ACTIVE and SPS3

ACTIVE
Another important study underway is ACTIVE
(Atrial fibrillation Clopidogrel Trial with Irbesartan
for Vascular Events). This multicenter trial plans
to enroll a total of 14,000 patients with AF and
at least 1 risk factor for stroke, including but not
limited to prior stroke or TIA.7
ACTIVE comprises 3 component trials—ACTIVE
W, ACTIVE A, and ACTIVE I. ACTIVE W is a
randomized, open, noninferiority trial comparing
oral anticoagulation therapy (target
international normalized ratio [INR] of 2 to 3)
with aspirin (75 to 100 mg/day) + clopidogrel
(75 mg/day).7 ACTIVE A, which included
patients ineligible for randomization to anticoagulation,
is a double-blind comparison of
clopidogrel + aspirin with aspirin alone.7
Patients participating in ACTIVE W or A could
be enrolled in ACTIVE I, a partial factorial,
double-blind trial in which irbesartan
(300 mg/day) or placebo is added to the
regimen of ACTIVE W or A.7
Planned follow-up is 3 years (mean).7 For
ACTIVE W and A, the primary outcome is the
composite of first occurrence of stroke,
non–central nervous system (non-CNS) systemic
embolism, myocardial infarction (MI), or
vascular death, with major bleeding as a
secondary outcome.7 ACTIVE I has 2-part
primary outcomes of stroke, MI, and vascular
death with and without hospitalization for
heart failure.7
Although ACTIVE A and I remain ongoing,16
ACTIVE W was recently terminated prematurely
because of “clear evidence of superiority of
anticoagulation therapy” compared with aspirin
+ clopidogrel.16 Oral anticoagulation provided
more effective prevention of the primary endpoint
events (P=.0003) and of stroke (P=.001;
Figure 2).16 Minor bleeding was more common
with aspirin + clopidogrel (P=.0009), with
major bleeding similar between the groups;
total incidence of hemorrhage was significantly
greater with aspirin + clopidogrel than with

SPS3

SPS3
Small subcortical strokes (S3), also known as
lacunar or small-vessel strokes, account for
about 25% of brain infarctions and are associated
with vascular dementia. These strokes are
especially frequent in younger and minority
populations, and patients with symptomatic S3
strokes have a recurrent stroke rate of 8%.8
Secondary Prevention of Small Subcortical
ASA = aspirin; ER-DP = extended-release dipyridamole; C = clopidogrel; T =telmisartan;
W = warfarin (or, in ACTIVE, the available vitamin K antagonist anticoagulant); I = irbesartan; S = simvastatin
TABLE 1
Brief Summary of Studies
STUDY PROJECTED N POPULATION DESIGN/COMPARISON PRIMARY OUTCOME
PRoFESS1,4,
10,11,12,13,15,17
20,333 Recent ischemic stroke
history
Randomized, double-blind, multicenter
2x2 factorial
ASA + ER-DP vs C; T in half of population
Time to second stroke
ACTIVE7,8,10,17 14,000 AF history with ³1 risk
factor for stroke (including
prior stroke/TIA)
All ACTIVE trials are multicenter
ACTIVE W (completed): randomized, open,
noninferiority trial W vs ASA + C
ACTIVE A: double-blind ASA + C vs ASA
ACTIVE I: partial factorial, double-blind
Irbesartan (I) or placebo added to regimen
of ACTIVE W or A
Composite of first
occurrence of stroke,
non-CNS systematic
embolism, MI, vascular
death (ACTIVE I
eliminates non-CNS
systemic embolism and
adds hospitalization for
heart failure
SPS324 2500 Small subcortical
stroke history
Factorial, multicenter
ASA + C vs ASA; hypertensive subset receives
usual or aggressive BP reduction therapy
Stroke prevention
CASTIA10,19-22 2400 Acute ischemic stroke/TIA
(first 24 h)
Randomized
ASA + C vs ASA
Composite of stroke,
new MRI-documented
infarction, MI,
vascular death
FASTER20,23 500 (pilot)
7500 (total)
Acute ischemic stroke/TIA
(first 24 h)
Randomized, double-blind, multicenter
2x2 factorial
4 arms of study:
ASA alone; ASA + C;
ASA + S; ASA + C + S
Recurrent stroke
ARCH9,17,25 1500 Atherosclerosis of
aortic arch
Recent (<6 months)
cerebral or peripheral
embolic event)
Open, randomized, multicenter
W vs ASA + C
Composite of recurrent
stroke, acute MI,
peripheral embolism,
vascular death

Strokes (SPS3) is a 45-center, randomized
trial that will assess stroke prevention (primary
endpoint) and cognition (secondary endpoint)
in a planned cohort of 2500 patients with a
history of S3.8,10,17 A factorial design will
compare aspirin + placebo vs aspirin +
clopidogrel; hypertensive patients in these
2 groups will also receive either usual blood
pressure control (to a target of 130-149
mmHg systolic BP) or intensive control (to a
target of <130 mmHg systolic BP).8 Mean
follow-up will be 3 years.8 SPS3 will provide
data on the stroke prevention with aspirin +
clopidogrel in a population with cerebrovascular
manifestations of atherothrombosis.18