Polypill Programs to Prevent Stroke and Cut Costs in Low Income Countries: Moving from Clinical Efficacy to Pragmatic Implementation

Abstract

Current projections are that the already overwhelming burden of strokes and atherosclerotic cardiovascular diseases (ASCVDs) in Low and Middle Income Countries (LMICs) will continue to rise over the coming decades as the prevalence of traditional vascular risk factors burgeon in these countries. Cardiovascular polypills containing combinations of antihypertensive(s), a statin, with or without aspirin or folic acid in the form of a single pill, represent a viable strategy for both primary and secondary prevention of ASCVDs in LMICs. Large multicenter trials in LMIC and high-income country (HIC) settings have now clearly demonstrated the beneficial effects of the cardiovascular polypill vs. placebo (or usual care) in reducing primary stroke risk by 50%. For survivors of a recent myocardial infarction residing in HICs, the polypill reduced risk of major cardiovascular events by 25% due to improved treatment adherence. Data on the clinical efficacy of the polypill for secondary stroke prevention are scanty both in HICs and LMICs. Cost effectiveness analyses data from LMICs suggest cost savings with the polypill for primary and secondary prevention of stroke and ASCVDs. However, major contextual barriers in LMICs need to be surmounted through mixed methods research and hybrid clinical trials to assess its real-world effectiveness, prior to the adoption of the polypill for primary and secondary ASCVD prevention in routine clinical practice.

Graphical Abstract

POLYPILL AS A CONCEPT FOR PREVENTION OF CARDIOVASCULAR EVENTS

The cardiovascular “polypill” refers to a combination pill containing 3-4 pharmaceutical classes of preventive medications designed to lower multiple cardiovascular risk factors simultaneously.¹ This “multi-purpose” cardiovascular polypill can be distinguished from “single-purpose” polypills containing two or more low-dose medications within a particular drug group used for managing a single cardiovascular risk factor such as hypertension or diabetes. These two types of cardiovascular polypills differ fundamentally in the target population for application and number of risk factors to be addressed. While the “multi-purpose” polypill strategy is intended to achieve cardiovascular risk reduction at a population level via mass administration, the “single-purpose” polypills target one specific risk factor at an individual level.

The polypill concept proposed by Wald and Law in 2003 had a central theme of modifying cardiovascular risk at a population level by treating everyone 55 years or older without consideration of measured blood pressure or lipids as well as those with established cardiovascular disease with a single, daily administered pill. The cardiovascular polypill for prevention of atherosclerotic cardiovascular disease (ASCVD) typically comprises of a statin, antihypertensive agent(s) plus or minus an antiplatelet or vitamins in fixed dose combinations. The projections based on clinical trial and meta-analytic data were that a polypill containing three classes of antihypertensive medications, a statin, aspirin and folic acid could reduce the occurrence of stroke by 80% and ischemic heart disease by 88%.¹

The composition of polypills were selected based on clinical trial efficacy and pharmacological interaction data² with the objectives of improving drug adherence by reducing pill burden. Polypills are therefore expected to improve risk factor control and potentially reduce vascular event risk as a cost-effective intervention.³ Feasibility studies have been conducted using polypills vs. ‘usual care’, with strong evidence for improved adherence,^4–6 superior or at least non-inferior efficacy in systolic blood pressure (BP) and low-density lipoprotein (LDL-C) control,^4–9 better acceptability^4–6 and comparable safety profile. In this commentary, we argue that polypills are effective both for primary and secondary prevention of vascular diseases. Furthermore, we discuss the polypill as a cost-effective intervention within a holistic strategy for reducing vascular disease burden in low-and-middle income countries (LMICs).

CLINICAL EFFECTIVENESS OF THE POLYPILL

Five major international randomized controlled trials (RCTs) on polypills powered to assess major adverse cardiovascular events (MACE) have been completed or are currently on-going. Two of these-The International Polycap Study 3 (TIPS-3),¹⁰ and HOPE-3,¹¹ were primary prevention studies, two others- the Preventative Role of a fixed dose combination Pill in Stroke (PROPS)¹² and the Secondary Prevention of Cardiovascular Disease in the Elderly Trial (SECURE)¹³ are secondary prevention trials while the PolyIran study¹⁴ aimed at both primary and secondary cardiovascular disease (CVD) prevention. The key outcomes of these studies are summarized in Table 1 but outcomes specifically related to stroke prevention are emphasized.

Table 1.

Effect of Polypill on CVD outcomes for primary and secondary prevention

Name of Study Study objective	Countries	LMICs site included in trial	Trial design	Study population	Active Intervention	Comparator(s)	Outcome measures
TIPS-3 10 Primary prevention	Bangladesh, Canada, Colombia, India, Malaysia, Philippines, Tanzania, Tunisia	Yes	2 x 2 x 2 factorial RCT	Men ≥50 years and women ≥55 years without CVDs with an elevated INTERHEART Risk Score	40mg simvastatin, 100mg atenolol, 25mg hydrochlorothiazide, 10mg ramipril and 75mg Aspirin	Aspirin (75mg) or Placebo daily or Vitamin D	Primary outcome: Deaths from CVDs occurred in 4.4% who received Polypill + Aspirin vs 5.5% in placebo, HR of 0.79 (0.63–1.00)
HOPE-3 11 Primary prevention	21 countries on six continents	Yes	2 x 2 factorial RCT	Men ≥55 years and women ≥65 years without CVD with one/ two CVD risk factors	10mg rosuvastatin, 16mg candesartan and 12.5mg hydrochlorothiazide	Placebo Lipid lowering alone BP lowering alone	Primary outcome: CV death/MI/Stroke occurred in 3.6% vs 5.0% in placebo, HR of 0.71 (95% CI: 0.56-0.90)
PROPS 12Secondary prevention	U.K.	No	1:1 parallel RCT	Stroke or TIA (>55 years)	20mg Atorvastatin, 5mg ramipril, Aspirin 100mg	Usual care	Yet to report study outcomes. BP, Lipids, Adverse effects and CV events, QOL
SECURE 13 Secondary prevention	Spain, Italy, Germany, France, Hungary, Poland, Czech	No	1:1 parallel Open-label RCT	Myocardial Infarction (>65 years)	20mg/40mg Atorvastatin, ramipril 2.5, 5 or 10mg; and Aspirin 100mg	Individual lipid lowering, antiplatelet and RAAS blockers	Primary outcome: cardiovascular death, nonfatal type 1 MI, nonfatal ischemic stroke, or urgent revascularization occurred in 9.5% in the polypill arm vs 12.7% in the active comparator arm, HR of 0.76 (95%CI: 0.60 – 0.96).
PolyIRAN 14 Primary & Secondary prevention	Iran	Yes	2 group, cluster RCT	Men or women ≥50 years with and/or without CVDs (excluding stroke)	20mg Atorvastatin, 12.5mg hydrochlorothiazide, enalapril 5mg/valsartan 40mg, aspirin 81mg	Lifestyle advice	Primary outcome: Major CV events death /MI /Stroke occurred in 5.9% vs 8.8% in placebo, HR of 0.66 (95% CI: 0.49-0.75).

The primary prevention trials generally included men ≥50 years and women ≥55 years with intermediate to high CV risk without major CVD at enrollment across high, middle, and low-income countries. Overall, the polypill was more effective than placebo in reducing hard composite clinical outcome measures such as cardiovascular (CV) deaths, stroke and myocardial infarction (MI) (see Table 1). Regarding stroke prevention in the primary prevention trials, HOPE-3 showed that fixed dose combination of candesartan, hydrochlorothiazide and rosuvastatin reduced stroke by 44%, a hazard ratio (HR) of 0.56 ( 95% CI: 0.36 to 0.87) compared with a double placebo group.¹¹ The PolyIRAN study demonstrated a beneficial effect of the polypill for both primary and secondary CV risk reduction overall, reducing fatal stroke occurrence by 62%, adjusted HR of 0.38 (95% CI: 0.18 to 0.82) and non-fatal strokes by 56%, HR of 0.44 (95%CI: 0.23 to 0.82).¹⁴ Finally, the TIPS study showed that polypill containing aspirin reduced stroke risk by 58%, HR of 0.42 (95%CI: 0.20 to 0.89) compared with double placebo.¹⁰

The absolute number of stroke events in these primary prevention studies were generally low and the effect size of stroke reduction by 80% proposed by Wald and Law were not achieved in these landmark trials. Indeed, a meta-analysis of individual participant data from these three trials, n=18,162 found that 36 (0.8%) strokes occurred in the combined polypill arm vs 73 (1.6%) in the control arm.¹⁵ Overall, the polypill reduced stroke by 41%, HR of 0.59 (95%CI: 0.45-0.78), MI by 38%, HR of 0.62 (0.38-0.70), revascularization by 46%, HR of 0.54 (0.36-0.80) and CV death by 35%, HR of 0.65 (0.52-0.81).¹⁵ A major reason for the failure to achieve to CVD reduction margins proposed by Wald and Law is a smaller than expected reduction in blood pressure and LDL-cholesterol levels observed in these major polypill clinical trials. Wald and Law proposed based on meta-analysis of randomized trials, that simultaneously achieving reductions in diastolic BP of 10 mmHg and LDL-cholesterol of 1 mmol/l would for instance translate into a relative risk (RR) reduction in stroke by 0.4 and 0.9 respectively. The combined CV effect of achieving these levels of blood pressure and LDL-cholesterol reductions could be derived by multiplying 0.4 by 0.9 = 0.36, translating into a 64% reduction in stroke risk.¹ However, a meta-analysis of 8 clinical trials with 25,584 subjects reported only modest diastolic BP reduction of 1.30 mmHg (95%CI: −2.42 to −0.19), and no differential reductions in total cholesterol or LDL-cholesterol by the polypill compared with comparator.¹⁶

Furthermore, from a safety perspective, a meta-analysis of early primary prevention trials of aspirin suggests that the clinical benefit of aspirin for prevention of first stroke or MI is marginal and is offset by the excess risk of bleeding.¹⁷ This warrants a thoughtful consideration of polypills containing aspirin for primary prevention. The US Preventive Services Task Force has recently recommended against the use of Aspirin for primary CV prevention among persons aged 60 or older and level C recommendation for persons aged 40-59 years with elevated CV risk.¹⁸ A meta-analysis of 3 large primary prevention trials however reported a low rate of gastrointestinal bleeding of 0.4% in the polypill vs 0.2% in the control arm, p=0.15 with no differences in rates of hemorrhagic stroke, fatal bleeding and peptic ulceration.¹⁵ Overall, these trials have clearly demonstrated beneficial effects of the cardiovascular polypill in reducing stroke risk by about 50% and by similar margins for other ASCVDs as a primary prevention strategy compared with placebo.

Of the two major secondary prevention trials with the polypill, PROPS¹² is yet to report study outcomes while SECURE¹³ has just published its main outcome measures. SECURE demonstrated that treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after a myocardial infarction compared with usual care resulted in a primary event rate of 118 out of 1237 (9.5%) in the polypill arm vs 156 out of 1229 (12.7%) in the usual care arm, a 24% reduction, HR of 0.76 (95% CI: 0.60-0.96).¹³ There are however important caveats regarding the generalizability of the two major secondary prevention trials with the polypill (SECURE and PROPS) worth noting. SECURE for instance recruited an elderly European population >65 years old with a prior history of ischemic heart disease.¹³ However, stroke and other ASCVD events requiring secondary prevention can occur below 65 years, and data on the efficacy of the polypill in younger populations with CVDs are needed. Secondly, both PROPS and SECURE tested a polypill with one antihypertensive drug class, however stroke survivors for instance often require an average of 3 classes of antihypertensive medications to achieve blood pressure control due to high burden of resistant hypertension.¹⁹ A pilot trial titled Stroke Minimization through Additive Anti- atherosclerotic Agents in Routine Treatment which tested the safety of a polypill combination of 3 antihypertensives- ramipril, hydrochlorothiazide, atenolol, a statin -simvastatin and aspirin for recent Ghanaian ischemic stroke survivors for 12 months has been completed and due to report study findings soon.²⁰

POTENTIAL BENEFITS OF POLYPILL FOR ASCVD PREVENTION IN LMICs

LMICs currently bear the greatest burden of stroke worldwide accounting for 86% of deaths and 89% of disability-adjusted life years lost.²¹ Data from sub-Saharan Africa (SSA) for instance show an age-standardized stroke incidence of 316 per 100,000 ²², and prevalence rate of 1.4 per 1000 population.²³ Outcomes of stroke in SSA are abysmal with 1-month case fatality at 30% and 3-year mortality rate of 84%.^24–28 Stroke in LMICs affects a predominantly young to middle age group^29,30 and is associated with profound diminution in quality of life, and productivity.

A constellation of adverse factors in LMICs such as uncoordinated health systems, under-controlled vascular risk factors, lack of care affordability, lack of healthcare providers and limited knowledge and awareness of cardiovascular risk factors contributes to high burden of adverse outcomes after an incident stroke. Secondary prevention guidelines recommend that antihypertensive, statin and anti-platelet therapy, should be initiated promptly after ischemic stroke and adhered to in a persistent fashion to achieve optimal vascular risk reduction. ^31,32 However, these goals are seldom realized in routine clinical care settings in LMICs. These contextual factors in LMICs underscore a need to identify relatively simple strategies such as use of polypills that can be applied broadly as a cost-effective strategy for both primary and secondary prevention of stroke and ASCVD in resource-constrained settings.

COST EFFECTIVENESS OF THE POLYPILL IN LMIC SETTINGS

A major consideration for widespread uptake of the cardiovascular polypill for both primary and secondary prevention of stroke worldwide is its cost effectiveness. Cost effectiveness analysis (CEA) is a key method for evaluating health costs of an intervention and refers to analysis that examine the ratio of the cost of a particular intervention (e.g., polypill) to a chosen unit of effectiveness (e.g. quality of life years (QALY) or disability-adjusted life years (DALY), and so forth. A fundamental consideration in cost effectiveness analysis is the point of view for the analysis referred to as ‘perspective’. Perspectives taken in cost effectiveness analysis may include patient, hospital practice, insurance payers, or pharmacies. The Panel on Cost-effectiveness in Health and Medicine³³ however recommends a broader societal perspective such as healthcare perspective which incorporates all costs regardless of who they may fall for public health interventions. When comparing cost effectiveness of two interventions (for example polypill vs usual care), studies often report an incremental cost-effectiveness ratio (ICER) as a single value representing comparative cost-effectiveness. The ICER can be interpreted as the cost of obtaining an extra unit of effectiveness (e.g. DALY or deaths averted) from one intervention over the other and it quantifies the trade-offs between clinical outcomes gained and resources spent.

POLYPILL COST EFFECTIVENESS FOR PRIMARY PREVENTION OF ASCVDs IN LMICS

An understanding of the cost effectiveness of the polypill for primary prevention of stroke and other CVDs would be instrumental for policymakers especially in LMICs in determining its coverage, reimbursement and making decisions on the optimal allocation of limited financial resources. A 2022 systematic review of the polypill for primary prevention included 14 studies of which 4 originated from LMICs (2 from Argentina, 1 from Latin America, and Thailand) and the remaining 10 from high-income countries.³⁴ We will focus our discussion on the cost effectiveness analysis data from LMICs in a systematic review conducted by Jahangiri et al.³⁴ First, Bautista et al, reported an adjusted ICER of $176-895 per QALY in women and 365-933 per QALY in men based on CVD risk reduction using a polypill vs no intervention as a comparator with a lifetime horizon for a Latin American population assuming a healthcare perspective.³⁵ Second, Rubinstein et al, found adjusted ICERs of $4,274, $4,884 and $ 5,383 per DALY for individuals with 20%, 10% and 5% CVD risks respectively using a polypill vs active comparators with a 10-year time horizon assuming a payer perspective.³⁶ Third, Rubinstein et al, again reported cost-saving outcomes for the polypill compared with no active comparator with a 5-year time horizon on the assumptions of a healthcare perspective.³⁷ Finally, Khonputsa et al reported a dominant effect of a polypill containing 3 antihypertensives and a statin compared with no active comparator with a lifetime horizon and a healthcare perspective.³⁸ (See Table 2)

Table 2:

Summary of findings of cost-effectiveness analysis of the polypill for CVD prevention for LMICs.

Author (Year)	Country	Type of prevention	Perspective	Time horizon	Components of polypill	Comparator	Effectiveness unit	Adjusted ICER (2020 US dollars)
Bautista et al. (2013)35	Latin America	Primary	Healthcare	Lifetime	Thiazide, atenolol, ramipril, simvastatin and aspirin	No intervention	QALY	Women: $176-895 per QALY Men: $365-933 per QALY
Rubinstein et al. (2009)36	Argentina	Primary	Payer	10-years	Thiazide, enalapril, atorvastatin and aspirin	Lowering salt intake Education via mass media	DALY	20% CVD risk: $4,274 per DALY averted 10% CVD risk: $4,884 per DALY averted 5% CVD risk: $5,383 per DALY averted
Rubinstein et al. (2009)37	Argentina	Primary	Healthcare	5-years	Hydrochlorothiazide, enalapril, atorvastatin and aspirin	No intervention	DALY	Cost saving
Khonputsa et al. (2012)38	Thailand	Primary	Healthcare	Lifetime	3 antihypertensives and a statin	No intervention	DALY	Dominant
Lin et al. (2019)39	China, India, Mexico, Nigeria, and South Africa	Secondary	Healthcare	Lifetime	Aspirin, simvastatin, lisinopril and atenolol	Usual care	DALY	China: $172 India: $169 Mexico: $90 Nigeria: $372 South Africa: $65
Singh et al. (2018)40	India	Secondary	Healthcare	15-month	Aspirin, statin and two antihypertensive meds	Usual care	Increase in adherence with reductions in LDL-C and SBP	Dominant

ICER: incremental cost-effectiveness ratio; DALY: Disability-adjusted Life-years; QALY: Quality-Adjusted Life-Years; ACE-I: Angiotensin converting enzyme inhibitor; LDL-C = Low density lipoprotein cholesterol; SBP = Systolic blood pressure

POLYPILL COST EFFECTIVENESS FOR SECONDARY PREVENTION OF ASCVDs IN LMICS

A microsimulation model study reported the cost effectiveness of a polypill containing aspirin, lisinopril, atenolol, and simvastatin for secondary prevention of ASCVDs in China, India, Mexico, Nigeria and South Africa in 2019.³⁹ Cost effectiveness of the polypill was assessed at prices in the public health sector and on the retail market with key outcomes being major adverse cardiovascular events (MACE) over a 5-year period and the ICER from the perspective of the health sector and lifetime analytical horizons. The investigators assumed a cost-effectiveness threshold equal to each country’s per capita gross domestic product (GDP) per DALY averted in examining the population health effect achievable by increasing the uptake of the polypill in the eligible population. Among adults aged 30-84 years with established atherosclerotic CVD, adoption of the polypill for secondary prevention compared with current usual care (4 individual medications i.e., aspirin, atenolol, lisinopril and simvastatin) in LMICs settings would avert 40-54 MACEs for every 1000 patients treated for 5 years. The ICER of the polypill compared with usual care over a lifetime analytical horizon was $172 per DALY averted in China, $169 in India, $90 in Mexico, $372 in Nigeria and $65 in South Africa amounting to 0.4 – 6.2% of the per capita GDP in these countries.³⁹

Many of the cost effectiveness analyses for the cardiovascular polypill for both primary and secondary prevention have used simulated modelling approaches. However, a cost effectiveness analysis from the UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) trial was performed using within-trial healthcare resource utilization cost data from India with polypill price ranging from $0.06 to $0.94/day. The UMPIRE trial was conducted in India and Europe, using a polypill containing (aspirin, atorvastatin, ramipril and atenolol) vs. aspirin 75mg once daily among individuals with established ASCVD or at an estimated 5-year CVD risk of 15% or greater. The median follow-up was 15 months (IQR: 12-18 months). Clinical effectiveness data showed a significant improvement in adherence in the polypill arm at 86% vs 65% in the usual care arm, a relative difference of 33% (95% CI: 26 – 41%) accompanied by modest reductions in systolic BP and LDL-cholesterol.⁵ The cost-effectiveness of the polypill was measured as additional cost for 10% increase in adherence, and per unit reduction in SBP and LDL-cholesterol. Overall, the mean cost per patient was significantly lower with the polypill strategy (−$203 per person: 95% CI: −286, −119) with scenario analyses under varying polypill price assumptions suggesting an ICER for the polypill strategy demonstrating a cost-saving of up to $75 per 10% increase in adherence for polypill price of $0.94 per day.⁴⁰

It is important to emphasize that the use of evidence-based therapies for vascular risk reduction among stroke patients receiving conventional care in LMIC is extremely low. Thus, it has been posited that if used at the current rates of prescription of secondary prevention drugs, the polypill will have only a modest impact on reducing DALYs in LMICs. An incremental benefit is projected by increasing the use of the polypill up to 50% - 75% of the eligible population in these settings.³⁹ The implication is that achieving impactful reductions in adverse cardiovascular outcomes among stroke survivors in LMICs with the polypill will require more than a simple inclusion of the polypill into a country’s formulary. Resource allocation and concerted efforts are simultaneously needed to augment the accuracy of stroke diagnosis and proper identification of its primary types, the uptake of and adherence to guideline-directed medical treatment among stroke survivors by healthcare providers, as well as ensuring reliable access to affordable polypill formulations, and monitoring patients’ adherence. Altogether, the polypill is a promising and potentially cost-effective intervention which should be incorporated into a multi-pronged and holistic strategy for prevention of ASCVD in LIMCs. Given the considerable heterogeneity of LMIC settings, additional real-world cost effectiveness data from hybrid clinical trial designs are still needed.

FUTURE DIRECTIONS

After almost 20 years of conception of the CVD polypill, substantial evidence has accumulated regarding the effects of polypill-based strategies for global ASCVD prevention and control. In spite of the evidence of efficacy of the polypill for primary prevention and accumulating data for secondary prevention, there has been limited uptake of this intervention into routine practice. The lack of traction of polypill into practice and policy may in part be due to low acceptability of the polypill by clinicians and lack of evaluation of implementation outcome measures in the clinical trials designed to assess its efficacy. Huffman et al ⁴¹ in a 2019 JAMA Opinion piece highlighted three persisting barriers impeding the acceptance of the polypill namely: (i) polypills have limited allowance for dose titration; (ii) the polypill is a proposed treatment for everyone over a certain age with a risk for mass medicalization of populations and (iii) the polypill should be used only in LMICs, although substantial inequities in cardiovascular care persist in HICs. Additional barriers include the financial burden of lifelong therapy, addition of healthy lifestyle measures, monitoring for adverse events, and dealing with outdated medications in LMICs settings.

There is therefore an urgent need to explicitly deploy implementation science frameworks to identify context specific implementation barriers, strategies, and outcome measures for the polypill. Implementation strategies should be devised based on evaluation of the polypills’ relative advantage, compatibility, trialability, and observability to inform local adaptation and refinements via multi-stake holder engagements with patients, clinicians and policy makers. An example of an implementation framework is the Consolidated Framework for Implementation Research (CFIR), ⁴² a comprehensive framework with 5 major domains and 39 underlying constructs and sub-constructs that could be deployed to evaluate implementation factors that could potentially influence efforts to enhance the uptake of the polypill. The CFIR major domains include the intervention characteristics; the inner and outer contexts; the individual; or the process of implementation for enhanced uptake of the cardiovascular polypill for stroke prevention. (Figure 1). Other potential barriers for implementation include those at the patient-level (e.g. fear of side effects), provider-level (e.g. misconceptions such as inability to titrate polypill dosages or other add-on therapies), or at health-system and policy-level (e.g. engagement with pharmaceutical companies for high volume, inclusion of polypills into the national essential medicines list for insurance coverage). Concerning flexibility in adjusting dosages of polypill formulation, the CNIC (Centro Nacional de Investigaciones Cardiovasculares, Ministerio de Ciencia e Innovación, España) polypill is available in two dose formats for atorvastatin (20mg and 40mg) and three doses of ramipril (2.5mg, 5mg or 10 mg) plus aspirin 100mg giving a total of 6 versions of the polypill for enhanced flexibility and ease of dose adjustment.

Figure 1:

Consolidated Framework for Implementation Research (CFIR) domains for polypill implementation

CONCLUSIONS

Current projections are that the already overwhelming burden of strokes and other CVDs in LMICs will continue to escalate over the coming decades as traditional vascular risk factors burgeon in these populations. The polypill could potentially reduce the risk of occurrence of major CVDs and prevent recurrent vascular events across most LMICs at a lower cost. More secondary prevention clinical trial data are however needed from the LMIC regions. Importantly, implementation trials which elicit implementation barriers and facilitators as well as assess real-world implementation outcomes such as its cost-effectiveness will significantly enhance the uptake of the polypill as a viable part of a holistic strategy for prevention of atherosclerotic CVDs in LMICs.

Non-standard Abbreviations and Acronyms

CEA

Cost effectiveness analysis

DALY

disability-adjusted life years

GDP

gross domestic product

HICs

High Income Countries

HR

Hazards ratio

ICER

incremental cost-effectiveness ratio

IQR

interquartile range

LMICs

Low- and Middle-Income Countries

MACE

major adverse cardiovascular events

PAF

Paroxysmal Atrial Fibrillation

PROPS

Preventative Role of a fixed dose combination Pill in Stroke

QALY

quality of life years

RCTs

randomized controlled trials

SECURE

Secondary Prevention of Cardiovascular Disease in the Elderly Trial

SIREN

Stroke Investigative Research and Education Networks

SSA

Sub-Saharan Africa

TIPS-3

The International Polycap Study 3

UMPIRE

Use of a Multidrug Pill in Reducing Cardiovascular Events