The Lancet June 10, 2006

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

ACTIVE Writing Group on behalf of the ACTIVE Investigators

Bottom Line

The ACTIVE W trial demonstrated that oral anticoagulation with a vitamin K antagonist is significantly superior to dual antiplatelet therapy with clopidogrel and aspirin for preventing vascular events in patients with atrial fibrillation, without significantly increasing the risk of major bleeding.

Key Findings

1. The trial was terminated early by the Data and Safety Monitoring Board due to clear superiority of oral anticoagulation therapy over dual antiplatelet therapy.

2. The primary composite endpoint (stroke, non-CNS systemic embolus, myocardial infarction, or vascular death) occurred in 3.93% per year of patients on oral anticoagulation compared to 5.60% per year on clopidogrel plus aspirin (RR 1.44, 95% CI 1.18-1.76; p=0.0003).

3. Oral anticoagulation significantly reduced the rate of stroke (1.4% vs. 2.4% per year; p=0.001) and non-CNS systemic embolism (0.10% vs. 0.43% per year; p=0.005).

4. There were no significant differences between the oral anticoagulation and clopidogrel plus aspirin groups regarding myocardial infarction (0.55% vs. 0.86% per year; p=0.09) or vascular death (2.52% vs. 2.87% per year; p=0.34).

5. Major bleeding rates were similar between the two treatment arms (2.2% per year for oral anticoagulation vs. 2.4% per year for clopidogrel plus aspirin; p=0.53), establishing that dual antiplatelet therapy offers no safety advantage.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

6,706

Patients

Duration

1.28 yr

Median

Setting

Multicenter, global

Population Patients with documented atrial fibrillation and at least one additional risk factor for stroke (e.g., age >= 75 years, systemic hypertension, prior stroke/TIA, left ventricular ejection fraction < 45%, peripheral arterial disease, or age 55-74 years with coronary artery disease or diabetes).

Intervention Clopidogrel 75 mg/day plus aspirin 75-100 mg/day.

Comparator Oral anticoagulation with a vitamin K antagonist, dynamically adjusted to maintain a target international normalized ratio (INR) of 2.0 to 3.0.

Outcome The first occurrence of a composite of stroke, non-central nervous system systemic embolus, myocardial infarction, or vascular death.

Study Limitations

• The trial utilized an open-label design, which inherently risks bias, although clinical outcome events were rigorously adjudicated by a blinded committee (PROBE design).

• Early termination of the trial (median follow-up of 1.28 years) may have statistically exaggerated the magnitude of the observed treatment effect.

• Patients randomized to oral anticoagulation achieved a time in therapeutic range (TTR) of 64%; while typical for large global trials of that era, this is clinically suboptimal and may have understated the true benefit of stringently managed warfarin.

• The superiority of oral anticoagulation was largely driven by the cohort of patients already established on this therapy prior to randomization, creating some uncertainty regarding the immediate net clinical benefit for anticoagulation-naïve patients.

Clinical Significance

ACTIVE W definitively established that oral anticoagulation (vitamin K antagonists) is vastly superior to the combination of clopidogrel and aspirin for stroke prevention in patients with atrial fibrillation. Importantly, it revealed that dual antiplatelet therapy provides inferior antithrombotic efficacy while carrying a similar risk of major bleeding, explicitly warning clinicians against substituting warfarin with dual antiplatelet agents out of perceived safety concerns.

Historical Context

Prior to the ACTIVE W trial, aspirin monotherapy was known to provide modest stroke protection in atrial fibrillation, but many patients and physicians remained averse to warfarin due to the required INR monitoring, bleeding risks, and drug-food interactions. Because dual antiplatelet therapy (clopidogrel plus aspirin) had proven superior to aspirin alone in acute coronary syndromes, researchers hypothesized it could rival oral anticoagulation in AF. ACTIVE W unequivocally dispelled this hope, cementing vitamin K antagonists as the incontrovertible standard of care for stroke prevention in high-risk AF until the advent of direct oral anticoagulants (DOACs).

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the pathophysiology of thrombus formation in atrial fibrillation differ from that in acute coronary syndromes, and how does this explain why oral anticoagulants outperformed dual antiplatelet therapy in the ACTIVE W trial?

Key Response

Thrombi in atrial fibrillation are primarily 'red clots' formed by blood stasis in the left atrial appendage, which are rich in fibrin and red blood cells, making them highly responsive to anticoagulants (like vitamin K antagonists). In contrast, acute coronary syndromes involve 'white clots' triggered by endothelial injury and plaque rupture, which are platelet-rich and respond best to antiplatelets (like clopidogrel and aspirin).

Resident

Given the ACTIVE W findings that DAPT is inferior to OAC for AF stroke prevention without offering a lower risk of major bleeding, how do you approach the management of an AF patient who requires OAC for stroke prevention but recently underwent PCI with stenting?

Key Response

This addresses the clinical challenge of needing both therapies. ACTIVE W showed DAPT fails for AF stroke prevention, but OAC alone is inadequate for early stent thrombosis prevention. Residents must recognize that this necessitates a careful regimen of 'triple therapy' (OAC + DAPT) transitioning early to 'dual pathway therapy' (DOAC + single antiplatelet) to balance stroke/stent thrombosis prevention against compounded bleeding risks.

Fellow

The ACTIVE W trial was stopped early due to clear superiority of OAC. However, how does the quality of anticoagulation, measured by Time in Therapeutic Range (TTR), affect the relative efficacy and safety of OAC versus clopidogrel plus aspirin in real-world application?

Key Response

Fellows must understand the nuance of VKA therapy. The superiority of warfarin over DAPT is highly dependent on a good TTR (typically >65%). In subgroup analyses and real-world data, poor INR control can negate the stroke prevention benefits of OAC and significantly increase bleeding, making the risk-benefit ratio of DAPT versus poorly managed VKA much more complex.

Attending

The ACTIVE W trial highlighted that DAPT in AF provides inferior efficacy to OAC while carrying a similar major bleeding risk. From a teaching perspective, how did this 'bleeding risk fallacy' of DAPT pave the way for the rapid adoption of DOACs?

Key Response

Attendings should contextualize practice shifts. Historically, practitioners used DAPT or aspirin to 'avoid bleeding' in frail AF patients. ACTIVE W proved this was a fallacy: DAPT caused nearly as much major bleeding as warfarin but failed to prevent strokes. This created a massive unmet clinical need for an agent safer than warfarin but more effective than DAPT, setting the perfect stage for the landmark DOAC trials.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ACTIVE W trial was terminated prematurely by the Data Safety Monitoring Board (DSMB) due to the clear superiority of the OAC arm. What are the statistical and epidemiological risks of stopping a trial early for benefit, and how might this impact the estimation of the true effect size?

Key Response

Early termination of a trial often truncates data collection at a 'random high' of treatment effect, statistically exaggerating the benefit (the 'winner\'s curse'). PhD researchers should critically evaluate stopping rules (e.g., O'Brien-Fleming boundaries) and recognize that premature cessation can lead to overestimation of OAC efficacy and under-powering of long-term safety/adverse event profiles for the DAPT arm.

Journal Editor

ACTIVE W utilized a PROBE (Prospective Randomized Open, Blinded End-point) design. As an editor evaluating the manuscript, what specific biases are introduced by the open-label administration regarding safety outcomes, and how would you evaluate the robustness of the blinded endpoint adjudication?

Key Response

A seasoned reviewer would flag that while strokes and mortality are objective, reporting of transient ischemic attacks or bleeding events in an open-label trial is heavily susceptible to investigator and patient bias. Knowing the patient is on warfarin might lower the threshold to report a bleed. The editor must scrutinize whether the blinded adjudication committee had access to truly objective source documents unredacted for treatment allocation.

Guideline Committee

Based on the ACTIVE W results demonstrating OAC superiority and similar major bleeding rates to DAPT, how did this specific trial shape the ACC/AHA/ESC guideline recommendations regarding antiplatelet therapy for stroke prevention in atrial fibrillation?

Key Response

ACTIVE W provided the definitive evidence to downgrade and eventually remove DAPT as a viable alternative for stroke prevention in AF. Current ACC/AHA and ESC guidelines give a Class III (Harm) recommendation against using antiplatelet therapy (aspirin or DAPT) solely for stroke prevention in AF, emphasizing that patients unsuited for VKA should be evaluated for DOACs or left atrial appendage occlusion rather than relying on antiplatelets.

Clinical Landscape

Noteworthy Related Trials

2009

ACTIVE A Trial

n = 7,554 · NEJM

Tested

Clopidogrel plus Aspirin

Population

AF patients with increased stroke risk unsuitable for VKA therapy

Comparator

Aspirin plus Placebo

Endpoint

Composite of stroke, MI, non-CNS systemic embolism, or vascular death

Key result: Adding clopidogrel to aspirin reduced the risk of major vascular events, primarily stroke, but significantly increased the risk of major bleeding.

2009

RE-LY Trial

n = 18,113 · NEJM

Tested

Dabigatran 110mg or 150mg twice daily

Population

AF patients with increased risk of stroke

Comparator

Warfarin (target INR 2.0-3.0)

Endpoint

Stroke or systemic embolism

Key result: Dabigatran 150mg was superior to warfarin for stroke prevention with similar bleeding, while 110mg was non-inferior for stroke with lower bleeding risk.

2011

AVERROES Trial

n = 5,599 · NEJM

Tested

Apixaban 5mg twice daily

Population

AF patients at risk for stroke who were unsuitable for VKA therapy

Comparator

Aspirin 81-324mg daily

Endpoint

Stroke or systemic embolism

Key result: Apixaban significantly reduced the risk of stroke or systemic embolism compared to aspirin without significantly increasing the risk of major bleeding.

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