Echo Parameters Identify At-Risk Asymptomatic Patients With Severe AS

Patients with asymptomatic aortic stenosis (AS) followed at specialty heart-valve hospitals are at a low risk of sudden cardiac death and have “good midterm survival” outcomes, suggest the results of a new analysis.

However, asymptomatic patients with very severe AS, specifically those with markers of impaired valve hemodynamics or heart function, fared worse than individuals with less severe AS, suggesting that certain patients might benefit from an earlier valve intervention, according to investigators.

“We don’t know exactly how to manage these patients with asymptomatic severe aortic stenosis,” lead investigator Patrizio Lancellotti, MD, PhD (University of Liège Hospital, Belgium), told TCTMD. “The guidelines recommend ‘watchful waiting,’ but I would prefer to say it’s ‘active follow-up.’ An active follow-up means we need to clearly follow patients and identify any occurrence of symptoms or clinical deterioration. But with asymptomatic patients, we don’t know when to intervene or if we intervene whether it would be associated with improved outcomes.”

In their analysis, which was published October 3, 2018, in JAMA Cardiology, peak aortic velocity greater than 5 m/s and LVEF less than 60% were associated with an increased risk of all-cause and cardiovascular mortality without an aortic valve replacement procedure. LVEF less than 60% was a particularly robust predictor of all-cause and cardiovascular death, and this cutoff is higher than the threshold currently used in clinical guidelines to determine whether or not to proceed with valve replacement, said Lancellotti.  

“We found out that some conventional parameters are clearly associated with very worse outcomes,” he said. “These parameters would probably change our minds, and also hopefully the guidelines, about when to intervene in patients with severe aortic stenosis when the patient is still asymptomatic.”

Tom Cahill, MBBS (Oxford University Hospitals, England), who was not involved in the study, praised the robust analysis, and said these new data suggest the current strategy of simply waiting for symptoms to develop before intervening isn’t the right approach for every patient.

“We would typically wait for patients to develop angina or exertional breathlessness, presyncope, or syncope before offering them an intervention, be it surgical aortic valve replacement or TAVR,” said Cahill. “What this study—a large, contemporary, global series with long-term follow-up—clearly tells us is that’s not the right strategy for everybody. In fact, there’s an appreciable mortality in patients with asymptomatic severe aortic stenosis.”

One of the major issues going forward is to identify the appropriate asymptomatic patient, either with biomarkers or imaging findings, that physicians should be referring for aortic valve replacement. To TCTMD, Cahill highlighted the ongoing EVOLVED study, which is testing whether cardiac fibrosis detected on MRI can successfully guide early valve replacement in asymptomatic patients with severe AS.

“The key question is precisely who these patients are,” said Cahill. “How can we be sure we’re selecting out the right people to take forward to valve replacement, and how can we continue to drive down the procedural risks of valve replacement so that we can take somebody who is walking around asymptomatic and replace their valve with a safe procedure?”

‘Watch and Wait’ in Most Asymptomatic Patients

The American Heart Association (AHA) and American College of Cardiology (ACC) recommend a watch-and-wait approach that includes serial clinical and echocardiographic examinations for patients with asymptomatic AS. Surgical valve replacement is recommended in asymptomatic severe AS patients with impaired valve hemodynamics and/or impaired LVEF (less than 50%) at low- or intermediate-risk for surgery. Valve replacement is also recommended if the patient is undergoing concomitant valve or coronary surgery or has induced symptoms on a treadmill stress test. TAVR is not indicated unless symptoms are present.

The researchers analyzed outcomes from 1,375 patients treated at dedicated heart valve centers in Europe, Canada, and the United States between 2001 and 2014. To TCTMD, Lancellotti said they selected heart valve centers because they wanted to accurately identify the natural history of asymptomatic AS in patients who would be stringently followed over time and managed and/or treated according to the clinical guidelines.

At 2, 4, and 8 years, respectively, 93%, 86%, and 75% of patients with moderate and severe AS managed with medical therapy were alive. The cardiovascular death-free survival rates at 2, 4, and 8 years were 96%, 90%, and 83%, respectively. Of the 104 patients who died while being managed with medical therapy, 57 died from cardiovascular causes, including 38 from heart failure and seven from sudden cardiac death.

Overall, 861 patients had severe AS defined as an aortic valve area less than 1.0 cm2. Among these patients, 92% were alive at 2 years, 80% at 4 years, and 65% at 8 years. For those who did not undergo SAVR or TAVR, the survival rates at 2, 4, and 8 years in these patients were 54%, 32%, and 12%, respectively. Of the 64 patients with severe AS who died while managed with medical therapy, 32 died from cardiovascular causes, with heart failure the leading cause of death. Aortic valve replacement was performed in 388 of the patients with severe AS, with more than 94% undergoing the procedure after a change in status lead to a class I indication. In these patients, the mean time from the inclusion in the study to valve replacement was 14.4 months.

For the 514 patients with moderate AS at baseline, 154 underwent aortic valve replacement (71.4% with SAVR vs 28.6% with TAVR) after progressing to echocardiography-confirmed severe AS. In the entire cohort of patients with moderate AS at study entry, the mean survival rate at 2, 4, and 8 years was 94%, 89%, and 78%, respectively.

At 30-day follow-up, the mortality rate for patients undergoing valve replacement was 0.9%. Patients with severe AS at baseline—those with higher peak aortic velocity or a lower LVEF—had lower postoperative survival rates after aortic valve replacement compared with those with better baseline values.

To TCTMD, Lancellotti said the overall rate of sudden cardiac death during follow-up—0.65%—is lower than in previous studies. For patients without an increase peak aortic jet velocity or LVEF less than 60%, they can be safely followed every 6 months or annually in the heart valve clinic without significant risks, he said.  

Symptoms Are Soft, Subjective Measures

In an editorial accompanying the study, Patrick O’Gara (Brigham and Women’s Hospital, Boston, MA), and Robert Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), said the association between peak aortic jet velocity (> 5 m/s) and LVEF (< 60%) with all-cause and cardiovascular mortality could influence the timing of surgical referral if the results are validated in other studies.    

For Cahill, one of the challenges of guideline-recommended watchful waiting for asymptomatic severe AS patients is that identifying symptoms can be challenging.

“We can ask people if they develop breathlessness or lightheadedness, but those are somewhat soft,” said Cahill. “Clearly, it’s different if a patient develops clear-cut angina or has syncope, but some symptoms are subjective and that makes relying on them so difficult. In the future, what we’re looking to do is move toward harder, objective markers to complement the symptoms so we can pick out the right patients for earlier valve intervention.”

To TCTMD, Cahill pointed out that individuals with elevated peak velocity and reduced LVEF fared less well than individuals without these impairments, even after valve replacement, “suggesting that we may have missed the boat by even waiting too long in that subgroup,” said Cahill.

The ongoing EARLY TAVR study, led by Philippe Généreux, MD (Morristown Medical Center, NJ), is currently testing whether replacing the aortic valve in patients with asymptomatic severe AS is superior to the standard of watchful waiting. In the trial, patients will be classified as asymptomatic based on their ability to perform a treadmill stress test (patients who are symptomatic based on those findings will be included in a registry), and the primary endpoint is a 2-year composite that includes all-cause mortality, all strokes, and unplanned cardiovascular hospitalization.