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| title= Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial | | title= Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial | ||
| abbreviation=PROTECT AF | | abbreviation=PROTECT AF | ||
| expansion= | | expansion=WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation | ||
| published=2009-11-07 | | published=2009-11-07 | ||
| author=Holmes DR, | | author=Holmes DR, et al | ||
| journal=Lancet | | journal=Lancet | ||
| year=2009 | | year=2009 | ||
| Line 15: | Line 15: | ||
| status=Reviewable | | status=Reviewable | ||
| subspecialty=Cardiology | | subspecialty=Cardiology | ||
| disease=Atrial Fibrillation | | disease=Atrial Fibrillation | ||
| otherDisease1=Stroke | | otherDisease1=Stroke | ||
| intervention1=Left atrial appendage occlusion device | | intervention1=Left atrial appendage occlusion device | ||
| intervention2= | | intervention2=Warfarin | ||
| briefDesignDescription= | | briefDesignDescription= LAA closure vs. warfarin in AF | ||
| briefResultsDescription= | | briefResultsDescription=LAA closure was noninferior to warfarin therapy | ||
| trainingLevel=Intern | | trainingLevel=Intern | ||
}} | }} | ||
==Clinical Question== | ==Clinical Question== | ||
Among patients with non-valvular atrial fibrillation, is percutaneous left atrial appendage closure with the WATCHMAN device non-inferior to warfarin for prevention of | Among patients with non-valvular atrial fibrillation, is percutaneous left atrial appendage closure with the WATCHMAN device non-inferior to warfarin for the prevention of vascular events? | ||
==Bottom Line== | ==Bottom Line== | ||
Among patients with non-valvular atrial fibrillation, percutaneous left atrial appendage closure with the WATCHMAN device is non-inferior to warfarin for prevention of | Among patients with non-valvular atrial fibrillation, percutaneous left atrial appendage closure with the WATCHMAN device (without continued anticoagulation) is non-inferior to warfarin for the prevention of vascular events. | ||
==Major Points== | ==Major Points== | ||
It is estimated that only 50% of patients with non-valvular atrial fibrillation who qualify for warfarin are actually treated.<ref> AS | It is estimated that only 50% of patients with non-valvular atrial fibrillation who qualify for warfarin are actually treated.<ref>Go AS, et al. Warfarin use among ambulatory patients with non valvular atrial fibrillation: the coagulation and risk factors in atrial fibrillation (ATRIA) study Ann Intern Med, 131 (1999), pp. 927–934</ref> This is a concern as the annual risk of stroke among those who are not anticoagulated range from 1.5% in individuals aged 50–59 years to 23.5% for those aged 80–89 years.<ref> PA Wolf, RD Abbott, WB Kannel. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study Stroke, 22 (1991), pp. 983–988</ref> Alternatives to anticoagulation have thus been pursued. One strategy involves obliteration of the left atrial appendage (LAA) since this site is a common location of clot formation in non-valvular AF. | ||
PROTECT AF was a randomized controlled trial conducted in the US and Europe which randomized 707 patients with non-valvular AF and CHADS2 score of ≥1 to either LAA closure with the WATCHMAN device or to warfarin control in a 2:1 fashion. Those randomized to LAA closure discontinued their warfarin therapy 6 weeks after device placement. The study's objective was to determine noninferiority of LAA closure compared to warfarin. Patients were followed for the primary composite outcome of stroke, cardiovascular or unexplained death, or systemic embolism. With a median follow-up of 18 months, the primary outcome rate was 3.0 per 100 person-years in the LAA closure group compared to 4.9 per 100 person-years in the warfarin control (RR 0.62) and non-inferiority criteria were met. Adverse events were more common in the device group compared to warfarin controls (RR 1.69); in the device group these occurred early, whereas in the warfarin group these occurred late. Notably ischemic strokes were more common in the device group than in the warfarin controls, and most of the events in the device group were attributed to periprocedural air embolism. The authors conclude that LAA closure may be a reasonable option for patients in whom long-term anticoagulation is not desirable. The 2014 AHA/ASA guidelines contend that LAA closure with the WATCHMAN device may be most appropriate for patients with AF at high risk of stroke who are poor candidates for anticoagulation. | |||
The PREVAIL Trial, a subsequent 2014 trial involving the WATCHMAN device following the original PROTECT AF protocol, failed to prove non-inferiority to warfarin using the same primary composite endpoint but had significantly lower adverse events.<ref>Holmes J, David R, Kar S, Price MJ, 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. Journal of the American College of Cardiology. 2014;64:1.</ref> | In 2013, further follow up data from the original patients were published providing more longitudinal safety information. <ref> Reddy V, Doshi S, 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;127:720-729.</ref> The PREVAIL Trial, a subsequent 2014 trial involving the WATCHMAN device following the original PROTECT AF protocol, failed to prove non-inferiority to warfarin using the same primary composite endpoint but had significantly lower adverse events when performed by more experienced operators.<ref>Holmes J, David R, Kar S, Price MJ, 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. Journal of the American College of Cardiology. 2014;64:1.</ref> The subsequent follow up [[ASAP]] study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) showed the safety of using dual antiplatelets only without the warfarin bridging period allowing the device to be used in patients with absolute contraindications to any length of warfarin use.<ref>Reddy VY, Möbius-Winkler S, Miller MA, 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(25):2551-2556. doi:10.1016/j.jacc.2013.03.035.</ref> | ||
==Guidelines== | ==Guidelines== | ||
;AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack 2014 | ; <ref>[http://stroke.ahajournals.org/content/strokeaha/45/7/2160.full.pdf AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack] (2014, adapted) | ||
: The usefulness of closure of the left atrial appendage with the WATCHMAN device in patients with ischemic stroke or TIA and AF is uncertain (Class IIb; Level of Evidence B). | : The usefulness of closure of the left atrial appendage with the WATCHMAN device in patients with ischemic stroke or TIA and AF is uncertain (Class IIb; Level of Evidence B). | ||
==Design== | ==Design== | ||
* Multicenter, open label, randomized control trial. | * Multicenter, open label, randomized control trial. | ||
* | * N=707 patients with paroxysmal, persistent, or permanent non-valvular AF | ||
** | ** LAA closure (n=463) | ||
** | ** Warfarin control (n=244) | ||
* | * Setting: 59 centers in USA and Europe | ||
* | * Enrollment: 2005-2008 | ||
* | * Mean follow-up: 18 months | ||
* | * Analysis: Intention to treat | ||
* | * Primary outcome: Composite of stroke (including ischemic and hemorrhagic), systemic embolism and cardiovascular or unexplained death | ||
==Population== | ==Population== | ||
===Inclusion Criteria=== | ===Inclusion Criteria=== | ||
* | * Age ≥18 years | ||
* Paroxysmal, persistent or permanent non-valvular | * Paroxysmal, persistent, or permanent non-valvular AF | ||
* CHADS2 score | * CHADS2 score ≥1 | ||
===Exclusion Criteria=== | ===Exclusion Criteria=== | ||
* Contraindicated for warfarin | * Contraindicated for warfarin | ||
* Contraindicated for aspirin or clopidogrel (Plavix) | * Contraindicated for aspirin or clopidogrel (Plavix) | ||
* | * Comorbidity other than AF requiring chronic warfarin use | ||
* | * NYHA class 4 HF | ||
* Implanted mechanical valve | * Implanted mechanical valve | ||
* Atrial septal or | * Atrial septal or PFO device | ||
* Platelets < | * Platelets <100K or hemoglobin <10 g/dL | ||
* LAA thrombus | * LAA thrombus | ||
* A patent foramen ovale with atrial septal aneurysm and right-to-left shunt | * A patent foramen ovale with atrial septal aneurysm and right-to-left shunt | ||
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* Left ventricular ejection fraction (LVEF) < 30% | * Left ventricular ejection fraction (LVEF) < 30% | ||
Patients underwent transoesophageal | Patients underwent transoesophageal echocardiography prior to enrollment to assess for exclusion criteria | ||
===Baseline Characteristics=== | ===Baseline Characteristics=== | ||
''Results are from the LAA closure group.'' | |||
* Mean | * Mean age (years): 71.7 | ||
* Male: 326 (70.4%) | * Male: 326 (70.4%) | ||
* Race/ethnicity: | * Race/ethnicity: | ||
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==Interventions== | ==Interventions== | ||
* | * Patients underwent transesophageal echocardiography during screening phase to evaluate for exclusion criteria. | ||
** | |||
* Randomization to: | |||
** '''LAA closure''' with the WATCHMAN device (Atritech, Plymouth, MN, USA). The device is a self-expanding nickel titanium (nitinol) frame structure with fixation barbs and a permeable polyester fabric cover (which diameters from 21 mm to 33 mm to fit patient anatomy). Device placed using trans-septal catheter based approach guided by fluoroscopy and TEE. TEE imaging was done at 45 days, 6 months, and 12 months. Patients discontinued warfarin therapy if the 45-day TEE showed either complete closure of the LAA or residual peri-device flow (jet <5 mm in width). Once daily clopidogrel (75 mg) and aspirin (81–325 mg) until 6 month post procedure, then aspirin indefinitely. | |||
** '''Warfarin control''': Warfarin titrated to target INR of 2.0-3.0. INR checked at least every 2 weeks for 6 months and at least once a month thereafter. | |||
==Outcomes== | ==Outcomes== | ||
''Comparisons are LAA closure vs. warfarin control unless otherwise specified.'' | |||
===Primary Outcome=== | |||
; Composite end-point (event/patient year): 21/694.1 vs. 18/370.8, RR=0.62 (95% CI 0.35–1.25), non-inferiority probability >99.9%, superiority probability=90.0% | |||
=== | ===Secondary Outcomes=== | ||
; Successful LAA device implantation | |||
: 88% (408/463) of patients assigned to this intervention | |||
; Therapeutic INR on warfarin | |||
: 66% of the time in patients on this intervention | |||
; Ischaemic stroke (event/patient year): 15/694.6 vs. 6/372.3, RR= 1.34 (95% CI 0.60–4.29), non-inferiority probability=71·8%, superiority probability=20·1% | ; Ischaemic stroke (event/patient year): 15/694.6 vs. 6/372.3, RR= 1.34 (95% CI 0.60–4.29), non-inferiority probability=71·8%, superiority probability=20·1% | ||
; Cardiovascular/unexplained death (event/patient year): 5/708.4 vs. 10/374.9, RR= 0.26 (95% CI 0.08–0.77), non-inferiority probability>99·9%, superiority probability=99·3% | ; Cardiovascular/unexplained death (event/patient year): 5/708.4 vs. 10/374.9, RR= 0.26 (95% CI 0.08–0.77), non-inferiority probability>99·9%, superiority probability=99·3% | ||
; Haemorrhagic stroke (event/patient year): 1/708.4 vs. 6/373.4, RR=0.09 (95% CI 0.00–0.45), non-inferiority probability >99·9%, superiority probability=99·8% | ; Haemorrhagic stroke (event/patient year): 1/708.4 vs. 6/373.4, RR=0.09 (95% CI 0.00–0.45), non-inferiority probability >99·9%, superiority probability=99·8% | ||
; Systemic embolism (event/patient year): 2/707.8 vs 0/374.9 | ; Systemic embolism (event/patient year): 2/707.8 vs 0/374.9 | ||
; All stroke (event/patient year): 16/694.6 vs. 12/370.8, RR= 0.71 (95% CI: 0.35–1.64), non-inferiority probability 99·3%, superiority probability=76·9% | |||
; | |||
; All-cause mortality (event/patient year): 21/708.4 vs. 18/374.9, RR= 0·62 (95% CI: 0·34–1·24), non-inferiority probability >99·9%, superiority probability=90·7% | ; All-cause mortality (event/patient year): 21/708.4 vs. 18/374.9, RR= 0·62 (95% CI: 0·34–1·24), non-inferiority probability >99·9%, superiority probability=90·7% | ||
===Subgroup Analysis=== | |||
===Subgroup Analysis | |||
* HR with treatment in men was lower than that for women (p=0·03; all other interaction tests p>0·40). | * HR with treatment in men was lower than that for women (p=0·03; all other interaction tests p>0·40). | ||
** For men, HR=0.32 (95% CI= 0.13–0.77) | ** For men, HR=0.32 (95% CI= 0.13–0.77) | ||
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No other significant subgroup effects were seen (including age, CHADS2 score, type of AF, LAA size, LVEF). This did not change with the publication of the follow up data in 2013. | No other significant subgroup effects were seen (including age, CHADS2 score, type of AF, LAA size, LVEF). This did not change with the publication of the follow up data in 2013. | ||
===Adverse Events | ===Adverse Events=== | ||
; Serious pericardial effusion (need for percutaneous or surgical drainage): 22 (4.8%) vs. 0 | ; Serious pericardial effusion (need for percutaneous or surgical drainage): 22 (4.8%) vs. 0 | ||
; Major bleeding (required at least 2 units of packed red blood cells or surgery to correct): 16 (3.5%) vs. 10 (4·1%) | ; Major bleeding (required at least 2 units of packed red blood cells or surgery to correct): 16 (3.5%) vs. 10 (4·1%) | ||
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; Procedure-related ischaemic stroke: 5 (1·1%) vs. 0 | ; Procedure-related ischaemic stroke: 5 (1·1%) vs. 0 | ||
; Device embolisation: 3 (0·6%) vs. 0 | ; Device embolisation: 3 (0·6%) vs. 0 | ||
; Other procedural complications: 2 (0·4%) vs. 0 ( | ; Other procedural complications: 2 (0·4%) vs. 0 (esophageal tear and procedure-related arrhythmia) | ||
==Criticisms== | ==Criticisms== | ||
* Non-inferiority was not proven for prevention of ischemic stroke | * Non-inferiority was not proven for prevention of ischemic stroke, which is the primary goal of intervention for AF | ||
* Intervention patients are left on ASA long term, which itself offers mild stroke prevention benefit for patients with atrial fibrillation | * Intervention patients are left on ASA long term, which itself offers mild stroke prevention benefit for patients with atrial fibrillation | ||
* Hemorrhagic stroke is included in the primary vascular endpoint as well as with adverse events, contributing to overall non-inferiority result of primary endpoint | * Hemorrhagic stroke is included in the primary vascular endpoint as well as with adverse events, contributing to overall non-inferiority result of primary endpoint | ||
==Funding== | ==Funding== | ||
Atritech, maker of the WATCHMAN device | Atritech, maker of the WATCHMAN device. | ||
==Further Reading== | ==Further Reading== | ||
<references/> | <references/> | ||