebo-controlled trial was prematurely discontinued because of an increased incidence of cardiovascular events among patients who received testosterone therapy.14 However, subsequent meta-analyses showed variable results and most, including a recent patient-level meta-analysis,15 did not confirm these findings. Cardiac events in those trials were not uniformly adjudicated, definitions were broad and inconsistent, and the trials were not adequately powered for cardiovascular outcomes. Retrospective observational studies, which were limited by potential confounding and selection bias, also showed conflicting findings,1-5 although one analysis from a large health care database suggested that an age of 65 years or older or preexisting cardiovascular disease might be important modifiers of increased risk with testosterone-replacement therapy.2 Nearly half the patients enrolled in the current trial were 65 years of age or older, and more than half had preexisting cardiovascular disease. The 372 adjudicated primary end-point events that occurred in this trial were greater in number than those in all previous randomized trials of testosterone combined.
The incidence of pulmonary embolism was higher with testosterone than with placebo. Although most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia,16 a meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations.15 Our findings support current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events.17There were more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury among patients who received testosterone than among those who received placebo; these adverse events were not expected. A cohort study suggested that normalization of low testosterone levels by testosterone-replacement therapy was associated with a decrease in the incidence of atrial fibrillation.18 In the current trial, the small increase in blood pressure observed in the testosterone group was similar to that reported previously with other testosterone formulations.19
Our trial design specified that noninferiority testing for cardiovascular safety be performed in the population of all patients who had undergone randomization and who had received at least one dose of testosterone or placebo. This modified intention-to-treat analysis preserves the integrity of randomization but may attenuate differences between trial groups and bias toward noninferiority when patients are not adherent to or discontinue their assigned testosterone or placebo. We therefore planned three on-treatment sensitivity analyses and specified that the trial would not conclude until accrual of at least 256 primary end-point events that met the criteria for the principal sensitivity analysis. By considering only those end-point events that occurred while patients were receiving testosterone or placebo or within a time frame of physiologic effect after discontinuation of testosterone or placebo, on-treatment analyses can strengthen safety signals by providing a more specific accounting of outcomes related to testosterone therapy. These sensitivity analyses provided support for the noninferiority conclusions.
The incidence of adherence and of retention was lower in this trial than in most cardiovascular outcome studies. Similar levels of adherence and retention have been reported in other trials of testosterone20,21 as well as other therapies for symptomatic conditions such as menopause,22,23obesity,24,25 and chronic pain.26 These findings reflect the challenge of retaining patients who have persistent symptoms and choose to switch medications or discontinue trial participation. The consistency of the results from the intention-to-treat and on-treatment sensitivity analyses suggests that nonadherence was unlikely to have had an impact on the noninferiority conclusions. The effect of nonretention, however, is more difficult to quantify, and the possibility of bias due to informative censoring cannot be ruled out despite a similar incidence of nonretention in the two trial groups. It is somewhat reassuring that of the patients who discontinued trial participation, nearly half did so after end-of-trial visits began, and outcome data were available for more than 80% of the potential person-time follow-up.
Controlled trials have shown that the use of testosterone in older men improves sexual function,27-29 increases volumetric and areal bone mineral density,30 corrects unexplained anemia,31,32 and moderately reduces depressive symptoms.33 However, because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has weighed on treatment decisions by clinicians and patients.17 Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism.
Among men with hypogonadism and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone-replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low.
