By using a large cohort of men in a national cancer registry, this analysis demonstrated that patients treated by WW/AS had an even higher risk of CVM than patients treated with primary ADT. Given that the baseline demographics and comorbidity status of the WW/AS and primary ADT groups were similar, this suggests that unmeasured factors affecting treatment selection may confound the association between ADT and cardiovascular risk. In an attempt to control for these factors, a propensity-matched analysis was performed, which failed to demonstrate an increased risk of CVM in those patients who received ADT.
A previously published observational study of 73,196 Medicare enrollees with localized prostate cancer assessed whether treatment with GnRH agonists or orchiectomy was associated with diabetes or cardiovascular events.10
The authors found that GnRH agonist use was associated with an increased risk of diabetes (HR, 1.44; P
< .001), coronary heart disease (HR, 1.11; P
= .03), myocardial infarction (HR, 1.11; P
= .03), and sudden cardiac death (HR, 1.16; P
= .004). However, men treated with orchiectomy only had an increased risk of diabetes (HR, 1.34; P
< .001) and had no increased risk of the above-mentioned cardiovascular events. Another study examining 22,816 men with prostate cancer who were identified retrospectively from a population-based registry assessed the affect of ADT on subsequent cardiovascular morbidity.26
Within this cohort, 21% of patients received ADT at some point during treatment. The authors found that those who received ADT for at least 1 year had a 20% higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT.
Finally, a study by Tsai et al,12
which also used the CaPSURE database, described an increased risk of CVM with ADT use. The authors assessed 3,262 patients treated with radical prostatectomy and 1,630 patients treated with external-beam radiation therapy, brachytherapy or cryoablation, of which 1,015 of the total cohort had been treated with neoadjuvant or adjuvant ADT. They compared the use of ADT with time to death as a result of cardiovascular causes between ADT users and nonusers. Among the 266 men undergoing neoadjuvant ADT before prostatectomy only (8.1% of the patients who underwent prostatectomy), the authors reported a significant association between ADT use and CVM (HR, 2.6; 95% CI, 1.4 to 4.7; P
= .002). There was no similar association between ADT use and CVM in the radiation therapy group.
There is concern, however, in the above-mentioned studies that unmeasured factors maybe confounding the relationship between ADT use and CVM. In the study by Tsai et al,12
the analysis for cardiovascular risk adjusted only for age and the presence of coronary disease and diabetes. Furthermore, although the authors saw an increased CVM in men using ADT in the radical prostatectomy group, they did not see this association in the nonsurgical group despite a similar exposure to ADT (4.1 v
4.3 months, respectively). Assessing CVM rather than PCSM end points can be more challenging when using administrative data or data from registries intended to study prostate cancer. Although CaPSURE included comorbidity checklists for diabetes and congestive heart disease, for example, it did not include hemoglobin A1c levels, heart failure severity classifications, or other important indicators of cardiovascular disease risk.
Other reports corroborate findings of the current analysis. A study that used administrative databases in Ontario, Canada, compared 19,079 men who used ADT to 19,079 men who did not to assess the development of acute myocardial infarction, sudden cardiac death, and diabetes.16
These men were matched one-to-one on age, prior cancer treatment, and year of diagnosis, and they were propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. The analysis did not identify an association between ADT use and acute myocardial infarction (HR, 0.91; 95% CI, 0.8 to 1) or sudden cardiac death (HR, 0.96; 95% CI, 0.8 to 1.1).
Two secondary analyses of large, randomized trials have also supported the findings of the present study. One randomized, phase III trial examining 945 men compared the effects of radiation therapy and adjuvant ADT to radiation therapy alone. After 9 years of follow-up, CVM for men receiving adjuvant ADT was 8.4% compared with 11.4% for men treated without adjuvant ADT, and no significant difference was appreciated between the two arms.18
Another recent study analyzing 1,554 men who were randomly assigned to radiation therapy and 4 months or 28 months of adjuvant ADT found no association between the duration of ADT and CVM.17
The major advantage of these trials is their ability to control, through random assignment, for both known and unknown factors that may confound the association between ADT and CVM; thus, these findings may be more reliable.
Our study had several strengths, including a large data set of 7,248 men, of whom 195 had cardiovascular events. Another advantage was the addition of a propensity-adjusted and matched analysis to elucidate the effect of ADT on CVM. The study also has limitations. Although we were unable to see a significant association between ADT and CVM in the matched analysis, the CIs around our risk estimate ranged from a small protective effect to an almost two-fold increase in risk, suggesting a possible lack of power to identify this association. No a priori sample size calculation was performed, because this study was limited to the patients and events within the CaPSURE database.
Second, death certificates were used to determine the cause of mortality. Previous studies have shown that death certificates can be unreliable, particularly when reporting mortality related to cardiovascular causes.27–29
Therefore, there is a possibility of misclassification of CVM as an end point, which may be reflected by the increase in all-cause mortality in ADT users compared with nonusers. However, this increase in overall mortality may be due to many other reasons, such as sequelae of skeletal complications that are unrelated to cardiovascular effects of treatment. Third, evaluation of CVM end points in a registry intended to study prostate cancer can be challenging, because CaPSURE does not include all the important indicators of cardiovascular disease risk. Therefore, this study may also be affected by potential unmeasured confounders, which may affect the observed results. Attempts to minimize this effect were made by using a propensity-matched algorithm to compare ADT users to nonusers.
Another limitation and potential bias was that 31% of the cohort were missing comorbidity data. However, these patients were equally distributed among the treatment groups, and 25% to 30% of patients in each treatment group were missing comorbidity data. These patients were included in the analysis; however, a sensitivity analysis in which these patients were excluded failed to show any significant changes in the risk estimates. In addition, there were concerns regarding the reliability of data pertaining to duration of ADT use. As a result, a distinction between patients on continuous versus intermittent ADT could not be made. Finally, CaPSURE did not differentiate between men on AS and those on WW. These limitations are common to observational studies that use large disease registries.
When studying a large cohort of men with propensity analysis, we were unable to identify an association between ADT use and CVM, which suggests that previous studies that found an association may have been confounded by unmeasured variables that affected both treatment selection and various non–prostate cancer–specific outcomes, including CVM. However, this information does not preclude the need for cardiovascular risk assessment in men being treated with ADT as well as a careful and complete discussion of the need for and risks and benefits of ADT in those being considered for such therapy.