By Jeffrey Zimmet, MD, PhD
Synopsis: In this multicenter, randomized trial comparing transcatheter aortic valve replacement (TAVR) with active surveillance in patients with asymptomatic severe aortic stenosis (AS), early TAVR showed an advantage regarding the composite endpoint of death, stroke, or unplanned hospitalization for cardiovascular causes. This result was driven primarily from the progression to severe symptomatic AS among the surveillance group, with no significant difference in mortality.
Source: Généreux P, Schwartz A, Oldemeyer JB, et al. Transcatheter aortic-valve replacement for asymptomatic severe aortic stenosis. N Engl J Med. 2024; Oct 28. doi:10.1056/NEJMoa2405880. [Online ahead of print].
Patients with severe aortic stenosis (AS) who have symptoms attributable to their valvular disease typically are referred expediently for valve replacement, whether by surgical or transcatheter means. However, when patients have severe AS by echocardiogram parameters but have no symptoms, the landscape becomes murkier.
Smaller studies of surgical aortic valve replacement (AVR) in asymptomatic patients have demonstrated benefit over waiting, especially in patients with very severe AS. Until now, no randomized studies have addressed this question in patients being considered for transcatheter aortic valve replacement (TAVR).
The EARLY TAVR study sought to answer this issue definitively, examining the issue in patients 65 years of age or older with normal ejection fraction and asymptomatic severe AS. Most patients also were assessed by treadmill exercise stress testing to confirm asymptomatic status; 9.4% of patients were classified as asymptomatic on the basis of history alone.
Ultimately, 901 patients were randomized at 75 sites in the United States and Canada, with 455 patients randomized to TAVR and 446 assigned to clinical surveillance. Included patients had a mean age of 75.8 years, and 69.1% were men. Echocardiogram demonstrated clearly severe AS in most patients, with peak aortic velocity of 4.3 m/sec and mean gradient of 47 mmHg.
Over a median follow-up time of 3.8 years, the composite outcome of all-cause death, stroke, or unplanned hospitalization occurred in 122 patients (26.8%) in the TAVR group and 202 patients (45.3%) in the clinical surveillance group (hazard ratio, 0.50; 95% confidence interval, 0.40-0.63; P < 0.001). Notably, progression to symptomatic AS requiring TAVR was assessed as an unplanned hospitalization for the purposes of the primary endpoint.
Conversion to TAVR occurred in 105 patients in the surveillance group within six months of randomization. By the end of the surveillance period, 88% of patients had undergone TAVR, with a median time to procedure of just more than 11 months.
Death overall was not significantly different between the two groups, although six cardiovascular deaths occurred in the clinical surveillance group before conversion to TAVR. The authors concluded that early TAVR was superior to clinical surveillance for the combined endpoint of death, stroke, and unplanned cardiac hospitalization.
Commentary
EARLY TAVR set out to address an important clinical question in cardiology. The study is the largest of its kind to date, enrolled real-world asymptomatic TAVR patients, and was rigorously performed. It clearly was designed to be a positive trial based on its choice of primary endpoint. However, in my view, it does little to inform clinical practice. It also is worth noting that the study was sponsored by the manufacturer of the balloon-expandable valve used exclusively in the trial.
The authors reported superiority of the immediate TAVR strategy among patients with severe asymptomatic AS. However, the primary endpoint was driven almost entirely by what they termed “unplanned hospitalization for cardiac causes,” and this included admission for TAVR.
By design, patients with asymptomatic AS who are being surveilled are monitored for progression of symptoms that will trigger referral for TAVR. Including this normal progression as part of the primary endpoint essentially guaranteed a positive finding and dilutes, in my view, the effect of the trial’s conclusions.
Patients in this trial were older (average age 75 years) consistent with a contemporary TAVR practice. A clear trend in the United States has been the application of TAVR to both a less sick and a younger population compared with historical averages. Although most patients in the conservative group underwent TAVR during the trial period, a substantial proportion (approximately 30% at two years) did not. These patients did not experience adverse outcomes. For younger patients, a significant delay like this prior to undergoing TAVR may have advantages in the downstream need for additional interventions, in patients whose lifespan is likely to exceed valve durability.
Some argue that the relatively rapid progression of AS in these patients, coupled with the observed high safety profile of the TAVR procedure itself, means that patients similar to those in the trial may be referred for TAVR without waiting for symptoms. For many patients, particularly in those for whom symptoms are difficult to assess or for whom close surveillance is difficult, early TAVR may indeed be confidently offered. That is quite different from saying that all patients meeting these criteria should be referred immediately for TAVR.
The result of this trial is not compelling enough to make such a change in guideline recommendations; each patient with asymptomatic severe AS still warrants an individualized approach to management.
Jeffrey Zimmet is Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center.
In this multicenter, randomized trial comparing transcatheter aortic valve replacement (TAVR) with active surveillance in patients with asymptomatic severe aortic stenosis (AS), early TAVR showed an advantage regarding the composite endpoint of death, stroke, or unplanned hospitalization for cardiovascular causes. This result was driven primarily from the progression to severe symptomatic AS among the surveillance group, with no significant difference in mortality.
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