Primary and secondary prevention interventions for cardiovascular disease in low-income and middle-income countries: a systematic review of economic evaluations

Cardiovascular disease (CVD) is the number one cause of mortality globally, accounting for about 31% of worldwide deaths. Estimates from the Global Burden of Disease (GBD) 2015 study showed that there were 422 million cases of CVD globally, and deaths from CVD have increased from 12.6 million in 1990 to 17.9 million in 2015 [1]. Over four-fifths of premature mortality (deaths before age 70 years) from non-communicable disease (NCD) occurs in low-income and middle-income countries (LMICs), and over a third is caused by CVD [2]. While the trend (1990–2015) in age-standardized prevalence of CVD is declining in high-income countries (HIC), this is not very obvious for most LMICs, where current rates are > 9000 prevalent cases per 100,000 persons. Likewise, there have been significant declining trends in age-standardized CVD mortality rates in all HICs, however similar changes have not been observed for the majority of sub-Saharan Africa and Southeast Asia [1].

The epidemiologic transition and demographic changes (population growth and ageing) have contributed to the CVD burden in LMICs. Evidence from research on early life (in utero) exposures, genes, and the environment have added to the understanding of the development and occurrence of CVDs in adulthood. Furthermore, metabolic (high blood pressure, high blood glucose, dyslipidemias, obesity) and behavioural (tobacco use, unhealthy diet, physical inactivity) risk factors are time-honored drivers fueling this CVD epidemic around the world [3]. A number of these risk factors are modifiable, and are targeted to curtail this burden via preventive and or treatment strategies.

There are several models of prevention, including population-wide and individual approaches targeting either individual risk factors, or multiple risk factors [4]. These strategies may be geared towards individuals with risk factors to prevent incidence of CVD events like cerebrovascular accidents and ischaemic heart disease (primary prevention) or in those with CVD events to prevent recurrence (secondary prevention) or reduce long-term impairment and disability resulting from a CVD event (tertiary prevention) [4]. Preventive interventions include (but are not limited to) medical procedures, pharmacological (blood pressure and cholesterol lowering medication, anti-platelet aggregants, thrombolytic agents) and non-pharmacological (health education, taxation, legislation) interventions.

Recognizing the plethora of individual country healthcare needs, and ever limited resources, the requisite for economic evaluation of interventions has been increasingly acknowledged [5]. This economic evidence forms one of the parameters for government and health policy makers as they decide on where to invest [6].

While there is overwhelming evidence in HICs from economic evaluations on the cost-effectiveness of interventions for CVD prevention, this is not the case for LMICs. Moreover, the transferability and implementation of interventions trailed in HIC to LMICs is debatable [7]. Among others, there are differences in effectiveness and cost related to variations in socio-cultural, environmental, demographic, disease profiles and importantly, human and financial resources. Especially in Africa, LMICs are not only faced with the growing NCD burden, but are also afflicted by still-large burdens of infectious disease, nutritional disorders, neonatal and maternal mortality [8]. Thus, considering the inherent limited financial resources amidst these colossal health needs (communicable and non-communicable), their governments are faced with a greater challenge in choosing interventions that offer good value for money.

Based on the above, there is great need for robust evidence on which interventions are cost-effective to inform policy decisions. We must acknowledge that this is not the first review on economic evaluations for CVD. Suhrcke et al. [7] and Shroufi et al. [9] have previously reviewed the topic, though their work included studies only up to 2009 and 2010, respectively. The study by Suhrcke and colleagues had a number of limitations. While they used a reasonably sensitive database search strategy, they did not assess grey literature and so it is likely that they might have missed some important studies. Also, their quality assessment was based on authors’ statements on methods, instead of objective quality assessment tools. Furthermore, it is unclear why the study by Shroufi et al. included few studies. However, we noticed that in terms of geography, they used continental or regional names in their search. Including specific country names would likely have increased the sensitivity of their search strategy in capturing more studies.

Considering the time since the conduct of these studies and the above shortcomings, there is a clear need to provide updated and contemporary evidence of interventions providing the most health gains with minimal costs, in the prevention CVD in LMICs.

This systematic review has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [10], (Additional file 1). Our review was registered in the PROSPERO International prospective register of systematic reviews (registration number: CRD42016043510) at the Centre for Reviews and Dissemination, University of York, UK and the protocol has been published [11].

The evidence on cost-effectiveness of interventions for CVD prevention is growing rapidly, with the majority of studies being modelled economic evaluations in the middle-income countries. Primary prevention studies outnumbered those for secondary prevention. Most economic evaluations were for pharmacological interventions focusing on blood pressure, cholesterol lowering and antiplatelet aggregants. BP lowering interventions (mostly diuretics and its combinations) were cost-effective, especially in high risk populations. While some cholesterol lowering interventions alone were not cost-effective, treatment interventions based on absolute CVD risk were mostly cost-effective, with the polypill being most economically attractive. Population-based interventions were few and mostly targeted reduction in sodium intake and tobacco control strategies, and were usually cost-saving.

We observed that the number of publications on economic evaluations for CVD prevention have steadily increased, especially during the last decade. This coincides with, and might arguably be thanks to, the efforts of the Disease Control Priorities Project (DCP2) in 2006, which explored among others the cost-effectiveness of various interventions to combat NCDs. Additionally, the earlier publication of the WHO guide to cost-effectiveness analysis in 2003 [6], and availability of WHO-CHOICE methods [65] are likely catalysts for this observed surge in publications.

For primary prevention, the majority are pharmacological interventions and target high blood pressure, high cholesterol and antiplatelet therapy either singly or in combination. Individual strategies focusing on BP lowering therapies have shown that compared to other antihypertensive drug classes, diuretics are consistently the most cost-effective as monotherapy. Other classes like beta-blockers, ACE inhibitors and calcium channel blockers tend to be favourable mostly when used in combination. Individual treatments with statins are cost-effective in some settings and are not in others, in part due to the different statin drugs evaluated with differing prices across countries. Studies that have evaluated the hypothetical polypill show that it is a very cost-effective option. However, controversy still looms as regards large scale implementation especially in relation to consequences/side-effects of mass treatments and stretching of limited budgets in LMICs [7].

Secondary prevention strategies are similarly geared towards pharmacological strategies, and besides blood pressure and cholesterol lowering interventions; there has also been some focus on thrombolysis and medical procedures. Pharmacological interventions are mostly cost-effective, though with some specifics worth considering. Population-based interventions are relatively few but are cost-effective and or cost-saving. Differences in demographics and epidemiology, modelling assumptions, intervention costs and effectiveness across settings, economic perspectives and time horizons for which interventions are assessed and variation in compliance levels, likely account for the dissimilar conclusions across studies.

Other individual strategies to control smoking like treatments with Bupropion and nicotine replacement therapy are not cost-effective options in the LMICs, although some reports from HICs have shown promise [66].

Population-based interventions have mostly focused on reduction in salt (sodium) intake and smoking. These appear to be the most attractive population-wide interventions, being either very cost-effective or cost-saving in CVD prevention. In a recent systematic review, Hope and colleagues [67] summarized the evidence on economic evaluations of population-based sodium reduction interventions. Similar to our findings, they highlighted that salt reduction interventions offer good value for money. However, similar to ours, they noted that there are few studies assessing the impact of salt tax legislation [67]. Most of the salt reduction interventions focused on health education via mass media campaigns, product reformulation and relabeling.

With respect to tobacco smoking control strategies, contrary to a previous review [66] that suggested majority of interventions focused on nicotine replacement therapy (NRT) and self-help therapies, we found that mass media campaigns, increasing taxes and smoke-free laws were the predominant interventions studied. It is likely that the search strategy and comparatively limited number of databases searched in the prior review, coupled with a focus on high-income countries, might explain the difference. It should be noted, however that we found no economic evaluations of school-based cessation programs, smoking quitlines and tobacco control programs in pregnant women, which have been shown to be cost-effective and potentially cost-saving elsewhere [68‐70]. The absence of such economic evidence might be due to the non-existence of such programs or studies evaluating them in LMICs. This constitutes a gap in the strategies to tackle the tobacco epidemic.

With respect to medical procedures, we found very few studies have assessed their cost-effectiveness in LMICs, with the available studies mostly done in Latin American countries. In Brazil for example, early and new generation stents were considered cost-effective, though with limited benefit for moving from early to the new generation stents. Considering the limited available evidence here and the fact that many other regions have not evaluated the use of stents and ICDs, it is difficult to draw reasonable conclusions. However, on a case by case basis, clinicians will be required to strike a balance between long term clinical efficacy and costs to patients and health system.

Screening strategies have been less well explored compared to other interventions. The few existing studies suggest that some strategies are potentially cost-effective. In a bid to enhance their economic attractiveness, their implementation must be stratified for specific population age groups and gender, as well as tailored to account for countries’ specific needs.

As observed in previous reviews [7, 9], there are still few economic evaluations of interventions targeting other risk factors like physical activity, alcohol consumption and body mass. These are established drivers for CVD, and it is important that future studies should consider evaluating interventions targeting those drivers, so as to provide broad perspectives for consideration in stemming the CVD burden.

The majority of included studies are modelled evaluations, with the majority using Markov modelling. This modelling approach has been widely discussed to be suited in modelling chronic diseases such as cardiovascular disease [71]. While model-based evaluations might not be same as real life situations, they are increasingly gaining place in economic evaluation, for a number of reasons. Firstly, economic evaluations conducted alongside RCTs are likely to be limited in time horizon as it is costly for trials to extend for several years [72]. Secondly, the majority of RCTs have intermediate endpoints (such as change in BP or change in cholesterol) as their outcome and very few extend to final end points (CVD event or death, let alone QALYs or DALYs). As such, these are unlikely to reveal the complete picture of costs and benefits of an intervention. Model-based evaluations have the potential to address these problems by using long time horizons [72]. This is particularly seen for smoking-related interventions whose benefits generally accrue in the fourth or fifth decades following implementation of the intervention [73]. Contrary to previous reviews, which found no cost–benefit analysis, we found a single study using this evaluation method. While there is clearly a dearth in studies using this method for evaluation, cost–benefit analyses are likely to be also relevant to policy makers as it allows for direct comparison of health interventions with interventions in other sectors [13].

Up to one-fifth of included studies either did not assess, or failed to incorporate, uncertainty around their ICER estimates. This is particular, as most of the parameters used in modelling studies come from multiple sources, from contexts that differ from those of the target population. It is important to determine the uncertainty around the benefits and costs, and how this affects the ICER estimates. The uncertainty around the cost-effectiveness of interventions is important for policy makers, as they broadly assess and compare the potential gains or losses from implementing one intervention over another [74].

About two-thirds of included studies received some form of funding, mostly from government ministries and universities or educational institutes. We noted that four studies were funded by pharmaceutical industries. Lundh and colleagues in a Cochrane review discussed the impacts of industry funding on research outcomes, in which they highlight that most industry-funded trials are likely to report drugs as efficacious or less harmful [75]. This bias is similarly likely to occur in economic evaluation studies, with such [industry-funded] studies likely to report an intervention or drug as being cost-effective. It is difficult to say with certainty the accuracy of conclusions drawn from the four studies in our review which received pharmaceutical industry funding; with two having low risk of bias [52, 59] and two of moderate risk [37, 60]. It is possible that eliminating these studies, especially those with moderate risk may potentially influence some of our conclusions. We again highlight that interpretation of such findings should be done with caution.

As regards methods for defining an intervention as cost-effective or not, the majority of studies used the WHO Commission on Macroeconomics and Health approach of multiples of GDP per capita, and only very few used a priori willingness-to-pay thresholds. While the proposed WHO method is good at determining those interventions that have good or very good value for money, Bertram and colleagues recently argued about the misuse of these thresholds for decision-making [76]. Modelled cost-effectiveness ratios are amongst others dependent on the construct and validity of the models, variable sources of input parameters; they suggest that for priority setting, decision makers should, besides cost-effectiveness thresholds, take into account other factors such as budget impact, affordability, feasibility of implementation and fairness [76]. Similarly, Remme and co-workers have recently proposed a multi-sectoral perspective for resource allocation, arguing that multiple sectors potentially contribute to health gain and that the goods and services obtained from health sector or interventions can have multiple benefits outside health [77].

In a number of LMICs, Health Technology Assessment (HTA) is currently being considered to guide policy makers in priority setting for the allocation of scarce resources. Over the last decade, NICE International and Thailand’s Health Intervention and Technology Assessment Program (HITAP) agreed to create partnerships to improve priority setting in LMICs for HTA. Their efforts are well underway in Latin American and Asian countries like Colombia, Vietnam, India, Myanmar and the Philippines [78]. In Africa, some strides have been made in countries like Ghana and South Africa, however, there are still huge gaps including absence of dedicated HTA institutions and limited research capacity [79, 80]. While countries, especially those that have adopted universal health care (UHC) are pushing for HTA to assist them allocate resources appropriately and equitably, as they sustain the UHC programs, studies have suggested that local evidence to inform HTA is limited [81], and further widens the gap between research and policy which is already challenged by low awareness and lack of will among policymakers in the region. We believe our efforts in this review will be very beneficial for policymakers in two facets. First, to feed countries with existing HTA institutions with comprehensive local evidence on interventions that have good value for money as they identify where to invest and guide their HTA efforts. Secondly, our findings will contribute in narrowing the existing knowledge gap on cost-effectiveness on CVD preventive interventions, while highlighting the importance of economic evaluations of interventions as an important guide to resource allocation and priority setting in LMICs with already strained financial resources.

This systematic review has provided contemporary evidence on the interventions that offer good value for money for the prevention of CVD in LMICs. The bulk of studies focused on pharmacological and other individual-level interventions, which often were found to be cost-effective. Population strategies, though under-represented in the evidence base, are similarly very attractive economically. The available evidence suggests that stemming the CVD epidemic in LMICs would require both individual and population-based strategies to achieve maximal health gains at lowest possible costs. Additionally, there is need for a focus on interventions to address other risk factors like physical inactivity, low fruits and vegetable consumption, alcohol intake and body mass. Decision makers must however not rely exclusively on cost-effectiveness thresholds, but take into account multi-sectoral approaches, and other country and context-specific factors as budget impact, affordability, fairness and implementation as they contemplate which interventions to invest in. Finally, governments in LMICs need to strongly consider strengthening and building research capacity on economic evaluations of interventions, health technology assessment, as well as bridging the gap between research and policy in order to make informed decisions for priority setting towards the allocation of their scarce resources.