Trial DesignRationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial
Section snippets
Methods
The AVATAR is a prospective, multicenter, randomized, controlled, parallel group, event-driven trial that will evaluate the safety and efficacy of elective AVR in the treatment of isolated asymptomatic severe AS patients with normal LVEF. The trial will include up to 15 clinical sites in 10 countries. Each participating center will be approved by its local Ethical committee. No extramural funding outside from each participating center financial research resources was used to support this work.
Study population
The study population will consist of 312 consecutive asymptomatic patients with isolated severe AS and normal LVEF. All patients will have to undergo all necessary diagnostic procedures prior to the study inclusion, provide informed consent, and be able to comply with study procedures and follow-up. Inclusion and exclusion criteria are listed in Table I, Table II.
Randomization
Upon receipt of both informed consents and satisfactory documentation that the patients meet all eligibility criteria, the patients will be randomized to either the elective AVR group or a medical treatment group until symptom onset or a decrease in LVEF < 50%. Allocation will be assigned according to a predefined randomization list, with each treatment arm having an allocation probability of a half (0.50). Patients randomized to medical treatment will be treated according to existing
Study hypothesis
The primary study hypothesis is that elective AVR in asymptomatic patients with severe AS and normal LVEF will reduce a primary composite outcome comprising the first event occurring among the following: all-cause death, acute myocardial infarction (AMI), stroke (cerebrovascular insult), or unplanned hospitalization for heart failure (HF) requiring intravenous treatment, as compared with severe AS patients with normal LVEF treated with medical management and AVR after the symptom onset.
Study outcomes
Primary outcome measure is a global composite outcome comprising: all-cause death, AMI, cerebrovascular insult, and unplanned hospitalization for HF requiring intravenous treatment.
Secondary study outcomes include a safety analysis. We will test the hypothesis that there will be no significant increase in operative and in-hospital mortality in the treatment group, as well as in surgical and implanted valve–related complications compared with a control (after symptom onset operated patients) at
Echocardiography
The diagnosis of severe AS will be established according to standard echocardiographic criteria,2, 3 in order to maintain consistency across investigator sites. In each participating Institute, all echocardiographic examinations will be performed by 2 expert operators using commercially available equipment with a 2.0- to 3.5-MHz transducer. Multiple views will be recorded including parasternal long- and short-axis (basal, mid, apical), apical 2-, 3-, and 4-chamber and the subcostal view. All
The AVR procedure
Patients will be informed about the advantages and disadvantages of each AV prosthesis type before the AVR. The choice of the aortic valve prosthesis will be made in accordance with the patient's choice, as indicated by the actual aortic valve surgery guidelines14, 15 and the surgeon's decision according to institutional protocols. After the complete analysis of each patient, the surgeon will decide on the surgical approach between conventional and minimally invasive, using full-median
Sample size and statistical considerations
The AVATAR trial will use “event-driven” design to power the trial.16, 17 There are multiple advantages of the event-driven design as compared with a “fixed time end-point, i.e. fixed follow-up” design:
- 1.
The clinical relevance of the events as they occur in control vs treatment groups is more important than cumulative events at a fixed point in time.
- 2.
The sample size of the trial is smaller, and depending on event frequency, the trial may be shorter.
- 3.
The adaptive design can be implemented to assure
Study organization
Steering Committee: the steering committee will provide clinical guidance on protocol development, study implementation and conduct, and interpretation of results.
Data and Safety Monitoring Committee: the Data and Safety Monitoring Committee will monitor the trial progress, review data from one interim efficacy analysis, and ensure the safety of patients enrolled in the study.
Event adjudication Committee: an independent committee blinded to treatment assignment and consisting of a cardiologist,
Substudies
The clinical and functional effect of elective AVR will be further evaluated with cardiopulmonary exercise testing (CPX) in comparison between the electively operated group (treatment group), after the symptom onset operated group (control group), and unoperated patients. The CPX testing will be done at the screening and after 1-year follow-up. For operated patients, the minimum time between AVR and CPX testing will be 3 months.
Comprehensive 2- and 3-dimensional Doppler and speckle tracking
Discussion
The timing and treatment modality for asymptomatic patients with severe AS and normal ejection fraction is one of the biggest challenges in contemporary cardiovascular medicine. This study details the rationale and design of the first large prospective multicenter randomized trial addressing a possible need for early AVR. The trial will test the hypothesis that elective AVR is superior to medical management until symptom onset in asymptomatic patients with isolated severe AS and normal LVEF.
Summary
The AVATAR trial will address an important question regarding the treatment of asymptomatic patients with severe isolated AS and normal LVEF. To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicentre clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.
Disclosures
The AVATAR trial is registered with the ClinicalTrials.gov identifier NCT 02436655. This is an investigator-initiated trial. All data will be received, checked, and analyzed at the Cardiology Department, University Clinical Centre of Serbia, Belgrade, Serbia, and Cardiovascular Centre Aalst, Aalst, Belgium, as the coordinating centers.
Acknowledgments
We thank Ms Susan Bryan, Mrs Brandy Johns, Mr Miodrag Jovanovic, and Mrs Jelena Dudic for their help in manuscript preparation.
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2021, Archives of Cardiovascular DiseasesCitation Excerpt :Of great concern is the lack of ET in the ongoing EARLY TAVR prospective trial [72], as well as in EVoLVeD [73] and EASY-AS [74] (Table 2). Negative ET is required for inclusion in the AVATAR [75] and ESTIMATE trials [76] (Table 2). However, patients randomized into the conservative care group are asked to report symptoms promptly, but do not benefit from planned serial ET during follow-up.
Poor Long-Term Survival in Patients With Moderate Aortic Stenosis
2019, Journal of the American College of CardiologyCitation Excerpt :However, consistent with our overall finding that the adjusted mortality risk associated with moderate and severe AS appeared to merge over time, there is preliminary evidence to support a discussion and further investigations around the risk-to-benefit ratio of management strategies in patients with either asymptomatic severe AS or moderate AS (22–24). In this respect, the results of the ongoing AVATAR (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) randomized trial (with appropriate testing to unmask symptoms and/or coronary artery disease requiring revascularization) will be important in clarifying these early, positive signals (25). We considered that AR could be a potential confounder of the mortality gradient observed.
RCT No. NCT02436655.
Stefan James, MD, PhD served as guest editor for this article.