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

Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
The Lancet (Impact Factor: 45.22). 01/2011; 377(9762):312-20. DOI: 10.1016/S0140-6736(10)62003-X
Source: PubMed


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.
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, number NCT00797862.
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.
We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended.
Novartis Pharma AG.

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Available from: Thomas Macdonald, Apr 06, 2014
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    • "This suggests that some patients initially unresponsive to monotherapy may eventually achieve BP goal if continued on the same treatment at the same or a higher dose of monotherapy. However, the time taken to achieve BP goal is also an important risk factor [32–36]. Therefore, due to greater likelihood of goal attainment and greater SBP/DBP reduction, early treatment with SPC therapy may be preferable to quickly achieve and maintain BP goal. "
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    ABSTRACT: Hypertensive patients unable to reach blood pressure (BP) targets with antihypertensive monotherapy may be switched to a combination of two medications with complementary modes of action for improved treatment response. This post hoc analysis pools data from 2812 patients, 1891 of whom were not at goal (diastolic BP [DBP] <90 mm Hg) with amlodipine 5 mg (A5) monotherapy who subsequently switched to telmisartan 40 or 80 mg (T80)/A5 single-pill combination (SPC) or amlodipine 10 mg (A10) monotherapy, and considers an additional 921 patients, 616 of whom were not at goal with A10 monotherapy who switched to telmisartan/amlodipine SPC. Patients switched to telmisartan/amlodipine SPC achieved significantly greater BP reductions compared with continued monotherapy (P < 0.0001) with reductions of -15.2/-10.9 mm Hg seen with T80/A5 after 8 weeks in patients switched from A5. BP goal (<140/90 mm Hg), systolic BP goal (<140 mm Hg), and DBP goal (<90 mm Hg) were reached by significantly more patients with telmisartan/amlodipine than with monotherapy (P < 0.0001 for all comparisons; 56.1%, 69.7%, and 66.9%, resp., in patients who switched from A5 to T80/A5). Early use of such combination therapy should be considered to quickly reach BP targets, particularly in patients with added risk.
    Full-text · Article · Jun 2013 · International Journal of Hypertension
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    • "Blood pressure-lowering efficacy has been shown for combinations of amlodipine with angiotensin receptor blockers26 and renin inhibitors,27 and based upon the complementary mechanisms of action of these agents it would be logical to suggest that they would produce at least similar reductions in CVD risk. Trials examining effects of amlodipine/newer RAS blockade agents on CVD outcomes are underway and results pending.28 "
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    ABSTRACT: Amlodipine is a long-acting, dihydropyridine calcium antagonist now widely used for lowering of elevated blood pressure. In recent years it has been shown to be effective in reducing both blood pressure and risk of cardiovascular (CV) events when used in combination with other antihypertensive agents of different classes. Strong evidence of cardiovascular benefit has been attained for combination of amlodipine with diuretics or angiotensin converting enzyme (ACE) inhibitors in a number of high-risk CV groups, including those with established coronary artery disease, diabetes, and at risk of renal disease. Combination therapies of amlodipine with other agents eliciting renin-angiotensin-aldosterone system blockade (angiotensin II receptor blockers or renin inhibitors) have been shown to be effective blood pressure-lowering strategies, but await the results of ongoing trials for direct evidence of benefit for renal disease progression and CV morbidity and mortality.
    Full-text · Article · Jan 2012 · Integrated Blood Pressure Control
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    • "The organ protective effect of direct renin inhibitors has been shown to be more pronounced for the kidney.24 Direct renin inhibitors showed a good and rapid blood pressure-lowering response when used in combination with a calcium channel antagonist in a recently published hypertension study.25 Used alone or in combination, direct renin inhibitors have great potential in the treatment of hypertension in high-risk patients. "
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    ABSTRACT: Patients are considered to be at high risk of cardiovascular events if they have diabetes, chronic kidney disease, stroke, established coronary artery disease, or a coronary artery disease equivalent. Blood pressure-lowering therapy has been shown to reduce cardiovascular events in these patients significantly. Identification of high-risk patients by global risk evaluation is recommended for every hypertensive patient. Treatment of hypertension in high-risk patients with an angiotensin-converting enzyme inhibitor or an angiotensin receptor antagonist, with or without addition of a dihydropyridine calcium channel antagonist, is a reasonable approach based on current clinical trials.
    Full-text · Article · Mar 2011 · Vascular Health and Risk Management
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