VALVENOR Study Helps Clarify Risks in Moderate AS Patients

For patients with symptomatic aortic stenosis (AS), mortality risk tracks with disease severity. But if symptoms aren’t present, moderate AS carries no higher risk of dying than does mild AS, new research suggests.

The notion that a symptom-based “wait and see” approach might be warranted in moderate-risk patients adds some color to a gray area in AS care, namely, whether intervening earlier might save lives and if so, what degree of disease might warrant such an intervention.

“Although the observed mortality in patients with mild AS could not be distinguished from the expected mortality in the general population, patients with moderate AS displayed an increased risk of cardiovascular mortality without reaching severe AS,” lead author Augustin Coisne, MD, PhD (Lille University Hospital, France), told TCTMD. “The increased mortality in moderate AS was only observed in symptomatic patients. By contrast, in asymptomatic patients, the cardiovascular mortality of moderate AS was similar to that of patients with mild AS.”

These observations remained valid after adjustment for baseline characteristics and also after accounting for progression of AS. Differences in causes of death according to symptom status were observed, with sudden death being more prevalent among those with asymptomatic severe AS and congestive HF being the main culprit in symptomatic severe AS.

“If you look at the survival curve of our study, there is no doubt that we can wait for at least 1 year if you have symptoms or 2 years if you don't have symptoms to intervene,” Coisne added. “In the patient with moderate AS, the curves are the same and superimposable to patients with mild AS.”

Among asymptomatic patients, the HR for CV mortality was 0.99 (95% CI 0.44-2.21) for moderate versus mild AS.

As such, say Coisne and colleagues, the VALVENOR data “support the need for frequent reevaluations of patients with AS by echocardiographic grading as well as symptomatic assessment.”

Commenting on the study for TCTMD, Philippe Généreux, MD (Morristown Medical Center, NJ), said it highlights how much is still unknown about the natural history of AS, including how, when, and in whom it progresses.

“There’s a growing desire to know more about which phenotype of moderate AS is associated with increased risk of mortality. In other words, which moderate patient looks like a severe AS patient,” he said. “To me, these data highlight the need for better designed prospective trials to understand the natural history of this disease.”

The study was published online ahead of print in JAMA Cardiology.

Patterns of All-Cause and CV Deaths

For VALVENOR, Coisne and colleagues enrolled 2,703 outpatients with AS who were seen by 117 cardiologists at multiple centers in France. AS was assessed by transthoracic echocardiography (TTE), and the degree of disease was classified according to peak aortic jet velocity as mild (2.5-2.9 m/s; 42.7%), moderate (3.0-3.9 m/s; 41.5%), or severe (≥ 4 m/s; 15.8%). There were no significant baseline differences between groups in terms of age, sex, CV risk factors, or underlying CV disease.

At follow-up, 775 patients showed progression of AS on repeat TTE. Of those, 45.2% progressed from mild to moderate, 7.7% from mild to severe, and 47.1% from moderate to severe. Aortic valve replacement (AVR) was performed in 634 of the 775 patients with disease progression; 3.4% of those with mild disease, 20.2% of those in the moderate group, and 54.6% of those in the severe group. The remaining 141 patients met the criteria for AVR but did not undergo intervention during follow-up for reasons ranging from patient refusal to contraindications and death while waiting for the procedure.

In the cohort as a whole, most CV deaths were due to HF and sudden death. By disease severity, there was an upward trend of death occurring in 14.1% of those with mild disease, 17.6% of those with moderate disease, and 20.6% of those with severe disease. Similarly, the 2-year cumulative risk of all-cause death was 11.6%, 15.7%, and 25.6%, respectively.

An analysis using disease severity as a time-dependent variable confirmed that compared with mild disease, all-cause death was higher in those with either moderate (HR 1.54 95% CI 1.24-1.92) or severe AS (HR 2.65; 95% CI 2.06-3.41). The same pattern also was seen for increased CV mortality: HR 1.49 (95% CI 1.06-2.10) for moderate disease and HR 3.46 (95% CI 2.40-4.99) for severe disease. By symptom status, all-cause mortality in patients with mild disease was higher in those with versus without symptoms (HR 2.49; 95% CI 1.76-3.51), as was CV mortality (HR 3.31; 95% CI 1.87-5.88).

Ongoing Questions

Coisne and colleagues say their findings are consistent with earlier studies suggesting that moderate AS is not a benign condition and that death rates in these patients may be as much as 1.5 to 2 times higher than in age- and sex-matched patients without AS. To TCTMD, Coisne said it’s unclear whether some moderate AS patients progress quickly to severe AS, or die from moderate AS without progression.

Généreux noted that the ability to predict disease progression in moderate AS is an important focus of ongoing research. Not only will that help quantify the optimal timing of valve replacement to prevent death, it also may go a long way toward preventing patients from developing irreversible A-fib or low ejection fraction.

“We’re still trying to understand the optimal timing of AVR and whether we should wait until AS is severe,” he said. “It’s an open question, and it’s going to depend a lot on whether the valves and the techniques are good enough to allow us to do such early intervention.”

Généreux added that moderate aortic stenosis is a moving target. “We will learn a lot from current ongoing trials such as TAVR UNLOAD, which is studying patients with moderate AS and heart failure. Also, the PROGRESS trial will be starting very soon and will be looking at patients with moderate AS, with or without symptoms, who will be treated with TAVR versus clinical surveillance,” he said.

Note: Coisne is a research fellow with the Cardiovascular Research Foundation, the publisher of TCTMD.