Asymptomatic Aortic Stenosis: The Next Frontier for TAVR?

As the potential pool of patients with symptomatic aortic stenosis (AS) who may benefit from TAVR expands to lower risk candidates, some researchers believe the time has come to study the benefit of intervening early in those with asymptomatic disease, compared with current recommendations for ‘watchful waiting.’ 

The lack of randomized data make it impossible to know if there is a true signal that early intervention could prevent future events in these patients, proponents of a trial argue. There is also the question of when is the best time to intervene, and in whom.

“We should do a randomized trial to finally answer this important question for good,” said Philippe Généreux, MD, of the Hôpital du Sacré-Coeur de Montréal (Montréal, Canada), in an interview with TCTMD.

On the other hand, such a trial very well could be viewed as a way of drumming up more patients for an expensive procedure they may not need.

“That’s a valid argument, but then you also have papers out there suggesting that we should be operating on people earlier based on observational data,” Robert O. Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), told TCTMD. In the CURRENT AS registry, for example, initial aortic valve replacement (AVR) in asymptomatic patients with severe AS was associated with a lower risk of mortality and heart failure hospitalization compared with a conservative treatment strategy. “There’s no perfect scenario, but there is uncertainty and many of us are pushing for a trial to go forward at this point.”

While none of the people who spoke with TCTMD would confirm that a trial is in the works, Creighton W. Don, MD, PhD (UW Medicine, Seattle, WA), noted during a moderated poster presentation at the recent American College of Cardiology 2016 Scientific Sessions that he believed Columbia University Medical Center was spearheading such a trial.

Any such trial in asymptomatic patients will inevitably spur new questions as to the societal costs of intervening in patients who, at least at the outset, do not believe themselves to be ill. Experts who spoke with TCTMD agreed that it was too early to speculate on economic issues.

Baseline Data Needed

The 2014 AHA/ACC practice guidelines state that asymptomatic patients with AS should be followed with a strategy of watchful waiting that involves serial clinical and echocardiographic examinations unless they have LVEF < 50%, are scheduled to undergo other cardiac surgery, have valve-related symptoms that are unmasked by stress testing, have an abnormal exercise stress test, or have hemodynamically very severe AS.

But, as Généreux and colleagues point out in a state-of-the-art review published online earlier this month in the Journal of the American College of Cardiology, determining who is truly asymptomatic is complicated by the subjective nature by which symptoms are defined and reported. “AS typically progresses slowly, and symptoms may be nonspecific,” they write. “Patients may therefore relate their symptoms to poor overall stamina. They may also relate their symptoms to a concomitant medical condition. Alternatively, they may adjust their activity and/or exercise level to avoid symptoms.”

Yet another possibility, Généreux told TCTMD, is that some elderly patients will deny symptoms to avoid what they believe will be dangerous surgery.

According to Mario Goessl, MD (Minneapolis Heart Institute, Minneapolis, MN), who was not an author on that paper, in-depth questioning about symptoms is a crucial part of evaluation because so many older patients either deny or fail to recognize that they have AS symptoms.

“I ask if they have shortness of breath. I ask if they have chest pain. I ask if they have palpitations,” he said. “Many patients say, ‘I don’t think so,’ because they have adjusted their lifestyle [to their symptoms]. . . . And when you ask why they stopped doing a specific thing that they used to do, often they will say, ‘Because I’m getting older.’ It’s all in the questioning and in how you approach the patient. Sometimes they are not telling you because they don’t want to tell you, but that is not always the case.”

The JACC review paper cites data from one observational study of over 620 asymptomatic patients that found that 5 years after diagnosis, approximately two-thirds of those managed conservatively developed symptoms, while 75% had either died or undergone AVR.

Bonow, a coauthor of both the review paper and the 2014 practice guidelines, added that as with many things in medicine where there are no clinical trial data to back up decisions, clinicians and patients are left in a predicament as to how to proceed.

“A clinical trial would [provide] baseline data in these individuals such as biomarkers and exercise data, so we can begin to see how well these things do shape up as being predictive both in people who have surgery now versus patients in whom you wait,” Bonow said. “I think [such a trial] is worthwhile, but getting it funded and getting it off the ground is something else. It’s certainly a question that has been out there for a long time without there being a trial to address it.”

Bonow added that by using TAVR as the intervention, as opposed to surgery, “this kind of trial becomes much more realistic when you are talking about randomizing people who are asymptomatic, because you might get more patients agreeing to have early intervention if it’s going to be done with a less invasive approach.”

Guidelines Work in Theory

Goessl noted that the state-of-the-art review and the talk of a trial come on the heels of an abstract presented at the recent ACC meeting looking at the value of diligent watchful waiting. The study of 200 asymptomatic patients with severe aortic stenosis compared those with and without adherence to the serial evaluations recommended in the national practice guidelines. Over 3 years, those who were adherent (ie, followed every 6 to 12 months with echocardiograms and physical exams) were much more likely to undergo surgical AVR or TAVR than those who were not adherent (47.2% vs 18.3%; P = 0.001). Adherent patients also had greater survival free from hospitalization for heart failure (59.2% vs 52.6%; P = 0.02).

“The watchful waiting did what it was supposed to do, and it was certainly better than not following patients as carefully,” commented Bonow. “But what it doesn’t tell you is if you operated on those patients from day 1, maybe their survival would better. All it tells us is watchful waiting is better than not doing watchful waiting, but whether surgery or TAVR is better than watchful waiting, again, is not clear.”

Généreux, too, reiterated that the guidelines do not go far enough in encouraging screening for symptoms.

“We need to be more aggressive about screening asymptomatic patients with AS to identify symptoms that may be present but for whatever reason are not reported or not detected,” he said. “Stress tests should be done more liberally if there is any doubt about whether they are having symptoms, because 50% of asymptomatic patients with severe AS will have a positive stress test, which is a Class I indication for aortic valve replacement.”

On the whole, randomized data on the impact of AVR in asymptomatic patients is lacking, but in a meta-analysis of four retrospective studies published between 1990 and 2015, Généreux and colleagues found that the rate of all-cause death was roughly 3.5-fold higher with an observation strategy compared with AVR over follow-up periods that ranged from 21 to 45 months.

“If you decide on a conservative observational strategy, the occurrence of symptoms or of sudden death is very unpredictable,” Généreux noted. “Up to 2% of patients who are thought to have no symptoms may have sudden death while waiting. Also, when we say ‘I’ll see you in 3 to 6 months, or 6 to 9 months,’ a lot of those patients are going to be lost to follow-up, or they come back a few years later and now they have a drop in LVEF or new-onset A-fib because they have been waiting too long.”

‘Rigorous, Active Medical Surveillance’

Among the challenges for physicians, said Danny Dvir, MD (St. Paul’s Hospital, Vancouver, Canada), is that there is no validated protocol describing the best way to follow asymptomatic patients.

“The guidelines tell us to do another echo in 6 to 12 months, but this is not based on scientific data. It may be a shorter time that we should do the next echo,” he told TCTMD in an interview. “We just do not know.”

But Dvir said he agrees that a trial in asymptomatic patients “has merit” and that efforts should be made to focus on optimal intervention and observation.

Généreux added that a randomized trial would need to have “rigorous, active medical surveillance” at designated time points with inclusion of echocardiography and a thorough questionnaire aimed at teasing out symptoms patients either do not recognize or acknowledge. These elements would ensure that “watchful waiting does not turn into wishful thinking. On the other hand, we want to make sure that intervening early will not induce complications or expose the patient to a higher risk than they would have by waiting,” he said.

Overall, Dvir said he was surprised by how many patients with severe AS were considered asymptomatic. “It brings up an important concern because many times, especially with very old patients, it is very difficult to know [if they have symptoms],” he said.

Both Généreux and Dvir said age is likely to play a factor when considering intervention in an asymptomatic patient. “But this is something to analyze on a case-by-case basis,” Généreux added, “because we all know very vibrant 90-year-olds, but we also know morbid 75-year-olds.”

Dvir said he tends to believe that younger patients with few comorbidities are probably a good group to target among asymptomatic patients, but “we need many, many patients to make a solid trial that would have good statistical power.”

Just as important as identifying who will benefit, he observed, is identifying those who are truly asymptomatic and will do fine with appropriate observation. “I’m sure that there are patients who are truly asymptomatic,” Dvir noted. “We see them all the time in the clinic. Some of them will be referred for exercise stress test, and there will be no issues at all.”

However, risk of sudden death is 1.5% per year in asymptomatic patients, Dvir said, citing data from the CURRENT AS registry. “So when you consider that and you consider a watchful waiting approach,” he said, “what is it you are waiting for? For them to die at home, when we have the ability to replace the valve—at least in some of them—in a less invasive way with low complication rates?” He added that he believes the percentage of asymptomatic AS patients who do not have reduced EF, risk for rapid progression of stenosis, or critical AS is overall “a very selective group of patients.”

Note: Généreux as well as two other coauthors on the JACC paper, Gregg W. Stone and Martin B. Leon, are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.



  • Généreux reports speaker fees from Edwards Lifesciences. 
  • Dvir reports consulting for Edwards Life Sciences, Medtronic, and St Jude. 
  • Bonow and Goessl report no relevant conflicts of interest. 


  • Généreux P, Stone GW, O’Gara PT, et al. Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol. 2016;Epub ahead of print.