BARCELONA — Modest-dose testosterone therapy brought significant functional and symptomatic improvement in men with moderate chronic heart failure in a yearlong double-blind randomized trial, Dr. Christopher J. Malkin said at the joint congress of the European Society of Cardiology and the World Heart Federation.
“This is the largest-ever prospective study of testosterone in chronic heart failure patients,” said Dr. Malkin. “Testosterone is a naturally occurring and cheap hormone that seems to improve functional capacity and New York Heart Association class, compared to placebo in men with chronic heart failure. We've seen effects with achievement of levels within the normal physiologic range.”
The clinical improvements were all the more impressive given that many patients weren't able to take the full prescribed dose of testosterone replacement therapy because of recurrent skin rashes caused by the adhesive used in the 5-mg Androderm patches. Indeed, only 42 of the original 78 participants completed the full study year for that reason.
“The testosterone increases we achieved were actually very small. We had hoped to get them up by 10 nmol/L. We achieved only about half of that,” said Dr. Malkin of Royal Hallamshire Hospital, Sheffield, England.
The rationale for the clinical trial lay in the observation that heart failure (HF) entails a metabolic derangement characterized by catabolism and loss of skeletal muscle bulk due to prolonged activation of neurohormones and inflammatory cytokines.
Androgens not only play a key role in maintaining physical strength in men, they also have vasodilatory and anti-inflammatory effects highly relevant in the HF setting. Androgen levels decline with age and tend to run especially low in men with HF. In fact, at baseline, one-quarter of subjects were biochemically androgen deficient as defined by a serum testosterone below 11 nmol/L.
The men at baseline had NYHA class II or III disease with left ventricular ejection fractions of 30%–35% and moderately elevated brain natriuretic peptide levels. Few of the men were cachectic; the average body mass index was 28 kg/m
The primary study end point was change in exercise capacity as measured by an incremental shuttle walk test. The walk distance improved in the testosterone group by a mean of 19% over the 180 meters at baseline, while declining in the placebo group.
At follow-up, the testosterone group also displayed significantly increased handgrip strength. Intriguingly, their mean left ventricle (LV) mass index fell by 12.7 g/m
“Whether the increase in LV cavity length and decrease in LV mass are clinically relevant needs to be investigated further. It looks as if they could be emergent favorable left ventricular remodeling,” Dr. Malkin said.
However, the men treated with testosterone showed no change over time in body mass index, brain natriuretic peptide levels, ejection fraction, several other echocardiographic parameters, thickness of skeletal muscle measured across the thigh, or any of the proinflammatory cytokines investigators measured.
Some men remained androgen deficient despite testosterone therapy because the dose was so small. “If we can improve their testosterone levels further we may see even better effects than in this study,” the physician speculated.
Audience members congratulated Dr. Malkin for bringing scientific rigor to an area often dominated by anecdotal fountain-of-youth testimonials. But they worried about possible cardiotoxic effects of exogenous testosterone in a vulnerable HF population.
“I don't think there's any doubt that supraphysiologic levels of testosterone cause cardiotoxicity. But we're not advocating supraphysiologic levels at all. Our target was high physiologic levels—20–30 nmol/L, levels about what we'd see in elite athletes,” Dr. Malkin replied.
He and his coworkers are planning a new study of testosterone therapy with or without a structured aerobic exercise program in a 2 × 2 factorial design. They'll scrap the poorly tolerated patch in favor of either a gel preparation or 3-month depot injections, which patients most prefer.
Testosterone is a 'cheap hormone that seems to improve functional capacity and New York Heart Association class.' DR. MALKIN