Elsevier

The Lancet

Volume 377, Issue 9762, 22–28 January 2011, Pages 312-320
The Lancet

Articles
Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial

https://doi.org/10.1016/S0140-6736(10)62003-XGet rights and content

Summary

Background

Short-term studies have suggested that the use of initial combination therapy for the control of blood pressure improves early effectiveness. We tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy.

Methods

We did a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16–32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862.

Findings

318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001). At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI −0·05 to 2·9; p=0·059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension.

Interpretation

We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended.

Funding

Novartis Pharma AG.

Introduction

Hypertension is a complex disorder, and target blood pressure in most patients cannot be achieved with monotherapy.1 Yet guidelines give muted advice on starting treatment with a combination of drug classes, and only the β blocker–diuretic combinations are licensed for this use in the UK.2, 3 There are two reasons why initial treatment with combination regimens might be advantageous for patients. First is the short-term gain from the rapid reduction of the patient's risk from raised pressure. Second is the gain from improved long-term blood pressure control. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study, in which there was a 3·8/2·2 mm Hg difference in blood pressure between the valsartan and amlodipine groups after treatment for 3 months, provides circumstantial evidence for both gains.4 There was a 75% early excess of cardiovascular morbidity and an almost three-times increase in all-cause mortality in the valsartan group, and 5 years later blood pressure was still 1·8/1·5 mm Hg higher in this group despite greater use of diuretic add-on treatment. Put simply, blood pressure control never caught up. Similar early and later differences in blood pressure have been recorded in other trials, such as the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT).5, 6

Previous comparisons of combination treatment with monotherapy have been short-term (average 6 weeks) and included too few patients at high doses to exclude symptomatic hypotension as a complication.7 In most of the trials, patients were transferred from previous treatment rather than receiving the combination de novo.

To test whether long-term blood pressure might be determined by initial treatment we designed a trial in which all patients at the time of the trial's primary endpoint were in receipt of the same treatment—a combination of amlodipine and aliskiren—but half the patients would start the combination 6 months earlier and half would start monotherapy with either amlodipine or aliskiren. Our hypothesis was that initial treatment with two drugs of complementary mechanisms would achieve earlier, larger, and more sustained reductions in blood pressure than a sequential add-on regimen. The mechanistic rationale for this hypothesis was that compensatory haemodynamic or neuroendocrine responses to individual drugs might attenuate their effectiveness, prevent catch up when a second drug is added, and contribute to adverse events that lead to the discontinuation of treatment.

Section snippets

Participants

We did a double-blind, randomised, parallel-group, superiority trial in 146 primary and secondary care sites in ten countries (Canada, Costa Rica, France, Germany, Greece, Guatemala, South Africa, Switzerland, the UK, and Venezuela), with enrolment from Nov 28, 2008, to July 15, 2009. Patients of both sexes aged 18 years or older were eligible if seated systolic blood pressure at the time of random assignment was between 150 mm Hg and 180 mm Hg, and diastolic blood pressure was less than 110

Results

Figure 1 shows the allocated drugs and doses used in our study and figure 2 shows the trial profile. Table 1 shows the demographic and baseline characteristics of the patients. 812 patients assigned to a treatment group were recruited in Europe (France, Germany, Greece, Switzerland, UK); 247 in Latin America (Costa Rica, Guatemala, Venezuela), 148 in South Africa, and 47 in Canada.

The primary endpoint of mean adjusted reduction in systolic blood pressure from baseline over weeks 8 to 24, was

Discussion

Our findings show that patients randomly assigned to initial combination treatment with both aliskiren and amlodipine had substantially better mean blood pressure reduction over the first 24 weeks than did patients starting on either drug as monotherapy, with no cost in adverse events or withdrawals. Once the monotherapy patients progressed to combination therapy, their blood pressure fell towards, but never numerically caught up with, that of the initial combination group. Although the

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