CLOSURE-AF
Left Atrial Appendage Closure or Medical Therapy in Atrial Fibrillation
Clinical Question
In AF patients at high risk for both stroke and bleeding, is catheter-based LAA closure noninferior to physician-directed best medical care (including DOACs if eligible) for a composite of stroke, systemic embolism, major bleeding, or cardiovascular or unexplained death?
Bottom Line
LAA closure was NOT noninferior to best medical care (including DOACs if eligible) in high-risk AF patients: composite endpoint 16.8 vs 13.3 per 100 patient-years (adjusted RMST difference -0.36 years; 95% CI -0.70 to -0.01; P=0.44 for noninferiority). Stroke rates were similar (2.6 vs 2.7/100 pt-yr), but LAA closure had more major bleeding (7.4 vs 6.2/100 pt-yr) driven by periprocedural events (18 procedure-related bleeds; 52 additional bleeds were non-procedure-related). First large RCT comparing LAA closure vs a DOAC-dominant control.
Major Points
- FAILED noninferiority: composite 16.8 vs 13.3/100 pt-yr (adjusted RMST difference -0.36 yr; 95% CI -0.70 to -0.01; P=0.44 for NI). The HR 1.3 was the prespecified noninferiority margin, not the reported effect estimate.
- Stroke rates similar: 2.6 vs 2.7/100 pt-yr (27 events each group) — device provides comparable stroke prevention.
- Major bleeding was NOT reduced with device: 70 events (7.4/100 pt-yr) vs 61 (6.2/100 pt-yr). Of the 70 device-group bleeds, 18 were procedure-related and 52 were NON-procedure-related; the 18 periprocedural events offset any long-term bleeding reduction.
- Very high-risk cohort: mean age 78, CHA2DS2-VASc 5.2, HAS-BLED 3.0. Prior major bleeding in 30.4%. Stage IV CKD in 24.1%.
- First large RCT vs a DOAC-dominant control: 85.1% of medical group on DOACs (prior trials PROTECT-AF/PREVAIL compared vs warfarin; prior LAAO-vs-DOAC data are limited, e.g., Osmancik 2020).
- Periprocedural complications within 7 days post-implant occurred in 5.7% of patients. Table 3 breakdown: 5 pericardial tamponades (4 treated with pericardiocentesis, 1 surgically), 18 major bleeding events requiring transfusion, 1 device embolization requiring surgical removal, 1 procedure-related TIA, 1 peripheral embolism, and 2 deaths within 7 days of implantation.
- Procedural success 96.4%. Device success 98.3% (414/421). Watchman/FLX 54.3%, Amplatzer/Amulet 41.8%, LAmbre 3.9% (bailout at selected sites).
- CV or unexplained death numerically higher with device: 9.5 vs 7.7/100 pt-yr (adjusted RMST difference -0.19; 95% CI -0.50 to 0.11).
- Sample size was reduced twice: 912 patients enrolled vs 1,586 originally planned; 282 primary events observed vs 467 needed at 80% power. Per the paper, the sequential design was abandoned and recruitment stopped after 912 were enrolled because published data from another trial (Osmancik 2020, ref 20) suggested this trial might already be overpowered — not for efficacy/safety concerns and not driven by LAAOS III.
- Key implication: in the DOAC era, LAA closure does not offer a net clinical benefit over medical therapy, even in high-bleeding-risk patients.
- Despite NI failure on the primary composite, device-group patients had numerically MORE hospitalizations for bleeding or CV events (53.0 vs 39.4 per 100 pt-yr; adjusted RMST difference -0.44 years, 95% CI -0.80 to -0.09). Per the paper, secondary endpoint CIs are not adjusted for multiplicity and cannot be interpreted as hypothesis tests — but the direction reinforces that LAA closure does not reduce cardiovascular burden in this high-risk population.
Design
Study Type: Pragmatic, prospective, open-label, multicenter, randomized, controlled trial with blinded outcome adjudication (PROBE design)
Randomization: 1
Blinding: Open-label; blinded outcome adjudication by independent clinical events committee. 1:1, stratified by site.
Enrollment Period: March 2018 to May 2024
Follow-up Duration: Median 3.0 years (IQR 1.7-4.7); maximum 6.7 years.
Centers: 42
Countries: Germany
Sample Size: 888
Analysis: Intention-to-treat. Noninferiority design with prespecified HR margin of 1.3. Cox model with RMST used due to non-proportional hazards. Planned 1,586, enrolled 912; 888 in analysis.
Registration: NCT03463317
Inclusion Criteria
- Adult with AF (paroxysmal, persistent, or permanent).
- CHA2DS2-VASc score ≥2.
- High bleeding risk: at least one of: HAS-BLED ≥3, prior intracranial/intraspinal/intraocular bleeding, prior BARC 3a/3b hemorrhage, Stage IV CKD (eGFR 15-29), recurrent bleeding precluding long-term anticoagulation.
- OR contraindications to long-term anticoagulation.
Exclusion Criteria
- Detailed criteria in Supplementary Table S4 (not enumerated in main manuscript).
Arms
| Field | LAA Closure | Control |
|---|---|---|
| Intervention | Catheter-based LAA closure: Watchman/FLX (54.3%), Amplatzer/Amulet (41.8%), LAmbre (3.9%, available at selected sites as a bailout device). Attempted in 421/446 (94.4%). Post-implant: DAPT recommended for ≥3 months, then aspirin until 6 months. High-bleed-risk option: DAPT 6 weeks, aspirin 3 months. | Physician-directed: 85.1% DOAC, 3.2% VKA, 1.6% single antiplatelet, 0.7% DAPT, 7.5% no antithrombotics. DOAC as default for anticoagulation-eligible patients. 18 patients (4.1%) crossed to LAA closure. |
| Duration | Single procedure + median 3.0 years follow-up | Median 3.0 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite: stroke (ischemic or hemorrhagic), systemic embolism, major bleeding (BARC ≥3), or cardiovascular or unexplained death | Primary | 127 events; 13.3/100 pt-yr (127/957.0) | 155 events; 16.8/100 pt-yr (155/920.8) | 0.44 for noninferiority (FAILED) | |
| Ischemic or hemorrhagic stroke | Secondary | 27/1015.1 (2.7/100 pt-yr) | 27/1019.0 (2.6/100 pt-yr) | ||
| Ischemic stroke | Secondary | 15/1022.7 (1.5/100 pt-yr) | 18/1022.8 (1.8/100 pt-yr) | ||
| Hemorrhagic stroke | Secondary | 13/1037.4 (1.3/100 pt-yr) | 10/1039.5 (1.0/100 pt-yr) | ||
| Major bleeding (BARC ≥3) | Secondary | 61/978.7 (6.2/100 pt-yr) | 70/941.5 (7.4/100 pt-yr) | ||
| Cardiovascular or unexplained death | Secondary | 81/1045.4 (7.7/100 pt-yr) | 99/1045.2 (9.5/100 pt-yr) | ||
| Death from any cause | Secondary | 141/1045.4 (13.5/100 pt-yr) | 155/1045.2 (14.8/100 pt-yr) | ||
| Systemic embolism | Secondary | 1/1045.4 (0.1/100 pt-yr) | 3/1042.7 (0.3/100 pt-yr) | ||
| Myocardial infarction | Secondary | 20/1016.9 (2.0/100 pt-yr) | 14/1021.8 (1.4/100 pt-yr) | ||
| Transient ischemic attack (time-to-event over follow-up) | Secondary | 10/1028.6 (1.0/100 pt-yr) | 9/1029.1 (0.9/100 pt-yr) | ||
| Stroke or systemic embolism composite | Secondary | 28/1015.0 (2.8/100 pt-yr) | 29/1016.5 (2.9/100 pt-yr) | ||
| Hospitalization for bleeding or cardiovascular event | Secondary | 250/633.9 (39.4/100 pt-yr) | 284/535.9 (53.0/100 pt-yr) | ||
| Major adverse cardiac and cerebrovascular event (MACCE) | Secondary | 81/988.6 (8.2/100 pt-yr) | 92/988.3 (9.3/100 pt-yr) | ||
| Periprocedural complications (≤7 days) | Adverse | 24/421 (5.7%) | |||
| Pericardial tamponade | Adverse | 5 (4 pericardiocentesis, 1 surgical) | |||
| Periprocedural major bleed requiring transfusion (BARC 3-5) | Adverse | 18 | |||
| Device embolization | Adverse | 1 (surgical removal) | |||
| Death within 7 days after implantation | Adverse | 2 (paper describes as periprocedural deaths) | |||
| Procedure-related TIA | Adverse | 1 | |||
| Peripheral embolism | Adverse | 1 | |||
| Non-procedure-related major bleeding (device group) | Adverse | 52 patients | |||
| SAEs | Adverse | 342 (77.4%) | 368 (82.5%) |
Subgroup Analysis
Prespecified subgroups in Supplementary Figures S5-S6. Main text states results 'appeared consistent with primary analysis.' Details in supplement.
Criticisms
- FAILED noninferiority — confidence interval for the primary RMST difference did not cross zero in favor of device.
- Sample size was reduced twice: original plan 1,586 patients for 467 primary events at 80% power, but recruitment was stopped after 912 were enrolled because published data from another trial (Osmancik 2020, ref 20) suggested this trial might already be overpowered. Observed 282 events; failure of noninferiority could reflect either a true negative result or a power shortfall given the sample size reduction.
- Germany only (93.6% White) — limited generalizability.
- Open-label — clinical events committee could not be blinded to procedural complications.
- Periprocedural bleeding (18 events in the device group) drove the lack of bleeding reduction — 52 additional device-group bleeds were non-procedural. The device's long-term bleeding benefit may improve with operator experience and refined peri-implant antithrombotic strategies.
- More lost to follow-up in medical group (5.2% vs 2.2%); more withdrawals in device group (12.6% vs 10.9%).
- 18 crossovers from medical to LAA closure.
- Device selection limited to Watchman/FLX, Amplatzer/Amulet, and LAmbre (3.9%, bailout at selected sites) — newer devices may perform differently.
- High event rate in medical group (13.3/100 pt-yr) reflects genuinely high-risk population.
- Per-protocol sensitivity analysis confirmed the primary result (RMST -0.40 years, 95% CI -0.76 to -0.04) — also failed noninferiority.
Funding
German Center for Cardiovascular Research (DZHK) — public grant. Coordinated by Charité University Medicine Berlin.
Based on: CLOSURE-AF (The New England Journal of Medicine, 2026)
Authors: U. Landmesser, C. Skurk, P. Kirchhof, ..., for the CLOSURE-AF Trial Investigators
Citation: N Engl J Med 2026. DOI: 10.1056/NEJMoa2513310.
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