Early Valve Replacement Cuts Death and Heart Failure in ‘Moderate’ Aortic Stenosis, Landmark Trial Finds

Replacing a narrowed aortic valve before the disease turns severe cut the combined risk of death or a heart-failure event by a third in patients whose condition had been classified as only “moderate”, according to results from a landmark international trial presented on Monday and published simultaneously in The New England Journal of Medicine. A second study released the same day, covering more than 53,000 real-world patients, found that nearly four in five people with moderate aortic stenosis already carry warning signs that double their risk of dying or being admitted to hospital with heart failure within two years.

Together, the two studies — both unveiled at the Transcatheter Cardiovascular Therapeutics (TCT) 2026 symposium in San Diego — challenge one of cardiology’s longest-standing rules: that a moderately narrowed aortic valve should simply be watched until it becomes severe. The evidence now suggests that for a large and identifiable group of patients, waiting is itself the risk.

“The clinical significance of moderate [aortic stenosis] should not be underestimated, and these patients should be referred promptly to a valve clinic for comprehensive evaluation to establish the optimal management strategy,” said Dr Philippe Généreux, the trial’s lead investigator and director of the structural heart programme at Atlantic Health Morristown Medical Center, according to the American College of Cardiology. “The PROGRESS trial shows that patients with moderate [aortic stenosis] and at-risk features can safely benefit from earlier TAVR and should not wait for disease progression, ultimately achieving a better quality of life and avoiding decline in their health status.”

TAVR — transcatheter aortic valve replacement — is a procedure in which a replacement valve is delivered through a catheter, usually inserted through an artery in the groin, and expanded inside the patient’s own diseased valve. Unlike open-heart surgery, it does not require the chest to be opened or the heart to be stopped, and most patients leave hospital within a day or two.

The PROGRESS trial: earlier treatment, fewer events

The PROGRESS trial enrolled 744 patients aged 65 and older at 74 centres in six countries — the United States, Japan, Australia, Canada and countries in Europe — all of whom had moderate aortic stenosis plus at least one feature indicating increased risk, such as symptoms or abnormalities in the heart’s structure or function. The patients, whose average age was 78, were randomly assigned to undergo TAVR with a valve from Edwards Lifesciences’ SAPIEN 3 platform, or to receive guideline-recommended clinical surveillance, with valve replacement available later if it became indicated. Of the group, 373 patients received TAVR and 371 were assigned to surveillance.

After two years, 16.7% of the patients who received early TAVR had died or experienced a heart-failure event, compared with 23.9% of those managed with surveillance — a risk difference of 7.2 percentage points and a relative reduction of about a third, according to the American College of Cardiology. The result met the trial’s pre-specified test for superiority, with a p-value of 0.02.

The advantage was driven largely by heart failure. Heart-failure events occurred in 10.8% of the TAVR group compared with 19% of the surveillance group, according to Edwards Lifesciences, which funded the trial. Hospital admissions for heart failure were halved: 7.4% of TAVR patients were admitted, against 14.9% of those under surveillance — 26 patients versus 52. A broader secondary measure combining death, stroke or heart-failure hospitalisation at two years also favoured early treatment, at 17.7% versus 23.3%.

Quality of life improved as well. Some 39% of patients who received TAVR survived with an improvement of at least 10 points on the Kansas City Cardiomyopathy Questionnaire, a standard measure of how heart failure affects daily life, compared with 23.2% of those under surveillance. Patients in the TAVR group reported a 15.5-point improvement in that score within 30 days of the procedure, according to the company’s announcement.

The trial also showed how quickly moderate disease can advance. More than half of the patients assigned to surveillance — 57% — ended up undergoing valve replacement within two years, and 27% did so within the first year. Of the 204 surveillance patients who eventually received a valve, about 80% had progressed to severe aortic stenosis by the time of the procedure, according to the American College of Cardiology.

“More than half of the patients initially assigned to surveillance underwent valve replacement within two years, suggesting that the disease can progress quickly from moderate to severe in some patients,” said Dr Aakriti Gupta, a study co-author and assistant professor at Cedars-Sinai’s Smidt Heart Institute, which enrolled more patients than any other participating centre.

On safety, Edwards Lifesciences said TAVR delivered “unparalleled safety at 30 days with no mortality and no disabling strokes”. The researchers plan to follow participants for 10 years to determine whether the early reduction in heart-failure events translates into longer survival, and to assess valve durability, the possible need for future procedures and which patients are most likely to benefit.

The trial was led by Dr Généreux, with Dr Raj Makkar, vice president of cardiovascular innovation and intervention at Cedars-Sinai, as national principal investigator. It was presented as late-breaking data at TCT 2026 on 2 November and published simultaneously in The New England Journal of Medicine. The trial is registered as NCT04889872.

The registry study: most “moderate” patients are already high-risk

The second study, published simultaneously in the Journal of the American College of Cardiology (JACC) and also presented at TCT 2026, explains why the trial’s findings matter to so many people. It analysed de-identified electronic health records and echocardiograms from the egnite Registry, covering nearly 15 million patients and 6.5 million echocardiograms at 48 institutions in the United States, and identified 53,994 adults diagnosed with moderate or severe aortic stenosis since January 2022.

Moderate disease outnumbered severe disease by nearly two to one: 35,343 patients had moderate aortic stenosis, against 18,651 with severe disease. And most of the moderate group was not low-risk at all. Some 78.7% of patients with moderate aortic stenosis had at least one at-risk feature, and even when symptoms were excluded from the definition, 69.9% still carried at least one.

The at-risk features were valve-related symptoms, a left ventricular ejection fraction below 60%, grade 2 or higher diastolic dysfunction, a low stroke volume index, atrial fibrillation, or elevated natriuretic peptides — blood markers that rise when the heart muscle is under strain.

Over two years, patients with moderate disease and at least one at-risk feature died at more than double the rate of those without such features: 20.1% versus 9.0%. Admissions to hospital with heart failure showed the same pattern, at 44.6% versus 21.9%. After statistical adjustment for other illnesses, the at-risk features remained associated with roughly twice the risk of death and of hospitalisation with heart failure, according to the study’s authors.

Perhaps the most striking finding was the timing. On the last echocardiogram taken before the event, 86% of heart-failure hospitalisations and 90% of deaths among moderate aortic stenosis patients occurred while the disease was still classified as moderate, with no evidence that it had progressed to severe. In other words, the harm arrived before the threshold at which guidelines currently permit treatment.

Current guidance from the American College of Cardiology and the American Heart Association recommends an echocardiogram every one to two years for moderate aortic stenosis, with valve replacement deferred until severe criteria are met. In the registry, only 20% to 23% of moderate patients had a valve replacement documented within two years, compared with 50.1% of those with severe disease.

Dr Généreux also announced a follow-on study, ACTIVATE AS, described as the first prospective multicentre study to use egnite’s CardioCare platform to identify and follow patients with moderate aortic stenosis. About 700 patients will be identified through the platform and followed rigorously in dedicated valve clinics, with multiparametric evaluation every six months, including core-laboratory echocardiography, natriuretic peptide testing and CT calcium scoring of the aortic valve. Enrolment is expected to begin in 2027, with Atlantic Health Morristown Medical Center as the lead site and coordinating centre. The study is investigator-initiated and funded by an unrestricted grant from Edwards Lifesciences.

What aortic stenosis is — and why “moderate” misleads

Aortic stenosis is a narrowing of the aortic valve, the one-way door through which blood leaves the heart’s main pumping chamber and enters the aorta on its way to the rest of the body. The narrowing is usually caused by calcium deposits that stiffen the valve’s leaflets over years, so that the valve opens less fully with each heartbeat. The heart must then work harder to push blood through a smaller opening, and over time the muscle thickens, stiffens and weakens.

The disease affects more than 3% of adults aged 65 and older, according to Cedars-Sinai, and its prevalence rises steeply with age. In its early stages it often causes no symptoms, which is one reason it is frequently discovered by chance — a heart murmur heard during a routine examination, or an echocardiogram performed for another reason. As the narrowing worsens, patients may develop breathlessness, chest pain, dizziness or fainting, and eventually heart failure.

Doctors grade the severity of the narrowing mainly by ultrasound measurements: the speed of blood flowing through the valve, the pressure difference across it, and the calculated area of the valve opening. On those measurements, “moderate” sits between mild and severe. But the labels describe the valve, not the patient. A moderately narrowed valve in a heart that is already strained — by a weakened pumping chamber, an irregular rhythm, or stiff walls that cannot relax properly — can cause as much damage as a severely narrowed valve in a healthier heart. That distinction is at the heart of both new studies.

The at-risk features identified in the registry are, in effect, signs that the heart is already struggling. A reduced ejection fraction means the heart’s main chamber is pumping less blood with each beat. Diastolic dysfunction means it cannot relax and fill properly. Atrial fibrillation, the commonest heart-rhythm disorder, makes the heartbeat irregular and less efficient. Elevated natriuretic peptides are a chemical signal of cardiac stress. Any one of these, the registry suggests, marks a patient whose “moderate” label understates the danger.

“Patients with moderate aortic stenosis can already have symptoms and signs that their heart is under strain,” said Dr Makkar. “These results show that for selected patients with at-risk features, treating the valve earlier can reduce the risk of heart-failure events before the narrowing becomes severe.”

A decade of moving treatment earlier

The PROGRESS results are the latest step in a steady shift away from watchful waiting in aortic stenosis, a shift driven by the falling risk of the procedure itself. When TAVR was first introduced, it was reserved for patients too ill for open-heart surgery. As the technology improved and evidence accumulated, it was extended to high-risk, then intermediate-risk, then low-risk patients with severe symptomatic disease. Each expansion was preceded by a randomised trial showing that intervening earlier was safe and effective.

The most recent precedent came with the EARLY TAVR trial, published in The New England Journal of Medicine in 2025 and presented at TCT the previous year. That trial randomised 901 patients with severe aortic stenosis but no symptoms to early TAVR or clinical surveillance, and found that prompt treatment reduced the composite risk of death, stroke or unplanned cardiovascular hospitalisation through five years. At a median follow-up of 3.8 years, the primary endpoint had occurred in 26.8% of the TAVR group compared with 45.3% of the surveillance group. In May 2025, the US Food and Drug Administration approved the SAPIEN 3 platform for patients with asymptomatic severe aortic stenosis — the first such approval for TAVR.

Even surgical valve replacement has shown the same pattern. The RECOVERY trial, whose extended follow-up was reported in The New England Journal of Medicine in March 2026, found that early surgery for very severe but asymptomatic aortic stenosis was associated with substantially lower long-term mortality than waiting: over 10 years, all-cause death occurred in 15% of patients assigned to early surgery, compared with 32% of those assigned to conservative care.

PROGRESS extends that logic one step further down the severity scale, from severe disease without symptoms to moderate disease with signs of cardiac strain. It is the first randomised trial to test TAVR in moderate aortic stenosis, and the first to show a benefit in that population.

The speed of progression seen in the trial underlines the point. In EARLY TAVR, more than a quarter of surveillance patients had crossed over to TAVR within six months, and 47% within a year, with nearly 40% of those presenting with advanced symptoms. In PROGRESS, 27% of surveillance patients needed a valve within a year and 57% within two. The pattern in both trials is the same: the patients doctors are watching are, in large numbers, the patients who will need treatment soon — and a substantial share of them arrive at that treatment sicker than they needed to be.

Caution, costs and the funding question

The findings come with important qualifications, and the trial’s own authors and commentators have stressed them. In an accompanying editorial in The New England Journal of Medicine, Dr Catherine M. Otto wrote that “TAVR is not appropriate for most adults with moderate [aortic stenosis]; however, the findings from this trial suggest that it may be considered in selected older patients with coexisting conditions at high risk of adverse outcomes when other treatment approaches are not effective.”

That distinction matters. The PROGRESS trial enrolled only patients with moderate disease plus at least one at-risk feature; it says nothing about the roughly one in five moderate patients who have no such features, and its participants were on average 78 years old. As Cedars-Sinai noted, researchers will also examine whether the findings apply to younger patients or to those without the at-risk features studied in PROGRESS.

There is also the question of durability. A replacement valve implanted in a 78-year-old will usually last the rest of that patient’s life, but the same cannot be assumed for a valve implanted a decade earlier in a younger person, and a second procedure — a valve inside a valve — is more complex than the first. The 10-year follow-up now planned for PROGRESS participants is designed to answer that question, but the answer will not arrive for years.

Both studies were funded by Edwards Lifesciences, the maker of the SAPIEN 3 valve used in the trial: the company funded PROGRESS directly, and the registry analysis was supported by a study grant from the company. That is standard practice in device research — the manufacturer funds the trials that test its products — but it is a reason to read the results with care rather than to dismiss them. The trials were randomised, independently monitored, and published in peer-reviewed journals, and the registry analysis was published in JACC with its observational limitations stated. Transparency about the funding is part of the evidence, not a footnote to it, and clinicians weighing the findings will weigh the funding alongside the data.

Cost is the other unavoidable question. TAVR is an expensive procedure, and extending it to the much larger population of patients with moderate disease would carry a substantial bill for health systems. The counter-argument, made by the trial’s supporters, is that heart-failure admissions are themselves among the most expensive events in medicine, and that halving them — as PROGRESS did — offsets much of the cost. Neither claim has yet been tested in a formal cost-effectiveness analysis of early TAVR for moderate disease, and that analysis will be one of the first things health-technology agencies ask for.

Access is a further consideration. TAVR requires a specialist heart team, a catheterisation laboratory and an experienced operator. In many parts of the world, including much of South Asia and Africa, such facilities are scarce, and even the echocardiography needed to identify at-risk patients is not universally available. A finding that helps patients in well-resourced centres does not automatically help patients elsewhere, and the gap between what the evidence supports and what health systems can deliver is part of the story of this trial, as of every advance in cardiac care.

Analysis: Why It Matters

1. “Moderate” was never a promise of safety

The most important idea in these two studies is a simple one: the word “moderate” describes a measurement, not a prognosis. For years, patients and many doctors have treated it as reassurance — the disease is present, but not yet dangerous, and there is time. The registry data show that for four out of five patients, that reassurance was misplaced. A fifth of them were dead within two years, and nearly half had been admitted to hospital with heart failure. Those are not the outcomes of a benign condition. They are the outcomes of a disease that was already doing damage while everyone waited for a number on an ultrasound report to cross a line. The lesson is that risk in aortic stenosis lives in the whole patient — the valve, the muscle, the rhythm, the blood markers — and a grading system that looks at the valve alone will keep missing it.

2. The trial answers the question the registry raised

Observational studies can show that a group of patients does badly; they cannot prove that treating them earlier would help, because the patients who get treated early are often different from those who do not. That is why the pairing of these two studies matters so much. The registry, with 53,994 patients, established the scale of the problem and identified exactly who is at risk. The PROGRESS trial, randomised and controlled, then tested the intervention in precisely that group and showed that it worked. Neither study alone would have been enough: the registry without the trial would have been a warning without a remedy, and the trial without the registry would have been a result without a population. Together they form a complete argument — here is who is in danger, and here is what helps them. That is how medical practice changes, and it is why guideline committees will find these results difficult to set aside.

3. Watchful waiting is becoming the exception, not the rule

Step back, and the direction of travel is unmistakable. A decade ago, the standard of care for aortic stenosis was to wait for symptoms. Then trials showed that treating severe disease before symptoms appeared was better. Now a trial shows that treating moderate disease with signs of strain is better. Each step has been resisted on the same grounds — the procedure carries risks, the evidence is early, the guidelines should not move too fast — and each time the evidence has eventually prevailed. The underlying reason is technological: as TAVR has become safer, the balance of risk has tilted. When a procedure carried a significant chance of stroke or death, waiting was rational. When, as in PROGRESS, there was no mortality and no disabling stroke at 30 days, the cost of waiting — heart failure, hospitalisation, decline — begins to outweigh the cost of acting. The question for guideline writers is no longer whether to move treatment earlier, but how far, and for whom.

4. The real bottleneck is finding the patients

The harder problem these studies expose is not treatment but detection. The registry’s at-risk patients were identified from echocardiograms and blood tests that had already been performed; the challenge is that millions of people with moderate aortic stenosis have never had an echocardiogram at all, or had one years ago and were told their valve was “only moderate” and sent away. The at-risk features that matter — a falling ejection fraction, diastolic dysfunction, a raised natriuretic peptide — are not things a patient can feel until they are advanced. Finding them requires systems: routine echocardiography in older adults with a murmur, automated flagging of at-risk measurements in electronic records, and referral pathways that send the right patients to valve clinics rather than back to routine review. That is what the ACTIVATE AS study is designed to test — whether a structured, technology-assisted pathway can find these patients and follow them properly. The trial shows the treatment works; the registry shows the population is large; the unanswered question is whether health systems can organise themselves to connect the two.

5. A result that will be argued over — and should be

This is not a result that should be accepted uncritically. The funding came from the device manufacturer. The follow-up is two years, not ten. The patients were old, and the findings may not apply to the young. The cost-effectiveness case has not been made. All of those are legitimate grounds for argument, and the argument will happen — in guideline committees, in health-technology assessments, and in cardiology conferences over the next year. But argument is not the same as inaction. The history of aortic stenosis over the past decade is a history of cautious institutions being proved too cautious by randomised evidence, and of patients paying for the delay with avoidable heart failure. The right response to PROGRESS is not to rush every moderate patient to the catheterisation laboratory, and it is not to file the result away until 2036. It is to do what the trial’s authors themselves propose: send the at-risk patients to a valve clinic, evaluate them properly, and treat the ones whose hearts are already under strain.

What to Watch Next

1. Guideline updates: The American College of Cardiology and the American Heart Association, whose guidance currently recommends surveillance every one to two years for moderate aortic stenosis, will face pressure to revise their recommendations. Watch for interim statements from the societies and for the next full valvular heart disease guideline.
2. Regulatory decisions: Edwards Lifesciences is expected to seek an expanded indication for the SAPIEN 3 platform to cover moderate aortic stenosis with at-risk features, following the path taken after EARLY TAVR for asymptomatic severe disease. The US Food and Drug Administration’s response will be a key signal.
3. ACTIVATE AS enrolment: The prospective follow-on study of about 700 moderate aortic stenosis patients is due to begin enrolment in 2027, testing whether structured six-monthly follow-up in dedicated valve clinics changes management. Its design and early recruitment will show how quickly the field moves from evidence to practice.
4. Ten-year PROGRESS follow-up: The trial’s investigators plan to follow participants for a decade. Long-term survival, valve durability and the need for repeat procedures will determine whether early TAVR’s two-year advantage endures — and whether it should be offered to younger patients.
5. Cost-effectiveness and access: Health-technology agencies will assess whether earlier TAVR represents value for money, and whether health systems — particularly outside well-resourced centres — can deliver the echocardiography, referral pathways and catheterisation capacity the findings imply.

Sources

• American College of Cardiology — PROGRESS: TAVR Superior to Clinical Surveillance in Patients With Moderate AS With At-Risk Features
• Cedars-Sinai — Early TAVR Benefits Some Patients With Moderate Aortic Stenosis
• Edwards Lifesciences (Business Wire) — PROGRESS Trial Demonstrates Edwards TAVR Is Superior to Clinical Surveillance for Moderate AS Patients With At-Risk Features
• egnite Health (PR Newswire) — Majority of Patients with Moderate Aortic Stenosis Carry Features Linked to Twice the Risk of Death, egnite Registry Study Finds
• Clinical Trial Vanguard — 78% of Moderate Aortic Stenosis Patients Have High-Risk Features, Study Finds