Elsevier

American Heart Journal

Volume 174, April 2016, Pages 147-153
American Heart Journal

Trial Design
Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial

https://doi.org/10.1016/j.ahj.2016.02.001Get rights and content

Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, left ventricular function, and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal left ventricular ejection fraction. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms.

The AVATAR trial will aim to assess outcomes among asymptomatic AS patients randomized to either elective early AVR or medical management with vigilant follow-up. In the latter group, AVR would be delayed until either the onset of symptoms or changes in predefined echocardiographic parameters.

To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicenter clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.

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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    RCT No. NCT02436655.

    Stefan James, MD, PhD served as guest editor for this article.

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