Does Testosterone Increase the Chance for a Heart Attack?

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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 Sixty-three percent had testosterone patches, which were withdrawn because of high rates of skin irritation which would have been expected to contribute to high discontinuation rates [Schoenfeld et al. 2013].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
 
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The Effect of Low Testosterone and Estrogen Levels on Progressive Coronary Artery Disease in Men
rbmb.net 2019, 8(2): 165-171

Mansoureh Bajelan, Negar Etehad Roodi, Mahdy Hasanzadeh Daloee, Mansoureh Farhangnia, Ali Samadi Kuchaksaraei *

Cellular and Molecular Research Centre, Iran University of Medical Science, Tehran, Iran. & Cardiovascular Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Abstract:
Background: Age-related morbidity and mortality rates from coronary heart disease (CHD) are higher in men than in women. Abnormal androgen levels cause a variety of abnormal symptoms in men. Testosterone and estrogen are the main sex hormone in men and women, respectively, and studies have shown that they have important roles in cardiovascular health and disease.

Methods: We measured testosterone and estrogen in 102 men with coronary heart disease and 45 controls. Blood samples were collected from subjects and plasma testosterone and estrogen were measured by ELISA.

Results: Men with coronary heart disease had less testosterone (OD Ratio: 0.782) and estrogen (OD Ratio: 0.955) than controls.

Conclusions: Low testosterone and estrogen levels correlate with coronary artery disease.
Keywords: Coronary artery disease, Estrogen, Testosterone.
 
Journal Scan / Research · March 08, 2017

Testosterone Treatment Increases Coronary Artery Plaque Volume in Older Men With Low Testosterone
JAMA: The Journal of the American Medical Association

MPORTANCE
Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.

OBJECTIVE
To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.

DESIGN, SETTING, AND PARTICIPANTS
Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.

INTERVENTION
Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.

MAIN OUTCOMES AND MEASURES
The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).

RESULTS
Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, −27 Agatston units; 95% CI, −80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.

CONCLUSIONS AND RELEVANCE
Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.

COMMENT:

Written by Wayne J G Hellstrom MD, FACS Written by Kenneth J Delay MD
The controversy regarding testosterone replacement therapy (TRT) in hypogonadal men and its association with cardiovascular (CV) events continues.

Two articles from JAMA seek to shed light on the impact of TRT on CV status and outcomes of hypogonadal men. An article by Cheetham et al describes a large database (>40,000 men over a 12-year period) from Kaiser Permanente, and results showed that the hypogonadal patients who received any TRT had a lower risk of stroke, cardiac events, and overall death.1 The rates of the composite CV endpoints were 23.9 vs 16.9 per 1000 persons-years in the never-TRT and the ever-TRT groups, respectively.

Another manuscript by Budoff et al does not look at a clinical event but the impact of TRT on the growth of coronary artery plaques.2 The conclusion of the manuscript appears to be that there may be CV risk associated with TRT due to increased rate of coronary artery plaque expansion in men receiving TRT compared with placebo. It is curious that, at baseline, the placebo group had significantly larger plaques and, despite the increased growth of these plaques in men on TRT, at the end of the study the men receiving TRT still had smaller plaques than the men in the placebo arm. Given this baseline disparity, it is hard to draw firm conclusions. Even assuming that TRT causes coronary artery plaque growth, the clinical significance of this is uncertain, as there were no differences in CV events between the two groups of men. The reality is, now that concerns about CV safety with TRT have been raised, large prospective randomized trials are needed to answer these questions definitively.

References

Cheetham TC, An J, Jacobsen SJ, et al. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency [published online February 21, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2016.9546. Testosterone Replacement and Cardiovascular Outcomes
Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017;317(7):708-716. Testosterone Treatment and Coronary Artery Plaque Volume in Men With Low Testosterone
 
 
 
 

Conclusions
In conclusion, this meta-analysis found no statistically significant difference between the risk of MI and testosterone therapy in hypogonadal men compared to non-treated hypogonadal men. As there are no long-term prospective placebo-controlled trials to investigate the MI risks and benefits of testosterone therapy in men with hypogonadism, we do not believe that this finding provides definitive evidence for cardiovascular safety in the use of testosterone replacement TRT in hypogonadal men. However, findings from this paper may aid doctors counseling hypogonadal men about the benefits and risks of TRT before initiating the treatment. Moreover, our study warrants the need for more future RCTs measuring more specific parameters such as the duration of testosterone therapy, the methods of testosterone therapy, and the normalization of testosterone level in hypogonadal men with greater population size, which could produce more solid results, allowing more definitive conclusions to be made on this topic.
 

 
 
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Evaluating the impact of testosterone replacement therapy on carotid atherosclerosis: a systematic review and meta-analysis

Syed Hamza Haider, Areeka Irfan, +4 authors Alishba Raza
Published in Future Science OA 25 August 2024

Meta-analysis shows no relation between TRT and CIMT or other markers, allowing its safe usage for hypogonadal males, allowing its safe usage for hypogonadal males.

Abstract
Aim: This meta-analysis investigates the association between testosterone replacement therapy [TRT] and carotid artery atherosclerosis. Methods: 3 databases were searched for studies up to June 2023 per the PRISMA guidelines. The eligibility criteria comprised RCTs and observational studies involving hypogonadal males receiving exogenous testosterone, in which CIMT was assessed. CAA was the primary outcome, whereas secondary outcomes included HDL, LDL, CRP, total cholesterol and total testosterone. The statistical analysis was performed using Review Manager. Results: Statistical analysis revealed no association between TRT and assessed outcomes. There was a significant increase in total testosterone levels, depicting indirect anti-atherosclerotic effects of TRT. Conclusion: Meta-analysis shows no relation between TRT and CIMT or other markers, allowing its safe usage for hypogonadal males.
 
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