ABSTRACT
Background
For patients with moderate aortic stenosis (AS), current US guidelines recommend clinical surveillance every 1 to 2 years. However, moderate AS has been associated with increased morbidity and mortality in multiple observational studies, suggesting a possible role for earlier treatment with transcatheter aortic valve replacement (TAVR). To date, no large, randomized trial has examined whether an early intervention with TAVR will improve outcomes among these patients.
Study Design and Objectives
The PROGRESS trial is a prospective, open-label, randomized, controlled, multicenter trial that includes up to 750 patients with moderate AS and at-risk features randomized 1:1 to either clinical surveillance or transfemoral TAVR with the SAPIEN 3/SAPIEN 3 Ultra/SAPIEN 3 Ultra RESILIA transcatheter heart valve (Edwards Lifesciences, Irvine, CA). Patients are stratified by site, left ventricular ejection fraction, and peak jet velocity. The primary effectiveness endpoint is the composite of death or heart failure event with or without hospitalization at 2 years. The primary safety endpoint (evaluated in the TAVR arm only) is a composite of death, stroke, life threatening or fatal bleeding, acute kidney injury stage 4, hospitalization due to device- or procedure-related complications, or valve dysfunction requiring reintervention at 30 days. Patients will be followed annually through 10 years.
Conclusions
The PROGRESS trial is the first large, randomized trial assessing the role of early intervention among patients with moderate AS with at-risk features compared to clinical surveillance.
Trial Registration Number
ClinicalTrials.gov identifier: NCT04889872
Aortic stenosis (AS) is frequent among the elderly population and affects >3% of adults above 65 years of age. ,,, AS is known to be a progressive disease, with a highly variable and unpredictable rate of progression. , More importantly, the severity of AS and its impact on cardiac function and structure, and on patient health status in general, is also variable and not fully understood. , Current guidelines recommend aortic valve replacement (AVR) for patients with severe AS who are either symptomatic (spontaneous symptoms or triggered on exercise stress test) or asymptomatic with a reduced left ventricular ejection fraction (LVEF). For patients with moderate AS, routine clinical and echocardiographic follow-up every 1 to 2 years is recommended, with AVR being a Class IIb recommendation for patients with another indication for cardiac surgery (eg, coronary artery bypass graft or mitral valve replacement). Whether earlier intervention, before AS becomes severe, could lead to improved outcomes remains unknown.
Several studies suggest that moderate AS is not benign and is associated with increased mortality and morbidity, ,,,,,,,,,,, especially when LV function is reduced, ,,,,,, extravalvular cardiac damage is present, ,,,, or there are signs and symptoms of heart failure. ,, Histopathology and cardiac magnetic resonance imaging studies have demonstrated that progressive pressure overload can lead to fibrosis before AS becomes severe. ,, Recent data also suggest that the rate of progression of mild-moderate AS to more severe AS is highly variable, unpredictable, and that some subgroups of patients with moderate AS have a prognosis similar to that seen with severe AS. ,,,, Multiple small, observational studies have demonstrated potential benefits of AVR compared to clinical surveillance (CS) in patients with moderate AS. ,,,, However, this benefit was not observed in the randomized TAVR UNLOAD trial, which enrolled patients with moderate AS and heart failure with reduced LVEF, potentially because the trial was underpowered since the enrollment target was not met. , Considering the absence of strong evidence supporting an AVR strategy for patients with moderate AS, a large, randomized trial is warranted. Herein we present the methodology of the Prospective, Randomized, Controlled Trial to Assess the Management of Moderate Aortic Stenosis by Clinical Surveillance or Transcatheter Aortic Valve Replacement (PROGRESS; NCT04889872 ).
Methods
Design of the PROGRESS Trial
PROGRESS is a multicenter, prospective, open-label, randomized controlled trial designed to evaluate the safety and effectiveness of a strategy of early intervention with TAVR compared with CS among patients with moderate AS. The study planned to enroll up to 750 patients with moderate AS ( Figure 1 ).
PROGRESS study flow chart . The PROGRESS trial investigates whether early intervention with transfemoral TAVR is superior to a strategy of clinical surveillance among patients with moderate AS and at-risk features. Patients with confirmed moderate AS by the echocardiographic core laboratory and suitable anatomy for transfemoral TAVR using the Edwards Lifesciences SAPIEN 3/SAPIEN 3 Ultra/SAPIEN 3 Ultra RESILIA transcatheter heart valve will be randomized 1:1 to TAVR or clinical surveillance. Patients randomized to clinical surveillance who develop an indication for aortic valve replacement will be treated as per current ACC/AHA guideline recommendation or regional guidelines. ,, Patients will be followed for 10-years post randomization. AVR, aortic valve replacement; TAVR, transcatheter aortic valve replacement *Per American Society of Echocardiography guidelines †Assessed against a performance goal of 13.7%
The study is funded by Edwards Lifesciences and is being conducted at up to 80 sites in United States, Canada, Europe, Japan, and Australia. In addition to oversight by the Sponsor, the study utilizes independent groups for review including a screening case review board, clinical events adjudication committee (Cardiovascular Research Foundation, New York, NY), data safety monitoring board (Baim Institute, Boston, MA), echocardiographic core laboratory (Quebec Heart & Lung Institute, Laval University, Quebec City, Canada) computed tomography core laboratory (University of British Columbia, Vancouver, British Columbia, Canada), and a biomarker core laboratory (Vanderbilt University Medical Center, Nashville, TN).
Study population
The study population comprises patients with moderate, calcific AS ( Table 1 ) with appropriate anatomy for transfemoral TAVR with the SAPIEN 3/SAPIEN 3 Ultra/SAPIEN 3 Ultra RESILIA transcatheter heart valve (THV). Complete inclusion and exclusion criteria are shown in Table 1 . Briefly, patients must be ≥65 years of age with moderate AS per the Echo Core Lab and at least one of the following at-risk features: valve-related symptoms, LVEF <60%, diastolic dysfunction ≥Grade 2 (ie, E/e’ > 14, left atrial volume index >34 mL/m 2, or tricuspid regurgitation velocity >2.8 m/sec), stroke volume index <35 mL/m 2, persistent or any episode of paroxysmal atrial fibrillation within 6 months prior to randomization, NT-Pro BNP >3 times normal, or elevated aortic valve calcium score as assessed by the Computed Tomography Core Lab (>1,200 AU for females or >2,000 AU for males).
Table 1
PROGRESS trial inclusion and exclusion criteria.
Inclusion Criteria
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Exclusion Criteria
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Abbreviations: AS, aortic stenosis; AVA, aortic valve area index; AVAi, aortic valve area index; CT, computed tomography; TAVR, transcatheter aortic valve replacement; THV, transcatheter heart valve.
All study subjects provide written informed consent as approved by the institutional review board/ethics committee of the respective clinical site. Key exclusion criteria include anatomy not suitable for transfemoral TAVR using the balloon expandable SAPIEN 3/SAPIEN 3 Ultra/SAPIEN 3 Ultra RESILIA THV, LVEF <20% and any concomitant valvular disease requiring surgical or transcatheter intervention or significant untreated coronary artery disease requiring revascularization.
Primary and secondary endpoints
The primary effectiveness endpoint is a nonhierarchical composite of death or heart failure event with or without hospitalization at 2 years, assessed in all randomized patients from the time of randomization (intent-to-treat [ITT] population). Definitions for heart failure event and heart failure hospitalization were adapted from the Heart Failure Collaboratory and Academic Research Consortium and are provided in Supplementary Table 1. Briefly, a patient is classified as having a heart failure event if they meet all 3 of the following criteria: (1) development of at least 1 new or worsening symptom of heart failure; (2) meeting at least 2 objective evidence criteria of worsening heart failure per physical, laboratory, or invasive exam findings; and (3) receipt of a heart failure specific treatment. A heart failure event with an admission to a hospital for over 24 hours or a change in calendar day is counted as a heart failure hospitalization. An AVR is not considered a primary endpoint event unless all 3 heart failure event criteria are met. The primary safety endpoint is a nonhierarchical composite of death, stroke, life-threatening or fatal bleeding, acute kidney injury stage 4 (per Valve Academic Research Consortium 3), hospitalization due to device- or procedure related complication, or valve dysfunction requiring reintervention at 30 days; the primary safety endpoint is only evaluated in the TAVR arm among patients who underwent the index procedure (as-treated [AT] population) ( Table 2 ).
Table 2
Primary and secondary endpoints.
Primary Endpoint
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| Secondary Endpoints The following will be assessed at 2 years: |
The following secondary endpoints will also be evaluated: (1) A composite of death, stroke, or heart failure hospitalization at 2 years; (2) A composite of alive at 2 years with KCCQ Overall Summary score improvement ≥ 10 points from baseline at both 1 and 2 years; (3) Heart failure hospitalization at 2 years; (4) Left ventricular (LV) mass index at 2 years; (5) Diastolic dysfunction ≥ Grade 2 at 2 years (per American Society of Echocardiography criteria.
Randomization
Subjects who provide written informed consent, meet all inclusion criteria and no exclusion criteria, and are approved by the Case Review Board are randomized 1:1 to CS or TAVR. Randomization is stratified by site, LVEF (LVEF <50% or ≥50%), and peak velocity (<3 m/s or ≥3 m/s) at baseline. All randomized patients will be considered part of the ITT population.
Study procedure and treatment arm
TAVR arm
Patients will undergo TAVR as per standard technique. The valve implant procedure is recommended to occur within 2 weeks of randomization.
CS arm
During the course of the trial, patients who meet regional (ie, country-specific) guideline-recommended criteria for AS intervention can undergo AVR, if appropriate. Echocardiography and clinical details for all CS subjects under consideration for AVR will undergo independent review prior to the procedure to confirm guideline criteria are met, when possible, but the decision to intervene was ultimately at the discretion of the provider and patient.
Follow-up
Subjects randomized to TAVR are assessed at discharge, 30-days postprocedure, and annually through 10-years postrandomization. Patients randomized to CS undergo clinical and echocardiographic assessments annually through 10 years postrandomization. Patients in the CS arm who undergo delayed AVR are also assessed prior to the procedure and at discharge and 30-day postprocedure. The primary endpoint and other relevant events (eg, stroke, etc.) will be adjudicated by a central clinical events committee. All echocardiograms will be independently analyzed by the echo core lab.
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