PREVAIL

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Holmes DR, 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):1-12.
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Clinical Question

In patients with nonvalvular atrial fibrillation, how does the safety and efficacy of the Watchman left atrial appendage closure device compare with long-term warfarin therapy for stroke prevention?

Bottom Line

Left atrial appendage (LAA) occlusion with the Watchman device was noninferior to warfarin in the prevention of ischemic stroke or systemic embolism.

Major Points

PROTECT AF showed that the Watchman LAA closure device was noninferior to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), but a periprocedural safety hazard was identified. The PREVAIL study was designed to provide additional information on the safety and efficacy of the LAA closure technology. PREVAIL randomized an additional 407 patients with nonvalvular AF in a 2:1 fashion to either LAA closure with the Watchman device or to a control arm which received antithrombotic therapy alone. The analysis was an intention-to-treat noninferiority analysis studying short- and long-term efficacy and safety outcomes. The first efficacy outcome, a composite of stroke, systemic embolism, or cardiovascular/unexplained death did not meet the noninferiority criterion. Noninferiority was achieved with the other two outcomes, namely the rate of late ischemic events (after 7 days of randomization), and the rate of early ischemic events and device/procedural complications (within 7 days of procedure). The authors conclude that LAA closure with the Watchman device may be appropriate for selected patients. Guidelines issued in 2019 recommend consideration of LAA closure for patients who are not candidates for long-term anticoagulation, although PREVAIL did not study such a population.

Guidelines

AHA/ACC/HRS focused update of the 2014 guideline (2019, adapted)[1]

  • Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation. (COR IIb, LOE B-NR)
  • Surgical occlusion of the LAA may be considered in patients with AF undergoing cardiac surgery, as a component of an overall heart team approach to the management of AF. (COR IIb, LOE B-NR)

Design

  • Prospective, multicenter, randomized controlled trial
  • N=407 patients with atrial fibrillation
    • Watchman device (n=269)
    • Warfarin (n=138)
  • Setting: 50 US sites, including ≥20% of randomized patients enrolling in sites who had not participated in prior Watchman studies, and ≥25% of patients were to be treated by new operators
  • Mean follow-up: 11.8 months
  • Analysis: Intention-to-treat
  • Three coprimary outcomes:
    1. Composite of stroke, systemic embolism, cardiovascular/unexplained death
    2. Composite of ischemic stroke or systemic embolism >7 days after randomization
    3. Composite of all-cause death, ischemic stroke, systemic embolism, or device/procedure-related events requiring major intervention within 7 days of the procedure

Population

Inclusion Criteria

  • Paroxysmal, persistent, or permanent NVAF
  • Eligible for long-term warfarin therapy
  • Eligible to discontinue warfarin therapy
  • CHADS2 score of ≥2, or score of 1 with one additional risk factor:
    • Female age ≥75 years
    • Baseline LVEF ≥30% and <35%
    • Aged 65-74 years with diabetes or CAD
    • Aged ≥65 years with CHF

Exclusion Criteria

  • Indication for long-term anticoagulation other than AF
  • Contraindication to warfarin or aspirin
  • Indicated for clopidogrel therapy or has taken clopidogrel within 7 days prior to enrolment
  • History of atrial septal repair or has an ASD/PFO device
  • Implanted mechanical valve prosthesis
  • NYHA class IV CHF
  • Resting heart rate >110 bpm
  • Participated previously in the PROTECT AF or CAP Registry studies
  • LVEF <30%
  • Existing pericardial effusion >2mm
  • High risk PFO
  • Significant mitral valve stenosis
  • Complex atheroma with mobile plaque of the descending aorta and/or aortic arch
  • Cardiac tumor

Baseline Characteristics

Comparisons are device vs. control groups

  • Mean age: 74 vs. 74.9
  • Height: 68.4 vs. 68.5 inches
  • Weight: 196.3 vs. 197.1 lbs
  • Female sex: 32.3% vs. 25.4%
  • Race/ethnicity:
    • Asian: 1/269 (0.4%) vs. 1/138 (0.7%)
    • Black/African American: 6/269 (2.2%) vs. 1/138 (0.7%)
    • White: 253/269 (94.1%) vs. 131/138 (94.9%)
    • Hispanic/Latino: 6/269 (2.2%) vs. 5/138 (3.6%)
    • Native American Indian/Alaskan Native: 1/269 (0.4%) vs. 0/138 (0.0%)
    • Other: 2/269 (0.7%) vs. 0/138 (0.0%)
  • CHADS2 score: (mean 2.6 vs. 2.6)
    • 1: 21/269 (7.8%) vs. 12/138 (8.7%)
    • 2: 137/269 (50.9%) vs. 62/138 (44.9%)
    • 3: 65/269 (24.2%) vs. 36/138 (26.1%)
    • 4: 33/269 (12.3%) vs. 21/138 (15.2%)
    • 5: 12/269 (4.5%) vs. 7/138 (5.1%)
    • 6: 1/269 (0.4%) vs. 0/138 (0.0%)
  • CHF: 63/269 (23.4%) vs. 32/138 (23.2%)
  • HTN: 238/269 (88.5%) vs. 134/138 (97.1%)
  • Age ≥75 years: 140/269 (52.0%) vs. 78/138 (56.5%)
  • Diabetes: 91/269 (33.8%) vs. 41/138 (29.7%)
  • Previous TIA/ischemic stroke: 74/269 (27.5%) vs. 39/138 (28.3%)
  • AF pattern:
    • Paced: 7/269 (2.6%) vs. 5/138 (3.6%)
    • Paroxysmal: 131/269 (48.7%) vs. 71/138 (51.4%)
    • Permanent: 42/269 (15.6%) vs. 22/138 (15.9%)
    • Persistent: 85/269 (31.6%) vs. 39/138 (28.3%)
    • Unknown: 4/269 (1.5%) vs. 1/138 (0.7%)
  • LVEF mean (%): 55.4 vs. 56.0
  • CHADS2-VASc score (mean 3.8 vs. 3.9)
    • 1: 0/269 (0.0%) vs. 1/138 (0.7%)
    • 2: 19/269 (7.1%) vs. 7/138 (5.1%)
    • 3: 78/269 (29.0%) vs. 44/138 (31.9%)
    • 4: 95/269 (35.3%) vs. 35/138 (25.4%)
    • 5: 50/269 (18.6%) vs. 37/138 (26.8%)
    • 6: 20/269 (7.4%) vs. 12/138 (8.7%)
    • 7: 6/269 (2.2%) vs. 3/138 (2.2%)
    • 8: 1/269 (0.4%) vs. 0/138 (0.0%)

Interventions

  • Participants were randomly assigned to the device intervention or the control group (2:1 ratio).
  • Device group:
    • Treated with warfarin (goal INR 2-3) and aspirin 81 mg/d for 45 days after implantation.
    • TEE was performed at 45 days, 6 months, and 12 months after procedure.
    • If the 45-day TEE documented either complete closure of the LAA or if residual peridevice flow was <5 mm in width and there was no definite visible large thrombus on the device, warfarin was discontinued
    • After discontinuation of warfarin, only clopidogrel 75 mg/d and aspirin 81-325 mg/d were prescribed until the 6-month follow-up visit, at which time clopidogrel was discontinued and aspirin alone was continued indefinitely
  • Control group:
    • Control patients received warfarin during the duration of the study (goal INR 2-3).
    • Follow-up visits were at 45 days, 6 months, 9 months, and every 2 years thereafter. Neurologic assessment was performed at baseline, 12 months, and 24 months, as well as whenever a neurologic event was suspected or had occurred.

Outcomes

Comparisons are device vs. control group

Primary Outcomes

Composite of stroke, systemic embolism, cardiovascular/unexplained death at 18 months
0.064 versus 0.063 (rate ratio 1.07; 95% CI 0.57-1.89; noninferiority was not achieved since the upper bound exceeded the presepcified noninferiority margin of 1.75)
Composite of ischemic stroke or systemic embolism >7 days after randomization
0.0253 vs. 0.0200 (rate ratio 1.6; 95% CI 0.5-0.42; noninferiority was achieved)
Composite of all-cause death, ischemic stroke, systemic embolism, or device/procedure-related events requiring major intervention within 7 days of the procedure
2.2% of device patients experienced a safety event (less than the upper bound of 2.652%) and noninferiority was achieved

Secondary Outcomes

Procedural success
95.1% overall
96.3% with experienced operators
93.2% with new operators
Composite of cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, other vascular complications within 7 days after implant
4.2%
Pericardial effusions requiring surgical repair
0.04%
Pericardial effusion requiring pericardiocentesis or pericardial window
1.5%
Procedural and device-related strokes
0.4%

Criticisms

  • The PREVAIL study has been used to support LAA closure among patients ineligible for long-term anticoagulation, but the study inclusion criteria required that patients were candidates for anticoagulation.
  • The control group used warfarin for anticoagulation, and therefore efficacy of the Watchman device versus direct oral anticoagulants (DOACs) is unknown.

Funding

This study was sponsored by Atritech/Boston Scientific Corporation.

Further Reading

  1. January CT et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019. 74:104-132.