Which antihypertensive medications are the most effective in treating hypertension in African Americans and older adults?

Comparative effectiveness of combination treatment for hypertension in black Africans

1. http://orcid.org/0000-0002-2420-0811Igho Onakpoya

1. Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

1. Correspondence to Dr Igho Onakpoya, Nuffield Department of Primary Care Health Sciences, University of Oxford, OX2 6GG, UK; igho.onakpoya{at}phc.ox.ac.uk

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

• hypertension
• therapeutics

Although different combination therapies are currently used for treating hypertension among blacks, the authors of a recently published trial suggest amlodipine plus either hydrochlorothiazide or perindopril is a more effective combination.

Calcium channel blockers are usually recommended as first-line treatment for control of hypertension.1 Among blacks, one or more antihypertensive medications are added to calcium channel blockers when sole treatment is inadequate for blood pressure control. However, there is uncertainty about which drug combination is more effective for use as combination therapy. In the UK for instance, the National Institute for Health and Care Excellence recommends use of either an ACE inhibitor, an angiotensin receptor blocker (ARB), or a thiazide-like diuretic as second-line.2

In a recently published single-blinded, three-arm, multicountry study (n=728),3 the authors compared the effectiveness of 5 mg of amlodipine (a calcium channel blocker) plus 12.5 mg of hydrochlorothiazide (a thiazide), 5 mg of amlodipine plus 4 mg of perindopril (an ACE inhibitor) or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide in the management of uncontrolled hypertension among blacks living in the sub-Saharan Africa. Their primary outcome was the mean change in 24-hour ambulatory systolic blood pressure between baseline and at 6 months. Secondary outcomes included mean change in 24-hour ambulatory diastolic blood pressure between baseline and at 6 months, change in mean daytime and mean night time ambulatory blood pressures.

At 6 months, and after adjusting for baseline ambulatory systolic blood pressure, participants who received either of the two amlodipine combinations had significantly larger reductions in mean ambulatory systolic blood pressure than those who received perindopril plus hydrochlorothiazide: −3.14 mm Hg (p=0.03); and mean difference (MD) −3.00 mm Hg (p=0.04), respectively. Similar results were observed for mean daytime and night time ambulatory blood pressures. There was no significant difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril: MD −0.14 mm Hg (p=0.92). There were no significant differences in ambulatory diastolic blood pressures between groups.

The investigators used electronic methods to ensure adequate randomisation, there was a high completer rate (95.9%), and appropriate statistical tests were performed. The investigators also included an independent statistician to analyse the trial results.

However, there were limitations. Although the trial was reported as single-blind (investigators), the participants may not have been totally blinded because the interventions were only repackaged—their appearances, shape and taste essentially remained the same. The study did not include participants with comorbidities.

Results of a large observational study have shown that ACE inhibitors may not be effective for treatment of hypertension in blacks.4 Indeed in the UK, ARBs are preferred to ACE inhibitors as second-line.5 Therefore, it seems unlikely the results of this study will change current clinical practice guidelines on blood pressure management in black populations. Future studies in this area should include an ARB arm (and/or other antihypertensives with different mechanisms of action) to assess the comparative effectiveness of drug combination therapies.

EBM verdict

EBM Verdict on: Comparison of dual therapies for lowering blood pressure in black africans. N Engl J Med 2019;380:2429–39. doi: 10.1056/NEJMc1909844.

• Among blacks with hypertension, amlodipine plus either hydrochlorothiazide or perindopril could be a more effective combination for second-line treatment.

Read the full text or download the PDF:

Log in using your username and password

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.

Evidence:
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).

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.   

References:

1. Ojji DB, Mayosi B, Francis V, et al. Comparison of dual therapies for lowering blood pressure in black Africans. N Engl J Med. 2019. doi: 10.1056/NEJMoa1901113.

2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: a report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014;311(5):507-20. doi: 10.1001/jama.2013.284427.

3. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. 

4. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community. J Clinical Hypertension. 2013;16(1). doi:10.1111/jch.12237.

5. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart J. 2018;39(33):3021-3104. doi:10.1093/eurheartj/ehy339.

What is the best antihypertensive for African Americans?

What is the first line antihypertensive for African American?

Why are calcium channel blockers preferred in African American?

Why are ACE inhibitors not first line for African Americans?