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REVIEW

Initial combination therapy for hypertension in patients of African ancestry: a systematic review and meta-analysis

Brewster, Lizzy M.a,b; Boermeester, Amber S.c; Seedat, Yackoob K.d; Van Montfrans, Gert A.e

Author Information
doi: 10.1097/HJH.0000000000003074

Abstract

BACKGROUND

Uncontrolled hypertension is a major risk factor for years of life lost [1–7]. The high risk for premature death differs significantly from controlled hypertension or normotension, with a hazard ratio for cardiovascular mortality of two to three times that of normotensives [5]. With a global burden of hypertension of around one billion people, control rates of less than 25% in most countries, and more than 10 million deaths yearly, achieving blood pressure control in the general population is one of the most pressing public health challenges [6].

Sub-Saharan African (African ancestry) patients are known to experience a relatively high burden of hypertension. Higher mean blood pressure, greater prevalence of uncontrolled hypertension and early end organ damage tend to result in higher premature mortality than European ancestry populations, as observed in American, African, and European studies [1–10]. A recent analysis from the United States of America indicated an age-adjusted mortality rate per 100 000 population for hypertension-related cardiovascular deaths for African vs. European ancestry patients of 1.76 [95% confidence interval (CI) 1.73;1.80] for men and 1.63 [1.60;1.66] for women [8].

It should be noted that persons of African ancestry are diverse in genetic background and social-economic circumstances. Nonetheless, in consideration of the increased cardiovascular risk, intensive management of hypertension is generally regarded to be imperative for this population subgroup, with attention for interpersonal and structural racism-related social disadvantages [9], as well as for clinical management with life style modification and drug therapy [10].

Hypertensive African ancestry patients tend to respond better to calcium channel blockers (CCBs) and diuretics than to ACE inhibitors (ACEIs), angiotensin II type-1-receptor antagonists (ARBs) and β-adrenergic blockers (BBs), but monotherapy is insufficient in most patients [1–3,11–16]. Because of greater patients’ adherence, faster achievement of goal blood pressure (GBP), and less adverse effects than up-titrated monotherapy, current guidelines suggest to use initial dual combination therapy, preferably as a single pill [1–3].

However, it remains unclear which drug combinations are most effective to improve outcomes in African ancestry patients, and current guidelines differ in their recommendations. The European Society of Cardiology/European Society of Hypertension guideline suggests prescribing a CCB combined with a renin angiotensin system (RAS) blocker, a diuretic + RAS blocker, or CCB + diuretic [2]. The International Society of Hypertension [1] advises CCB + ARB or CCB + thiazide-like diuretic, while the American College of Cardiology/American Heart Association [3] only recommends including a CCB or a thiazide-type diuretic in the drug regimen. Hitherto a systematic review was lacking. Therefore, we systematically reviewed the existing evidence on the efficacy of different initial dual combination therapies in reducing blood pressure and cardiovascular events in African ancestry patients with systemic arterial hypertension.

METHODS

The data that support the findings of this study are publicly available or can otherwise be obtained upon request from the corresponding author.

Protocol

We and others had previously published reviews on antihypertensive monotherapy in African ancestry patients [11–16], but no published or ongoing systematic review was retrieved on initial dual combination therapy (Supplement S.I. A, Supplemental Digital Content, https://links.lww.com/HJH/B829). We used the Cochrane Handbook for Systematic Reviews of Interventions [17,18], the International Prospective Register of Systematic Reviews (PROSPERO) Guidance notes for registering a systematic review protocol [19], the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement [20], and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE system) [21] to develop, conduct, and report this systematic review. The review protocol was published in the PROSPERO database on March 25, 2021.

Eligibility criteria

We included original reports with numerical data from randomized controlled trials of at least two weeks duration in adult non-pregnant African ancestry patients with systemic arterial hypertension, which addressed the differential efficacy of initial dual antihypertensive combination drug therapy and provided data on blood pressure, morbidity or mortality. We did not include trials conducted exclusively in patients with diabetes or trials that compared drugs within one drug class, except for thiazide-type vs. thiazide-like diuretics. African ancestry was defined as of (self-defined) sub-Saharan African ancestry, including patients belonging to the sub-Saharan African diaspora community, native sub-Saharan African patients, or as defined by the authors.

Outcomes

Predefined main outcomes were the difference in efficacy of initial combination therapies to reduce blood pressure and morbidity or mortality. We collected data on systolic (SBP) and diastolic blood pressure (DBP), and the percentage of patients reaching GBP as defined by the authors; measured in the sitting position (or as reported by the authors). Morbidity and mortality outcomes were collected as reported. In accord with current guidelines [1–3,21], main comparisons were: CCB + ACEI or ARB vs. diuretics + ACEI/ARB; CCB + diuretics vs. diuretics + ACEI/ARB; and CCB + ACEI/ARB vs. CCB + diuretics. We also collected data on adverse effects, dropouts, risk of bias (RoB) and certainty assessment. Predefined subgroup analyses were by severity of hypertension, sex, age groups and geographical location (in Europe, America, or Africa).

Information sources and search strategy

We sought to identify all trials that fulfilled the eligibility criteria. Adapting our previously published search strategies [11–15], we searched electronic databases (including PubMed; the Cochrane Library Central Register of Controlled Trials (CENTRAL), Embase, preprint servers, and clinical trial registers) from their inception to March 20, 2021, without language or time period restriction. The full search strategies, including filters and limits used are provided in Supplement S.I. A, Supplemental Digital Content, https://links.lww.com/HJH/B829.

Data extraction

Trial retrieval and data extraction procedures were conducted independently by two review authors (L.B. and A.B.). Details are provided in Supplement S.I. A, Supplemental Digital Content, https://links.lww.com/HJH/B829.

Risk-of-bias and certainty assessment

The Jadad score was assigned 0 to 5 points based on whether the study described methods of randomization and double-blinding, and reported the reason, number, and treatment arm of withdrawals and dropouts, basing the score on African ancestry patients. RoB, certainty assessment, and metabias were assessed according to the current guidelines [18,21,22] (see Supplement S.I. B, Supplemental Digital Content, https://links.lww.com/HJH/B829).

Effect measures

Our measure of effect for each study was difference in means (in mmHg) for systemic arterial blood pressure (continuous measure), and risk ratio (RR) for dichotomous data.

Synthesis methods

We used a combination of narrative and meta-synthesis. Quantitative analyses of outcomes were based on intention-to-treat results (primary) and per protocol analysis (secondary). We clinically assessed studies for heterogeneity in trial design, patient's characteristics, interventions, and outcomes before applying approximate chi-square tests for heterogeneity, using I2 statistics to quantify the heterogeneity. We addressed limitations when aggregating results with a high variation across studies because of heterogeneity (I2 ≥ 75%). We conducted random-effects meta-analysis primarily, with the DerSimonian and Laird method. We performed sensitivity analyses by reanalyzing data with fixed-effect meta-analysis using the inverse-variance method and by reanalyzing data after excluding studies with potential bias, such as with African ancestry patients as a subgroup, studies with imputed SDs, crossover studies, studies that used per protocol analysis, or other potential sources of bias. Statistical analysis was performed using Cochrane Review Manager (RevMan) software, version 5.4.1 (The Cochrane Collaboration, Oxford, United Kingdom). See Supplement S.I., Supplemental Digital Content, https://links.lww.com/HJH/B829 for extended methods.

RESULTS

Trial retrieval

Trial flow is depicted in Fig. 1. The 1728 records retrieved yielded 13 randomized controlled trials (29 treatment arms) of at least two antihypertensive combination therapies conducted mainly in North America and sub-Saharan Africa, involving six classes of drugs in 3843 hypertensive adults [23–53]. The full search results for all databases, details on trial flow, and excluded trials are in Supplement S.I. and S.II, Supplemental Digital Content, https://links.lww.com/HJH/B829.

F1
FIGURE 1:
Flow diagram of the search and selection process. With extra reports for the following studies, Cushman et al. [36], EVALUATE [37]; VITAE [38]; Calhoun et al. [39–41]; TRINITY [42–44]; CREOLE [45]; ACCOMPLISH [46–50]; AMORE [52]; and NOAAH [53,54]. See Table 1 for abbreviations and Supplement S.II., Supplemental Digital Content, https://links.lww.com/HJH/B829 for systematic search details.

Methodological quality of included studies

Four trials reported the method of randomization, nine were double blind, and three reported the method of blinding (Table 1). Three trials published a protocol in a peer-reviewed journal before trial ending [27,28,30], and recent trials had a protocol available in trial registers [25–30,35]. Most studies did not report how the drug dose for the experimental and control arms was chosen. Six trials used single-pill combination therapy [28–30,33–36]. Two trials included a triple therapy arm [25,26], but none compared triple therapies. The majority of the included trials (n = 9) employed an upper limit for blood pressure at inclusion [23–25,27,29,30,33–35]. Six trials reported adjusted blood pressure as a main outcome [23–27,35,36], which was not prespecified in a published protocol [23–26,35,36], or with a crude analysis prespecified [27,45]. Four trials used per protocol analysis as primary analysis [27,31,33,34], and one additional trial gave only numerical results for the per protocol analysis [32]. Seven trials were in African ancestry patients only [27,29,30–32,34,35], other trials included these patients as subgroups (non-stratified). Adverse effects and drop outs for African ancestry patients were reported in respectively 10 and six trials, with the Jadad score ranging from 2 to 4 (median 3). Two trials reported subgroup analyses by severity of baseline blood pressure [26,32], and none by sex or age. Two crossover studies were included [31,32]. Neither provided separate data before and after cross-over, but Manyemba [32] analyzed for period effects, which were not found.

TABLE 1 - Randomized controlled trials comparing initial dual combination therapy for hypertension in African ancestry patients
Trial Site Funding N AA Women Age (y) Inclusion BP Outcome Dual therapy comparison (drug and max daily dose in mg) Duration‡ Jadad§ CochraneRoB Certainty
(%) (%) Incl. (μ/s) (mmHg) D+ C+ D + C/O R B D T RoB score GRADE
EVALUATE [23,37] AME Novartis 79 (17) 44 ≥18 (53/8) SBP 160−199DBP < 120 SiOBPABP HCT 25Val 320 HCT 25Aml 10 4 w 1 1 0 2 High Low
VITAE [24,38] AME Novartis 126 (37) 78 ≥40 (53/8) SBP ≥150-180DBP < 110+AO SiOBPABP HCT 25Val 320 - HCT 25Aml 10 8 w 1 1 0 2 Interm. Moderate
Calhoun et al.[25,39–41] AMEEUR Novartis 291 (17) nd 18-85No mean SBP ≥145-200DBP ≥100-120 SiOBPABP HCT 25Val 320 Aml 10Val 320 HCT 25Aml 10 8 w 1 2 0 3 High Low
TRINITY [26,42–44] AME Daiichi Sankyo 573 (31) nd ≥ 18 (52/10) BP ≥140/100 SiOBP HCT 25Olm 40 Aml 10Olm4 0 HCT 25Aml 10 8 w 1 1 0 2 Interm. Moderate
CREOLE [27,45] AFR GSKAspenAcademia 728 (100) 63 30−79 (51/11) SBP ≥140−159 SiOBPABP HCT 25Per 8 Aml 10 Per 8 HCT 25Aml 10 26 w 2 0 1 3 High Low
ACCOMPLISH [28,46–51] AMEEUR Novartis 1414 (12) 60 ≥55 (67/7) SBP ≥160 + EOD SiOBPABPMorbMort HCT 25Ben 40 Aml 10Ben 40 3 y (BP: 3 m) 2 2 0 4 Interm. Moderate
AMORE [29,52] AME Daiichi Sankyo 66 (100) 62 18–75 (50/13) SBP ≤180DBP ≤110+MS cOBPABPSiOBP HCT 25Los 100 Aml 10Olm 40 14 w 1 0 1 2 Low Moderate
NOAAH [30,53,54] AFR Novartis/Academia 183 (100) 52 30−69 (51/9) SBP 140−179DBP 90−109 SiOBPcOBP HCT6.25Bis 10† Aml 10Val 160 26 w 1 0 1 2 Interm Moderate
Poulter et al. [31] AFR Wellcome 37 (100) nd 30-69 (no mean) DBP > 105 SuBPStBP HCT 25Prop 80 HCT 25Nif 20 6 w 1 1 1 3 Interm Moderate
Manyemba [32] AFR CAPS Pharma 32 (100) 81 18−70 (47/10) BP > 140/95on 25 mg HCT SiOBP HCT 25Res 0.5 HCT 25 Nif 40 4 w 2 0 1 3 Low High
Seedat et al.[33] AFR Bristol Mead-Johnson/ SAMRC 25 (100) nd Adults DBP 100-105 SuOBPStOBP HCT 50Sot 320 HCT 50Res 0.2 12 w 2 1 0 3 Low High
Maharaj et al. [34] AFR Bristol Meyers Squibb 52 (100) 0 18−65 (no mean) DBP 95−115 SuOBPStOBP CTD 25 Ate 100 HFM 100Res 0.25 8 w 1 2 0 3 Interm High
Cushman et al.[35,36] AME Takeda 237 (22) 46 ≥18 (53/9) SBP 160−190DBP ≤119 SiOBPABP CTD 25Azi 40 HCT 25 Olm 40 12 w 1 1 1 3 High Low
All studies were controlled trials in AA patients randomized to at least two different dual antihypertensive combination therapies, with blood pressure or morbidity and mortality outcomes.EVALUATE, The Evaluation of Valsartan's Uniqueness and Twenty-Four Hour Blood Pressure Efficacy trial; VITAE, Valsartan and hydrochlorothiazide in hypertensive abdominally obese patients trial; TRINITY, Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension trial; CREOLE, comparison of three combination therapies in lowering blood pressure in Black Africans trial; ACCOMPLISH, avoiding cardiovascular events through combination therapy in patients living with systolic hypertension trial; AMORE, African Americans with metabolic syndrome: changes in endothelial function and biomarkers trial; NOOAH, newer vs. older antihypertensive agents in African hypertensive patients trial.AA. African ancestry, AME, American continent, EUR, Europe; AFR, sub-Saharan Africa; GSK, GlaxoSmithKline; SAMRC, South African Medical Research Council; N, AA, African ancestry patients randomized to initial dual combination therapy; Age, Incl.(μ/s), inclusion criteria for age, mean age/SD of included patients. Blood pressure, SBP/DBP, systolic/diastolic blood pressure; ABP, ambulant brachial blood pressure; Si/St/SuOBP, sitting/standing/supine brachial office blood pressure; cOBP, central office blood pressure. Additional inclusion criteria, AO, abdominal obesity; EOD, end organ damage; MS, metabolic syndrome. Comparisons, D+; C+; D+C/O, diuretic, CCB, or diuretic + CCB (or other drugs); HCT, hydrochlorothiazide; Val, valsartan; Olm, olmesartan; Per, perindopril; Ben, benazepril; Los, losartan; Bis, bisoprolol; Prop, propranolol; Aml, amlodipine; Nif, nifedipine; Res, reserpine; Sot, sotalol; CTD, chlorthalidone; Azi, Azilsartan; HFM, hydroflumethiazide. Treatment duration, w, week; m, month; y, year. Evaluation, Jadad score, R randomization 1 point (p.), method of randomization 1 p.; D, double blind 1p., method of blinding 1 p., D, dropouts reported in AA patients (1p.; T, total max 5p.); RoB, risk of bias, please see Methods; Interm., intermediate; GRADE, Grading of Recommendations, Assessment, Development and Evaluation Working Group method of grading certainty of evidence [21]. Symbols: primary outcome; plus alpha-methyldopa 0.5−2 g a day if not controlled; duration of active dual combination therapies; §Jadad methodological quality score.

Risk-of-bias and Grading of Recommendations, Assessment, Development and Evaluations assessment

The median RoB score was “intermediate,” with some concerns regarding potential reporting bias (Figure S1, Supplemental Digital Content, https://links.lww.com/HJH/B829). Outcomes generally favored the industry-sponsored drug (Table S1, Supplemental Digital Content, https://links.lww.com/HJH/B829). The adjusted outcomes reported by the majority of industry trials might be a better mathematical reflection of the data, but regression model development and characteristics were rarely disclosed, which may lead to biased results [18,23–27,35,36]. Adjusted outcomes also reduce the directness as used in clinical practice in the GRADE score (Table S1, Supplemental Digital Content, https://links.lww.com/HJH/B829).

Metabias

Trials were generally underpowered to assess African ancestry patients as a subgroup [23–26,28,35], emphasizing the need for a meta-analysis. These subgroup data were often incomplete, presented in reports separate from the main paper, or otherwise difficult to retrieve (Supplement S.II., Supplemental Digital Content, https://links.lww.com/HJH/B829) [23–26,28,35–41,46–51]. Furthermore industry sponsors might have restricted principal investigators’ rights to discuss or publish trial results after the trial was completed [51]. Finally, multiple trials on a drug combination conducted by the same sponsor might not have been fully independent replications [23–25]. We accounted for these potential biases in sensitivity analyses.

Data synthesis

Clinical heterogeneity

Studies generally included patients with primary uncomplicated hypertension and a negative history of cardiovascular events, except for the “Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension” (ACCOMPLISH) trial (Table 1) [48,46–51].

Heterogeneity in outcomes

All trials had reported office brachial blood pressure, mainly in the sitting position, with three trials reporting supine and standing blood pressure [31,33,34]. Blood pressure was reported after 4−26 weeks (median 8) of treatment (n = 13) [23–38], with only the ACCOMPLISH trial reporting end point data, after 3 years [48,46–51].

Meta-analysis

Blood pressure as continuous outcome

With the random effects model, blood pressure reduction of CCB + ACEI/ARB vs. HCT + ACEI/ARB, was SBP −2.02 [−4.50;0.47], DBP −1.73 [−3.50;0.04] and for CCB + HCT vs. HCT + ACEI/ARB, SBP −2.64 [−5.72;0.44], DBP −2.05 [−4.33;0.23] (Fig. 2). SBP was significantly higher on BB combinations, 3.80 [0.82;6.78] mmHg. Differences in SBP between CCB + ACEI/ARB vs. CCB + HCT, chlorthalidone (CTD) vs. thiazide-type combinations, and reserpine combinations vs. other combinations were not significant, respectively −0.6, −2.2, and −0.4 mmHg, and comparable results for DBP (Fig. 2).

F2
FIGURE 2:
Effect of initial dual antihypertensive therapy on blood pressure in patients of African ancestry. Panel a. Systolic blood pressure. Panel b. Diastolic blood pressure. Legend (Panel a and b): Squares are weighted mean differences (WMD) in reduction of systolic/diastolic (SBP)/DBP) blood pressure (mmHg). The size of the squares and horizontal lines represent study weight and 95% confidence intervals (CIs), respectively. Black diamonds are pooled estimates. CCB, calcium channel blockers; A, ACEI or ARB; HCT, hydrochlorothiazide; BB, β-adrenergic blockers, CTD, chlorthalidone; TTD, thiazide type diuretic; combin., combination. See Table 1 for other abbreviations and drug doses.
F3
FIGURE 2 (Continued):
Effect of initial dual antihypertensive therapy on blood pressure in patients of African ancestry. Panel a. Systolic blood pressure. Panel b. Diastolic blood pressure. Legend (Panel a and b): Squares are weighted mean differences (WMD) in reduction of systolic/diastolic (SBP)/DBP) blood pressure (mmHg). The size of the squares and horizontal lines represent study weight and 95% confidence intervals (CIs), respectively. Black diamonds are pooled estimates. CCB, calcium channel blockers; A, ACEI or ARB; HCT, hydrochlorothiazide; BB, β-adrenergic blockers, CTD, chlorthalidone; TTD, thiazide type diuretic; combin., combination. See Table 1 for other abbreviations and drug doses.
Blood pressure control

Most trials used <140 mmHg SBP and <90 mmHg DBP as target blood pressure level (Table S2.A, Supplemental Digital Content, https://links.lww.com/HJH/B829). Outcomes for goal blood pressure were similar to the results for blood pressure reduction (Figure S2, Supplemental Digital Content, https://links.lww.com/HJH/B829).

Statistical heterogeneity

Statistical heterogeneity was mainly detected in comparisons of trials with African ancestry patients in subgroups (Fig. 2).

Sensitivity analyses

When using the fixed-effect model, blood pressure with CCB + ACEI/ARB or CCB + HCT was significantly lower than with HCT + ACEI/ARB (Fig. 2). Excluding trials with high RoB, with imputed SDs, crossover studies, trials using per protocol analysis, and trials including African ancestry patients subgroups (vs. including African ancestry patients only), resulted in comparable magnitudes and directions of effects as the main analyses, although some outcomes of borderline significance became statistically significant. Notably, after exclusion of trials with African ancestry patients as subgroups, the difference between CCB + ACEI/ARB (n = 230) vs. HCT + ACEI/ARB (n = 225) became −6.40 [−10.43; −2.36] for SBP and −4.28 [−6.97;−1.60] for DBP; with the results for CCB + HCT vs. HCT + ACEI/ARB also significant favoring CCB/HCT (other data not shown).

Subgroup analyses

In two trials reporting [26,32], blood pressure control depended on baseline blood pressure as expected (Table 1). In the “Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension” (TRINITY) trial [26], only 22.8−27.8% of the patients with baseline SBP > 180 mmHg or DBP > 110 mmHg achieved BP goal, vs. 37−44% of all included patients, with similar findings in the smaller trial by Manyemba [32]. We did not retrieve data on subgroups by sex or age, and found no evidence of differential effect of drugs by geographical location (data not shown) [27,30–34].

Other outcomes

Adherence, adverse effects, and drop outs are summarized in Table S2.B, Supplemental Digital Content, https://links.lww.com/HJH/B829. Three trials reported adherence assessed by pill counts, with similar results between treatment arms (>80%) [27,30,32]. Adverse effects, reported in 10 of 13 trials, included more hypokalemia and hyperglycemia with diuretics and peripheral edema with CCB's as expected. In the “Comparison of three combination therapies in lowering blood pressure in Black Africans” (CREOLE) trial, 5–6% of the patients receiving ACEI developed a dry cough vs. none with HCT/CCB [27].

Morbidity and mortality

A single study reported morbidity and mortality data in African ancestry patients in a prespecified subgroup analysis [28,46–51]. The trial included 11 506 hypertensive patients from five countries with a history of end organ damage or diabetes mellitus. Patients received amlodipine/benazepril (5/20) or HCT/benazepril (12.5/20 mg), which could be increased within 3 months to 10/40 mg and 25/40 mg, respectively, while BB, alpha-adrenergic blockers, clonidine or spironolactone could be added after 3 months to achieve control. Target blood pressure was <140/90 (<130/80 mmHg for patients with diabetes or with an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2). Time-to-first-event of composite cardiovascular morbidity and mortality was the primary endpoint. The main renal endpoint was doubling of serum creatinine or end-stage renal disease (eGFR < 15 ml/min per 1.73 m2 or renal replacement therapy) [28,46–51]. The trial was terminated early (mean follow up 3 years) [55], at 552 primary-outcome events in the amlodipine/benazepril group (9.6%) vs. 679 in the benazepril/HCT group (11.8%), an absolute increase of 2.2% (relative increase 22.9%, P < 0.05).

In the prespecified subgroup of African ancestry patients (n = 1414), the primary endpoint was in harmony with the main outcome, 6.6% on amlodipine/ benazepril (n = 696) vs. 8.9% on HCT/benazepril (n = 718), an absolute increase of 2.3% [−0.5%;5.1%], relative increase 35%, RR 1.35 [0.94;1.94]), P = 0.1. Ambulatory or endline blood pressure, the main renal outcome, adverse effects, losses to follow up, or subgroup analyses by sex or age were not reported for African ancestry patients [28,47]. RoB was judged intermediate (Figure S1, Supplemental Digital Content, https://links.lww.com/HJH/B829), with moderate certainty (Table S1, Supplemental Digital Content, https://links.lww.com/HJH/B829).

DISCUSSION

The burden of hypertension and associated disability and death is unacceptably high in African ancestry patients [1–3,56]. Pharmacotherapy is an essential part of hypertension management, and trial evidence is expected to reflect this clinical need in providing high quality evidence on drug efficacy and safety [1–3,56].

Existing evidence

Previous systematic reviews had confirmed clinical observations of lower efficacy of antihypertensive monotherapy with BB (in reducing SBP), and ACEI (in achieving GBP) in African ancestry populations [11–15]. Diuretics and CCB were highly effective, albeit with only CCB better than placebo when baseline blood pressures were high. Despite the metabolic side effects of diuretics, compelling indications, as well the affordability and availability of these drugs might render their use imperative. With stepped-care, treatment outcomes were similar except for initial monotherapy with ACEI or ARB (but not BB), which may be associated with greater risk of cardiovascular events [11–15] (Table S3.A, Supplemental Digital Content, https://links.lww.com/HJH/B829). Recent guidelines suggest using different strategies for African ancestry patients than for other patients, but are not in agreement regarding which combination to use (Table S3.B, Supplemental Digital Content, https://links.lww.com/HJH/B829) [1–3].

What this review adds

Except for higher SBP with BB-combinations, meta-analysis indicated small differences in blood pressure-lowering efficacy between different combinations studied. The point estimates of the aggregated data indicated greater blood pressure reduction with CCB + ACEI/ARB combinations or CCB + HCT than HCT + ACEI/ARB combinations, but this was not of robust significance across different statistical tests. Difference in blood pressure reduction with CCB combinations vs. diuretic + ACEI/ARB did not reach statistical significance when using the random effects model, a rather conservative model that assumes the true effect varies between studies, with an inherently low power to detect differences when the number of studies is small [17]. Inclusion of small subgroups from six trials as full trials might have added to underestimation of the true effects and potential differences between treatment arms [57]. The differences between CCB combinations and diuretic + ACEI/ARB were significant in the fixed effect model (which assumes one true effect size shared by the included studies), and when trials with African ancestry patients in subgroups were omitted from the meta-analysis, which reduced heterogeneity. In the trial with endpoint data, results in African ancestry patients were in harmony with the main trial result of lower mortality with amlodipine + benazepril vs. HCT + benazepril [28,46–51,57]. When subgroup analyses are in harmony with — thus not contradicting — the overall results of the trial, a higher alpha (with a subgroup of the size of 12%, typically, alpha = 0.25) is suggested to accept that the results are as valid as the main outcome of the study, as in the ACCOMPLISH trial [57].

Strengths and limitations of the evidence

The main strength of this systematic review is the rigorous methodology, with extended retrieval strategies resulting in a complete overview of conducted trials. The included studies had some methodological issues as commonly occurs in systematic reviews [17,18], but all trials were randomized and controlled.

Whether African ancestry patients respond differently to antihypertensive drugs than other patients [16] is not addressed in this review. Furthermore, this systematic review is limited to available evidence, and we cannot exclude bias in the selection of the specific drugs brought to clinical trials or the dose used. Except for diuretics, differences within one drug class and assessment of drug doses were beyond the scope of this review. Typically, as in trials with initial monotherapy [11–15], up to 25 mg HCT/day was used for initial combination therapy. European and international hypertension guidelines refrain from suggesting a daily dose, but the American guideline recommends 25–50 mg HCT/day as monotherapy, referring to combinations with 12.5–25 mg HCT [1–3]. Higher HCT doses might have been more effective, but the crux of initial combination therapy is the low dose of the components, to enhance efficacy and reduce adverse effects, with the latter being a main cause of non-adherence [1–3,58]. Also, trials with HCT monotherapy to 50 mg/day found that CCB were still more effective in blood pressure lowering than diuretics when baseline blood pressures were high [11–15]. However, we cannot exclude that trials might have relatively underdosed comparator drugs vs. sponsored drugs, including HCT, and this might have affected the outcomes. Finally, limited evidence was available on efficacy in reducing GBP < 130/80 mm Hg, on ambulatory blood pressure reduction, outcomes by sex, age, or overweight/obese status, or on patients with coronavirus disease 2019 (COVID19) or human immunodeficiency virus infections, which may be syndemic with hypertension and cardiovascular disease.

Implications of the available evidence

Implications for practice

Time spent at blood pressure target decreases risk of premature death [59], but blood pressure control is low globally, despite availability of antihypertensive drugs [5]. Main barriers to blood pressure control include the need for multiple medications, doctors’ therapeutic inertia, and concerns regarding adverse effects [1–3,58]. Initial low-dose combination therapy has been advocated to reduce blood pressure with greater efficacy than standard doses of monotherapy [1–3,58]. This work indicates that blood pressure-lowering efficacy of different initial combination treatment strategies was comparable. Hence, there is room for individual therapeutic approaches to reach the “lower, faster, better” goal [1–3,32,58,60,61]. However, a single trial with morbidity and mortality outcomes supports the CCB + ACEI combination, as recommended in some guidelines as first-line therapy when compelling indications are absent (Table S3.B, Supplemental Digital Content, https://links.lww.com/HJH/B829). ACEI are not indicated for women intending to become pregnant, and need to be discontinued when angioedema or disabling cough occur [1–3], but cough is reported to occur less frequently when CCB and ACEI are combined [62].

Implications for research

Knowledge gaps on morbidity and mortality outcomes with initial combination therapy include the efficacy and optimal dose of HCT (vs. CTD), of ARB (vs. ACEI), and of CCB + diuretics. CTD has been recommended over HCT because of presumed greater efficacy with fewer adverse outcomes [63,64], but no direct comparison is available [11–15] (Table S3.A, Supplemental Digital Content, https://links.lww.com/HJH/B829). Moreover, recent retrospective comparisons suggest that HCT is more effective and has less adverse effects than CTD [64,65]. The ongoing Veterans Affairs (VA) Diuretic Comparison Project is expected to provide more data [66]. African ancestry patients (in particular women, the elderly and smokers) may be more likely to develop ACEI-induced angioedema [1–3,11–15], creating a need for comparative endpoint data using other drugs than ACEI. Importantly, with many patients needing 3 or more drugs to achieve control, main research challenges are how to decrease hypertension burden, while improving access to and retention in care and sustainably implementing life style interventions [1–3,11–15,26,27,30,32–34,59–61]. Less advanced care, distrust created by racism in health systems, and racism in the society contribute to health disparities and early death in African ancestry patients [67,68]. These issues need to be addressed. Finally, it is debated whether African ancestry should be used as a proxy for hypertension risk or response to therapy [67,69,70,72]. Ongoing research on markers to substitute race/ancestry includes studies on the pressor enzyme creatine kinase [69–72], and the Ancestry Informative Markers in HYpertension program (AIM-HYINFORM) trial [73].

In summary, most hypertensive patients need multiple drugs to achieve treatment targets [1–3,74]. In this systematic review on African ancestry patients, the available evidence indicates that all drug combinations reduce blood pressure, although initial combinations including BB seem less effective. Furthermore, fewer adverse effects occurred with CCB + ACEI/ARB compared to diuretic-combinations. Importantly, a single trial reported lower cardiovascular mortality using initial combination therapy of amlodipine + ACEI vs. HCT + ACEI, with the effect in African ancestry patients in harmony with the main effect. Greater efforts should be made to include African ancestry patients in clinical trials, to enable adequately powered, prospective analyses by ancestry and sex. Aside the search for the most effective drug combination, research should further address barriers to hypertension detection, treatment and control and the impact of racial discrimination and social disadvantage on cardiovascular health in African ancestry populations.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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    Keywords:

    African continental ancestry group; antihypertensive combination therapy; hypertension

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