New England Journal of Medicine May 02, 2019

Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients

Jeffrey J. Popma, G. Michael Deeb, Steven J. Yakubov et al.

Bottom Line

In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self-expanding bioprosthesis was noninferior to surgical aortic valve replacement regarding the composite of death or disabling stroke at 24 months.

Key Findings

1. The 24-month estimated incidence of the primary composite endpoint of all-cause mortality or disabling stroke was 5.3% in the TAVR group compared to 6.7% in the SAVR group (difference, -1.4 percentage points), easily meeting noninferiority (posterior probability >0.999).

2. At 30 days, TAVR demonstrated significantly lower rates of disabling stroke (0.5% vs. 1.7%), bleeding complications (2.4% vs. 7.5%), acute kidney injury (0.9% vs. 2.8%), and atrial fibrillation (7.7% vs. 35.4%).

3. TAVR was associated with a higher 30-day incidence of permanent pacemaker implantation (17.4% vs. 6.1%) and moderate or severe paravalvular aortic regurgitation (3.5% vs. 0.5%).

4. Hemodynamic performance at 12 months favored TAVR, demonstrating lower mean aortic-valve gradients (8.6 mm Hg vs. 11.2 mm Hg) and larger effective orifice areas (2.3 cm² vs. 2.0 cm²) compared to surgery.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

1,468

Patients

Duration

24 mo

Median

Setting

Multicenter, international

Population Patients with severe symptomatic aortic stenosis who were deemed to be at low surgical risk (predicted 30-day risk of death with surgery of 3% or less).

Intervention Transcatheter aortic-valve replacement (TAVR) with a self-expanding, supra-annular bioprosthesis (Medtronic CoreValve, Evolut R, or Evolut PRO).

Comparator Surgical aortic-valve replacement (SAVR) with a commercially available bioprosthetic valve.

Outcome Composite of death from any cause or disabling stroke at 24 months, evaluated for noninferiority using Bayesian methodology.

Study Limitations

• A 24-month follow-up period is insufficient to establish long-term structural valve durability, a critical concern for younger, low-risk patients with longer life expectancies.

• The high rate of new permanent pacemaker implantation in the TAVR group may have detrimental long-term clinical implications, such as pacing-induced cardiomyopathy.

• The open-label study design introduces the potential for ascertainment bias, particularly for subjective or non-mortality secondary endpoints.

• The trial exclusively evaluated a self-expanding valve platform (Medtronic CoreValve/Evolut), meaning findings may not perfectly extrapolate to balloon-expandable systems (though PARTNER 3 showed similar results).

Clinical Significance

Published concurrently with the PARTNER 3 trial, the Evolut Low Risk trial fundamentally shifted the treatment paradigm for severe aortic stenosis. By proving that TAVR is safe, hemodynamically superior, and noninferior for major clinical outcomes compared to open-heart surgery in low-risk patients, it catalyzed the FDA's decision to expand TAVR indications to patients across all surgical risk strata. Today, TAVR is a standard first-line therapy for the vast majority of patients with severe aortic stenosis.

Historical Context

Historically, surgical aortic valve replacement (SAVR) was the definitive gold standard for severe symptomatic aortic stenosis. Over a decade, TAVR was progressively proven effective in inoperable cohorts (PARTNER 1B), high-risk cohorts (PARTNER 1A, CoreValve High Risk), and intermediate-risk cohorts (PARTNER 2A, SURTAVI). The Evolut Low Risk trial, alongside PARTNER 3, was the final frontier, testing the procedure in the lowest surgical risk cohort, which constitutes the majority of the aortic stenosis population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the classic symptoms of severe aortic stenosis that would prompt consideration for intervention, and why is the transition from asymptomatic to symptomatic disease a critical inflection point in the natural history of this condition?

Key Response

The classic triad is angina, syncope, and heart failure. Understanding the natural history of AS is foundational; once symptoms develop, mortality increases dramatically, making timely valve replacement critical.

Resident

Based on the findings of the Evolut Low Risk trial, how do the complication profiles of TAVR with a self-expanding valve and SAVR differ, particularly regarding permanent pacemaker implantation and atrial fibrillation, and how does this influence patient counseling?

Key Response

TAVR is associated with higher rates of permanent pacemaker implantation and paravalvular leak, whereas SAVR is associated with higher rates of new-onset atrial fibrillation, acute kidney injury, and severe bleeding. Residents must weigh these trade-offs when counseling low-risk patients.

Fellow

The Evolut Low Risk trial excluded patients with bicuspid aortic valves. How does the presence of bicuspid aortic valve anatomy complicate the use of a self-expanding TAVR system, and what specific imaging findings must be evaluated prior to off-label use?

Key Response

Bicuspid AS often presents with asymmetric calcification, a dilated ascending aorta, and an elliptical annulus, increasing risks of annular rupture, significant paravalvular leak, and asymmetric deployment. Fellows must understand how calcium distribution and raphe characteristics on CT guide valve sizing.

Attending

Given the noninferiority of TAVR in low-risk patients at 24 months, how should the unknown long-term durability of transcatheter valves compared to surgical bioprostheses influence shared decision-making in a 65-year-old active patient considering their lifetime management of aortic valve disease?

Key Response

The lifetime management strategy is paramount. A 65-year-old will likely outlive their first bioprosthetic valve. Attendings must consider sequence strategy (TAVR-in-TAVR vs. SAVR-then-TAVR), structural valve deterioration rates, and future coronary access issues when choosing the first intervention.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial utilized a Bayesian adaptive design with predetermined interim analyses for noninferiority. What are the methodological advantages and potential pitfalls of using a Bayesian approach to declare early success in device trials, particularly regarding the precision of secondary safety endpoints?

Key Response

Bayesian adaptive designs allow for predictive probability of trial success and potentially smaller sample sizes. However, early stopping for noninferiority on the primary endpoint can leave the trial underpowered to detect meaningful long-term differences in secondary endpoints like valve durability or late pacemaker requirements.

Journal Editor

In reviewing the composite primary endpoint of death or disabling stroke, how might the ascertainment bias related to differential follow-up or the subjective components of the modified Rankin Scale for stroke evaluation impact the validity of the noninferiority margin?

Key Response

Disabling stroke assessment relies on the modified Rankin Scale, which can be subjective. If unblinded assessors (due to obvious surgical scars vs. groin access) score stroke severity differently, the noninferiority margin could be artificially met. Reviewers must scrutinize blinding protocols for clinical event committees.

Guideline Committee

How does the evidence from the Evolut Low Risk trial influence the ACC/AHA guidelines regarding the age threshold for TAVR, and how should guidelines mandate the Heart Team's approach to anatomical exclusions like bicuspid valves that were not represented in the trial?

Key Response

While the trial supports TAVR in low-risk patients, current ACC/AHA guidelines emphasize age and life expectancy (e.g., favoring SAVR in patients <65 years). Guidelines must integrate these findings by expanding shared decision-making for patients aged 65-80 while explicitly maintaining SAVR as the standard for bicuspid valves or complex anatomies excluded from the trial.

Clinical Landscape

Noteworthy Related Trials

2015

NOTION Trial

n = 280 · JACC

Tested

TAVR with a self-expanding valve (CoreValve)

Population

All-comers with severe aortic stenosis, predominantly at low surgical risk

Comparator

Surgical Aortic-Valve Replacement (SAVR)

Endpoint

Composite of death from any cause, stroke, or myocardial infarction at 1 year

Key result: There was no significant difference between TAVR and SAVR in the primary composite endpoint at 1 year, though TAVR was associated with higher rates of pacemaker implantation.

2017

SURTAVI Trial

n = 1,660 · NEJM

Tested

TAVR with a self-expanding valve (CoreValve or Evolut R)

Population

Patients with severe aortic stenosis at intermediate surgical risk

Comparator

Surgical Aortic-Valve Replacement (SAVR)

Endpoint

Composite of death from any cause or disabling stroke at 24 months

Key result: TAVR was noninferior to surgery for the primary endpoint of all-cause mortality or disabling stroke at 2 years.

2019

PARTNER 3 Trial

n = 1,000 · NEJM

Tested

TAVR with a balloon-expandable valve (SAPIEN 3)

Population

Patients with severe aortic stenosis and low surgical risk

Comparator

Surgical Aortic-Valve Replacement (SAVR)

Endpoint

Composite of death from any cause, stroke, or rehospitalization at 1 year

Key result: TAVR with a balloon-expandable valve was superior to surgery for the primary composite endpoint at 1 year.

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