Percutaneous Left Atrial Appendage Closure vs. Warfarin for Atrial Fibrillation
Editor's Note: Commentary based on Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988-98.
The risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF) is 3-5% per year, which is five-fold higher than in patients without AF.1-5 Oral anticoagulation (OAC) is the standard treatment to prevent stroke and systemic embolism in patients with AF with a CHA2DS2-VASc stroke risk score ≥2.5 Since the left atrial appendage (LAA) has been identified as the site where more than 90% of thrombi were detected in patients with NVAF in transesophageal studies,6 several procedures to isolate the LAA have been developed. However, the safety and efficacy of these novel approaches have yet to be demonstrated in large randomized studies.
WATCHMAN Left Atrial Appendage Closure (LAAC) Device for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF) was a multicenter, randomized, unblinded, Bayesian-designed clinical trial conducted at 59 hospitals of 707 patients with NVAF and at least ONE additional stroke risk factor (CHADS2 score ≥1).7 Patients were randomized (2:1) to either WATCHMAN device implantation or warfarin therapy in an unblinded fashion.9 After the device implantation, concomitant antithrombotic medication was given to facilitate device endothelialization: warfarin and aspirin (81-325 mg) for 45 days, followed by aspirin and clopidogrel until month six, after which aspirin alone was used. Transesophageal echocardiography (TEE) was performed at 45 days, six months, and 12 months; if the device did not have adequate seal or if thrombi were present, then warfarin was continued. Non-inferiority required a posterior probability greater than 97.5%, and superiority required a probability of 95% or greater; the non-inferiority margin was a rate ratio of 2.0 comparing event rates between treatment groups.7
Primary study results have been previously published,8 but this manuscript reported the long-term results. At a mean follow-up of 3.8 years, there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient-years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient-years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41-1.05), meeting pre-specified criteria for both non-inferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%).7
Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient-years for the device group vs. 2.4 events per 100 patient-years with warfarin; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.21-0.75; P = 0.005) and all-cause mortality (3.2 events per 100 patient-years for the device group vs. 4.8 events per 100 patient-years with warfarin; HR, 0.66; 95% CI, 0.45-0.98; P = 0.04).7
After 3.8 years of follow-up in patients with NVAF at elevated risk for stroke, percutaneous LAA closure met criteria for both non-inferiority and superiority, compared with warfarin therapy, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular mortality and all-cause mortality.7
In patients with NVAF, embolic stroke is most frequently associated with LAA thrombi.10 Since the current standard of care is lifelong OAC for the majority of patients, other strategies that do not require daily therapy and chronic risk of bleeding have been sought.
The Stroke Prevention in Atrial Fibrillation (SPAF)-I, SPAF-II, and SPAF-III trials, and Copenhagan AFASAK, Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF), Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial, and Canadian Atrial Fibrillation Anticoagulation (CAFA) trial compared warfarin, placebo, or aspirin and demonstrated that anticoagulation with adjusted-dose warfarin significantly reduces clinical stroke risk when compared to placebo.11-16 Overall, adjusted-dose warfarin reduces the risk of stroke by two-thirds compared to no antithrombotic therapy, with the expected degree of absolute benefit dependent on baseline risk.17-19 In recent clinical trials, newer OACs have been found to be non-inferior when compared to warfarin in preventing stroke and systemic thromboembolism with significantly lower rates of major bleeding and death from cardiovascular causes.20-24
Among patients with NVAF and at least one CHADS2 risk factor for stroke, LAA closure reduced the endpoint of stroke, systemic embolism, and cardiovascular death by 40% (5.5% absolute reduction) compared with warfarin anticoagulation.7 In addition, both cardiovascular and overall mortality were lower in patients who received an LAA closure device.
Nonetheless, there are several details regarding the study protocol to consider when interpreting the trial results. First, the group randomized to LAA closure was required to undergo three TEEs (on day 45, month 6, and month 12) to assess the seal of the device and to evaluate for the presence of thrombi, which is not the current standard of care, and carries with it cost and a low risk of complications. Secondly, the LAA closure group received a three-tiered level of concomitant antithrombotic therapy that included warfarin for at least the 45 days, dual antiplatelet therapy, and then finally aspirin monotherapy, as guided by the TEE results. Patients and physicians were not blinded, and the use of aspirin and clopidogrel were at the discretion of the treating physician (guided by TEE results in the device group), which increases the risk of bias and makes it difficult to assess the contribution of these antiplatelet agents to ischemic and bleeding events.
Limitations of this study include the exclusion of patients with a patent foramen ovale with atrial septal aneursym, left ventricular ejection fraction <30%, mobile aortic atheromata, or symptomatic carotid disease, thus affecting the generalizability of the findings. In addition, 34% of the trial population had a CHADS2 score of 1. According to professional society guidelines at that time, those patients should have been treated with aspirin rather than oral anticoagulation therapy.25 Lastly, the study did not include patients who had contraindications to oral anticoagulation, refused to take warfarin, or who were treated with a non-vitamin K oral anticoagulant (NOAC). The introduction of NOACs that are at least as effective and safer than warfarin require further randomized trials to further evaluate the potential role of LAA closure devices in the modern era.26
- Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57.
- Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946-52.
- Sandercock P, Bamford J, Dennis M, et al. Atrial fibrillation and stroke: prevalence in different types of stroke and influence on early and long term prognosis. BMJ 1992;305:1460-5.
- Wolf PA, Benjamin EJ, Belanger AJ, et al. Secular trends in the prevalence of atrial fibrillation: the Framingham Study. Am Heart J 1996;131:790-5.
- Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82(8A):2N-9N.
- Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755-9.
- Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988-98.
- 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 randomized non-inferiority trial. Lancet 2009;374:534-42.
- Fountain RB, Holmes DR, Chandrasekaran K, et al. The PROTECT AF (WATCHMAN left atrial appendage system for embolic PROTECTion in patients with Atrial Fibrillation) Trial. Am Heart J 2006;151:956-61.
- Holmes DR, Reddy VY, Turi ZG, et al. PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial. Lancet 2009;374:534-42.
- The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990;323:1505-11.
- Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527-39.
- Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994;343:687-91.
- Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989;1:175-9.
- Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;327:1406-12.
- Conolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-55.
- Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
- McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003;139:1018-33.
- De Backer O, Arnous S, Ihlemann N, et al. Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update. Open Heart 2014;1:e000020.
- Giugliano RP, Ruff CT, Braunwald E, et al. Endoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
- Connolly SJ, Ezekowitz MD, Phil D, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
- Waksman R, Pendyala LK. Overview of the Food and Drug Administration Circulatory System Devices Panel Meetings on WATCHMAN Left Atrial Appendage Closure Therapy. Am J Cardiol 2015; 115:378-84.
- Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet 2014;383:955-62.
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