Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis

Study Overview
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Brief Summary
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Whether to intervene in asymptomatic patients with severe aortic stenosis and normal left ventricular ejection fraction remains controversial. The investigators therefore try to compare clinical outcomes of elective aortic valve replacement to conventional treatment and watchful waiting strategy in a prospective randomized trial.

Detailed Description
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Aortic valve replacement (AVR) therapy is obvious choice in symptomatic severe aortic stenosis (AS) patients, because it improves symptoms, LV function and survival. Therefore, the accurate diagnosis of the disease, determination of its severity and precise evaluation of patients' clinical status is essential. However, the treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction (LV EF) are vague and the subject of ongoing debate. The most recent European and American guidelines have class I indication for AVR in asymptomatic severe AS patients with normal LV EF only in patients already scheduled for other cardiac surgery (for example by-pass surgery). In the case of symptom positive stress test American and European guideline differs, with European guidelines having class I indication and American guidelines only IIb indication. In all those cases of asymptomatic severe AS patients with normal LV EF the level of evidence is C, in other words there are no randomized trials. The consequence is that the decisions are made individually, patient by patient, and for this reason a patient with identical echocardiographic/clinical characteristics might be operated in USA but not in Europe (or any other part in the world), and vice-versa. With the experience that has accumulated so far, there are retrospective and observational data that elective AVR might lead to favorable outcome compared to late (after symptom onset) surgery. This may especially come to attention with the understanding that annual risk of sudden cardiac death in asymptomatic severe AS patients with normal LV EF might be very similar or even a bit higher than operative mortality in experienced cardiac surgery centers. Nevertheless, the majority of cardiologist worldwide are reluctant to send their asymptomatic patient with isolated severe AS and normal LV EF to AVR, and it will probably stay like that till randomized trials give us an answer whether elective AVR is beneficial.

Official Title
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Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: (AVATAR Trial): A Multicentre Randomized Controlled Trial

Conditions
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Aortic Stenosis

Intervention / Treatment
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* Procedure: surgical aortic valve replacement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women of any ethnic origin aged ≥18 years Written informed consent V max across the aortic valve > 4m/s or Pmean ≥ 40mmHg and AVA ≤ 1cm2 or AVAi ≤ 0.6cm2/m2 at rest Without reported symptoms Society of Thoracic Surgeons (STS) score < 8% Exclusion Criteria: Participation in another clinical trial within 30 days prior randomization Pregnant or nursing women Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study or to follow the protocol Positive stress-test defined as: Anginal chest pain during testing Syncope, dizziness during testing Decrease in systolic blood pressure during exercise ≥ 20mmHg Malignant arrhythmia during exercise testing (VT or VF) Left ventricular ejection fraction < 50% at rest Very severe AS (defined as Vmax > 5.5 m/s at rest) Significant disease of other valves (Mitral stenosis with Pmean > 5mg, or any significant regurgitation ≥ 3+ Recent AMI (< 1 year) Need for additional by-pass surgery or for aortic root replacement (i.e Bentall) or ascending aorta in asymptomatic patients undergoing AVR Previous by-pass surgery Previous any heart valve surgery Impaired renal function, i.e. creatinine >200 µmol/L or glomerular filtration rate < 30 mL/min/1.73 m2 Significant pulmonary hypertension at rest (PASP > 50mmHg) Uncontrolled hypertension at rest (systolic >180 mmHg and diastolic >100 mmHg) Significant co-morbidity with reduced life expectance (< 3 years) Uncontrolled Diabetes Mellitus (HbA1C > 9 %) Significant COPD (FEV1 < 70% of predicted value) Permanent or paroxysmal atrial fibrillation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: conventional drug treatment<br>conservative treatment and watchful waiting till symptom onset (then aortic valve replacement). Other indications for aortic valve replacement include reduced left ventricular systolic function | |
| Active Comparator: elective aortic valve replacement<br>elective aortic valve surgery (replacement) within 4 weeks after randomization | Procedure: surgical aortic valve replacement<br>* open heart aortic valve replacement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all cause death, Major Adverse Cardiac Event (MACE) including: ( Acute Myocardial Infarction - AMI, Stroke - CVI, unplanned hospitalization for Heart failure (HF) needing intravenous treatment |  | 36 months | 
| all cause death, Major Adverse Cardiac Event (MACE) including: ( Acute Myocardial Infarction - AMI, Stroke - CVI, unplanned hospitalization for Heart failure (HF) needing intravenous treatment |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| in-hospital and 30 days operative mortality in operated patients in both groups |  | 30 days | 
| repeat aortic valve surgery in operated patients in both groups |  | 5 years | 
| major bleeding according to consensus report from the Bleeding Academic Research Consortium |  | 5 years | 
| thromboembolic complications based on clinical symptoms, signs and imaging studies |  | 5 years | 
| repeated major adverse cardiovascular events |  | 5 years | 
| all-cause death + heart failure hospitalization |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aortic stenosis, normal ejection fraction, asymptomatic