“It has been a good day for TAVI [transcatheter aortic valve implantation],” commented Raj Makkar (Cedars-Sinai, Los Angeles, USA) at this year’s TCT meeting (23–26 October, San Francisco, USA), reflecting optimism regarding trial results presented during the congress on TAVI in the low-risk patient population.
Though the latest results continue to fuel expectation over the performance of TAVI among lower risk patients, surgical societies continue to sound a note of caution before physicians opt to pursue a TAVI-first strategy in those at low surgical risk.
Makkar was speaking on a TCT panel dissecting the five-year results from the PARTNER 3 trial, looking at outcomes among aortic stenosis patients deemed to be at low risk for surgery who received the Sapien 3 (Edwards Lifesciences) balloon-expandable transcatheter valve. During the session, speakers weighed up the PARTNER 3 data alongside four-year findings from the Evolut Low Risk trial, also investigating TAVI among low surgical risk aortic stenosis patients, albeit using CoreValve, Evolut R or Evolut PRO (Medtronic), self-expanding valves.
Both trials, which randomised patients to undergo either TAVI or surgical aortic valve replacement (SAVR), formed the centrepiece of the first late-breaking clinical trial session at the 2023 TCT meeting, and the results have stoked optimism over the longer-term performance of TAVI among low-risk patients, where transcatheter procedures continue to gain ground at the expense of more invasive, surgical procedures.
However, within the surgical community, some questions remain over the generalisability of the findings, due to what has been described as a high proportion of concomitant procedures among patients undergoing SAVR in both trials.
Five-year results from PARTNER 3, delivered by Marty Leon (Columbia Irving Medical Center/New York Presbyterian, New York, USA) and published simultaneously in The New England Journal of Medicine (NEJM) continued to show equivalent performance between TAVI with the Sapien 3 device and surgery against a primary composite endpoint of death, stroke or rehospitalisation. However, Leon reported that there was an attenuation of the differences between the two groups in the primary endpoint out to five years, which had initially favoured TAVI at both one and two years.
The trial enrolled 1,000 patients with severe symptomatic aortic stenosis between March 2016 and October 2017 to undergo TAVI using the Sapien 3 balloon-expandable valve (n=503) or surgery (n=497) for severe aortic stenosis. Outcomes are due to be reported out to 10 years.
At one- and two-year timepoints PARTNER 3 demonstrated superior or similar results for TAVI for its primary endpoint, Leon said in his presentation. Presenting the primary endpoint results at five years, Leon reported a non-hierarchical composite of all-cause death, all stroke, or rehospitalisation of 22.8% in the TAVI arm, versus 27.2% in the SAVR arm, a narrowing of the difference seen between the two therapies from the trial’s earlier results.
In the TAVI arm, all-cause mortality was 10%, cardiovascular mortality was 5.5% and disabling stroke was 2.9% at five years. Leon pointed out that there were similar rates of cardiovascular death in both arms but noted that there was a higher prevalence of non-cardiovascular death in the patients who received TAVI. Rehospitalisation was less than 3% per year over five years. Valve durability indicators were also stable over time with no difference in the incidence of bioprosthetic valve failure related to structural valve deterioration (1.4% vs. 2%) or reintervention rates (2.6% vs. 3%) between TAVI and SAVR.
“We can tell our patients who have low risk aortic stenosis that at five years more than 70% will be alive with a KCCQ [Kansas City Cardiomyopathy Questionnaire] score of greater than 75, which means either no or very mild symptoms,” Leon said, summarising the key messages of the trial. “We can also tell them that after five years, more than 85% would be alive with a durable valve, [and] no bioprosthetic valve failure with either treatment.
“We would conclude that in low risk, severe symptomatic aortic stenosis patients treated with either Sapien 3 TAVI or surgery over five years [of] follow-up, both TAVI and surgery were associated with similar and low clinical event rates,” he concluded, adding that the findings reaffirm the clinical and echocardiographic benefits of TAVI with the Sapien 3 valve as a “meaningful alternative” to surgical therapy for low-risk severe symptomatic aortic stenosis patients.
Stephan Windecker (Bern University Hospital, Bern, Switzerland), who acted as the discussant for the study during the TCT late-breaking clinical trial session, commented that the “most important observation is that the early advantage of TAVI over SAVR attenuates over time” in his appraisal of the findings.
Windecker also highlighted the proportion of patients who withdrew from the trial, which was particularly pronounced in the surgical arm, as well as the disproportionate number of non-cardiovascular deaths among TAVI patients, as points for further discussion. Furthermore, he pointed to a disparity in concomitant procedures, which saw those undergoing surgery more frequently having coronary artery bypass graft (CABG) surgery, as well as other procedures, and he questioned whether these may have had an effect on later outcomes.
Following Leon’s PARTNER 3 presentation, Michael J Reardon (Methodist DeBakey Heart & Vascular Center, Houston, USA) delivered the findings at four years from the Evolut Low Risk trial, which were also published as a research letter in the Journal of the American College of Cardiology.
“We have all seen TAVI explode into our field of structural heart,” Reardon said in the introduction to his presentation, noting that the procedure has grown rapidly in the USA in recent years. “This has been driven largely by the randomised trials, like the one I am talking about and the one you have just heard about.”
There is little reason to believe that the growth of TAVI will stop, he commented. “The question is, do we have data to support that?”
Reardon focused on the association between valve performance and clinical outcomes, commenting that reporting the results more frequently in the low-risk population “will help establish the relationship between valve performance and clinical outcomes to help inform out heart teams and our patients of the appropriate treatment options”.
The Evolut Low Risk trial is a randomised, non-inferiority trial, comparing TAVI to SAVR in patients who had severe, symptomatic aortic stenosis and were at low surgical risk. Patients enrolled in the trial at 61 sites throughout the USA and 25 in Canada, Europe, Japan, Australia, New Zealand, are due to be followed out to 10 years.
Early advantage maintained?
From May 2016 to May 2019, 1,414 patients were randomised 1:1 to undergo TAVI (n=730) or SAVR (n=684). At four years, 94.7% of TAVI and 89.2% of SAVR patients were available for evaluation. The primary endpoint of all-cause mortality or disabling stroke at four years was 10.7% for TAVI vs. 14.1% for SAVR.
“We all know that TAVI has an early advantage to surgery. The question has always been: ‘will this hold up or will surgery catch up to TAVI?’,” Reardon commented on the primary endpoint trend over the four years of the study, noting that the delta between the two arms has widened from 1.8% at one year to 3.4% at four years, in favour of TAVI. “This is the first time we have seen a transcatheter valve not only maintain its early advantage, but actually widen that advantage over time,” he commented.
The results for the individual components of the primary endpoint were 9% compared to 12.1% for all-cause mortality and 2.9% vs. 3.8% for disabling stroke for TAVI versus SAVR. The composite of all-cause mortality, disabling stroke, or aortic valve rehospitalisation was 18% with TAVI and 22.4% with SAVR. In addition, TAVI had significantly better haemodynamics as well as significantly less mean gradients greater than or equal to 20mmHg (4% vs. 8.9%,) or severe prosthesis-patient mismatch, Reardon reported.
Reaction from the wider surgical community, however, reflects a level of caution over the generalisability of the results from both trials. In a joint statement, the Society of Thoracic Surgeons (STS) and the European Association for Cardio-Thoracic Surgery (EACTS) assert that while the trial data provide interesting insights, “given the highly selected cohorts of these carefully adjudicated, industry sponsored trials, we feel that some of the statements made were appropriately weighted with equipoise, but some were not”.
“When you look at isolated surgical aortic valve replacement for aortic stenosis that is one group of patients that has an expected prognosis over time,” STS president Thomas MacGillivray (MedStar Heart and Vascular Institute, Washington DC, USA) tells Cardiovascular News commenting on the reasons for this caution. STS and EACTS contend that the number of surgical patients in the PARTNER 3 and Evolut Low Risk trials who underwent concomitant procedures, which they say stands at around 26%, may colour the outcome of the comparison between the surgical and transcatheter patients.
Surgical concerns
“If you look at patients who have aortic stenosis and coronary artery disease, that is a different disease and the treatments, survival and complication rates are different. If you group them together, that does not really speak to the prosthesis or the procedure. You have to take into consideration the underlying disease and the treatment that is done.
“If you look at both the PARTNER 3 and the Evolut Low Risk Trial, a quarter of those [SAVR] patients had other procedures, whereas most of the TAVI patients had isolated procedures. It is a different patient population. Even if you look at the surgical outcomes between PARTNER 3 and Evolut Low Risk, they are different,” says MacGillivray.
In their statement, STS and EACTS point toward a real-world analysis of patients undergoing low-risk isolated SAVR from the STS Adult Cardiac Surgery Database, authored by Vinod Thourani (Piedmont Heart Institute, Atlanta, USA) and co-authored by MacGillivray as well as others. The analysis, which was published in the Annals of Thoracic Surgery ahead of the TCT meeting found that among patients undergoing isolated SAVR, 92.9% survived after five years, while at eight years, survival was close to 90%.
“The sample size was over 42,000 patients in the total cohort, with over 19,000 patients at risk for five-year survival,” the statement notes. “These data provide the real-world benchmark from which to interpret current and future analyses in low-risk patients receiving therapy for aortic stenosis.”
The societies call for the investigators from the PARTNER 3 and Evolut Low Risk trials to publish the results for isolated SAVR and isolated TAVI sub-cohorts from their trial arms in order to shed more light on this question.
“Until we have these data, any statements or conclusions from these trials are interesting but still hypothesis generating and speculative,” the societies state. “STS and EACTS therefore recommend caution prior to adopting a TAVI-first strategy in low-risk patients, particularly those patients with characteristics not specifically studied in these low-risk trials.”
