Although some previous research has indicated that the use of androgen deprivation therapy to treat prostate cancer may increase the risk of dying from cardiovascular causes, a meta-analysis of previous randomized trials did not find this association among men with unfavorable-risk, nonmetastatic prostate cancer but did find an associated lower risk of prostate cancer-specific death and all-cause death with androgen deprivation therapy, according to a study in the December 7 issue of JAMA.

Androgen deprivation therapy (ADT) in the form of a gonadotropin-releasing hormone (GnRH) agonist is a mainstay of prostate cancer treatment. The finding in several studies that this therapy may increase the risk of cardiovascular death prompted a U.S. Food and Drug Administration safety warning and a joint statement by multiple medical societies to raise awareness of a potential linkage between ADT and cardiovascular events, according to background information in the article. However, other studies have not confirmed these findings.

Paul L. Nguyen, M.D., of the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, and colleagues performed a meta-analysis of randomized controlled trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer-specific mortality (PCSM), and all-cause mortality in men with unfavorable-risk, nonmetastatic prostate cancer. A review of the medical literature identified eight randomized trials (n = 4,141 patients) that met inclusion criteria for the cardiovascular death meta-analysis. Median follow-up in these trials ranged between 7.6 and 13.2 years.

Among the 2,200 patients who were treated with ADT, there were 255 cardiovascular deaths, corresponding to an overall incidence of cardiovascular death of 11.0 percent; for the control group, there were 1,941 patients and 252 cardiovascular deaths, for an overall incidence of 11.2 percent. Among patients in short-course ADT trials (6 months or less), the incidence of fatal cardiovascular events for ADT vs. control was 10.5 percent vs. 10.3 percent, respectively. Among patients in long-course ADT trials (3 years or longer), the incidence of fatal cardiovascular events for ADT was 11.5 percent, vs. 11.5 percent for the control group.

The researchers also found that the age of the patients did not influence the findings, as there was no association between ADT and cardiovascular death whether the median age was older or younger than 70 years.

There were 443 PCSM deaths among 2,527 patients in the ADT group and 552 PCSM deaths among 2,278 patients in the control group. Men receiving ADT had a 31 percent lower relative risk of PCSM, with an incidence of 13.5 percent vs. 22.1 percent for controls. There were 1,140 total deaths among patients in the ADT group and 1,213 total deaths among patients in the control group, with analysis indicating that men receiving ADT had a 14 percent lower relative risk of all-cause mortality compared to the control group (incidence, 37.7 percent vs. 44.4 percent, respectively).

"Overall, the results of our study should be generally reassuring to most men with unfavorable-risk prostate cancer considering ADT, because it was associated with improved survival without a measurable excess in cardiovascular mortality, but a few important points need to be raised. First, none of the trials were stratified by preexisting cardiovascular comorbidity; therefore, our study cannot exclude the possibility that a small subgroup of men with underlying cardiac disease (even if controlled) could experience excess cardiovascular mortality due to ADT. … A second issue is that although our study assessed total cardiovascular deaths, it could not exclude the possibility that cardiovascular deaths happen earlier in men receiving ADT," the authors write.

"In conclusion, our meta-analysis of more than 4,000 patients could not find any evidence that ADT increases the risk of cardiovascular death among men with unfavorable-risk, nonmetastatic prostate cancer, but did find a significant association between ADT and improved prostate cancer-specific survival and overall survival."

William K. Kelly, D.O., and Leonard G. Gomella, M.D., of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, write in an accompanying editorial that with more than 600,000 patients in the United States with prostate cancer being treated with ADT, the benefits and short-term and long-term risks of ADT need to be clearly outlined.

"… men with cardiac disease who have the highest risks from complications from ADT should follow the appropriate secondary preventive measures from the American Heart Association (lipid-lowering therapy, antihypertensive therapy, glucose-lowering therapy, and antiplatelet therapy). Although ADT has been part of the treatment regimen for several decades, clinicians treating patients with prostate cancer are still understanding the short-term and long-term biological effects of biochemical castration but now have better appreciation of these complications."