Best two-drug antihypertensive combinations for black African patients

Michelle Mages, Pharm.D., Hennepin Healthcare

Background: Black patients have a higher prevalence of hypertension, treatment resistant hypertension, and poorer blood pressure control. It is known that certain antihypertensive agents work better and have different adverse drug event frequencies in black patient populations, which guides monotherapy. However, various guidelines provide different direction on which two-drug combination is best to treat hypertension in black patients.

Current Guidelines
The American College of Cardiology and American Heart Association 2017 hypertension guidelines suggest initial therapy of a calcium channel blocker (CCB) or thiazide diuretic for black patients. Further, it states that two drugs are often needed for treatment of hypertension in black patients. When guiding two-drug combination selection comorbid conditions are considered, however the guideline ultimately endorses any combination including a CCB or thiazide diuretic with each other, an angiotensin converting enzyme inhibitor (ACE-I), or angiotensin-receptor blocker (ARB). 

Joint National Committee 8 recommends initial therapies of a thiazide diuretic or CCB in black patients, but does not provide specific guidance on the best second agent to choose. In general, it recommends adding a CCB, thiazide diuretic, ACE-I, or ARB as a second drug if a patient is not responding to monotherapy.

The American Society of Hypertension and the International Society of Hypertension recommends a CCB or thiazide diuretic (CCB preferred, but thiazide diuretic if cost is a concern) as initial drugs of choice for black patients. If additional treatment is indicated, they suggest adding an ACE-I or ARB. If ACE-Is and ARBs are not available, a CCB or thiazide diuretic, whichever the patient is not already taking, may be added as a second agent.  

The European Society of Cardiology and European Society of Hypertension suggest that black patients be initiated on two drugs to start. The guideline states that black patients respond better to thiazide diuretics or CCBs, and the combination or addition of an ACE-I or ARB can be used. 

CREOLE Study 2019
The CREOLE study is a randomized, single-blind, multicenter, three-group trial that compared the safety and efficacy of three different two-drug combinations for the treatment of hypertension. Throughout six countries in sub-Saharan Africa, 621 black participants were randomized to the following groups in a 1:1:1 ratio: amlodipine 5 mg and hydrochlorothiazide 12.5 mg, amlodipine 5 mg and perindopril 4 mg (approximately equivalent to lisinopril 10 mg), or perindopril 4 mg and hydrochlorothiazide 12.5 mg. At two months, doses were doubled if the patient was tolerating the medication. The primary outcome was ambulatory systolic blood pressure at baseline and 6 months. Of participants, 63% were female, the mean age was 51 years old, and 4% of participants had diabetes. The combinations including amlodipine were shown to be more effective than the combination without amlodipine (Table 1).

Table 1. CREOLE comparison of two-drug combinations

Two-drug combinations

Mean difference (95% confidence interval)

P Value

amlodipine 5 mg and hydrochlorothiazide 12.5 mg vs. perindopril 4 mg and hydrochlorothiazide 12.5 mg

-3.14 mm Hg (-5.90 to -0.38)


amlodipine 5 mg and perindopril 4 mg vs.

perindopril 4 mg and hydrochlorothiazide 12.5 mg

-3.00 mm Hg (-5.8 to -0.20)


amlodipine 5 mg and hydrochlorothiazide 12.5 mg vs. amlodipine 5 mg and perindopril 4 mg

-0.14 mm Hg (-2.90 to 2.61)


Discussion: CREOLE shows two-drug combinations including amlodipine are superior to non-CCB combinations. Most guidelines thus far have advised the use of a CCB or thiazide diuretic first and to add on the opposite, an ACE-I, or an ARB for combination therapy. The CREOLE study provides evidence to support the addition of a thiazide or an ACE-I to a CCB. Of note, ARBs were not included in this study.  

The CREOLE study is limited because it only looked at sub-Saharan African patients and was single blinded. In spite of these limitations, the recommendations provided from this study not only represent current standards of care, but specifically outline the best dual therapy for black patients for the treatment of hypertension. 

Clinical Impact: When adding a second antihypertensive agent or initiating a two-drug combination for a black African patient, CREOLE demonstrates there are superior combinations to decrease systolic blood pressure over six months. Aside from other comorbidities that may influence drug selection, it may be beneficial to select combination therapy that includes a CCB.   


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