Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis (EARLY TAVR)

Authors, Journal, Affiliations, Type, DOI

• Authors: Philippe Généreux, Allan Schwartz, J. Bradley Oldemeyer, Philippe Pibarot, David J. Cohen, Philipp Blanke, Brian R. Lindman, Vasilis Babaliaros, William F. Fearon, David V. Daniels, Adnan K. Chhatriwalla, Clifford Kavinsky, Hemal Gada, Pinak Shah, Molly Szerlip, Thom Dahle, Kashish Goel, William O'Neill, Tej Sheth, Charles J. Davidson, Raj R. Makkar, Heather Prince, Yanglu Zhao, Rebecca T. Hahn, Jonathon Leipsic, Björn Redfors, Stuart J. Pocock, Michael Mack, Martin B. Leon — for the EARLY TAVR Trial Investigators
• Journal: New England Journal of Medicine (online October 28, 2024; print January 16, 2025)
• Affiliations: Gagnon Cardiovascular Institute (Morristown, NJ); Columbia University Medical Center/Cardiovascular Research Foundation (New York); Laval University (Quebec); Vanderbilt University; Emory University; Stanford/VA Palo Alto; McMaster University; Cedars-Sinai; Edwards Lifesciences (sponsor); 75 sites across United States and Canada
• Type: Prospective, multicenter, open-label, randomized controlled trial (1:1); intention-to-treat analysis; superiority testing
• DOI: https://doi.org/10.1056/NEJMoa2405880
• Funder: Edwards Lifesciences (SAPIEN 3/3 Ultra balloon-expandable valves; ClinicalTrials.gov NCT03042104)

Overview

The EARLY TAVR trial randomized 901 patients (mean age 75.8 years; 83.6% low surgical risk) with asymptomatic severe aortic stenosis and confirmed negative treadmill stress test to early transfemoral TAVR (SAPIEN 3/3 Ultra) or guideline-recommended clinical surveillance across 75 US/Canadian centres. At a median follow-up of 3.8 years, early TAVR reduced the composite primary endpoint of death, stroke, or unplanned cardiovascular hospitalisation by 50% (26.8% vs 45.3%; HR 0.50; P<0.001), with the benefit driven predominantly by reduced unplanned cardiovascular hospitalisations. Mortality (HR 0.93) and stroke (HR 0.62) were not significantly different as individual endpoints. Notably, 87% of the surveillance arm ultimately underwent aortic valve replacement (median 11.1 months), and 39.2% presented with advanced symptoms before conversion, reinforcing that "watchful waiting" in asymptomatic AS carries hidden decompensation risk.

Keywords

Asymptomatic aortic stenosis; transcatheter aortic valve replacement (TAVR/TAVI); early intervention; clinical surveillance; randomized trial; SAPIEN 3; balloon-expandable valve; EARLY TAVR

Key Takeaways

Background and Rationale

• Aortic stenosis affects >3% of adults ≥65 years; current guidelines recommend 6–12-month clinical surveillance for asymptomatic severe AS with preserved LVEF ≥50% and no other Class I indication for AVR
• Prior RCTs of early surgical AVR in asymptomatic AS (RECOVERY/AVATAR) were limited by small sample sizes, younger patients, and predominantly very severe disease (e.g., Vmax ≥4.5 m/s in RECOVERY) — none used TAVR
• EARLY TAVR was designed specifically to test early TAVR vs surveillance, addressing the gap in evidence for the transcatheter approach

Patient Population

• Enrolled: 1,578 screened → 901 randomised (March 2017–December 2021); 455 TAVR, 446 surveillance
• Eligibility: Age ≥65 years; asymptomatic severe AS; anatomy suitable for transfemoral TAVR; LVEF ≥50%; STS-PROM ≤10%; confirmed asymptomatic by negative treadmill stress test (90.6%) or physician assessment (9.4%)
• Baseline: Mean age 75.8 years; 30.9% women; STS-PROM 1.8%; 83.6% low surgical risk by local heart team; peak AV velocity 4.3 m/s; LVEF 67.4%; mean KCCQ 92.7; bicuspid AV 8.4%
• TAVR group: Median time to procedure 14 days (IQR 9–24 days); transfemoral SAPIEN 3 or SAPIEN 3 Ultra

Primary Endpoint — Death, Stroke, or Unplanned CV Hospitalisation

• Primary composite (any cause death + stroke + unplanned CV hospitalisation): 122 (26.8%) TAVR vs 202 (45.3%) surveillance; HR 0.50 (95% CI 0.40–0.63; P<0.001) — superiority demonstrated
• Kaplan-Meier 3.5-year estimates: TAVR 35.1% vs surveillance 51.2% — consistent, widening separation
• Death from any cause: 8.4% vs 9.2% (HR 0.93; NS) — no significant difference; 47.4% vs 56.1% of deaths were cardiovascular
• Stroke: 4.2% vs 6.7% (HR 0.62; 95% CI 0.35–1.10; NS) — lower in TAVR but not statistically significant; unexpected finding; further study needed
• Unplanned hospitalisation for CV causes: 20.9% vs 41.7% (HR 0.43; 95% CI 0.33–0.55) — the dominant driver; includes conversions to AVR within 6 months (105 in surveillance arm counted as events)
• Exploratory — HF hospitalisation: HR 0.32 (95% CI 0.18–0.58) — strongly favours TAVR
• Exploratory — CV death or stroke: HR 0.74 (95% CI 0.48–1.14); death, stroke, or HF hosp: HR 0.60 (0.44–0.83)
• Results consistent across all prespecified subgroups

Secondary Endpoints (Hierarchical Testing)

• Favorable outcome at 2 years (alive + KCCQ ≥75 without ≥10-point decline): 86.6% TAVR vs 68.0% surveillance (P<0.001) — met
• Integrated LV/LA health at 2 years (GLS ≥15% absolute + LVMi <115/95 g/m² + LAVi ≤34 mL/m²): 48.1% vs 35.9% (P=0.001) — met; suggests cardiac damage accumulates during asymptomatic surveillance
• LVEF change from baseline to 2 years: No significant difference between groups — EF preserved similarly
• New-onset AF: 13.0% vs 12.4% (HR similar; not significant in hierarchical testing) — threshold not met; AF burden similar despite TAVR procedure
• Death or disabling stroke: 9.7% vs 11.2% (HR NS) — not significant
• KCCQ scores at 2-year follow-up: 94.0 vs 93.0 — high in both groups, consistent with preserved functional status across arms

Clinical Surveillance Group — What Actually Happened

• 388/446 patients (87.0%) eventually underwent AVR during follow-up
• Median time from randomisation to conversion: 11.1 months (IQR 5.0–19.7)
• 26.2% converted at 6 months; 47.2% at 1 year; 71.4% at 2 years
• 39.2% of those converting had advanced signs/symptoms of AS at time of conversion (including 37.9% of those converting within first 6 months)
• Median time from symptom onset/decision to procedure: 32 days; 87.9% underwent procedure within 3 months
• LVEF ≤60% increased from 12.7% at screening to 20.7% at conversion; NT-proBNP rose from 298.6 to 462.2 pg/mL; 6MWT distance decreased 46.4 m; KCCQ decreased 14.8 points — demonstrating subclinical cardiac damage accumulated during watchful waiting
• 11 deaths in surveillance arm before conversion (6 CV, including 3 sudden deaths)

Safety

• No cardiovascular deaths within 30 days of procedure in either group
• 30-day stroke: 0.9% TAVR vs 1.8% surveillance-to-AVR conversions (NS)
• No significant differences in other periprocedural complications between TAVR group and surveillance crossover patients

Limitations of the Document

• Open-label adjudication: Independent clinical events committee was aware of treatment-group assignment — potential for adjudication bias, particularly for subjective endpoints like hospitalisations
• Generalisability: Results apply only to patients ≥65 years, predominantly low surgical risk, with anatomy suitable for transfemoral TAVR; STS-PROM ≤10% excludes very high-risk patients
• Device: Only balloon-expandable valves (SAPIEN 3/3 Ultra; Edwards Lifesciences); results may not apply to self-expanding valves
• High surveillance crossover: 87% of surveillance patients underwent AVR; trial effectively compares immediate vs delayed TAVR rather than TAVR vs truly indefinite watchful waiting
• Quality of surveillance: High-quality clinical surveillance (preemptive procedural planning, rapid conversion within 3 months of symptom onset) may not be replicable in real-world settings where AS is frequently undertreated
• Race/ethnicity: Majority White; limited generalisability to other racial/ethnic groups
• COVID-19 effect: Part of trial conducted during pandemic; may have affected outcomes and follow-up timing
• Short follow-up for mortality: Median 3.8 years may be insufficient to detect a survival benefit; long-term follow-up ongoing

Key Concepts Mentioned

• concepts/Aortic-Stenosis — primary disease; asymptomatic severe AS management
• concepts/TAVI — intervention being studied; SAPIEN 3/3 Ultra device
• concepts/Valvular-Heart-Disease — broader classification
• concepts/Structural-Valve-Deterioration — long-term valve durability concern

Key Entities Mentioned

• entities/Edwards-Lifesciences — trial funder and device manufacturer (SAPIEN 3/3 Ultra)

Wiki Pages Updated

• Created wiki/sources/tavi-earlytavr-nejm-2025.md
• Updated wiki/concepts/Aortic-Stenosis.md — added full EARLY TAVR trial section; updated contradictions
• Updated wiki/concepts/TAVI.md — added EARLY TAVR trial section; updated connections and sources
• Updated wiki/sourceindex.md — added new entry
• Updated wiki/wikiindex.md — updated TAVI and Aortic-Stenosis entries