FormalPara Key Summary Points

Why carry out this study?

Once-daily, single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide is an effective and well-tolerated first-line treatment for arterial hypertension, and has recently been recommended.

We aimed to investigate whether this approach improves treatment adherence and hypertension control also in rural areas of sub-Saharan Africa.

What was learned from the study?

A program for diagnosis and management of hypertension showed that this treatment strategy is feasible and successful in a rural sub-Saharan Africa setting.

The implementation of antihypertensive single-pill combinations into national essential medicines lists and their availability on the market would represent a key step in promoting cardiovascular health in sub-Saharan Africa.

Introduction

Arterial hypertension is worldwide the most important preventable and modifiable risk factor for cardiovascular disease and its associated adverse outcomes, including cardiovascular events, disability, and death [1, 2]. Despite extensive knowledge on hypertension diagnosis, prevention, and treatment, its global incidence, prevalence, and associated cardiovascular complications remain alarmingly high, as recently documented in a dedicated World Health Organization report [3].

Abundant clinical data indicate that lowering blood pressure with antihypertensive drugs effectively reduces cardiovascular morbidity and mortality [2]. Following lifestyle modification, for the initial pharmacological treatment of hypertension, single-pill, low-dose combinations have recently been recommended because they allow achieving better treatment adherence and higher rates of hypertension control than usual care, and are generally well tolerated [2, 4].

Treatment with a single-pill combining the angiotensin II receptor antagonist olmesartan, the calcium channel blocker amlodipine, and the thiazide-type diuretic hydrochlorothiazide is associated with a higher blood pressure reduction rate compared with dual combination therapy or monotherapy [5]. Single-pill combination therapy is expected to improve treatment adherence and hypertension control also in rural areas of low- and middle-income countries, where access to healthcare facilities is limited and people are often not inclined to adhere to pharmacological therapy with multiple drugs [1]. For these reasons, the above-mentioned triple drug combination was employed to control blood pressure in hypertensive individuals identified within the “Study for Better Blood Pressure and Cardiovascular Risk Control in a rural area of the District of Nyaruguru (Rwanda)” (Rwanda National Ethics Committee approval Nr. 752/RNEC/2019), which was endorsed by the World Hypertension League. In this report, we present preliminary data from this treatment experience.

Methods

General Information

Between February and July 2020, a community-based, house-to-house blood pressure screening was carried out in 12 of the 16 villages of Mata Sector in the District of Nyaruguru, a remote, rural sub-Saharan region in the Southern province of Rwanda at an altitude of approximately 1900 m above sea level. The screening identified hypertensive blood pressure values in 12% of approximately 7000 participants [6]. After a pause due to the COVID-19 pandemic, between May and June 2022, individuals previously identified with elevated blood pressure values underwent a second identical screening. Among those confirmed with a diagnosis of arterial hypertension, a first cohort of 229 individuals was invited to enter the subsequent phase of the program.

This third phase was conducted by a committed team composed of two Italian near-graduate medical students, a local nurse with a bachelor’s degree in general nursing, and one local assistant. They were supported by the principal investigators and study supervisor, from whom they received specific training. The project was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments. The project was approved by the Rwanda National Ethics Committee (RNEC) as “Study for better Blood Pressure and Cardiovascular Risk Control in a rural area of the District of Nyaruguru” (RNEC Approval Nr 752/RNEC/2019). Written and verbal informed consent in Kinyarwanda, the national spoken language, was obtained from all participants.

Study Design

This third phase was conducted between July and December 2022 at the hypertension outpatient clinic of the Health Care Center of Nyamyumba, one of Mata Sector’s villages. Only adults on no previous antihypertensive treatment were eligible for inclusion. Collected data encompassed socio-demographic characteristics, medical history including self-reported previous diagnosis of diabetes mellitus (with or without treatment), and habits of tobacco smoking, alcohol consumption, and adding extra salt to food. Apart from diabetes mellitus, in order to be included, subjects needed to have no previously known comorbidity. Measurements included body anthropometrics, blood pressure, and resting heart rate. At the following outpatient clinics, i.e., after 4, 8, 12, and 16 weeks, only blood pressure and resting heart rate were recorded.

Weight was measured using a digital Tanita® platform scale (Tanita Corporation, Tokyo, Japan), height using a 220-cm Seca 206® roll-up wall-attached measuring tape (Seca GmbH & Co.KG., Hamburg, Germany). Waist circumference was measured at the narrowest point between the lower costal border and the top of the iliac crest in standing and outbreathing position (using a non-stretching tape measure). The waist-to-height ratio was calculated dividing waist circumference by height in centimeters.

Blood pressure was assessed following the European Society of Hypertension recommendations for blood pressure measurements in the office and at home [7], using a validated, automated, oscillometric OMRON M7 IT-HEM-7322-E blood pressure monitor with Intelli Wrap Cuff (HEM-FL31-E) technology (Omron Healthcare UK Ltd, Milton Keynes, UK) [8, 9]. Resting heart rate was recorded with the same device.

Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg [7]. The diagnosis was established during the first outpatient clinic based on the mean of blood pressure readings recorded during the 2020 and 2022 house-to-house screening visits, and the office blood pressure measurements on that day. Arterial hypertension was classified as grade I (systolic 140–159 and/or diastolic 90–99 mmHg), grade II (systolic 160–179 and/or diastolic 100–109 mmHg), or grade III (systolic ≥ 180mmHg and/or diastolic ≥ 110 mmHg) [7]. After recommending appropriate lifestyle changes, as indicated in the recent ESH Guidelines [7], an antihypertensive, low-dose, single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide (OLM/AML/HCTZ) was prescribed to newly diagnosed patients. This medication was available in two fixed-dosage combinations (20/5/12.5 and 40/10/12.5 mg). A third dosage (10/2.5/6.2 mg) was obtained by halving the former with a pill-splitter. A hypertension specialist determined the dosage of the medication based on age, weight, and the degree of hypertension. Each patient received an envelope with reported medication name, dose, and regimen, containing 1-month therapy, plus some spare pills. Patients were recommended to take the prescribed treatment once daily, early in the morning. They were also provided with culturally adapted notions of health care education related to cardiovascular diseases and hypertension and informed about possible side effects of this therapy, such as dizziness, fatigue, headaches, palpitations, peripheral edema, musculoskeletal pain, nausea, diarrhea, or constipation. Medication tolerance was considered excellent in cases without any of the mentioned side effects.

For each patient, blood pressure and heart rate readings as well as the assigned therapy and the following appointment were recorded into a personal booklet to gather at each subsequent visit along with any remaining pill (drug reconciliation). Patients were received at the outpatient clinic after 4, 8, 12, and 16 weeks from the initial visit to perform a clinical examination, verify drug tolerance, and adjust, if needed, their treatment regimen. When needed, dose was increased in order to attain a target clinic blood pressure of < 140/90 mmHg.

Statistical Analysis

Nominal and dichotomous categorical variables are expressed as counts and were analyzed by means of the χ2 test [10]. The normality D’Agostino-Pearson omnibus test [11] disclosed that age, weight, height, waist-to-height ratio, blood pressure, and resting heart rate did not follow a Gaussian distribution. Consequently, continuous data are presented as median and interquartile range and were analyzed using the non-parametric Mann–Whitney–Wilcoxon U test and the Friedman test with the Dunn post hoc multiple comparison [10]. Blood pressure and resting heart rate are presented also in box-and-whisker plots (the bottom and top of the box represent the 25th and 75th centile, the middle band the median, and the ends of the whiskers the 10th and the 90th centile) [12]. Two-sided P values of < 0.05 were considered significant. GraphPad Prism for Macintosh 10.0.3 (GraphPad Software, San Diego, CA, USA) was used for statistical comparisons.

Results

Seventy-two of the cohort of 229 presumably hypertensive individuals invited to the hypertension outpatient clinic in Nyamyumba did not attend their appointment. Of the remaining 157 individuals, 59 were found with normal office blood pressure readings. Hence, the diagnosis of hypertension was made in 98 participants, who were enrolled in the treatment phase. Throughout this phase, 19 participant dropouts were recorded, while 79 individuals adhered to the prescribed schedule and treatment regimen (Fig. 1).

Fig. 1
figure 1

Flowchart of study participants

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The characteristics of the 98 included patients with hypertension (71 females and 27 males, aged 65 [55–71] years) are presented in Table 1. Less than 5% of individuals had a previous diagnosis of diabetes mellitus (with or without treatment), and reported their habit of adding extra salt to food. By contrast, 19% showed a positive history of tobacco smoking and 96% of alcohol consumption. Compared to dropouts, completers were significantly younger (by 9 years, P = 0.0005) and less frequently (11 vs. 53%) smokers (P = 0.0002). Furthermore, their systolic blood pressure was higher by 10 mmHg (P = 0.0152). Correspondingly, completers more frequently had grade II or III office blood pressure readings as compared to dropouts (P = 0.0004).

Table 1 Characteristics of 98 included hypertensive individuals
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Blood pressure and resting heart rate values obtained before and during treatment with the single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide are presented in Table 2 and Fig. 2. In completers, medication decreased systolic, respectively diastolic, blood pressure by 30 [22 to 40] / 13 [5 to 18] mmHg at week 4. The subsequent changes were less striking: 10 [0 to 19] / 5 [ – 2 to 11] mmHg between week 4 and 8, 3 [– 4 to 13] / 3 [– 3 to 7] mmHg between week 8 and 12, and 0 [– 11 to 10] / 0 [– 5 to 4] mmHg between week 12 and 16. Forty-four (56%) patients reached blood pressure values < 140/90 mmHg at week 4, 62 (78%) at week 8, 69 (87%) at week 12, and 74 (94%) at week 16. Moreover, 55 out of the 79 completers (70%) achieved a target blood pressure of < 130/80 mmHg. Resting heart rate decreased by 2 [– 6 to 8] beats/min at week 4, by 2 [– 6 to 10] beats/min between week 4 and 8, by 5 [– 1 to 11] beats/min between week 8 and 12, and by - 2 [– 9 to 4] beats/min between week 12 and 16. For simplicity, significant P values appear in Table 2, upper panel, and in Fig. 2. Similarly, dropouts also showed a clinically significant decrease in blood pressure and heart rate (Table 2, lower panel). Single-pill prescription was customized according to blood pressure values and clinical characteristics, and subsequently adjusted, if needed, at each outpatient clinic (Table 2 and Fig. 2). Medication tolerance was excellent in most of both completers and dropouts (Table 2).

Table 2 Blood pressure and resting heart rate of 79 completers (upper panel) and 19 dropouts (lower panel) before and during treatment with the single-pill combination olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ)
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Fig. 2
figure 2

Systolic blood pressure (A), diastolic blood pressure (B), prevalence of blood pressure < 140/90 mm Hg (C), resting heart rate (D), and medication dosage (E) in 79 completers before () and during () treatment with the single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide (OLM/AML/HCTZ) 10/2.5/6.2 mg (), 20/5/12.5 mg (), and 40/10/12.5 mg (). Data contained in panels A, B, and D are presented as box-and-whisker plots (the bottom and top of the box represent the 25th and 75th centile, the middle band the median, and the whiskers’ ends the 10th and the 90th centile, respectively)

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Discussion

The data presented in this report were collected in the District of Nyaruguru, a remote, rural sub-Saharan region in the Southern province of Rwanda. The results document that, in addition to recommended lifestyle changes, after 16 weeks of once-daily treatment with a single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide, blood pressure was reduced to < 140/90 mmHg in approximately 95% of patients. Comparable results were obtained with this combination in North America, Europe, and Asia [13].

The initial and early pharmacological management of hypertension with low-dose single-pill combinations is nowadays extensively supported and widely recommended [2]. Indeed, there is a strong consensus to replace traditional add-on drug treatment strategies with low-dose combinations as first-line therapy [14]. Single-pill combinations enhance treatment efficacy by simultaneously addressing various pathophysiological pathways involved in the development of hypertension [5, 15]. This increases the effectiveness of the initial medication and decreases the reluctance to escalate treatment when blood pressure remains uncontrolled [4, 16]. Furthermore, single once-daily therapy reduces pill burden and enhances medication adherence and persistence [4]. The antihypertensive action of low-dose combinations is additive, unlike their side effects [17]. Taken together, these features ultimately lead to better blood pressure control. Depending on regional circumstances, single-pill combinations may also be cost-effective.

In the sub-Saharan setting, single-pill combinations are established as first-line treatment for tuberculosis [18], HIV [19], malaria [20], and hepatitis C [21]. However, antihypertensive single-pill combinations are still rather uncommon [22]. Their implementation into national essential medicines lists and national hypertension guidelines as well as availability on the market would represent key facilitators to promote this treatment strategy [23].

Resting heart rate slightly decreased on medication. These agents primarily target blood pressure and fluid balance rather than directly affecting heart rate. We speculate that this (somewhat unexpected) result on heart rate may be due to the indirect cross-effect between the renin–angiotensin–aldosterone system inhibition and the sympathetic nervous system [24]. Furthermore, it might be postulated that, by improving cardiovascular function, these agents could indirectly lead to a reduced heart rate.

The dropout rate of about 20% observed in our study is consistent with that reported in the literature [25]. It is likely not related to a high prevalence of side effects, as evidenced by a high proportion of excellent tolerance also among dropouts (Table 2). Conversely, it is plausible that factors prior to attendance, such as age, distance from our clinic, difficulties in transportation, and lost productivity due to interruption of their work schedule, influenced patients’ adherence to the study protocol [26].

This program has some noteworthy strengths. First, the diagnosis of hypertension was established over three sets of blood pressure measurements taken by trained healthcare personnel at three different visits on separate days, employing a clinically validated, automated, oscillometric device [8, 9] and carefully following international blood pressure measurement recommendations [7]. This resulted in an accurate estimate of blood pressure values in each participant. Second, we introduced an effective and manageable medication regimen whose titration was individually tailored at each outpatient clinic. Achieving a success rate of 94% is remarkable in Africa, considering the pretty modest results previously obtained, with control rates between 0.4% and 50% [1, 27, 28]. Very promisingly, the investigated approach allowed achieving the World Hypertension League’s goal of 80% of treated patients with hypertension in Africa being controlled [1]. Third, we also promoted culturally adapted education and lifestyle modifications related to hypertension and cardiovascular risk factors. The positive results achieved also encourage forthcoming efforts to aim at achieving treated blood pressure values of < 130/80 mmHg [7].

However, we also acknowledge a few limitations of this study. Admittedly, cardiovascular risk factors, such as tobacco smoking, alcohol consumption, and adding extra salt to food, should have been better quantified. Furthermore, electrolyte levels and kidney function would have been reliable indicators of medication tolerability. Moreover, 24-h ambulatory blood pressure monitoring allows confirming and assessing hypertension, including identification of white-coat and masked hypertension, and characterization of nocturnal blood pressure phenotypes [7]. In this study in a remote, rural sub-Saharan region, this was unfortunately not possible. Nevertheless, the study design reflects everyday clinical life in low-income countries. Indeed, while ambulatory blood pressure monitoring is commonly employed in high-income countries, its expense prohibits its recommendation for use in sub-Saharan Africa [1]. Finally, we recognize that medication side effects should have been systematically explored in a more granular way. Future studies should gather this information.

Conclusions

The single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide is an effective and practical initial treatment of hypertension also in rural sub-Saharan Africa.

This study represents real-life evidence in favor of extensive implementation of single-pill combination therapy also in low- and middle-income countries. Local healthcare authorities should include recommendation on their use in national guidelines and should also make them available in rural and remote areas at low or no cost, as reliable first-line treatment strategy in daily practice.