Warfarin anticoagulation in patients with cardiovascular disease in sub-Saharan Africa The War-PATH NIHR Global Research Group is between the University of Liverpool and two low and middle income countries (LMICs), Uganda and South Africa. It will focus on a clinically important noncommunicable 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 (because of difficulties in monitoring) or are poorly anticoagulated because of poor dosing guidelines. This results in potentially preventable morbidity and mortality which affects the 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 began incorporating genetic factors. By contrast, in our two collaborating partner countries, no good dosing algorithms exist, even those which only take into account clinical factors. The situation in these 2 countries is further complicated by the fact that there is a high prevalence of HIV and TB, which make anticoagulation harder because (a) they increase the risk of thrombosis, and (b) the drugs used for treatment interact with warfarin. Our research will focus 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 dosing 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 local capability and capacity. We will also train 4 students to Masters level, and 2 post-doctoral researchers will be seconded to Liverpool to gain training in high-end genomics. We will also engage with regional health policy makers in both countries to develop the best pathways for implementing the research findings to improve anticoagulation care, for the benefit of patients, the local society and ultimately the economy. We will also work with technology companies to develop long-term cost-effective strategies to implement novel technologies that will allow for point-of-care testing of anticoagulation, and also of genetic markers. • Evaluate the quality of anticoagulant services in Cape Town and rural and urban Uganda taking into account the indications, anticoagulant clinic set-up and quality of anticoagulation control (phase 1); • Recruit patients currently on warfarin to identify clinical and other non-genetic factors associated with poor anticoagulation control (phase 2). • Develop a warfarin clinical dosing algorithm (phase 2); • Evaluate genes specific to the local African populations in Uganda and South Africa that can impact on anticoagulation control, and the development of a novel genetic dosing algorithm (Phase 2). • Initiate a study to implement the clinical dosing algorithm in the two sites (phase 3). In the 3-year timeframe of the programme of work, we will not have time to evaluate the utility of the genetic algorithm, but will be evaluating some novel point-of-care INR testing and genotyping technologies. The involvement of Ugandan and South African partners will ensure that the solution being developed is appropriate to and informed by local contexts. Both partners have already played a large role in identifying needs and will continue to do so in all stages through to evaluation. Correct identification of indications for warfarin therapy is limited outside national referral centres in Uganda. Once a diagnosis is made, there are challenges in terms of INR monitoring due to expense and the need to travel to different facilities. In South Africa, INR monitoring is available via the national health laboratory service but results are frequently only available the following day. Thus, strengthening laboratory facilities and consideration of near-patient testing has the potential to significantly reduce these barriers. The health systems research will elucidate these challenges, enabling specific solutions to be designed. We are developing an educational package to improve local capacity in anticoagulation practices and capability to perform drug safety research. This includes 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 one year MRes students), as well as placements within our facilities at UoL for training in high-end genomics, statistical genetics and bioinformatics. Regional health policy experts will be engaged form the beginning of the program to ensure that health policy outcomes are capable of implementation. We will work with technology companies to develop long-term cost-effective implementation strategies including the use of point of care platforms (INR and genetic testing) and mobile health approaches. Success will be measured by the quality of anticoagulation practices before and after our project. The development of better dosing algorithms is likely to have the greatest impact on the poorest sector. Better anticoagulation practices, and better INR control strategies, will improve the benefit-risk ratio of warfarin, improving its effectiveness and reducing its risk, which will impact on the economy.