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Brain Trauma Stroke
The ACTIVE A Study – An Alternative to
parallel, randomised, controlled evaluation of clopidogrel plus ASA
Warfarin for Patients with
with factorial evaluation of irbesartan for the prevention of vascular
events in patients with AF. The study started after the CURE study
ended. The ACTIVE study consisted of three separate but related
trials: ACTIVE W (clopidogrel plus ASA versus warfarin; n=6,706),
ACTIVE A (clopidogrel plus ASA versus ASA alone; n=7,554) and
ACTIVE I (irbesartan versus placebo; n>10,000).
Professor, Department of Medicine, University of Toronto
End-points of ACTIVE W were stroke, non-central nervous system
It is useful to put new therapies for cardioembolic stroke with AF in (CNS) systemic embolism, MI and VD. Results were presented in
context alongside established therapies. A meta-analysis by Hart et 2006, and showed that patients on dual antiplatelet therapy have a
al., which was initially published in 1999 and re-analysed in 2007, worse outcome than patients on oral anticoagulant therapy, with a
looked at all trials of antithrombotic therapies in AF with an end- relative risk of 1.44 (p=0.0003). Owing to clear evidence of the
point of ischaemic stroke, haemorrhagic stroke and subdural superiority of warfarin, the trial was stopped early after 1.25 years.
haematomas. There were three groups of studies: warfarin versus ACTIVE W concluded that, for patients who can take warfarin, it is a
control, which showed a risk reduction of 64%; ASA versus control, preferable therapy over clopidogrel plus ASA.
There are patients
which showed a 19% risk reduction; and warfarin versus ASA, with who for a variety of reasons cannot take warfarin, and ACTIVE A
a 39% risk reduction (see Table 4).
investigated whether clopidogrel plus ASA is a reasonable
alternative for these patients.
The hypothesis is that in patients
with AF who are unsuitable for warfarin, the addition of clopidogrel
There are patients who for a variety
to ASA would reduce the risk of vascular events with an acceptable
risk of bleeding.
of reasons cannot take warfarin,
and ACTIVE A investigated whether
The eligibility criteria for ACTIVE A were identical to those of ACTIVE
W: documented AF, one or more risk factor for stroke and absence
clopidogrel plus acetylsalicylic acid is a
of major risk factors for bleeding. The assessment of a patient’s
reasonable alternative for these patients.
suitability for ACTIVE W versus ACTIVE A was left to the
investigators. Of those enrolled into ACTIVE A, half were deemed
inappropriate for warfarin by the physician and 23% had a relative
A number of guidelines have been published based on these risk for bleeding (including predisposition to falling, persistent high
studies. For example, the guidelines from the American Heart blood pressure, previous serious bleeding on warfarin, severe
Association (AHA), the American College of Cardiology (ACC) and alcohol abuse, peptic ulcer disease and thrombocytopenia), while
the European Society for Cardiology (ESC) on antithrombotic agents the remainder of patients simply decided they did not want to take
for AF were published in 2006. The message of these is that the warfarin. All patients in ACTIVE A received ASA at a low level
therapy must be individualised depending on the risk–benefit (75–100mg), then were randomised to receive either clopidogrel or
patterns for each patient. The risk factors for stroke are the basis of placebo. Most of the baseline demographics were the same
risk factor score and include age >75 years, for ACTIVE A as for W, except the baseline use of warfarin and ASA.
hypertension, heart failure, diabetes and previous stroke or TIA. The mean age of the patients was 71 years and the mean CHADS
Previous stroke or TIA contribute a score of two points, while score was 2.0.
the others contribute one point. In a patient having no risk
factors, where the risk of stroke is small, ASA will suffice. In a
patient with a CHADS
score of one, either ASA or warfarin is
The hypothesis is that in patients with
recommended. With a CHADS
score of two or more, or any other
atrial fibrillation who are unsuitable for
high-risk factor (mitral stenosis or prosthetic heart valve), warfarin
warfarin, the addition of clopidogrel to
acetylsalicylic acid would reduce the risk
Dual Antiplatelet Therapy
Platelets are known to be involved in the thrombotic complications
of vascular events with an acceptable
of AF. Platelet function studies in AF patients show increased
risk of bleeding.
platelet activation. ASA alone modestly reduces the risk of stroke in
AF (by around 19%).
In the Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE) study,
the addition of clopidogrel Results
to ASA was shown to suppress platelet activity more than ASA Over more than four years, the primary outcome (stroke, MI,
alone, and a combination of these two agents in patients with acute systemic embolism or VD) was lower in the group assigned to
coronary syndrome (ACS) reduced future coronary events by 20%. clopidogrel plus ASA, with a relative risk/hazard ratio of 0.89
ASA with clopidogrel is now the standard therapy for patients post- (p=0.014; 95% CI 0.81–0.98). This difference was driven primarily by
ACS and for patients with stents. a reduction in the incidence of stroke, with a relative risk of 0.72
(p=0.00002; 95% CI 0.62–0.83). The curves showing cumulative
The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention incidence of stroke for the two groups diverge before one year and
of Vascular Events (ACTIVE) was a phase III multicentre, multinational, are still separating at four years (see Figure 4).
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