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