In the largest-ever randomized trial of antihypertensive drug treatment in sub-Saharan Africa, two medication combinations including the long-acting calcium channel blocker amlodipine outperformed a third two-drug combination featuring a diuretic and an angiotensin-converting-enzyme (ACE) inhibitor.
The results could have implications in Africa, which has the highest hypertension rates of any continent, as well as for African-Americans, experts said at the American College of Cardiology’s scientific sessions. The study, dubbed CREOLE, was presented March 18 during that annual meeting in New Orleans and published simultaneously online in the New England Journal of Medicine.
CREOLE enrolled 728 black patients from six countries—Cameroon, Kenya, Mozambique, Nigeria, South Africa and Uganda—who had an office systolic blood pressure above 140 mm Hg while taking one or zero antihypertensive agents. Numerous randomized trials and population-based studies have suggested that at least two antihypertensive drugs are needed to meet even conservative blood pressure targets, but the most effective two-drug combinations haven’t been established for an African population.
To address this question, lead author Dike B. Ojji, MD, PhD, and colleagues randomized the patients—average age 51; 63 percent women—to one of three daily treatment regimens for two months:
- 5 mg of amlodipine plus 12.5 mg of hydrocholorthiazide (A/H), a thiazide diuretic
- 5 mg of amlodipine plus 4 mg of perindopril (A/P), an ACE inhibitor
- 4 mg of perindopril plus 12.5 mg of hydrocholorthiazide (P/H)
After that two-month period, the doses of each medication were doubled for another four months, and then 24-hour ambulatory systolic blood pressure (SBP) served as the primary endpoint.
The two combinations featuring amlodipine were the most effective in lowering ambulatory SBP, with A/H achieving an average 18.1 mm Hg drop and A/P resulting in an average 17.1 mm Hg reduction. Compared to the third combination, these two treatments were associated with additional drops of 3.14 mm Hg and 3 mm Hg, respectively—both statistically significant differences.
For the secondary endpoint of office blood pressure readings, the average reduction was 7.15 mm Hg greater with A/H and 5.55 mm Hg greater with A/P compared to P/H.
“Our results suggest that a long-acting dihydropyridine calcium-channel blocker (in this case, amlodipine) may be critical to more efficacious blood-pressure lowering among black patients as part of the two-drug combinations used here,” Ojji, of the College of Health Sciences at the University of Abuja, Nigeria, and colleagues wrote. “These results contrast with recommendations for black patients in the most recent U.S. guidelines, which advise the use of either a calcium-channel blocker or a diuretic in combination with a different drug class.”
At the six-month mark, patients’ ambulatory SBP was 128 mm Hg on average, which falls under the recently lowered bar for hypertension in the U.S. (130/80 mm Hg).
“The efficacy of amlodipine in reducing blood pressure and cardiovascular events has been partly attributed to its effect on enhancing the bioavailability of vascular endothelial nitric oxide levels,” the researchers wrote. “This factor may be particularly relevant to blood-pressure reduction in black patients with hypertension because this population is reported to have lower bioavailability of nitric oxide than white patients.”
Despite the positive BP-lowering effects, the authors noted 5.3 percent of patients in the A/H group—the calcium channel blocker plus the diuretic—experienced a drop in blood levels of potassium below the normal range. In a press release, Ojji indicated patients taking this combination of drugs should have their potassium levels checked often and be encouraged to eat potassium-rich foods such as vegetables and bananas.
Ojji et al. noted caution is warranted when extrapolating the results to populations outside of sub-Saharan African. It is also unknown whether other agents in the same drug classes would have had similar BP-lowering effects, or whether using thiazide-like diuretics rather than hydrocholorthiazide would have changed the results.