Two trials delivered in late 2024 have offered fresh evidence on the potential role that early intervention could play in the treatment of aortic stenosis, as well as shedding new light on the progression of the disease that investigators say could provide important insights for heart teams when considering treatment strategies.
Garnering many headlines at the time of their release in late October, EARLY TAVR and EVOLVED both investigated a strategy of pre-emptive treatment for asymptomatic aortic stenosis. However, diverging results seen across the two trials have fuelled discussion over whether watchful waiting should continue to be the favoured approach among those patients who are at high risk—albeit yet to develop symptoms of aortic valve disease—or if heart teams have the necessary evidence to buy in to the preventive strategy.
EARLY TAVR, which enrolled more than 900 patients who were deemed to be eligible through the use of a treadmill stress test, compared early intervention with transcatheter aortic valve implantation (TAVI) to clinical surveillance—meeting its endpoint of a reduction in a composite of death, stroke or unplanned cardiovascular hospitalisation between the two arms out to two years, driven largely by a reduction in hospitalisations in the TAVI group. EVOLVED, meanwhile, involved more than 200 patients with asymptomatic severe aortic stenosis and mid-wall myocardial fibrosis, assessed via cardiac magnetic resonance (CMR) imaging, who underwent either early intervention with TAVI or surgical aortic valve replacement (SAVR) or received guideline-directed conservative management. Unlike the EARLY TAVR trial, EVOLVED ultimately fell short in demonstrating a clinically meaningful difference in outcomes for patients undergoing the early intervention strategy against a primary endpoint of all-cause death or unplanned aortic stenosis-related hospitalisation.
Trials in surgical valve replacement
Prior to these latest studies, two smaller scale trials—AVATAR and RECOVERY—had investigated the potential benefit of early surgical valve replacement among patients with severe, asymptomatic aortic stenosis, with both indicating that initiating surgery early could lead to better clinical outcomes compared to conservative management. Marko Banovic (University of Belgrade Medical School, Belgrade, Serbia), principal investigator in the AVATAR trial, tells Cardiovascular News that the two latest trials are “landmark trials that deliver an additional degree of evidence supporting the consideration of early aortic valve replacement” on top of the existing evidence.
“As a cardiologist seeing these patients in daily clinical practice and following the evolution within the randomised controlled trials [including EARLY TAVR and EVOLVED], I would say that the totality of available randomised data supports the option for offering the patient pre-emptive treatment in shared decision making, tailoring the choice for the intervention to the patient’s risk profile,” he comments.
This sentiment was echoed by Rebecca Hahn (Columbia University Irving Medical Center, New York, USA), who, speaking during a spotlight session on the implications of the latest data for heart teams at PCR London Valves 2024 (24–26 November, London, UK), said: “The trials give us a justification for speaking to our patients about the safety of early intervention and give us a better timeline of when symptoms will occur and how short it [the timeline] is.”
One important talking point to have emerged from the latest round of trials is the speed at which symptoms appear to develop among patients who had previously been considered asymptomatic.
“In the current guidelines it is suggested that the development of symptoms may take years, but it was less than a year mean time—[in EARLY TAVR]—the median time was 11 months to develop symptoms, so it is actually much shorter. That helps patients to decide whether or not they go early, or they wait,” commented Hahn.
According to Banovic, the timing of adverse events is an important common thread seen in both the AVATAR and EARLY TAVR trials. “It is of note that event rates start to increase rather early from the time of diagnosis of significant aortic stenosis, on average 11 months in EARLY TAVR and 15 months in the AVATAR trial. Here, the adverse events in the watchful strategy arm remained higher after valve replacement as compared to those undergoing early valve replacement,” he comments. “Thus, these data provide me with a greater confidence to discuss the pre-emptive intervention in the setting of severe asymptomatic AS and normal LV function and overall low risk profile.
“Re-establishing the natural history”
EARLY TAVR principal investigator Philippe Généreux (Morristown Medical Center, Morristown, USA) tells Cardiovascular News that one of the important legacies of the research will be in “re-establishing the natural history of the progression of aortic stenosis”, pointing out that as many as 26% of patients in his trial’s clinical surveillance arm developed symptoms at six months, and 47% at one year, all of whom ultimately required TAVI.
Some critics have questioned whether the rapid rate of crossover between the surveillance and TAVI arms seen in EARLY TAVR could be attributed to patients essentially convincing themselves of the presence of symptoms due to their enrolment in the trial, a point that was highlighted by Davide Capodanno (University of Catania and G Rodolico-San Marco, Catania, Italy) in his appraisal of the research at PCR London Valves.
“The question is: you had a negative exercise test and you are totally asymptomatic, then you are randomised and you rapidly start developing symptoms. Something is strange there. If I imagine myself in that situation, I believe I would be thinking, thinking and thinking, that this disease is deadly, that I have been randomised to the unlucky arm, because I will not receive any intervention, and of course start to develop anxiety,” he said. However, regardless of the rate at which symptoms occur, many, including Capodanno, acknowledge that the progressive nature of aortic stenosis means that waiting will only delay the inevitable need for an intervention.
“The vast majority of patients with moderate aortic stenosis are going to go through this phase of mild-to-moderate stenosis, and then moderate stenosis, and then severe stenosis [with] no symptoms, and eventually severe aortic stenosis with symptoms,” Généreux comments on this point. “To wait a very long time it is going to [become] severe aortic stenosis with depressed cardiac function, and then death.
“From a philosophical point of view, all patients with aortic stenosis will at some point reach this zone of moderate-to-severe aortic stenosis with no symptoms. Now we are entering an era of preventive valve therapy we are more proactive and less reactive, we don’t wait until it is too late, we don’t wait until the patient has severe or critical aortic stenosis with symptoms.”
Timing is key
Généreux also notes that the results of the two latest trials bring into stark focus the importance of the timing of the intervention, pointing out the significant differences in the initiation of “early” treatment seen in both the EARLY TAVR and EVOLVED trials. Though patients randomised to the early intervention group in EVOLVED were treated on average 15 months before those undergoing conservative treatment, they still faced vastly greater waiting times than patients undergoing early treatment in the EARLY TAVR trial, who were typically treated within two weeks of their assignment to a treatment group.
“The EVOLVED trial showed, without a doubt, that waiting for symptoms kills,” he comments, pointing out that in the EVOLVED trial, some deaths occurred in the early intervention arm whilst patients were waiting to undergo their treatment. This point touches upon one of the major areas of contention regarding the two trials—whether an early intervention approach is practical in a real-world setting, given the waiting times faced within many healthcare systems, including the UK’s National Health Service (NHS) where most of the patients for EVOLVED were recruited.
“This is important for me to discuss,” Généreux says in response to this point. “People say that this is the system they are living in, well they need to change the system, because patients are dying because of that. It is time to elevate aortic stenosis to the level of cancer—when you have it, treat it. We need to have a sense of urgency around aortic stenosis. A lot of people are complacent, and the mentality of waiting for symptoms has been ingrained for 50 years. So, I think it is going to take time before we change people’s perceptions of the disease.”
Trial pipeline
Pooling data from the four available trials is likely to offer further insight on any potential beneficial impact of early intervention, and Généreux confirms that investigators are conducting a meta-analysis of the four trials to bring together the insights from across the datasets. Additionally, he singles out the ongoing PROGRESS trial, looking at TAVI or clinical surveillance in patients with moderate aortic stenosis as being a further important trial to watch in this arena, as it will add some fresh data on whether the presence of cardiac damage puts patients at higher risk for more rapid disease progression.
For Banovic, research into the field of preventive treatment for aortic stenosis remains an important live topic—whilst he hopes to see more focus on the question of where SAVR or TAVI should be favoured in this scenario.
“This is a very dynamic field of clinical research,” he comments. “There are still a few ongoing trials in the setting of asymptomatic severe aortic stenosis, in particular EASY AS which is planned to include more than 2,500 patients. These trials will shed further light on this important question.
“An additional, highly important question to address is the choice of optimal treatment strategy: either transcatheter or surgical. This question is of paramount importance in the current times with increasing, often uncontrolled use of TAVI in younger patients with consequences for lifetime management. The direct randomised comparison of the surgical versus the transcatheter approach in patients younger than those included in the EARLY TAVR trial is, in my view, important and very timely to consider.”
A further trial in this space, DANAVR, will also compare SAVR and TAVI in asymptomatic severe aortic stenosis, enrolling more than 1,700 patients, although results from either this trial or EASY AS are not anticipated until the latter half of the decade.
Though the evidence to date has yet to conclusively show that pre-emptive intervention should be considered in all cases, many are reassured that the safety of early aortic replacement seen across the four trials should mean it is on the table for a greater number of patients in future.
“What we can say is that early aortic valve replacement does not harm, that is an important piece of information, and that sooner or later treatment is needed,” Capodanno said in summing up his view of the new evidence at PCR London Valves. “What we cannot say is that early AVR is a strict necessity, because patients may base their choices on personal preferences and their own philosophy to risk.
“My take is that we have to explain to our patients the pros and cons of earlier intervention versus watchful waiting and now we have data in order to do so. Also, we have to consider the quality of the clinical surveillance in our centre. If we can deliver prompt aortic valve replacement when symptoms arise is one matter—if not—it is probably better to go earlier.”
