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


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. ( number, NCT00170950.)

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Available from: Eric J Velazquez
    • "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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    • "Antihypertensive drugs are not always effective in normalizing BP, and two or three drugs are often required [Mancia, 2009]. Moreover, these drugs are not particularly effective in reducing TOD and adverse effects are common [Jamerson et al. 2008]. Thus, there is a need to develop more effective antihypertensive drugs to normalize BP, reduce cardiovascular and renal remodeling, and increase compliance. "
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    ABSTRACT: The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling. © The Author(s), 2015.
    Full-text · Article · Aug 2015 · Therapeutic Advances in Cardiovascular Disease
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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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    ABSTRACT: Hypertension is a major problem among European ethnic minority groups. We assessed the current situation of hypertension prevalence and its management among a multi-ethnic population in Amsterdam, The Netherlands. Data from the HELIUS study were used including 12,974 participants (1871 Ghanaian, 2184 African Surinamese, 2278 South-Asian Surinamese, 2277 Turkish, 2222 Moroccan and 2142 Dutch origin people), aged 18-70years. Comparisons among groups were made using proportions and age-adjusted prevalence ratios (PRs). Hypertension prevalence ranged from 24% and 16% in Moroccan men and women to 52% and 62% in Ghanaian men and women. Except for Moroccan women, age-adjusted PR of hypertension was higher in all the ethnic minority groups than in Dutch. Among hypertensives, ethnic minority groups generally had higher levels of hypertension awareness and BP lowering treatment than Dutch. Moreover, prevalence rates for the prescription of more than one BP lowering drug were generally higher in African and South-Asian origin groups compared with Dutch origin people. By contrast, BP control levels were lower in all the ethnic groups than in Dutch, with control rates being significantly lower in Ghanaian men (26%, PR=0.49; 95% CI, 0.37-0.66) and women (45%, PR=0.64; 0.52-0.77), African-Surinamese men (30%, PR=0.61; 0.46-0.81) and women (45%, PR=0.72; 0.51-0.77), and South-Asian Surinamese men (43%, PR=0.77; 0.61-0.97) and women (47%, PR=0.76; 0.63-0.92) compared with Dutch men (53%) and women (61%). Our findings indicate poor BP control in ethnic minority groups despite the high treatment levels. More work is needed to unravel the potential factors contributing to the poor control in order to improve BP control in ethnic minority groups, particularly among African and South-Asian origin groups. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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