New England Journal of Medicine May 02, 2019

Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients

Michael J. Mack, Martin B. Leon, Vinod H. Thourani, et al.

Bottom Line

In patients with severe aortic stenosis and low surgical risk, TAVR was superior to surgical aortic-valve replacement in reducing the composite rate of death, stroke, or rehospitalization at 1 year.

Key Findings

1. The primary composite endpoint (death, stroke, or rehospitalization at 1 year) was significantly lower in the TAVR group compared to the surgery group (8.5% vs. 15.1%; absolute difference, -6.6 percentage points; HR 0.54, 95% CI 0.37-0.79; P=0.001 for superiority) [1.1].

2. At 30 days, TAVR resulted in significantly lower rates of stroke (0.6% vs. 2.4%; P=0.02) and a lower composite rate of death or stroke (1.0% vs. 3.3%; P=0.01) compared to surgery.

3. New-onset atrial fibrillation at 30 days was markedly less frequent in the TAVR group (5.0% vs. 39.5%; P<0.001).

4. Index hospitalization was significantly shorter for TAVR patients (mean 3 days vs. 7 days).

5. There were no significant between-group differences in major vascular complications, new permanent pacemaker insertions (7.3% vs. 5.4%), or moderate/severe paravalvular regurgitation at 30 days.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

1,000

Patients

Duration

1 yr

Median

Setting

Multicenter

Population Patients with severe, symptomatic aortic stenosis who were deemed to be at low surgical risk (mean Society of Thoracic Surgeons risk score of 1.9%).

Intervention Transcatheter aortic-valve replacement (TAVR) with transfemoral placement of a balloon-expandable valve (SAPIEN 3).

Comparator Surgical aortic-valve replacement (SAVR).

Outcome A composite of death from any cause, stroke, or rehospitalization at 1 year.

Study Limitations

• The trial was open-label, which may have introduced bias, particularly concerning the subjective components of the rehospitalization endpoint.

• The primary publication reports only 1-year follow-up; establishing the long-term structural durability of the bioprosthetic valve is critical for younger, low-risk patients with longer life expectancies [1.8].

• Patients with bicuspid aortic valves, severe coronary artery disease, or other complex anatomical challenges were excluded, limiting the generalizability of the findings.

• The study was powered for a composite primary endpoint, meaning individual hard clinical endpoints like mortality and stroke were underpowered despite the observed superiority.

Clinical Significance

The PARTNER 3 trial demonstrated that TAVR is superior to SAVR for the combined endpoint of death, stroke, or rehospitalization at 1 year in low-risk patients. Combined with drastically reduced hospital length of stay and lower rates of new-onset atrial fibrillation, these findings established TAVR as a safe, effective, and often preferred frontline treatment for severe symptomatic aortic stenosis across all surgical risk categories, provided patients have suitable anatomy.

Historical Context

Initially developed as a life-saving procedure for inoperable patients (PARTNER 1) and later proven noninferior in intermediate-risk patients (PARTNER 2), TAVR's role was historically limited by surgical risk profiles. Surgery remained the definitive standard of care for low-risk patients. The simultaneous publication of the PARTNER 3 and Evolut Low Risk trials in 2019 decisively upended this paradigm, precipitating an FDA indication expansion that transformed standard cardiovascular practice.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the pathophysiology of severe aortic stenosis, why does the development of symptoms such as syncope or angina dramatically change the urgency of interventions like TAVR or SAVR?

Key Response

Tests foundational knowledge of the classic symptom triad (syncope, angina, dyspnea) and the sharp decline in survival once symptoms appear, making mechanical relief of the obstruction critical to prevent sudden cardiac death and heart failure.

Resident

When evaluating a 65-year-old low-risk patient with severe symptomatic aortic stenosis for TAVR versus SAVR, what anatomical and clinical factors must be assessed to determine if they are an appropriate candidate for TAVR as done in the PARTNER 3 trial?

Key Response

Emphasizes practical workup such as CT for annular sizing, coronary height, bicuspid versus tricuspid morphology, and access vessel caliber, recognizing that bicuspid valves were excluded from PARTNER 3, which is critical for clinical decision-making.

Fellow

While PARTNER 3 showed superiority of TAVR at 1 year for the primary composite endpoint, how should the higher rates of new left bundle branch block and potential for mild paravalvular leak in TAVR patients influence long-term structural heart management in younger, low-risk populations?

Key Response

Dives into the advanced implications of PVL and conduction abnormalities, which are critical in younger patients with longer life expectancies due to risks of left ventricular dyssynchrony, heart failure, and the potential need for future pacemaker implantation.

Attending

Given the 1-year superiority of TAVR in the PARTNER 3 trial, how do you approach shared decision-making with a healthy 62-year-old low-risk patient regarding the uncertainties of valve durability and the potential need for future valve-in-valve procedures over their lifetime?

Key Response

Focuses on the art of medicine and shared decision-making, balancing short-term TAVR benefits against long-term uncertainties regarding structural valve deterioration and lifetime management strategies in younger patients who may outlive their bioprosthesis.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PARTNER 3 trial used a composite primary endpoint driven heavily by rehospitalization. How does the inclusion of rehospitalization affect the statistical power and clinical interpretation of a trial comparing a percutaneous versus surgical approach?

Key Response

Critiques the composite endpoint design, noting that rehospitalization can be a softer endpoint that drives statistical superiority, potentially masking non-significant differences in harder, objective endpoints like mortality or disabling stroke.

Journal Editor

In evaluating the methodology of PARTNER 3, how does the open-label nature of the trial, combined with a primary endpoint that includes rehospitalization, introduce potential assessment bias, and what safeguards should reviewers expect to see?

Key Response

Highlights a major threat to validity: patients and clinicians know who received TAVR versus SAVR, which can heavily influence thresholds for hospital admission, demanding rigorous, blinded independent clinical event committee adjudication to mitigate bias.

Guideline Committee

Following the PARTNER 3 trial, how should guidelines balance the robust 1-year superiority of TAVR against the lack of 10-year durability data when assigning a class of recommendation for patients under 65 years old with low surgical risk?

Key Response

Addresses the direct impact on the ACC/AHA Valvular Heart Disease guidelines, which ultimately recommended shared decision-making but favored SAVR in patients under 65 (Class I) due to durability concerns, while giving TAVR a Class I recommendation for older patients based on these low-risk trials.

Clinical Landscape

Noteworthy Related Trials

2015

NOTION Trial

n = 280 · JACC

Tested

Self-expanding transcatheter aortic valve replacement

Population

All-comers with severe aortic stenosis (predominantly low surgical risk)

Comparator

Surgical aortic valve replacement (SAVR)

Endpoint

Composite of all-cause death, 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.

2016

PARTNER 2 Trial

n = 2,032 · NEJM

Tested

Balloon-expandable transcatheter aortic valve replacement

Population

Patients with severe aortic stenosis at intermediate surgical risk

Comparator

Surgical aortic valve replacement (SAVR)

Endpoint

Composite of death or disabling stroke at 2 years

Key result: TAVR was noninferior to surgery for the primary composite endpoint, and the transfemoral cohort showed superiority.

2019

Evolut Low Risk Trial

n = 1,468 · NEJM

Tested

Self-expanding transcatheter aortic valve replacement

Population

Patients with severe aortic stenosis at low surgical risk

Comparator

Surgical aortic valve replacement (SAVR)

Endpoint

Composite of death or disabling stroke at 24 months

Key result: TAVR was noninferior to SAVR for the composite of death or disabling stroke at 24 months.

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