SA JOURNAL OF DIABETES & VASCULAR DISEASE
DRUG TRENDS
VOLUME 8 NUMBER 3 • SEPTEMBER 2011
141
Drug Trends
South Africa’s poor warfarin control raises questions of benefit above
other anticoagulant therapies in atrial fibrillation
S
outh African patients entered into the
ACTIVE-W trial were outside the ideal INR
targets of 2–3 for 60% of the time while on
warfarin therapy. This poor control of war-
farin reduces benefit and raises the question
as to whether other newer anticoagulant
therapies should be used for stroke preven-
tion in atrial fibrillation. New management
strategies are also needed to improve war-
farin control.
Poor control of warfarin was a very signif-
icant feature of the South African-entered
patients and, in fact, South Africa as a coun-
try was at the bottom of the log of achieved
time in therapeutic range (TTR) (See Table 1,
amended from reference 1). Furthermore,
no South African patients were in the upper
quartiles of TTR control.
South Africa entered patients with atrial
fibrillation into the ACTIVE-W (Atrial fibril-
lation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events) trial, in which
patients were randomised to receive dual
antiplatelet therapy (clopidogrel 75 mg/day
plus aspirin 75–100 mg/day or oral antico-
agulation). In South Africa, the vitamin K
antagonist used was warfarin. Ninety-eight
South African patients were randomised to
warfarin therapy and included in the
post
hoc
study on the influence of INR control on
ACTIVE-W results.
The overall outcome (stroke, myocardial
infarction, systemic embolism or vascular
death) was found to be increased with clopi-
dogrel plus aspirin, compared to oral antico-
agulation. The mean TTR for all patients in
ACTIVE-W was 63.4% (median 65%).
While there are differences between cen-
tres within a particular country, South Afri-
can centre-specific data was not disclosed.
However, the authors noted that in the three
countries with the lowest mean TTRs (South
Africa, Brazil and Russia), 86% of patients
had TTRs below the mean. In South Africa’s
case, 86% of patients therefore had mean
TTRs even lower than 46.3. Overwhelm-
ingly, these data point to very poor warfarin
control-to-target INRs in South Africa.
Effect of TTRs on treatment
effect of warfarin
The effect of TTRs on treatment benefit
of warfarin was evaluated in terms of TTR
achieved at a particular centre. This was also
adjusted for the patients’ characteristics
and then evaluated in terms of the patients’
CHADS
2
score (≥ 2 vs < 2), and finally, in
a population-averaged model reflecting a
country-level response.
Under all four criteria, patients in the
lowest quartile of TTR in terms of their cen-
tres did not benefit and were at greater risk
on their warfarin therapy then they would
have been on anti-platelet therapy: clopi-
dogrel plus aspirin. Across all these factors,
the observed effect of the TTR quartile on
warfarin or alternative oral treatment was
robust and determined the level of benefit
for individual patients.
Using these data in a population-aver-
aged model, this study was able to estimate
the minimum TTR needed to have at least
some benefit from oral anticoagulation. This
level was determined to be above 58%, a
countrywide objective that South Africa did
not reach.
The role of self-monitoring could be help-
ful in the South African situation, as can the
newer anticoagulants such as dabigatran,
which is registered in the United States for
stroke prevention in atrial fibrillation. In the
RE-LY trial and further evaluation of dabigat-
ran’s efficacy and safety, the advantages of
dabigatran remained, irrespective of the
centres’ quality of INR control. In fact, for all
vascular events, non-haemorrhagic events
were greater at sites with poor INR control
than at those with good INR control.
2
J Aalbers, Special Assignments Editor
Connolly SJ, Pogue J, Eikelboom J, Flaker G,
1.
Commerford P,
et al
. on behalf of the ACTIVE-W
investigators. Benefit of oral anticoagulation over
antiplatelet therapy in atrial fibrillation depends
on the quality of international normalized
ratio control achieved by centres and countries
as measured by time in therapeutic range.
Circulation
2008;
118
: 2029–2037. DOI: 10.1161/
CIRCULATIONAHA.107.750000
Wallentin L, Yusuf S, Ezekowitz MD, Alings M,
2.
Flather M, Grazia Franzosi M, Pais P,
et al
. on behalf
of the RE-LY investigators. Efficacy and safety of
dabigatran compared with warfarin at different
levels of international normalized ratio control for
stroke prevention in atrial fibrillation: an analysis
of the RE-LY trial.
Lancet
, published online Aug 29
2010. DOI: 10.1016/S0140-6736(10)61194-4.
Table 1.
TTR and time of risk of stroke, myocardial infarction, systemic embolism, vascular death, or major haemorrhage for some of the 15 countries
participating in Active-W
Patients per TTR quartile
(low to high) (
n
)
Clopidogrel +
aspirin
OAC
Clopidogrel + ASA
vs OAC
Country
1
2
3
4
Mean
TTR Events %/y Events
%/y RR
95% CI
p
South Africa
55
43
0
0 46.3 5
8.42 8
14.94 0.57
0.19–1.75
0.33
Brazil
188
25
25
8 47.1 13
9.38 14
9.43 1.01
0.47–2.15
0.98
Russia
188
28
0
41 53.4 13
7.92 7
4.16 1.88
0.75–4.70
0.18
United States
135
460
363
116 62.9 59
8.02 48
6.6
1.25
0.85–1.83
0.26
Netherlands
65
98
163
49 64.0 15
6.65 7
3.17 2.12
0.86–5.20
0.10
Australia
5
12
54
145 74.5 18
12.92 5
3.76 3.60
1.34–9.71
0.01
United Kingdom 2
34
59
199 74.8 12
7.03 7
3.97 1.79
0.71–4.55
0.22
ASA: acetylsalicyclic acid; OAC: oral anticoagulation; RR: relative risk, rows are ordered by mean TTR.
