Download Rationale and design of ACTIVE

Rationale and design of ACTIVE: The atrial fibrillation
clopidogrel trial with irbesartan for prevention of
vascular events
The ACTIVE Steering Committee on behalf of the ACTIVE Investigators Hamilton, Ontario, Canada
Background Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical
consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The
addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations.
Irbesartan is an angiotensin receptor–blocking agent that reduces blood pressure and has other vascular protective effects.
Methods and Results
ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in
patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel
in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral
anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind,
placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these
studies are composites of vascular events. A total of 14 000 patients will be enrolled in these trials.
Conclusions ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role
of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in
patients with AF. (Am Heart J 2006;151:1187-93.)
Atrial fibrillation and
cardiovascular events
Atrial fibrillation (AF) is the most common cardiac
arrhythmia with potential for serious consequences. It
affects N1% of the population and is common in the
elderly. In those older than 75 years, its prevalence is
N10%.1 One of the serious outcomes associated with AF
is stroke, which occurs at an annual rate of 4.5% in
patients with AF.2,3 About 15% of all strokes are
attributable to AF, and in those older than 80 years, a
4
quarter of strokes are attributable to AF. About two
thirds of strokes in patients with AF are estimated to be
cardioembolic.5 In a meta-analysis of trials of anticoagulation versus aspirin (ASA) therapy in AF,6 there were
a total of 514 cardiovascular events (stroke, non –central
nervous system [CNS] systemic embolism, myocardial
infarction [MI], or vascular death), of which 48% (248)
were ischemic strokes.
From the Population Health Research Institute, Hamilton, Ontario, Canada.
Submitted April 25, 2005; accepted June 15, 2005.
Reprint requests: Stuart J. Connolly, McMaster University, 237 Barton St. E., Hamilton,
Ontario, Canada L8L 2X2.
E-mail: [email protected]
0002-8703/$ - see front matter
n 2006, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2005.06.026
Antithrombotic therapy in AF
Six trials evaluating warfarin or other oral anticoagulants have reported relative risk reductions in stroke
between 33% to 78%. A meta-analysis of the first 5 of
these trials7 concluded that the relative risk of stroke
was significantly reduced by 67% and the risk of total
vascular events was significantly reduced by 42%,
whereas the risk of major bleeding increased from 1.0%
to 1.3% per year. A sixth placebo-controlled trial of
warfarin, the EAFT, evaluated patients with prior stroke
or transient ischemic attack (TIA) and reported a similar
benefit for anticoagulant therapy.8
Several of these trials have compared ASA with
placebo at doses varying from 100 to 1200 mg/d. A metaanalysis of these trials concluded that ASA significantly
reduces the risk of stroke by 22% (95% CI 2%-38%), with
no significant increase in the risk of major hemorrhage.9
Six trials have compared oral anticoagulation to ASA in
AF. In 2 of these, the ASA patients also received a very
low dose of oral anticoagulation that did not affect the
international normalized ratio (INR). A meta-analysis6
reported that compared with ASA, anticoagulation
reduced the risk of total cardiovascular events (hazard
ratio [HR] 0.71, 95% CI 0.29 - 0.85, P b .001) and of
stroke (HR 0.55, 95% CI 0.43 - 0.71, P b .001). Major
bleeding (excluding the trials with combination ASA and
low-intensity warfarin) was increased (HR 1.93, 95% CI
1.30 -2.88, P = .001).
American Heart Journal
June 2006
1188 The ACTIVE Steering Committee
A consensus statement from American and European
cardiology societies10 recommends that patients with AF
who have risk factors for stroke and who do not have an
excessive risk of bleeding receive oral anticoagulation.
Aspirin is recommended for patients with a low risk of
stroke and is also used in patients for whom oral
anticoagulation is contraindicated.
Problems with warfarin and other oral
anticoagulants
trial (CREDO)23 reported a 27% relative reduction in
cardiovascular events at 1 year with addition of
clopidogrel to ASA (95% CI 3.9%-44.4%). On the other
hand, MATCH,24 in high- risk patients with recent
ischemic stroke or TIA, has reported that adding ASA to
clopidogrel confers no significant benefit.
Hypertension and AF
The problems of using oral anticoagulant therapy are
well known. The therapeutic range of 2.0 to 3.0 for the
INR of the prothrombin time has been well validated by
clinical studies.11-13 International normalized ratio values
fall out of range a third of the time under the stringent
conditions of clinical trials14 and, undoubtedly, much
more often in real world practice. The effects of oral
anticoagulant agents are modulated by variations in both
hepatic function and gut flora. They are subject to
complex and numerous drug and dietary interactions.15
This leads to a highly variable dose response, a
requirement for permanent monitoring and ultimately to
difficulties with patient compliance.
Contraindications to anticoagulation are common in
patients with AF. Surveys 16,17 suggest that about 20% of
patients with AF are reported to have contraindications
to oral anticoagulation, similar to those used in the
pivotal clinical trials. In addition, a substantial proportion of patients who do not have contraindications are
unwilling to use anticoagulation, and even compliant
patients would prefer an alternative.18-20
Surveys of oral anticoagulant therapy use among
patients with AF consistently show low rates of use. In
2000, Bungard et al 19 reviewed 16 surveys done since
1990 and observed that even in patients without
contraindications to oral anticoagulation, warfarin use
was observed in b 50% of patients. Recently, an analysis
of the National Ambulatory Medical Care Survey of the
United States, based on 1355 visits to patients with AF,
reported that in high-risk patients, oral anticoagulant use
remains b 50%.20
Hypertension is major risk factor for development of
AF and is observed in a majority of patients with
nonrheumatic AF.25 Among patients with AF, hypertension significantly increases the risk of stroke.7,10 The
baseline prevalence of hypertension requiring treatment
has been very high in patients participating in recent
major AF trials: 71% of patients in AFFIRM26 and N72% of
patients in SPORTIF III.14
Angiotensin II receptor blockers (ARBs) are drugs that
block angiotensin AT1 receptors, which are found in
large numbers in smooth muscle, liver, kidney, heart,
and vascular walls.27 The main effect of ARBs is to
antagonize the systemic vasoconstrictor and adrenal
steroidogenesis effects of the renin-angiotensin-aldosterone system. Activation of AT1 receptors leads to release
of numerous growth factors, cell hypertrophy and
proliferation, and numerous metabolic effects. As a class,
the ARBs are as effective as other antihypertensive
agents in lowering blood pressure (BP) and are very well
tolerated.28 Important vascular protective effects of
ARBs, in addition to direct antihypertensive actions,
have been demonstrated in patients with left ventricular
hypertrophy and hypertension and in proteinuric kidney
disease.29,30 In addition, angiotensin-converting enzyme
(ACE) inhibitors have been shown to reduce the risk of
major vascular events in nonhypertensive high-risk
populations, despite only causing small reductions in BP
in the HOPE and EUROPA trials.31,32 Irbesartan is an ARB
with an excellent pharmacokinetic profile.33 It has
predictable and dose-dependent effects on BP in
hypertensive patients with excellent tolerability.34 It
has been shown to slow the progression of renal
dysfunction in proteinuric states.32
Clopidogrel plus ASA
Design of ACTIVE
A synergistic effect of clopidogrel and ASA has been
repeatedly observed in experimental thrombosis.21 In
man, the benefits of combining a thienopyridine with
ASA were first conclusively demonstrated in trials of patients undergoing percutaneous coronary intervention.
The CURE trial22 established that the addition of
clopidogrel to usual care with ASA in acute coronary
syndrome reduced the risk of vascular death, recurrent
infarction, or recurrent ischemia (relative risk 0.80, 95%
CI 0.72-0.90, P = .00009). In patients undergoing
percutaneous coronary intervention, a large controlled
Three separate interrelated trials are included in
ACTIVE, known as ACTIVE W, ACTIVE A, and ACTIVE I.
ACTIVE W is an open noninferiority trial of clopidogrel
plus ASA versus oral anticoagulation in patients with AF
and at least 1 risk factor for stroke. ACTIVE A is a doubleblind, placebo-controlled trial of clopidogrel in similar
patients with AF and at least 1 risk factor for stroke who
receive ASA because they have a contraindication to oral
anticoagulation or because they are unwilling to take an
oral anticoagulant. ACTIVE I is a partial factorial, doubleblind, placebo-controlled trial of irbesartan in patients
American Heart Journal
Volume 151, Number 6
The ACTIVE Steering Committee 1189
Figure 1
Flow diagram of ACTIVE.
participating in ACTIVE A or ACTIVE W who do not
require an angiotensin receptor–blocking agent and
whose systolic BP is at least 110 mm Hg.
Patient selection
To be eligible for ACTIVE (either A or W), patients
must have permanent AF or at least 2 episodes of
intermittent AF in the past 6 months. There must also be
at least 1 of the following risk factors: (a) age z75 years;
(b) on treatment of systemic hypertension; (c) prior
stroke, TIA, or non-CNS systemic embolus; (d) left
ventricular dysfunction with left ventricular ejection
fraction b45%; (e) documented peripheral vascular
disease; ( f) age 55 to 74 years and either (1) diabetes
mellitus requiring drug therapy or (2) documented
previous MI or documented coronary artery disease.
Major exclusions are requirement for clopidogrel or
for oral anticoagulant (such as prosthetic mechanical
heart valve), documented peptic ulcer disease within
the previous 6 months, prior intracerebral hemorrhage, significant thrombocytopenia (platelet count
b50 times; 109/L), and mitral stenosis.
Patients with contraindications to oral anticoagulation
are eligible for ACTIVE A. Patients who refuse to take oral
anticoagulation may also be enrolled in ACTIVE A. Investigators are required to specify in detail the factors that
influence the decision whether to enroll in ACTIVE A or W.
Patients will be eligible for ACTIVE I if they are
enrolled into either ACTIVE A or W (Figure 1) and if
they also meet the following additional criteria:
(a) systolic BP of at least 110 mm Hg; (b) not anymore
receiving an angiotensin receptor–blocking agent,
unless they are willing and able to be changed to
another antihypertensive agent; (c) no previous intolerance to angiotensin receptor–blocking agents; (d) no
proven indication for angiotensin receptor–blocking
agents, unless an ACE inhibitor can be substituted; and
(e) not a nursing mother.
Study treatments and duration
In ACTIVE W, patients are randomized to receive open
clopidogrel plus ASA or oral anticoagulation. Patients
randomized to oral anticoagulation are monitored to an
INR between 2.0 and 3.0. Patients randomized to
clopidogrel plus ASA receive tablets containing clopidogrel 75 mg once daily in addition to ASA (recommended dose of 75 to 100 mg/d). In ACTIVE A, all
patients receive ASA (recommended dose of 75 to
100 mg/d). In addition, patients are randomized to
receive either double-blind clopidogrel 75 mg or
placebo. In ACTIVE I, patients are randomized to receive
double-blind irbesartan once daily or placebo. The
starting dose is 150 mg/d for 2 weeks, which is titrated
up to 300 mg/d if the patient is free of adverse effects of
American Heart Journal
June 2006
1190 The ACTIVE Steering Committee
irbesartan (light-headedness or dizziness). Patients who
undergo cardioversion will follow local guidelines for
antithrombotic therapy. Aspirin therapy (recommended
dose of V100 mg/d) is allowed for patients in the
ACTIVE W study.
Study outcomes
The primary outcome of ACTIVE A and ACTIVE W is
the first occurrence of stroke, non-CNS systemic embolism, MI, or vascular death. There are 2 coprimary
outcomes for ACTIVE I. The first coprimary is the first
occurrence of stroke, MI, or vascular death; the second
coprimary is the first occurrence of any of the events
in the first coprimary plus hospitalization for heart
failure. The secondary outcomes are total mortality and
stroke. Major bleeding is a secondary safety outcome in
ACTIVE A and ACTIVE W. Other secondary outcomes of
importance are being collected in different subset of
patients. These include recurrence of AF, microalbuminuria, cognitive function, quality of life, and structural
changes in the left ventricle and atrium measured by
magnetic resonance imaging. A detailed economic
analysis will be performed.
Sample size and statistical analysis
The goal of ACTIVE W is to establish that clopidogrel
plus ASA is noninferior to standard oral anticoagulation
therapy. We have chosen to design this trial with
power to show that clopidogrel plus ASA maintains at
least 50% of the smallest likely benefit of warfarin
defined by the lower bound of the 95% CI seen in a
meta-analysis of total vascular events in the anticoagulation trials in AF. To do this, the upper limit of the 1sided 97.5% CI of the comparison of clopidogrel plus
ASA to warfarin must not exceed 1.186. A trial of 6500
patients is planned because it will provide 88% power
to show that clopidogrel plus ASA maintains 50% of the
efficacy of oral anticoagulation.
ACTIVE A is designed to show that clopidogrel plus
ASA is superior to ASA alone. We are estimating an
annual vascular event rate of 8%.35 Enrolment of
7500 patients will provide 88% power to detect a
relative risk reduction of 15% with clopidogrel plus ASA.
We anticipate that 9000 patients will be enrolled in
ACTIVE I, which will result in 89% power to detect a
15% risk reduction in the first coprimary outcome if the
event rate is 7% per year and 92% power to detect a 15%
risk reduction in the second coprimary outcome.
The Data and Safety Monitoring Board will provide
ongoing review of the safety of the investigational
treatments in ACTIVE. For ACTIVE A and ACTIVE I,
treatment effects will be assessed by the Data and Safety
Monitoring Board for greater-than-expected efficacy for
the primary outcome using a modified Haybittle-Peto
Table I. Baseline characteristics of first 10 000 patients
enrolled in ACTIVE
ACTIVE A ACTIVE W ACTIVE I
No. of patients enrolled
Mean age (y)
Duration of AF N2 y ( %)
% Men
% Age z75 y
1. Medical history
% Hypertension
% Stroke or TIA
% MI
% Peripheral vascular disease
% Heart failure
% Diabetes
BP systolic sitting (mean)
2. Baseline medication
% Taking ASA
% Taking oral anticoagulant
% Taking ACE I
% Taking statin
% Taking antiarrhythmic drug
3. Electrocardiogram
% AF
% Sinus rhythm
% Pathological Q waves
% Left ventricular hypertrophy
3456
71.3
55.3
58.6
42.5
6544
70.2
59.4
66.2
36.6
5988
69.7
56.8
62.0
34.6
83.0
12.9
15.5
2.5
32.6
18.4
136
81.6
15.1
17.3
3.5
30.4
21.2
133
86.8
13.9
14.5
2.5
30.7
19.8
138
78.6
10.9
53.7
23.4
24.0
27.9
76.8
53.8
37.4
18.8
47.2
51.0
59.9
29.8
22.3
72.9
21.0
8.1
17.4
81.3
12.7
10.2
13.5
77.3
17.2
9.0
16.9
boundary 36 of 4 SDs in the first half of the study and
3 SDs in the second half. ACTIVE A and W are eventdriven trials, and thus, enrollment and follow-up may be
increased to achieve the target numbers of primary
outcome events, which are 1450 for ACTIVE W and
1600 for ACTIVE A.
Study progress
Target enrollment into ACTIVE W was completed
N6 months ahead of schedule in December 2004.
Enrollment in ACTIVE A has been more challenging,
but it is scheduled for completion by December 2005.
Enrollment into ACTIVE I has occurred in 62% of all
ACTIVE patients, and N6000 have already been enrolled. The baseline characteristics for selected parameters for the first 10 000 patients enrolled are shown
in Table I.
Discussion
Role of antiplatelet agents in AF
The benefits of antiplatelet agents (eg, ASA and
clopidogrel) have been firmly established in patients at
risk for vascular events.37 Addition of 2 antiplatelet
agents has been clearly established in stroke (ASA and
dipyridamole) and in acute coronary syndrome (clopidogrel plus ASA).22,38 Would there be a benefit of
combining antiplatelet agents in diseases where the
cause of thrombus formation is stasis in the deep leg
American Heart Journal
Volume 151, Number 6
veins or in left atrial appendage? The effectiveness of
antiplatelet therapy in preventing thromboembolic
events related to stasis has been suggested by the results
of randomized trials of ASA. The Antiplatelet Trialists
Meta-analysis37 reported that antiplatelet therapy
(mainly ASA) significantly reduced the odds of developing deep venous thrombosis by 39%. The odds of
developing a pulmonary embolism was also significantly
reduced by 64%. Recently, the PEP trial 39 enrolled
13 336 patients after hip fracture or hip replacement
surgery who were randomized to preoperative initiation
of ASA or placebo in addition to other antithrombotic
treatment already being taken. Aspirin reduced the risk
of deep venous thrombosis or pulmonary embolism by
36% ( P = .003).
The value of parallel noninferiority and
superiority trials
Given the problems associated with oral anticoagulation, establishing the noninferiority of an easy-to-use and
potentially safer treatment will provide a convincing
reason to adopt the newer therapy. However, noninferiority trial designs necessarily involve agreement on
a noninferiority margin that is somewhat arbitrary and
open to criticism. That there are many high-risk patients
with AF who do not receive oral anticoagulation
because of contraindications or unwillingness allows
one to ethically perform a parallel superiority trial of
clopidogrel plus ASA versus ASA in these patients.
Statistical interpretation of a superiority trial poses less
challenges, and the results of a superiority trial will
complement the noninferiority trial by providing independent, clear confirmation of the biologic activity of
clopidogrel in AF.
The choice of the primary outcome in AF trials
Trials of antithrombotic therapy in AF have tended to
focus on the outcome of stroke; however, only about
two thirds of strokes in AF trials are thought to be
embolic.5 Patients with AF also face a substantial burden
of serious vascular events other than stroke because the
risk factors for developing AF (hypertension, advanced
age, and heart failure) also increase the risk of MI
and death from vascular causes.6 To focus only on
stroke, to the exclusion of other serious vascular complications, is arbitrary because these different events are
pathophysiologically related, of comparable clinical
severity, and reasonably common in these patients.
Choice of ASA dose
Aspirin has been studied in randomized trials in AF at a
range of doses from b50 to N1200 mg/d. Although the
only trial of ASA in AF which independently reported a
statistically significant effect of ASA against placebo used
a dose of 325 mg/d, the EAFT 8 study, which had far more
events, observed a relatively small, nonsignificant relative
The ACTIVE Steering Committee 1191
Table II. Dose of ASA and risk of bleeding in CURE
ASA
dose
(mg/d)
Placebo
major
bleeding (%)
Clopidogrel
major
bleeding (%)
Relative
risk
95% CI
V100
101-200
N200
1.9
2.8
3.7
3.0
3.4
4.9
1.60
1.21
1.32
1.13-2.28
0.82-1.79
0.99-1.77
Data from Peters et al.40
risk reduction of 11% with a similar dose of ASA (300 mg).
Thus, there is no convincing relationship between dose of
ASA used in AF trials and observed benefit. In analysis of
the effects of ASA in a broader range of vascular
conditions, the Antiplatelet Trialists Collaboration Metaanalysis reported strong evidence that doses of ASA
between 75 and 1500 mg/d appear to be equally effective
against vascular events in a wide variety of patients at risk
for vascular events. Table II shows the absolute rates of
major bleeding related to doses of ASA in CURE.40 It is
clear that increasing the dose of ASA increases the risk of
major bleeding. Therefore, to maximize benefit and to
minimize risk of hemorrhage, we have chosen to
recommend a dose of 75 to 100 mg/d of ASA in
combination with 75 mg/d of clopidogrel.
Why do we need a trial of antihypertensive therapy
in AF?
Hypertension is the third leading risk factor associated
with death worldwide.41 Prospective, unconfounded
epidemiologic studies suggest that lower levels of BP are
associated with a lower risk of vascular events, even to
levels as low as systolic BP of 110 mm.42,43 There is also
some evidence that ARBs reduce the recurrence of AF.44
The prevalence of hypertension in patients with AF is
very high, especially in those considered candidates for
aggressive antithrombotic therapy, and treated BPs
observed are typically in the high bnormalQ range. It is
likely that even a modest BP reduction in this population
will have an important effect on vascular events. In
addition, renin-angiotensin antagonism and blockade of
cardiac, vascular, and renal AT1 receptors may have
additional vascular benefits, as suggested by HOPE,
LIFE,29,31 and other recent trials.
ACTIVE is sponsored by Sanofi-Aventis and by
Bristol-Myers Squibb.
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Appendix A
Steering committee
S Connolly and S Yusuf (Chairs and Principal Investigators), A Budaj, J Camm, S Chrolavicius (Project
Manager), PJ Commerford, M Flather, KAA Fox, R Hart,
S Hohnloser, C Joyner (Chair of the Events Adjudication
Committee), M Pfeffer, I Anand, H Arthur, A Avezum,
M Bethala-Sithya, M Blumenthal, L Ceremuzynski,
R De Caterina, R Diaz, G Flaker, G Frangin, M-G Franzosi,
C Gaudin, S Golitsyn, S Goldhaber, C Granger, D Halon,
A Hermosillo, D Hunt, P Jansky, N Karatzas, M Keltai,
F Lanas, CP Lau, J-Y Le Heuzey, BS Lewis, J Morais,
C Morillo, A Oto, E Paolasso, RJ Peters, M Pfisterer,
L Piegas, T Pipillis, C Proste, E Sitkei, K Swedberg,
D Synhorst, M Talajic, V Trégou, V Valentin, W van
Mieghem, W Weintraub, and J Varigos.