Combination therapy with benazepril 40 mg and amlodipine 10 mg (B+A) has been shown to be more effective than benazepril 40 mg and hydrochlorothiazide (HCTZ) 25 mg (B+H) in reducing cardiovascular (CV) events in high-risk patients with stage 2 hypertension with similar blood pressure reductions. In the present post hoc analysis, we evaluated whether B+A is more effective than B+H for reducing CV events in patients with known coronary artery disease (CAD) at baseline in a subgroup analysis of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study. The main trial randomized 11,506 patients. Of those, 5,744 received B+A and 5,762 received B+H. Of the 11,506 patients, 5,314 (46%) were classified as having CAD at baseline. The mean patient follow-up period was 35.7 months for the B+A group and 35.6 months for the B+H group. The primary end point was the interval to the first event of composite CV morbidity and mortality. At baseline, significant differences were present between the 5,314 with CAD and the 6,192 without CAD. The patients with CAD had a lower systolic blood pressure and heart rate, a lower incidence of diabetes, and greater incidence of dyslipidemia. However, no baseline differences were found between the randomized B+A and B+H groups. In the patients with CAD, an 18% reduction occurred in the hazard ratio for CV events (primary end point) with B+A versus B+H (p = 0.0016). In a prespecified secondary analysis of the composite end point, including only CV death, myocardial infarction, and stroke, the hazard ratio in the patients with CAD was reduced by 25% (p = 0.0033) in the B+A group compared with the B+H group. B+A was more effective than B+H at comparable blood pressure reductions for reducing CV events in patients, regardless of the presence of CAD. In conclusion, our findings suggest that the combination of B+A should be preferentially used for older patients with high-risk, stage 2 hypertension.
The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH trial) demonstrated that a single pill combination of benazepril (B) with amlodipine (A) is more effective than the single pill combination of B and hydrochlorothiazide (H) in reducing cardiovascular (CV) events in high-risk elderly patients with stage 2 hypertension. This outcome difference was not explained by differences in office or ambulatory blood pressure. A secondary end point analysis confirmed the superiority of B+A compared with B+H, because amlodipine is known to reduce hospitalizations for unstable angina and the need for coronary revascularization We, therefore, analyzed the effects of B+A compared with those of B+H in patients with and without known coronary artery disease (CAD) at baseline.
Methods
The ACCOMPLISH trial rationale and design has been previously reported in detail. In brief, ACCOMPLISH was a prospective, randomized, double-blind clinical trial conducted in 548 centers in the United States, Sweden, Norway, and Finland. All patients enrolled had hypertension with a high risk of CV events, including a history of coronary events, myocardial infarction, revascularization, stroke, chronic kidney disease, peripheral arterial disease, left ventricular hypertrophy, or diabetes mellitus. Patients were classified at baseline as having CAD if they had a history of angina pectoris, myocardial infarction, or coronary revascularization, including coronary artery bypass grafting or percutaneous coronary intervention. These events were documented from the hospital records, angiographic reports, electrocardiogram, or other diagnostic noninvasive tests. All patients gave informed consent before study enrollment.
In the ACCOMPLISH study, the patients who were not receiving treatment at screening remained without treatment until they began their blinded medications. Those patients already receiving antihypertensive therapy continued their previous therapy until immediately switching to the randomized study drugs at randomization. The patients taking appropriate medications for concomitant conditions (including anti-anginal/anti-ischemic medications) continued those treatments throughout the study. At baseline, the eligible subjects were randomized to either a combination of B+A (20 mg/day; 5 mg/day) or B+H (20 mg/day; 12.5 mg/day), without washout of previous medications. One month after randomization, the B component in both groups was force titrated to 40 mg. Two months after randomization, the investigators could titrate to 40 and 10 of B+A or 40 and 25 mg of B+H, if needed, to achieve a target blood pressure of <140/90 mm Hg (or <130/80 mm Hg for patients with diabetes mellitus or chronic kidney disease). At 3 months after randomization and until trial end, add-on antihypertensive agents (excluding calcium channel blocking agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and thiazide diuretics) but included β blockers, α-adrenergic receptor blockers, clonidine, and spironolactone. β-Blockers were recommended as a second agent in both groups to achieve the blood pressure goal. Once-daily loop diuretics could be given for volume management. After the initial 3-month titration period, the patients returned at 6 months and then at 6-month intervals until trial end. Patient follow-up examinations for the end point evaluation continued until trial end, even if the study medication had been permanently discontinued.
The primary end point of the ACCOMPLISH trial was the interval to the first event of the composite CV morbidity and mortality. CV morbidity was defined as nonfatal, clinically evident acute myocardial infarction; nonfatal stroke; hospitalization for unstable angina pectoris; resuscitated sudden cardiac death; and coronary revascularization procedures. CV mortality was defined as death from sudden cardiac death, myocardial infarction, stroke, coronary intervention, congestive heart failure, or other CV causes. The prespecified secondary end points included a composite of death from CV causes, nonfatal stroke, and nonfatal myocardial infarction.
ACCOMPLISH was an event-driven trial designed to accrue 1,642 patients with a primary event, providing 90% power to detect a 155-risk reduction for the B+A group at a 2-sided significance level of 0.05, assuming an annual event rate of 3.5% for the B+H group. A central committee whose members were unaware of study group assignment adjudicated all prespecified end points using standard criteria. An independent data monitoring committee met twice yearly. Originally, 4-year formal interim analyses for efficacy were planned.
The analysis of the primary end point, its components, and all other efficacy end points followed the intention-to-treat principle. The Kaplan-Meier methods were used to construct cumulative time-to-event curves for the 2 groups, and the primary comparison was based on a log-rank test. Univariate Cox regression, which only included treatment in the model, was performed for the interval to the first primary event to obtain the point estimate and 95% confidence intervals for the hazard ratio between groups. Superior efficacy for the B+A treatment group was concluded if the log-rank test was significant with risk reduction. Interval-to-first event analyses using similar log-rank tests and univariate Cox regression were also performed for each component of the primary end point and all other efficacy end points, without censoring for previous events, including all patients with complete information for the respective end points. The specific details regarding the statistical analysis can be found in the main report of the ACCOMPLISH trial.
Results
The main trial randomized 11,506 patients. Of those, 5,744 received B+A and 5,762 received B+H. The mean patient follow-up was 35.7 months for the B+A group and 35.6 months for the B+H group. At trial completion, vital status could not be obtained for 17 patients (1%), who were lost to follow-up. The baseline characteristics, primary end points, blood pressure levels over time, and safety data in the intention-to-treat cohort have been previously reported.
Patients with CAD had a lower systolic blood pressure and heart rate, fewer strokes and diabetes, and more dyslipidemia and were taking more lipid-lowering agents, β blockers, and antiplatelet agents. However, no differences were seen at baseline between the B+A and B+H groups in the patients with and without CAD. The overall mean systolic/diastolic blood pressure after titration was 131/73 mm Hg in the B+A and 132/74 mm Hg in the B+H group (a mean difference of 1/1 mm Hg; p <0.0001) after 36 months. Blood pressure control was achieved by 75% and 72% of the patients in each group. A total of 5,314 patients were classified as having CAD at baseline and 6,191 as not having CAD. Significant differences were found in a number of baseline variables between those with CAD and those without CAD ( Table 1 ). Patients classified as having CAD at baseline were significantly older, more likely to be men, and more likely to be white than those without CAD. They were also significantly more likely to have received a lipid-lowering drug, β blocker, or an antiplatelet agent.
| Characteristic | CAD (n) | p Value | |
|---|---|---|---|
| Yes (n = 5,314) | No (n = 6,192) | ||
| Mean age (yrs) | |||
| ≥65 | 3,578 (67.3) | 4,062 (65.6) | 0.0515 |
| ≥70 | 2,257 (42.5) | 2,446 (39.5) | 0.0013 |
| Gender | |||
| Male | 3,692 (69.5) | 3,271 (52.8) | <0.0001 |
| Female | 1,622 (30.5) | 2,921 (47.2) | |
| Race | |||
| White | 4,689 (88.2) | 4,924 (79.5) | <0.0001 |
| Black | 442 (8.3) | 974 (15.7) | <0.0001 |
| Other | 183 (3.4) | 294 (4.7) | 0.0005 |
| Region | |||
| United States | 3,911 (73.6) | 4,241 (68.5) | |
| Nordic countries | 1,403 (26.4) | 1,951 (31.5) | <0.0001 |
| Blood pressure (mm Hg) | |||
| Systolic | 144.05 ± 18.1 | 146.45 ± 16.9 | 0.06 |
| Diastolic | 78.31 ± 10.6 | 79.12 ± 11.1 | 0.12 |
| Diabetes | 4,032 (75.8) | 3,298 (53.8) | 0.01 |
| Lipid-lowering therapy | 4,392 (82.6) | 3,430 (55.4) | <0.0001 |
In patients with CAD, the mean blood pressure for the B+A and B+H groups was 144 and 144 mm Hg (147 and 146 mm Hg for non-CAD patients) at baseline and 130 and 131 mm Hg (133 and 133 mm Hg for non-CAD patients) at the end of the follow-up period, respectively.
The interval to the first primary end point in each of the 2 treatment groups is shown in Figure 1 . Among the patients with CAD, 348 of 2,648 (13%) in the B+A group and 428 (16%) in the B+H group reached the primary end point, representing an absolute risk reduction of 3% and a hazard reduction of 18%. The difference in event rates of the composite primary end point between the B+A and B+H groups was significant (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69 to 0.92, p = 0.0016; Figure 2 ). The difference between the 2 treatment arms was mainly dependent on the significantly greater fatal and nonfatal event rate in the B+H group (HR 0.66, 95% CI 0.49 to 0.88, p = 0.0052). A trend toward lower rates of coronary revascularization with B+A was found (HR 0.84, 95 CI% 0.71 to 1.002, p = 0.051). Among the patients without CAD, fewer patients in the B+A treatment arm (204 of 3,096) reached the primary end point compared with those in the B+H arm (251 of 3,095). The difference in event rates between the B+A and B+H groups was significant (HR 0.81, 95% CI 0.67 to 0.98, p = 0.026; Figure 2 ). A comparison of patients with and without CAD event rates for the primary end points demonstrated that the patients with CAD had a greater CV event rate than those without CAD (15% vs 7%, p <0.0001).
The secondary end points in the 2 treatment arms are listed in Table 2 . The composite secondary end point of CV mortality, myocardial infarction, and stroke occurred in 155 (5.74%) in the B+A group and 205 (8%) in the B+H group, resulting in an absolute risk reduction of 1.95% and a hazard reduction of 25% (HR 0.73, 95% CI 0.59 to 0.9, p = 0.033; Table 2 ). The rate of all-cause mortality differed significantly between the 2 treatment arms (HR 0.77, 95% CI 0.6 to 0.99, p = 0.042). The rate of hospitalization for congestive heart failure did not differ between the 2 arms (HR 1.0, 95% CI 0.7 to 1.43). However, when heart failure hospitalizations were added to the primary end point, fewer events were found in the B+A group (387 of 2,648) than in the B+H group (464 of 2,666). Among the patients without CAD, the rates of CV mortality, myocardial infarction, and stroke did not differ between the 2 arms (HR 0.86, 95% CI 0.68 to 1.08; Table 2 ). The secondary end point events were lower in the group of patients without CAD.
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