Implementing Single-Pill Combination Therapy for Hypertension: A Scoping Review of Key Health System Requirements in 30 Low- and Middle-Income Countries

Objective: The World Health Organization (WHO) included single-pill combination (SPC) antihypertensive medications on their 2019 essential medicines list (EML) to encourage uptake and improved hypertension control. We documented key national-level facilitators (SPCs on national EMLs, recommendation for SPCs in national hypertension guidelines and availability of SPCs on the market) supporting uptake of SPCs in the 30 most populous low- and middle-income countries (LMICs). Methods: A hierarchical information gathering strategy was used including literature and web searches, the use of organisational databases and personal communications with colleagues to obtain information on (1) whether SPC antihypertensives are on national EMLs, (2) whether SPC antihypertensives are recommended in national hypertension guidelines and (3) whether SPCs are available on the market. Results: Eleven of 30 LMICs had all facilitators in place being Egypt, Kenya, Nigeria, Sudan, China, the Philippines, Thailand, Iran, Argentina, Colombia and Mexico. Twenty-six countries had national hypertension guidelines (or similar) in place with SPCs being recommended in 18 of these. Apart from Afghanistan, SPCs were available on the market in all countries. The facilitator least present was the inclusion of SPC antihypertensives on national EMLs at 12 of 29 (Turkey does not have an EML). Conclusion: This study demonstrated that many LMICs have made significant progress in their uptake of SPC antihypertensives and several had included SPCs on their EMLs and guidelines prior to their inclusion on the WHO EML. Despite this progress, the uptake of SPC antihypertensives in LMICs could be improved including through their further inclusion on EMLs.


INTRODUCTION
Raised blood pressure is the primary risk factor for cardiovascular disease and mortality worldwide [1,2], responsible for 10.8 million deaths in 2019 [2]. The number of adults with hypertension increased worldwide from 594 million in 1975 to 1.13 billion in 2015 and has transitioned from being a risk factor that predominantly affect high-income countries to one that is now more prevalent and increasing rapidly in low-and middle-income countries (LMICs) with Sub-Saharan Africa, south Asia and central and eastern European regions thought to have the highest prevalence [3,4].
Despite the existence of effective and affordable antihypertensive treatment, hypertension is not always well detected, treated, or controlled in high-income countries but even less so in LMICs [5,6]. In a nationally representative cross-sectional study of 1.1 million adults across 44 LMICs, of those with hypertension (17.5%), only 30% had received treatment and 10.3% had controlled hypertension [5].
Although the majority of patients with hypertension require a combination of 2-3 blood pressure-lowering medications to achieve control [7][8][9], most patients in LMICs still receive monotherapy [10]. The use of single-pill combination (SPC) therapy, also known as fixed-dose combination (single pills that contain a combination of two or more active ingredients) in the management of hypertension is largely accepted as a safe and efficient means of reducing treatment complexity and rapidly improving blood pressure (BP) control [1,[7][8][9]. First-line treatment with combination therapy has been associated with a significant (34%) risk reduction of cardiovascular events or all-cause death, when compared to those who received delayed combination treatment initiation due to initial monotherapy treatment [11]. This was primarily due to the more rapid and effective BP control [11]. Combination therapy is also associated with lower healthcare resource use, which is particularly important for LMICs [12].

ESSENTIAL MEDICINES LISTS
In 2019, the World Health Organization (WHO) included four SPC antihypertensive medications on its essential medicines list (EML) being lisinopril + amlodipine, lisinopril + hydrochlorothiazide, telmisartan + amlodipine and telmisartan + hydrochlorothiazide [13]. Although a broad range of medications are widely available in most markets for private purchase, EMLs are used by national governments and institutions to determine which medicines warrant being funded, stocked, prescribed and dispensed in public health services, which provide the majority of affordable care [14]. As such, EMLs at the WHO and national levels, can influence the medicines that people have access to and therefore, constitute a significant determinant of health [14].
Access to medicine is a known challenge in all countries, with context specific facilitators and barriers. There is limited data available on whether necessary macro level health system factors are in place in LMICs to support the widespread use of SPC antihypertensives.
We conducted a scoping review of three national-level facilitators likely to affect the implementation of SPC therapy for the treatment of hypertension in the top 30 most populous LMICs. These included: 1. The presence of national EMLs and whether SPC antihypertensives were included; 2. The presence of national hypertension treatment guidelines and whether SPC antihypertensives were recommended; and 3. The availability of both generic and branded SPC antihypertensives on the market in each country.

RESEARCH DESIGN
This scoping review used a hierarchical information gathering strategy. We considered Bigdeli et al.'s comprehensive framework on access to medicines which details multiple barriers which medications must traverse through the health system before reaching the patient [15], to identify key macro level facilitators including listing of SPCs on national EMLs, recommendations for use of SPCs in national treatment guidelines, and availability of SPCs on the market in each country.

COUNTRY SELECTION AND CHARACTERISTICS
We ranked and selected the top 30 LMICs according to their population size based on World Bank data (September 2020) and noted their economic stratum [16][17]. Data on hypertension prevalence for each country was obtained from the WHO Global Health Observatory, using the indicator 'Raised BP (SBP≥140 and/or DBP ≥90) (age standardized estimate)' [18]. This data was last updated on 17 November 2017 for estimates as of 2015.

SEARCH STRATEGY National Essential Medicines Lists
We accessed and reviewed EMLs uploaded to the WHO National Essential Medicines Lists Repository [19]. Due to the age of many documents and the fact that uploading EMLs is a voluntary exercise, we attempted to locate more recent versions through an online search (key words: [country's name] AND essential medicines list). We also used contacts from Resolve to Save Lives [20], to obtain more up to date EMLs. For countries where we could not find any online evidence of an EML, we contacted colleagues working in those countries for further information.

Hypertension treatment guidelines
For national hypertension treatment guidelines we searched several sources including the WHO Essential Medicines and Health Products Information Portal [21], the Hypertension Cardiovascular Outcome Prevention and Evidence in Asia (HOPE Asia) Network [22], and official websites of national hypertension societies. We also used PubMed and Google (key words: [country's name] AND hypertension treatment guidelines) to confirm and to identify additional guidelines not available elsewhere. The guidelines were reviewed for SPC recommendations if they were in English or able to be translated by commonly available language translation software. For guidelines where translation software was unable to be used, colleagues who were fluent in that language assisted where available.

Availability of SPC antihypertensives on the market
We used an online search strategy (key words: [country name] AND 'online pharmacy' in either English or translated to local language using translation software) to identify online pharmacy services located in the countries of interest. Where an online pharmacy was found, we searched for common SPC antihypertensives. For countries where online pharmacies were not identified, PubMed and Google searches were used to identify literature that documented the availability of SPC antihypertensives and/or generic versions for sale in each country (key words: [country's name] and a combination of 'hypertension' or 'antihypertensive' AND 'medication' or 'medicine' or 'drug' or 'treatment' AND/OR 'generic'). For countries where insufficient information was found online, colleagues working in those countries were contacted.

ETHICS
This study predominantly comprised an online scoping review and document analysis, hence ethics approval was not required.

RESULTS
The top 30 most populous LMICs spanned five geopolitical regions ( Table 1), including Africa (11 countries), Asia (10 countries), Europe (2 countries), Latin America (4 countries) and the Middle East (3 countries). Five countries were classified by the World Bank as low-income (LIC), 13 countries were lower-middle-income (LMIC) and 12 countries were upper-middle-income (UMIC) [16]. The total population of these 30 countries was approximately 5.45 billion, or 71% of the global population based on the UN estimate of 7.7 billion in 2019 [17]. Based on agestandardized rates of hypertension prevalence in adults aged 18 and above ( Not Available Yes -online pharmacy [45] Yes -online pharmacy [45] Egypt, Arab Republic Yes -online pharmacy [65] Yes -online pharmacy [65] ( Yes -national guidelines + literature [73] Yes -online pharmacy [74] (  [19], unless referenced otherwise. &Document not in a language where the investigators had access to a native speaker and has been interpreted using translation software.

NATIONAL EMLS AND INCLUSION OF SPCS
We were able to locate national EMLs for 28/30 countries (Turkey and Tanzania being the exceptions) from the WHO EML repository [19]. Through an online search, we were able to locate a national EML for Tanzania and more up to date EMLs for Kenya, Sudan, Ukraine and Ethiopia. We were able to access more recently updated national EMLs for China, the Philippines, Thailand and Vietnam through Resolve to Save Lives. There was no national EML that could be located for Turkey and research indicated its non-existence as of 2014 [23]. See Supplemental Digital Content 1 (SDC 1), which illustrates the data source for the most up to date national EMLs, national hypertension guidelines and availability of single-pill combination antihypertensives.
Twelve countries (40%) included some form of SPC antihypertensives on their national EMLs, with these countries covering several geopolitical regions and a broad range of economic strata (Table 1, Figure 1). Identified national EMLs were dated between 2010 to 2020 with a median publication year of 2016. There was no clear relationship between the year of the EML being updated and whether SPC antihypertensives were included on that EML. The most common forms of SPCs listed included Angiotensin Converting Enzyme Inhibitors (ACEI) + Hydrochlorothiazide (HCTZ), Angiotensin Receptor Blocker (ARB) + HCTZ, calcium channel blocker (CCB) + ARB and Amiloride + HCTZ combinations.

HYPERTENSION TREATMENT GUIDELINES Inclusion of SPCs in international guidelines
Many LMICs use international hypertension treatment guidelines or base their national hypertension guidelines on these [24]. The WHO 'Guideline for the pharmacological treatment of hypertension in adults' (published 24 August 2021) recommends combination therapy, preferably in the form of SPCs for initial treatment in adults [25].
The International Society of Hypertension 2020 guidelines recommend dual low dose SPCs as the optimal initial treatment for hypertension with the exception of 'low risk grade 1 hypertension or in very old (≥ 80 years) or frailer patients' who should be considered for monotherapy [26]. Similarly, the European Society of Cardiology 2018 guidelines recommend initial therapy with dual combination of ACEI or ARB with CCB or diuretic, preferably as SPC, with the same aforementioned recommendations of monotherapy in certain groups [27]. The 2017 American College of Cardiology/American Heart Association guidelines support initiation of dual combination therapy as either separate agents or SPCs in adults with grade 2 hypertension (defined as SBP ≥ 140mmHg and/or DBP ≥ 90mmHg) and an average BP > 20/10mmHg above their BP target [28].

Inclusion of SPCs in national guidelines
National hypertension guidelines were identified for most countries (26/30) (Figure 1, SDC 1). We were unable to confirm the existence of guidelines for either Algeria or Morocco; the Democratic Republic of Congo and Myanmar do not currently have official national hypertension treatment guidelines [29][30]. For Nigeria, Ukraine, and the Philippines, national guidelines exist, however, we were unable to obtain the official documents for review [31][32][33].  Of the 23 countries with national hypertension treatment guidelines available for review, 18 countries specifically recommended SPC antihypertensives, with the majority recommending them for second-line treatment if monotherapy is inadequate in lower risk patients to improve adherence or as an initial option in those with higher risk/elevated BP (above 160/100mmHg, or systolic pressure ≥ 20mmHg/diastolic pressure ≥ 10mmHg above target BP) ( Table 1). Notably, five countries (Indonesia, Pakistan, Russian Federation, Turkey and Vietnam), recommend SPCs as initial treatment regardless of BP level. Eight national guidelines did not explicitly recommend SPCs but did recommend combination therapy. In Nigeria and the Philippines, SPCs were recommended but we were unable to confirm in what context due to being unable to source the actual guidelines [33][34][35]. The guidelines were dated from 2012 to 2019 with a median publication year of 2016.

AVAILABILITY OF SPC ANTIHYPERTENSIVES ON THE MARKET
Data on the presence of SPCs on the market, including generic options, was obtained primarily through online and literature searches (SDC 1). For all countries, except for Afghanistan, we were able to document availability with twenty countries having evidence of both branded and generic SPC antihypertensives ( Table 1). Professional contacts also confirmed availability of generic SPC antihypertensives in an additional six countries. For four countries (Ethiopia, Morocco, Afghanistan and Turkey), we were unable to identify whether generic brands of SPC antihypertensives were available.

OVERALL AVAILABILITY OF NATIONAL-LEVEL FACILITATORS
Overall, 11 countries (37% -Egypt, Kenya, Nigeria, Sudan, China, the Philippines, Thailand, Argentina, Colombia, Mexico and Iran) had all national-level facilitators in place including (1) presence of a national EML with SPC antihypertensives included, (2) the presence of national hypertension treatment guidelines with recommendations for use of SPC antihypertensives, and (3) availability of SPC antihypertensives on the market including generics (Figure 2). Most of the remaining countries had at least one facilitator in place but 16/28 countries (57%) were primarily missing the inclusion of SPCs on national EMLs.

DISCUSSION
Despite the advantages of SPC antihypertensive medications in improving BP control, only 11 of the 30 countries (37%) under review had all national-level facilitators in place to ensure uptake (Figure 2). These countries are geographically diverse with a combined population of approximately 2.3 billion people and represent a range of income levels: one LIC, four LMICs and six UMICs.

INTERNATIONAL POLICY CONTEXT
International policies, especially those developed by the WHO, influence how LMICs develop their own [15,26]. WHO endorsement of four combinations of SPC antihypertensive medication is expected to provide confidence to LMICs to include such listings on their own national EMLs [36]. International treatment guidelines, including the WHO's recently published (24 August 2021) 'Guideline for the pharmacological treatments of hypertension in adults' also have the capacity to influence local treatment guidelines and/or impact prescriber practice [25]. International policy, incorporating international treatment guidelines as well as market availability and inclusion on the WHO EML, is thus now well aligned to support the use of SPC antihypertensives in the management of hypertension. The WHO and international organisations including the American, European and International Societies of Hypertension have taken significant steps in recommending the use of SPC antihypertensives and now it is up to national governments to translate this into local implementation.
While the WHO has taken important steps to recommend the use of SPC antihypertensives through their EML and most recently, through their guidelines, the absence of such resources and formal endorsement in the past may have contributed to delays in SPC uptake. This is particularly true for LMICs, who may rely on WHO guidance when implementing policy changes.

NATIONAL EMLS AND INCLUSION OF SPCS
We were able to access a national EML for 29/30 of the most populous LMICs, with the exception being Turkey. Of the national EMLs that we could access, 12 included SPC antihypertensives. SPC antihypertensives were included in the WHO EML in 2019, but many of the national EMLs we accessed were published prior to 2019, indicating several countries had included SPCs even before WHO listed them, but also indicating that country EMLs may not have had the opportunity to incorporate SPCs following listing by the WHO. If SPC antihypertensives are not included on a national EML, it is unlikely that they will be widely available in the public health system. However, inclusion of a medication on the WHO EML alone is not sufficient to affect uptake in LMIC settings [37], as implementation must be part of a larger strategy endorsed by the Ministry of Health with the aim of improving availability, affordability, accessibility, and medicine adherence, with the design of suitable health system delivery models [37].

HYPERTENSION TREATMENT GUIDELINES
Of the 30 countries included in this study, only 26 countries had national hypertension treatment guidelines or primary care guidelines with hypertension included. For certain presentations of hypertension, SPC antihypertensives were specifically recommended in 18 of the guidelines. A further eight guidelines recommended combination therapy for the treatment of hypertension but did not mention SPCs specifically.  Most patients with hypertension in LMICs receive monotherapy with relatively few on combination therapy, and even fewer on SPCs [10]. In a cross-sectional study on hypertension in HICs to LICs with more than 140,000 participants, the use of two or more medications was 18.1% in HICs (95% CI, 17.2%-19.1%), but 14.1% in LMICs (95% CI, 13.7%-14.6%) and only 1.6% in LICs (95% CI, 1.4%-1.8%) [10]. This aligns with many of the national hypertension treatment guidelines in LMICs, which tend to recommend monotherapy as first-line treatment (see Table 1). Where SPC antihypertensives are recommended as first-line treatment, it is predominantly for those with grade 2 hypertension, those with comorbidities and those with cardiovascular risk factors.
National EMLs and hypertension treatment guidelines provide guidance to the health sector to ensure national consistency in access to medicines and to improve hypertension control.
The inclusion of SPC antihypertensives in these guidelines could facilitate improvement in access through influencing prescribing practices [38]. However, whilst an important next step, guidelines are but one factor and are unable to change uptake and availability independently.

AVAILABILITY OF SPC ANTIHYPERTENSIVES ON THE MARKET
SPC antihypertensives are available in all countries under review (except Afghanistan), indicating good market access. Market availability is a significant initial step in ensuring accessibility to consumers as market forces are a key determinant of access to medicines [10]. It indicates that a regulatory pathway exists for approval of SPC antihypertensives as well as market interest from pharmaceutical companies in providing such products but does not equate to equitable access and availability.

AVAILABILITY OF GENERIC OPTIONS
Generic options of SPC antihypertensives were available in 26/30 countries. This is significant as medicine affordability is a key determinant of access to medicines, and relevant to LMICs where health budgets are limited. This is despite there being only 12 of the 30 countries with SPC antihypertensives included on their national EML and demonstrates active market forces despite a lack of policy support. The availability of generic options for SPC antihypertensives, combined with associated financing and subsidisation schemes would improve affordability.

STRENGTHS AND LIMITATIONS
This study is the first scoping review we are aware of which documents macro level health system factors that may facilitate the uptake of SPC antihypertensives in LMICs. Strengths of this study include coverage of the top 30 most populous LMICs, covering 71% of the global population and over a billion patients with hypertension. Whilst the decision to include the 30 most populous LMICs covers much of the world's population, they only represent 22% of the total number of LMICs (135 as of 2020) [39]. As a result, our findings may not be generalizable to other LMICs.
Identifying and sourcing relevant documents was challenging and time consuming and it has been difficult to ascertain the most recent EMLs and hypertension treatment guidelines which has potential implications for the currency of our data and consequentially, our interpretation.
Whilst this study includes several facilitators, they are limited to national policy contexts and the supply chain so do not encompass the complexity of health system factors affecting access to SPC antihypertensives including at the community, household and individual levels [10]. For example, physician awareness and adherence to hypertension treatment guidelines has been consistently documented to be highly variable [10,[40][41], and so are patient adherence to hypertension treatments in general [42][43]. Multiple other more complex and variable factors may include socio-political context, health system development and maturity, quality of health services and medication, pharmaceutical context and prescriber education and behaviour etc. We acknowledge that the factors we studied form a component of complex health systems impacting the use of SPC antihypertensives and do not indicate widespread accessibility or affordability. As previously noted however, these policy contexts can facilitate the availability and use of SPC antihypertensives.

COMPLEXITY OF IMPLEMENTATION CHALLENGES
While distinct, each aspect of the health system needed to successfully improve patient access to antihypertensive SPCs does not exist in isolation. They are mutually dependent and are influenced by the broader context of each country including culture, history, economic development and health system advancement, etc. Many countries in this study are adversely affected by ongoing wars or civil unrest, corruption, poverty, under-developed economies, and other competing public health challenges. Due to such heterogeneity, each LMIC requires a unique multifactorial approach that not only advances their hypertension management strategy but also other influential factors within the health system and evidently the holistic development of the country.

CONCLUSION
Market access and international policy support for the use of SPC antihypertensives is strong. There is evidence of widespread market availability of SPCs (including generics) in LMICs, but availability alone is not sufficient as supportive national policy is key. National hypertension treatment guidelines do not always align with international policy as monotherapy appears to be the dominant treatment strategy, and national EMLs do not include SPC antihypertensives in the majority of LMICs we reviewed. Opportunities for demonstrating the value of SPCs in hypertension management may include case studies of those countries with established national-level facilitators. Further research into the meso and micro level factors influencing the uptake of SPC antihypertensives may produce further learnings to support national governments, the health sector and industry (among others) in improving access to SPC antihypertensives.

ADDITIONAL FILE
The additional file for this article can be found as follows: • Supplemental Digital Content 1 (SDC 1).