Title: NIHR Global Health Research Group on warfarin anticoagulation in patients with cardiovascular disease in Sub-Saharan Africa, University of Liverpool
Funder: Department of Health and Social Care

Abstract: A.Personalised Health is a University wide research theme at UoL. Using our knowledge of clinical pharmacology, genomics and our understanding of diseases, our aim is for every patient to receive the right drugs at optimal doses, maximising efficacy and tolerability, and pre-empting adverse drug reactions. We have shown that personalising medicines to individual patients, based on their genetics, clinical and environmental factors, can reduce both risk and time it takes for the medicine to become effective. Our work has largely focused on developed countries; it is important that the drive towards personalised health does not ignore LMICs, which would exacerbate health inequalities. The WHO has stated that “genomic health divide must be kept in check and ultimately bridged through equitable economic investment, clinical research, and provision and use of genomic services and technologies globally”. Personalisation does not only depend on genomic testing, but can also be based on clinical algorithms. Our aim is to use our expertise in a clinically important NCD area (anticoagulation), which also represents an unmet clinical need in Sub-Saharan Africa, to identify needs and develop solutions that can be implemented cost-effectively. We have extensive experience of research with warfarin in the UK, EU and US, with 38 papers published since 2003 (2 in the NEJM). This project forms the pathway for increasing our LMIC work with the aim of improving the benefit-risk ratio of medicines. B. Underpinning Facilities. Liverpool is at the forefront of personalised health research, as evidenced by the award of the NHS Chair of Pharmacogenetics (2007), the development of the Wolfson Centre for Personalised Medicine (in 2009) and the award of the MRC Centre for Drug Safety Science (CDSS; in 2008, renewed in 2014). Our expertise is evidenced by publications (>400 over the last 10 years), funding record (>£60M in 10 years) and evidence of clinical translation including work with Industry (funding from Innovate UK, SBRI and i4i). We have developed a mature ecosystem for personalised health research across the four translational gaps. Our multidisciplinary team (n>70 staff) has expertise ranging from discovery to implementation (including access to trial methodologists, data management, informatics) which, through joint working with partners in the LMIC, will be invaluable in driving forward the planned work, as well as in developing further capabilities and capacity. The expertise is coupled with access to high-end equipment and facilities which allows us to undertake (and train in) state-of-the-art omics and bioanalytical work. C. Link to Existing Institutional Partnerships and Strategies. UoL has a long track record of work in LMICs, mainly in infectious diseases. CDSS, part of the University-wide personalised health research theme, has many collaborations nationally and internationally, and with regulators (MHRA) and industry (pharma, diagnostics and informatics). While we have undertaken drug safety investigations in LMIC countries (e.g. in anti-TB drug induced liver injury), drug safety has been under-studied in LMICs by the global research community. This therefore represents an unmet clinical and scientific need which will become increasingly important as access to treatments improves in LMICs. The development of a global health research group therefore represents a golden opportunity to begin tackling drug safety issues, by focusing on warfarin, a widely used but poorly understood drug in LMIC countries. Our aim is for this project to develop into a sustainable and world-leading program of research into drug safety in LMICs, whilst increasing capability and capacity in the LMICs. D. Programme of Activities. Thrombosis is a major contributor to disease burden globally (PMID: 25312343). Oral anticoagulation is needed for venous thromboembolism, valvular heart disease and stroke prevention in AF patients. Mixed levels of clinical expertise and resource for anticoagulation monitoring in LMICs can lead to variable anticoagulation treatment results. This can range from clinical settings that are unable to provide warfarin treatment to all necessary patients (because of low clinical expertise and confidence, or poor infrastructure) through to countries that have access to dedicated clinics but whose patients suffer from poor time in therapeutic range. Warfarin is cheap and effective with a readily-available biomarker, the international normalised ratio (INR). Warfarin remains the most likely choice in LMIC as the direct oral anticoagulants are too expensive, but control is poor (only 28% achieve a therapeutic INR; PMID 25425448). In Northern European populations, we have identified the genetic and clinical factors that determine individual daily dose requirements, and have developed a dosing algorithm, the utility of which was evaluated in the EU-PACT trial (PMID: 24251363). We have worked with a company (LGC) to refine the point-of-care genotyping platform such that we can genotype for 3 alleles (CYP2C9*2 and *3, and VKORC1) in 45min. This platform is being used in an implementation study in the NW to determine whether warfarin genotyping-guided dosing is effective in a real-world setting. There is no good clinical or genetic dosing algorithm for African patients; even the algorithm developed for African-Americans is poorly predictive. Dosing algorithms with or without genetics need to be stratified taking into account ethnic, clinical and geographical factors in order to increase time in therapeutic range, reduce bleeding and thrombotic risks, and clinic visits for INR monitoring. We propose to: 1.Evaluate the quality of anticoagulant services as a baseline in Cape Town and Kampala, taking into account the indications, anticoagulant clinic set-up (including INR monitoring facilities) and quality of anticoagulation control. 2.Recruit patients on warfarin, taking into account their age, weight, gender, co-morbidities, and quality of anticoagulant control. These data will be used to develop a clinical dosing algorithm, which will be validated as we have done previously (PMID: 22012312). DNA from these patients will be taken to determine African-specific CYP2C9 and VKORC1 alleles, and the effect of these alleles on improving the clinical algorithm. 3.The clinical algorithm, once developed, will be implemented in two sites (Kampala and Cape Town) to determine any issues in implementation and whether it improves anticoagulation control, compared with neighbouring clinics using conventional dosing. 4.To identify ethnic-specific genetic factors, we will undertake a GWAS; any novel factors will be incorporated into an improved algorithm which will be compared with the clinical algorithm. 5.We will recruit 750 patients from Uganda and 750 from South Africa; 1000 will undergo GWAS and 500 will be used for validation. With a derivation sample of 1000 and assuming a difference in stable dose of 1mg to be clinically important and a Type I Error Rate of 5 x 10-5 (nominal genome-wide significance threshold we would use to filter SNPs for replication) we estimate that we have 80% power to detect association with a SNP with moderate minor allele frequency (20%). Here, an estimate of standard deviation of stable dose, 2.66mg, is taken from a previously published study of warfarin pharmacogenetics in African Americans (PMID: 23755828). 6.We will also develop an educational package to improve local capacity and capability – this will include training from UK nurses, CPD lectures and a website. The capabilities of the local healthcare workforce will also be developed through Masters level qualifications (4 MRes students, 1 year course), as well as placements of post-docs/clinician scientists within our laboratories to be trained in high-end genomics, statistical genetics and bioinformatics. E. Commissioning Further Research In commissioning further research, our aim is to involve companies in developing novel point-of-care technologies which could be implemented in the future in LMICs in a cost-effective manner. We will focus on: • Working with Roche diagnostics, where we will undertake a feasibility study utilising their point-of-care devices for INR monitoring to assess whether this can be used to improve control (http://www.coaguchek.co.uk/). This will be linked to INR buddy, an INR reporting system via mobile phones, developed by MedETraX, a Liverpool SME (http://medetrax.com/inr-buddy/). • Using developed point-of-care genotyping technologies, we will work with LGC to develop assays specific for the African population for future implementation of genotype guided dosing in African countries. A particular issue here will be cost, which will be investigated in evaluating the different technologies available. F. Sustainability Plans Sustainability and long-term impact will be dependent on (a) interactions with policy makers within the respective countries from the beginning of the program to get buy-in, and develop plans for implementation especially of the clinical algorithms; (b) developing the evidence base for testing the utility of genotype guided dosing – this will require a RCT, which will be subject to further funding; (c) working with technology companies listed above to develop long-term cost-effective implementation strategies which lead to improved anticoagulation control and patient outcomes. 6-month delivery target: ensure all governance procedures have been completed, all the collaborating clinics have been involved in study design, and the evaluation of the current anticoagulation practices is underway. Medium-term objective: complete patient recruitment, development of clinical algorithm, and feasibility study for its implementation. Long-term objective: completion of genotyping and GWAS, and completion of feasibility studies with the technology companies.

Lay abstract: The NIHR Global Health Research Group on warfarin anticoagulation in patients with cardiovascular disease in Sub-Saharan Africa is a 3-year project between University of Liverpool, Infectious Diseases Institute, Makerere University, Uganda and University of Cape Town, South Africa. The project focuses on a clinically important non-communicable disease area which requires the use of anticoagulation. Anticoagulants, in particular warfarin, are used in these countries for the treatment of venous thromboembolism, rheumatic heart disease and prevention of strokes in patients with irregular heart rhythms (atrial fibrillation). Anticoagulation represents an unmet clinical need in Sub-Saharan Africa as patients either do not receive anticoagulation (due to difficulties in monitoring) or are poorly anticoagulated because of poor dosing guidelines. This results in potentially preventable morbidity and mortality which affects poorer sectors of the population in particular. We have extensive expertise in the UK and EU of improving the use of warfarin through the development of novel dosing algorithms, which have now begun incorporating genetic factors. By contrast, in our two collaborating partner countries, no good dosing algorithms exist, even those that only take into account clinical factors. The situation in these two countries is further complicated by the fact that there is a high prevalence of HIV and TB, which make anticoagulation harder because they increase the risk of thrombosis, and the drugs used for treatment interact with warfarin. Our research focus is on: a) evaluating the quality of anticoagulant services in Cape Town and Kampala taking into account the indications, anticoagulant clinic set-up and quality of anticoagulation control; b) recruiting patients currently on warfarin to identify clinical factors determining anticoagulation quality to develop a clinical algorithm; c) a study to implement the clinical algorithm in the two sites; and d) evaluating genes specific to the African population that can impact on anticoagulation control, and the development of novel genetic dosing algorithms. The work will be accompanied by education and training of the local workforce to improve capability and capacity. We are training four students to Masters level, one to PhD level, and two post-doctoral researchers will be seconded to Liverpool to gain training. Nurses from the UK will be visiting Africa to share best practice in anticoagulation research and patient management. By engaging with regional health policymakers in both countries, we plan to develop pathways for implementing the research findings to improve the quality of anticoagulation to benefit patients, the local society, and the economy. We are also working with technology companies to develop long-term cost-effective strategies to implement novel technologies that will allow for point-of-care testing of anticoagulation. Our work will benefit the two countries in several ways: it will improve anticoagulation practices reducing the morbidity and mortality in an area of unmet clinical need; it will increase the proportion of the population who can benefit from anticoagulation; by reducing morbidity associated with anticoagulation, it will have an impact on the economy; and in keeping with WHO’s aims, it will introduce novel technologies into Africa to improve the care of patients with long-term conditions reducing reliance and pressure on centralised healthcare facilities.

Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: BLOOD;CARDIOVASCULAR;STROKE