Clinical trial NCT03512080: Warfarin Anticoagulation in Patients in Sub-Saharan Africa
Official title: National Institute of Health Research (NIHR) Global Health Research Group on Warfarin Anticoagulation in Patients with Cardiovascular Disease in Sub-Saharan Africa
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cardiovascular Diseases
Keywords: Warfarin
Anticoagulation
Clinical Dosing Algorithm
Genetic Dosing Algorithm
International Normalised Ratio
Uganda
Cape Town
Cardiovascular Disease
Genome-wide Association Study
Stratified Medicine
Pharmacogenetics
Lead sponsor: University of Liverpool
Sponsor class: OTHER
First posted: 2018-04-30
Enrollment: 681
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Self-reported Black African ethnicity from Uganda and South Africa

Brief summary: This research programme aims to translate expertise in warfarin anticoagulation from resource-rich to low and middle income countries (LMIC)settings with the goal of improving patient health outcomes.

An observational study which will be used to develop warfarin dosing algorithms - the ultimate aim will be to ascertain whether these algorithms increase time in the therapeutic range, reduce bleeding and thrombotic risks, and clinic visits for International Normalised ratio (INR) monitoring. Two algorithms will be developed: the first will take into account clinical and geographical factors ("clinical algorithm"), while the second will also incorporate genetic factors in addition to the clinical and geographical factors ("genetic algorithm"). Patients will be recruited from sites in rural and urban Uganda, and in Cape Town, South Africa, to develop a clinical dosing algorithm. It is important to note that there is a wealth of literature data which will be used to define the clinical data that needs to be collected from these patients. To identify genetic factors in African patients, Genome-wide Association Study (GWAS) will be undertaken and any novel factors incorporated into the genetic algorithm - the percentage variation in warfarin dosing explained by the genetic algorithm will be compared with the clinical algorithm.

Detailed description: This project focuses on an area unmet clinical need, oral anticoagulation, in patients with a variety of cardiovascular diseases. The investigators' ambition is to translate their internationally renowned expertise in warfarin anticoagulation into low and middle income country (LMIC) settings where it can significantly improve health. By working with policy makers, the investigators will provide the required evidence to allow national roll out of new practices, including the introduction of 1mg warfarin tablets as a quick win to improve dosing accuracy.

This National Institute of Health Research (NIHR) Global Research Group is a collaboration between the University of Liverpool and two low and middle income countries (LMICs), Uganda and South Africa. It will focus 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, valvular heart disease including 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. The investigators have extensive expertise in the United Kingdom and European Union of improving the use of warfarin through the development of novel dosing algorithms, which have now begun incorporating genetic factors.

By contrast, in the investigators' two collaborating partner countries, no locally validated warfarin dosing algorithms exist, even those which only take into account clinical factors. This results in haphazard dosing with the attendant risks of thrombotic or bleeding complications. In both countries, monitoring requires frequent clinic visits, incurring transport costs and missed work days. Patients are often co-infected with human immunodeficiency virus (HIV) and/or Tuberculosis, requiring multiple concomitant medicines which complicate warfarin dosing and dose adjustment.

Eligibility criteria: Inclusion Criteria:

1. Consenting adult patients with either venous thromboembolism (VTE), atrial fibrillation (AF) on warfarin with a target International Normalised Ratio (INR) (INR range 2-3) or valvular heart disease with a target INR (INR range 3-4).
2. On a stable maintenance dose for two consecutive clinic visits within the last six months, and the INR was in the therapeutic range at each of those visits.
3. Age over 18 years.
4. Self-reported Black African ethnicity.
5. Signed or witnessed written (witnessed thumbprint for illiterate participants) informed consent.

Exclusion Criteria:

1. Patient unwilling to take part.
2. Patient is, in the opinion of the investigator, not suitable to participate.
3. Pregnant women.

Primary outcomes:
measure: Identification of demographic, clinical and genetic factors in an African population that determine daily warfarin dosing requirements
timeFrame: 1 year
measure: Development of a clinical algorithm taking into account patient factors, co-medications and underlying disease
timeFrame: 3 years
measure: Development of a validated warfarin dosing algorithm taking into account both clinical and genetic factors
timeFrame: 3+ years
Secondary outcomes:
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
Study officials:
affiliation: University of Liverpool
name: Munir Pirmohamed
role: PRINCIPAL_INVESTIGATOR
References:
citation: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996 Sep 7;348(9028):633-8.
citation: Avery PJ, Jorgensen A, Hamberg AK, Wadelius M, Pirmohamed M, Kamali F; EU-PACT Study Group. A proposal for an individualized pharmacogenetics-based warfarin initiation dose regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther. 2011 Nov;90(5):701-6. doi: 10.1038/clpt.2011.186. Epub 2011 Sep 28.
citation: Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006 Nov;62(5):509-11. doi: 10.1111/j.1365-2125.2006.02806.x. No abstract available.
citation: Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013 Dec 12;369(24):2294-303. doi: 10.1056/NEJMoa1311386. Epub 2013 Nov 19.
citation: Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004 Jul 3;329(7456):15-9. doi: 10.1136/bmj.329.7456.15.
citation: Sekaggya C, Nalwanga D, Von Braun A, Nakijoba R, Kambugu A, Fehr J, Lamorde M, Castelnuovo B. Challenges in achieving a target international normalized ratio for deep vein thrombosis among HIV-infected patients with tuberculosis: a case series. BMC Hematol. 2016 Jun 4;16:16. doi: 10.1186/s12878-016-0056-6. eCollection 2016.
citation: Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J. 2007 Apr;7(2):99-111. doi: 10.1038/sj.tpj.6500417. Epub 2006 Sep 19.
citation: Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 2012 Jul;8(4):563-76. doi: 10.2217/fca.12.31.
citation: Mouton JP, Mehta U, Parrish AG, Wilson DP, Stewart A, Njuguna CW, Kramer N, Maartens G, Blockman M, Cohen K. Mortality from adverse drug reactions in adult medical inpatients at four hospitals in South Africa: a cross-sectional survey. Br J Clin Pharmacol. 2015 Oct;80(4):818-26. doi: 10.1111/bcp.12567. Epub 2015 Jul 6.