Asymptomatic AS: “Time to Act” or Not So Fast?

A recent editorial claimed that “it’s time to act” in asymptomatic patients with severe aortic stenosis (AS). The expert authors, including eminent cardiologist Eugene Braunwald, MD, proposed that the aortic valve should be replaced sooner rather than later in such patients.

Their call to favor surgical or transcatheter aortic valve replacement (SAVR/TAVR) over clinical surveillance is on the basis of cumulative data from randomized controlled trials (RCTs) which they interpret as proof of greater benefit than risk. 

However, opinion on whether this evidence justifies a change in practice is not uniform. And wide adoption of valve replacement in patients with severe but asymptomatic AS would require a major change in both the United States and European.

Major Change in Guidelines Sought

The JAMA Cardiology editorialists wrote that “In our opinion, the routine and preferred strategy for asymptomatic patients with severe AS (stage C1) should shift from clinical surveillance, the current default strategy, to prompt performance of aortic valve replacement”. They listed only a few exceptions, such as unfavorable anatomy or comorbidities that might be regarded as a relative contraindication.

“We would support and hope for a change in the guidelines,” lead author Brian R. Lindman, MD, MSc, Structural Heart and Valve Center, Vanderbilt University Medical Center, Nashville, Tennessee, said in an interview. He and his coauthors also argued for a class I guideline recommendation to refer all patients with severe AS and a life expectancy of at least 1 year to a multidisciplinary heat valve team.

By email, Braunwald said that the guidelines should define both “severe” and “asymptomatic.” “Would a peak gradient of 45 mm Hg be considered severe? Would stopping after climbing one floor be considered symptomatic? Without analyses a yes or no can’t be answered”, he wrote.

While the “choice of TAVR vs SAVR should be made based on anatomical suitability, age, comorbidities, and patient preference,” the editorialists did not argue for one over the other in any specific population.

The 2src2src valvular heart disease guidelines from the American College of Cardiology and American Heart Association give a class I indication for aortic valve replacement in patients with severe asymptomatic AS if they have an impaired left ventricular (LV) ejection fraction (<5src%) or are undergoing cardiac surgery for another indication. All other indications are listed as class 2a or 2b.

According to 2src21 guidelines from the European Society of Cardiology, impaired LV function is the only class I indication for aortic valve replacement in asymptomatic AS. All others are labelled IIa.

Should SAVR Be Favored Over TAVR?

The controversy has a further twist. Even those who agree that prompt valve replacement should be the default do not necessarily agree that SAVR and TAVR are equivalent options, particularly in younger individuals.

Joanna Chikwe, MD, chair, Department of Cardiac Surgery, Smidt Heart Institute at Cedars-Sinai, Los Angeles, agrees with the premise that asymptomatic severe AS should be treated but not by any means.

“Advocating for TAVR in asymptomatic younger patients — many if not most of whom may have bicuspid aortopathy — is a triumph of interventional optimism over actual evidence,” she said.

Unlike the “ample randomized data demonstrating benefits of SAVR for asymptomatic severe aortic stenosis with long-term durability data to support this strategy in all valve morphology and patient age groups,” Chikwe considers the evidence insufficient to support TAVR in younger asymptomatic individuals.

Comparative trials have enrolled relatively few TAVR patients younger than 6src years, according to Chikwe (1src% by her estimate). She also pointed out that bicuspid aortic stenosis has generally been an exclusion for TAVR and that TAVR follow-up extending past 5 years is limited.

In a recently published analysis from the Society for Thoracic Surgeons Adult Cardiac Surgery Database, SAVR was associated with a survival benefit for patients 6src years of age or younger treated with a mechanical rather than a bioprosthetic valve after follow-up of up to 12 years. Chikwe, a coauthor, pointed out that comparable long-term data is not yet available for TAVR.

Given the longer life expectancy of younger patients after valve replacement, the question of relative durability of repairs after TAVR and SAVR is important.

Tom C. Nguyen, MD, director of Minimally Invasive Valve Surgery at the Miami Cardiac and Vascular Institute, Kendall, Florida, also expressed concern about “incomplete” follow-up for TAVR relative to SAVR. Seeing that as another reason to prioritize SAVR over TAVR in younger patients.

“I would argue that if TAVR and SAVR are truly equal in outcomes and durability, then SAVR wins since the periprocedural costs are lower,” he said.

Given more beneficial long-term data for SAVR, emerging evidence that mechanical valves may perform better over time, and the fact that SAVR might be more cost effective, Nguyen is not convinced these approaches are interchangeable even if he was careful not to rule out TAVR as an option.

Yet, he does support the larger premise that early treatment of asymptomatic severe AS makes sense.

“The pathophysiology of severe aortic stenosis even when asymptomatic remains clear and will ultimately lead to LV dysfunction and heart failure,” he said, supporting intervention for severe AS even when it is not yet symptomatic.

The RCTs Supporting Early Intervention

Of the three RCTs comparing SAVR to clinical surveillance, two were positive.

In RECOVERY, SAVR beat surveillance for a composite endpoint of operative mortality and cardiovascular death after a median 6-year follow-up. In AVATAR, SAVR beat watchful waiting for a composite endpoint of death, stroke, myocardial infarction, or heart failure hospitalization. Surgery also showed an advantage for all-cause mortality.

In EVOLVED, SAVR was not superior to surveillance for the composite endpoint of death or unplanned AS-related hospitalization, but the JAMA cardiology editorialists note that this could be due to the long delay between assignment and intervention. Even with the delay, SAVR was associated with significantly fewer AS-related hospitalizations.

The push for early intervention in asymptomatic patients intensified following publication of EARLY TAVR, the most recent and largest trial on the topic, and the first to test transcatheter valves. In this trial, TAVR was superior for the composite endpoint of death, stroke, or unplanned hospitalization for cardiovascular causes after a 3.8-year median follow-up.

Despite the positive results there have been concerns raised about the study design and the clinical interpretation of the results.

EARLY TAVR Trial Criticized for Design Flaws

In a Medscape perspective John M. Mandrola, MD, an electrophysiologist affiliated with the University of Louisville, Louisville, Kentucky, pointed out that the benefit was primarily driven by a reduction in unplanned hospitalizations, commonly considered a soft endpoint. There was no significant difference in death or stroke.

He cited a 2src18 paper, on ‘faith healing’ and ‘subtraction anxiety’ in unblinded trials which argued that soft clinical endpoints, such as symptoms or hospital admissions are not a substitute for objective endpoints, such as death for a potentially practice-changing trial. The authors called blinding essential because patients are irredeemably biased by knowing their assignment.

In an interview, lead author of the 2src18 paper, Christopher Rajkumar, MD, PhD, an interventionalist at Hammersmith Hospital and a member of the faculty at Imperial Medical College, both in London, England, explained that patients in the control group face anxiety about living with a disease they know is going untreated, whereas patients in the intervention group might benefit from a placebo effect.

The results of the EARLY TAVR trial are consistent with this pattern. For unplanned hospitalizations, the advantage for TAVR was seen almost immediately, a potential manifestation of anxiety in the control group hypervigilant about potential symptoms of their untreated disease.

“In a chronic progressive condition like AS, we expect to see events accumulate steadily with time. But if Kaplan-Meier curves diverge immediately and rapidly after randomization, we have to question whether these events reflect disease progression,” Rajkumar explained. In the absence of blinding, he further maintained that soft endpoints are particularly “vulnerable to psychological bias.”

Lindman, the lead author of the editorial advocating for prompt intervention in asymptomatic severe AS, is aware of this criticism of EARLY TAVR and of the limited evidence that TAVR offers a comparably durable result to SAVR. However, he still believes that the cumulative evidence supports valve replacement in severe asymptomatic AS and that TAVR and SAVR are both reasonable.

“I think blinding is less relevant concerning AS with TAVR or SAVR [regarding] the endpoints examined in these trials,” he said. As for durability, he pointed out that the RCTs have shown benefit for the endpoints studied with both SAVR and TAVR over the course of the follow-up evaluated.

A recent state-of-the-art review of TAVR included a section on its potential role in asymptomatic severe aortic stenosis. While the authors agreed that the concept is attractive for a condition known to be progressive, they called for more data. Specifically noting that longer follow-up for EARLY TAVR “will be crucial for investigating valve durability”. At this time, they characterized the indications for replacement in asymptomatic AS “unclear.” 

Senior author, Samin Sharma, MD, director of the Cardiovascular Clinical Institute at the Mount Sinai Hospital, New York City, said that “Based on the available clinical evidence and factoring in the prosthetic valve degeneration, it will be prudent to recommend TAVR or SAVR in asymptomatic severe AS patients above 75 years of age,”. But in younger patients, “we need to wait a little more before making the final recommendation”.

In 199src, Braunwald, argued against aortic valve replacement for asymptomatic AS, calling it “the most common cause of sudden death” in this group of patients. With the JAMA Cardiology editorial, his opinion has changed.

He and his coauthors wrote that procedural risks in the last 35 years have diminished whereas the evidence of benefit has reached a critical mass.

Not all agree and whether guidelines change remains to be seen.

Lindman reported financial relationship with Edwards Lifesciences and Medtronic. Chikwe, Nguyen, Mandrola, and Sharma reported no potential conflicts of interest. Rajkumar reported financial relationships with Menarini, Philips, and Mycardium.