Transcatheter aortic valve replacement (TAVR) has become the standard of care for inoperable and high surgical risk patients affected by symptomatic severe aortic stenosis (AS) (1,2). Recent studies also suggest favorable results with transfemoral (TF) TAVR compared to conventional surgery in patients at intermediate risk, both for self-expandable and balloon-expandable transcatheter heart valves (THV) (3-6). Notwithstanding, one of the main concerns regarding the application of TAVR to lower risk and younger patients is the paucity of long-term data on outcomes and prosthesis durability (7-12). Moreover, there are no studies that have compared the long-term hemodynamic performance of the self-expandable CoreValve (CV) and the balloon-expandable Edwards SAPIEN XT (ES) (Edwards Lifesciences, Irvine, California, USA) THV. Accordingly, we analyzed long-term outcomes and prosthesis performance in patients undergoing TAVR at our center with either CV or ES.
We performed a retrospective analysis of the Padua University REVALVing Experience (PUREVALVE) registry, in which data on all patients undergoing TAVR at our Institution since June 2007 was prospectively collected (13-15). Our study focused on 171 consecutive patients treated between June 2007 and December 2010, who were therefore eligible at least for a 5-year follow-up. All patients were affected by severe symptomatic AS and were considered suitable for TAVR according to current guidelines (16,17). Surgical risk was calculated using the logistic EuroSCORE and the Society of Thoracic Surgeons (STS) score (18,19). Demographic, clinical, echocardiographic and hemodynamic variables prior to TAVR were collected as previously reported (13-15). The study cohort complies with the Declaration of Helsinki and was approved by the local Ethics Committees, and all patients provided informed written consent before the procedure.
TAVR was performed using either the self-expandable CV Revalving System (Medtronic Minneapolis, Minnesota, USA) through the trans-femoral (TF) or trans-subclavian (TSub) approach, or the balloon-expandable ES through the TF or transapical (TA) approach. At the beginning of our TAVR program, the CV was the only THV available on site, while the ES was first introduced in our center in March 2009. The TF approach was used as the first choice, whenever possible. After TAVR, patients were treated with aspirin and clopidogrel for at least 3 months, and then with single antiplatelet therapy afterwards. When oral anticoagulation was indicated, patients were treated with a vitamin K antagonist and only one antiplatelet agent.
Procedural outcomes and follow-up events were classified according to Valve Academic Research Consortium (VARC) 2 definitions (20). Follow-up was conducted through clinical visits or telephone interview with the patient or the general practitioner, and scheduled at 1 and 12 months and yearly thereafter. Clinical endpoints were all-cause mortality, cardiovascular mortality, changes in the New York Heart Association (NYHA) functional class, re-hospitalization due to congestive heart failure (CHF), stroke, and acute myocardial infarction (MI). Transthoracic echocardiographic examinations were systematically performed at baseline, 48 h after TAVR, and at each follow-up time point to evaluate prosthesis performance [trans-prosthetic gradient, effective orifice area and aortic regurgitation (AR)] as well as global morphological and functional measurements. The severity of AR was graded from 0 to 4 using an integrative approach as recommended by guidelines (21,22). Late prosthesis failure was defined as mean aortic valve gradient ≥20 mmHg, effective orifice area ≤0.9–1.1 cm2 and/or Doppler velocity index <0.35 m/s and/or moderate or severe prosthetic valve regurgitation (20); the presence of leaflets thrombosis or valve endocarditis was excluded by computed tomography (CT) scan or autopsy.
Quantitative variables were analyzed descriptively, reporting mean ± standard deviation (SD) in case of normal distribution, median and 25th to 75th percentile [interquartile range (IQR)] otherwise. The CV and ES group were compared with Student’s t-test or Wilcoxon rank sum test, as appropriate. Categorical variables were reported as numbers and percentages and compared between CV and ES groups using Chi-square or Fisher’s exact tests, as appropriate. Survival analysis was conducted with the Kaplan-Meier method. Cox regression was used to identify univariate predictors of events from the major baseline and procedural characteristics. Variables with P<0.15 at the univariate analysis were subsequently considered in a multivariable Cox regression model to identify independent predictors of events. Results of the Cox regression were reported as hazard ratio (HR), 95% confidence interval (CI) and P values. Statistical analysis was conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) for Windows.
Out of 171 patients treated by TAVR for severe symptomatic AS at our Institution between June 2007 and December 2010, 87 received a CV and 84 underwent an ES THV (Figure 1). Baseline demographic, clinical, and echocardiographic characteristics are summarized in Tables 1 and 2. Mean age was 81 [78–85] years, mean logistic EuroSCORE and STS were 17.8% and 7.5%, respectively. The CV group had a higher rate of previous MI and worse left ventricular function compared to the ES group. The majority of patients were in NYHA functional class III or IV at baseline. Procedural characteristics are shown in Table 3. Hemodynamic and device success were high and similar between groups, with an overall intra-procedural mortality of 1.8%. Post-dilatation was performed more frequently for CV than ES (31.0% vs. 3.6%, P<0.001). The rate of permanent pacemaker (PPM) implantation was higher in the CV than in the ES group (37.9% vs. 5.9%, P>0.001).
Early and late clinical outcomes
Median follow-up in the overall population was 4.4 years (13 days–8 years), with a 94% compliance with follow-up. In-hospital and 30-day outcomes are reported in Table 4. All-cause 30-day mortality was 4.7%, without significant differences between groups (5.8% vs. 3.6%, P=0.72). Clinical efficacy at 1 year was higher in ES compared to the CV group (Figure 2A), mostly because of the lower rate of paravalvular leak (PVL) ≥2+ (Table 5). At 5 years, no difference between groups was observed in terms of all-cause death, cardiovascular-death, stroke, MI and CHF (Figure 2B). As shown in Figure 3, total and cardiovascular survival rate were similar between groups at 7 years. At multivariable analysis, presence of a PVL ≥2+, history of previous CHF, severe pre-existing mitral regurgitation and chronic obstructive pulmonary disease were independently associated with late mortality (Table 6). A significant and sustained improvement in NYHA functional class was observed in both valve groups (Figure 4). Restricting the analysis beyond 2009 (ES introduced), we failed to find differences in outcome between the two bioprostheses.
Early and late prosthesis performance
Prosthetic hemodynamic performances are reported in Figure 5. Mean trans-prosthetic gradient and effective orifice area remained stable over time in both groups (Table 5). Post-procedural mean gradient ≥20 mmHg was present in 2.3% of CV group and 4.7% of ES group (P=0.14). The rate of ≥2+ PVL was higher in the CV compared to ES group (11.5% vs. 1.2%, P=0.01). Out of the 11 patients with a ≥2+ PVL, 7 died within 48 months of follow-up. Among patients with trivial/mild PVL, no changes in leak severity were observed over time. Late prosthesis failure occurred in 4 patients (2.4%), with no other case occurring in patients alive at 8 years. Structural valve deterioration was confirmed by CT scan or autopsy, whenever possible. One patient developed both increased trans-prosthetic gradients and 3+/4 intra-prosthetic AR at 4 years and was treated with a valve-valve procedure; two patients had valve restenosis (mean gradients 38 and 43 mmHg, respectively) after 5 years; and one patient developed a severe intra-prosthetic AR at 7 years; all these three patients were treated conservatively because of their high frailty status. Notably, late prosthesis failure occurred in patients with chronic kidney disease implanted with an ES THV through TA approach.
The main findings of the current study analyzing long-term outcomes and prosthesis performance of the self-expandable CV and the balloon-expandable ES THV are: (I) clinical outcomes are favorable regardless of THV type, with most late deaths being non-cardiac; (II) besides some differences in acute results, both types of prostheses maintained a sustained and encouraging long-term hemodynamic performance in terms of mean trans-prosthetic gradient, effective orifice area and incidence of aortic regurgitation; (III) late prosthesis failure rate was under 3%.
Mid-term clinical outcomes after TAVR are reported to be favorable (23), but follow-up data over 3 years are scant, particularly those regarding “real world” populations included in registries (10,24,25). In our study, the overall 5-year survival rate was 44.9%, with no difference between valve types. To note, 78.3% of the 5-year observed total deaths were non-cardiac in origin, reflecting the relevant prognostic impact of comorbidities in this prohibitive/high-risk population. Similar results were observed in the 5-year analysis of the PARTNER 1 trial, in which over 2/3 of deaths were non-cardiovascular (8). Notably, our TAVR cohort 8-year survival rate (24.5%) was lower compared to the 8-year survival of the 81 years old general Italian population (53%, http://dati.istat.it), but comparable with long-term survival after surgical aortic valve replacement in a population aged ≥80 years (26,27). Regarding functional status, over 90% of our patients remained in NYHA class I–II during the whole follow-up period. Less than 15% of our population was re-hospitalized for CHF, which was associated in nearly half of the patients with the presence of severe MR, consistent with previous reports in the literature (11).
Our study is the first reporting on direct comparison between CV and ES THV hemodynamics at follow-up longer than 3 years, with previous studies focusing only on early and mid-term clinical outcomes (12,23,28-30). Based on our results, the implantation of both valves resulted in a significant reduction of mean aortic gradient, which remained low and stable over time. Patients receiving a CV seemed to have lower gradients and larger effective orifice area, but an initial higher rate of PVL, which seemed to remain stable over time. The latter finding was true also for the ES valve, confirming the PARTNER 1 trial results (31) and advocating stability of hemodynamic performance of both THV during the current follow-up period. Moreover, as shown by the 5-year PARTNER I echocardiographic data, hemodynamic performance of the SAPIEN THV was stable throughout follow-up and similar to that of the surgical bioprosthesis (31). These results are particularly encouraging in the light of the significantly lower PVL rate observed with newer generation devices (3,6), which will likely translate in improved long-term outcomes.
Toggweiler et al. (10) reported on clinical outcomes, valvular structural integrity, and hemodynamic changes evaluated a median of 5 years after TAVR with a balloon-expandable valve. They observed moderate prosthetic valve failure only in 3.4% of patients without severe regurgitation or stenosis. Barbanti and colleagues (11) reported late prosthetic valve failure at 5 years in 1.4% of patients included in the CV registry. In our study, no clinically relevant prosthesis restenosis was observed at 3-year follow-up. Between 3 and 7 years of follow-up, we reported only 4 cases of late prosthetic valve failure (2.4%).
This is a single-center, observational study with a fairly limited number of patients. Larger studies are warranted to confirm these results and the lack of difference in long-term outcomes between different THVs. Clinical and echocardiographic outcomes were self-reported, with inherent limitations and potential bias. However, data were prospectively collected in a dedicated database as shown by the detailed availability of clinical and echocardiographic data. Patients included in this study represent the early phase of the TAVR program at our institution, which may have influenced patient selection and thus long-term outcome. The impact of different learning curves cannot be tested. Even so, no differences emerged between the two bioprostheses after the introduction of ES in 2009. Furthermore, since baseline CT was not available in all patients, we cannot exclude that the difference in post-procedural aortic gradients between CV and ES could have been influenced by different aortic valve dimension and calcium distribution. Notwithstanding, stability of hemodynamic performance over time was reassuring for both valves.
Our study demonstrated favorable outcomes at long-term follow-up after successful TAVR, independently from THV type. Prostheses hemodynamic performance was encouraging and sustained, with a late prosthesis failure rate lower than 3%. Longer follow-up studies with newer generation devices are warranted before extending TAVR to lower risk and younger patients.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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