Background The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. Objective This study aims to evaluate the implementation of the “warfarin bundle,” a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. Methods Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. Results We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. Conclusions We anticipate that the “bundle of care,” which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. International Registered Report Identifier (IRRID) DERR1-10.2196/46710

BACKGROUND The quality of warfarin anticoagulation among sub-Saharan African patients is sub-optimal. This is due to several factors including lack of standardized dosing algorithms; difficulty in providing timely INR results; lack of patient feedback on their experiences on treatment; lack of education on adherence and inadequate knowledge and training of healthcare workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates including bleeding and thrombosis and poorer quality of life. OBJECTIVE This study aims to implement the ‘warfarin bundle’ -a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. METHODS Patients aged ≥ 18 years who are newly initiated on warfarin for venous thromboembolism (VTE), atrial fibrillation (AF) or valvular heart disease (VHD) will be enrolled and followed up for 3 months at clinics where the warfarin bundle is implemented. Retrospective review of clinical records of patients on warfarin treatment prior to implementation (controls) will be used for comparison. This study uses a mixed methods approach of implementation of patient and process -centred activities to improve the quality of anticoagulation. Patient-centred activities include use of dosing algorithms, adherence support and root cause analysis while process-centred activities include point of care INR testing, staff training and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the two groups as well as cost-effectiveness and acceptability of the package. RESULTS We started recruitment in June 2021 and stopped in August 2022 having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala and the University of Liverpool Research Ethics Committee. As of February 2023, we are undertaking data cleaning and formal analysis. We expect to publish full results by December 2023. CONCLUSIONS We anticipate that the ‘bundle of care’ that includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control; and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial in other sub-Saharan African countries.

Although chloroquine and hydroxychloroquine have not yet been shown to be safe or effective for the treatment or prevention of COVID-19, regulatory agencies in some countries have authorised their use in Coronavirus disease 2019 (COVID-19) due to the lack of available interventions. Several large clinical trials are currently underway to investigate these agents as potential therapeutic options for COVID-19. Previous research against similar pathogens that cause severe acute respiratory syndrome and Middle East respiratory syndrome has identified chloroquine and hydroxychloroquine as possible antiviral candidates against SARS-CoV-2. Despite promising pre-clinical evidence, data have thus far failed to confirm their efficacy, and recent studies suggest potential dose-related cardiotoxicity and mortality. Close monitoring for cardiac conduction abnormalities is advised with higher-than-approved doses. Additional, robust evidence from randomised controlled trials and meta-analyses are required to make informed risk-benefit assessments. Finally, the off-label prescription of these agents should be judiciously considered, and any such use should be conducted within clinical trials, or under the Monitored Emergency Use of Unregistered and Investigational Interventions framework.

Although chloroquine and hydroxychloroquine have not yet been shown to be safe or effective for the treatment or prevention of COVID-19, regulatory agencies in some countries have authorised their use in Coronavirus disease 2019 (COVID-19) due to the lack of available interventions. Several large clinical trials are currently underway to investigate these agents as potential therapeutic options for COVID-19. Previous research against similar pathogens that cause severe acute respiratory syndrome and Middle East respiratory syndrome has identified chloroquine and hydroxychloroquine as possible antiviral candidates against SARS-CoV-2. Despite promising pre-clinical evidence, data have thus far failed to confirm their efficacy, and recent studies suggest potential dose-related cardiotoxicity and mortality. Close monitoring for cardiac conduction abnormalities is advised with higher-than-approved doses. Additional, robust evidence from randomised controlled trials and meta-analyses are required to make informed risk-benefit assessments. Finally, the off-label prescription of these agents should be judiciously considered, and any such use should be conducted within clinical trials, or under the Monitored Emergency Use of Unregistered and Investigational Interventions framework.

The burden of adverse drug reactions (ADRs) in low-and middle-income countries (LMICs) may differ from that in high-income settings for a variety of reasons, including differences in disease burden, differences in drug utilization patterns, a potential lack of effective drug quality control, and the high risk for prescribing and dispensing errors that occur in overburdened healthcare systems. Previous systematic reviews summarizing the global burden of ADRs 1-6 included only a few surveys from LMICs, which limits the generalizability of their results to LMIC settings.In sub-Saharan Africa (SSA), an epidemiological transition is taking place, with high prevalence of both non-communicable