Editor’s Note: Based on Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720-9.

Introduction

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and is associated with a substantial risk of mortality and morbidity due to stroke and thromboembolism.¹ The left atrial appendage (LAA) has long been suspected to be the main site of thrombus formation in AF.² Systemic anticoagulant drug therapy is highly effective for reducing risk of stroke³ but it is difficult to sustain over time for many patients because of the frequent monitoring required and major bleeding complications.⁴ Therefore, non-pharmacological approaches are being developed to isolate the LAA from systemic circulation. The PROTECT AF trial (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation, NCT00129545) was designed to evaluate whether systemic anticoagulation with warfarin could be safely replaced by closure of the LAA with a Watchman device without sacrificing protection against stroke or systemic thromboembolism.^5,6 The device consists of a self-expanding nitinol frame with fixation barbs and a permeable, polyester fabric covering. It is positioned in LAA using a transseptal approach with fluoroscopic and TEE guidance.

Methods

The PROTECT AF trial was a prospective, unblinded, randomized trial conducted at 59 centers in the United States and Europe. The patients had paroxysmal, persistent, or permanent nonvalvular AF and at least one additional stroke risk factor (age ≥75 years, HTN, DM, CHF, or prior stroke, transient cerebral ischemic attack, or systemic thromboembolism) and were warfarin candidates. Patients with risk factors for thromboembolism unrelated to AF, such as mechanical prosthetic heart valve or symptomatic carotid artery disease (among other risks), were excluded from the trial. The mean age was 72 years, mean CHADS2 score was 2.2, and one in five had experienced prior stroke or transient ischemic attack. All patents were randomized in a 2:1 ratio either to undergo Watchman implantation or to continue warfarin treatment. Device position was assessed by TEE at 45 days, six months, and one year after deployment for stability, absence of flow leaks or thrombus formation. If LAA closure was satisfactory at 45 days after deployment, warfarin was stopped in intervention group, and clopidogrel (75 mg/d) plus aspirin (ASA, 81 to 325 mg/d) was substituted until 6 months after device implantation, after which clopidogrel was stopped, and aspirin alone was continued. The control group was monitored every 2 weeks for 6 months and monthly thereafter to maintain the INR between 2.0 and 3.0.

The trial was designed to determine whether the LAA closure strategy is noninferior to oral anticoagulation with respect to the composite primary efficacy end point of all stroke (ischemic or hemorrhagic), systemic embolism, or cardiovascular death (including unexplained death). The primary safety end point included both procedure-related and major bleeding events (intracranial bleeding or gastrointestinal bleeding requiring transfusion). Both the primary efficacy and safety analyses were based on intention-to-treat.

Results

The enrolled cohort consisted of 707 randomized patients; 463 and 244 patients were randomized to the LAA closure and control arms, respectively. Patients were followed up for an aggregate of 1588.4 patient-years with a mean follow-up interval of 2.3 years. Controls were in a therapeutic INR range 66% of time, which was comparable to controls in major AF anticoagulation trials such as the RE-LY⁷ and ROCKET-AF study.⁸ The Watchman device was successfully implanted in 88% of patients randomized to LAA closure. The majority of intervention patients had stopped warfarin after evaluations at 45 days, six months, and one year. In 6.8% of patients warfarin was continued beyond 12 months because of incomplete LAA closure or device thrombus (2.7%) or on the advice of the treating physician (4.1%). The composite primary efficacy event rate was 3.0% per year in the intervention group (2.15%–4.3% per year) and 4.3% per year (2.6%–5.9% per year) in the control group. Efficacy was consistent across a number of subgroups distinguished by sex, age, pattern of AF, LAA morphology and CHADS2 score>1.

The primary adverse outcome rate was higher in the LAA closure group than in the control group (5.5% versus. 3.6% per year) due to peri-procedural complications.

Secondary analysis after exclusion of events on the day of device deployment showed fewer primary efficacy events in Watchman group than in the control group (2.5% versus 4.3% per year). The same was true when analysis was confined to patients who were on ASA and clopidogrel after successful device deployment (2.3% versus 4.1% per year) and to those who were taking only ASA (2.3% per year compared versus 4.1% per year in the control group). These results suggest that after successful deployment, the WATCHMAN device was more effective than continued warfarin anticoagulation. Additionally, in 131 patients (19%) with a history of previous stroke or transient ischemic attack LAA closure device proved to be superior to warfarin in reducing risk of recurrent stroke (5.3% versus 8.2% events per year).

Conclusions

Investigators concluded that LAA closure was noninferior to systemic anticoagulation with warfarin. After exclusion of acute, procedure-related events, the LAA closure device was more effective at preventing stroke and thromboembolism than continued anticoagulation with warfarin.

Perspective

AF-related thromboembolic stroke accounts for 10% of all ischemic strokes and 50% of all cardioembolic strokes⁹ and tends to cause greater morbidity than strokes from other causes.¹⁰ Oral anticoagulation with warfarin is very effective in reducing AF-related strokes as compared to ASA or placebo.¹¹ However, patients maintain therapeutic INR only about 50% of the time and 22-33% of patients newly started on warfarin for AF discontinue therapy within the first year of treatment.⁴ This suboptimal adherence to warfarin therapy is partly related to the difficulty of long-term INR monitoring and its potential for causing significant bleeding complications.⁴ Newer antithrombotic agents such as Dabigatran, Rivaroxaban, and Apixaban appear to beat least as effective as warfarin, do not require monitoring or dietary adjustments, but also have a significant incidence of serious bleeding complications.^7,8,12

It has long been suspected that the LAA may be the major source for emboli in nonvalvular AF. An analysis of 23 studies utilizing echocardiographic, operative, and postmortem evaluations of the left atrium and LAA in patients with AF supports this contention.² LAA ligation is often performed as an adjunct procedure in AF patients undergoing CABG, Cox-Maze or valve surgery.¹³ Percutaneous LAA closure devices appeared as an alternative to surgical ligation in early 2000s and since then a large number of percutaneous devices and techniques have been tested.¹³ To date, the WATCHMAN device is the most studied LAA closure device and has received a class IIb recommendation in the 2012 guidelines of the European Society of Cardiology for use in AF patients with a contraindication to systemic anticoagulation.

PROTECT AF is the first prospective randomized control trial that directly compared LAA occlusion device head-to-head with warfarin therapy.^5,6 The efficacy of LAA closure was found to be noninferior to long-term warfarin, with lower rates of cerebral hemorrhage but similar overall stroke rates. When early post implant strokes were excluded from analysis, the WATCHMAN device appeared to be superior to warfarin.

This trial raises several questions. The rate of hemorrhagic stroke in the warfarin group (1.2 per 100 patient-years) was significantly higher than that reported in previous trials (0.5 per 100 patient-years in a meta-analysis of six randomized clinical trials 11 and this could have influenced the noninferiority results for primary efficacy. The upfront safety of the device represented a challenge with a periprocedural complication rate of approximately 8.9 %, pericardial effusion rate requiring drainage of 4.9% and failed implant rate of 9.1 %.^5,14

The findings on implant safety in PROTECT AF demanded improvements in design and implant safety. The safety and efficacy of the WATCHMAN device was further addressed by examining the performance of the device after some design modifications in the PREVAIL study which enrolled 407 patients randomized 2:1 to the device or warfarin.¹⁵ Safety data demonstrated an increase in implant success rate compared to PROTECT AF (95% versus 90.9%). Importantly, in the PREVAIL trial the pericardial effusions requiring intervention occurred at a rate of 1.5 % versus 4.9 % of those in PROTECT AF.¹⁶

Based on available data on safety and efficacy, the WATCHMAN device is unlikely to become a substitute for warfarin in AF patients who can safely tolerate oral anticoagulation. Clearly "local" therapy with LAA closure device will not protect against other sources of thromboembolism such as mobile aortic atheroma, LA and LV thrombi, and the cerebral vasculature. In addition, AF patients exhibit a systemic prothrombotic state that increases the chance of thromboembolism from sources other than the LAA.¹⁷ However, the WATCHMAN device may be an alternative to warfarin in patients at high risk of hemorrhage, those who have experienced thromboembolism despite oral anticoagulation, and patients with poor compliance.

References

1. Lip GY. Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. J Thromb Haemost 2011;9:344-51.
2. Contractor T, Khasnis A. Left Atrial Appendage Closure in Atrial Fibrillation: A World without Anticoagulation? Cardiol Res Pract 2011; 752808.
3. Wolf PA, Singer DE. Preventing stroke in atrial fibrillation. Am Fam Physician 1997;56:2242-2250.
4. Kneeland P, Fang M. Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism. Patient Prefer Adherence 2010;4:51-60.
5. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42.
6. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720-9.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
9. Hart RG, Pearce LA, Rothbart RM, McAnulty et al. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. JACC 2000; 35:183-187.
10. Anderson DC, Kappelle LJ, Eliasziw M, e al. Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002; 33:1963–1967.
11. Van Walraven C, Hart R. G., Singer D. E. et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. Journal of the American Medical Association 2002; 288:2441–2448.
12. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
13. Chatterjee S, Alexander JC, Pearson PJ, et al. Left Atrial Appendage Occlusion: Lessons Learned From Surgical and Transcatheter Experiences. Ann Thorac Surg 2011;92:2283-2292.
14. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123:417-24.
15. http://clinicaltrials.gov/show/NCT01182441
16. http://www.medscape.com/viewarticle/780535
17. Whitlock RP, Healey JS, Connolly SJ. Left atrial appendage occlusion does not eliminate the need for warfarin. Circulation 2009;120:1927-32.

Keywords: Aspirin, Atrial Fibrillation, Cerebral Hemorrhage, Europe, Pericardial Effusion, Stroke, Thromboembolism, United States, Warfarin

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