Breaking down barriers to transcatheter aortic-valve implantation in low surgical risk patients

Comment on the article ‘Transcatheter Aortic-Valve Replacement in Low-Risk Patients at Five Years’, published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2307447. The Placement of Aortic Transcatheter Valves (PARTNER) 3 trial was an industry-sponsored, multi-centre, randomized trial comparing transcatheter aortic-valve implantation (TAVI) using the balloon-expandable SAPIEN 3 valve (Edwards Lifesciences) with surgical aortic-valve replacement (SAVR) in patients with severe, symptomatic aortic stenosis (AS) at low surgical risk.1 Low surgical risk was defined by the heart team on the basis of clinical and anatomical assessment, including a Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score < 4%. Patients had to be eligible for TAVI through transfemoral access. At 1- and 2-year follow-up, TAVI was superior to SAVR in reducing the incidence of the composite endpoint of death, stroke, or re-hospitalization.1,2 The aim of the present study was to examine the 5-year outcomes in the two treatment groups.3 There were two co-primary endpoints. The first primary endpoint was a composite of all-cause death, stroke, or re-hospitalization related to the valve, the procedure, or heart failure. The second primary endpoint was a hierarchical composite of all-cause death, disabling and non-disabling stroke, and the number of re-hospitalization days analysed with the win ratio method. Secondary endpoints included: new-onset atrial fibrillation (AF), aortic-valve re-intervention, permanent pacemaker implantation, severe bleedings, and clinically significant valve thrombosis (defined according to Valve Academic Research Consortium 3 criteria). Echocardiographic data were collected, and functional status and quality of life were assessed with the Kansas City Cardiomyopathy Questionnaire-Overall Summary. A total of 1000 patients (mean age, 73 years; 31% female; mean STS-PROM score 1.9%) were enrolled between March 2016 and October 2017 at 71 sites and randomized 1:1 to either TAVI (n = 503) or SAVR (n = 497). After the exclusion of 52 patients, mostly due to withdrawal from the SAVR group of the trial, a total of 495 patients in the TAVI group and 453 patients in the SAVR group received the intended valve. After 5 years, follow-up data were available for 469 patients (95%) in the TAVI group and 401 patients (88%) in the SAVR group. The incidence of the first primary endpoint was not different between TAVI and SAVR [Kaplan–Meier estimates, 22.8% vs. 27.2%, respectively; difference, −4.3% points; 95% confidence interval (CI), −9.9 to 1.3; P = .07; hazard ratio, 0.79; 95% CI, 0.61–1.02]. The win ratio for the second primary endpoint was 1.17 (95% CI, 0.90–1.51; P = .25). The incidence of all-cause death was not significantly different between TAVI and SAVR (10.0% vs. 8.2%), as well as that of stroke (5.8% vs. 6.4%) and re-hospitalization (13.7% vs. 17.4%). As compared with patients in the SAVR group, those in the TAVI group showed lower incidence of new-onset AF (13.7% vs. 42.4%) and serious bleedings (10.2% vs. 14.8%) but slightly higher incidence of permanent pacemaker implantation (13.5% vs. 10.4%). The incidence of clinically significant valve thrombosis was higher in the TAVI group than in the SAVR group (2.5% vs. 0.2%). The echocardiographically assessed aortic-valve gradient was similar in the TAVI and SAVR groups at 5 years (12.8 ± 6.5 and 11.7 ± 5.6 mmHg, respectively). The incidence of paravalvular aortic regurgitation of mild or greater severity was significantly higher in patients in the TAVI group as compared with those in the SAVR group (20.8% vs. 3.2%). The incidence of bioprosthetic valve failure was similar in the TAVI and SAVR groups (1.4% and 2.0%), as well as that of aortic-valve re-intervention (2.2% and 2.6%). Functional outcomes and quality of life were comparable in the two groups. Aortic stenosis is the most frequent valvular heart disease in Western countries, carrying high mortality risk across all levels of severity if left untreated, approaching 50% at 4 years in patients with severe AS.4 Increased operator experience, technical advances, and excellent TAVI performance in randomized controlled trials have led to the progressive implementation of this treatment strategy in patients at high and intermediate surgical risk.5 Subsequently, the PARTNER 3 and Evolute Low Risk trials showed that TAVI was either non-inferior or superior to SAVR in patients at low surgical risk at 2- or 3-year follow-up.2,6 Based on the accumulated evidence, current European guidelines recommend that, in patients of at least 75 years of age and suitable for a transfemoral approach, TAVI should be the preferred treatment strategy regardless of surgical risk.5 However, as low-risk patients are usually younger and have longer life expectancy than those at high or intermediate risk, evidence derived from long-term outcomes and durability of transcatheter heart valves is of key relevance to support informed clinical decision-making in this group of patients. The results of the PARTNER 3 trial provide another essential piece of evidence, as they show that TAVI is comparable with SAVR with respect to the primary endpoint of death, stroke, or re-hospitalization after 5 years.3 The benefit initially observed with TAVI compared with SAVR at 1 year was progressively attenuated during further follow-up. This might be expected, as less invasive treatments usually perform better in the early months due to lower procedural complication rates, while the impact of surgery on clinical outcomes typically consolidates over time.7 Of note, a high proportion of SAVR patients withdrew from the trial, and loss to follow-up was significantly greater in the SAVR group than in TAVI group (12% vs. 5%), so that potential attrition bias cannot be completely ruled out.8 The 4-year follow-up data of the Evolut Low Risk trial showed that the early benefit in all-cause mortality or disabling stroke observed with self-expanding TAVI continues to increase, with a 26% relative risk reduction as compared with SAVR at 4 years.9 Taken together, the results from these two trials reinforce the evidence in favour of TAVI as a valid alternative strategy to surgery in low-risk patients. Yet, in a lifetime management perspective, a number of additional issues need to be considered and discussed, particularly with regard to younger patients, including valve durability and risk of permanent pacemaker implantation, paravalvular leak, patient–prosthesis mismatch, and re-intervention, as well as the presence of concomitant conditions, such as aortic dilatation and coronary artery disease.10 At present, the strongest argument raised against expanding the TAVI indication to younger patients at low surgical risk is valve durability.11 Haemodynamic valve performance at 5 years was not different with TAVI and SAVR in the PARTNER 3 trial, and rates of bioprosthetic valve failure and aortic-valve re-intervention were comparably low in the two groups. Although these data are reassuring and consistent with evidence from other trials,11,12 it will be important to confirm this finding in studies based on longer follow-up. Of note, the rates of two common and clinically relevant complications, such as AF and bleeding, were significantly lower in PARTNER 3 patients treated with TAVI than SAVR. On the other hand, rates of paravalvular aortic regurgitation of mild or greater severity and permanent pacemaker implantation were higher in the TAVI group than in the SAVR group. However, the incidence of these TAVI complications has been progressively decreasing thanks to the routine use of multi-slice computed tomography for annular sizing, improved valve design, and optimized implantation technique to limit the risk of atrioventricular block.10,11 Patients with high-risk anatomy (e.g. annular calcification and complex coronary artery disease), technical unsuitability for TAVI, or the presence of a bicuspid aortic valve were excluded from the trial, limiting the generalizability of the findings and preserving a role for SAVR in these patients. In conclusion, the long-term follow-up of the PARTNER 3 trial marks a meaningful progress in the contemporary management of AS, as it shows that patients with severe symptomatic AS at low surgical risk can get comparable benefits in terms of mortality, stroke, or re-hospitalizations up to 5 years by undergoing either TAVI or SAVR. The planned 10-year follow-up of the PARTNER 3 and Evolute Low Risk trials will allow assessing whether the benefits of TAVI are long-lasting, which is of uttermost importance, especially for younger patients with longer life expectancy. Although dampening the enthusiasm for a less invasive alternative to SAVR may represent a difficult challenge, any decision to perform TAVI in younger low-risk patients will require a careful heart team evaluation and adequate consideration of the patient’s values and preferences.10 R.V. received consulting or lecturing fees from Abbott Vascular, Abiomed, Amgen, Daiichi Sankyo, Medtronic, and Terumo, outside the submitted work.