AVATAR Makes Case for Early Surgery Over Watchful Waiting in Asymptomatic Severe AS
Adding to RECOVERY findings, AVATAR confirms early SAVR lowers MACE rates in very severe AS
Early surgery for asymptomatic severe aortic stenosis (AS) patients reduced the risk of major adverse cardiovascular events (MACE) compared to the conservative treatment of delaying surgery until symptom onset, AVATAR findings showed.
The ¡°event-driven¡± investigator-initiated prospective, multinational, parallel-group, randomized controlled AVATAR trial enrolled 157 severe AS patients without symptoms across seven European countries. The primary endpoint included all-cause mortality and MACE, comprised of acute myocardial infarction (MI), stroke, and unplanned heart failure (HF) hospitalization.
Results showed early surgical aortic valve replacement (SAVR) lowered the incidence of the primary composite endpoint than conservative treatment (HR 0.46, 95% CI 0.23-0.90, p=0.02).
All-cause mortality and first HF hospitalizations were numerically higher in the conservative treatment group, although not statistically significant.
Principal study investigator Marko Banovic, MD, PhD (University Clinical Centre of Serbia, Belgrade, Serbia) presented findings at the virtual American Heart Association (AHA) 2021 Scientific Sessions on Nov 13. The paper was published simultaneously in Circulation1.
¡°Early surgery was associated with lower incidence of the primary composite outcome comprised of all-cause death, acute MI, stroke, or unplanned HF hospitalization,¡± Banovic said. ¡°Operative mortality in the early surgery group was in line with anticipated mortality rates for elective isolated SAVR.¡±
Early SAVR grows promising for asymptomatic severe AS patients
The appropriate timing for intervention in asymptomatic patients with severe AS and normal left ventricular (LV) function had been a subject of debate.
Both the recent 2020 American College of Cardiology, American Heart Association, and Society of Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) joint guideline and the 2021 European Society of Cardiology and European Association for Cardio-Thoracic Surgery guideline recommend aortic valve replacement (AVR) only for patients with symptoms or LV systolic dysfunction (Class I).
To assess the optimal timing of intervention, the AVATAR trial enrolled 157 patients (mean age: 67, 57% male) from June 2015 to Sept 2020 and randomized them to receive either early surgery (n=78) or conservative treatment (n=79). Patients assigned to the early intervention group were scheduled for surgery within eight weeks of randomization.
The conservative care arm received treatment according to ESC guidelines: referral upon left ventricular ejection fraction (LVEF) drop <50% or increased peak aortic jet velocity per year (>0.3 m/s on follow-up echocardiography). The median time from randomization to surgery in the conservative care arm was 400 days.
Asymptomatic severe AS status was assessed according to the common criteria of valve area ¡Â1 cm2 with aortic jet velocity >4 m/s or a mean trans-aortic gradient ¡Ã40 mmHg. Negative exercise testing (positive test defined as the onset of AS symptoms, systolic BP drop ¡Ã20 mmHg from baseline; ECG/stress echo signs of myocardial ischemia) was mandatory for patients with normal LV function.
In such carefully evaluated patients with significant AS and normal LV function, the primary outcome and overall experience from AVATAR emerged as supportive for early surgery.
Key patient exclusion criteria included exertional dyspnea, syncope/presyncope, angina, LVEF <50%, very severe AS (maximal aortic jet velocity >5.5 m/s at rest), aortic regurgitation ¡Ã3+, significant mitral valve disease, previous cardiac surgery history, and atrial fibrillation. The event-driven trial was designed to reach at least 35 prespecified events.
A median of 32-month follow-up resulted in 13 events in the early SAVR arm and 26 events in the conservative care arm (16.6% vs. 32.9%), with statistical analysis on the primary intention-to-treat (ITT) analysis showing a significantly lower incidence of the primary endpoint in the early surgery arm (15.2% vs. 34.7%, HR 0.46, 95% CI, 0.23-0.90, p=0.02).
Sudden death occurred in six patients in the conservative group (three cases related to COVID-19) and three in the early SAVR group (one patient died before surgery). The incidence of serious adverse events (SAE) was also numerically higher in the conservative group.
Kaplan-Meier estimates of the individual endpoints of all-cause mortality and HF hospitalization showed higher trends in the conservative group compared to the early surgery group but did not reach statistical significance.
¡°These findings highlight the relevance of careful patient evaluation in asymptomatic AS patients, including exercise testing,¡± researchers wrote. ¡°In such carefully evaluated patients with significant AS and normal LV function, the primary outcome and overall experience from AVATAR emerged as supportive for early surgery.¡±
AVATAR adds to RECOVERY results with evidence in ¡®broader¡¯ patient scope
On the ¡°very important trial,¡± session panelist Victoria Delgado, MD, PhD (Leiden University Medical Center, South Holland, Netherlands) said: ¡°RECOVERY was the only prior randomized trial on 145 patients with severe AS [that showed benefits with early surgery]. AVATAR included severe, but not critical, AS patients and importantly conducted an exercise test on all patients to show outcomes similar to the RECOVERY trial.¡±
Last year¡¯s RECOVERY trial was the first randomized study that addressed the controversial question of when to treat asymptomatic severe AS, which accounts for nearly a third of the patient population with reports estimating prevalence to rise due to an aging population.
The study conducted in South Korea and published in the New England Journal of Medicine (NEJM) by Duk-hyun Kang, MD (Asan Medical Center, Seoul, South Korea) and colleagues was the first randomized controlled trial to report a lower incidence of composite operative mortality or death from cardiovascular causes with early SAVR (early SAVR 1% vs. conservative care 15%, HR 0.09, 95% CI, 0.01-0.67, p=0.003).
In contrast to RECOVERY, AVATAR included severe - but not critical - AS patients and demonstrated similar results.
In RECOVERY, all-cause mortality occurred in 7% of the early SAVR group and 21% of the conservative care group (HR 0.33, 0.12-0.90). The cumulative incidence of sudden death in the conservative-case group amounted to 4% at four years and 14% at eight years. At four years, the cumulative incidence of all-cause death was 4% in the early surgery group and 8% in the conservative group.
In contrast, AVATAR reported a 15% all-cause mortality rate in the early surgery group at four years and 25% in the conservative treatment group even though the trial included patients with severe but not critical AS and all underwent exercise testing.
Both AVATAR and RECOVERY indicate early surgical AVR in selected patients at specialized heart valve centers can lead to excellent surgical outcomes.
RECOVERY¡¯s principal investigator Kang told SummitMD: ¡°We have been waiting for prospective randomized trials to settle the intense debate between early AVR and watchful observation. Both RECOVERY and AVATAR trials delivered evidence that support early AVR in asymptomatic severe AS.¡±
¡°AVATAR has the upper hand with a broader scope of trial patients (peak aortic velocity >4 m/s), but limitations involve the inclusion of HF events in the primary endpoint, no significant difference in all-cause mortality, and worse long-term survival with less severe AS patients.,¡± Kang said.
Regarding major differences between the two, Kang added that: ¡°Exercise testing was performed to prove the asymptomatic status before enrollment in AVATAR. In contrast, RECOVERY enrolled entirely asymptomatic patients upon regular physical activity, with exercise testing performed selectively on patients with vague, non-specific symptoms.¡±
AVATAR researchers in their paper also pointed out: ¡°RECOVERY provided the first direct support for early surgery in a highly selective subset of asymptomatic patients with very severe AS. AVATAR expands these findings for truly asymptomatic patients with severe but not critical AS and normal LV function in a multinational trial compared to the single country-based RECOVERY trial.¡±
Earlier is better, but is data enough to change practice?
Despite positive findings, John Mandrola, MD (Baptist Health, Kentucky, USA), in a Medscape commentary,2 argued against early surgery after finding fault with the generalizability of findings in a population where early intervention carries substantial risks.
¡°The easy take home-message would be that dogma should change, and patients with severe AS should be offered surgery before symptoms,¡± Mandrola wrote. ¡°However, trial findings require further confirmation in a larger study [due to] the fragility of AVATAR results and the lack of external validity/generalizability.¡±
¡°Given our oath to first do no harm, preventive procedures used in people without complaints should pass a high bar of evidence,¡± Mandrola said. ¡°When the preventive procedure involves a sternotomy and cardiopulmonary bypass, the bar of evidence must be super high. Despite these two positive trials, we still need more data before upending the conservative approach in most AS patients without complaints.¡±
Despite two positive trials, we need more data before upending the conservative approach in most AS patients who have no complaints.
Kang noted that upcoming results from the large, randomized EARLY TAVR trial would shed more insight into the patient population where the consequences of waiting too long could cause irreversible damage.
¡°The risk of sudden death may be less than 1% per year in severe AS patients who are initially asymptomatic, but the mortality risk rises with disease progression when waiting too long for symptoms ; moreover, the risk of sudden death persists even with AVR when irreversible myocardial damage is present,¡± he said.
¡°These findings demonstrate that early surgical AVR is reasonable for asymptomatic patients with very severe AS (aortic-valve area ¡Â0.75 cm2 and aortic jet velocity ¡Ã4.5 m/s) at low surgical risk,¡± Kang said. ¡°Evidence from ongoing clinical trials can help extend indications for surgical AVR and further consider TAVR in asymptomatic patients with severe AS.¡±