TABLE 2.

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

DATA SOURCE	STUDY POPULATION	EVENTS	TIME TO CARDIOVASCULAR MORBIDITY: AHR (95% CI), P	TIME TO CARDIOVASCULAR DEATH: AHR OR POINT ESTIMATES (95% CI), P
Observational studies
SEER/Medicare¹	73,196 Men aged >65 y with local/regional prostate cancer	3917 MIs; 15,116 incident cases of coronary heart disease; 3301 sudden cardiac deaths	MI (ADT vs no ADT) 1.11 (1.01-1.21), .03; coronary heart disease (ADT vs no ADT) 1.16 (1.10-1.21), .001	Sudden cardiac death or life-threatening ventricular arrhythmia (ADT vs no ADT) 1.16 (1.05-1.27), .004
SEER/Medicare²	22,816 Men aged >65 y with prostate cancer, all stages	≈4321 Cardiovascular events (definition of cardiovascular event not provided)	Cardiovascular event (ADT vs no ADT) 1.20 (1.15-1.26), <.05	—
CaPSURE⁴	4892 Men with localized prostate cancer, all ages, including 3262 patients who had radical prostatectomy and 1630 men who had radiation	131 Total cardiovascular deaths; 61 deaths in radical prostatectomy group, 70 in radiation group	—	Radical prostatectomy group (ADT vs no ADT) 2.6 (1.4-4.7), .002; Radiation group (ADT vs no ADT) 1.2 (0.8-1.9), .40
Nanda et al³⁶	5077 With localized or locally advanced prostate cancer. Patients treated or not treated with adjuvant ADT on the basis of clinical indications	419 All-cause deaths; Subgroup of patients with CAD-induced CHF or MI had 25/95 deaths in ADT-treated patients;18/161 deaths in non–ADT- treated patients	—	No difference in all-cause mortality in entire cohort, 11.1% vs 7.0% 1.08 (0.88-1.33); Greater mortality in the subgroup of patients with CAD treated with ADT (vs no ADT) 1.96 (1.04-3.71)
Alibhai et al³⁴	Matched-cohort study of 19,079 prostate cancer patients treated with at least 6 mo of ADT	949 MIs in ADT users, 1085 MIs in nonusers; 399 sudden cardiac deaths in ADT users, 436 in nonusers	Diabetes (ADT vs no ADT) 1.16 (1.11-1.21); MI (ADT vs no ADT) 0.91 (0.84-1.00); Sudden cardiac death (ADT vs no ADT) 0.96 (0.83-1.10)	—
Postrandomization analyses
Pooled analysis of RCTs³	1372 Men of all ages with localized prostate cancer treated with radiation who enrolled in 1 of 3 ADT trials in which patients received 0 vs 3 vs 6 mo, 3 vs 8 mo, or 0 vs 6 mo of ADT	51 Cardiovascular deaths (due to MI)	—	Shorter time to fatal MI in those ≥65 y treated with 6 mo of ADT compared with those not treated with ADT (P=.017). Effect seen only in men aged ≥65 y.
RTOG 8610¹²	456 Men of all ages with locally advanced prostate cancer treated with radiation	348 Total deaths; 57 cardiovascular deaths	—	Estimates of fatal MI at 10 y with ADT 12.5 (8-17) Estimates of fatal MI at 10 y with no ADT 9.1 (5.3-13), .32
RTOG 9202³²	1554 Men with locally advanced prostate cancer all treated with radiation and 4 mo of ADT who were then randomized to no additional ADT or 24 additional mo of ADT	765 Total deaths; 185 cardiovascular deaths	—	Cardiovascular mortality (28 total mo of ADT vs 4 mo of ADT) 1.09 (0.81-1.47), .58
EORTC 30891³⁷	985 Men of all ages with locally advanced or node-positive disease not suitable for local curative treatment assigned to immediate vs deferred ADT	541 Total deaths; 185 cardiovascular deaths	—	Cardiovascular mortality after median 7.8-y follow-up: 17.9% in immediate-ADT group vs 19.7% in deferred-ADT group (P not given, but percentage was lower in the immediate-ADT group.)
RTOG 85-31³³	945 Men of all ages with locally advanced or node-positive prostate cancer treated with EBRT and then randomized to either long-term adjuvant ADT (Arm 1) or ADT therapy only for local and/or distant disease recurrence (Arm 2). Arm 1 median ADT Rx 4.2 y. In Arm 2, 64% of patients received salvage ADT a median of 3.0 y after EBRT.	574 Total deaths; 117 cardiovascular deaths	—	Cardiovascular mortality at 9 y: Arm 1 (EBR with ADT) =8.4%; Arm 2 (“salvage” ADT for recurrence)=11.4% (P=.17). Arm 2 vs Arm 1 0.73 (0.47-1.15), .16. No significant treatment-related effect found after censoring for salvage ADT
D’Amico et al¹¹	206 Men with localized but unfavorable-risk prostate cancer randomized to RT alone or RT plus 6 mo of ADT	74 Total deaths (44 in the RT-alone group and 30 in the RT plus ADT group; 13 cardiac deaths in each treatment group	—	In patients treated with ADT, there were more cardiac deaths (11 vs 2) in men with moderate to severe comorbidity than in those without such comorbidity, which led to a loss of the survival benefit in this subgroup.
Randomized study analysis
EORTC 22961³⁵	1113 Men with locally advanced prostate cancer randomized to brachytherapy and a total of 6 mo of ADT or brachytherapy and a total of 3 y of ADT	132 Deaths in short-term group, 98 deaths in long-term group; 31 cardiac deaths in short-term group, 25 in long-term group	—	No significant difference in fatal cardiac events (4.0% in short-term group; 3.0% in long-term group

AHR indicates adjusted hazard ratio; CI, confidence interval; SEER, Surveillance, Epidemiology, and End Results; CaPSURE, Cancer of the Prostate Strategic Urologic Research Endeavor, a longitudinal, observational registry of men with biopsy-proven prostate cancer; MIs, myocardial infarctions; ADT, androgen-deprivation therapy; CAD, coronary artery disease; CHF, congestive heart failure; RCTs, randomized controlled trials; RTOG, Radiation Therapy Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EBRT, external-beam radiation therapy; RT, radiation therapy; Rx, treatment.