Which trial demonstrates that the Watchman left atrial appendage closure device is non‑inferior to warfarin for stroke prevention in atrial fibrillation even in patients without a contraindication to oral anticoagulation?

PROTECT AF and PREVAIL Trials Established Watchman Device Efficacy in Patients Without Anticoagulation Contraindications

The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trials are the landmark studies that demonstrated the Watchman device is non-inferior to warfarin for stroke prevention in atrial fibrillation patients who were suitable for long-term anticoagulation—meaning these patients had no contraindication to warfarin. 1

Key Trial Design Features

Both PROTECT AF and PREVAIL specifically enrolled patients who were candidates for warfarin therapy, not patients with contraindications to anticoagulation. 1 This is a critical distinction:

• The FDA approval mirrors these trial inclusion criteria, restricting the device to patients deemed suitable for long-term warfarin but who have an appropriate rationale to seek a nonpharmacological alternative. 1
• Patients unable to take oral anticoagulation were explicitly excluded from both randomized trials. 1
• Even patients randomized to the Watchman arm received concomitant warfarin for approximately 45 days after implantation, followed by clopidogrel for 4.5 months and lifelong aspirin. 2

Efficacy Outcomes from PROTECT AF

The PROTECT AF trial enrolled 707 patients (463 Watchman, 244 warfarin) with nonvalvular atrial fibrillation and at least one stroke risk factor. 2

• After mean follow-up of 2.3 years (1,588 patient-years), the primary efficacy event rate (stroke, systemic embolism, cardiovascular death) was 3.0% per year in the Watchman group versus 4.3% per year in the warfarin group (relative risk 0.71), meeting criteria for non-inferiority. 2
• At 3.8 years mean follow-up, LAA closure was superior to warfarin for the primary efficacy endpoint. 1, 3
• Hemorrhagic stroke risk was markedly lower with Watchman versus warfarin (relative risk 0.09; 95% CI 0–0.45). 3, 4

Efficacy Outcomes from PREVAIL

The PREVAIL trial had mixed results on its co-primary endpoints. 4

• The first composite co-primary endpoint (stroke, systemic embolism, cardiovascular/unexplained death) did not achieve non-inferiority (posterior probability 88.4%). 4
• The second co-primary endpoint (post-procedure ischemic stroke/systemic embolism) did achieve non-inferiority (posterior probability 97.5%). 4
• The warfarin arm maintained an unusually low ischemic stroke rate (0.73% per year), which contributed to the inconclusive efficacy findings. 4

Combined 5-Year Meta-Analysis Results

A patient-level meta-analysis combining PROTECT AF and PREVAIL (1,114 patients, 4,343 patient-years) demonstrated: 1, 4

• The composite endpoint was similar between groups (HR 0.820; p=0.27). 4
• All-stroke/systemic embolism rates were comparable (HR 0.961; p=0.87). 4
• Ischemic stroke/systemic embolism was numerically higher with Watchman but not statistically significant (HR 1.71; p=0.080). 4
• Significant advantages favoring Watchman included:
  • Hemorrhagic stroke (HR 0.20; p=0.0022) 4
  • Disabling/fatal stroke (HR 0.45; p=0.03) 4
  • Cardiovascular/unexplained death (HR 0.59; p=0.027) 4
  • All-cause death (HR 0.73; p=0.035) 4
  • Post-procedure bleeding (HR 0.48; p=0.0003) 4

Critical Evidence Gap

No randomized trials have compared the Watchman device with direct oral anticoagulants (DOACs), which have superior safety profiles compared to warfarin. 5, 3 All trial data compare the device exclusively to warfarin, leaving a major evidence gap in contemporary practice where DOACs are first-line therapy. 5, 3

Current Guideline Position

Despite demonstrating non-inferiority in patients without contraindications to anticoagulation, current guidelines position the Watchman device as a second-line option:

• The 2019 AHA/ACC/HRS guidelines give percutaneous LAA occlusion a Class IIb recommendation (may be considered) specifically for patients with contraindications to long-term anticoagulation. 1
• Oral anticoagulation remains the preferred first-line therapy for stroke prevention in most patients with atrial fibrillation and elevated stroke risk. 1, 3

The Paradox of Post-Procedural Anticoagulation

A critical limitation is that patients receiving the Watchman device must tolerate at least 45 days of warfarin plus aspirin post-implantation, followed by dual antiplatelet therapy for 6 months. 1, 3

• This exposes patients to bleeding risks potentially equivalent to DOACs, creating a paradox for patients who received the device due to bleeding contraindications. 5
• The FDA labeling specifies patients must be deemed suitable for periprocedural anticoagulation. 1, 3

Alternative Evidence: The ASAP Study

The ASAP study (ASA Plavix Feasibility Study) represents a different population—150 patients with contraindications to warfarin who received Watchman without warfarin transition, using only aspirin and clopidogrel. 6

• Mean CHADS₂ score was 2.8±1.2; 93% had history of hemorrhagic/bleeding tendencies. 6
• Ischemic stroke rate was 1.7% per year, significantly lower than the 7.3% per year expected based on CHADS₂ scores. 6
• However, this was a non-randomized observational study with lower-quality evidence compared to PROTECT AF and PREVAIL. 6