Left atrial appendage occlusion should be offered only to select atrial fibrillation patients.

Abstract

Key Findings▪Percutaneous left atrial appendage (LAA) occlusion has emerged as an alternative strategy to oral anticoagulants in selected patients with atrial fibrillation.▪The landmark trials comparing LAA occlusion to an oral anticoagulation strategy enrolled patients with no apparent contraindications to the use of warfarin.▪LAA occlusion has limited head-to-head comparison against the direct-acting oral anticoagulants.▪Observational data to date have generally shown specific adverse events after LAA occlusion in specific subgroups of patients (women, patients with kidney disease and heart failure, patients belonging to racial/ethnic subgroups and with advanced age), but further large-scale studies are necessary to elucidate reasons for increased adverse events associated with LAA occlusion in these subgroups of patients before recommending this modality as first-line therapy in all patient groups. ▪Percutaneous left atrial appendage (LAA) occlusion has emerged as an alternative strategy to oral anticoagulants in selected patients with atrial fibrillation.▪The landmark trials comparing LAA occlusion to an oral anticoagulation strategy enrolled patients with no apparent contraindications to the use of warfarin.▪LAA occlusion has limited head-to-head comparison against the direct-acting oral anticoagulants.▪Observational data to date have generally shown specific adverse events after LAA occlusion in specific subgroups of patients (women, patients with kidney disease and heart failure, patients belonging to racial/ethnic subgroups and with advanced age), but further large-scale studies are necessary to elucidate reasons for increased adverse events associated with LAA occlusion in these subgroups of patients before recommending this modality as first-line therapy in all patient groups. Atrial fibrillation (AF) is the most prevalent arrhythmia encountered in clinical practice and is associated with significant morbidity and mortality.1Lloyd-Jones D.M. Wang T.J. Leip E.P. et al.Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Circulation. 2004; 110: 1042-1046Crossref PubMed Scopus (1564) Google Scholar,2Virani S.S. Alonso A. Benjamin E.J. et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2020 update: a report from the American Heart Association.Circulation. 2020; 141: e139-e596Crossref PubMed Scopus (3175) Google Scholar One of the most severe complications of AF is stroke, and AF associated strokes tend to be more disabling when compared to non-AF-related strokes.3Saposnik G. Gladstone D. Raptis R. Hart R.G. Atrial fibrillation in ischemic stroke: predicting response to thrombolysis and clinical outcomes.Stroke. 2013; 44: 99-104Crossref PubMed Scopus (97) Google Scholar,4Seet R.C. Zhang Y. Wijdicks E.F. Rabinstein A.A. Relationship between chronic atrial fibrillation and worse outcomes in stroke patients after intravenous thrombolysis.Arch Neurol. 2011; 68: 1454-1458Crossref PubMed Scopus (62) Google Scholar Oral anticoagulants (OACs) are currently the standard of care for mitigation of ischemic stroke risk in AF patients.5Connolly S.J. Ezekowitz M.D. Yusuf S. et al.RE-LY Steering Committee and Investigators Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8577) Google Scholar, 6Patel M.R. Mahaffey K.W. Garg J. et al.ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6878) Google Scholar, 7Granger C.B. Alexander J.H. McMurray J.J. et al.ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6379) Google Scholar, 8Giugliano R.P. Ruff C.T. Braunwald E. et al.ENGAGE AF-TIMI 48 InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3347) Google Scholar However, nearly half of eligible AF patients do not receive OACs, owing to a multitude of factors.9Al-Khatib S.M. Pokorney S.D. Al-Khalidi H.R. et al.Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: a population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).Am Heart J. 2020; 229: 110-117PubMed Google Scholar, 10Ogilvie I.M. Newton N. Welner S.A. Cowell W. Lip G.Y. Underuse of oral anticoagulants in atrial fibrillation: a systematic review.Am J Med. 2010; 123: 638-645Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar, 11Piccini J.P. Hernandez A.F. Zhao X. et al.Get With The Guidelines Steering Committee and Hospitals. Quality of care for atrial fibrillation among patients hospitalized for heart failure.J Am Coll Cardiol. 2009; 54: 1280-1289Crossref PubMed Scopus (112) Google Scholar, 12Suarez J. Piccini J.P. Liang L. et al.International variation in use of oral anticoagulation among heart failure patients with atrial fibrillation.Am Heart J. 2012; 163: 804-811Crossref PubMed Scopus (24) Google Scholar, 13Lubitz S.A. Khurshid S. Weng L.C. et al.Predictors of oral anticoagulant non-prescription in patients with atrial fibrillation and elevated stroke risk.Am Heart J. 2018; 200: 24-31Crossref PubMed Scopus (27) Google Scholar Approximately 90% of intracardiac thrombi originate in the left atrial appendage in AF patients.14Alkhouli M. Noseworthy P.A. Rihal C.S. Holmes Jr., D.R. Stroke prevention in nonvalvular atrial fibrillation: a stakeholder perspective.J Am Coll Cardiol. 2018; 71: 2790-2801Crossref PubMed Scopus (31) Google Scholar Recently, percutaneous left atrial appendage occlusion (LAAO) has been shown to be effective in minimizing the stroke risk in AF patients.15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google Scholar, 16Holmes Jr., D.R. Kar S. Price M.J. et al.Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014; 64: 1-12Crossref PubMed Scopus (997) Google Scholar, 17Kar S. Doshi S.K. Sadhu A. et al.PINNACLE FLX InvestigatorsPrimary outcome evaluation of a next-generation left atrial appendage closure device: results from the PINNACLE FLX trial.Circulation. 2021; 143: 1754-1762Crossref PubMed Scopus (59) Google Scholar, 18Lakkireddy D. Thaler D. Ellis C.R. et al.Amplatzer Amulet left atrial appendage occluder versus Watchman device for stroke prophylaxis (Amulet IDE): a randomized, controlled trial.Circulation. 2021; 144: 1543-1552Crossref PubMed Scopus (48) Google Scholar The 2 currently approved endocardial devices used for LAAO in the United States are the Watchman (Boston Scientific, Marlborough, MA) and Amplatzer Amulet (Abbott, Chicago, IL).17Kar S. Doshi S.K. Sadhu A. et al.PINNACLE FLX InvestigatorsPrimary outcome evaluation of a next-generation left atrial appendage closure device: results from the PINNACLE FLX trial.Circulation. 2021; 143: 1754-1762Crossref PubMed Scopus (59) Google Scholar,18Lakkireddy D. Thaler D. Ellis C.R. et al.Amplatzer Amulet left atrial appendage occluder versus Watchman device for stroke prophylaxis (Amulet IDE): a randomized, controlled trial.Circulation. 2021; 144: 1543-1552Crossref PubMed Scopus (48) Google Scholar In the PROTECT AF trial,15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google Scholar LAAO using an earlier-generation Watchman device (Boston Scientific, Marlborough, MA) was found to be noninferior to warfarin in reducing the incidence of stroke. The more recently conducted PINNACLE FLX trial17Kar S. Doshi S.K. Sadhu A. et al.PINNACLE FLX InvestigatorsPrimary outcome evaluation of a next-generation left atrial appendage closure device: results from the PINNACLE FLX trial.Circulation. 2021; 143: 1754-1762Crossref PubMed Scopus (59) Google Scholar further corroborated the safety and efficacy of the newer-generation Watchman FLX device (Boston Scientific, Marlborough, MA) in reducing the risk of stroke in AF patients. The Amulet IDE trial18Lakkireddy D. Thaler D. Ellis C.R. et al.Amplatzer Amulet left atrial appendage occluder versus Watchman device for stroke prophylaxis (Amulet IDE): a randomized, controlled trial.Circulation. 2021; 144: 1543-1552Crossref PubMed Scopus (48) Google Scholar also showed noninferiority of the Amplatzer Amulet device (Abbott, Chicago, IL) in reducing the stroke risk compared to the first-generation Watchman device (Boston Scientific, Marlborough, MA). In this viewpoint, we will respectfully present our perspective on why percutaneous LAAO should be offered only to selected AF patients for reduction of stroke risk by highlighting the significant methodological issues with the conduction of landmark PROTECT AF and PREVAIL trials, absence of comparable efficacy and safety data for percutaneous LAAO with respect to direct-acting oral anticoagulants (DOACs), and largely nonsupportive observational evidence for percutaneous LAAO implantation in certain subgroups of patients. The PROTECT AF and PREVAIL trials were the first randomized comparisons between percutaneous LAAO using an earlier-generation Watchman device (Boston Scientific, Marlborough, MA) and warfarin.15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google Scholar,16Holmes Jr., D.R. Kar S. Price M.J. et al.Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014; 64: 1-12Crossref PubMed Scopus (997) Google Scholar Several important methodological issues pertinent to the conduct of these trials need to be highlighted (Table 1). Both trials used a Bayesian method to determine the outcomes instead of a traditional frequentist method. Bayesian methodology incorporates prior probabilities in the statistical analysis and updates this probability as events accumulate.19Giovagnoli A. The Bayesian design of adaptive clinical trials.Int J Environ Res Public Health. 2021; 18: 530Crossref Scopus (3) Google Scholar, 20Ferguson J. Bayesian interpretation of p values in clinical trials.BMJ Evid Based Med. 23 September 2021; https://doi.org/10.1136/bmjebm-2020-111603Crossref PubMed Google Scholar, 21Ibrahim J.G. Chen M.H. Lakshminarayanan M. Liu G.F. Heyse J.F. Bayesian probability of success for clinical trials using historical data.Stat Med. 2015; 34: 249-264Crossref PubMed Scopus (10) Google Scholar, 22Bittl J.A. He Y. Bayesian analysis: a practical approach to interpret clinical trials and create clinical practice guidelines.Circ Cardiovasc Qual Outcomes. 2017; 10e003563Crossref Scopus (36) Google Scholar In this way investigators can reach the conclusion faster and with a small sample size. Therefore, Bayesian design is more flexible to determine the treatment effect but is inherently prone to extrapolate false-positive conclusions about the outcomes of interest.22Bittl J.A. He Y. Bayesian analysis: a practical approach to interpret clinical trials and create clinical practice guidelines.Circ Cardiovasc Qual Outcomes. 2017; 10e003563Crossref Scopus (36) Google Scholar Both trials used a wider noninferiority rate ratio margin for the primary efficacy endpoint (2 for the PROTECT AF trial and 1.75 for the PREVAIL trial) when compared to the earlier trials on DOACs.5Connolly S.J. Ezekowitz M.D. Yusuf S. et al.RE-LY Steering Committee and Investigators Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8577) Google Scholar, 6Patel M.R. Mahaffey K.W. Garg J. et al.ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6878) Google Scholar, 7Granger C.B. Alexander J.H. McMurray J.J. et al.ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6379) Google Scholar, 8Giugliano R.P. Ruff C.T. Braunwald E. et al.ENGAGE AF-TIMI 48 InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3347) Google Scholar Additionally, the PROTECT AF trial did not have a prespecified noninferiority margin for the primary safety endpoint. Both the PROTECT AF and PREVAIL trials incorporated “cardiovascular/unexplained death” as a component of the composite primary efficacy endpoint (the other 2 components were stroke and systemic embolism). Earlier trials studying DOACs only adjudicated stroke and systemic embolism as part of the primary efficacy endpoint and did not include cardiovascular/unexplained death. While it may be reasonable to include outcomes such as cardiovascular/unexplained death as an endpoint in the PROTECT AF and PREVAIL trials owing to procedural safety concerns, it also made noninferiority easier to reach for the LAAO arm, as this outcome was not frequent in both trial arms.23Mandrola J. Foy A. Naccarelli G. Percutaneous left atrial appendage closure is not ready for routine clinical use.Heart Rhythm. 2018; 15: 298-301Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The LAAO arm of the PROTECT AF trial had increased embolic stroke events (2.2 per 100 patient-years) when compared to the warfarin arm (1.6 per 100 patient-years), while the rate of hemorrhagic stroke was lower in the LAAO arm (0.1 per 100 patient-years) in comparison to the warfarin arm (1.6 per 100 patient-years). It is important that both referring and implanting physicians are aware of important limitations of the pivotal LAAO trials so they can best inform decisions on optimal patient selection for percutaneous LAAO.Table 1Summary of important trials of percutaneous left atrial appendage occlusion and associated limitationsTrialStudy armsSample sizeOutcomes of interestResultsImportant limitationsPROTECT AF15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google ScholarLAAO using first-generation Watchman vs warfarin, 2:1 randomization, noninferiority study design707(1) Primary efficacy endpoint = composite of stroke, SE, and CV/unexplained deaths(2) Primary safety endpoint = composite of significant bleeding or procedure-related complications (serious pericardial effusion, device embolization, and procedure-related stroke)(1) LAAO noninferior for the efficacy endpoint (95% credible interval 0.35–1.25, criteria for noninferiority <2)(2) High rate of significant pericardial effusion (4.8%), procedural stroke (1.1%), and embolization (0.6%) in the LAAO arm(1) Bayesian framework, cannot rule out false-positive conclusions for the outcomes of interest(2) Wider noninferiority margin of 2(3) High rate of procedural complications, especially serious pericardial effusion(4) No prespecified noninferiority margin for the primary safety endpointPREVAIL16Holmes Jr., D.R. Kar S. Price M.J. et al.Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014; 64: 1-12Crossref PubMed Scopus (997) Google ScholarLAAO using first-generation Watchman vs warfarin, 2:1 randomization, noninferiority study design407(1) First primary efficacy endpoint = composite of all stroke, SE, and CV/unexplained deaths(2) Second primary efficacy endpoint = composite of ischemic stroke and SE 7 days after implantation(3) Primary safety endpoint = composite of all-cause death, ischemic stroke, SE, and procedure-related complications within 7 days of implantation(1) LAAO was inferior for the first primary efficacy endpoint (95% credible interval 0.57–1.89, criteria for noninferiority <1.75)(2) LAAO was noninferior for the second primary efficacy endpoint (rate difference -0.0190 to 0.0273, criteria for noninferiority <0.0275)(3) Safety events 2.2% in the LAAO arm(1) Did not reach noninferiority for the first primary efficacy endpoint(2) Bayesian framework, cannot rule out false-positive conclusions for the outcomes of interest(3) Wider noninferiority margin of 1.75PINNACLE FLX17Kar S. Doshi S.K. Sadhu A. et al.PINNACLE FLX InvestigatorsPrimary outcome evaluation of a next-generation left atrial appendage closure device: results from the PINNACLE FLX trial.Circulation. 2021; 143: 1754-1762Crossref PubMed Scopus (59) Google ScholarSingle arm (LAAO using Watchman FLX)400(1) Primary efficacy endpoint = effective closure (device leak of ≤5 mm at 1 year)(2) Primary safety endpoint = death, ischemic stroke, SE, or device-related major events requiring surgery or endovascular interventions within 7 days of implant(1) Incidence of primary efficacy endpoint was 100%, which exceeds performance goal of 97%(2) Incidence of primary safety endpoint was 0.5% with 95% upper CI of 1.6, meeting the performance goal of <4.21(1) Single-arm study, no control group(2) The efficacy endpoint was reported as an effective seal at 1 year (≤5 mm device) and no rates of stroke and SE were reportedAMULET IDE18Lakkireddy D. Thaler D. Ellis C.R. et al.Amplatzer Amulet left atrial appendage occluder versus Watchman device for stroke prophylaxis (Amulet IDE): a randomized, controlled trial.Circulation. 2021; 144: 1543-1552Crossref PubMed Scopus (48) Google ScholarAmulet vs first-generation Watchman, 1:1 randomization, noninferiority study design1878(1) Primary efficacy endpoint = composite of ischemic stroke or SE(2) Primary safety endpoint = composite of procedure-related complications, all-cause death, and major bleeding(1) Amulet was noninferior to the Watchman device for the primary efficacy endpoint (2.8% vs 2.8%, P < .001 for noninferiority)(2) Amulet was noninferior to the Watchman device for the primary safety endpoint (14.5% vs 14.7%, P < .001 for noninferiority)(1) Comparison was made with the first-generation Watchman device and not with newer Watchman FLX device(2) High rates of pericardial effusion (4.5%) and device embolization (2.5%) with the Amulet devicePRAGUE-1732Osmancik P. Herman D. Neuzil P. et al.PRAGUE-17 Trial Investigators. 4-Year outcomes after left atrial appendage closure versus nonwarfarin oral anticoagulation for atrial fibrillation.J Am Coll Cardiol. 2022; 79: 1-14Crossref PubMed Scopus (13) Google ScholarLAAO vs DOACs, 1:1 randomization, noninferiority study design402Primary endpoint = composite of cardioembolic events (stroke, transient ischemic attack, and SE), cardiovascular death, clinically relevant bleeding, and procedure/device-related complicationLAAO was found to be noninferior to the DOACs for the primary endpoint (hazard ratio 0.81, 95% CI 0.56–1.18, P = .27, noninferiority criteria were P < .006)(1) Both efficacy and safety outcomes were combined in the primary endpoint(2) Clinically significant bleeding was not low in the LAAO arm compared to the DOAC arm(3) 5% of patients in the LAAO had a serious complication from the procedureCV = cardiovascular; DOAC = direct-acting oral anticoagulant; LAAO = left atrial appendage occlusion; SE = systemic embolism. Open table in a new tab CV = cardiovascular; DOAC = direct-acting oral anticoagulant; LAAO = left atrial appendage occlusion; SE = systemic embolism. The PROTECT AF and PREVAIL trials compared efficacy and safety of percutaneous LAAO versus warfarin, and enrolled patients with no apparent contraindications to long-term warfarin use.15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google Scholar,16Holmes Jr., D.R. Kar S. Price M.J. et al.Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014; 64: 1-12Crossref PubMed Scopus (997) Google Scholar LAAO is an attractive alternative for AF patients who cannot tolerate OACs long term and thus remain at heightened stroke risk. There are currently no randomized data evaluating the efficacy and safety of LAAO in patients with a strict contraindication to any OAC therapy. In a multicenter registry of 150 AF patients with a mean CHA2DS2-VASc score of 4.4 ± 1.7 and ineligibility for warfarin therapy, Reddy and colleagues24Reddy V.Y. Möbius-Winkler S. Miller M.A. et al.Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology).J Am Coll Cardiol. 2013; 61: 2551-2556Crossref PubMed Scopus (528) Google Scholar showed that LAAO using a Watchman device conferred 64% reduction in the risk of ischemic stroke when compared to a similar risk-matched AF cohort on aspirin and clopidogrel. In a large European multicenter EWOLUTION registry analyzing more than 1000 AF patients at increased risk of stroke (with OACs contraindicated in 72%), percutaneous LAAO was found to reduce the risk of ischemic stroke by 83% at 2 years of follow-up.25Boersma L.V. Ince H. Kische S. et al.following investigators and institutions participated in the EWOLUTION study. Evaluating real-world clinical outcomes in atrial fibrillation patients receiving the WATCHMAN left atrial appendage closure technology: final 2-year outcome data of the EWOLUTION trial focusing on history of stroke and hemorrhage.Circ Arrhythm Electrophysiol. 2019; 12e006841Google Scholar The 2 randomized trials ASAP TOO26Assessment of the WATCHMAN™ device in patients unsuitable for oral anticoagulation (ASAP TOO).https://clinicaltrials.gov/ct2/show/NCT02928497Date accessed: February 21, 2022Google Scholar and STROKE CLOSE27Prevention of stroke by left atrial appendage closure in atrial fibrillation patients after intracerebral hemorrhage (STROKE CLOSE).https://clinicaltrials.gov/ct2/show/NCT02830152Date accessed: February 21, 2022Google Scholar will provide further insights on the safety and efficacy of percutaneous LAAO in AF patients with contraindication to OACs. The ASAP TOO trial is not actively recruiting at the present time and the data on currently enrolled patients have not been publicly reported as of yet. LAAO is a technically challenging procedure to perform, with an associated learning curve, and although major complications associated with implantation such as pericardial effusion requiring drainage, device-related thrombus, and device embolization continue to decline in contemporary practice, such complications are associated with extensive patient morbidity and mortality.28Munir M.B. Khan M.Z. Darden D. et al.Contemporary procedural trends of Watchman percutaneous left atrial appendage occlusion in the United States.J Cardiovasc Electrophysiol. 2021; 32: 83-92Crossref PubMed Scopus (6) Google Scholar,29Munir M.B. Khan M.Z. Darden D. et al.Pericardial effusion requiring intervention in patients undergoing percutaneous left atrial appendage occlusion: prevalence, predictors, and associated in-hospital adverse events from 17,700 procedures in the United States.Heart Rhythm. 2021; 18: 1508-1515Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Additionally, the strategy of using percutaneous LAAO as an adjunct to long-term OAC therapy is not studied as of yet, but there is evidence of benefit with surgical LAAO and concomitant OAC treatment, as shown by the LAAOS III trial.30Whitlock R.P. Belley-Cote E.P. Paparella D. et al.LAAOS III InvestigatorsLeft atrial appendage occlusion during cardiac surgery to prevent stroke.N Engl J Med. 2021; 384: 2081-2091Crossref PubMed Scopus (96) Google Scholar Hence based on the current state of scientific evidence and especially the absence of any randomized data, the authors’ viewpoint is that percutaneous LAAO should generally be reserved for AF patients who cannot tolerate long-term anticoagulants. The last decade has witnessed widespread assimilation of DOACs into clinical practice and they are considered first-line treatment for stroke risk reduction across a broad spectrum of AF patients.31Perreault S. de Denus S. White-Guay B. et al.Oral anticoagulant prescription trends, profile use, and determinants of adherence in patients with atrial fibrillation.Pharmacotherapy. 2020; 40: 40-54Crossref PubMed Scopus (47) Google Scholar Studies have shown DOACs to be noninferior for stroke prevention and superior for bleeding risk compared to warfarin.5–8) DOACs have a quick onset of action, do not require frequent laboratory monitoring, and have minimal drug- and food-related interactions. There are limited randomized data on head-to-head comparison of DOACs with percutaneous LAAO.32Osmancik P. Herman D. Neuzil P. et al.PRAGUE-17 Trial Investigators. 4-Year outcomes after left atrial appendage closure versus nonwarfarin oral anticoagulation for atrial fibrillation.J Am Coll Cardiol. 2022; 79: 1-14Crossref PubMed Scopus (13) Google Scholar Recently, the 4-year follow-up data from the PRAGUE-17 trial32Osmancik P. Herman D. Neuzil P. et al.PRAGUE-17 Trial Investigators. 4-Year outcomes after left atrial appendage closure versus nonwarfarin oral anticoagulation for atrial fibrillation.J Am Coll Cardiol. 2022; 79: 1-14Crossref PubMed Scopus (13) Google Scholar (the only randomized trial in this realm to date) was published on more than 400 AF patients who were randomized 1:1 to either a DOAC or a percutaneous LAAO. The primary endpoint of the trial was a composite of cardioembolic events (stroke, transient ischemic attack, and systemic embolism), cardiovascular death, clinically relevant bleeding, and procedure/device-related complication (for the LAAO arm). At the end of follow-up period, LAAO was found to be noninferior to the DOACs for the primary endpoint (hazard ratio 0.81, 95% confidence interval [CI] 0.56–1.18, P = .27; noninferiority criteria were P < .006). Of note, in the PRAGUE-17 trial primary endpoint was composed of both efficacy and safety outcomes, in contrast to earlier PROTECT AF and PREVAIL trials,15Reddy V.Y. Sievert H. Halperin J. et al.PROTECT AF Steering Committee and InvestigatorsPercutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.JAMA. 2014; 312: 1988-1998Crossref PubMed Scopus (540) Google Scholar,16Holmes Jr., D.R. Kar S. Price M.J. et al.Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014; 64: 1-12Crossref PubMed Scopus (997) Google Scholar and clinically relevant bleeding was not significantly better in the LAAO arm when assessed separately. In the opinion of the authors, the PRAGUE-17 trial did not demonstrate any safety advantage of percutaneous LAAO with respect to DOACs, as clinically significant bleeding was not better in the LAAO arm and approximately 5% of patients had a serious complication after LAAO device implantation. Currently, 3 large randomized trials, CHAMPION-AF,33CHAMPION-AF Clinical Trial. https://clinicaltrials.gov/ct2/show/NCT04394546. Accessed February 21, 2022.Google Scholar CATALYST,34Clinical Trial of Atrial Fibrillation Patients Comparing Left Atrial Appendage Occlusion Therapy to Non-vitamin K Antagonist Oral Anticoagulants (CATALYST).https://clinicaltrials.gov/ct2/show/NCT04226547Date accessed: February 21, 2022Google Scholar and Occlusion-AF,35Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation. A Multicenter Randomized Clinical Trial (Occlusion AF).https://clinicaltrials.gov/ct2/show/NCT03642509Date accessed: February 21, 2022Google Scholar are being conducted that will evaluate the efficacy and safety of percutaneous LAAO with DOACs and will give further insight into the current topic. These trials have distinct efficacy and safety endpoints, unlike the PRAGUE-17, and both CHAMPION-AF and CATALYST trials will adjudicate safety outcomes with a superiority design framework. Furthermore, patients are enrolled in these trials based on stroke risk (as quantified by CHA2DS2-VASc score) and not by long-term DOAC ineligibility and therefore the results of these trials will inform the applicability of percutaneous LAAO to a broader AF population. Pending further evidence from these randomized controlled trials, the authors’ opinion is that DOACs should be the preferred modality of reducing stroke risk in AF patients if they are able to tolerate them without major adverse effects. The randomized clinical trials evaluating the efficacy and safety of percutaneous LAAO did not stratify outcomes based on various patient subgroups. It is importa