Evolut Low Risk

Published

Popma JJ, et al. "Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients". The New England Journal of Medicine. 2019. 380(18):1706-1715.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with severe aortic stenosis and low surgical risk, is transcatheter aortic valve replacement (TAVR) non-inferior to surgical aortic valve replacement (SAVR) in regards to death or disabling stroke?

Bottom Line

Among patients with severe AS and low surgical risk, TAVR was found to be non-inferior to SAVR in regards to the composite primary endpoint of all-cause mortality or disabling stroke at 24 months.

Major Points

TAVR was initially studied in patients with severe AS and extreme and high surgical risk through a parallel series of clinical trials evaluating the efficacy of the Edwards Sapien balloon-expandable bioprosthesis (PARTNER A and PARTNER B) and the Medtronic CoreValve and Evolut self-expanding bioprostheses (CoreValve Extreme Risk Pivotal Trial and U.S. CoreValve High Risk Study). In these studies, patients undergoing TAVR had significantly increased survival compared to SAVR, and subsequent ACC/AHA guidelines recommended TAVR in patients with prohibitive surgical risk (Class I) and TAVR or SAVR in patients with high surgical risk (Class I). Subsequent studies have demonstrated that TAVR with a balloon-expandable bioprosthesis (PARTNER 2) and self-expanding bioprosthesis (SURTAVI) is noninferior to SAVR for patients with severe AS and intermediate surgical risk, and 2017 AHA/ACC guidelines state that is is reasonable to consider TAVR in these patients (Class IIa). A small randomized trial (NOTION) of patients with severe AS and predominantly low surgical risk demonstrated similar outcomes with a self-expanding bioprosthesis.

The Evolut Low Risk trial was designed to further evaluate the efficacy of the Medtronic self-expanding bioprostheses (CoreValve, Evolut R, or Evolut PRO) in patients with severe AS and low surgical risk, defined as a Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) less than or equal to 3%. A total of 1,468 patients with an average STS-PROM of 1.9% were randomized to either TAVR or surgery, and the composite primary endpoint of all-cause mortality or disabling stroke at 24 months was 5.3% vs. 6.7%, which was significant for non-inferiority. Of note, the rate of disabling stroke was significantly lower for TAVR (1.1%) vs. SAVR (3.5%) at 2 years. The rate of permanent pacemaker implantation at 30 days was significantly higher for TAVR (17.4%) vs. SAVR (6.1%). The Evolut Low Risk trial was published simultaneously with PARTNER 3, which evaluated TAVR with a balloon-expandable bioprosthesis vs. SAVR in low-risk surgical patients with severe AS, demonstrated a significantly lower composite primary endpoint of death, stroke, or rehospitalization at 1 year in the TAVR group.

Three-year follow up of this trial published in 2023 reported death or disabling stroke in 7.4% of patients receiving TAVR and 10.4% of patients receiving SAVR (HR 0.70; 95% CI 0.49 to 1.00; P=0.051). The authors did not specify, but this comparison is probably a superiority analysis. It is reasonable to consider with the additional follow-up that TAVR was still non-inferior to SAVR in low risk patients for the primary outcome.

Guidelines

ACC/AHA valvular heart disease (2020, adapted)

• Among patients appropriate for a bioprosthetic valve with symptomatic, severe AS:
  • Who are <65 years old and life expectancy >20 years, recommend SAVR (COR 1, LOE A)
  • Who are 65-80 years old and without transfermoral TAVR anatomical contraindication, either SAVR or transfemoral TAVR is recommended, with choice guided by shared-decision making (COR 1, LOE A)
  • Who are >80 years old or with life expectancy <10 years and no transfemoral TAVR contraindication, transfemoral TAVR is recommended over SAVR (COR 1, LOE A)
• See Section 3.2.4.2 for other considerations, including asymptomatic patients, and Figure 3 for guidance on when to choice SAVR versus TAVR.

Design

• Multinational, randomized, noninferiority trial
• N=1,468
  • TAVR (n=734)
  • SAVR (n=734)
• Setting: 86 centers in Australia, Canada, France, Japan, the Netherlands, New Zealand, and the United States
• Enrollment: 2016-2018
• Follow-up: 12.2 months
• Analysis: As-treated (intention-to-treat was a secondary analysis) with Bayesian adaptive statistical methods with noninformative prior distributions
• Primary outcomes: Death or disabling stroke at 24 months

Population

Inclusion Criteria

• Severe aortic stenosis as defined by 1 of the following:
  • Symptomatic with aortic-valve area ≤1.0 cm2; or aortic-valve area index of ≤0.6 cm2/m2; or mean gradient ≥40 mm Hg; or maximal aortic-valve velocity ≥4.0 m/second.
  • Asymptomatic with aortic-valve area ≤1.0 cm2 or aortic-valve area index of ≤0.6 cm2/m2; and mean gradient ≥60 mm Hg or maximal aortic-valve velocity ≥5.0 m/second.
  • Asymptomatic with aortic-valve area ≤1.0 cm2 or aortic-valve area index of ≤0.6 cm2/m2; and an exercise tolerance test demonstrating limited exercise capacity, abnormal blood pressure response, or arrhythmia.
  • Asymptomatic with aortic-valve area ≤1.0 cm2 or less; or aortic-valve area index of ≤0.6 cm2 per square meter; or mean gradient ≥40 mm Hg; or maximal aortic-valve velocity ≥4.0 m/second; and LVEF <50%.
• Estimated 30-day mortality less than or equal to 3%

Exclusion Criteria

• Indication for mechanical aortic valve
• Contraindication to the following:
  • Aspirin or heparin and bivalirudin
  • Ticlodipine and clopidogrel
  • Nitinol
  • Contrast media
• Blood dyscrasias including:
  • Leukopenia (WBC <1000 cells per cubic mm)
  • Thrombocytopenia (Platelet count <50,000 cells per cubic mm)
  • Bleeding diathesis or coagulopathy
  • Hypercoagulable state
• Active infection
• Percutaneous coronary or peripheral intervention with a bare metal stent within 30 days or drug eluting stent within 180 days
• Multivessel CAD with SYNTAX score >22 and/or unprotected left main coronary artery
• Symptomatic carotid or vertebral artery disease or successful treatment of carotid artery stenosis within 10 weeks
• Cardiogenic shock as defined by one or more of the following:
  • Low cardiac output
  • Vasopressor dependence
  • Mechanical hemodynamic support
• Stroke or TIA in prior 2 months
• GI bleeding preventing use of anticoagulation
• Refusal of blood transfusions
• Severe dementia
• Life expectancy <24 months due to non-cardiac comorbidities
• Other medical, social, or psychological conditions that would preclude consent or adherence to the protocol
• MI in prior 30 days due to unstable CAD
• Need for emergency surgery
• Pregnancy or breastfeeding
• Less than legal age of consent, incompetent, or otherwise vulnerable.
• Anatomic considerations including:
  • Severe mitral regurgitation
  • Severe tricuspid regurgitation
  • Moderate to severe mitral stenosis
  • Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient
  • Bicuspid aortic valve
  • Prohibitive left ventricular outflow tract calcification
  • Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis
  • Aortic annulus diameter <18 mm or >30 mm
  • Aortopathy requiring ascending aortic replacement
  • Access vessel not amenable to TAVR

Baseline Characteristics

From the TAVR group.

• Demographics: Age 74 years, female sex 36%
• NYHA class: I 10%, II 64%, III 25%, IV <1%
• STS-PROM: 1.9 ± 0.7%
• Medical problems: Diabetes 31.4%, on HD 0%, hypertension 85%, PAD 8%, cerebrovascular disease 10%, COPD 15%,
• Serum creatinine >2 mg/dl: 0.4%
• Cardiac risk factors:
  • Syntax score: 1.9 ± 3.7
  • Previous CABG: 2.5%
  • Previous PCI: 14.2%
  • Preexisting pacemaker or defibrillator: 3.2%
  • Previous MI: 6.6%
  • Previous atrial fibrillation or atrial flutter: 15.4%
  • Aortic-valve gradient: 47.0 ± 12.1 mmHg
  • Aortic-valve area: 0.8 ± 0.2 square cm
  • Left ventricular ejection fraction: 61.7 ± 7.9%

Interventions

• Patients receiving TAVR were treated with the CoreValve, Evolut R, or Evolut PRO self-expanding bioprosthesis
• Patients receiving SAVR were treated with a bioprosthetic surgical valve at the discretion of the surgeon
• Evaluation was performed at baseline, at discharge, and at 1, 6, 12, 18, and 24 months, and echocardiographic studies were analyzed at an independent site
• Quality of life surveys were performed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)

Outcomes

Comparisons are TAVR vs. SAVR.

Primary Outcome

Death or disabling stroke

30 days: 0.8% vs. 2.6% (difference, -1.8; 95% BCI for the difference, -3.2 to -0.5)

12 months: 2.9% vs. 4.6% (difference, -1.8; 95% BCI for the difference, -4.0 to 0.4)

24 months: 5.3% vs. 6.7% (difference, −1.4; 95% BCI for the difference, −4.9 to 2.1; posterior probability of noninferiority, >0.999)

Secondary Outcomes

Death from any cause

30 days: 0.5% vs. 1.3% (difference, -0.8; 95% BCI for the difference, -1.9 to 0.2)

12 months: 2.4% vs. 3.0% (difference, -0.6; 95% BCI for the difference, -2.6 to 1.3)

Death from cardiovascular cause

30 days: 0.5% vs. 1.3% (difference, -0.8; 95% BCI for the difference, -1.9 to 0.2)

12 months: 1.7% vs. 2.6% (difference, -0.9; 95% BCI for the difference, -2.7 to 0.7)

Disabling stroke

30 days: 0.5% vs. 1.7% (difference, -1.2; 95% BCI for the difference, -2.4 to -0.2)

12 months: 0.8% vs. 2.4% (difference, -1.6; 95% BCI for the difference, -3.1 to –0.3)

All stroke

30 days: 3.4% vs. 3.4% (difference, 0.0; 95% BCI for the difference, -1.9 to 1.9)

12 months: 4.1% vs. 4.3% (difference, -0.2; 95% BCI for the difference, -2.4 to 1.9)

TIA

30 days: 0.6% vs. 0.8% (difference, -0.2; 95% BCI for the difference, -1.2 to 0.7)

12 months: 1.7% vs. 1.8% (difference, -0.2; 95% BCI for the difference, -1.6 to 1.3)

Life-threatening or disabling bleeding

30 days: 2.4% vs. 7.5% (difference, -5.1; 95% BCI for the difference, -7.5 to -2.9)

12 months: 3.2% vs. 8.9% (difference, -5.7; 95% BCI for the difference, -8.4 to -3.1)

Major vascular complication

30 days: 3.8% vs. 3.2% (difference, 0.6; 95% BCI for the difference, -1.4 to 2.5)

12 months: 3.8% vs. 3.5% (difference, 0.3; 95% BCI for the difference, -1.7 to 2.3)

AKI stage 2 or 3

30 days: 0.9% vs. 2.8% (difference, -1.8; 95% BCI for the difference, -3.4 to -0.5)

12 months: 0.9% vs. 2.8% (difference, -1.8; 95% BCI for the difference, -3.4 to -0.5)

Atrial fibrillation

30 days: 7.7% vs. 35.4% (difference, -27.7; 95% BCI for the difference, -31.8 to -23.6)

12 months: 9.8% vs. 38.3% (difference, -28.5; 95% BCI for the difference, -32.8 to -24.1)

Permanent pacemaker implantation

30 days: 17.4% vs. 6.1% (difference, 11.3; 95% BCI for the difference, 8.0 to 14.7)

12 months: 19.4% vs. 6.7% (difference, 12.6; 95% BCI for the difference, 9.2 to 16.2)

Myocardial infarction

30 days: 0.9% vs. 1.3% (difference, -0.4; 95% BCI for the difference, -1.5 to 0.7)

12 months: 1.7% vs. 1.6% (difference, 0.1; 95% BCI for the difference, -1.3 to 1.5)

Coronary artery obstruction

30 days: 0.9% vs. 0.4% (difference, 0.5; 95% BCI for the difference, -0.3 to 1.4)

12 months: 0.9% vs. 0.4% (difference, 0.5; 95% BCI for the difference, -0.3 to 1.4)

Endocarditis

30 days: 0.1% vs. 0.2% (difference, -0.1; 95% BCI for the difference, -0.7 to 0.3)

12 months: 0.2% vs. 0.4% (difference, -0.2; 95% BCI for the difference, -0.9 to 0.5)

Valve thrombosis

30 days: 0.1% vs. 0.1% (difference, 0.0; 95% BCI for the difference, -0.4 to 0.4)

12 months: 0.2% vs. 0.3% (difference, -0.1; 95% BCI for the difference, -1.0 to 0.9)

Aortic reintervention

30 days: 0.4% vs. 0.4% (difference, 0.0; 95% BCI for the difference, -0.8 to 0.7)

12 months: 0.7% vs. 0.6% (difference, 0.0; 95% BCI for the difference, -1.0 to 0.9)

Hospitalization for heart failure

30 days: 1.2% vs. 2.5% (difference, -1.3; 95% BCI for the difference, -2.8 to 0.1)

12 months: 3.2% vs. 6.5% (difference, -3.4; 95% BCI for the difference, -5.9 to -1.0)

Mean gradient at 12 months

8.6 ± 3.7 mmHg vs. 11.2 ± 4.9 mmHg (difference, -2.6, 95% BCI for the difference, -3.2 to -2.0, posterior probability of superiority, >0.999)

Mean effective orifice area at 12 months

2.3 ± 0.7 square cm vs. 2.0 ± 0.6 square cm (difference, 0.3; 95% BCI for the difference, 0.2 to 0.4, posterior probability of superiority, >0.999)

Mean KCCQ change from baseline to 30 days

20.0 ± 21.1 vs. 9.1 ± 22.3 (difference, 10.9; 95% BCI for the difference, 8.6 to 13.2, posterior probability of superiority, >0.999)

Criticisms

• The results are from a planned interim analysis.
• Blinded adjudication was not possible for all endpoints.
• Multiple bioprostheses were used, and only 22.3% were the latest generation Evolut PRO.
• The primary analysis was as-treated, but a secondary intention-to-treat analysis demonstrated the same result in regards to the primary outcome.

Funding

Medtronic.