CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
Warfarin: better the devil you know
Long-term anticoagulation with warfarin is recommended for
patients with atrial fibrillation (AF), valvular heart disease and
pulmonary embolus, as these conditions significantly increase
the risk for thromboembolic complications.
AF for example
increases the risk for ischaemic stroke four- to five-fold.¹
Warfarin has high efficacy in the prevention and treatment of
In AF patients, for example, warfarin
reduces stroke risk by 64% compared with placebo or no
treatment (absolute risk reduction 2.7% for primary prevention,
8.4% for secondary prevention), and by 38% when compared to
aspirin (absolute risk reduction 0.7% primary prevention, 7.0%
Importantly, for clinical practice, warfarin has a narrow
therapeutic window and requires regular monitoring in the form
of routine international normalised ratio (INR) measurements.
It has an unpredictable pharmacokinetic/pharmacodynamic
(PK/PD) profile, and to optimise efficacy and avoid toxicity,
INR monitoring is essential.
Sub-therapeutic warfarin doses increase the risk of thrombus
formation, while excess anticoagulation will increase the
probability of a life-threatening bleed.
control and monitoring is required throughout treatment.
Warfarin causes significant morbidity and is among the top
drugs leading to adverse drug reactions.
The risk of major
bleeding depends on the patient group and can range from 0.75
to 10.0% per annum.
In South Africa, bleeding due to warfarin is among the top five
adverse drug reactions (ADRs) resulting in hospital admission.
A multicentre, hospital-based survey in South African medical
wards to determine the burden of ADRs resulting in admission
and death revealed that ADRs accounted for 8.4% of medical
admissions and 2.9% of deaths.
In this study, haemorrhage was
the fourth most common cause, with warfarin accounting for
68% of these bleeds.
It is difficult to predict who is at increased risk for toxicity.
Many factors result in the inconsistent response to warfarin
therapy. These include its narrow therapeutic window,
unpredictable dose response, numerous drug–drug interactions
(importantly, non-steroidal anti-inflammatory drugs, rifampicin
and the enzyme-inducing anti-epileptics), diet containing high
levels of vitamin K, and patient co-morbid conditions.
In a South African black population, genetic modifications in
cytochrome P450 2C9 and vitamin K epoxide reductase subunit
1 resulted in approximately 45% of warfarin dosage variability.
Further research is required to establish whether routine genetic
testing and dose adjustment will lead to improved outcomes
when using warfarin.
Patient non-adherence and prescriber fear are important
causes of INR variability.
The Randomized Evaluation of
Long-Term Anticoagulation Therapy (RE-LY) study found that
adherence to a standardised warfarin dosing algorithm improved
The INR is used as a surrogate for treatment success. Patients’
INRs are routinely measured and used to assess the time in the
therapeutic range (TTR). TTR is defined as the duration of time
in which the patient’s INR values were within a desired range.
TTR strongly associates with bleeding and thromboembolic
risk, namely, a high TTR correlates with reduced risk of both
thromboembolic complications and major bleeding.
A study in patients with AF receiving warfarin found that even
a small 7% improvement in TTR reduced major haemorrhage
rates by one event per 100 patient years, and a 12% increase in
TTR reduced the thromboembolic rate by one event per 100
It is suggested that INR monitoring clinics aim
for a TTR between 70 and 80% to optimise benefits and reduce
analysis of the ACTIVE W study, which assessed
dual antiplatelet therapy versus warfarin in patients with AF,
found a mean TTR of 63.4%. Despite patients being managed
in the controlled environment of this clinical trial, the South
Africa cohort had a mean TTR of 46.3%; well below the widely
Countries that achieved a TTR of close to 75%
had improved clinical benefits from warfarin therapy.
Newer agents have been compared to warfarin in patients
with AF. The Africa cohort of the RE-LY study had a TTR of
58% compared to the overall population TTR of 64%.
South African patient population of the ROCKET-AF study
had a TTR of 54.8%.
Once again, the outcomes of the South
African cohort within the ROCKET-AF trial emphasise that
despite being evaluated under clinical trial conditions, there are
challenges to achieving therapeutic TTRs. Unfortunately, newer
warfarin dosing strategies (computer-aided dosing, speciality-
pharmacy clinics and genotype-guided dosing) have shown only
modest improvements in TTR.
In conclusion, warfarin remains an important agent for
the prevention of thrombosis and thromboembolism in high-
risk patients. Despite its clinically significant effectiveness, its
unpredictable bleeding risk must be respected. Before committing
to its prescription, clinicians must recognise and mitigate which
factors may contribute to this risk. Regular INR monitoring and
patient education can dramatically reduce this risk.
Department of Medicine, Division of Clinical Pharmacology,
Faculty of Health Sciences, University of Cape Town and
Groote Schuur Hospital, Cape Town, South Africa
Marc Blockman, MB ChB, BPharm, PG Diploma Int Res Ethics,