Several recently published reports1-5
have suggested that there may be an association between ADT with GnRH therapy (with or without an antiandrogen) or bilateral orchiectomy and incident cardiovascular disease and cardiovascular mortality. Two population-based studies1,2
using data from Surveillance Epidemiology and End Results (SEER)-Medicare reported that ADT is significantly associated with a greater incidence of cardiovascular disease. In 1 report, the use of a GnRH agonist in men with prostate cancer was associated with an increased risk of incident coronary heart disease (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.10 to 1.21), myocardial infarction (adjusted HR, 1.11; 95% CI, 1.01 to 1.21), and sudden cardiac death or life-threatening ventricular arrhythmia (adjusted HR, 1.16; 95% CI, 1.05 to 1.27).1
An increased risk of coronary heart disease was evident in those treated with a GnRH agonist for as few as 1 to 4 months. In the second report, the use of hormonal treatment was associated with a 20% higher risk of serious cardiovascular morbidity (HR, 1.20; 95% CI, 1.15 to 1.26) after more than 5 years of follow-up.2
Several subsequent studies have evaluated the relation between ADT and cardiovascular mortality. Analysis of data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database4
revealed a significantly increased risk of cardiovascular death over a median follow-up of 3.8 years in men with localized prostate cancer who were treated with radical prostatectomy and received GnRH agonist and/or an antiandrogen before surgery compared with those who did not (adjusted HR, 2.6, 95% CI, 1.4 to 4.7). Among patients treated with external-beam radiation therapy, brachytherapy, or cryotherapy, the adjusted HR, with ADT was 1.2 (95% CI, 0.8 to 1.9). In a post hoc pooled-data analysis of 3 randomized controlled trials of radiation therapy with or without hormonal androgen suppression therapy, 6 months of ADT use in men older than 65 years of age was associated with a shorter time to the occurrence of a fatal myocardial infarction (by 2 years) compared with men older than 65 years of age with no ADT use.3
In studies that have detected an increased risk with ADT, the differences in event rates or incidence of events between those treated with ADT and those not receiving ADT usually have been on the order of 1% to 6% of the study population.
Although the above-discussed studies have detected a relation between ADT and cardiovascular risk, not all published studies have reported such a relation. Four other post hoc analyses of randomized clinical trials12,32,33,37
reported no association between ADT and cardiovascular mortality (). In a trial of 206 men with localized but unfavorable-risk prostate cancer randomized to radiation therapy or to radiation therapy plus 6 months of ADT, cardiac death occurred in 13 patients in each treatment group. In those who received ADT, most cardiac deaths occurred among those with moderate to severe comorbidities (11 deaths compared with only 2 among those without significant comorbidity), which led to a loss of the overall survival benefit of ADT use in those with moderate or severe comorbidities. A history of myocardial infarction >6 months before study randomization was the most common factor that contributed to the designation of moderate or severe comorbidities.11
A recent large matched-cohort study comparing prostate cancer patients treated with at least 6 months of some form or combination of ADT found that although ADT treatment was associated with an increased risk of diabetes mellitus (HR, 1.16), neither use of ADT nor duration of ADT treatment was associated with an increased risk of myocardial infarction or sudden cardiac death.34
Results of a recently completed European Organization for Research and Treatment of Cancer (EORTC) randomized trial (Protocol 22961) comparing radiotherapy plus a total of 6 months of ADT to radiotherapy plus a total of 3 years of ADT in patients with locally advanced prostate cancer detected no significant difference in the incidence of fatal cardiac events at 5-year follow-up (4.0% vs 3.0%, respectively).35
Summary of Exploratory Studies Evaluating for the Presence of an Association Between ADT Use in the Treatment of Prostate Cancer and Cardiovascular Morbidity and Mortality
A recent retrospective analysis of 5077 men treated with brachytherapy at a single center compared all-cause mortality in those not treated with adjuvant ADT with those treated with ADT (median treatment duration 4 months); median follow-up was approximately 5 years. Treatment decisions regarding ADT were based on clinical indications at the time. Overall, ADT treatment was not associated with an increased risk of all-cause mortality. In subgroup analysis, ADT treatment was not associated with an increased risk of all-cause mortality in the subgroup of patients without cardiac risk factors or known cardiac disease or in the subgroup of patients with 1 cardiac risk factor. All-cause mortality was greater in the subgroup of patients with coronary artery disease-induced congestive heart failure or myocardial infarction, occurring in 25 of 95 ADT-treated patients (26.3%) and 18 of 161 non–ADT-treated patients (11.2%; adjusted HR, 1.96; 95% CI, 1.04 to 3.71, P
=.04). No data were given on the specific causes of death.36
Several potential explanations for the discordant observations regarding the association between ADT and cardiovascular mortality may include factors such as differences in patient populations studied, study design, selection bias in men offered ADT, and the limited number of cardiovascular events in some studies. A competing-risks issue has also been suggested to explain the findings in the studies that have not detected a relation between ADT and cardiovascular events,12,32,33,37
which emphasizes that the ability to measure an increase in the risk of cardiovascular mortality decreases as the risk of prostate cancer-specific mortality increases.5
It may also be that any increased risk occurs primarily in those with existing, overt coronary artery disease. Finally, another important potential explanation for the discordant findings is that there is no actual causal relation between ADT and cardiovascular mortality and that positive studies are the result of uncontrollable confounding factors or the result of post hoc analyses.
Not surprisingly, given all of these considerations, whether an association (or an actual cause-and-effect relation) between ADT use and cardiovascular events and mortality exists remains controversial and continues to be studied. The writing group believes that at this point, it is reasonable, on the basis of the above data, to state that there may be a relation between ADT and cardiovascular events and death. At present, there are no good data on the issue of ADT and stent thrombosis.