Could a Biomarker Take Aortic Valve Replacement to the New Aortic Stenosis Frontier?

May 29, 2019

Patients with asymptomatic severe aortic valve stenosis should probably be referred early for aortic valve replacement (AVR), especially if they have elevated natriuretic peptides, concluded researchers after a retrospective analysis of a 14-year single-center experience.

Patients at the center who were advised against AVR because they lacked symptoms, and so were managed conservatively, showed significantly worse survival over the next few years than those who went on to AVR surgery.

In a multivariate analysis, advanced age and elevated baseline levels of N-terminal B-type natriuretic peptide (NT-proBNP), a biomarker that reflects myocardial stretch, were significant predictors of death from any cause among those who didn't get the surgery.

The analysis adds to active ongoing research to determine AVR suitability in asymptomatic severe aortic stenosis, one of the valve field's big frontiers now that transcatheter AVR (TAVR) has broadened its purview to cover symptomatic patients with aortic stenosis at all levels of operative risk.

Anette Borger Kvaslerud

It also suggests that elevated NT-proBNP levels could potentially be used to select patients with asymptomatic severe aortic stenosis at especially high risk for death who might therefore benefit most from TAVR or surgical AVR, Anette Borger Kvaslerud, PhD, Oslo University Hospital Ullevål, Norway, told | Medscape Cardiology.

Mortality was significantly elevated at NT-proBNP levels higher than 126 pmol/L in the asymptomatic patients compared with those who received AVR, she noted.

Although such a retrospective analysis can only be hypothesis-generating, it suggests that when the natriuretic peptide is higher than that fairly low cut point, "maybe one should think more about early intervention in those patients," said Kvaslerud, who had presented the analysis here at European Society of Cardiology Heart Failure 2019.

Indeed, of the 114 asymptomatic patients in the analysis, who represented less than 5% of those with severe aortic stenosis evaluated at the center, 18 later developed symptoms but were by then considered too fragile or sick to undergo surgery, Kvaslerud said.

Of note, TAVR was primarily a dream for the future, and surgical AVR the only option, during most of the years covered by the analysis.

This and other observational studies suggest that watchful waiting just isn't good enough for most patients with asymptomatic severe aortic stenosis, agreed Chiara Bucciarelli-Ducci, MBBS, MD, PhD, University of Bristol, United Kingdom, who wasn't involved with the current study.

Whether a patient with even severe aortic stenosis gets any kind of AVR generally hinges on whether they have symptoms, she told | Medscape Cardiology. But when asymptomatic patients do worse without AVR, "it means there are things going on with them that we don't capture with symptoms only; hence, the need for better biomarkers, whether in the blood or by imaging, to intervene early before they develop symptoms."

The 114 patients with asymptomatic severe aortic stenosis who didn't get surgery were compared with 100 age- and sex-matched patients in the larger cohort with severe aortic stenosis who went on to AVR. The groups were similar with respect to mean age, body mass index, NT-proBNP level, and prevalence of coronary disease and diabetes.

Survival Rates for Patients With Severe Aortic Stenosis: Asymptomatic Patients Without AVR vs Those Referred for AVR
End Point Asymptomatic, No AVR (n = 114), % Referred for AVR (n = 100), % P Value
1 year 88 92 .44
2 years 75 83 .19
3 years 63 78 .02

Survival curves for the asymptomatic, nonsurgical patients and those referred for AVR diverged early and continued to separate throughout the mean follow-up to show a highly significant survival advantage for the AVR group by 4 years (  < .001).

Both age and NT-proBNP levels, but not peak aortic velocity, emerged as significant mortality predictors in the asymptomatic, non-AVR group.

Hazard Ratio (HR) for Predictors of Death From Any Cause in 114 Patients With Asymptomatic Severe Aortic Stenosis, Multivariate Analysis
End Point HR (95% CI) P Value
Age (per 1-y increase) 1.10 (1.02–1.19) .016
Systolic blood pressure
(per 1 mm Hg increase)
0.98 (0.97–1.00) .087
Peak aortic velocity (per m/s) 1.07 (0.62–1.85) .80
NT-proBNP (log pmol/L) 3.51 (1.40–8.83) .008


Bucciarelli-Ducci pointed to several ongoing randomized trials comparing conservative management with AVR in asymptomatic patients with severe aortic stenosis, and some of them are looking at biomarkers or other signals that might risk-stratify them.

For example, the Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe Aortic Stenosis (EVOLVED) study, with an estimated 1000 patients, is exploring whether myocardial fibrosis near the aortic valve by cardiac magnetic resonance (CMR) imaging can serve as a risk predictor.

It's unknown whether such fibrosis precedes or follows the natriuretic peptide responses to aortic valve disease, "that's why the research is ongoing to understand the best early predictor," Bucciarelli-Ducci said.

Other trials underway in this population include Early Surgery for Patients With Asymptomatic Aortic Stenosis (ESTIMATE), with an estimated 360 patients; Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis (EARLY TAVR), with 1109 patients; and Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis (AVATAR), with an estimated 312 patients.

Kvaslerud reports no conflicts. Bucciarelli-Ducci has previously disclosed being a consultant for Circle Cardiovascular Imaging.

European Society of Cardiology Heart Failure (ESC-HF) 2019: Abstract 833. Presented May 25, 2019.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from | Medscape Cardiology, follow us on Twitter and Facebook.


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