Cardiovascular Journal of Africa: Vol 28 No 6 (November/December 2017)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017 346 AFRICA
Cardiovascular Topics
A preliminary review of warfarin toxicity in a tertiary
hospital in Cape Town, South Africa
Annemarie Jacobs, Fatima Bassa, Eric H Decloedt
Abstract
Aim: Warfarin is a widely used anticoagulant for the preven-
tion and treatment of thromboembolism. We conducted a
retrospective review to determine the causes and management
of warfarin toxicity of patients admitted to Tygerberg hospi-
tal between June 2014 and June 2015.
Results: We identified and evaluated 126 patients who met the
inclusion criteria. The cause of warfarin toxicity was identi-
fied and addressed in only 14.3% (18/126) of patients. Where
the cause was identified, 56% (10/18) was due to dosing errors
and 17% (3/18) drug–drug interaction (DDI). However, 77%
(97/126) of patients were retrospectively identified as receiv-
ing concomitant medicines known to interact with warfarin
at the time of admission. Twenty-eight per cent (35/126) of
patients presented with major bleeding, which included seven
cases of intracranial haemorrhage. Patients were admitted
for a median of eight days at an average treatment cost of
R10 578.
Conclusion: We found that warfarin toxicity carries significant
mortality and cost, but little attention is paid to the causes of
toxicity.
Keywords: warfarin, toxicity, bleeding, treatment, cost
Submitted 1/3/17, accepted 16/5/17
Published online 21/6/17
Cardiovasc J Afr 2017; 28: 346–349
DOI: 10.5830/CVJA-2017-029
Warfarin is a widely used anticoagulant indicated for the
prevention and treatment of thromboembolism in patients
with atrial fibrillation, prosthetic heart valves and deep-vein
thrombosis. However, warfarin therapy is challenging. Sonuga
et al.1 reported in a study done at Victoria Hospital, Cape
Town, that a therapeutic international normalised ratio (INR)
outcome was achieved in only 48.5% of patients. The warfarin
dose–response curve is not predictable and requires regular INR
monitoring to optimise efficacy and minimise toxicity.2
Cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide
reductase complex subunit 1 (VKORC1) genetic polymorphisms
contribute to clinically significant variability in warfarin exposure
and efficacy. 2,3 Genetic polymorphisms in the CYP2C9 and
VKORC1 enzymes account for 10 to 15% and 20 to 35% of
inter-individual variance in warfarin dosing, respectively, with an
increase in genetic polymorphisms found in Caucasian populations
in comparison to African populations.3,4 Genetic polymorphisms
are associated with decreased metabolism of or increased sensitivity
to warfarin, as well as increased risk for bleeding events. 3
There is a direct relationship between increased INR and risk
of bleeding, with an INR > 4.0 associated with a high bleeding
risk.5 Various risk factors predispose patients with therapeutic
INRs to develop warfarin toxicity: dosing errors, drug–drug
interactions, acute illnesses (diarrhoea, cardiac failure, hepatic
impairment, fever) and dietary changes influencing vitamin
K intake.6,7 Bleeding associated with warfarin toxicity carries
a significant rate of morbidity and mortality. Risk factors
for warfarin-associated bleeding mortality are advanced age,
concomitant antiplatelet use, INR ≥ 4 at presentation, the
use of vitamin K during hospitalisation, and intracerebral
haemorrhage as a complication.8
Management of warfarin toxicity is determined by the degree
of INR elevation with or without bleeding, and in the event
of bleeding, the severity. Patients with an elevated INR and no
evidence of bleeding can be managed with vitamin K, with or
without omission of the next warfarin dose. Minor bleeding
can be managed in a similar manner. The presence of major
bleeding warrants immediate reversal of coagulopathy with the
administration of vitamin K in conjunction with fresh frozen
plasma (FFP) or 4-factor prothrombin complex concentrate (PCC).
FFP and 4-factor PCC are considered to have a similar efficacy.7
There are no published data evaluating the causes,
management and treatment costs of warfarin toxicity in South
African healthcare facilities. The aim of this study was to provide
an overview of warfarin toxicity, the management thereof and
cost implications to treat a patient with warfarin toxicity in an
academic hospital in South Africa.
Faculty of Medicine and Health Sciences, University of
Stellenbosch, Cape Town, South Africa
Annemarie Jacobs, MB ChB,
Division of Clinical Pharmacology, Department of
Medicine, Faculty of Medicine and Health Sciences,
University of Stellenbosch, Cape Town, South Africa
Eric H Decloedt, MB ChB, BSc Hons (Pharmacology), MMed (Clin
Pharm), FCCP (SA)
Division of Haematology, Department of Medicine,
Faculty of Medicine and Health Sciences, University of
Stellenbosch, Cape Town, South Africa
Fatima Bassa, MB ChB, FCPath (Haem), MMed (Haem)