For Moderate AS Patients, Baseline Factors Can Help ID Who’s Most at Risk

Nearly half of patients with moderate aortic stenosis (AS) will have a major adverse cardiovascular event within a year or so of their diagnosis, according to an analysis of data from the Cleveland Clinic. Researchers identified four independent predictors of worse outcomes that may help inform who would benefit most from treatment before the disease progresses to severe AS—assuming this strategy pans out in ongoing randomized trials.

“There’s been a lot of scrutiny on moderate aortic stenosis, given that some data in terms of its natural history has shown its outcomes to be almost as nasty as severe aortic stenosis,” senior author Rishi Puri, MBBS, PhD (Cleveland Clinic, OH), told TCTMD.

Many of these patients will eventually meet the bar for undergoing aortic valve replacement. This raises the question, being explored in the EXPAND TAVR II and PROGRESS clinical trials, of whether intervening earlier in the evolution of disease would lead to better outcomes. To explore this possibility, it’s necessary to identify which patients with moderate AS—defined as an aortic valve area of 1-1.5 cm², a mean gradient of 20-40 mm Hg, and a peak velocity of < 4 m/s—are most vulnerable and thus most apt to benefit, Puri said.

“In medicine, we like to dichotomize things as black or white . . . , but in nature everything exists as a continuum. For many patients, you don’t need to hit all of these arbitrary definitions that we’ve [used] to simplify our own lives and diagnostic criteria,” he said. “There are shades of gray across the full spectrum of severity of all diseases, and aortic stenosis is one of them.”

Some patients may not quite meet the criteria for severe AS but still be symptomatic and have rising NT-proBNP levels and signs of more-advanced cardiac damage, Puri pointed out. “Do we just wait and wait and wait until they meet these man-made criteria for severe aortic stenosis, or do we just sort of use common sense and pull the trigger early and say: ‘Look, the heart damage could be attributed to moderate aortic stenosis, or at least that’s the easiest thing we can fix, why don’t we fix that?’ That’s what this [paper] is really about: trying to identify those patients across the broader spectrum of moderate AS who we can really home in on . . . and then offer more-rapid aortic valve therapies.”

The results, with Travis Howard, MD (Cleveland Clinic), as lead author, were published recently in Circulation: Cardiovascular Imaging.

There are shades of gray across the full spectrum of severity of all diseases, and aortic stenosis is one of them. Rishi Puri

A total of 12,035 patients with moderate AS were treated at the Cleveland Clinic between January 2016 and June 2020. The researchers focused on the 674 patients (mean age 75.3 years; 57% men) within that larger group who most closely resembled the EXPAND TAVR II and PROGRESS populations. The two trials, Puri noted, are similar in their designs and enrollment criteria, with both comparing TAVI against ongoing medical therapy.

All had NT-proBNP levels available within 3 months of their index diagnosis, with a median value of 873 pg/mL and 74% above the age-related cutoff. Eight in 10 patients were hypertensive, 70% had a glomerular filtration rate < 60 mL/min/1.73 m², half had CAD, and 38% had diabetes. The mean LVEF was 60%.

In all, 19.6% of the patients died (at a median of 190 days after moderate AS diagnosis), 21.4% were hospitalized with heart failure (at a median of 86.5 days), and 16.9% underwent aortic valve replacement (at a median of 444 days) after their disease progressed to severe AS. Of the valve replacements, 49.5% were TAVI. When these events were combined as a composite, the overall MACE rate was 45.3%.

Independent predictors of MACE included elevated NT-proBNP (HR 1.41; 95% CI 1.01-1.85), diabetes (HR 1.46; 95% CI 1.08-1.96), elevated averaged mitral valve E/eʹ ratio (HR 1.57; 95% CI 1.18-2.10), and presence of atrial fibrillation at the time of index echocardiogram (HR 1.83; 95% CI 1.15-2.91).

“Patients are starting to have events within the first 6 to 12 months—the curves separate and continue to separate,” Puri pointed out, noting that there was a stepwise increase in MACE risk with each added predictor.

Based on his experience in clinical practice, Puri predicted EXPAND TAVR II and PROGRESS will be positive in showing it’s not always necessary to wait until AS becomes severe before taking action. However, “you have to prove it and trials are tricky,” he said. “Pivotal trials are always hard, because there’s a lot of scrutiny on these patients and you have to try to isolate the really ‘pure’ patients who are going to benefit, but hopefully these trials will answer that question in the coming years.”

A first step, as explored here, is to come up with ways to understand which patients with moderate AS are most vulnerable to MACE, said Puri. In their next analysis, the Cleveland Clinic researchers are looking at what happens when patients with aortic AS “are offered timely aortic valve replacement,” he said. “Does the baseline stage or comorbidity burden impact your ongoing trajectory beyond your seminal valve replacement, or does that [starting point] really change your trajectory once and for all?”

At this point, however, class I evidence specifies that severe AS is required before AVR, Puri added.

Until that changes, clinicians can look at the whole picture, not just strict definitions, and be alert to any progression, he said. “The way in which we define aortic stenosis and the multiparametric means by which we assess and adjudicate whether a valve is more on the severe, as opposed to moderate, spectrum requires a practitioner to look at a variety of parameters . . . [and] the patient in front of you, not just going off a mean gradient and valve area and then making those decisions.”