Mortality in Untreated Moderate AS Keeps Pace With What’s Seen in More Severe Disease

In a large Australian registry, 5-year all-cause and CV mortality were similar for both, suggesting moderate AS isn’t benign.

Mortality in Untreated Moderate AS Keeps Pace With What’s Seen in More Severe Disease

Patients with either severe or moderate aortic stenosis (AS) have poor long-term survival when left untreated, according to data from an Australian registry of nearly 250,000 people presented in a late-breaking trial session at the European Society of Cardiology Congress 2019.

In the study, 5-year mortality rates were 67% in patients with high-gradient or low-gradient severe AS and 56% in those with moderate AS.

“While lacking clinical granularity, the size and scope of identified patients with AS and their linked mortality data is substantially greater than previous observational studies used to inform current clinical practice,” write Geoff Strange, PhD (University of Notre Dame School of Medicine, Fremantle, Australia), and colleagues in a paper published simultaneously September 3, 2019, ahead of print in the Journal of the American College of Cardiology.

According to the researchers, the findings confirm that moderate AS is not benign and that current recommendations for how to manage these patients should be reevaluated. Strange and colleagues say the new data “provide a clear signal as to the likely survival” of individuals with mean aortic valve (AV) gradient of 20.0 mm Hg or peak AV velocity of 3.0 m/s.

Philippe Généreux, MD (Morristown Medical Center, NJ), who was not involved in the study, told TCTMD that while there is a need to better define the natural history of moderate AS and how it varies among patient groups, he would urge caution in suggesting that a gradient or peak AV velocity cutoff is predictive of outcome in every situation.

“Not all 20-mm Hg gradient patients are similar. There is a spectrum of moderate AS. You have the mild-moderate, and you have the moderate-severe,” he observed. “It may take 10 years in some cases for it to progress, and in others it may progress rapidly.”

Strange and colleagues used the National Echo Database Australia to identify 241,303 patients with varying degrees of AS:

  • None (mean gradient < 10 mm Hg and/or peak velocity < 2.0 m/s and/or an AV area > 1 cm2 )
  • Mild (mean gradient 10.0-19.9 mm Hg and/or peak velocity 2.0-2.9 m/s and/or an AV area > 1 cm2 )
  • Moderate (mean gradient 20.0-39.9 mm Hg and/or peak velocity 3.0-3.9 m/s and/or an AV area > 1 cm2 )
  • Severe high-gradient (mean gradient > 40.0 and/or peak velocity > 4.0 m/s with or without an AV area ≤ 1 cm2 ) or severe low-gradient (AV area ≤ 1 cm2 in the absence of high-gradient AS)

In addition to the increased 5-year mortality among the moderate and severe groups, the investigators also found higher rates of all-cause mortality and CV events in these patients. The adjusted risk of all-cause and CV mortality at 5 years was 1.34 (95% CI 1.23-1.46) and 1.22 (95% CI 1.11-1.34), respectively, in mild compared with no AS. For moderate AS, the values were 2.17 (95% CI 1.82-2.60) and 2.08 (95% CI 1.75-2.48), and for severe AS, they reached 2.76 (95% CI 2.44-3.11) and 2.36 (95% CI 2.11-2.63), respectively, for all-cause and CV mortality (P < 0.001 for all comparisons). Further analysis of mortality according increasing peak AV velocity, mean AV gradient, and AV area showed near-equivalent 5-year mortality rates between moderate and severe AS regardless of concurrent left heart disease.

Closer Follow-up Needed

Strange et al offer two plausible explanations for the findings. One is that those with an AV gradient in the moderate range may die from comorbid disease that would not necessarily require proactive management of the AS itself. The second possibility is that “a significant portion of those determined as moderate AS at baseline may have reached a tipping point of disease progression that inevitably led them to rapidly develop severe AS and a high risk of death,” they write.

If we only base our assessment of moderate AS on a single yearly echo, we may miss the boat. Philippe Généreux

Current guidelines from the American College of Cardiology/American Heart Association recommend that moderate AS patients be followed up with transthoracic echocardiography (TTE) every 1 to 2 years, a so-called “watchful waiting” approach. These new data, the researchers argue, point to the need not only for closer surveillance, but also to consider the potential value of more timely interventions in moderate AS patients.

Intervening earlier in the course of AS is being actively studied in the EARLY-TAVR (asymptomatic severe AS) and EVoLVeD (severe AS and LV decompensation) trials, but according to Généreux, the next important step in AS management is to develop prediction methods for determining which subgroups of moderate AS patients need the closer monitoring approach and/or intervention. Rather than TTE alone every 1 or 2 years, he said a multimodality approach that utilizes TTE, MRI, and biomarkers may be the best option on a yearly basis for moderate AS, although that theory is still untested.

“A multimodality approach helps to better characterize patients and you have less chance of technical error with one modality or another,” he noted. In the current study, Généreux added, there is no way to know the quality of the echocardiograms, which vary across technicians and centers, raising the possibility that some patients were mischaracterized as having moderate AS who actually had severe AS.

“If we only base our assessment of moderate AS on a single yearly echo, we may miss the boat,” he concluded.

  • The study was funded by support from Actelion Pharmaceuticals, Bayer Pharmaceuticals, GlaxoSmithKline, and a National Health and Medical Research Council of Australia grant.
  • Strange reports no relevant conflicts of interest.
  • Généreux reports consulting for Edwards Lifesciences and serving as PI of the ongoing EARLY-TAVR trial, sponsored by Edwards Lifesciences.