Therapeutics
Mechanical left atrial appendage closure was noninferior and superior to warfarin in atrial fibrillation Clinical impact ratings:
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Question In patients with atrial fibrillation (AF), is mechanical left atrial appendage (LAA) closure noninferior to warfarin?
Methods Design: Randomized controlled trial (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation [PROTECT AF] trial). ClinicalTrials.gov NCT00129545. Allocation: {Concealed}*.† Blinding: Unblinded.† Follow-up period: Mean 3.8 years. Setting: 59 clinical centers in Europe and the USA. Patients: 707 adults ≥ 18 years of age (mean age 72 y, 70% men) who had nonvalvular AF (paroxysmal, persistent, or permanent) and ≥ 1 CHADS2 risk factor (age ≥ 75 y; prior stroke or transient ischemic attack; or diabetes, hypertension, heart failure, or left ventricular systolic dysfunction) and were eligible for long-term anticoagulation with warfarin. Exclusion criteria included left ventricular ejection fraction < 30%, symptomatic carotid disease, patent foramen ovale with atrial septal aneurysm, atrial septal defect, mechanical valve prosthesis, or mobile aortic atheromata. Intervention: Mechanical LAA closure (n = 463) or warfarin, with a target international normalized ratio of 2 to 3 (n = 244). In the LAA closure group, the WATCHMAN device was implanted under transesophageal echocardiographic guidance. Outcomes: Primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular (CV) death (including unexplained death). Secondary efficacy outcomes included components of the primary outcome and all-cause mortality. Primary safety outcome was a composite of procedure-related events or major bleeding. The trial had 80% power to reject the inferiority null hypothesis with a noninferiority margin of 2.0 for the rate ratio (␣ = 0.05). Patient follow-up: 85% (intention-to-treat analysis).
Main results Bayesian Poisson analyses showed that LAA closure was noninferior and superior to warfarin for the primary efficacy compos-
Mechanical left atrial appendage (LAA) closure vs warfarin in patients with atrial fibrillation‡ Outcomes
Stroke, systematic embolism, or CV or unexplained death
Events/100 patient-y
Rate ratio (95% credible interval)
LAA closure
Warfarin
2.3
3.8
0.60 (0.41 to 1.05)§ 0.68 (0.42 to 1.37)
Stroke
1.5
2.2
Systemic embolization
0.2
0
CV or unexplained death
1.0
2.4
0.40 (0.23 to 0.82)
Procedure-related events or major bleeding
3.6
3.1
1.17 (0.78 to 1.95)||
3.2
4.8
ite outcome and noninferior for the primary safety outcome (Table). Other results are in the Table.
Conclusion In patients with atrial fibrillation, mechanical left atrial appendage closure was noninferior and superior to warfarin. *Information provided by author. †See Glossary. Source of funding: Atritech. For correspondence: Dr. V. Reddy, Mount Sinai School of Medicine, New York, NY, USA. E-mail [email protected].
Commentary The previously reported PROTECT AF trial results showed noninferiority of LAA closure with the Watchman device compared with warfarin for prevention of the composite outcome, stroke, systemic embolism, or CV death at 18 months of follow-up (1). Now, further follow-up of PROTECT AF participants (mean 3.8 y) not only confirms noninferiority but, in secondary analyses, suggests superiority of the Watchman device over warfarin for both stroke and mortality. These new follow-up data from PROTECT AF must be cautiously interpreted. First, the stroke and mortality benefits of the Watchman device might simply be explained by higher-than-expected rates of hemorrhagic stroke in the warfarin group (1.1 events/100 patient-y). In recent AF trials, both warfarin and non–vitamin K antagonist oral anticoagulants were associated with substantially lower rates of hemorrhagic stroke than those seen in the PROTECT AF trial (2), raising the possibility that the PROTECT AF results overestimate the benefits of the Watchman device. Second, follow-up was incomplete in 15% of patients. It is unclear how this high rate of loss to follow-up might have affected the results. Third, although the greatest potential for use of the Watchman device is in AF patients in whom anticoagulation is contraindicated, the PROTECT AF trial did not include these patients. PROTECT AF provides proof-of-concept of the efficacy of the Watchman device for stroke prevention in patients with AF. We need further studies comparing the device with non–vitamin K antagonist oral anticoagulants, which are becoming the new standard of care for anticoagulation in these patients. In the meantime, the results of PROTECT AF suggest that it is reasonable to use the Watchman device in patients with AF who are at high risk for stroke and unable to be treated long-term with an oral anticoagulant. Vinai Bhagirath, MD Jacqueline Bosch, PhD John Eikelboom, MBBS McMaster University Hamilton, Ontario, Canada
Not applicable
Hazard ratio (95% confidence interval) All-cause mortality
Reddy VY, Sievert H, Halperin J, et al; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988-98.
0.66 (0.45 to 0.98)
References 1. 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 randomised non-inferiority trial. Lancet. 2009;374:534-42. 2. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110:453-60.
‡CV = cardiovascular. §Meets criteria for noninferiority and superiority. ||Meets criterion for noninferiority.
姝 2015 American College of Physicians JC4 ACP Journal Club Downloaded From: http://annals.org/ by a University of Manitoba User on 06/19/2015
Annals of Internal Medicine
21 April 2015
Mechanical left atrial appendage closure was noninferior and superior to warfarin in atrial fibrillation Clinical impact ratings:
多多多多多多夞
多多多多多多夞
多多多多多夞夞
Question In patients with atrial fibrillation (AF), is mechanical left atrial appendage (LAA) closure noninferior to warfarin?
Methods Design: Randomized controlled trial (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation [PROTECT AF] trial). ClinicalTrials.gov NCT00129545. Allocation: {Concealed}*.† Blinding: Unblinded.† Follow-up period: Mean 3.8 years. Setting: 59 clinical centers in Europe and the USA. Patients: 707 adults ≥ 18 years of age (mean age 72 y, 70% men) who had nonvalvular AF (paroxysmal, persistent, or permanent) and ≥ 1 CHADS2 risk factor (age ≥ 75 y; prior stroke or transient ischemic attack; or diabetes, hypertension, heart failure, or left ventricular systolic dysfunction) and were eligible for long-term anticoagulation with warfarin. Exclusion criteria included left ventricular ejection fraction < 30%, symptomatic carotid disease, patent foramen ovale with atrial septal aneurysm, atrial septal defect, mechanical valve prosthesis, or mobile aortic atheromata. Intervention: Mechanical LAA closure (n = 463) or warfarin, with a target international normalized ratio of 2 to 3 (n = 244). In the LAA closure group, the WATCHMAN device was implanted under transesophageal echocardiographic guidance. Outcomes: Primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular (CV) death (including unexplained death). Secondary efficacy outcomes included components of the primary outcome and all-cause mortality. Primary safety outcome was a composite of procedure-related events or major bleeding. The trial had 80% power to reject the inferiority null hypothesis with a noninferiority margin of 2.0 for the rate ratio (␣ = 0.05). Patient follow-up: 85% (intention-to-treat analysis).
Main results Bayesian Poisson analyses showed that LAA closure was noninferior and superior to warfarin for the primary efficacy compos-
Mechanical left atrial appendage (LAA) closure vs warfarin in patients with atrial fibrillation‡ Outcomes
Stroke, systematic embolism, or CV or unexplained death
Events/100 patient-y
Rate ratio (95% credible interval)
LAA closure
Warfarin
2.3
3.8
0.60 (0.41 to 1.05)§ 0.68 (0.42 to 1.37)
Stroke
1.5
2.2
Systemic embolization
0.2
0
CV or unexplained death
1.0
2.4
0.40 (0.23 to 0.82)
Procedure-related events or major bleeding
3.6
3.1
1.17 (0.78 to 1.95)||
3.2
4.8
ite outcome and noninferior for the primary safety outcome (Table). Other results are in the Table.
Conclusion In patients with atrial fibrillation, mechanical left atrial appendage closure was noninferior and superior to warfarin. *Information provided by author. †See Glossary. Source of funding: Atritech. For correspondence: Dr. V. Reddy, Mount Sinai School of Medicine, New York, NY, USA. E-mail [email protected].
Commentary The previously reported PROTECT AF trial results showed noninferiority of LAA closure with the Watchman device compared with warfarin for prevention of the composite outcome, stroke, systemic embolism, or CV death at 18 months of follow-up (1). Now, further follow-up of PROTECT AF participants (mean 3.8 y) not only confirms noninferiority but, in secondary analyses, suggests superiority of the Watchman device over warfarin for both stroke and mortality. These new follow-up data from PROTECT AF must be cautiously interpreted. First, the stroke and mortality benefits of the Watchman device might simply be explained by higher-than-expected rates of hemorrhagic stroke in the warfarin group (1.1 events/100 patient-y). In recent AF trials, both warfarin and non–vitamin K antagonist oral anticoagulants were associated with substantially lower rates of hemorrhagic stroke than those seen in the PROTECT AF trial (2), raising the possibility that the PROTECT AF results overestimate the benefits of the Watchman device. Second, follow-up was incomplete in 15% of patients. It is unclear how this high rate of loss to follow-up might have affected the results. Third, although the greatest potential for use of the Watchman device is in AF patients in whom anticoagulation is contraindicated, the PROTECT AF trial did not include these patients. PROTECT AF provides proof-of-concept of the efficacy of the Watchman device for stroke prevention in patients with AF. We need further studies comparing the device with non–vitamin K antagonist oral anticoagulants, which are becoming the new standard of care for anticoagulation in these patients. In the meantime, the results of PROTECT AF suggest that it is reasonable to use the Watchman device in patients with AF who are at high risk for stroke and unable to be treated long-term with an oral anticoagulant. Vinai Bhagirath, MD Jacqueline Bosch, PhD John Eikelboom, MBBS McMaster University Hamilton, Ontario, Canada
Not applicable
Hazard ratio (95% confidence interval) All-cause mortality
Reddy VY, Sievert H, Halperin J, et al; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988-98.
0.66 (0.45 to 0.98)
References 1. 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 randomised non-inferiority trial. Lancet. 2009;374:534-42. 2. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110:453-60.
‡CV = cardiovascular. §Meets criteria for noninferiority and superiority. ||Meets criterion for noninferiority.
姝 2015 American College of Physicians JC4 ACP Journal Club Downloaded From: http://annals.org/ by a University of Manitoba User on 06/19/2015
Annals of Internal Medicine
21 April 2015
