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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017



Cardiovascular Topics

A preliminary review of warfarin toxicity in a tertiary

hospital in Cape Town, South Africa

Annemarie Jacobs, Fatima Bassa, Eric H Decloedt



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.


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.


We found that warfarin toxicity carries significant

mortality and cost, but little attention is paid to the causes of



warfarin, toxicity, bleeding, treatment, cost

Submitted 1/3/17, accepted 16/5/17

Published online 21/6/17

Cardiovasc J Afr



: 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



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.


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.


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.


Genetic polymorphisms

are associated with decreased metabolism of or increased sensitivity

to warfarin, as well as increased risk for bleeding events.


There is a direct relationship between increased INR and risk

of bleeding, with an INR


4.0 associated with a high bleeding



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.


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.


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.


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)