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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 2, March 2013
AFRICA
19
Comparative evaluation of warfarin utilisation in two
primary healthcare clinics in the Cape Town area
XOLANI W NJOVANE, PIUS S FASINU, BERND ROSENKRANZ
Abstract
Background:
Although warfarin remains the anticoagulant
drug of choice in a wide range of patients, its narrow thera-
peutic window makes patients susceptible to a high risk of
bleeding complications or failure to prevent clotting. This
has necessitated therapeutic monitoring in warfarinised
patients. Factors that could be responsible for the fluctuat-
ing responses to warfarin vary from pharmacogenetic to
concomitant morbidity, diet and medication. In order to
assess the quality of management of warfarin treatment in
a local primary-care setting, the current study evaluated
warfarin utilisation and monitoring records in two hospitals
with different patient groups.
Methods:
A retrospective study was undertaken in the special-
ised warfarin clinics at Wesfleur and Gugulethu hospitals
(Western Cape, South Africa) covering all warfarin-related
therapy records over a 12-month period. Data extracted
from the patients’ folders included age, gender, race, weight,
address, concurrent chronic illnesses, treatment and medica-
tion, indication for warfarin and INR history.
Results:
A total of 119 patients’ folders were analysed.
Attendance at the clinics reflects the demographics and
racial distribution of the host location of the hospitals.
While all the patients were maintained above the minimum
international normalised ratio (INR) value of 2, about 50%
had at least one record of INR above the cut-off value of 3.5.
However, over a third of the patients (32.2%) had at least
one record of INR greater than 3.5 in Gugulethu Hospital,
compared to over half (58.3%) in Wesfleur Hospital.
In total, atrial fibrillation was the most common indica-
tion for warfarinisation while hypertension was the most
common concurrent chronic condition in warfarinised
patients. All patients who received quinolone antibiotics had
INR values above the cut-off point of 3.5 within the same
month of the initiation of antibiotic therapy, suggesting
drug-induced warfarin potentiation. Other co-medications,
including beta-lactam antibiotics, non-steroidal anti-inflam-
matory drugs (NSAIDs) and anti-ulcer drugs appeared
to alter warfarin responses as measured by recorded INR
values.
Conclusion:
The study found inter-individual variability in
the response to warfarin therapy, which cut across racial
classifications. It also confirms the possible influence of
concomitant morbidity on patient response to anticoagulant
therapy.
Keywords:
warfarin, drug monitoring, international normalised
ratio, anticoagulant, warfarinisation
Submitted 27/3/12, accepted 16/10/12
Published online 13/11/12
Cardiovasc J Afr
2013;
24
: 19–23
www.cvja.co.zaDOI: 10.5830/CVJA-2012-072
Warfarin is a racemic mixture of two optically active (R and
S) isomers in roughly equal proportions, which is employed
for the prevention and treatment of thrombosis signalled by
atrial fibrillation, venous thromboembolism and prosthetic heart
valves. Warfarin inhibits vitamin K epoxide reductase complex
1 (VKORC1), preventing the intrahepatic recycling of vitamin
K epoxide to vitamin K, thus effectively supressing the vitamin
K-dependent activation of clotting factors.
1-4
In addition, warfarin interferes with the function of two
important physiological anticoagulant proteins, C and S.
S-warfarin has about five times the potency of the R-isomer
with regard to vitamin K antagonism.
5,6
Rapidly absorbed
following oral absorption, S-warfarin undergoes CYP2C9-
mediated metabolism to form 7-hydroxywarfarin, while the
metabolism of the R-isomer is catalysed by CYP1A2 to 6- and
8-hydroxywarfarin, by CYP3A4 to 10-hydroxywarfarin, and by
carbonyl reductases to distereo-isomeric alcohols.
7-9
Warfarin has a narrow therapeutic window and to achieve
treatment goals with the lowest risk of treatment failure or
bleeding complications, therapeutic anticoagulation, as measured
by the international normalised ratio (INR), must be achieved
and sustained in patients. The dose response for warfarin is
unpredictable in individual patients. It is therefore recommended
that the INR is monitored daily during the initiation phase, on
alternate days for a week after achieving the desired target,
and once stabilised, once a month.
10-12
The importance of
therapeutic monitoring of warfarin is further emphasised by the
fact that warfarin therapy is contraindicated in cases when INR
monitoring is not feasible.
13
Recommended therapeutic ranges of INR are 2.0–3.0 for most
disease indications, and 2.0–3.5 with cardiac valve prostheses.
14
Values outside this range may pose safety concerns. Various
factors responsible for fluctuating INR in warfarin therapy
include poor compliance, dosage error, concurrent illness, liver
and kidney dysfunction, concomitant use of other drugs, dietary
interaction, laboratory error, and ageing.
15,16
Inter-individual responses to warfarin may vary due to genetic
factors.
17,18
The effects of concomitantly administered drugs
on the pharmacokinetics of warfarin have been extensively
investigated.
19-21
The pharmacodynamic activity of warfarin
is strongly related to the fractions of free (unbound) drug.
Therefore drugs that alter the plasma protein binding of warfarin,
including valproic acid and non-steroidal anti-inflammatory
drugs (NSAIDs), can potentiate the anticoagulant effects of
Division of Pharmacology, Faculty of Medicine and Health
Sciences, University of Stellenbosch, Cape Town, South
Africa
XOLANI W NJOVANE, MB ChB, BSc (Hons)
PIUS S FASINU, MSc Med,
16669967@sun.ac.zaBERND ROSENKRANZ, MD, PhD, FFPM