Elsevier

The Lancet

Volume 374, Issue 9689, 15–21 August 2009, Pages 534-542
The Lancet

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Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial

https://doi.org/10.1016/S0140-6736(09)61343-XGet rights and content

Summary

Background

In patients with non-valvular atrial fibrillation, embolic stroke is thought to be associated with left atrial appendage (LAA) thrombi. We assessed the efficacy and safety of percutaneous closure of the LAA for prevention of stroke compared with warfarin treatment in patients with atrial fibrillation.

Methods

Adult patients with non-valvular atrial fibrillation were eligible for inclusion in this multicentre, randomised non-inferiority trial if they had at least one of the following: previous stroke or transient ischaemic attack, congestive heart failure, diabetes, hypertension, or were 75 years or older. 707 eligible patients were randomly assigned in a 2:1 ratio by computer-generated randomisation sequence to percutaneous closure of the LAA and subsequent discontinuation of warfarin (intervention; n=463) or to warfarin treatment with a target international normalised ratio between 2·0 and 3·0 (control; n=244). Efficacy was assessed by a primary composite endpoint of stroke, cardiovascular death, and systemic embolism. We selected a one-sided probability criterion of non-inferiority for the intervention of at least 97·5%, by use of a two-fold non-inferiority margin. Serious adverse events that constituted the primary endpoint for safety included major bleeding, pericardial effusion, and device embolisation. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00129545.

Findings

At 1065 patient-years of follow-up, the primary efficacy event rate was 3·0 per 100 patient-years (95% credible interval [CrI] 1·9–4·5) in the intervention group and 4·9 per 100 patient-years (2·8–7·1) in the control group (rate ratio [RR] 0·62, 95% CrI 0·35–1·25). The probability of non-inferiority of the intervention was more than 99·9%. Primary safety events were more frequent in the intervention group than in the control group (7·4 per 100 patient-years, 95% CrI 5·5–9·7, vs 4·4 per 100 patient-years, 95% CrI 2·5–6·7; RR 1·69, 1·01–3·19).

Interpretation

The efficacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fibrillation.

Funding

Atritech.

Introduction

Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting an estimated 6 million individuals in the USA.1 Since atrial fibrillation mainly affects elderly people, its prevalence is expected to increase in parallel with the increasing age of the population, with a predicted 15·9 million cases by 2050.1, 2, 3, 4, 5 The lifetime risk for development of atrial fibrillation is one in four in men and women 40 years of age and older.6 Stroke, the most serious complication of atrial fibrillation, occurs in 5% of non-anticoagulated patients every year. The risk of stroke increases substantially with age, from 1·5% in individuals aged 50–59 years to 23·5% for those aged 80–89 years.6, 7, 8, 9 Stroke is the third most frequent cause of death in the USA and the leading cause of serious disability. Therefore, stroke prophylaxis is a crucial component of management of atrial fibrillation.

Although membrane-active antiarrhythmic drugs10, 11, 12, 13 and catheter ablation provide symptomatic relief for patients with atrial fibrillation, neither method is sufficiently reliable in preventing thromboembolic events, and long-term oral anticoagulation therapy is recommended irrespective of the rhythm management strategy. Randomised controlled trials have shown that warfarin is effective in preventing stroke, more so than aspirin and combination aspirin-clopidogrel.14, 15, 16, 17, 18, 19, 20, 21 Despite its proven efficacy, warfarin is often not well tolerated by patients, has a very narrow therapeutic range, and has a high risk for bleeding complications.22 Furthermore, the effectiveness of anticoagulation varies because of interactions with some foods and other medications; even with frequent monitoring and dose adjustments, patients' test results are outside of the therapeutic range in up to half of all blood drawings.23 Partly for these reasons, only around 50% of patients who are eligible for long-term warfarin are treated with it.24

Pharmacological alternatives to warfarin have been investigated,25, 26, 27, 28 and several new anticoagulants seem promising;29 even if they prove to be safe, however, they will not address many of the problems related to bleeding or compliance or the need for lifelong treatment. On the basis of echocardiography and autopsy studies showing that the left atrial appendage (LAA) was the source of thrombi in more than 90% of patients with non-valvular atrial fibrillation,30, 31, 32 percutaneous catheter-based devices have been developed to close and thereby effectively exclude the LAA from the systemic circulation. Pilot studies have shown acceptable risk-to-benefit ratios for these non-pharmacological alternatives to chronic warfarin therapy.33, 34, 35, 36, 37, 38

The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) study36 examined the efficacy and safety of percutaneous closure of the LAA in patients with non-valvular atrial fibrillation. The study was designed to assess the non-inferiority of the device against chronic warfarin therapy.

Section snippets

Patients

This prospective, randomised controlled trial was undertaken at 59 sites in the USA and Europe. Enrolment began in February, 2005, and ended in June, 2008. Patients aged 18 years or older with paroxysmal, persistent, or permanent non-valvular atrial fibrillation were eligible for enrolment if they had a CHADS2 risk score of 1 or more (ie, at least one of the following: previous stroke or transient ischaemic attack, congestive heart failure, diabetes mellitus, hypertension, or were 75 years or

Results

Figure 1 shows the trial profile. Patients were followed for an aggregate of 1065 patient-years. Mean follow-up per patient was 18 months (SD 10). Table 1 shows the baseline characteristics and risk factors of the study participants.

The device was successfully implanted in 88% (408/463) of patients assigned to this intervention and in 91% (408/449) of those in whom implantation was attempted (figure 1). At the 45-day follow-up, 349 (86%) of 408 patients with an implanted device met TEE criteria

Discussion

In view of the prevalence of atrial fibrillation and the difficulties associated with chronic treatment with warfarin—such as complications related to bleeding and the need for continuous monitoring of INR—new approaches for stroke prevention in cases of atrial fibrillation have been pursued. The strategy of LAA obliteration evolved from the finding that in patients with non-valvular atrial fibrillation, the LAA is the most common site of thrombi.30, 31, 32, 45 This randomised controlled trial

References (50)

  • PB Sick et al.

    Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation

    J Am Coll Cardiol

    (2007)
  • Y Miyasaka et al.

    Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980–2000, and implications on the projections for future prevalence

    Circulation

    (2006)
  • EJ Benjamin et al.

    Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study

    JAMA

    (1994)
  • BM Psaty et al.

    Incidence of and risk factors for atrial fibrillation in older adults

    Circulation

    (1997)
  • S Stewart et al.

    Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study

    Heart

    (2001)
  • DM Lloyd-Jones et al.

    Lifetime risk for development of atrial fibrillation: the Framingham Heart Study

    Circulation

    (2004)
  • PA Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

    Stroke

    (1991)
  • HJ Lin et al.

    Stroke severity in atrial fibrillation. The Framingham Study

    Stroke

    (1996)
  • DG Sherman et al.

    Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study

    Arch Intern Med

    (2005)
  • DG Wyse et al.

    A comparison of rate control and rhythm control in patients with atrial fibrillation

    N Engl J Med

    (2002)
  • IC Van Gelder et al.

    A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation

    N Engl J Med

    (2002)
  • DG Sherman

    Stroke prevention in atrial fibrillation pharmacologic rate versus rhythm control

    Stroke

    (2007)
  • Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia

    N Engl J Med

    (1995)
  • The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation

    N Engl J Med

    (1990)
  • Stroke Prevention in Atrial Fibrillation study. Final results

    Circulation

    (1991)
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