Anticoagulation in sub-Saharan Africa: Are direct oral anticoagulants the answer? A review of lessons learnt from warfarin.

Warfarin has existed for >7 decades and has been the anticoagulant of choice for many thromboembolic disorders. The recent introduction of direct-acting oral anticoagulants (DOACs) has, however, caused a shift in preference by healthcare professionals all over the world. DOACs have been found to be at least as effective as warfarin in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism. In sub-Saharan Africa, however, the widespread use of DOACs has been hampered mainly by their higher acquisition costs. As the drugs come off patent, their use in sub-Saharan Africa is likely to increase. However, very few trials have been conducted in African settings, and safety concerns will need to be addressed with further study before widespread adoption into clinical practice.

Safety and efficacy of hydroxychloroquine for treatment of non-severe COVID-19 among adults in Uganda: a randomized open label phase II clinical trial.

BACKGROUND: Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness. DESIGN: We conducted a randomized open label Phase II clinical trial from October-December 2020. METHODS: Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load (CT values) from RT-PCR testing of samples collected using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6. RESULTS: Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p = 0.457. There were no significant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no significant differences in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group. CONCLUSION: Our results show that HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution among adults with COVID-19 in Uganda. TRIAL REGISTRATION:  NCT04860284.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

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.

A cross-sectional evaluation of five warfarin anticoagulation services in Uganda and South Africa.

INTRODUCTION: Warfarin is the most commonly prescribed oral anticoagulant in sub-Saharan Africa and requires ongoing monitoring. The burden of both infectious diseases and non-communicable diseases is high and medicines used to treat comorbidities may interact with warfarin. We describe service provision, patient characteristics, and anticoagulation control at selected anticoagulation clinics in Uganda and South Africa. METHODS: We evaluated two outpatient anticoagulation services in Kampala, Uganda and three in Cape Town, South Africa between 1 January and 31 July 2018. We collected information from key staff members about the clinics' service provision and extracted demographic and clinical data from a sample of patients' clinic records. We calculated time in therapeutic range (TTR) over the most recent 3-month period using the Rosendaal interpolation method. RESULTS: We included three tertiary level, one secondary level and one primary level anticoagulation service, seeing between 30 and 800 patients per month. Care was rendered by nurses, medical officers, and specialists. All healthcare facilities had on-site pharmacies; laboratory INR testing was off-site at two. Three clinics used warfarin dose-adjustment protocols; these were not validated for local use. We reviewed 229 patient clinical records. Most common indications for warfarin were venous thrombo-embolism in 112/229 (49%), atrial fibrillation in 74/229 (32%) and valvular heart disease in 30/229 (13%). Patients were generally followed up monthly. HIV prevalence was 20% and 5% at Ugandan and South African clinics respectively. Cardiovascular comorbidity predominated. Furosemide, paracetamol, enalapril, simvastatin, and tramadol were the most common concomitant drugs. Anticoagulation control was poor at all included clinics with median TTR of 41% (interquartile range 14% to 69%). CONCLUSIONS: TTR was suboptimal at all included sites, despite frequent patient follow-up. Strategies to improve INR control in sub-Saharan patients taking warfarin are needed. Locally validated warfarin dosing algorithms in Uganda and South Africa may improve INR control.

Carcinoma of the colon in a 40 year old female: a case report.

We present a histologically proven mucinous adenocarcinoma of the colon in a 40 year old female from Gulu, Northern Uganda. Her elder sister died at 25 years with advanced adenocarcinoma of colon similarly with her mother who died of the same illness 10 years apart. Using the Amsterdam criteria for the diagnosis of the carcinoma of the colon, this is descriptive of Hereditary Non Polyposis Colorectal Carcinoma (HNPCC). Blood examinations revealed microcytic hypochromic anaemia. The Renal and Liver function parameters were essentially normal. The abdominal ultrasonography showed an ill-defined mass in the right hypochondrial region which was heterogeneous with central echogenicity approximately 7.2cm wide and with no intra-abdominal lymphadenopathy or ascitis. At laparotomy, the sonographic findings were confirmed with a demonstrable mass in the hepatic flexure of the colon with hyperemic areas on its serosa. Macroscopically, there was an annular fungating mass with a central necrosis in the hepatic flexure measuring over 7.0cm. Histology of the colonic tumour showed a mucinous adenocarcinoma of the colon (Duke's B). This finding highlights the occurrence of colonic adenocarcinoma in the young person in Northern Uganda, a finding which draws the attention of the medical community towards having a higher index of suspicion for carcinoma of the colon in patients with similar presentation.

Nodding syndrome: recent insights into etiology, pathophysiology, and treatment.

Nodding syndrome is an enigmatic neuropsychiatric and epileptiform disorder associated with psychomotor, mental, and physical growth retardation. The disorder affects otherwise previously normal children aged 3-18 years, with a slight preponderance for the male child. Nodding syndrome has been described in rural regions of some low-income countries in sub-Saharan Africa including northern Uganda, South Sudan, and a mountainous region of southern Tanzania. The cause of the disorder has hitherto eluded scientists. Neuroimaging studies show involvement of the nervous system with associated severe cortical atrophy in the affected children. The affected communities have generated a number of perceived causes including some conspiracy theories related to intentional poisoning of water sources and foods, and causes related to fumes and chemicals from ammunitions used during civil wars in the affected regions. From biomedical perspectives, the treatment of the affected children is geared towards symptoms control and rehabilitation. There is evidence that seizures and behavioral problems including wandering and episodes of aggressions are controllable with anticonvulsants, especially sodium valproate and antipsychotics. No treatments have proven effective in reversing the course of the disorder, and cure remains a distant goal. Community members have used indigenous medicines, cleansing rituals, and prayer interventions, but have not perceived any reasonable improvements. A randomized controlled clinical trial is ongoing in northern Uganda to test the efficacy and effectiveness of doxycycline in the treatment of nodding syndrome. The hypothesis underlying the doxycycline trial underscores the role of antigenic mimicry: that antibodies generated against an antigen of a microorganism that resides inside the black fly-transmitted parasite, Onchocerca volvulus becomes directed against nervous tissue in the brain. This paper reviews some of the recent advances in researches on the etiologies, pathophysiology, and treatment of nodding syndrome.