New data from the EARLY TAVR trial programme have been released, looking in detail at the use of treadmill stress testing as a tool to inform treatment choices in patients with severe aortic stenosis (AS) who have yet to report any symptoms.
Detailing their results in JAMA Cardiology, Philippe Généreux (Morristown Medical Center, Morristown, USA) and colleagues note that one in six patients who underwent the test, who were otherwise thought to be asymptomatic, had criteria that would make them eligible for aortic valve replacement under current guidelines.
The investigators say that the findings demonstrate the safety and utility of treadmill stress tests as a first step in triaging patients with an established indication for aortic valve replacement where delaying treatment may not be desirable.
Headline results from EARLY TAVR were first released in late 2024. The trial, which enrolled more than 900 patients with severe asymptomatic aortic stenosis, compared early intervention with transcatheter aortic valve implantation (TAVI) to clinical surveillance. Results demonstrated a reduction in a composite of death, stroke or unplanned cardiovascular hospitalisation out to two years among patients who underwent early intervention, driven largely by a reduction in hospitalisations in the TAVI group.
The trial’s headline results have contributed to the ongoing debate over whether ‘watchful waiting’ should be the favoured approach for patients who are at high risk but are yet to develop symptoms of aortic valve disease, or if heart teams have the necessary evidence to buy in to a preventive treatment strategy. Already the results have contributed to a change in labelling for Edwards Lifesciences’ Sapien 3 TAVI valve, which is now US Food and Drug Administration (FDA) approved to include asymptomatic severe AS patients.
In the latest of a series of publications from the EARLY TAVR study programme, investigators report the results of a prespecified registry involving 105 patients who were screened, but ultimately ineligible, for inclusion in the main trial when their symptoms or other aortic valve replacement indications were flagged up following their treadmill test.
The registry study sought to establish the safety of using this method as a screening tool in asymptomatic patients, as well as documenting how often a positive result may occur; what is the mortality rate over time for these patients; the predictors of a positive test result, and; what is the timing of aortic valve replacement in the event of a positive stress test.
In the EARLY TAVR enrolment phase, prospective candidates—who were identified as having asymptomatic but severe aortic stenosis—were assessed for inclusion by undergoing a low-intensity treadmill test. They were deemed to have a positive result if they met one or more criteria during or immediately after the test that included the onset of syncope or presyncope, angina, limiting dyspnoea, a drop in systolic blood pressure, or severe ventricular arrhythmia.
Those with normal test results were placed into the main trial and randomised to TAVI or clinical surveillance, whereas those with positive stress test results were invited to enrol in the prospective registry and followed up through two years. Of 1,250 patients screened, 146 (15.2%) returned a positive score and 105 consented to be included in the registry.
Among the registry patients, the mean age was 76.1 years, and 76.2% were male—similar to those who had a normal test result. They were found to have higher Society of Thoracic Surgeons (STS) predicted risk of mortality scores, shorter six-minute walk test distance, more frequent prior coronary artery bypass graft (CABG) surgery, more severe AS, lower left ventricular ejection fraction (LVEF) and higher NT-pro-BNP than those with a normal test result.
The most commonly reported symptom seen during stress testing was the occurrence of limiting dyspnoea or decreased exercise tolerance, occurring in 50.5% of patients, alongside angina (16.2%), presyncopal episodes or severe dizziness (2.9%). A drop in systolic blood pressure was seen in 36.2% of cases, and significant ventricular arrhythmias were seen in 14.3% of cases.
Investigators used multivariable logistic regression models to assess baseline demographic, echocardiographic, or laboratory predictors of a positive test result, finding that lower LVEF, higher peak velocity, prior CABG, and prior stroke were significantly associated with a positive stress test result.
Looking at clinical outcomes and the timing of treatment, the investigators found that, at two years, the Kaplan-Meier mortality rate for patients with a positive stress test was 5.7%. When comparing patients with a positive result due to symptoms during the test—which would constitute a class I indication for aortic valve replacement under current US treatment guidelines—with those who experienced a drop in systolic blood pressure (class IIa) and those who had significant ventricular arrhythmias.
At six months, 75.8% of the patients had undergone aortic valve replacement, rising to 79.9% at one year and 85.9% at two years. Of the 16 patients who did not have aortic valve replacement within two years, two died prior to being treated and 14 remained untreated at two years.
There were no differences in timing of aortic valve replacement after a positive treadmill stress test result by reason for having a positive test result, the investigators report, noting that aortic valve replacement rates at two years were 87.9% in patients with a class I indication, 84.2% in those who had a class IIa indication, and 81.8% for significant ventricular arrhythmias only. Baseline characteristics were compared for patients who were treated with aortic valve replacement and alive at two years, those who were not treated within two years and died, and those who were not treated and were alive at two years, with no substantial differences observed.
“Among patients with asymptomatic severe AS, performing a treadmill stress test to unmask symptoms or suboptimal haemodynamic or electrical response was shown to be safe and identified a high proportion of patients (one of six) with an established aortic valve replacement indication,” Généreux and colleagues write in the concluding remarks of their JAMA Cardiology paper. “Despite this, undertreatment of those patients remains high, with nearly 20% still untreated at one year, highlighting real-world limitations to delivering prompt aortic valve replacement, even in the presence of a class I indication. Broadening and democratising the use of stress testing among patients with asymptomatic severe AS, paired with rigorous follow-up and prompt referral for timely treatment when aortic valve replacement indications emerge, seems crucial to improving outcomes of patients with AS.”
The study’s authors acknowledge several limitations to their investigation, notably the size of the study, and that only mortality was assessed as a clinical endpoint for the registry, with data on treadmill stress test performance and echocardiographic data site reported and not adjudicated. Inclusion of other criteria such as ST-segment depression to define a positive test result may also have influenced results, they note.
