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PROTECT AF

Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation: A Randomized Clinical Trial

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Year of Publication: 2014

Authors: Vivek Y. Reddy, MD; Horst Sievert, MD; Jonathan Halperin, ..., BSEE; David Holmes

Journal: JAMA

Citation: JAMA. 2014:312(19):1988-1998.

Clinical Question

In patients with nonvalvular atrial fibrillation (AF) and at least one additional stroke risk factor, is mechanical left atrial appendage (LAA) closure with the Watchman device noninferior to chronic warfarin therapy?

Bottom Line

After a mean follow-up of 3.8 years, percutaneous LAA closure with the Watchman device was superior to warfarin in preventing the primary composite outcome of stroke, systemic embolism, and cardiovascular death. The device was also associated with significantly lower rates of both cardiovascular and all-cause mortality.

Major Points

  • PROTECT AF was a multicenter, randomized trial comparing LAA closure with the Watchman device to warfarin in 707 patients with nonvalvular AF and a CHADS2 score ≥1.
  • The primary efficacy endpoint was a composite of stroke, systemic embolism, and cardiovascular/unexplained death.
  • At a mean follow-up of 3.8 years, the primary event rate was significantly lower in the device group (2.3 events per 100 patient-years) compared to the warfarin group (3.8 events per 100 patient-years), meeting prespecified criteria for both noninferiority and superiority.
  • The device group had significantly lower rates of cardiovascular mortality (HR, 0.40; P=.005) and all-cause mortality (HR, 0.66; P=.04).
  • While the device group had a higher rate of early, procedure-related complications (e.g., pericardial effusions), the overall primary safety endpoint rates were similar between groups over the long term due to the accumulation of bleeding events with warfarin.

Design

Study Type: Multicenter, randomized (2:1), unblinded, Bayesian-designed trial.

Randomization: 1

Blinding: Unblinded.

Enrollment Period: February 2005 to June 2008.

Follow-up Duration: Mean of 3.8 years.

Centers: 59

Countries: United States, Europe

Sample Size: 707

Analysis: Intention-to-treat, using a Bayesian model.

Inclusion Criteria

  • Age 18 years or older.
  • Paroxysmal, persistent, or permanent nonvalvular AF.
  • At least one CHADS2 risk factor (score ≥1).
  • Eligible for long-term anticoagulation with warfarin.

Exclusion Criteria

  • Patent foramen ovale with atrial septal aneurysm or an atrial septal defect.
  • Mechanical valve prosthesis.
  • LV ejection fraction less than 30%.
  • Mobile aortic atheromata or symptomatic carotid disease.

Arms

FieldControlLAA Closure Device (Watchman)
InterventionLong-term warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0.Percutaneous implantation of the Watchman LAA closure device. Post-implant regimen consisted of warfarin and aspirin for 45 days, followed by clopidogrel and aspirin until 6 months, then aspirin monotherapy indefinitely.
DurationLifelongLifelong implant with a defined post-procedural medication regimen.

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
A composite efficacy endpoint including stroke, systemic embolism, and cardiovascular/unexplained death.Primary3.8 events per 100 patient-years 2.3 events per 100 patient-years 0.6Superiority met (posterior probability, 96.0%)
All-cause mortalitySecondary4.8 events per 100 patient-years 3.2 events per 100 patient-years HR 0.66 (95% CI, 0.45-0.98) 0.04
Cardiovascular mortalitySecondary2.4 events per 100 patient-years 1.0 events per 100 patient-years HR 0.40 (95% CI, 0.21-0.75) 0.005
Hemorrhagic strokeSecondary1.1 events per 100 patient-years 0.2 events per 100 patient-years Rate Ratio 0.15 (95% CrI, 0.03-0.49)
Ischemic strokeSecondary1.1 events per 100 patient-years 1.4 events per 100 patient-years Rate Ratio 1.26 (95% CrI, 0.72-3.28)
Primary composite safety endpoint (major bleeding and procedure-related events)Adverse3.1 events per 100 patient-years 3.6 events per 100 patient-years Rate Ratio 1.17 (95% CrI, 0.78-1.95)
Serious pericardial effusionAdverse0%4.8% (22/463)
Procedure-related ischemic strokeAdverse1.3% (6/463)

Subgroup Analysis

The efficacy results were consistent across a number of subgroups including sex, age, AF pattern, CHADS2 score, and prior warfarin use.

Criticisms

  • Patients and physicians were not blinded to treatment assignment, which could introduce bias.
  • The trial randomized LAA closure against warfarin, but not against the new oral anticoagulants (NOACs).
  • The study excluded patients with a left ventricular ejection fraction less than 30%.
  • A high proportion of patients (22.5%) withdrew from the warfarin group, which could bias the results.

Funding

Funded by the manufacturer of the device, Atritech (now owned by Boston Scientific).

Based on: PROTECT AF (JAMA, 2014)

Authors: Vivek Y. Reddy, MD; Horst Sievert, MD; Jonathan Halperin, ..., BSEE; David Holmes

Citation: JAMA. 2014:312(19):1988-1998.

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