New insights from the early and delayed aortic valve replacement implant patients: a sub-analysis of the Early TAVR trial
Reported from ACC.25
Luigi Biasco provides his take on a sub-analysis of the Early TAVR trial about the early and delayed aortic valve replacement implant patients presented by Philippe Genereux at ACC.25 in Chicago.
A relevant sub-analysis derived from the recently published EARLY TAVI trial (Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis) has been presented on the 31st of March during the Featured Clinical Research session at ACC 2025 in Chicago by study PI Dr. P. Genereux (Morristown Medical Center, NJ).
Why this study – the rationale/objective?
The EARLY TAVI trial study is a strategy trial that evaluated in truly asymptomatic patients with severe aortic stenosis the prognostic impact of an early transcatheter aortic valve replacement with the BEV SAPIEN 3/SAPIEN 3 Ultra THV via transfemoral approach as compared to an active clinical surveillance.
Between 2017 and 2021, 901 patients (aged > 65 years with severe normal-flow normal-gradient valvular aortic stenosis) were randomised between early TAVI treatment (n = 455) and the clinical surveillance arm (n = 456).
Primary endpoint of the study was a composite of death from any cause, stroke, or unplanned hospitalisation for cardiovascular causes.
After a mean follow-up of 3.8 years the primary endpoint occurred in 122 (26.8 %) in the TAVI group and in 202 (45.3 %) in the clinical surveillance group (Hazard Ratio 0.50, 95 % CI 0.40-0.63; p < 0.001; NNT -6 at 2 years) demonstrating a superiority of an early TAVI strategy over clinical surveillance.
After trial presentations, some criticisms were raised as the primary endpoint was driven by significant differences in the rate of unplanned hospitalisation for cardiovascular causes (TAVI n = 95; Clinical surveillance n = 186. HR 0.43; 95 % CI: 0.33-0.55) with a steep increase of event rate in the clinical surveillance group occurring in the first 6 months after randomisation. High rates of conversion to delayed aortic valve replacement was observed in the clinical surveillance group with 105 of the 186 unplanned hospitalisations observed in this subgroup related to aortic valve interventions occurring within 6 months after randomisation.
The present analysis provides a further insight into the clinical evolution of trial patients with a particular focus on those enrolled in the clinical surveillance group who required aortic valve replacement at follow-up.
How was it executed – the methodology?
The purpose of this analysis was to re-analyse trial data to compare outcomes between patients undergoing early TAVI and those randomised to clinical surveillance who subsequently underwent delayed aortic valve replacement. In addition, the study aimed to assess the impact of clinical presentation at the time of conversion to intervention.
Clinical presentation at the time of AVR in patients originally enrolled in the clinical surveillance group and subsequently treated by aortic valve replacement were also analysed.
Primary endpoint was the composite of all-cause death, stroke or HF hospitalisation at a 2-year follow-up.
Study population:
901 patients aged > 65 years with severe normal-flow normal-gradient valvular aortic stenosis enrolled in the study were randomised to early TAVI (n = 455) or clinical surveillance (n = 446). From them, 832 underwent AVR (n = 444 in the treatment group, while n = 388 originally enrolled in the clinical surveillance group were referred at follow-up), representing the study population of this analysis.
Follow-up data at 2 years were available in 409 patients from the early TAVI group, and 277 from the delayed AVR group.
Methodology:
Data of patients enrolled in the EARLY TAVI trial were re-analysed.
Clinical presentation at AVR was classified according to 3 categories:
- Asymptomatic: indication to AVR required by additional medical conditions or requiring other medical procedures (e.g. need for major surgery while still asymptomatic).
- Progressive valve syndrome: indication to AVR supported by presence of mild symptoms such as dyspnoea (NYHA class II), need for increased HF medication, mild (< 1.5 but < 3-fold) increase in NT-pro-BNP from baseline (i.e. basically fulfilling current guidelines indications for AVR).
- Acute valve syndrome: indication to AVR supported by the occurrence of severe symptoms such as of dyspnoea (NYHA class III/IV), syncope, AF, ventricular arrhythmias, resuscitated sudden cardiac death, HF hospitalisation, drop of LVEF below 50 % or >3-fold increase in NT-pro-BNP from baseline.
What is the main result?
Patients originally enrolled in the clinical surveillance group who received a delayed AVR had a progressive decline in their functional capacity and quality of life at follow-up (assessed by means of 6 min-walking test and KCCQ score). Moreover, an increase in the NTproBNP levels as compared to baseline was also evident.
From an echocardiographic standpoint, patients in the clinical surveillance group showed a progression in the severity of the aortic stenosis evident as a decrease in the aortic valve area and an increase in peak transvalvular velocity along with a slight decrease in LVEF.
At a follow-up of 60 months, 95,2 % of patients originally enrolled in the clinical surveillance group were effectively treated by aortic valve replacement. Almost half of them underwent AVR within 12 months from randomisation. According to their clinical presentation at the time of AVR, they were classified as having a progressive valve syndrome in 60 %, acute valve syndrome in about 40 % of cases while only a minority of patients required AVR while remaining asymptomatic.
Overall, a strategy of early TAVI was associated with borderline non-significant 35 % reduction of the incidence of the primary endpoint of all-cause death, stroke or HF hospitalisation at 2 years (Early TAVI group 6.8 % vs Delayed AVR 10.6 %; HR 0.65, 95 % CI 0.40-1.05; p = 0.08).
The individual components of the primary endpoint in the whole population were as follows:
- All-cause death: Early TAVI group 3.8 % vs Delayed AVR 5.6 %, (HR 0.70, 95 % CI 0.36-1.34; p = 0.28).
- Stroke: Early TAVI group 4.5 % vs Delayed AVR 2.7 %, (HR 0.60, 95 % CI 0.29-1.28; p = 0.19).
- Death or Stroke: Early TAVI group 6.1 % vs Delayed AVR 8.9 % (HR 0.69, 95 % CI 0.41-1.16; p = 0.17).
- HF hospitalisations: Early TAVI group 2.6 % vs Delayed AVR 1.6 % (HR 0.67, 95 % CI 0.25-1.81; p = 0.43).
An interesting perspective has been provided by a further analysis obtained by stratifying outcomes according to the clinical presentation at the time of AVR.
In patients presenting with acute valve syndrome (thus the worse clinical scenario at justifying AVR) the observed 2-year rates of:
- All-cause death were 7.9 % vs 4.4 % in those with progressive valve syndrome as compared to 3.8 % in the early treatment group (Log-rank = 0.142)
- Death, stroke or hospitalisation were 14.9 % vs 8.2 % in those with progressive valve syndrome as compared to 6.8 % in the early treatment group (Log-rank = 0.008);
- Death or stroke were 13.7 % vs 6.2 % in those with progressive valve syndrome as compared to 6.1 % in the early treatment group (Log-rank = 0.009);
- Stroke were 8.3 % vs 2.7 % in those with progressive valve syndrome as compared to 2.3 % in the early treatment group (Log-rank = 0.006).
- HF hospitalisations were 3.5 % vs 2.0 % in those with progressive valve syndrome as compared to 1.6 % in the early treatment group (Log-rank = 0.274).
Dr. Genereux concluded that a delayed referral for AVR was associated with an increased risk of adverse clinical events within 2 years post-procedure, and that the occurrence of an acute valve syndrome was frequent (40 % of cases) and associated with worse outcomes, providing a rationale for prompt intervention in asymptomatic severe AS patients.
Critical reading and the relevance for clinical practice
Data derived from this sub-analysis of the EARLY TAVI trials adds on the current knowledge regarding the clinical history of severe aortic stenosis in contemporary elderly patients. However, the dilemma regarding treatment of truly asymptomatic patients with severe AS still remains to be solved.
As already evident from the primary analysis, this trial better clarifies the natural history of severe asymptomatic aortic stenosis showing that, after reaching echocardiographic criteria of severity, symptoms do occur within a relatively short time frame (between 6-12 months).
The adjunctive data provided by this analysis clarify that, in more than half of the patients, mild symptoms do become manifest as dyspnoea (NYHA class II), need for increased HF medication or a mild increase in NT-pro-BNP from baseline (i.e. fulfilling current guidelines indications for AVR) in a relatively short time frame following confirmation of AS severity. In this subclass of patients event-free curves for the composite primary endpoint as well as for any of its individual components remain superimposed to those observed in the treatment arm of the trial (i.e. early intervention). This finding confirms current indications but strengthens the clinical need for a tight clinical follow up of asymptomatic patients with severe AS in order to propose AVR as soon as mild symptoms do occur.
From a practical perspective, these data support the initiation of the TAVI work-up soon after the confirmation of AS severity in order to wisely use time between diagnosis and appearance of symptoms to get ready for AVR.
This message is also strengthened by the worse clinical outcomes observed in patients presenting with acute aortic syndrome that clearly represent a subgroup commonly encountered in clinical practice with higher event rate and worse prognosis in the short term.
We are only a few months away from the release of ESC guidelines on the management of patients with valvular heart disease. Whether the new indications will support treatment of asymptomatic patients with severe AS according to the EARLY TAVI trial will be disclosed in August. Nonetheless, according to previous and newer data from the EARLY TAVI trial, redefinition of referral-pathways of patients with severe AS candidate for TAVI should be implemented in order to facilitate their access to treatment and shorten their time in waiting list.
Author
No comments yet!