Combination therapy for hypertension in the elderly: a sub-analysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) Trial

Abstract

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a b-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; o140/ 90 mm Hg). We further evaluated the efficacy and safety of these combination therapies in older (X65 years) and younger (o65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (1533X65 years old and 1760 o65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a b-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P¼0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; b-blocker vs. thiazide, P¼0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; b-blocker vs. ARB, P¼0.043) for newonset diabetes. Thus, benidipine combined with an ARB, a b-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a b-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.

Guidelines for the Primary Prevention of Stroke

“…238 Subgroup analyses from 1 major trial suggest that the benefit of diuretic therapy over ACEI therapy is especially prominent in blacks, 239 and subgroup analysis from another large trial found that β-blockers were significantly less effective than thiazide diuretics and ARBs at preventing stroke in those ≥65 years of age than in younger patients. 240 The results of a recent trial of the direct renin inhibitor aliskiren in patients with type 2 diabetes mellitus plus chronic kidney disease or prevalent CVD did not find evidence that aliskiren reduced cardiovascular end points, including stroke. 241 In general, therefore, although the benefits of lowering BP as a means to prevent stroke are undisputed, there is no definitive evidence that any particular class of antihypertensive agents offers special protection against stroke in all patients.…”

Effects of a benidipine-based combination therapy on the risk of stroke according to stroke subtype: the COPE trial

“…The rationale, design, trial management and results of the COPE trial have previously been reported. [16][17][18] In brief, participants with a sitting systolic BP of 140 mm Hg or more and/or a diastolic BP of 90 mm Hg or more, whether untreated or treated, were men and women aged 40 to 85 years who did not achieve the target BP in a sitting position at our clinic following monotherapy with benidipine at a dose of 4 mg day -1 during the run-in phase (4-8 weeks). These patients were randomly assigned to receive benidipine combined with an ARB, a BB or a thiazide.…”

“…The trial results demonstrated that although the percentage of subjects achieving the target BP and the incidence of primary composite cardiovascular end points were similar among the benidipine-thiazide diuretic (TD), benidipine-angiotensin receptor blocker (ARB) and benidipine-b-blocker (BB) groups, second analyses suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-thiazide combination, predominantly in the elderly. [16][17][18] Although all benidipine-based regimens were well tolerated, the following adverse events were more frequent than in the other groups: new-onset diabetes and bradycardia in the benidipine-BB group; hyperuricemia, hypokalemia and increased levels of serum creatinine in the benidipine-thiazide group; hyperkalemia in the benidipine-ARB group; vertigo in the benidipine-BB and benidipine-thiazide groups; and increased levels of alanine aminotransferase in the benidipine-ARB and benidipine-thiazide groups. 17 It remains unknown which benidipine-based combination therapy was valuable for preventing the occurrence of specific types of stroke during treatment for hypertension in the COPE trial.…”

Effects of Calcium-Channel Blocker Benidipine-Based Combination Therapy on Cardiac Events ― Subanalysis of the COPE Trial ―

“…15 Secondary analyses suggested that benidipine combined with a β-blocker was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. [15][16][17] However, it remains unknown from the COPE trial which benidipine-based combination therapy is most useful for preventing the occurrence of specific types of cardiac events during treatment for hypertension. Thus, in this prespecified subanalysis of the COPE trial, we further evaluated the treatment effects of the 3 benidipine-based regimens in relation to different cardiac events.…”