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Assessing Therapeutic Options and Individualising Treatment According to Patient Needs
The addition of clopidogrel to ASA effectively reduces the primary Table 4: Meta-Analysis of Antithrombotic Therapy Trials
event rate from 7.6% per year to 6.8%, and reduces the stroke rate
to Prevent Stroke in the Atrial Fibrillation Population
from 3.3 to 2.4% per year (a 28% risk reduction). There is also a
No. Trials No. Patients No. Strokes* Relative Risk
non-significant trend to a lower MI rate (from 0.9 to 0.7%; p=0.08).
Reduction
The rates of VD and non-CNS systemic embolism were unchanged. (95% CI)
Adjusted-dose 6 2,900 186 64% (49–74)
Different types and severity of strokes were also investigated. The
warfarin versus
greatest reduction is in the number of ischaemic strokes (this
control
category also included strokes of uncertain type), from 3.2% per
ASA versus 7 3,990 388 19% (1–35)
control
year to 2.1%: a relative risk of 0.68 (p<0.001). Haemorrhagic strokes
Warfarin versus 9 4,620 330 39% (19–53)
showed a trend to increase, but this was non-significant (p=0.27)
ASA
(see Figure 5).
38
It should be noted that the reduction in stroke rates
ASA = acetylsalicylic acid; CI = confidence interval. *Ischaemic strokes, haemorrhagic
was seen in both non-disabling strokes and disabling or fatal 34
strokes and subdural haematomas. Adapted from Hart et al. 2007.
stroke categories. Thus, this combination therapy is effective in all
types of stroke.
Figure 4: Difference in Stroke Risk in ACTIVE A
As with any antithrombotic therapy, the advantage of a lower
0.15
clotting risk is always balanced by an increased risk of bleeding; the
HR 0.72 (0.62–0.83); p=0.00002
question is, how much? In the ACTIVE programme, definition of
major bleeding was either an overt bleed requiring ≥2 units
ates
Placebo + aspirin
0.10
of transfusion or a severe bleed, for example one that caused a
drop in haemoglobin of ≥5 gm/dl or was fatal. Within ACTIVE A the
addition of clopidogrel to ASA caused the major bleeding rate to
increase from 1.3 to 2.0% per year, a relative risk of 1.57 (95% CI
0.05
1.29–1.92; p<0.001). The rate of severe bleeds had the same
Cumulative hazard r Clopidogrel + aspirin
relative risk outcome. Both intracranial and extracranial bleeds
increased, with relative risks of 1.87 (p=0.006) and 1.51 (p<0.001)
0.00
012 34
respectively. The majority of the extracranial bleeds were Years
gastrointestinal (GI)-based.
No. at risk
C+A 3,772 3,491 3,229 2,570 1,203
ASA 3,782 3,491 3,229 2,570 1,186
In terms of the overall risk and benefit, treating 1,000 patients for
38
ASA = acetylsalicylic acid. Adapted from Connolly et al. 2009.
three years using clopidogrel plus ASA will prevent 28 strokes
(including 17 fatal or disabling) and six MIs. By contrast, there
Figure 5: Number of Fatal Strokes Prevented
will be an extra 20 non-stroke major bleeds, three of which will
be fatal.
100
ASA
It is not possible to compare this regimen directly with warfarin, but
-23
Clopidogrel and ASA
using the results from a meta-analysis of warfarin trials it is
80
possible to see the relative effects of the two therapies. Warfarin
-26
versus ASA has a relative risk reduction of 38% for stroke, but an
60
increase of 128% for intracranial bleeds and 70% for extracranial
bleeds (see Table 5 ). While clopidogrel plus ASA is less effective
than warfarin in preventing stroke, with only a 28% risk reduction, it
40
Number of strokes
also causes fewer bleeds. This emphasises the need to individualise
treatment to ensure that patients have the most effective therapy
20
with the lowest risk for their disease.
+3
Summary and Conclusions
0
Total Ischaemic/Uncertain Haemorrhagic
For most patients with AF, the recommended antithrombotic
Type of stroke
therapy is warfarin. Nevertheless, for those unable or unwilling to
38
ASA = acetylsalicylic acid. Adapted from Connolly et al., 2009.
take warfarin, there is now an alternative. The addition of
clopidogrel to an ASA regimen does reduce major vascular events,
Table 5: Safety Outcomes for Major Antithrombotic
primarily through reduction in stroke. There is an increase in major Comparisons by Treatment Regimen
bleeding as a side effect, but as it is less than that with warfarin,
this will be an acceptable risk for many patients.
Effects Warfarin versus Clopidogrel + ASA
ASA versus ASA
Meta-analysis* (RRR) ACTIVE A (RRR)
For each patient it is important that the physician make an Reduction in stroke –38% –28%
individual risk–benefit assessment regarding choice of therapy. The Increase in intra-cranial bleed +128% +87%
results of the ACTIVE A trial will affect the way that cardiologists
Increase in extra-cranial bleed +70% +51%
and other physicians prescribe antithrombotic therapy for AF.
34
RRR – relative risk reduction; ASA = acetylsalicylic acid. Adapted from Hart et al., 2007.n
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