Combination therapy with calcium channel blockers and angiotensin II receptor blockers is recommended as one of the effective therapies for hypertension. However, it remains unclear whether this combination reduces major adverse cardiovascular events (MACEs) in patients with hypertension with coronary artery disease (CAD). The purpose of the present study was to examine the effects of amlodipine plus candesartan on MACEs in patients with hypertension with CAD. The study population was drawn from The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE), which was a multicenter, prospective, randomized controlled trial including 2,049 patients with hypertension with angiographically documented CAD. Subgroup analysis was performed in patients treated with amlodipine at baseline (n = 388). The median follow-up period was 4.3 years. Treatment using amlodipine plus candesartan reduced the risk for MACEs by 39% (p = 0.015) compared to that using amlodipine without angiotensin II receptor blockers. Among the individual events constituting MACEs, the incidence of unstable angina pectoris requiring hospitalization was significantly lower, by 52% (p = 0.007). In conclusion, amlodipine plus candesartan demonstrated a more favorable effect on reducing cardiovascular events in patients with hypertension with CAD compared to amlodipine-based therapy without candesartan.
The impact of combination therapy with amlodipine and angiotensin II receptor blockers (ARBs) on long-term outcomes in patients with hypertension with coronary artery disease (CAD) has not been investigated. The aim of the present study was to examine the effects of combination therapy with amlodipine and candesartan on major adverse cardiovascular events (MACEs) in a post hoc subgroup analysis of The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE).
Methods
The study population, undergoing antihypertensive amlodipine treatment, was drawn from HIJ-CREATE, which was a multicenter, prospective, randomized, open-label, blinded–end point trial that compared the effects of candesartan-based therapy with those of non-ARB-based standard therapy on MACEs in patients with hypertension with angiographically documented CAD.
The study methods and main results of HIJ-CREATE have been published previously. In brief, a total of 2,049 patients with angiographically documented CAD, admitted to 14 medical centers in Japan, were registered in HIJ-CREATE study and randomly assigned to receive either candesartan-based pharmacotherapy (n = 1,024) or non-ARB-based pharmacotherapy, including angiotensin-converting enzyme (ACE) inhibitors (n = 1,025), from June 2001 to April 2004. In the 2 treatment arms, the titration of antihypertensive agents or combined medications was performed at the discretion of the responsible physician to reach a target blood pressure of <130/85 mm Hg. Its main analysis comparing candesartan-based and non-ARB-based therapy groups showed that the risk for MACEs was 11% lower in the candesartan group, although not statistically different.
The participants were followed by the hospital doctors or other general practitioners. The incidence of end point events was determined during the scheduled 6-, 12-, 24-, 36-, 48-, and 60-month visits; through contact with each patient; or via access to certificates issued by administrative authorities, if necessary. All patients were followed for >36 months. All trial data were processed at a statistical data center (STATZ Institute, Tokyo, Japan). In this study, a safety monitoring committee evaluated safety information.
The primary end point in the present study was the incidence of MACEs, including cardiovascular death, nonfatal myocardial infarction, unstable angina, heart failure, stroke, and other cardiovascular events requiring hospitalization.
Baseline characteristics are reported as mean ± SD and as percentages, with p values calculated using 1-way analysis of variance or Student’s t tests. Data were analyzed according to patients’ treatment assignments regardless of their subsequent medications (intent-to-treat analysis). The log-rank test and a Cox proportional-hazards model were used for treatment comparison. The independent statistical data center (STATZ Institute) performed the analysis using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina).
Results
Among the total of 2,049 patients enrolled in HIJ-CREATE, 388 patients aged 20 to 80 years underwent amlodipine treatment. The group that underwent candesartan-based therapy with amlodipine included 170 patients, and the group that underwent non-ARB-based therapy with amlodipine included 218 patients. Follow-up was completed in June 2007. The flow of patients through the study is shown in Figure 1 . During the median follow-up period of 4.3 years, 1 patient in the candesartan arm was lost to follow-up, resulting in a follow-up rate of 99.6%. The baseline characteristics of patients are listed in Table 1 . The baseline characteristics of the 2 treatment groups were well balanced, except for gender.
| Baseline Characteristics | Candesartan (n = 170) | Non-ARB (n = 218) | p Value |
|---|---|---|---|
| Age (years) | 66 ± 9 | 66 ± 8 | 0.347 |
| Men | 146 (85.9%) | 166 (76.1%) | 0.017 |
| Body mass index (kg/m 2 ) | 25 ± 3 | 25 ± 3 | 0.595 |
| Blood pressure (mm Hg) | |||
| Systolic | 135 ± 17 | 135 ± 16 | 0.991 |
| Diastolic | 75 ± 12 | 75 ± 11 | 0.836 |
| Acute coronary syndromes | 35 (20.6%) | 49 (22.4%) | 0.654 |
| Stable CAD | 135 (79.4%) | 169 (77.5%) | 0.654 |
| Medical history | |||
| Dyslipidemia ⁎ | 104 (61.2%) | 130 (59.6%) | 0.758 |
| Diabetes mellitus | 77 (45.3%) | 85 (39.0%) | 0.212 |
| Percutaneous coronary intervention | 146 (85.9%) | 195 (89.4%) | 0.258 |
| Coronary artery bypass graft surgery | 19 (11.2%) | 28 (12.8%) | 0.617 |
| Myocardial infarction | 73 (42.9%) | 79 (36.2%) | 0.18 |
| Stroke | 17 (10.0%) | 25 (11.5%) | 0.644 |
| Atrial fibrillation | 9 (5.3%) | 13 (6.0%) | 0.777 |
| Number of diseased coronary arteries | |||
| 1 | 88 (51.8%) | 118 (54.1%) | 0.643 |
| 2 | 82 (48.2%) | 100 (45.9%) | |
| Median C-reactive protein (mg/l) | 2 | 2 | 0.769 |
| Estimated creatinine clearance (ml/min) | 64 ± 18 | 60 ± 17 | 0.053 |
| Concomitant medications | |||
| Statins | 80 (47.1%) | 93 (42.7%) | 0.387 |
| Diuretics | 9 (5.3%) | 14 (6.4%) | 0.641 |
| β-Blockers | 87 (51.2%) | 105 (48.2%) | 0.556 |
| Aspirin | 165 (97.1%) | 202 (92.7%) | 0.057 |
| ACE inhibitors | — | 136 (62.4%) | — |
| Nitrates | 80 (47.1%) | 109 (50.0%) | 0.565 |
⁎ Current use of cholesterol-lowering drugs or a total cholesterol value > 220 mg/dl and/or a low density lipoprotein cholesterol value > 140 mg/dl.
Table 1 also lists the treatments and concomitant medications for patients in the 2 groups. ACE inhibitors had been prescribed in 62.4% of the patients in the amlodipine and non-ARB group. Figure 2 illustrates the mean systolic and diastolic blood pressures for the 2 treatment groups. The mean blood pressure at rest while seated at baseline averaged 135.2/75.1 mm Hg in the amlodipine and candesartan group and 135.1/74.8 mm Hg in the amlodipine and non-ARB group. The mean blood pressure during follow-up was reduced by 2.6/1.7 mm Hg in the amlodipine and candesartan group and changed by −0.4/+1.0 mm Hg in the amlodipine and non-ARB group (p for trend profile = 0.726 and 0.313, respectively).
The primary end point occurred in 37 patients (21.8%) in the amlodipine and candesartan group and 70 patients (32.1%) in the amlodipine and non-ARB group. Figure 3 illustrates the point estimates and 95% confidence intervals for the primary end point and individual components of this end point. The primary end point was reduced in the amlodipine and candesartan group compared to the amlodipine and non-ARB group, with a hazard ratio of 0.61 (95% confidence interval 0.41 to 0.91, p = 0.015). The most frequent component of the primary end point, unstable angina pectoris requiring hospitalization, was reduced in the amlodipine and candesartan group from 21.6% to 11.2% (hazard ratio 0.48, 95% confidence interval 0.28 to 0.82, p = 0.007). Figure 4 illustrates the cumulative event rates for the primary end point in the 2 treatment groups.
Figure 5 shows relative risks and 95% confidence intervals for the primary end point according to selected demographics. Most point estimates demonstrated similar hazard ratios, and no statistical heterogeneity was identified among subgroups. Among them, male gender, impaired renal function (creatinine clearance <60 ml/m 2 ), body mass index <25 kg/m 2 , and a lower level of C-reactive protein (<2 mg/L) were associated with a significant reduction in MACEs, without any significant interactions among patient characteristics.
