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One in 3 adults in the United States have high blood pressure (HBP), which equates to more than 74 million people.1 From 1996 to 2006 the death rate due to HBP increased 19.5%. Blood pressure (BP) control in men <60, 60 to 79, and ≥ 80 years of age has been reported as 38%, 36%, and 38% respectively; for women in the same age groups it was 38%, 28%, and 23%, respectively.2 Achieving a target BP is obviously a problem and many guidelines recommend initial combination therapy if the patient needs ≥ 20 mmHg reduction in their systolic blood pressure (SBP). However, this leads to the next question, which combination? The landmark trial, ACCOMPLISH, provided important data indicating that achieving a target BP with combination therapy was not enough.3 Major adverse cardiovascular events (MACE) were lower in an angiotensin converting-enzyme inhibitor (ACEI) + amlodipine regimen versus the traditional diuretic-based regimen despite virtually identical (<1 mmHg SBP difference) control. These results led to the next question; is blood pressure reduction a valid surrogate outcome for MACE? Perhaps it is not whether you reach your target BP but rather how you reach it!

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Brown and colleagues recently published the results of the Aliskiren and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension (ACCELERATE) trial.4 The authors performed a double-blind, randomized, parallel-group, superiority trial in 146 sites in ten countries (Canada, Costa Rica, France, Germany, Greece, Guatemala, South Africa, Switzerland, the UK, and Venezuela). Men and women aged 18 years and older with seated SBP between 150 and 180 mm Hg and diastolic blood pressure (DBP) < 110 were eligible. Subjects entered into a 2 to 4 week placebo run-in phase during which existing antihypertensive medications were stopped. The study consisted of three sequential phases of double-blinded active treatment. In phase 1 (weeks 0 to 16), half of the patients started monotherapy with either aliskiren (150 mg) or amlodipine (5 mg) and the other half started a combination regimen of aliskiren (150 mg) + amlodipine (5 mg). At 8 weeks the doses of each were doubled. In phase 2 (weeks 16 to 24), all patients received the same combination of aliskiren (300 mg) + amlodipine (10 mg). During the final phase (weeks 24 to 32), patients received the addition of hydrochlorothiazide (HCTZ 12.5 mg) or placebo depending on their BP (SBP > 140 mm Hg or DBP > 90 mm Hg). There were two sequential primary endpoints; the first, a mean reduction from baseline of SBP over weeks 8, 16, and 24, testing for superiority between the initial combination regimen versus each of the monotherapies. The second hypothesis was only tested if the first hypothesis was positive; was SBP reduction at week 24 greater in patients initially treated with combination therapy?

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Twelve hundred fifty four patients were randomized; 318 to aliskiren, 316 to amlodipine, and 620 to combination therapy. The average age of the cohorts was 58 years, approximately half were women, and most were white (77 to 79%). Five hundred patients had newly diagnosed HBP. The baseline SBP in all groups was ~ 161 mm Hg. The mean adjusted reduction in SBP from baseline compared to weeks 8 to 24 was 25.3 mm Hg in the combination group and 18.9 mm Hg in the monotherapy groups. At week 24 when all patients were on a combination of aliskiren 300 mg daily + amlodipine 10 mg daily, the cohort initially assigned to combination therapy had a SBP 1.4 mm Hg lower than the cohorts initially treated with monotherapy. Patient withdrawals due to adverse events occurred in 14% of the initial aliskiren + amlodipine group, 14% of the aliskiren monotherapy group, and 18% of the amlodipine monotherapy group. The authors concluded that initial combination therapy using aliskiren + amlodipine could be recommended in patients whose baseline SBP was > 150 mm Hg.

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One should proceed with caution when recommending initial treatment for HBP. We now know that BP reduction per se is not a valid surrogate outcome for decreasing MACE. Even some of ...

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