Fixed‐dose combination therapy to reduce the growing burden of cardiovascular disease in low‐ and middle‐income countries: feasibility and challenges

Abstract

Cardiovascular disease (CVD) has become a major concern in low‐ and middle‐income countries, which bear about 80% of the cardiovascular mortality worldwide. Curbing the burden of CVD implies the management and control of many cardiovascular risk factors that act synergistically to increase cardiovascular mortality. Such actions may require expensive polymedications in a context of limited resources. Therefore, alternative solutions for CVD prevention in low‐ and middle‐income countries are urgently needed. In this context, the concept of a fixed‐dose combination therapy, a polypill composed of drugs known to effectively treat or prevent CVD, has been proposed as a scalable strategy to overcome nonadherence to polymedications and reduce costs. While this has recently been approved in more than 30 countries across America and Europe, there is a crucial need to analyze the potential benefits and challenges related to cardiovascular polypills implementation and vulgarization in low‐ and middle‐income countries, the epicenter of CVD.

1. INTRODUCTION

Although the incidence and mortality rates associated with cardiovascular disease (CVD) are declining in high‐income countries, they are rising globally as a result of the increasing incidence in low‐ and middle‐income countries (LMICs).1 Approximately 80% of worldwide CVD‐related deaths arise from LMICs, where it is expected that the condition will surpass communicable diseases as the leading cause of death by 2030.2 This high burden of CVD in developing countries is attributable to changes in lifestyle (including poor dietary habits and lack of physical activity) and rapid urbanization, collectively with a sharp increase in CVD risk factors such as hypertension, dyslipidemia, obesity, diabetes mellitus, HIV infection, and air pollution.1, 3, 4, 5 CVD carries a huge economic burden especially in LMICs, where it often occurs at a younger age, thus having a greater effect on loss of income during productive years.6 As a consequence, CVD worsens poverty and vice versa.

A great proportion of the economic impact of CVD is explained by the limited effect of pharmacological treatments resulting from nonadherence or poor adherence to medication.7 For instance, recent data indicate a low adherence rate to medications used for secondary prevention in patients with established CVD, the situation being the worst in low‐income countries.8 Thereby, special efforts to encourage adherence to medication are mobilizing the world's attention from patients, healthcare providers, regulators, and funders. A wide range of interventions have been proposed including blister packaging, case management, education with behavioral support, reminder calls, pharmacist‐led multicomponent interventions, collaborative care, and shared decision making, but not all interventions showed evidence of benefit.9

The concept of a fixed‐dose combination therapy, a polypill composed of medications known to effectively treat CVD, was also proposed as a scalable strategy to overcome nonadherence to medication and reduce the risk of premature deaths from CVD. Polypills are generally made of a fixed combination of one or two antihypertensive agents, a lipid‐lowering medicine and sometimes an antiplatelet drug. Several studies have demonstrated that cardiovascular polypills may simplify treatment algorithms, improve patients’ adherence, increase accessibility, and reduce cardiovascular events and associated costs as compared with usual care.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 However, cardiovascular polypills have not gained much popularity when compared with fixed‐dose combinations for other diseases such as HIV, tuberculosis, and malaria. They are still facing a huge challenge to their implementation, especially in LMICs.11

While polypills have just been approved in more than 30 countries across America and Europe, and have been given consideration for introduction in the World Health Organization (WHO) 20th model list of essential medicines,11 there is a crucial need to analyze the potential benefits and challenges related to the implementation and vulgarization of cardiovascular polypills in LMICs, the epicenter of CVD.

2. EXPECTED BENEFITS OF POLYPILLS IN LMICS

2.1. From a patient's viewpoint

The current literature is clear about the fact that polypills increase adherence to medication.10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23 Nonadherence to medication has been shown to be more prevalent in LMICs. For instance, the PURE (Prospective Urban Rural Epidemiology) study demonstrated that in LMICs, only 3% of participants with a history of coronary heart disease or stroke were still taking drugs for secondary prevention of CVD 5 years post‐event.8 It is generally admitted that adherence is a complex concept, determined by the interplay of socioeconomic and medication‐, condition‐, health system–, and patient‐related factors.24 The situation is aggravated in LMICs where poor availability and affordability of medication are common.25, 26 Furthermore, the complexity of treatment and the daily number of prescribed pills seem to constitute the most important factors responsible for lack of adherence to treatment.7, 10, 17, 22, 27

Hence, the vulgarization of polypills would be mostly beneficial in LMICs. The advantages of polypills to the patient include ease and convenience of taking the drugs, cost‐saving benefits, reduced inappropriate drug interactions and adverse outcomes, and improved safety caused by decreased risk of confusion between tablets or accidental overdosing.13, 17, 22, 27 Ease, convenience, safety, and simplicity of manipulation offered by polypills are tremendously interesting for LMICs mainly characterized by low literacy rates and poor level of knowledge about CVD and their risk factors.28 This represents a major impediment to patients’ therapeutic education, especially in a context of chronic diseases and polymedication, which requires good knowledge of the different molecules to be taken and respective dosages.

Further, it was shown that polypills may be more available and could be accessed at lower prices than usual CVD medications,11, 13 which make them particularly suitable in a context of poverty and low economic background, characteristics of populations living in LMICs. Moreover, fixed‐dosed combinations are being used in other diseases such as HIV, tuberculosis, and malaria, which remain preponderant in LMICs. Considering the satisfactory experience and acceptance yielded by combined medications used for these infectious diseases in LMICs, it is expected that cardiovascular polypills could also receive positive reactions in these regions.11, 13

2.2. From a physician's viewpoint

The first and foremost benefit of polypills to a physician is ease of prescription alongside increase in patient adherence. Indeed, polypills simplify treatment algorithms, which make them easy to be prescribed by nonspecialists and/or in primary healthcare settings.11, 13 Given that LMICs remain characterized by a dire lack of qualified workforce, especially in underserved rural areas,29 polypills offer a great opportunity to deliver adequate CVD care when indicated. General practitioners, nurses, or even pharmacists could thereby be brought into play to manipulate polypills, hence reducing the heavy patient loads of specialist clinicians, which remains frequent in LMICs and obstructs quality of care.30

Another important point for a physician is to be sure that the drug prescribed “works,” is safe, and has few undesirable effects. Polypills have been shown to reduce cardiovascular events and risk factor levels (blood pressure and lipid levels for instance) in primary or secondary CVD prevention. Furthermore, the drugs were well tolerated with few serious adverse events and discontinuations.11, 13, 21, 31 It is true, however, that most of these effects were not significantly different from those induced by usual medications.11, 12, 13, 31 Results from ongoing trials (SECURE [Secondary Prevention of Cardiovascular Disease in the Elderly Trial; NCT02596126] and INTEGRATE [Integrated Combination Therapy, Electronic General Practice Support Tool, Pharmacy Led Intervention and Combination Therapy Evaluation; ACTRN12616000233426]32 and the SCCS Polypill Pilot [NCT02278471] and PolyIran [NCT01271985] trials and the related PolyIran Liver [NCT01245608],33 TIPS‐3 [The International Polycap Study 3; NCT01646437], and HOPE‐4 [Heart Outcomes Prevention and Evaluation 4; NCT01826019]34 trials) are urgently awaited to clarify these issues. Nonetheless, polypills seem to surpass usual cardiovascular treatments when considering the ease of prescription and significant increase in adherence.

2.3. From Governments’ and Organizations’ viewpoints

Polypills have been presented as a simple, innovative, scalable, and cost‐effective public health strategy to combat the CVD epidemic on a global scale, specifically in LMICs.11, 12, 13, 14, 17, 21 In fact, these drugs could contribute to reduce the risk of premature mortality from CVD by 25% by 2025, a goal set by the WHO.2 A paramount condition to reach this goal is that each and every patient who needs care for CVD receives safe and effective treatment. However, health systems remain weak in LMICs and healthcare coverage is practically nonexistent,29 a reality that significantly impedes the fulfillment of the aforementioned goal. Fortunately, the remarkable improvement in accessibility to medications and adherence to treatment offered by polypills can be of substantial help in reaching this goal in LMICs.11, 13 In fact, polypills constitute a vital strategy for expansion of CVD treatment.

Furthermore, polypills’ health economics benefits (cost‐savings and cost‐effectiveness) would be of particular relevance to LMICs. A recent pharmacoeconomic analysis revealed that the incremental cost‐effectiveness ratio of polypills’ use for secondary prevention of CVD in developing countries was between $306 and $388 per quality‐adjusted life‐years.35 Similarly, a model developed in the United Kingdom showed that for each 10% increase in adherence, an additional 6.7% of fatal and nonfatal cardiovascular events can be prevented, with an incremental cost‐effectiveness ratio of £8200 per quality‐adjusted life‐years gained.36 Two other reports claimed the cost‐effectiveness advantage of polypills, especially if the drug prices are sufficiently low.19, 20

Another important point of action should be the advocacy for the adoption and use of polypills, which requires endorsement from national key opinion leaders and national bodies.13 For instance, the Spanish Society of Cardiology, together with various primary care associations, developed a consensus document for the use of polypills in the secondary prevention of CVD.23 Likewise, other societies such as the European Society of Hypertension took position towards polypills’ usage in clinical care.22 These examples should be copied by LMIC scientific societies to support polypill implementation and manipulation in this part of the world.

3. POTENTIAL BARRIERS TO POLYPILL IMPLEMENTATION IN LMICS

Despite their well‐proven efficacy on adherence and control of cardiovascular risk factors, polypills are still facing a challenge for their implementation, especially in the developing world, attributable to a myriad of reasons. Until recently, there was a relatively low level of global pharmaceutical manufacturing investment explained by technical challenges associated with creating polypills, perceived low financial margins, uncertainty related to intellectual property, and absence of bulk prepurchasing contracts to mitigate financial risk. This resulted in little enthusiasm from pharmaceutical companies to develop polypills despite a large target population.11, 15 Hopefully, this trend seems to be turning, with the recent introduction of polypills in more than 30 countries in Europe and Latin America (Table). In addition, the introduction of polypills in the WHO model list of essential medicines could boost polypills’ manufacturing for a wider availability at affordable prices.

Table 1.

List of available cardiovascular polypills11, 13

Name	Composition	Pharmaceutical company
Atamra CV kit	Atorvastatin, ramipril, and clopidogrel	Amra Remedies
CV‐Pill kit	Ramipril, metoprolol, atorvastatin, and aspirin	Torrent Pharmaceuticals
GSK3074477a	Amlodipine and rosuvastatin	GlaxoSmithKline
Heart Pill	Ramipril, atorvastatin, and aspirin	Excella Pharma
Livalo fixed‐combination druga	Pitavastatin and valsartan	JW Pharmaceutical
Polycap	Simvastatin, atenolol, hydrochlorothiazide, ramipril ± aspirin	Cadila Pharmaceuticals
Polypill‐E	Aspirin, atorvastatin, hydrochlorothiazide, and enalapril	Alborz Darou Pharmaceuticals
Polypill‐V	Aspirin, atorvastatin, hydrochlorothiazide, and valsartan	Alborz Darou Pharmaceuticals
Ramitorva	Aspirin, ramipril, and atorvastatin	Zydus Cadila Healthcare
RIL–AA	Ramipril, atorvastatin, and aspirin	East West Pharma
Starpill	Aspirin, losartan, atenolol, and atorvastatin	Cipla
Trinomia	Atorvastatin or simvastatin, ramipril, and aspirin	Ferrer
Triveram	Perindopril, amlodipine, and atorvastatin	Servier
Unnameda	Irbesartan and atorvastatin	Sanofi
Unnameda	Valsartan and rosuvastatin	EMS
ZYCAD‐4 kit	Ramipril, metoprolol, atorvastatin, and aspirin	Zydus Cadila Healthcare

^aThese drugs have not yet received marketing approval.

Barriers pertaining to patients include little advocacy for the right to access cardiovascular medicines, fear of managing side effects and risk of stopping or discontinuing the pills, and uncertainty about cost.11 In this respect, populations should be sensitized and educated on the potential benefits of polypills based on the current evidence, which will contribute to reducing these fears. On the other hand, these drugs should be subsidized by local governments and/or nongovernmental organizations as is currently the case with other fixed‐dosed combinations used in HIV, tuberculosis, and malaria. It was shown that low‐priced cardiovascular polypills could constitute a cost‐effective solution when compared with usual CVD medications.19, 20 Moreover, this subsidization will surely increase affordability of polypills alongside accessibility, even in remote and economically deprived areas.

According to previous studies, the idea of a polypill for CVD prevention and control has not gained much appreciation among (specialist) physicians who expressed negative perceptions about lack of effectiveness, safety, and flexibility in dosing, and concerns about loss of autonomy in clinical decision making.11, 15 Polypills are generally made of a fixed combination of at least one antihypertensive, a lipid‐lowering medicine, and sometimes an antiplatelet drug (Table), which makes it difficult to adjust the treatment depending on the patient's clinical presentation, tolerance, and needs. For instance, some clinicians have claimed that the effects of potentially switching on and off polypills (eg, the need to stop an antiplatelet drug around the time of an ophthalmic surgery without stopping the other components) require further study before regulatory approval.11 Currently, however, multiple dose versions of both the statin and antihypertensive components are available, allowing for increased flexibility in prescription and use. Furthermore, as other manufacturers start marketing polypills, there will likely be substantially more variety available.11

Although polypills have demonstrated efficacy in reducing CVD events and risk levels, their superiority to usual medications remains a topic of debate. Reports from a systematic review revealed that in some studies, the number of CVD events was even greater with polypills, although nonsignificant.31 On the other hand, adverse effects were a matter of concern as they seemed to appear at higher rates, especially for polypills containing an antiplatelet such as aspirin, which can cause severe bleeding.11, 12, 13, 31 Nonetheless, it is worth mentioning that most of these studies were not powered enough to detect any difference between polypills and usual treatments.11, 13, 31 Results of various under way trials (SECURE, PolyIran, TIPS‐3, and HOPE‐4, among others) are expected to provide the evidence about the effects and safety of polypills.32, 33, 34

It is also worth highlighting that many trials that have evaluated the clinical benefits of cardiovascular polypills only had a relatively short follow‐up period31; hence, their results might not reflect the dynamic nature of CVD and the constantly changing clinical profile and/or risk level of patients with CVD. This is in contrast to communicable diseases, for which the treatment is either short‐lived (malaria or tuberculosis) or has the same goal throughout life (limiting the replication of the virus in HIV infection). Therefore, while advocating the implementation of treatment with cardiovascular polypills, governments and public health organizations should also make it clear that a “fixed‐dosed polypill” does not equate to “fixed treatment.” Healthcare providers should be encouraged to be vigilant and perform regular reassessments of their patients’ cardiovascular risk in order to perform timely adjustments of therapy. Otherwise, the vulgarization of treatment with polypills might lead to a rebound effect in the long run, leading to an increase in the incidence of cardiovascular events after an initial drop because of poor long‐term monitoring.

Moreover, while the benefits of polypills for secondary prevention of CVD are quite well established, their efficacy for primary prevention is yet to be demonstrated.11, 13, 21 The concept of polypills in the primary prevention of CVD was first introduced by Wald and Law,14 who presented these drugs as a mass treatment strategy to reduce CVD by more than 80%. In fact, polypills are mainly indicated for high‐risk primary prevention,11 which requires assessment of the global CVD risk of patients. Unfortunately, no risk assessment tool has been developed in LMICs, specifically those in Africa,37, 38 making it difficult to identify populations at high risk for CVD and therefore eligible for polypills. Thus, local tools should be developed accordingly. On the other hand, the indication of polypills containing aspirin for the primary prevention of CVD remains controversial, considering the lack of current evidence on the usefulness of aspirin for CVD.37, 38 Further studies are needed in LMICs, which will permit support of this clinical attitude. For now, the expected clinical benefits of prescribing aspirin for patients, either for the primary or secondary prevention of CVD, should be balanced against the risk of bleeding. If the latter outweighs the benefits, then aspirin should not be prescribed.37, 38

Clearly, in each case, prescribing a polypill in patients should proceed from an individual clinical evaluation. First, the risk of CVD needs to be evaluated and CVD risk factors identified. Thereafter, the specific medications, if required, should be identified to control the various risk factors and added to the change in lifestyle habits. Hence, the physician could search for the fixed‐combination therapy comprising the various medications that the patient has to take. Furthermore, clinicians have to search for specific conditions restricting the prescription of a particular drug. Hence, in the presence of any specific contraindication, the polypill containing that particular drug should not be prescribed. For example, if patients are allergic to ramipril, they should not be prescribed a polypill containing ramipril. They also need to be continuously evaluated and the medication readapted accordingly. Moreover, although LMICs share the same socioeconomic realities, the epidemiology of CVD is country‐dependent. For instance, stroke is more prevalent in some sub‐Saharan African countries,39 while ischemic heart disease is more prevalent in others or in Asian/Latin American countries.40 Therefore, indicating which polypill should be made available in all LMICs would be inappropriate. Finally, each LMIC should define the list of polypills that could be made available in their environment, taking into account the local epidemiological patterns of CVD and cost of medicines.

4. CONCLUSIONS

While inclusion of cardiovascular polypills in the WHO essential medicines list is being discussed, it appears opportune to look at the advantages and challenges of their implementation in LMICs. A clear analysis of potential benefits of polypills reveals that polypills, although not to be considered as the miracle solution, could greatly improve the prevention and control of CVD in LMICs, where the disease is becoming a major public health issue, and help to achieve the objective of reducing premature CVD mortality by 25% by 2025. However, further trial data and clinical experience reports are urgently warranted to determine how polypills can best be implemented to achieve this goal, in addition to education, advocacy, endorsement, and implementation by key global agencies, national clinical bodies, and governments.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

AUTHORS’ CONTRIBUTIONS

JJN conceived the study. JRN and ATT drafted the first article. JJN, JRN, ATT, and JKT revised the article for intellectual content. All authors approved the final version.

Nansseu JR, Tankeu AT, Kamtchum‐Tatuene J, Noubiap JJ. Fixed‐dose combination therapy to reduce the growing burden of cardiovascular disease in low‐ and middle‐income countries: feasibility and challenges. J Clin Hypertens. 2018;20:168–173. 10.1111/jch.13162