AVR in Asymptomatic AS: Look to the ‘Sweet Spot’ for Timing

MUNICH, Germany—How soon is soon enough, but not too early, to intervene in severe aortic stenosis (AS)? Following the release of EARLY TAVI in late 2024, this question has been on the minds of many cardiologists attempting to interpret the data as they treat the patient in front of them.

At last week’s European Association of Percutaneous Cardiovascular Interventions (EAPCI) Summit, the issue of asymptomatic AS received close attention in a session co-hosted by the EAPCI and the European Association for Cardio-Thoracic Surgery.

Anna Sonia Petronio, MD (Pisa University Hospital, Italy), and Stefan Blankenberg, MD (University Heart & Vascular Center, Hamburg, Germany), engaged in a formal debate over the advantages and drawbacks of prompt treatment versus close surveillance.

Intervene in All Cases

Petronio kicked off her talk by sharing an iconic image published in 1968 by Circulation. The figure charts the natural history of AS, a path that begins with a long latent period.

“But then there is a moment, which is a sweet spot where everything changes and the patient goes [through] a very rapid history of morbidity towards mortality,” she told the audience. “Now, it is very difficult to realize exactly when this happens. And the progression of the illness, it is very hard to understand. It is related to the heavy calcification of the valve while the [disease] progresses, there is maladaptive remodeling of the heart and of the ventricle that causes cardiac damage.”

Cardiac damage in the setting of severe AS, asymptomatic or not, is well understood to increase morbidity and mortality, said Petronio. This shift toward harm “happens with big variability from patient to patient,” making it hard to gauge in individual cases. Even when it’s treated, the damage can influence outcomes as well as quality of life, she added.

Observational data initially provided clues that treating asymptomatic AS promptly would improve patients’ trajectories. The randomized EARLY TAVR trial, published in the New England Journal of Medicine, bolstered that idea and led to the US Food and Drug Administration’s subsequent decision to expand TAVI to patients with asymptomatic severe AS.

Data from EARLY TAVR demonstrate that AS does not stand still during surveillance, said Petronio. “Even at 6 months, one in four patients has symptoms and conversion to treatment,” she said. “After 2 years, more than 70% of all the patients are treated. And they all have not one symptom but a complex combination of symptoms,” both acute and chronic.

Petronio pointed out that the 2025 European guidelines for the management of valvular heart disease have evolved the indications for intervention in asymptomatic AS. In the 2021 iteration, invasive treatment was recommended for asymptomatic patients only when they had an LVEF < 50% without another known cause or when they had demonstrable symptoms on exercise testing. It could be considered for patients with other indicators, such as biomarkers or heavy calcification. Now, she said, the guidelines less strongly emphasize LVEF as a rationale for intervention in these asymptomatic patients at low surgical risk.

Importantly, “intervention” does not apply exclusively to TAVI, she pointed out. Both the RECOVER and the AVATAR trials supported early SAVR over watchful waiting, with less rosy data coming from EVOLVED. Combined with EARLY TAVR in a meta-analysis, the trials show that “these patients, if treated, will have less hospitalization for heart failure and unplanned hospitalization for cardiovascular events, and also they can have [fewer] strokes,” Petronio said.

The disparate results across the individual studies may arise from differences in how long patients had to wait for intervention after symptoms developed, she noted. In EARLY TAVR, this amounted to 1 month, but in the others, treatment was delayed by up to several months.

Petronio said that forthcoming data from a new trial, EASY-AS, will hopefully provide additional clarity.

Based even on the current evidence base, “we know that if we treat these patients, they will certainly have a low risk of hospitalization and a significant improvement in quality of life, which is not something that is unimportant in elderly patients,” she concluded. Yet for these benefits to be realized, Petronio added, it’s necessary to consider each patient’s expected lifespan.

Watchful Waiting a Good Option

For Blankenberg, too, that 1968 image made an impression, though he framed it in a new way.

“Please allow a slightly different interpretation,” Blankenberg said. It’s true that naturally there is a latent period followed by symptom onset, “then the problems start.” He credited Eugene Braunwald, MD, who created the image, for his insights but pointed out, “the limitations of [Braunwald’s] hand-drawn figure was that the patient here was 63 years old and unfortunately at that time we didn’t have echocardiography.”

Like Petronio, he also pointed to the shift in European guidelines, which as of 2025 list numerous factors for consideration—high-gradient AS, severe calcification and V_max progression, elevated BNP or NT-proBNP levels attributable to AS, LVEF < 55% attributable to AS, and exercise test with sustained fall in BP > 20 mm Hg—beyond simply an LVEF cutoff.

“Overall, it’s an attempt [to move] towards what we definitely, even in interventional cardiology, need to achieve, which is personalized medicine,” said Blankenberg. “Asymptomatic AS intervention is only recommended, if at all, in selected patients, and symptoms certainly remain a cornerstone of AS management.”

Moreover, Blankenberg viewed the trial data from a different lens. RECOVERY, he said, is limited by the fact that 60% of participants had bicuspid anatomy and the average age was merely 64 years. AVATAR involved exercise testing for all patients, allowing for personalization. Like AVATAR, the EVOLVED trial “phenotyped carefully at the beginning, in terms of myocardial fibrosis by MRI,” he noted.

A personalized approach also was evident in EARLY TAVR, with 90% of participants undergoing a treadmill stress test. Data from the trial also point to quite a short latent period before symptoms emerged, noted Blankenburg. “The transition towards symptoms happened very early in a high percentage of patients, and during the course of the trial—even until half the trial period—the vast majority of patients [became symptomatic].”

Among the four studies, only RECOVER showed lower mortality with early intervention. Thus, he said, “watchful waiting seems to be a very reasonable approach in terms of hard clinical endpoints.

The current era of precision medicine means that many tools are available to guide management of asymptomatic AS. “Why [is it we are] always discussing black or white, yes or no? That’s wrong,” stressed Blankenship. “I think we need to balance this in a personal way and stratify the risk as most economically and as most precisely as possible—balancing out the contrast [between] watchful waiting and prophylactic AVR.”

NT-proBNP is a powerful predictor that reflects cardiac damage, he said. Aortic valve calcification similarly can help identify the “sweet spot” to tilt the choice toward AVR.

Blankenberg pointed to the staging of cardiac damage, as outlined in a 2019 JACC paper, as an interesting approach. Stages “clearly define [when] a patient, even if asymptomatic, reaches a point of specific cardiac damage, you need to intervene,” he explained. “This is something we can have as a very supportive tool to make clinical decisions.”

Harkening back to the editorial he wrote last year to accompany the original EARLY TAVR results, Blankenberg concluded: “Expanding early or preemptive interventional treatment to all asymptomatic patients who might formally meet hemodynamic and anatomical criteria may be premature. For now, awaiting symptoms remains a justifiable strategy.”

“Today, 1 year later, I could add: in carefully selected patients with high-risk features, early intervention could be considered,” said Blankenberg.

If you are in a country where you cannot perform very good follow-up and you have a long waiting list, clearly you have to send them—even if asymptomatic—for either surgery or TAVI. Cristina Gavina

Discussing the debate, surgeon Mohammed Saad, MD (Sana Klinikum Coburg, Germany), said the choice to intervene should reflect guidelines, with observation being suitable for patients who lack elevated NT-proBNP or symptoms during stress testing.

Panelist Cristina Gavina, MD, PhD (Faculty of Medicine - University of Porto, Portugal), for her part, called for context.

“The problem here is going to be that you have to think about where you are. If you are in a country where you cannot perform very good follow-up and you have a long waiting list, clearly you have to send them—even if asymptomatic—for either surgery or TAVI, mostly TAVI of course,” she noted.

“Also, I think that it is important to realize that these patients are going to have cardiac damage much before they can even have any kind of symptoms. Many of them are going to have raised NT-proBNP,” Gavina said, noting that each patient’s variability in the biomarker would be more informative than a universal cutoff.