Article

Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients

Division of Cardiovascular Medicine, University of Michigan Health System, 24 Frank Lloyd Wright Dr., Lobby M, Ann Arbor, MI 48106, USA.
New England Journal of Medicine (Impact Factor: 55.87). 01/2009; 359(23):2417-28. DOI: 10.1056/NEJMoa0806182
Source: PubMed

ABSTRACT

The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic.
In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.
The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs.
The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)

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    • "In any of the meta-analyses with more than two RCTs was a trial found to have an excessive influence. Separate secondary meta-analyses including also RCTs allowing inclusion of mild heart failure (also listed in Table 2)[37,45,50,57,65,66,75]gave results overlapping with those of the primary analyses shown in Fig. 4b.Effects on 'new-onset' heart failure of calcium antagonists in randomized controlled trials allowing or forbidding the simultaneous use of drugs active in heart failure treatment Of the 13 comparisons of calcium antagonists with other classes of BP-lowering drugs in 12 RCTs excluding preexisting heart failure at baseline, four were in RCTs, the design of which allowed the concomitant use of diuretics, b-blockers or renin–angiotensin system blockers in the calcium antagonist group: in ACCOMPLISH[46], patients[37](MOSES)[65]INSIGHT[59](ABCD-H)[45](MOSES)[65](NAGOYA)[65]JMIC-B[61](CAPPP)[50](NAGOYA)[66](VALUE)[75]MIDAS[64](VALUE)[75]NICS-EH[67]NORDIL[68]VHAS[76](ABCD-H)[45](IDNT)[37](MOSES)[65](NAGOYA)[66](VAUE)[75]ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BBs, b-blockers; CAs, calcium antagonists; HF, heart failure; RASbs, renin–angiotensin system blockers. Trials indicated by their acronyms or first author. "
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    ABSTRACT: Background and objectives: Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization. Methods: Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions. Results: First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]. Conclusion: BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists.
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    • "and ethnic differential response to BP-lowering agents [23] [24] [25] may play a major role. In a qualitative study in Amsterdam, African Surinamese and Ghanaian residents perceived psychosocial stress as an important contributor to their high levels of hypertension and felt that a return to their homeland could even cure hypertension, as they perceived their BP to be low when they are in their country of origin. "
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