Evolut Low Risk

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In Review
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) noninferior to surgical aortic valve replacement (SAVR) in regards to death or disabling stroke?

Bottom Line

The Evolut Low Risk trial was designed to evaluate the efficacy of the Medtronic self-expanding bioprostheses in 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 (5.3% vs. 6.7%, posterior probability of noninferiority >0.999).

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 ACC/AHA guidelines now recommend TAVR in patients with prohibitive surgical risk (Class I) and TAVR or SAVR in patients with high surgical risk (Class I).[1] 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%).

An increasing number of patients with severe AS are currently undergoing TAVR; however, most patients with severe AS are of low surgical risk. This trial has the potential to significantly change current practices regarding the treatment of these low surgical risk patients with severe AS. Further support for these findings comes from the simultaneously published PARTNER 3 trial, 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. It is important to note that the currently described findings are the result of a planned interim analysis and the long term follow up with be required to determine the durability of the results. Additional limitations include exclusion of patients with bicuspid aortic valves, a predominance of high-gradient aortic stenosis, and a low proportion of women. Further studies addressing these issues will be required for generalization of these results.

Guidelines

As of May 2019, no guidelines have been published that reflect the results of this trial.

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: March 2016 to November 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 one of the following:
    • Symptomatic with aortic-valve area of 1.0 cm2 or less; or aortic-valve area index of ≤0.6 cm2 per square meter; or mean gradient of 40 mm Hg or more; or maximal aortic-valve velocity of 4.0 m or more per second.
    • Asymptomatic with aortic-valve area of 1.0 cm2 or less or aortic-valve area index of ≤0.6 cm2 per square meter; and mean gradient of 60 mm Hg or more or maximal aortic-valve velocity of 5.0 m or more per second.
    • Asymptomatic with aortic-valve area of 1.0 cm2 or less or aortic-valve area index of ≤0.6 cm2 per square meter; and an exercise tolerance test demonstrating limited exercise capacity, abnormal blood pressure response, or arrhythmia.
    • Asymptomatic with aortic-valve area of 1.0 cm2 or less; or aortic-valve area index of ≤0.6 cm2 per square meter; or mean gradient of 40 mm Hg or more; or maximal aortic-valve velocity of 4.0 m or more per second; and left ventricular ejection fraction less than 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 within 2 months
  • GI bleeding that would preclude anticoagulation
  • Patient refuses blood transfusions
  • Severe dementia
  • Estimated life expectancy less than 24 months due to non-cardiac comorbidities
  • Other medical, social, or psychological conditions that would preclude consent or adherence to the protocol
  • Evidence of MI within 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

Bulleted list of baseline characteristics of the study population. Point out between-group differences that are clinically relevant. Pick only one of the groups to summarize. For RCTs, please omit P-values if presented by the journal.

From the TAVR group.

  • Mean age: 74.1 ± 5.8 years
  • Female sex: 36.0%
  • NYHA class I: 10.5%
  • NYHA class II: 64.4%
  • NYHA class III: 25.0%
  • NYHA class IV: 0.1%
  • STS-PROM: 1.9 ± 0.7%
  • Diabetes mellitus: 31.4%
  • Serum creatinine >2 mg/dl: 0.4%
  • Dialysis: 0%
  • Hypertension: 84.8%
  • Peripheral arterial disease: 7.5%
  • Cerebrovascular disease: 10.2%
  • COPD: 15.0%
  • 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)

Subgroup Analysis

No subgroup analyses were performed.

Adverse Events

No adverse events other than the outcomes listed above were reported.

Criticisms

  • The results are from a planned interim analysis, so follow up is not yet complete.
  • 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

The study was funded by Medtronic.

Further Reading

  1. ↑ Nishimura RA et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017. 135:e1159-e1195.
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