Erratum: “Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer” by Keating et al. [J. Natl Cancer Inst 2009; 102(1): 39–46].
In the original analyses, a programming error resulted in overestimation of the number of men with diagnoses of diabetes and heart disease. However, after the error was corrected, the outcomes were affected only minimally and did not change the conclusions of the study. In the following, each original section is followed by the corrected text.
Abstract results, p. 39
Original text. “Overall, 14 597 (39%) of the 37 443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50).”
Corrected text. “Overall, 13,620 (36%) of the 37443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significant increased risks of incident diabetes (36.1 events per 1000 person years on GnRH agonist therapy [95% confidence interval [CI] = 32.8 to 39.3] vs 21.1 events [95% CI = 20.0 to 22.3] on no androgen deprivation therapy; adjusted hazard ratio [aHR] = 1.48, 95% CI = 1.31 to 1.67), incident coronary heart disease (aHR = 1.17, 95% CI = 1.06 to 1.30), myocardial infarction (12.5 events per 1000 person years on GnRH agonist therapy [95% CI = 10.8 to 14.1] vs 7.3 on no androgen deprivation therapy [95% CI = 6.8 to 8.1]; aHR = 1.21, 95% CI = 1.01 to 1.44), sudden cardiac death (aHR = 1.28, 95% CI = 1.05 to 1.57), and stroke (aHR = 1.18, 95% CI = 1.02 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of diabetes (aHR = 1.40, 95% CI = 1.01 to 1.93) and incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53) and orchiectomy was associated with coronary heart disease (aHR = 1.48, 95% CI = 1.00 to 2.20), myocardial infarction (aHR = 1.98, 95% CI = 1.15 to 3.41), and stroke (aHR = 1.81, 95% CI = 1.15 to 2.84).”
Patients and Methods, p. 40.
Original text. “The 15 087 (40.3%) men with prevalent diabetes and the 14 375 (29.5%) men with coronary heart disease were excluded from analyses of incident diabetes or coronary heart disease, respectively.”
Corrected text. “The 7941 (21.2%) men with prevalent diabetes and the 6477 (17.3%) men with coronary heart disease were excluded from analyses of incident diabetes or coronary heart disease, respectively.”
Results, p.41–42
Original text. “Overall, 14 597 (39%) of the 37 443 men received some form of androgen deprivation therapy during follow-up (Table 1), primarily with GnRH agonists (14 037 or 37.5%). Few were treated with bilateral orchiectomy (308 or 0.8%) or oral antiandrogen monotherapy (1229 or 3.3%) at any time. Use of combined androgen blockade (for more than 6 weeks at the start of GnRH agonist therapy) was also infrequent (1838 or 4.9%). Overall rates of androgen deprivation therapy were highest for men diagnosed in 2001 because they had the longest duration of follow-up.
Table 1.
Original Table 1, p. 42
Patient characteristics and receipt of androgen deprivation therapy*
| Characteristic | No. (%) | % who received ADT during follow-up |
|---|---|---|
| Total | 37443 (100) | 39.0 |
| Age at diagnosis, y | ||
| ≤55 | 4110 (11) | 23.6 |
| 56–60 | 5369 (14) | 24.9 |
| 61–65 | 6412 (17) | 33.0 |
| 66–70 | 8036 (21) | 39.5 |
| 71–75 | 7173 (19) | 46.7 |
| >75 | 6343 (17) | 57.6 |
| Race or ethnicity | ||
| White | 24979 (67) | 38.1 |
| Black | 8896 (24) | 39.2 |
| Hispanic | 2138 (6) | 50.1 |
| Other or unknown | 1430 (4) | 36.3 |
| Marital status | ||
| Married | 20578 (55) | 39.4 |
| Unmarried | 16040 (43) | 38.5 |
| Unknown | 825 (2) | 38.4 |
| Census division | ||
| New England | 1483 (4) | 40.4 |
| Mid Atlantic | 3949 (11) | 35.4 |
| East North Central | 3751 (11) | 37.1 |
| West North Central | 3156 (9) | 38.1 |
| Pacific | 3507 (10) | 26.2 |
| Mountain | 2273 (6) | 36.4 |
| West South Central | 5288 (15) | 40.5 |
| East South Central | 3010 (9) | 44.8 |
| South Atlantic | 8680 (25) | 45.4 |
| Median household income in zip code of residence at diagnosis | ||
| Quartile 1 (lowest) | 8852 (24) | 43.5 |
| Quartile 2 | 8855 (24) | 40.9 |
| Quartile 3 | 8849 (24) | 37.3 |
| Quartile 4 (high) | 8850 (24) | 34.1 |
| Unknown | 2037 (5) | 39.8 |
| % high school graduates in census tract of residence at diagnosis | ||
| Quartile 1 (lowest) | 8852 (24) | 40.6 |
| Quartile 2 | 8849 (24) | 42.1 |
| Quartile 3 | 8854 (24) | 38.1 |
| Quartile 4 (high) | 8846 (24) | 34.9 |
| Unknown | 2042 (5) | 39.8 |
| Tumor grade (Gleason score) | ||
| Well differentiated (2-4) | 1552 (4) | 28.8 |
| Moderately differentiated (5-7) | 22626 (60) | 31.4 |
| Poorly differentiated or undifferentiated (8-10) | 11688 (31) | 54.7 |
| Unknown | 1577 (4) | 41.5 |
| DCG comorbidity score | ||
| Quartile 1 (lowest) | 9418 (25) | 36.3 |
| Quartile 2 | 9315 (25) | 37.9 |
| Quartile 3 | 9353 (25) | 39.9 |
| Quartile 4 (high) | 9357 (25) | 41.8 |
| Year of diagnosis | ||
| 2001 | 9240 (25) | 45.1 |
| 2002 | 9479 (25) | 41.0 |
| 2003 | 9387 (25) | 37.6 |
| 2004 | 9337 (25) | 32.3 |
| Primary treatment received in the 6 months after diagnosis | ||
| Radical prostatectomy | 9025 (24) | 15.2 |
| Radiation therapy | 13490 (37) | 44.3 |
| Neither | 14478 (39) | 48.8 |
| Prevalent diabetes | ||
| No | 22356 (60) | 33.3 |
| Yes | 15087 (40) | 47.4 |
| Prevalent coronary heart disease | ||
| No | 26387 (70) | 34.9 |
| Yes | 11056 (30) | 48.7 |
*DCG = Diagnostic Cost Groups.
Table 1.
Corrected Table 1
Patient characteristics and receipt of androgen deprivation therapy*
| Characteristic | No. (%) | % who received ADT during follow-up |
|---|---|---|
| Total | 37443 (100) | 36.4 |
| Age at diagnosis, y | ||
| ≤55 | 4110 (11) | 22.7 |
| 56–60 | 5369 (14) | 23.9 |
| 61–65 | 6412 (17) | 30.0 |
| 66–70 | 8036 (21) | 35.6 |
| 71–75 | 7173 (19) | 43.4 |
| >75 | 6343 (17) | 55.3 |
| Race or ethnicity | ||
| White | 24979 (67) | 35.2 |
| Black | 8896 (24) | 37.1 |
| Hispanic | 2138 (6) | 48.3 |
| Other or unknown | 1430 (4) | 34.1 |
| Marital status | ||
| Married | 20578 (55) | 36.3 |
| Unmarried | 16040 (43) | 36.5 |
| Unknown | 825 (2) | 36.0 |
| Census division | ||
| New England | 1483 (4) | 36.5 |
| Mid Atlantic | 3949 (11) | 33.4 |
| East North Central | 3751 (11) | 35.0 |
| West North Central | 3156 (9) | 35.7 |
| Pacific | 3507 (10) | 24.6 |
| Mountain | 2273 (6) | 32.9 |
| West South Central | 5288 (15) | 15.1 |
| East South Central | 3010 (9) | 41.6 |
| South Atlantic | 8680 (25) | 42.7 |
| Median household income in zip code of residence at diagnosis | ||
| Quartile 1 (lowest) | 8852 (24) | 40.9 |
| Quartile 2 | 8855 (24) | 38.1 |
| Quartile 3 | 8849 (24) | 34.7 |
| Quartile 4 (high) | 8850 (24) | 31.7 |
| Unknown | 2037 (5) | 36.4 |
| % high school graduates in census tract of residence at diagnosis | ||
| Quartile 1 (lowest) | 8852 (24) | 37.9 |
| Quartile 2 | 8849 (24) | 39.3 |
| Quartile 3 | 8854 (24) | 35.4 |
| Quartile 4 (high) | 8846 (24) | 32.8 |
| Unknown | 2042 (5) | 36.4 |
| Tumor grade (Gleason score) | ||
| Well differentiated (2-4) | 1552 (4) | 25.1 |
| Moderately differentiated (5-7) | 22626 (60) | 28.4 |
| Poorly differentiated or undifferentiated (8-10) | 11688 (31) | 52.9 |
| Unknown | 1577 (4) | 39.0 |
| DCG comorbidity score | ||
| Quartile 1 (lowest) | 9537 (25) | 28.1 |
| Quartile 2 | 9295 (25) | 37.4 |
| Quartile 3 | 9355 (25) | 38.4 |
| Quartile 4 (high) | 9347 (25) | 41.7 |
| Year of diagnosis | ||
| 2001 | 9240 (25) | 41.9 |
| 2002 | 9479 (25) | 37.9 |
| 2003 | 9387 (25) | 35.1 |
| 2004 | 9337 (25) | 30.7 |
| Primary treatment received in the 6 months after diagnosis | ||
| Radical prostatectomy | 9025 (24) | 12.5 |
| Radiation therapy | 13490 (37) | 41.5 |
| Neither | 14478 (39) | 46.3 |
| Prevalent diabetes | ||
| No | 29502 (79) | 35.3 |
| Yes | 7941 (21) | 40.5 |
| Prevalent coronary heart disease | ||
| No | 30966 (83) | 35.4 |
| Yes | 6477 (17) | 41.1 |
*DCG = Diagnostic Cost Groups; ADT = androgen deprivation therapy.
After prostate cancer diagnosis, 847 (2.3%) of the 37 443 men had a myocardial infarction, 1337 (3.6%) had sudden cardiac death or life-threatening ventricular arrhythmia, and 1188 (3.2%) had an ischemic stroke or transient ischemic attack during follow-up. Among the 22 356 men without prevalent diabetes, 4967 (22.2%) developed diabetes, and among the 23 068 without prevalent coronary heart disease, 4775 (20.7%) developed coronary heart disease.
The unadjusted rates per 1000 person-years for developing diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke during treatment or no treatment with androgen deprivation therapy are included in Table 2. We found higher unadjusted rates for each outcome for men who were receiving GnRH agonists therapy or orchiectomy than for men who were not (Table 2). For example, rates of incident diabetes were 159.4 (95% confi dence interval [CI] = 150.6 to 158.3) per 1000 person-years for men on GnRH agonist treatment vs 87.5 (95% CI = 84.6 to 90.4) per 1000 person-years for men on no therapy, and rates of myocardial infarction were 12.8 (95% CI = 11.1 to 14.4) per 1000 person-years for men on GnRH agonist treatment vs 7.3 (95% CI = 6.4 to 7.9) per 1000 person-years for men on no therapy. Higher rates of diabetes, coronary heart disease, and sudden cardiac death were observed during periods when men were on combined androgen blockade (Table 2). Higher rates of diabetes and coronary heart disease were observed for men during periods on oral antiandrogen monotherapy (Table 2).
Table 2.
Original Table 2, p.43
Unadjusted rate of incident diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke associated with androgen deprivation therapy*
| Treatment | Incident diabetes | Incident CHD | Myocardial infarction | Sudden cardiac death | Stroke | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | |
| No androgen deprivation therapy | 87.5 (84.6 to 90.4) | - | 81.4 (78.7 to 84.2) | - | 7.3 (6.4 to 7.9) | - | 11.5 (10.7 to 12.3) | - | 10.8 (10.0 to 11.5) | - |
| GnRH agonist | 159.4 (150.6 to 168.3) | <.001 | 144.0 (135.7 to 152.2) | <.001 | 12.8 (11.1 to 14.4) | <.001 | 21.6 (19.4 to 23.7) | <.001 | 18.5 (16.5 to 20.5) | <.001 |
| Orchiectomy | 190.4 (137.6 to 243.2) | <.001 | 210.5 (150.9 to 270.0) | <.001 | 24.3 (12.4 to 36.3) | .005 | 23.3 (11.5 to 35.1) | .05 | 26.2 (13.8 to 38.7) | .015 |
| Combined androgen blockade | 144.6 (117.2 to 172.0) | <.001 | 157.7 (129.4 to 186.0) | <.001 | 10.2 (5.2 to 15.2) | .26 | 20.1 (13.0 to 27.2) | .02 | 14.8 (8.8 to 20.9) | .19 |
| Oral antiandrogen | 126.8 (82.9 to 170.8) | .08 | 143.2 (97.1 to 189.4) | .009 | 11.2 (2.3 to 20.1) | .40 | 18.8 (7.2 to 30.5) | .22 | 14.9 (4.6 to 25.2) | .43 |
* Rate = number of events per 1000 person-years; CHD = coronary heart disease; GnRH = gonadatropin releasing hormone.
† P values were based on two-sample z tests that evaluated whether the rate of each outcome for men during treatment with any of the treatments differed from the rate under no androgen deprivation therapy, accounting for censoring. Patients with prevalent diabetes and coronary heart disease did not contribute data to the rates for incident diabetes and coronary heart disease, respectively. All statistical tests were two-sided.
Table 2.
Corrected Table 2
Unadjusted rate of incident diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke associated with androgen deprivation therapy*
| Treatment | Incident diabetes | Incident CHD | Myocardial infarction | Sudden cardiac death | Stroke | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | Rate (95% CI) | P value† | |
| No androgen deprivation therapy | 21.1 (20.0 to 22.3) | - | 29.7 (28.3 to 31.0) | - | 7.4 (6.8 to 8.1) | - | 5.3 (4.7 to 5.8) | - | 11.3 (10.5 to 12.2) | - |
| GnRH agonist | 36.1 (32.8 to 39.3) | <.001 | 47.4 (43.7 to 51.1) | <.001 | 12.5 (10.8 to 14.1) | <.001 | 9.3 (7.8 to 10.7) | <.001 | 18.7 (16.7 to 20.8) | <.001 |
| Orchiectomy | 30.3 (14.4 to 46.2) | .26 | 61.3 (33.7 to 84.8) | .009 | 23.7 (11.3 to 36.1) | .01 | 15.1 (5.2 to 25.0) | .05 | 34.7 (19.5 to 50.0) | .002 |
| Combined androgen blockade | 34.5 (23.8 to 45.2) | .01 | 52.7 (39.8 to 65.7) | <.001 | 10.2 (5.2 to 15.2) | .28 | 8.3 (3.8 to 12.8) | .19 | 14.7 (8.7 to 20.8) | .26 |
| Oral antiandrogen | 30.3 (13.2 to 47.5) | .29 | 56.2 (33.2 to 79.2) | .02 | 11.1 (2.2 to 20.-) | .42 | 12.8 (3.3 to 22.3) | .12 | 16.6 (5.8 to 27.4) | .34 |
* Rate = number of events per 1000 person-years; CHD = coronary heart disease; GnRH = gonadatropin releasing hormone.
† P values were based on two-sample z tests that evaluated whether the rate of each outcome for men during treatment with any of the treatments differed from the rate under no androgen deprivation therapy, accounting for censoring. Patients with prevalent diabetes and coronary heart disease did not contribute data to the rates for incident diabetes and coronary heart disease, respectively. All statistical tests were two-sided.
By use of Cox proportional hazards models that adjusted for patient and tumor characteristics, we found that current use of a GnRH agonist, compared with no androgen deprivation therapy, was associated with a statistically significantly increased risk of developing incident diabetes (adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36) (Table 3). Orchiectomy was statistically signifi cantly associated with an increased risk of incident coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen use via combined androgen blockade, compared with no androgen deprivation therapy, was associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53) but not with risk for diabetes, myocardial infarction, sudden cardiac death, or stroke. Oral antiandrogen monotherapy was not associated with any outcome examined.
Table 3.
Original Table 3, p.44
Association between androgen deprivation therapy and diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke*
| Treatment | Adjusted hazard ratio (95% CI) | ||||
|---|---|---|---|---|---|
| Diabetes | Coronary heart disease | Myocardial infarction | Sudden cardiac death | Stroke | |
| No androgen deprivation therapy | Reference | Reference | Reference | Reference | Reference |
| GnRH agonist | 1.28 (1.19 to 1.38) | 1.19 (1.10 to 1.28) | 1.28 (1.08 to 1.52) | 1.35 (1.18 to 1.54) | 1.21 (1.05 to 1.40) |
| Orchiectomy | 1.16 (0.87 to 1.54) | 1.40 (1.04 to 1.87) | 2.11 (1.27 to 3.50) | 1.29 (0.76 to 2.18) | 1.49 (0.92 to 2.43) |
| Combined androgen blockade | 1.17 (0.96 to 1.42) | 1.27 (1.05 to 1.53) | 1.03 (0.62 to 1.71) | 1.22 (0.85 to 1.76) | 0.93 (0.61 to 1.42) |
| Oral antiandrogen | 1.02 (0.72 to 1.45) | 1.10 (0.80 to 1.53) | 1.05 (0.47 to 2.35) | 1.06 (0.57 to 1.99) | 0.86 (0.43 to 1.73) |
* Cox proportional hazards models were adjusted for age, race or ethnicity (white, black, Hispanic, or other or unknown), marital status (married, unmarried, or unknown), Census division, zip code level measures of income and education (categorized in quartiles), tumor grade (well differentiated, moderately differentiated, poorly differentiated, or unknown), comorbidity score, year of diagnosis, stage (regional or local), primary therapy (radical prostatectomy or radiation therapy), prostate-specific antigen level at diagnosis (categorized in quintiles or unknown), cholesterol level at baseline (categorized in quintiles or unknown), baseline statin use, baseline finasteride use, prevalent coronary heart disease, prevalent diabetes, and development of new diabetes, coronary heart disease or myocardial infarction, sudden cardiac death, and stroke during follow up, except that the diabetes, coronary heart disease, and sudden death models do not control for past occurrences of the same condition. The diabetes and coronary heart disease models excluded patients with prevalent diabetes and coronary heart disease, respectively. GnRH = gonadotropin-releasing hormone; CI = confidence interval.
Table 3.
Corrected Table 3
Association between androgen deprivation therapy and diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke*
| Treatment | Adjusted hazard ratio (95% CI) | ||||
|---|---|---|---|---|---|
| Diabetes | Coronary heart disease | Myocardial infarction | Sudden cardiac death | Stroke | |
| No androgen deprivation therapy | Reference | Reference | Reference | Reference | Reference |
| GnRH agonist | 1.48 (1.31 to 1.67) | 1.17 (1.06 to 1.39) | 1.21 (1.01 to 1.44) | 1.28 (1.05 to 1.57) | 1.18 (1.02 to 1.36) |
| Orchiectomy | 1.36 (0.79 to 2.31) | 1.48 (1.00 to 2.20) | 1.98 (1.15 to 3.41) | 1.70 (0.86 to 3.34) | 1.81 (1.15 to 2.84) |
| Combined androgen blockade | 1.40 (1.01 to 1.93) | 1.29 (1.00 to 1.66) | 0.99 (0.59 to 1.64) | 1.05 (0.60 to 1.87) | 0.91 (0.60 to 1.39) |
| Oral antiandrogen | 1.33 (0.75 to 2.36) | 1.30 (0.85 to 1.20) | 0.98 (0.43 to 2.19) | 1.48 (0.69 to 3.14) | 0.89 (0.46 to 1.73) |
* Cox proportional hazards models were adjusted for age, race or ethnicity (white, black, Hispanic, other or unknown), marital status (married, unmarried or unknown), Census division, zip code level measures of income and education (categorized in quartiles), tumor grade (well differentiated, moderately differentiated, poorly differentiated or unknown), comorbidity score, year of diagnosis, stage (regional, local), primary therapy (radical prostatectomy or radiation therapy), PSA at diagnosis (categorized in quintiles or unknown), cholesterol level at baseline (categorized in quintiles, or unknown), baseline statin use, baseline finasteride use, prevalent coronary heart disease, prevalent diabetes, and development of new diabetes, coronary heart disease or myocardial infarction, sudden cardiac death, and stroke during follow up, except that the diabetes, coronary heart disease, and sudden death models do not control for past occurrences of the same condition. The diabetes and coronary heart disease models excluded patients with prevalent diabetes and coronary heart disease, respectively. GnRH = gonadotropin-releasing hormone; CI = confidence interval.
When we repeated analyses by comparing ever use of androgen deprivation therapy with no androgen deprivation therapy, we found that, after adjustment for patient and tumor characteristics, ever use of androgen deprivation therapy was associated with diabetes (aHR = 1.28, 95% CI = 1.20 to 1.37, P <.001), coronary heart disease (aHR = 1.17, 95% CI = 1.09 to 1.25, P <.001), sudden cardiac death (aHR = 1.44, 95% CI = 1.28 to 1.64, P <.001), and stroke (aHR = 1.17, 95% CI = 1.03 to 1.33, P =.02). The risk for myocardial infarction was no longer statistically significant (aHR = 1.11, 95% CI = 0.95 to 1.30, P =.18) in this analysis, indicating that the association with myocardial infarction may be more directly related to current use of androgen deprivation therapy than any use.”
Corrected text. Overall, 13620 (36%) of the 37443 men received some form of androgen deprivation therapy during follow-up (Table 1), primarily with GnRH agonists (13065 or 34.9%). Few were treated with bilateral orchiectomy (268 or 0.7%) or oral antiandrogen monotherapy (1230 or 3.3%) at any time. Use of combined androgen blockade (for more than 6 weeks at the start of GnRH agonist therapy) was also infrequent (1829 or 4.9%). Overall rates of androgen deprivation therapy were highest for men diagnosed in 2001 because they had the longest duration of follow-up.
After prostate cancer diagnosis, 832 (2.2%) of the 37443 men had a myocardial infarction, 593 (1.6%) had sudden cardiac death or life-threatening ventricular arrhythmia, and 1231 (2.7%) had an ischemic stroke or transient ischemic attack during follow-up. Among the 29502 men without prevalent diabetes, 1787 (6.1%) developed diabetes and among the 30,966 without prevalent coronary heart disease, 2559 (8.3%) developed coronary heart disease.
The unadjusted rates per 1000 person-years for developing diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke during treatment or no treatment with androgen deprivation therapy are included in Table 2. We found higher unadjusted rates for each outcome for men who were receiving GnRH agonist therapy than for men who were not (Table 2). For example, rates of incident diabetes were 36.1 (95% confidence interval [CI] = 32.8 to 39.3) per 1000 person-years for men on GnRH agonist treatment vs 21.1 (95% CI = 20.0 to 22.3) per 1000 person-years for men on no therapy and rates of myocardial infarction were 12.5 (95% CI = 10.8 to 14.1) per 1000 person-years for men on GnRH agonist treatment versus 7.4 (95% CI = 6.8 to 8.1) per 1000 person-years for men on no therapy. Higher rates of coronary heart disease, myocardial infarction, sudden cardiac death, and stroke were seen for men treated with orchiectomy. Higher rates of diabetes and coronary heart disease were observed during periods when men were on combined androgen blockade (Table 2). Higher rates of coronary heart disease were observed for men during periods on oral antiandrogen monothearpy (Table 2).
By use of Cox proportional hazards models that adjusted for patient and tumor characteristics, we found that current use of a GnRH agonist, compared with no androgen deprivation therapy, was associated with a statistically significantly increased risk of developing incident diabetes (adjusted hazard ratio [aHR] = 1.48, 95% CI = 1.31 to 1.67), incident coronary heart disease (aHR = 1.17, 95% CI = 1.06 to 1.30), myocardial infarction (aHR = 1.21, 95% CI = 1.01 to 1.44), sudden cardiac death (aHR = 1.28, 95% CI = 1.05 to 1.57), and stroke (aHR = 1.18, 95% CI = 1.02 to 1.36) (Table 3). Orchiectomy was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.48, 95% CI = 1.00 to 2.20) and myocardial infarction (aHR = 1.98, 95% CI = 1.15 to 3.41). Oral antiandrogen use via combined androgen blockade, compared with no androgen deprivation therapy, was associated with an increased risk of incident diabetes (aHR = 1.40, 95% CI = 1.01 to 1.93) and coronary heart disease (aHR = 1.29, 95% CI = 1.00 to 1.66), but not with risk for myocardial infarction, sudden cardiac death, or stroke. Oral antiandrogen monotherapy was not associated with any outcome examined.
When we repeated analyses by comparing ever use of androgen deprivation therapy with no androgen deprivation therapy, we found that, after adjustment for patient and tumor characteristics, ever use of androgen deprivation therapy was associated with diabetes (adjusted hazard ratio [aHR] = 1.45, 95% confidence interval [CI] = 1.30 to 1.62, P<.001), coronary heart disease (aHR = 1.13, 95% CI = 1.03 to 1.23, P=.008), sudden cardiac death (aHR = 1.26, 95% CI = 1.05 to 1.52, P=.01), and stroke (aHR = 1.21, 95% CI = 1.06 to 1.37, P =.005). The risk for myocardial infarction was no longer statistically significant (aHR = 1.11, 95% CI = 0.95 to 1.30, P =.20) in this analysis, indicating that the association with myocardial infarction may be more directly related to current use of androgen deprivation therapy than any use.
Peter Albertsen, author of the accompanying editorial, “Does the Benefit Justify the Risk?”, [J. Natl Cancer Inst 2009; 102(1): 4-5], has given permission to correct the following text from the original editorial:
“Although ADT was more common among men with poorly differentiated disease, more than 25% of the men with well-differentiated disease (Gleason 2 – 4) and more than 30% of men with moderately differentiated disease were treated. We do not know whether these treatments have prolonged survival, but Keating et al. confirm that this approach has the potential for substantial unintended side effects. Almost 25% of the men treated with ADT developed diabetes and 20% developed coronary heart disease. These rates are considerably higher than those found among men who did not receive ADT.”
Corrected text.
“Although ADT was more common among men with poorly differentiated disease, approximately 25% of the men with well-differentiated disease (Gleason 2 – 4) and almost 30% of the men with moderately differentiated disease were treated. We do not know whether these treatments have prolonged survival, but Keating et al. confirm that this approach has the potential for substantial unintended side effects. The rates of diabetes and coronary heart disease were considerably higher in men treated with ADT than in men who did not receive ADT.”
The authors regret these errors.
DOI: 1093/jnci/djp404
Published by Oxford University Press 2009