This editorial aims to inform policy development to increase the availability, affordability and acceptability of non-vitamin K antagonists oral anticoagulant (NOACs), for instance by adding NOACs into the National Essential Medicines lists, following the addition of this class of medicines to WHO Model List of Essential Medicines (EML). It includes the perspectives of several key constituencies, including academia, policy and advocacy, and the World Heart Federation’s leadership, and considers relevant COVID-19 developments for NOACs and cardiovascular health.
Atrial fibrillation (AF) is associated with a higher risk of hospital admissions, cerebrovascular and cardiovascular conditions, and premature death. Over 37.5 million people are affected by AF , with 58% of those suffering from it aged 70 years and over. Current projections suggest an expected increase in the incidence and prevalence in the next three decades due to population growth, ageing, and better survival among patients with AF [2, 3, 4]. By 2020, an estimated 17.9 million people in low- and middle-income countries (LMICs) will be living with nonvalvular atrial fibrillation (NVAF) . Many of those affected by AF in LMICs are, less likely to access preventive measures and to receive a timely diagnosis (e.g., lack of access to ECG) and the anti-coagulation treatment they require as per AF management guidelines (see Table 1), which leads to significant health and economic burden [6, 7, 8].
|Low stroke risk (CHADSVASC = 0)||Moderate stroke risk (CHADSVASC = 1)||High stroke risk (CHADSVASC ≥ 2)|
|AHA/ACC||No anticoagulants||OACs or aspirin (LOE IIb)||NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin (IA)|
|ESC||No antiplatelet or anticoagulant treatment (IIIB)||OAC should be considered (IIaB)||NOAC (IA)c, VKA (IA)c,d|
|NICE||No antithrombotic therapy||Consider OAC (Warfarin or NOACs Apixaban, Dabigatran, Rivaroxaban)||Offer OAC (Warfarin or NOACs Apixaban, Dabigatran, Rivaroxaban)|
|ASIA PACIFIC||No anticoagulants||OACs||NOACs preferred to warfarin|
|CANADA||No antithrombotic therapy||OAC or Aspirin||NOACs|
|AUSTRALIA||No anticoagulants||OACs (GRADE: Strong; Evidence: Moderate).||Warfarin, NOAC (apixaban, dabigatran or rivaroxaban) (GRADE: Strong; Evidence:High.)|
|ARGENTINA||No anticoagulants||OACs or aspirin (LOE I B)||OAC (IA) with Warfarin or NOACs|
|MEXICO||Dabigatran or Warfarin (Recommended 2011)|
|BRAZIL||No anticoagulants||OAC (LOE IIaC)||OAC (IA) with Warfarin or NOACs|
Vitamin K Antagonist (VKAs) oral anticoagulants are effective in preventing AF-related strokes ; however, patients treated with VKAs must be carefully monitored to effectively reduce the risk of embolic stroke while minimizing bleeding risks. In fact, factors like illness, consumption of vitamin K-rich foods, alcohol, and medications can interfere with patients’ ability to stay within the therapeutic range. Furthermore, the regular monitoring required for VKA treatment is particularly challenging for patients and health systems, especially in remote and resource-limited settings where health systems are often poorly equipped to care for people affected by AF. This regular monitoring can be even more challenging during public health crises such as the COVID-19 pandemic, which led to a decrease in the volume of cardiology visits around the world [10, 11, 12].
In the past ten years, the introduction of NOACs, a class of medicines which includes dabigatran, apixaban, edoxaban and rivaroxaban , has resulted in improvements in the safety and efficacy of NVAF treatment for stroke prevention, with significant reductions in stroke, intracranial haemorrhage, and mortality . The advantage of NOACs over VKAs is that patients on NOACs do not require routine monitoring and are not subject to the same treatment interference challenges such as the risk of bleeding, drug-drug interactions, dietary restrictions. Accordingly, major clinical practice guidelines worldwide recommend NOACs over VKAs for initial treatment of NVAF for stroke prevention . Unfortunately, NOACs are less available and affordable in LMICs where they are most needed .
For these reasons, a team of World Heart Federation Emerging Leaders led efforts to add NOACs to the WHO Model List of Essential Medicines (EML). The team involves experts in cardiology, neurology and public health from ten countries which concluded, in their successful appeal to WHO, that NOACs were not only safer (lower risk of major bleeding) and more effective, but also more cost-effective than VKAs in preventing stroke and systemic embolism in NVAF patients . These conclusions were based on findings from pivotal randomized controlled trials [16, 17, 18, 19] and large-scale, real-world registries [20, 21, 22]. This new application overcame the limitations of a previous attempt  to add NOACS to the EML which was rejected for several reasons, including the belief that evidence based only on trial populations would not be representative of patients who would receive such treatment in real-world practice, the lack of specific antidotes at the time to reverse anti-coagulation, and the higher costs compared to warfarin and to the overall benefits to patients [24, 25, 26].
The designation as an essential medicine by the WHO signifies the therapeutic value and importance of NOACs. The WHO EML listing is meant to lead to a cascade of actions that will improve equitable access to essential medicines, considering that many governments utilize the WHO EML as a model for setting their own medicine priorities . Bringing NOACs within reach of those who need them most, especially in low- and middle-income countries, is the next frontier in ensuring access to anti-coagulation therapy, successfully managing NVAF and lowering the risk of stroke. To achieve this, we recommend the following policy actions.
Making quality NOACs available, affordable, acceptable and accessible in-country will often require governments to include them in their national essential medicines list, clinical treatment guidelines, and other policy tools that ensure their supply and provision in health facilities and pharmacies.
According to data from 2017, 14 countries, primarily in the WHO Europe Region, had listed dabigatran on their national essential medicines lists prior to the WHO recommendation and a subset of those countries also listed apixaban and/or rivaroxaban . This number has already and is expected to further increase after the WHO listing, as medicines listed by WHO tend to be included by a greater number of national EMLs over time, especially in lower-middle and low-income countries . While medicines listed on national EMLs generally become more available and affordable than other medicines, a multitude of diverse factors likely affect priority-setting for national EMLs and various policy and health system barriers must be overcome to ensure equitable access to essential medicines [29, 30]. For example, pricing of medicines influences EML inclusion; low-income countries with poor government control on prices appear to be less likely to adopt the WHO EML if the drug prices are deemed too high .
Work is also required to increase the acceptability of NOACs, for example, by including it in national guidelines for the management of NVAF and in training packages for healthcare providers. Alignment of policies such as clinical treatment guidelines and EMLs at national and subnational levels can reduce unnecessary policy barriers to care.
In the case of NOACs, the cost is likely one important barrier. Although it is deemed cost-effective, all four NOACs—dabigatran, rivaroxaban, apixaban and edoxaban—remain patent protected in several countries,1 and their cost can vary widely. This variation in cost can hinder availability and make NOACs prohibitive in some low-income settings. For example, dabigatran costs USD$65 in the UK and USD$222 in China and rivaroxaban costs approximately USD$60 per patient per month in Kenya [14, 32]. Yet factoring in costs associated with VKAs treatment — medication (available at a price as low as USD$1 per month) and health care system costs, such as monitoring requirements — suggests that NOACs are expected to have a lower cost over time .
We can learn from actions that have resulted in improvements in global access to expensive, patented HIV and hepatitis C treatments, following their additions to the WHO EML in 2001 and 2015, respectively. These actions include the promotion of generic competition, voluntary licensing of products such as through the Medicines Patent Pool (MPP), and invoking flexibilities enshrined in the World Trade Organization’s Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement [33, 34]. MPP reported that generic versions of dabigatran currently exist on the Indian private market, priced as low as between USD$15 and USD$22 per month (the recommended dose of dabigatran is 150 mg twice a day).2 Cost of production modelling further indicated that NOACs could be produced at even lower costs, and thus it is expected that with greater volumes and market shares, it could be made available at lower prices while maintaining profitability . Moving forward, it is estimated that licensing NOACs to MPP could allow generic entry years before patent expiry in a large number of LMICs and thereby “facilitate up to [an additional] 1.9 million patient-years of treatment for both nonvalvular atrial fibrillation and venous thromboelism .”
In order for NOACs to be affordable to households, governments should consider including them in health insurance packages and other financial schemes, in addition to efforts to lower costs already discussed.
Taken together, these solutions have the potential to accelerate more equitable global access to care and essential medicines for people affected by NVAF and at risk of stroke who may otherwise not benefit from anti-coagulation therapy because of the high monitoring costs of VKAs and the lifestyle challenges of remaining within the therapeutic range. These solutions are also in line with the World Heart Federation’s policy recommendations on ensuring access to medicines for circulatory diseases, including strengthening health systems, designing and implementing creative financing models and investing in the health workforce .
1According to https://www.medspal.org/, as of August 2020, there were patents pending or granted on the dabigatran compound or its salt form in Argentina, Belarus, Brazil, Chile, China, Colombia, Egypt, India, Indonesia, Kazakhstan, Kyrgyzstan, Malaysia, Mexico, Montenegro, Pakistan, Peru, Philippines, Russian Federation, Serbia, South Africa, Thailand, Turkey, Ukraine, Uzbekistan, Venezuela and Vietnam. There were patents pending or granted on apixaban in Albania, Argentina, Brazil, Chile, China, Georgia, India, Indonesia, Kosovo, Kyrgyz Republic, Malaysia, Mexico, Montenegro, North Macedonia, Pakistan, Philippines, Russian Federation, Serbia, South Africa, Thailand, Turkey, Ukraine, Venezuela and Vietnam. Rivaroxaban had patents pending or granted in Albania, Argentina, Belarus, Bosnia and Herzegovina, Brazil, Chile, China, Colombia, Cuba, Dominican Republic, El Salvador, Guatemala, Honduras, India, Indonesia, Jamaica, Mexico, Morocco, North Macedonia, Pakistan, Peru, Philippines, Russian Federation, Serbia, South Africa, Trinidad and Tobago, Turkey, Ukraine, Uruguay and Venezuela. Edoxaban had patents pending or granted in Argentina, Brazil, China, Egypt, India, Indonesia, Malaysia, Mexico, Pakistan, Philippines, Russian Federation, South Africa, Thailand, Turkey and Vietnam.
2The price is as found on www.1mg.com for Dabipla/Goodflo (150mg twice per day for 30 days).
EJZ received speaker fees from Novartis, Pfizer and Bayer unrelated to this research.
Institute for Health Metrics and Evaluation. Global burden of disease compare. 2017. https://vizhub.healthdata.org/gbd-compare/.
Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J. 2013; 34(35): 2746–51. DOI: https://doi.org/10.1093/eurheartj/eht280
Lip GYH, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: A systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest. 2012; 142(6): 1489–98. DOI: https://doi.org/10.1378/chest.11-2888
Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006; 114(2): 119–25. DOI: https://doi.org/10.1161/CIRCULATIONAHA.105.595140
Medicines Patent Pool. Exploring the expansion of the Medicines Patent Pool’s mandate to patented essential medicines. A feasibility study of the public health needs and potential impact. Geneva, CH: Medicines Patent Pool; 2018. 75. https://medicinespatentpool.org/uploads/2018/05/Octo2018_Feasibility-Study-Expansion-of-the-MPP-Mandate-Appendix.pdf.
Murphy A, Banerjee A, Breithardt G, Camm AJ, Commerford P, Freedman B et al. The World Heart Federation roadmap for nonvalvular atrial fibrillation. Global Heart. 2017; 12(4): 274. https://www.world-heart-federation.org/cvd-roadmaps/whf-global-roadmaps/atrial-fibrillation/.
Chugh SS, Roth AR, Gillum RF, Mensah GA. Global Burden of Atrial Fibrillation in Developed and Developing Nations. Global Heart. 2014; 1: 113–119. DOI: https://doi.org/10.1016/j.gheart.2017.01.015
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007; 146(12): 857–67. DOI: https://doi.org/10.7326/0003-4819-146-12-200706190-00007
Goel S, Sharma A. COVID-19 pandemic and its impact on cardiology and its subspecialty training. Prog Cardiovascu Dis; 2020. DOI: https://doi.org/10.1016/j.pcad.2020.05.004
Krumholz HM. Where have all the heart attacks gone. Except for treating Covid-19, many hospitals seem to be eerily quiet. The New York Times. 2020. https://www.nytimes.com/2020/04/06/well/live/coronavirus-doctors-hospitals-emergency-care-heart-attack-stroke.html.
European Society of Cardiology. Fear of COVID-19 keeping more than half of heart attack patients away from hospitals. European Society of Cardiology. 2020. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Fear-of-COVID-19-keeping-more-than-half-of-heart-attack-patients-away-from-hospitals. DOI: https://doi.org/10.1016/j.pcad.2020.05.004
Barnes GD, Ageno W, Ansell J, Kaatz S. Recommendation on the nomenclature for oral <nticoagulants: Communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis. 2015; 12(6): 1154–1156. DOI: https://doi.org/10.1111/jth.12969
Karmacharya B, Adeoye A, Di Cesare M, Hakim F, Huffman MD, Katbeth A et al. Application for inclusion of non-vitamin K antagonists oral anticoagulant (NOACs) for the treatment of non-valvular atrial fibrillation in the WHO Model List of Essential Medicines. 2019. https://www.who.int/selection_medicines/committees/expert/22/applications/s10.2_dabigatran.pdf?ua=1.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139–51. DOI: https://doi.org/10.1056/NEJMoa0905561
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365: 883–91. DOI: https://doi.org/10.1056/NEJMoa1009638
Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365: 981–92. DOI: https://doi.org/10.1056/NEJMoa1107039
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369: 2093–104. DOI: https://doi.org/10.1056/NEJMoa1310907
Larsen TB, Skjoth F, Nielsen PB, Kjaeldgaard JN, Lip GY. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2016; 353: i3189. DOI: https://doi.org/10.1136/bmj.i3189
Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. 2018; 362: k2505. DOI: https://doi.org/10.1136/bmj.k2505
Forslund T, Wettermark B, Andersen M, Hjemdahl P. Stroke and bleeding with non-vitamin K antagonist oral anticoagulant or warfarin treatment in patients with non-valvular atrial fibrillation: a population-based cohort study. Europace. 2018; 20(3): 420–8. DOI: https://doi.org/10.1093/europace/euw416
Neumann I, Schünemann HJ. Application for inclusion of novel oral anticoagulants for the treatment of non-valvular atrial fibrillation in the who model list of essential medicines 2015; 2014. World Health Organization. https://www.who.int/selection_medicines/committees/expert/20/applications/NOACs/en/.
World Health Organization. Report of the WHO Expert Committee on the Selection and Use of Essential Medicines; 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). WHO/MVP/EMP/IAU/2019.10. WHO Technical Report Series 248. https://www.who.int/medicines/publications/essentialmedicines/UNEDITED_TRS_2019_EC22_Sept.pdf?ua=1.
Neumann I, Schünemann HJ. Application to add Direct Oral Anticoagulants (DOAC) to WHO Model List of Essential Medicines as a medicine for treatment of non-valvular atrial fibrillation and treatment venous thromboembolism. 2018. https://www.who.int/selection_medicines/committees/expert/22/applications/s10.2_DOACs.pdf?ua=1.
Laing R, Waning B, Pharm AG, Ford F, Hoen E. 25 years of the WHO essential medicines lists: progress and challenges. The Lancet. 2003; 361 (9370): 1723–1729. https://www.sciencedirect.com/science/article/pii/S0140673603133752?via%3Dihub. DOI: https://doi.org/10.1016/S0140-6736(03)13375-2
Persaud N, Jiang M, Shaikh R, Bali A, Oronsaye E, Woods H. Comparison of essential medicines lists in 137 countries. Bull. World Health Organ. 2019; 97: 394–404C. https://www.who.int/bulletin/volumes/97/6/18-222448/en/.
Bazargani YT, Ewen M, De Boer A, Leufkens HGM, Mantel-Teeuwisse AK. Essential medicines are more available than other medicines around the globe. PLOS One. 2014; 9(2): e87576. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087576. DOI: https://doi.org/10.1371/journal.pone.0087576
Wirtz VJ, Hogerzeil HV, Gray AL, et al. Essential medicines for universal health coverage. The Lancet. 2017; 389(10067): 403–76. https://www.ncbi.nlm.nih.gov/pubmed/27832874. DOI: https://doi.org/10.1016/S0140-6736(17)31209-6
IMS Institute for Healthcare Informatics. Understanding the role and use of essential medicines lists. Durham, NC, USA: IMS Institute; 2015. 16. http://apps.who.int/medicinedocs/documents/s21980en/s21980en.pdf.
Medicines Patent Pool. Exploring the expansion of the Medicines Patent Pool’s mandate to patented essential Medicines. 75. https://medicinespatentpool.org/uploads/2020/04/Executive-Summary-Exploring-the-Expansion-of-the-Medicines-Patent-Pool%E2%80%99s-Mandate-to-Patented-Essential-Medicines-A-Feasibility-Study-of-the-Public-Health-Needs-and-Potential-Impact.pdf.
Simmons B, Cooke GS, Miraldo M. Effect of voluntary licenses for hepatitis C medicines on access to treatment: a difference-in-differences analysis. The Lancet Global Health. 2019; 7(9): e1189–e1196. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(19)30266-9/fulltext.
Hoen FM, Veraldi J, Toebes B, Hogerzeil HV. Medicine procurement and the use of flexibilities in the Agreement on Trade-Related Aspects of Intellectual Property Rights, 2001–2016. Bull. World Health Organ. 2018; 96: 185–193. https://www.who.int/bulletin/volumes/96/3/17-199364/en/. DOI: https://doi.org/10.2471/BLT.17.199364
World Heart Federation. Improving access to essential medicines for circulatory diseases. A Call to Action; 2019. https://www.world-heart-federation.org/wp-content/uploads/2019/09/Improving-Access-to-Essential-Medicines-for-Circulatory-Diseases-WEB.pdf.