Clinical trial NCT02436655: Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis
Official title: Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: (AVATAR Trial): A Multicentre Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Aortic Stenosis
Keywords: aortic stenosis
normal ejection fraction
asymptomatic
Lead sponsor: Clinical Centre of Serbia
Sponsor class: OTHER
First posted: 2015-05-07
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. Anginal chest pain during testing
  2. Syncope, dizziness during testing
  3. Decrease in systolic blood pressure during exercise ≥ 20mmHg
  4. 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

Primary outcomes:
measure: all cause death, Major Adverse Cardiac Event (MACE) including: ( Acute Myocardial Infarction - AMI, Stroke - CVI, unplanned hospitalization for Heart failure (HF) needing intravenous treatment
timeFrame: 36 months
measure: all cause death, Major Adverse Cardiac Event (MACE) including: ( Acute Myocardial Infarction - AMI, Stroke - CVI, unplanned hospitalization for Heart failure (HF) needing intravenous treatment
timeFrame: 5 years
Secondary outcomes:
measure: in-hospital and 30 days operative mortality in operated patients in both groups
timeFrame: 30 days
measure: repeat aortic valve surgery in operated patients in both groups
timeFrame: 5 years
measure: major bleeding according to consensus report from the Bleeding Academic Research Consortium
timeFrame: 5 years
measure: thromboembolic complications based on clinical symptoms, signs and imaging studies
timeFrame: 5 years
measure: repeated major adverse cardiovascular events
timeFrame: 5 years
measure: all-cause death + heart failure hospitalization
timeFrame: 5 years
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Cardiovascular Center Aalst
city: Zagreb
country: Croatia
facility: University Clinical Center "Rebro"
city: Zagreb
country: Croatia
facility: University Clinical Center ''Sestre milosrdnice''
city: Brno
country: Czechia
facility: University Hospital Brno
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine (IKEM)
city: Pessac
country: France
facility: Hôpital Cardiologique de Haut Lévèque
city: Galway
country: Ireland
facility: University Hospital Galway
city: Turin
country: Italy
facility: Città della Salute e della Scienza di Torino
state: Piedmont
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu klinikos
city: Katowice
country: Poland
facility: Medical University of Silesia
city: Belgrade
country: Serbia
facility: Cardiovascular Center 'Dedinje"
city: Belgrade
country: Serbia
facility: CCSerbia
city: Belgrade
country: Serbia
facility: University Clinical Centre Zvezdara
city: Novi Sad
country: Serbia
facility: Insitute for Cardiovascular Diseases "Sremska Kamenica"
Study officials:
affiliation: Cardiology Department, University Clinical Centre of Serbia
name: Marko Banovic, MD, PhD, FESC, FACC
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiac Surgery Department, University Clinical Centre of Serbia
name: Svetozar Putnik, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Banovic M, Iung B, Bartunek J, Asanin M, Beleslin B, Biocina B, Casselman F, da Costa M, Deja M, Gasparovic H, Kala P, Labrousse L, Loncar Z, Marinkovic J, Nedeljkovic I, Nedeljkovic M, Nemec P, Nikolic SD, Pencina M, Penicka M, Ristic A, Sharif F, Van Camp G, Vanderheyden M, Wojakowski W, Putnik S. 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. Am Heart J. 2016 Apr;174:147-53. doi: 10.1016/j.ahj.2016.02.001. Epub 2016 Feb 9.
citation: Banovic M, Iung B, Bartunek J, Penicka M, Vanderheyden M, Casselman F, van Camp G, Nikolic S, Putnik S. The Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A protocol update. Am Heart J. 2018 Jan;195:153-154. doi: 10.1016/j.ahj.2017.10.005. Epub 2017 Oct 14. No abstract available.
citation: Banovic M, Putnik S, Penicka M, Doros G, Deja MA, Kockova R, Kotrc M, Glaveckaite S, Gasparovic H, Pavlovic N, Velicki L, Salizzoni S, Wojakowski W, Van Camp G, Nikolic SD, Iung B, Bartunek J; AVATAR Trial Investigators*. Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial. Circulation. 2022 Mar;145(9):648-658. doi: 10.1161/CIRCULATIONAHA.121.057639. Epub 2021 Nov 13.
citation: Zelis JM, Tonino PAL, Pijls NHJ, De Bruyne B, Kirkeeide RL, Gould KL, Johnson NP. Coronary Microcirculation in Aortic Stenosis: Pathophysiology, Invasive Assessment, and Future Directions. J Interv Cardiol. 2020 Jul 22;2020:4603169. doi: 10.1155/2020/4603169. eCollection 2020.