Cardiovascular diseases (CVDs) are the most common cause of death worldwide with more than 17 million deaths annually [1]. Global estimates show that CVDs such as ischemic heart disease and cerebrovascular disease will still be the primary cause of death by 2030 and will be associated with productivity loss and catastrophic healthcare costs [2, 3].

Ongoing changes in low and middle income countries (LMICs), accelerated by urbanization and socio-economic development, have increased the exposure to health related risks such as tobacco smoking, unhealthy diet and reduced physical activity [4]. Together with ageing of the population these changes have led to an increase in the incidence of non-communicable diseases including CVDs in these countries [1, 4]. Appropriate preventive measures should be taken to slow down this detrimental developments and treatment of these diseases should be prioritized. This notion has been accentuated in various international meetings and governments have made a variety of commitments in this direction [5, 6]. Evidence indicates that more than 80% of global cardiovascular deaths occur in LMICs which is (partly) due to the lack of access to healthcare including skilled human resources, equipped facilities and medicines [7, 8]. Medicines are more available for treatment of infectious disease as opposed to CVDs or other non-communicable diseases [9]. In order to change this inequality, essential medicines could be instrumental. The WHO has compiled and revises a list of medicines which is considered essential to meet global health needs, the so-called WHO essential medicines list. It is recommended by the WHO that countries make use of this list as a guide to prepare their own national essential medicines lists (NEMLs). A NEML is supposed to respond to the health care priorities of each individual country as determined by the national burden of disease and national health care priorities. It is shown that essential medicines are more available than other medicines across LMICs, hence NEMLs play indeed a role in supply of medicines (at least) in the public sector. A NEML often constitutes a basis for district level medicines lists and hospital formularies [10, 11]. Therefore, a preliminary step in guaranteeing equitable access to medicines in LMICs, is adopting a NEML with a rational and balanced approach in selection of essential medicines.

This study will assess selection of essential medicines for the prevention and treatment of a selection of CVDs on NEMLs of LMICs. Potential determinants for this selection, namely income level and geographic region of countries, national burden of CVDs and update of NEMLs on selection will be studied. Additionally, the extent to which different CVDs can be treated according to the guidelines by the selected essential medicines will be explored.

CVDs own a substantial share in the total burden of non-communicable diseases [49]. Therefore it is important to evaluate whether adequate steps have been made by LMICs to confront this still growing burden. Selection of appropriate essential medicines on NEMLs is one of the first steps studied here in detail.

The main medicine classes for the management of CVDs were represented on NEMLs. Suboptimal selection of medicines for the prevention and treatment of CVDs was however observed for ADP receptor inhibitors, selected by less than half of the countries studied, and statins, thrombolytic agents, medicines for pharmacological cardioversion and medicines for maintaining sinus rhythm which were not selected by nearly a quarter of the countries. The total number of selected essential medicines for the prevention and treatment of cardiovascular diseases differed across income levels and regions. Over 75% of the NEMLs included adequate treatment for the primary and secondary prevention of CVDs and for the majority of acute cardiovascular events. However, management of acute coronary syndrome, especially myocardial revascularization with PCI with dual platelet therapy, could only be covered in less than half of the countries by the current selection, whereas cilostazol or naftidrofuryl for peripheral arterial disease was only found on the NEML in 1 country.

In LMICs, high cholesterol is the second highest risk factor which contributes substantially to the burden of CVDs [50]. Despite this fact, statins were missed on the NEMLs of approximately 25% of LMICs in this study while no alternative lipid lowering agents were selected in those countries. This was particularly notable in the African region. In addition, the African region had the lowest median number of essential medicines for the management of CVDs. Unlike all the other regions in the world where CVDs are the leading cause of death, in Africa mortality due to infectious diseases exceeds mortality due to CVDs [51]. Nevertheless, in the absolute term, the burden of NCDs (including CVDs) in Africa is also high and is projected to exceed communicable disease as the most common cause of death by 2030.

RAAS inhibitors were selected by all the studied countries due to extensive selection of ACE inhibitors. Nevertheless, a fraction of patients (5–35%) may not be able to benefit from ACE inhibitors because of dry cough as an adverse effect [52]. Guidelines have consensually recommended ARBs instead of ACE inhibitors for this group of patients. However, ARBs were only selected by nearly half of the countries studied.

Among non-dihydropyridine calcium channel blockers, diltiazem is the preferred treatment for stable angina pectoris, particularly in case of monotherapy [53]. Diltiazem was only selected by 44% of the countries, and is not included in the WHO model list of essential medicines [54]. Instead, the model list selected verapamil, which was also predominantly observed for the NEMLs studied. However, diltiazem is mostly well tolerated and very effective in the prophylaxis of angina whereas verapamil has negative inotropic effects and is less appropriate for this indication [23, 45].

Streptokinase was included in about 75% of the countries studied, unlike rt-PAs selected in 15% of the countries. Streptokinase, which is currently included in the complementary list of the WHO model list of essential medicines, is deemed unacceptable by some guidelines, owing to its high rate of bleeding and frequent allergic reactions (43). In addition, rt-PAs have shown to be cost-effective in both developed and developing countries [55‐58]. However, infrastructural and economic constraints might have restricted their selection [59]. Similarly, LMWHs (e.g. enoxaparin) have recently been added to the WHO model list of essential medicines while they were underrepresented in a majority of the NEMLs studied. LMWHs are documented to have a better safety profile, more predictable pharmacokinetics and comparable clinical outcomes with UFH [54, 60‐62].

Despite the fact that all the studied countries selected at least a selective beta blocker, the choice was dominated by atenolol (selected in all countries). Atenolol has been replaced with bisoprolol (or alternatively, metoprolol or carvedilol) for angina, arrhythmia and heart failure in the WHO model list of essential medicines [54]. As these specific beta blockers are evidence based treatments for heart failure, it is worthwhile considering them while prioritizing choices for an NEML. In the current study, these evidence based beta blockers were only found in slightly over half of the NEMLs, which varied greatly across different income levels.

Antiarrhythmic medicines indicated for rhythm control in atrial and ventricular fibrillation were absent in a quarter of countries studied while this group of medicines are life saving for patients in critical conditions. Vitamin K antagonists, e.g. warfarin were available in 32 (94%) of NEMLs whereas DOACs were not included in any of the NEMLs studied. These newer anticoagulant medicines are shown to be cost effective in health care settings in developed countries compared to vitamin K antagonists, e.g. in secondary prevention of stroke in atrial fibrillation [63, 64] albeit with a high budget impact [65]. As innovative medicines, acquisition costs of these medicines might momentarily be unaffordable for health care settings in LMICs. However, management of warfarin therapy including INR monitoring is reported to be poor in LMICs, resulting in higher rates of stroke in AF patients (between 2 and 5 time as high in LMICs compared to the developed countries) and more frequent episodes of major bleedings [66]. DOACs are shown to be superior to warfarin with respect to the occurrence of major bleeding events and do not require frequent monitoring of the anticoagulant effects [66]. This might provide additional advantages for DOACs across LMICs compared to developed countries from a health systems perspective. Yet, further studies are required to assess costs and cost effectiveness of these new medicines across LMICs [66, 67].

Essential medicines are shown to be more available compared to other medicines worldwide [7]. This indicates the importance of essential medicines to ensure access to pharmaceutical treatment. Although cardiovascular medicines were widely selected according to our analysis, selection might not have been translated in adequate access to essential cardiovascular medicines. The availability of medicines for chronic disease (including CVDs) was reported to be less than 30% in public facilities across six LMICs, while a wide variation was observed in affordability of a month of coronary heart disease treatment, ranging from 1.5 to 18.4 days of a minimum official salary [68]. Other components of access to medicines framework (particularly sustainable financing and a well-structured health care system) should as well be studied to unravel the existing suboptimal access. Integration of cost-effective non-communicable disease interventions into the basic primary health care package and finance them through sustainable financing mechanisms is necessary to support the selection of essential medicines, as recommended in the draft of the WHO NCD action plan “appendix 3” [69].

This study has a number of limitations. The number of low income countries was lower compared to the other income levels. Regional results should be interpreted cautiously since the African region was only represented by low income countries. Besides, treatment of comorbidities (e.g. diabetes) and special patient groups (e.g. elderlies, comorbid patients) were out of scope of this study. Guidelines vary in recommendations while we only included the essence of the treatments in this study, and in particular we excluded innovative medicines suggested by some of the guidelines (GP IIb/IIIa inhibitors) because of the scope of this study being limited to LMICs. Selection of oxygen and analgesics (e.g. morphine) was not assessed in the current study, but there are concerns about their availability and accessibility [70, 71]. More generally, pharmacological treatment of CVDs was the only focus of this study whereas guidelines for treatment of CVDs also incorporate non-pharmacological prevention, early diagnosis and surgical interventions. Therefore, other studies are needed to assess the integrated care options for CVDs. From a health system perspective, the example of stroke suggests that well equipped facilities are not adequately found in the public sector in LMICs, except in some upper middle income countries [59]. Geographic access to the existing centers is also a concern, where in some LMICs less than 15% of patients with stroke could reach a hospital within the first 3 h of the event [72]. It is unclear whether the observed suboptimal selection in this study, owes to differences among national treatment guidelines or not. These guidelines might exist in local languages or just be published at a national level. Nevertheless, it is questionable, whether a national guideline would not have referred to statins or thrombolytic agents. Considering the differences between health systems in countries, each jurisdiction has its specific challenges in access to medicines. This study (in part) utilises a collective approach in categorising countries (e.g. income levels), which has an inherent limitation of overlooking within category differences. There are undeniable differences between countries within each category in their economies, health systems, extent of evidence-based selection of essential medicines and use of essential medicines lists, which makes intra-category comparisons and case studies at a country level an important addition to the current study. Lastly, the latest available NEML for each country in the WHO database of essential medicine lists at the time of collection was considered to be the last update of an NEML in practice. Beyond this credible database, we were unable to verify if a country has a newer NEML unless the it appeared in the database. In studying determinants of selection, the factors we could study do not represent all potential influential factors. A plethora of issues might be involved in decision making for selection of essential medicines, including but not limited to the selection procedure itself. The results should therefore be interpreted cautiously. However, this study at least provides some insight in a number of factors which might influence the selection of medicine.

In conclusion, essential medicines for the management of CVDs were widely selected in LMICs. This has been translated into inclusion in NEMLs of essential pharmacological treatment according to evidence-based guidelines for the majority of CVDs. Nevertheless, empirical evidence suggests limited access to medicines for CVDs to this end.