Not All Moderate Aortic Stenosis Is the Same—Neither Is Prognosis

A sizeable proportion of patients diagnosed with moderate aortic stenosis (AS) will have hemodynamic parameters on echocardiography that don’t match the standard definition, and many may be at greater risk of mortality than the “moderate” label implies, a new study suggests.

Current guidelines from the American College of Cardiology/American Heart Association and the European Society of Cardiology/European Association for Cardio-Thoracic Surgery define moderate aortic stenosis as an aortic valve area of 1.0-1.5 cm², a mean gradient of 20-40 mm Hg, and a peak aortic jet velocity of 3.0-4.0 m/s and 3.0-3.9 m/s in the European and US recommendations, respectively.

“Although this definition is easy to use when these three parameters are concordant, patients with moderate AS often present with discordant parameters (eg, aortic valve area 1.0-1.5 cm² but a mean gradient < 20 mm Hg). This raises uncertainty as to the actual severity of AS and it could have prognostic implications,” lead author Jan Stassen, MD (Leiden University Medical Center, the Netherlands), wrote in an email to TCTMD.

The study by Stassen and colleagues, published today in the Journal of the American College of Cardiology, found that 40% of the moderate AS patients studied had discordant findings. At 5 years, the rate of all-cause mortality was 47% in the discordant group versus 36% in the concordant group (P < 0.001).

“First of all, the study shows that we should better phenotype patients with moderate AS, because not all patients with moderate AS are the same,” Stassen observed. This point is further illustrated by the finding that while mortality at 1, 3, and 5 years was higher in patients with paradoxical low-flow, low-gradient moderate AS and classical low-flow, low-gradient moderate AS than in concordant patients, it was not higher in patients with normal flow, low-gradient moderate AS.

The researchers say the implication of the findings is that patients with discordant moderate AS, especially those with classical and paradoxical low-flow, low-gradient AS phenotypes, need closer follow-up than what the guidelines currently recommend.

“In my opinion (and based on the 1- and 2- year mortality rates in the current study), I would suggest to lower the time frame [for follow-up] from 1-2 years to 6-12 months for patients with discordant moderate AS,” he told TCTMD.

In an accompanying editorial, Jae K. Oh, MD, and Saki Ito, MD (both Mayo Clinic, Rochester, MN), suggest that systolic or diastolic dysfunction most likely contribute to the poorer outcome in the subsets of patients with classical or paradoxical low-flow, low-gradient moderate AS and say the study also highlights reduced stroke volume or stroke volume index as an important prognostic factor.

“Management of the underlying conditions responsible for reduced stroke volume, if possible, is as important as AVR to improve patients’ long-term outcomes,” they write.

Independent Association With Mortality

Nearly 2,000 patients (mean age 73 years; 51% men) from three registries based in the Netherlands and Singapore were included in the study. All were first assessed for concordant or discordant moderate AS on echocardiography. Those with discordant findings were further categorized into: normal-flow, low-gradient AS (55%); classical low-flow, low-gradient AS (31%); and paradoxical low-flow, low-gradient AS (14%).

Compared with those who had concordant findings, the discordant patients were older and more likely to have arterial hypertension, diabetes, prior MI, impaired renal function and symptomatic status. On echocardiography, discordant patients had larger LV end-systolic volumes, lower LVEF and stroke volume index, more-impaired right ventricular systolic function, and more concomitant moderate-to-severe mitral and tricuspid regurgitation. At follow-up, fewer patients in the discordant group than in the concordant group had undergone AVR (17% vs 40%; P < 0.001).

On multivariable analysis, paradoxical low-flow, low-gradient moderate AS (HR 1.46; 95% CI 1.07-1.98) and classical low-flow, low-gradient moderate AS (HR 1.71; 95% CI: 1.27-2.30) were independently associated with all-cause mortality.

Stassen and colleagues note that reduced flow despite preserved LVEF has been associated with increased mortality in patients with severe AS and may indicate a more advanced stage of AS. However, other comorbidities can cause inappropriate remodeling, resulting in reduced flow in moderate AS, they note.

More Answers Needed on Moderate AS

Oh and Ito say ongoing trials such as PROGRESS and EXPAND are expected to shed more light on the most important clinical question with regard to moderate AS, addressing “whether an earlier aortic valve replacement can benefit those patients who have underlying myocardial disease and AS whose severity is less than severe as currently defined.”

PROGRESS lead investigator Philippe Généreux, MD (Morristown Medical Center, NJ), said the current study and the ongoing trials illustrate the complexity of the diagnosis and management of moderate AS, as well as the limitations of echocardiography, which may have variable results depending on the technician doing the imaging or even from one day to the next in certain patients.

“Those limitations are the reason why when we see a patient in clinic with moderate AS we often do a biomarker [test] and sometimes we do a CAT scan . . . and sometimes we do cardiac MRI,” he said. “Patients can come one day and it's low flow, and another day it could be normal flow. This is why we have to be very careful about putting patients in one box and saying this is moderate AS and this patient will be fine. AS is still a mysterious disease, and its expression in patients is very variable.”

What remains unknown and what the PROGRESS study is hoping to find out, he added, is what type of moderate AS may be putting patients at risk of cardiac events and how to intervene before that happens.