The aim of the present study was to clarify the influence of candesartan-based therapy on subsequent carcinogenesis and cancer death in patients with coronary artery disease with hypertension in a substudy of a multicenter, prospective, randomized, controlled trial. That trial compared the effects of candesartan-based therapy with those of non-angiotensin receptor blocker (ARB)-based standard therapy on major adverse cardiovascular events. Hypertensive patients with coronary artery disease were randomly assigned to receive either candesartan-based (n = 1,024) or non–ARB-based pharmacotherapy, including angiotensin-converting enzyme inhibitors (n = 1,025). During a median follow-up of 4.2 years, 1,606 adverse events (798 in the candesartan group and 808 in the non-ARB standard group) were reported. Among them, new cancer occurred in 5.37% of subjects in the candesartan group and 5.66% of subjects in the standard therapy group (hazard ratio 0.95, 95% confidence interval 0.65 to 1.38). Cancer deaths occurred in 1.66% in the candesartan group and 2.44% in the standard therapy group, respectively (hazard ratio 0.74, 95% confidence interval 0.39 to 1.39). Kaplan-Meier estimates of survival without new cancer and cancer deaths demonstrated that candesartan-based therapy does not accelerate the occurrence of new cancer (log-rank, p = 0.84) or cancer death (p = 0.39) compared to standard therapy. Advanced age and male gender were independently and significantly correlated with the subsequent incidence of cancer. In conclusion, the results of the present study suggest that candesartan-based therapy is not associated with either carcinogenesis or cancer death compared to non-ARB standard therapy.
A recent meta-analysis demonstrated that angiotensin receptor blockers (ARBs) were associated with a modestly increased risk of overall cancer incidence compared to placebo or comparator drugs. Another meta-analysis demonstrated that common antihypertensive drugs, including ARBs, do not increase the risk of cancer or cancer-related deaths. Furthermore, recent large-scale nationwide cohort studies have demonstrated that ARB therapy was not associated with an increased risk of cancer. The relation between ARB therapy and the incidence of cancer is still controversial. The relation between ARBs and organ-specific cancer risk also remains unclear. The purpose of the present substudy of a randomized controlled trial was to clarify the influence of candesartan-based therapy on subsequent carcinogenesis and on cancer death in patients with coronary artery disease (CAD) and hypertension.
Methods
The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE) was a multicenter, prospective, randomized, controlled study that compared the effects of candesartan-based therapy to those of non–ARB-based standard therapy on major adverse cardiovascular events in 2,049 hypertensive patients with CAD. Hypertensive patients with angiographically documented CAD were randomly assigned to receive either candesartan-based (n = 1,024) or non–ARB-based pharmacotherapy, including angiotensin-converting enzyme (ACE) inhibitors (n = 1,025) from June 2001 to April 2004.
During the median follow-up period of 4.2 years (interquartile range 3.5 to 4.9), 3 patients in the candesartan arm and 5 in the non-ARB arm were lost to follow-up, resulting in a follow-up rate of 99.6%. The study methods and main results of HIJ-CREATE have been previously published. The present trial was conducted in accordance with the principles of the Declaration of Helsinki. The institutional review board or relevant ethics committee of each participating medical center approved the protocol, and all patients provided written informed consent before trial enrollment.
The primary end point of our substudy was the new occurrence of any type of cancer. The secondary end points included cancer subgroups by anatomic site and cancer mortality. The occurrence of cancer was diagnosed by cancer diagnosticians who were unaware of the patients’ treatment assignments and was confirmed by an events committee. The cause of cancer death was determined from a review of the available clinical autopsy records and/or death certificates.
Descriptive statistics are expressed as the mean ± SD or medians with interquartile ranges for continuous variables and as the frequency and percentage for nominal variables. p Values were calculated using 1-way analysis of variance or Student’s t tests. All statistical analyses were based on the intent-to-treat analysis. Time-to-event curves were generated using Kaplan-Meier estimates. The log-rank test and a Cox proportional hazards model were used for treatment comparisons. p <0.05 was considered statistically significant. All analyses were performed using Stata statistical software, version 10.0 (StataCorp, College Station, Texas).
Results
A total of 2,049 patients with CAD and hypertension were enrolled in the present trial. Among these patients, 1,024 were randomized to the candesartan-based treatment arm and 1,025 to the non–ARB-based treatment arm ( Table 1 ). Patients with a known malignant neoplasm were excluded from the HIJ-CREATE study.
| Variable | Standard Therapy (n = 1,025) | Candesartan-Based Therapy (n = 1,024) | p Value |
|---|---|---|---|
| Women | 219 (21.4%) | 186 (18.2%) | 0.069 |
| Age (years) | 65.0 ± 8.9 | 64.5 ± 9.4 | 0.272 |
| Diagnosis, acute coronary syndrome | 378 (36.9%) | 346 (33.8%) | 0.144 |
| Revascularization | |||
| Percutaneous coronary intervention | 844 (82.3%) | 852 (83.2%) | 0.606 |
| Coronary artery bypass grafting | 112 (10.9%) | 124 (12.1%) | 0.402 |
| Dyslipidemia | 612 (59.7%) | 604 (59.0%) | 0.739 |
| Diabetes mellitus | 401 (39.1%) | 379 (37.0%) | 0.325 |
| Current smoker | 377 (36.8%) | 401 (39.2%) | 0.194 |
| Cerebrovascular disease | 94 (9.2%) | 111 (10.8%) | 0.208 |
| Previous myocardial infarction | 373 (36.4%) | 406 (39.6%) | 0.129 |
| Body mass index (kg/m 2 ) | 24.7 ± 3.1 | 24.6 ± 2.9 | 0.585 |
| Systolic blood pressure (mm Hg) | 135.5 ± 17.5 | 135.0 ± 18.5 | 0.522 |
| Diastolic blood pressure (mm Hg) | 75.8 ± 11.7 | 75.6 ± 12.1 | 0.802 |
| Left ventricular ejection fraction (%) | 55.1 ± 11.3 | 53.9 ± 11.2 | 0.022 |
| Total cholesterol (mg/dl) | 192.4 ± 34.9 | 193.5 ± 34.7 | 0.488 |
| Creatinine clearance (ml/min) | 62.0 ± 19.3 | 62.6 ± 19.9 | 0.469 |
| Medications before randomization | 960 (93.7%) | 933 (91.1%) | 0.03 |
| Angiotensin-converting enzyme inhibitors | 389 (38.0%) | 370 (36.1%) | 0.394 |
| Diuretics | 79 (7.7%) | 99 (9.7%) | 0.115 |
| Calcium channel blockers | 586 (57.2%) | 557 (54.4%) | 0.206 |
| β Blockers | 440 (42.9%) | 418 (40.8%) | 0.334 |
| Angiotensin II receptor blockers | 224 (21.9%) | 218 (21.3%) | 0.756 |
| Medications at discharge | |||
| Angiotensin-converting enzyme inhibitors | 723 (70.5%) | 8 (0.8%) | <0.001 |
| Diuretics | 82 (8.0%) | 103 (10.1%) | 0.104 |
| Calcium channel blockers | 574 (56.0%) | 457 (44.6%) | <0.001 |
| β Blockers | 506 (49.4%) | 464 (45.3%) | 0.066 |
| Statins | 447 (43.6%) | 459 (44.8%) | 0.58 |
| Nitrates | 526 (51.3%) | 503 (49.1%) | 0.32 |
| Aspirin | 935 (91.2%) | 948 (92.6%) | 0.26 |
During a median follow-up of 4.2 years, a total of 1,606 adverse events (798 in the candesartan group and 808 in the non-ARB standard group) were reported. Among them, new cancer occurred in 5.37% of patients in the candesartan group and 5.66% of patients in the standard therapy group (hazard ratio 0.95, 95% confidence interval 0.65 to 1.38). Cancer deaths occurred in 1.66% of patients in the candesartan group and 2.44% of patients in the standard therapy group (hazard ratio 0.74, 95% confidence interval 0.39 to 1.39). When the cancer incidence was analyzed by site, candesartan-based therapy showed no significant excess among any particular site-specific cancer compared to standard therapy ( Table 2 ).
| Variable | Candesartan-Based Therapy (n = 1,024) | Standard Therapy (n = 1,025) | Odds Ratio | 95% CI | p Value |
|---|---|---|---|---|---|
| Cancer death | 17 (1.66%) | 23 (2.24%) | 0.74 | 0.39–1.39 | 0.340 |
| Cancer incidence | 55 | 58 | 0.95 | 0.65–1.38 | 0.776 |
| Esophagus | 4 | 1 | 4.02 | 0.45–35.99 | 0.179 |
| Gastric | 6 | 3 | 2.01 | 0.50–8.05 | 0.316 |
| Colon | 11 | 10 | 1.10 | 0.47–2.61 | 0.825 |
| Liver | 2 | 2 | 1.00 | 0.14–7.12 | 0.999 |
| Gallbladder | 0 | 2 | Excluded | ||
| Lung | 6 | 13 | 0.46 | 0.17–1.21 | 0.107 |
| Lymphoma | 2 | 1 | 2.00 | 0.18–22.13 | 0.563 |
| Pancreas | 0 | 3 | Excluded | ||
| Kidney | 3 | 2 | 1.50 | 0.25–9.01 | 0.654 |
| Bladder | 4 | 2 | 2.01 | 0.37–10.98 | 0.413 |
| Prostate | 8 | 12 | 0.66 | 0.27–1.63 | 0.370 |
| Uterine | 1 | 0 | Excluded | ||
| Brain | 1 | 1 | 1.00 | 0.06–16.02 | 0.999 |
| Breast | 0 | 1 | Excluded | ||
| Skin | 3 | 0 | Excluded | ||
| Unknown origin | 4 | 5 | 0.80 | 0.21–2.99 | 0.739 |
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