ACTIVE W

Published

Connolly SJ, et al. "Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.". The Lancet. 2006. 367(9526):1903-12.
PubMed • Full text • PDF

Clinical Question

Among patients with nonvalvular AF, how does combination aspirin/clopidogrel compare to warfarin in reducing the incidence of stroke, systemic embolism, MI, or CV death?

Bottom Line

Among patients with nonvalvular AF, combination aspirin/clopidogrel is inferior to warfarin for the prevention of stroke, systemic embolism, MI, and CV death, and appears to cause at least as much bleeding.

Major Points

The 2006 Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) randomized 6,706 patients with nonvalvular AF and one or more additional risk factors for stroke to open treatment with either aspirin/clopidogrel or warfarin. At a mean follow-up of 1.3 years, combination aspirin/clopidogrel was inferior to anticoagulation at reducing the composite incidence of stroke, non-CNS systemic embolus, MI, or CV death (annual risk 5.6% vs. 3.9%) and was associated with increased bleeding (15.4% vs. 13.2%). A post hoc subgroup analysis suggested that anticoagulation conferred no benefit over antiplatelet therapy among patients receiving low-quality anticoagulation (ie, those time in therapeutic range <58%).

The ideal choice of agent for stroke prevention in AF has been debated, with warfarin remaining the mainstay of therapy for decades. Warfarin's superiority to aspirin for stroke prevention in AF was first demonstrated in SPAF (1991). Since warfarin requires frequent monitoring and a therapeutic range is achieved only 60% of the time, the floodgates have opened with investigators seeking drugs with reliable pharmacokinetics that obviate the need for monitoring. Several trials have investigated alternative agents in AF, including RE-LY (dabigatran, 2009) and ROCKET AF (rivaroxaban, 2011), but ACTIVE W was among the first. ACTIVE W was unique among these trials in that it studied two antiplatelet agents rather than bonafide anticoagulants. What is clear from ACTIVE W is that anticoagulation should remain the standard of care for patients with AF and at least one other stroke risk factor.

How aspirin/clopidogrel compares to aspirin alone was answered in the related ACTIVE A trial (2009). ACTIVE A demonstrated moderate efficacy of aspirin/clopidogrel compared to aspirin in AF patients who were deemed poor candidates for anticoagulation. However, this increased efficacy was offset by increased bleeding, and there was no net benefit to dual antiplatelet therapy over single-agent aspirin. Based on ACTIVE A and ACTIVE W, the AHA/ASA guidelines recommend oral anticoagulation as first-line therapy. They reserve aspirin/clopidogrel as a reasonable alternative in patients with a high risk of bleeding, although the increased bleeding associated with aspirin/clopidogrel makes this a controversial recommendation. Of note, the AVERROES trial (2011) demonstrated improvement in stroke reduction with apixaban over aspirin in patients with AF who were poor or unwilling VKA candidates without an increased rate of bleeding.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)

• In patients with nonvalvular AF with prior stroke, TIA, or CHA₂DS₂-VASc score ≥2, recommend oral anticoagulation with:
  • Warfarin, goal INR 2-3 (class I, level A)
  • Dabigatran (class I, level B)
  • Rivaroxaban (class I, level B)
  • Apixaban (class I, level B)
• In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
• In patients with nonvalvular AF with moderate or severe CKD with CHA₂DS₂-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
• In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
• In patients with a mechanical heart valve, do not use dabigatran (class III, level B)

Design

• Randomized, open treatment, controlled trial
• N=6,706
  • Aspirin/clopidogrel (n=3,371)
  • Warfarin (n=3,335)
• Setting: Multiple centers in >30 countries
• Enrollment: 2003-2005
• Mean follow-up: 1.3 years
• Analysis: Intention-to-treat
• Primary outcome: First occurrence of stroke, non-CNS systemic embolus, MI, or CV death

Population

Inclusion Criteria

• Atrial fibrillation
• At least one additional stroke risk factor:
  • Age ≥75 years
  • Age 55-74 years with either T2DM or prior CAD
  • Receiving HTN treatment
  • Prior stroke, TIA, or non-CNS systemic embolic event
  • LVEF <45%
  • PAD

Exclusion Criteria

• Contraindication to clopidogrel or oral anticoagulation
• Documented PUD in prior 6 months
• Prior ICH
• Plt <50k
• Mitral stenosis

Baseline Characteristics

• Demographics: Age 70.2 years, male 67%
• Baseline health data: BP 133/79 mmHg, HR 74 BPM,
• CHADS² score 2
• AF Type: Permanent 69%, persistent 13%, paroxysmal 18%
• AF duration
  • <6 months 21%
  • 6-24 months 19%
  • >24 months 60%
• PMH: HTN 83%, stroke/TIA 15%, MI 15%, CABG 9%, angiographic CAD 10%, DM 21%, PAD 4%, HF 30%, Pacemaker 14%
• Baseline EKG: AF 81%, AFL 1%, sinus 13%, LVH 13%
• Baseline medications
  • Oral anticoagulation 76%
  • Aspirin 30%
  • Clopidogrel 3%
  • ARB 15%
  • ACE 53%
  • Beta-blocker 58%
  • Digoxin 37%
  • Antiarrhythmic 19%
  • Statin 38%

Interventions

• Randomized to
  • Combination aspirin 75-100mg daily plus clopidogrel 75mg daily, or
  • Warfarin (or the VKA used in the patient's country), targeting INR 2-3
• Outcomes were adjudicated by blinded committee, strokes adjudicated by neurologists

Outcomes

Comparisons are aspirin/clopidogrel vs. oral anticoagulation.

Primary Outcome

Stroke, non-CNS systemic embolus, MI, or CV death

5.60% vs. 3.90% (RR 1.44; 95% CI 1.18-1.76; P=0.0003)

Stroke: 2.39% vs. 1.40% (RR 1.72; 95% CI 1.24-2.37; P=0.001)

Non-CNS systemic embolism: 0.43% vs. 0.10% (RR 4.66; 95% CI 1.58-13.8; P=0.005)

MI: 0.86% vs. 0.55% (RR 1.58; 95% CI 0.94-2.67; P=0.09)

CV death: 2.87% vs. 2.52% (RR 1.14; 95% CI 0.88-1.48; P=0.34)

Secondary Outcomes

Primary outcome event, major hemorrhage, death

8.32% vs. 6.45% (RR 1.31; 95% CI 1.12-1.54; P=0.0008)

Adverse Events

Major hemorrhage

2.42% vs. 2.21% (RR 1.10; 95% CI 0.83-1.45; P=0.53)

Criticisms

• A large fraction of patients had previously received oral anticoagulation compared to the small number who previously received aspirin/clopidogrel, which may cause selection bias in favor of oral anticoagulation (this may have selected for patients with high medication compliance, etc.)

Funding

Sponsored by Sanofi-Aventis and Bristol-Myers Squibb.