Amlodipine the Key Component in Dual BP Therapy in Sub-Saharan Africa: CREOLE

NEW ORLEANS, LA—For black patients in sub-Saharan Africa, adding amlodipine to either hydrochlorothiazide (HCTZ) or perindopril is the best way to reduce blood pressure over 6 months, according to data from the CREOLE randomized trial. That combination surpasses the effectiveness of HCTZ and perindopril paired together.

CREOLE is a rare look at the needs of this population, for whom the burden of hypertension and its complications are high, Dike Ojji, MD, PhD (University of Abuja, Nigeria), told attendees at the American College of Cardiology 2019 Scientific Session last week. “Most patients with hypertension require at least two antihypertensive agents to reach current BP targets,” he said. “Hitherto, no RCTs have compared the efficacy of contemporary two-drug combination therapies in this population.”

To fill this gap, Ojji and colleagues tested whether a calcium channel blocker (amlodipine) plus a thiazide diuretic (HCTZ) would outperform either a calcium channel blocker plus an ACE inhibitor (perindopril) or a diuretic plus an ACE inhibitor.

We know cardiovascular disease is worldwide and having a better understanding of exactly how it expresses itself is extremely important. Eileen Handberg

Speaking at a media briefing, Ojji said these particular medications were chosen because they are commonly prescribed and recommended in sub-Saharan Africa.

He told TCTMD that the drugs are “widely available but sometimes, because of cost, getting them becomes a problem.” Ninety percent of the time, he said, patients lack health insurance. Even with many generics on the market in the region, out-of-pocket costs can be prohibitive for some individuals.

Controlling BP in Sub-Saharan Africa

CREOLE, a single-blind trial conducted in six countries across sub-Saharan Africa, enrolled 728 black patients (mean age 51 years; 63% women) who had uncontrolled hypertension, defined as ≥ 140/90 mm Hg without treatment or while taking only one antihypertensive drug. The patients were randomized to receive one of three daily regimens for 2 months: 5 mg amlodipine plus 12 mg HCTZ, 5 mg amlodipine plus 4 mg perindopril, or 4 mg perindopril plus 12.5 mg HCTZ. Doses were then doubled, and patients continued taking their medications for another 4 months.

Fully 95.9% of patients completed the trial, and 85.3% had ambulatory BP measurements at baseline and 6-month follow-up. Based on pill counts, adherence to the study drugs was similar across all three arms.

Mean change in 24-hour ambulatory systolic BP between baseline and 6 months, the primary endpoint, was greatest for the two amlodipine groups and did not differ between them. Both were more effective than perindopril plus HCTZ.

24-Hour Ambulatory Systolic BP: Mean Change From Baseline to 6 Months

The researchers identified similar differential effects for office and ambulatory diastolic BP, the BP control rate, and the response rate.

Ojji said in his presentation that side effects will likely be what guides the choice between the two amlodipine combinations. Dry cough and angioedema affected 5.8% and 0.8%, respectively, of patients taking amlodipine plus perindopril, whereas none of the amlodipine plus HCTZ patients had these side effects.  And with amlodipine plus HCTZ, 5.3% had hypokalemia (vs 0.4% with amlodipine plus perindopril). With amlodipine overall, 3.9% of patients developed pedal edema, with no differences seen between the amlodipine/perindopril and amlodipine/HCTZ groups.

“Pending trial evidence comparing the effects of these combinations on cardiovascular outcomes, these unique data may be useful to influence antihypertensive drug selection for black patients, at least those from sub-Saharan Africa,” Ojji concluded.

Notably, the CREOLE findings “contrast with recommendations for black patients in the most recent US guidelines, which advise the use of either a calcium channel blocker or a diuretic in combination with a different drug class,” the researchers point out. “The findings also contrast with European guidelines, which recommend the use of a combination of a calcium channel blocker with a diuretic or with an ACE inhibitor or a combination of an ACE inhibitor with a diuretic.”

Discussing the results during the media briefing, Eileen Handberg, PhD (University of Florida, Gainesville), said CREOLE is noteworthy for its scope.

“The importance of this trial revolves around understanding the epidemic of hypertension in Africa,” she commented. For Handberg, CREOLE had numerous strengths—its enrollment across Nigeria, Cameroon, Uganda, South Africa, Mozambique, and Kenya; the high proportion of women; and a large segment of previously untreated patients.

In particular, the details on side effect profiles can inform the design of future trials looking at cardiovascular outcomes, she suggested. “We know cardiovascular disease is worldwide and having a better understanding of exactly how it expresses itself is extremely important.”

To TCTMD, Ojji said the research group is now studying ways to expand access to hypertension treatment in Nigeria.

“One of the things we are trying to do to get to the community now is train nonphysicians to be able to measure blood pressure . . . , because a lot of people are dying because of [hypertension],” he explained. “You can imagine: people come to us for the first time and by the time they come they’ve had heart failure because of [high] blood pressure. So you do echos for them and see ejection fractions of 15% or 20%. Or they come in with kidney failure. . . . We need a lot of education.”