CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 4, July/August 2011
220
AFRICA
South Africa’s poor warfarin control raises questions of benefit
above other anticoagulant therapies in atrial fibrillation
South 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 warfarin reduces benefit and
raises the question as to whether other
newer anticoagulant therapies should be
used for stroke prevention in atrial fibril-
lation. New management strategies are
also needed to improve warfarin control.
Poor control of warfarin was a very
significant feature of the South African-
entered patients and, in fact, South Africa
as a country was at the bottom of the log
of achieved time in therapeutic range
(TTR) (See Table 1, amended from refer-
ence 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 fibrillation 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 aspi-
rin 75–100 mg/day or oral anticoagula-
tion). In SouthAfrica, the vitamin K antag-
onist 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, myocar-
dial infarction, systemic embolism or
vascular death) was found to be increased
with clopidogrel plus aspirin, compared
to oral anticoagulation. The mean TTR
for all patients in ACTIVE-W was 63.4%
(median 65%).
While there are differences between
centres within a particular country, South
African centre-specific data were 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. Overwhelmingly, 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’ charac-
teristics 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
centres did not benefit and were at greater
risk on their warfarin therapy then they
would have been on anti-platelet therapy:
clopidogrel 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 esti-
mate the minimum TTR needed to have
at least some benefit from oral antico-
agulation. This level was determined to be
above 58%, a countrywide objective that
South Africa did not reach.
The role of self-monitoring could be
helpful in the South African situation, as
can the newer anticoagulants such as dabi-
gatran, which is registered in the United
States for stroke prevention in atrial fibril-
lation. In the RE-LY trial and further eval-
uation of dabigatran’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
1.
Connolly SJ, Pogue J, Eikelboom J, Flaker
G, Commerford P,
et al
. on behalf of the
ACTIVE-W investigators. Benefit of oral
anticoagulation over antiplatelet thera-
py 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
2.
Wallentin L,Yusuf S, Ezekowitz MD, Alings
M, 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 interna-
tional normalized ratio control for stroke
prevention in atrial fibrillation: an analy-
sis of the RE-LY trial.
Lancet
, published
online Aug 29 2010. DOI: 10.1016/S0140-
6736(10)61194-4.
TABLE 1. TTRAND TIME TO RISK OF STROKE, MYOCARDIAL INFARCTION, SYSTEMIC EMBOLISM, VASCULAR DEATH,
OR MAJOR HAEMORRHAGE FOR SOME OF THE 15 COUNTRIES PARTICIPATING INACTIVE-W
Patients per TTR quartile
(low to high) (
n
)
Mean
TTR
Clopidogrel
+
aspirin
OAC
Clopidogrel
+
ASA vs OAC
Country
1
2
3
4
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.
