PREVAIL (Atrial Fibrillation)

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Holmes DR Jr, 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". JACC. 2014. 64(1):1-12.
PubMedFull text

Clinical Question

In patients with nonvalvular atrial fibrillation, how does the safety and efficacy of the Watchman LAA Closure Technology compare with long-term warfarin therapy for stroke prevention?

Bottom Line

LAA occlusion was noninferior to warfarin for ischemic stroke prevention or systemic embolism (SE) >7 days post-procedure.

Major Points

The PROTECT AF trial showed that the Watchman LAA Closure Technology was noninferior to warfarin for stroke prevention in patients with 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 provided additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF. It should be noted that noninferiority was not achieved for overall efficacy, however procedural safety had significantly improved.

Guidelines

  • Guideline recommendations for LAA occlusion for stroke prevention are substantially more limited due to the lack of clinical trials data for any devices aside from the WATCHMAN
  • The current ACC/AHA/HRS Guideline for the Management of Patients with Atrial Fibrillation does not include recommendations for the use of LAA occlusion devices because of the lack of adequate data and the absence of an FDA-approved LAA closure device labeled for the indication of stroke prevention at the time of their development

Design

  • Prospective, randomized, multicenter control trial
  • N=407
    • Device group (n=269)
    • Control group (n=138)
  • Setting: 50 investigational sites in the United States
  • Mean follow-up: 11.8 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • 7-Day procedure rate of death, ischemic stroke, systemic embolism and complications requiring major cardiovascular or endovascular intervention
    • Comparison of the composite of stroke, systemic embolism and cardiovascular/unexplained death
    • Comparison of ischemic stroke and systemic embolism occurring greater than 7 days post randomization.

Population

Inclusion Criteria

  • Paroxysmal, persistent or permanent non-valvular AF
  • Eligible for long-term warfarin therapy
  • Eligible to come off warfarin therapy
  • Calculated CHADS2 score of 2 or greater. Also patients with a CHADS2 score of 1 may be included if any of the following apply:
    • Female age 75 or older
    • Baseline LVEF ≥ 30 and < 35%
    • Aged 65-74 and has diabetes or coronary artery disease
    • Aged 65 or greater and has congestive heart failure

Exclusion Criteria

  • Contraindicated/allergic to 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

Echo Exclusion Criteria:

  • 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 (in): 68.4 vs. 68.5
  • Weight (lbs): 196.3 vs. 197.1
  • Sex:
    • Female: 87/269 (32.3%) vs. 35/138 (25.4%)
    • Male: 182/269 (67.7%) vs. 103/138 (74.6%)
  • 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%)
  • Hx of HTN: 238/269 (88.5%) vs. 134/138 (97.1%)
  • Age >= 75 yrs: 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 and ASA 81mg for 45 days post implantation to prevent large thrombus formation on the device during endothelialization
    • TEE was performed at 45 days, 6 months, and 12 months follow-up.
    • 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 daily clopidogrel 75 mg and aspirin 81 to 325 mg 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 dura- tion of the study with a target international normalized ratio between 2.0 and 3.0. This ratio was monitored at least every 2 weeks for 6 months and at least 1 month thereafter to assess the need for dose adjustment
    • Follow-up visits occurred at 45 days, 6 months, 9 months, and biannually 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 group vs. control group

Primary Outcomes

Coprimary Efficacy Endpoint Results (Stroke, Systemic Embolism, or Cardiovascular/Unexplained Death) 18-month rate
0.064 vs. 0.063 (Rate ratio 1.07 (95% CI 0.57, 1.89))
Rate Ratio Noninferiority Criterion - 95% CI upper bound <1.75
Late-Ischemic Coprimary Endpoint 18-month rate
0.0253 vs. 0.0200 (Rate ratio 1.6 (95% CI 0.5, 4.2))
Rate Ratio Noninferiority Criterion - 95% CI upper bound <2.0
Safety Coprimary Endpoint Results (Device Group Only)
2.2% (95% CI upper bound 2.652%)
Success for this endpoint was defined as being achieved if the percentage of patients experiencing one of the events was statistically less than the performance goal, defined as 2.67%

Criticisms

Funding

This study was sponsored by Atritech/Boston Scientific Corporation.

Further Reading