Cardiovascular Journal of Africa: Vol 24 No 2 (March 2013)

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 2, March 2013

AFRICA

to 58.3% for Wesfleur Hospital. INR values above 3.5 generally

signify high risks of bleeding. The fact that these high records

were present despite monthly monitoring further underscores the

importance of monitoring of warfarin therapy. It is an indication

that without the hospital facility for monitoring, bleeding

complications would have arisen in many of the patients.

More female patients (68%) were enrolled in the clinics

than males. Considering gender and INR values, female

patients’ responses to warfarin in Wesfleur Hospital suggested

sensitivity, with 61% of them recording at least one INR

above 3.5, compared with 23% in Gugulethu Hospital. While

gender-based conclusions cannot be made based merely on this

observation, several other unreported factors could account for

the higher sensitivity in the female patients. This may include

concomitant use of birth-control pills and differences in the

use of complementary medicines or diets. Differences in body

protein-to-fat ratio may also influence the effective plasma

warfarin concentration in men and women, with the resultant

differences in sensitivity.

Discussion

There appeared to be differences in INR values along age and

racial classification. About 64% of Coloured patients above

the age of 40 years had INRs above 3.5 in Wesfleur Hospital,

whereas in Gugulethu, only 33% of black patients in same age

group had a record of at least one INR above 3.5. Although,

no study has reported ethnic/genotype variations in warfarin

response between Coloured and black people in South Africa, the

body of evidence supporting genetic factors as a key influence

on the response to warfarin therapy is increasing.

Scott and co-workers

investigated the genetic influence on

the inter-individual warfarin dose variability among various

racial groups. The results revealed significant variation in the

genetic expression of CYP2C9, VKORC1 and CYP4F2 in

different ethnic groups. The study identified this variation as

a major reason why current genotype-guided warfarin dosing

algorithms in America may not yield similar results in all

ethnic groups. In another study, age, body size and CYP2C9

genotype were found to be crucial determinants of warfarin dose

requirements in different racial and ethnic groups.

Earlier findings have shown evidence of the influence of

several genes on the response to warfarin therapy, particularly the

polymorphisms in CYP2C9 and VKORC1.

These studies have

consistently revealed that such genetic influence is less common

in African–Americans compared to European–Americans and

Asians.

The recent report of a new genetic variant in VKORC1

among African–American populations, supported by various

other warfarin pharmacogenetic studies, suggests a different

warfarin maintenance dosing requirement based on genetic

composition.

30-33

Seventy-two per cent of patients with a body weight above 70

kg and 55% below 70 kg in Wesfleur Hospital had an INR above

3.5. In Gugulethu Hospital, 35.7% of those who weighed more

than 70 kg and 33.3% of those who weighed less than 70 kg had

records of an INR above 3.5. This underscores the absence of

weight as a factor in the fluctuation of INR values.

High body weight is an important risk factor of the indications

for warfarin therapy in patients with cardiovascular disorders.

The pharmacokinetic disposition and activity of warfarin may be

influenced by body weight. The effects of weight may therefore

be a necessary consideration in the attainment of a stable INR in

warfarinised patients.

When the concurrent chronic diseases of patients attending

the warfarin clinics were evaluated, hypertension was the most

common disease in both hospitals (57.9% in Wesfleur and 51.4%

in Gugulethu Hospital). Hypertension is a chronic lifestyle-

related disease with body weight and genetic factors as main

risk factors. The maintenance of INR values within an acceptable

therapeutic range will be particularly taxing in patients with

hypertension and other cardiovascular disorders. In addition to

the effects of the cardiovascular medications, fluctuations in

cardiac function, such as cardiac output and peripheral vascular

resistance may play a significant role in the body distribution of

and sensitivity to warfarin.

Hypertension may therefore play a significant role in the

warfarin response in these patients. Long-standing hypertension

is associated with complications such as atrial fibrillation.

This is reflected in the data, as atrial fibrillation was the most

common clinical indication for the initiation of warfarin therapy

at Wesfleur Hospital (47%), and the second most common

indication (39%) in Gugulethu Hospital (Table 2).

Concurrent medications that were commonly prescribed

for patients on warfarin therapy were antibiotics, especially

fluoroquinolones, beta-lactams and metronidazole; non-steroidal

anti-inflammatory drugs; paracetamol; and anti-ulcer drugs

(Table 3). Quinolones were prescribed at only Wesfleur Hospital,

and an elevated INR above the cut-off value of 3.5 was recorded

in all the patients concerned in the month that these drugs were

taken concurrently.

A similar occurrence was observed with beta-lactams in both

hospitals; 71.4% of patients treated with these antibiotics had

INR values above 3.5. The effects of broad-spectrum antibiotics

on the vitamin K-producing gastrointestinal microflora can

potentiate the anticoagulant effects of warfarin. This may

explain the observation of elevated INR in warfarinised patients

on concomitant antibiotic therapy. In addition, quinolones are

TABLE 2. INDICATIONS FORWARFARIN THERAPY FOR

PATIENTS FROMWESFLEURAND GUGULETHU HOSPITALS

(SOME PATIENTS HAD MULTIPLE INDICATIONS)

Indication

Wesfleur (%)

Gugulethu (%)

Myocardial infarction

0.3

Valve replacement

Mixed valve disease

Atrial fibrillation

Thrombosis/embolism

TABLE 3. COMPARISON OF DATA FOR CONCURRENT

MEDICATION PRESCRIBEDVS INR IN PATIENTSAT FOR

PATIENTS FROMWESFLEURAND GUGULETHU HOSPITALS

Wesfleur

Gugulethu

Medications

INR

3.5 INR

3.5

Quinolones

Beta-lactams

Metronidazole

NSAIDs

Paracetamol

Anti-ulcer drugs