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




Warfarin: better the devil you know

Marc Blockman

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

thromboembolic disease.


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%

secondary prevention).


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.


Therefore, meticulous

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

patient control.


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

patient years.


It is suggested that INR monitoring clinics aim

for a TTR between 70 and 80% to optimise benefits and reduce

patient harm.



post hoc

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

accepted range.


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,