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Intermediate Clinical and Hemodynamic Outcomes After Transcatheter Aortic Valve Implantation
Intermediate Clinical and Hemodynamic Outcomes After Transcatheter Aortic Valve Implantation Augusto D’Onofrio, MD, PhD, Michela Facchin, MD, Laura Besola, MD, Erica Manzan, MD, Chiara Tessari, MD, Eleonora Bizzotto, MD, Roberto Bianco, MD, Giuseppe Tarantini, MD, PhD, Massimo Napodano, MD, Chiara Fraccaro, MD, PhD, Paolo Buja, MD, PhD, Elisa Covolo, MD, Ermela Yzeiraj, MD, Demetrio Pittarello, MD, Giambattista Isabella, MD, Sabino Iliceto, MD, and Gino Gerosa, MD Divisions of Cardiac Surgery, Cardiology, and Anesthesiology, University of Padova, Italy
Background. Concerns still exist regarding long-term results and freedom from valve-related adverse events in transcatheter aortic valve implantation (TAVI). The aim of this single-center retrospective study was to assess intermediate-term (up to 5-year) clinical and hemodynamic outcomes in patients undergoing TAVI. Methods. From 2007 through 2013, 338 consecutive patients underwent TAVI at our institution. Preoperative variables were defined according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) definitions, and outcomes were reported according to the Valve Academic Research Consortium (VARC)-2 definitions. Multivariate logistic regression analysis was performed to identify independent predictors of mortality at follow-up. Results. transfemoral (TF) and transapical (TA) TAVI were performed in 233 (69%) and 105 (31%) patients, respectively. All-cause 30-day mortality was 4.4%, with no differences between TA and TF procedures. Thirtyday cardiovascular death, stroke, and myocardial infarction were not different between groups. The acute kidney
injury (AKI) rate was higher in the TA group (30.5% versus 11.2%; p < 0.001). Access-related complications were more frequent in the TF group (36.1% versus 11.4%; p < 0.001). Mean follow-up was 22.3 ± 17.8 months (range, 1–74 months). Overall survival rates at 1, 3, and 5 years were 85.5% ± 2.1%, 69.9% ± 3.2%, and 61% ± 4.3%, respectively. Independent predictors of all-cause mortality at follow-up were previous myocardial infarction (odds ratio [OR], 2.7), any grade of paravalvular leak (PVL) (OR, 2.5), and AKI (OR, 3.1). Mean gradient and effective orifice area at follow-up were 10.7 ± 12.0 mm Hg and 1.1 ± 0.9 cm2/m2, respectively. Conclusions. Our data show that TAVI has good early and intermediate-term clinical and hemodynamic outcomes in high-risk or inoperable patients with severe symptomatic aortic valve stenosis. PVL of any grade has a significant impact on survival.
T
early and intermediate-term (up to 5 years) clinical data and hemodynamic performance of all patients who underwent TAVI at our institution.
ranscatheter aortic valve implantation (TAVI) is now a well-established therapeutic option in high-risk or inoperable patients with severe symptomatic aortic stenosis (AS) because it has been demonstrated to be noninferior to or even better than surgical aortic valve replacement (AVR) in high-risk operable patients [1, 2] and better than optimal medical therapy (including balloon aortic valvuloplasty) in inoperable patients [3]. However, the extension of TAVI indications for intermediate-risk as well as younger patients is somehow restrained by some concerns regarding TAVI late results. In fact, there are few data available about late clinical and hemodynamic outcomes of TAVI. Therefore, in this single-center retrospective study we aimed at reporting
Accepted for publication Aug 8, 2015.
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods We reviewed the entire TAVI experience of our institution since the first case in 2007. All patients underwent TAVI for severe symptomatic AS. Implanted devices were the self-expanding CoreValve (Medtronic, Minneapolis, MN) from June 2007 to November 2009 and the balloonexpandable Edwards SAPIEN, SAPIEN XT, and SAPIEN 3 (Edwards Lifesciences, Irvine, CA) from March 2009 until December 2013. All patients who received the CoreValve underwent a retrograde approach (transfemoral [TF] and transsubclavian), whereas SAPIEN valves were implanted in both antegrade (transapical
Presented at the Fifty-first Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 24–28, 2015. Address correspondence to Dr D’Onofrio, Division of Cardiac Surgery, Azienda Ospedaliera-University of Padova, Centro Gallucci, Via Giustiniani, 2, 35128, Padova, Italy; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
Drs D’Onofrio and Tarantini disclose a financial relationship with Edwards Lifesciences.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.08.032
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Table 1. Preoperative Clinical and Hemodynamic Characteristics of the Entire Population and of the Transfemoral and Transapical Cohorts
Baseline Age Male sex BMI Arterial hypertension Diabetes History of smoking Hypercholesterolemia Carotid artery disease Peripheral artery disease Chronic kidney failure Creatinine clearance, mL/min COPD Previous myocardial infarction Previous stroke Previous cardiac operation Previous PCI Atrial fibrillation Porcelain aorta, NYHA class I-II III-IV Angina Syncope Logistic EuroSCORE Additive EuroSCORE EDV (mL/m2) LVEF AVA (cm2/m2) Peak gradient (mm Hg) Mean gradient (mm Hg) Aortic regurgitation 1þ/4þ 2þ/4þ 3þ/4þ Mitral regurgitation 1þ/4þ 2þ/4þ 3þ/4þ Pulmonary pressure (mm Hg) Wedge pressure (mm Hg) Coronary artery disease Preoperative hemoglobin, g/dL
All N ¼ 338 n (%)
TF n ¼ 233 n (%)
TA n ¼ 105 n (%)
80.3 6.7 181 (53.6) 26.4 6.5 306 (90.5) 91 (27.0) 92 (27.2) 210 (62.2) 105 (31.1) 33 (9.8) 175 (51.8) 57.4 22.5 98 (29.2) 66 (19.5) 43 (12.7) 68 (20.1) 109 (32.3) 116 (34.3) 54 (16.3)
80.5 7.0 126 (54.1) 26.8 7.4 209 (89.7) 62 (26.6) 61 (26.2) 139 (59.7) 70 (30.0) 13 (5.6) 116 (49.8) 57.5 22.8 71 (30.6) 45 (19.3) 28 (12) 37 (15.9) 72 (30.9) 80 (34.3) 29 (12.4)
80.2 6.1 55 (52.4) 25.2 3.6 97 (92.4) 29 (27.6) 31 (29) 71 (67.6) 35 (33.3) 20 (19.0) 59 (56.2) 56.1 22.5 27 (25.7) 21 (20) 15 (14.3) 31 (29.5) 37 (35.2) 36 (34.3) 25 (23.8)
100 (29.6) 238 (70.4) 105 (31.2) 59 (17.5) 17.3 3.0 10.0 2.4 66.9 23.4 55.0 12.3 0.45 0.12 73.1 43.9 43.8 14.9
67 (28.8) 166 (71.2) 66 (28.6) 43 (18.5) 12.5 1.7 10.2 2.4 66.8 24.1 54.9 12.9 0.46 0.14 75.1 26.3 50.0 14.9
33 (31.4) 72 (68.6) 39 (37.1) 16 (15.2) 19.2 5.5 10.1 2.1 66.7 21.8 55.0 10.9 0.45 0.12 74.9 24.2 43.5 13.8
167 (49.4) 49 (14.5) 18 (5.3)
111 (47.6) 35 (15.0) 14 (6.0)
56 (53.3) 14 (13.3) 4 (3.8)
190 (56.2) 68 (20.1) 9 (2.7) 25.8 16.0 16.0 8.0 193 (57.1) 12.1 1.6
139 (59.7) 46 (19.7) 4 (1.7) 26.1 12.3 16.5 7.9 129 (55.4) 12.2 1.7
51 (48.6) 22 (21.1) 5 (4.8) 24.7 9.9 14.5 7.9 64 (61.0) 11.9 1.6
p Value 0.308 0.814 0.177 0.436 0.864 0.374 0.132 0.612 <0.001 0.275 0.856 0.387 0.725 0.572 0.005 0.167 0.215 0.003 0.089
0.031 0.260 0.050 0.237 0.206 0.179 0.653 0.337 0.240 0.291
0.726
0.413 0.975 0.358 0.253
AVA ¼ aortic valve area; BMI ¼ body mass index; COPD ¼ chronic obstructive pulmonary disease; EDV ¼ end-diastolic volume; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; TA ¼ transapical; TF ¼ transfemoral.
[TA]) and retrograde fashion (transaortic and TF). All patients gave informed consent for the procedure and for data collection; the local ethics committee approved data collection and analysis. Our institution follows a “TF first policy.” Data were prospectively collected in our TAVIdedicated database. Clinical and echocardiographic
evaluation was performed at hospital admission, before discharge, 1 to 3 months postoperatively, 6 to 9 months postoperatively, and on a yearly basis thereafter in a TAVI-dedicated outpatient clinic. In this setting, all patients underwent bidimensional and 3-dimensional transthoracic echocardiography using an iE33
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Table 2. Procedural and Hospital Results of the Entire Population and of the Transfemoral and Transapical Cohorts All N ¼ 338 n (%)
Results Device success (VARC-2) Conversion to surgical procedure Device embolization TAV in TAV Coronary obstruction Paravalvular leak None/trivial 1þ/3þ 2þ/3þ Access-related complications Minor Major Bleeding Minor Major Life-threatening AKI AKI needing dialysis Immediate procedural mortality 30-day mortality 30-day cardiovascular mortality Stroke Acute myocardial infarction Permanent pacemaker implantation 30-d safety 1-y efficacy AKI ¼ acute kidney injury; Consortium.
TA ¼ transapical;
TF n ¼ 233 n (%)
TA n ¼ 105 n (%)
322 6 6 12 1
(95.1) (1.8) (1.8) (3.6) (0.3)
224 3 4 9 1
(96.1) (1.3) (1.7) (3.9) (0.4)
98 3 2 3 0
(93.3) (2.9) (1.9) (2.9) (0)
210 100 28 96 58 38
(62.1) (29.6) (8.3) (28.4) (17.2) (11.2)
143 70 20 84 54 30
(61.4) (30.0) (8.6) (36.1) (23.2) (12.9)
67 30 8 12 4 8
(63.8) (28.6) (7.6) (11.4) (3.8) (7.6)
44 64 12 58 16 4 15 10 10 7 77 273 234
(12.9) (18.9) (3.6) (17.2) (4.7) (1.2) (4.4) (3) (3) (2.1) (22.8) (80.7) (69.2)
36 38 7 26 9 3 11 6 7 6 66 197 163
(15.5) (16.3) (3.0) (11.2) (3.9) (1.3) (4.7) (2.6) (3.0) (2.6) (28.3) (84.6) (70.0)
8 26 5 32 7 1 4 4 3 1 11 76 71
(7.1) (24.7) (4.8) (30.5) (6.7) (1.0) (4.0) (4.0) (3.0) (1.0) (10.5) (72.4) (67.6)
TAV ¼ transcatheter aortic valve;
echocardiography system (Philips Healthcare, the Netherlands), following the recommendations from the specific guidelines for echocardiography in transcatheter interventions for valvular heart disease [4]. If a more detailed evaluation was needed, transesophageal echocardiography was performed. For patients unable to come to our hospital for follow-up evaluation (<10%), we performed telephone interviews and asked for a copy of the most recent echocardiographic examination. Preoperative clinical variables were defined according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) definitions [5]. Postoperative outcomes and clinical end points were reported following the updated Valve Academic Research Consortium (VARC)-2 recommendations [6, 7]. Postoperative aortic regurgitation (AR) was graded as no or trivial AR, mild AR (1þ/3þ), moderate AR (2þ/3þ), and severe AR (3þ/3þ). In particular, the presence and severity of AR was based on the evaluation of both central and paravalvular components with a combined measurement of total AR. The assessment of AR was performed according to current guidelines [4, 6, 7] using quantitative (regurgitant volume, regurgitant fraction, and effective regurgitant orifice area) and semiquantitative (diastolic flow reversal in the
TF ¼ transfemoral;
p Value 0.185 0.105 0.908 0.639 0.500 0.506
<0.001 <0.001 0.113 0.063
<0.001 0.611 0.789 0.724 0.837 0.827 0.350 0.008 0.012 0.149
VARC ¼ Valve Academic Research
descending aorta, circumferential extent of prosthetic valve paravalvular regurgitation) methods. According to VARC-2, we analyzed the following composite end points: (1) early safety, defined as absence of procedural mortality and correct positioning of a single prosthetic heart valve into the proper anatomic location and intended performance of the prosthetic heart valve (no prosthesis/patient mismatch and mean aortic valve gradient <20 mm Hg or peak velocity <3 m/s and no moderate or severe prosthetic valve regurgitation); (2) 1-year efficacy, which includes all-cause mortality, all-stroke (disabling and nondisabling), requirment of hospitalization for valve-related symptoms or worsening congestive heart failure, New York Heart Association (NYHA) class III or IV, valve-related dysfunction (mean aortic valve gradient 20 mm Hg, effective orifice area 0.9–1.1 cm2 or dimensionless valve index <0. 35 (or both), or moderate or severe prosthetic valve regurgitation (or both). The incidence of mortality, stroke, and acute myocardial infarction at 1 year includes perioperative events.
Statistical Analysis For continuous variables, data are reported as mean with standard deviation. For categorical variables, data are
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reported as frequency (percentage). Comparison between groups for continuous variables was made using the t test or the Wilcoxon/Mann Whitney test as appropriate; comparison between groups for categorical variables was made using the c2 or the Fisher’s exact test as appropriate. Late results are expressed as percentage after the exclusion of patients who had died by 30 days after the procedure. Cox proportional hazard regression analysis was performed to identify independent predictors of mortality at follow-up, which are reported as hazard ratios (HRs), 95% confidence intervals (CIs), and p values. Preoperative and perioperative variables that were found significant at univariate analysis were included in the multivariate analysis. Cumulative survival was estimated using the KaplanMeier method. Survival rates were compared using the log-rank test. All statistical tests were 2-sided, and p values of 0.05 or less were considered statistically significant. Statistical analyses were conducted using IBM SPSS Statistics, version 19 (SPSS, Inc, Chicago, IL).
Results
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Early Results Procedural and early results are shown in Table 2. Overall all-cause 30-day mortality was 4.4% (15 patients); allcause 30-day mortality in the TF and TA groups was 4.7% (11 patients) and 3.8% (4 patients), respectively (p ¼ 0.72). Patients undergoing TA TAVI had a significantly higher incidence of AKI (30.5% versus 11.2%; p < 0.001), whereas patients undergoing TF TAVI had a higher incidence of access-related complications of any severity (36.1% versus 11.4%; p < 0.001) and permanent pacemaker implantation (28.3% versus 11%; p ¼ 0.008). The incidence of permanent pacemaker implantation in patients with CoreValve and SAPIEN devices was 41% (34 patients) and 16.9% (43 patients), respectively (p < 0.001). Overall VARC-2 early safety at 30 days was 78.4% (265 patients); 30-day safety in the TF and TA groups was 84.5% (197 patients) and 72.4% (76 patients), respectively (p ¼ 0.01). At discharge, aortic insufficiency was absent in 210 patients (62.1%), 1þ/3þ AR was present in 100 patients (39.6%), and 2þ/3þ AR was seen in 28 patients (8.3%). There were no patients with severe AR at discharge.
Study Population Between January 2007 and December 2013, 350 consecutive patients with severe symptomatic AS underwent TAVI at our institution. Transaortic and transsubclavian TAVI procedures were performed in 6 patients each, and because of this small number they were excluded from the analysis. In the remaining 338 patients, who represent the population of this study, TF and TA TAVI were performed in 233 (69%) and 105 (31%) patients, respectively. The implanted prostheses were CoreValve in 83 patients (24.6%) and SAPIEN with its evolutions in 255 (75.4%) patients. In particular, the new SAPIEN 3 valve was implanted in 34 patients. Preoperative variables of the entire cohort and of the 2 subgroups, TA and TF, are shown in Table 1. Unsurprisingly, patients who underwent TA TAVI had a higher logistic EuroSCORE (19% 5% versus 13% 2%; p ¼ 0.05) and they were also more likely to have peripheral vascular disease (19% versus 5.6%; p < 0.001). Fig 1. Kaplan-Meier overall survival in the entire population and in the transfemoral (TF) and transapical (TA) cohorts.
Late Results Overall mortality from all causes at 1 year was 13.9% (45 patients), and all-cause 1-year mortality in the TF and TA groups was 15.3% (34 patients) and 10.8% (11 patients), respectively (p ¼ 0.38). Cardiovascular death at one year in the entire cohort occurred in 27 patients (8.4%); 18 (8.1%) and 9 (8.9%) in TF and TA patients, respectively (p ¼ 0.72). The incidence of stroke and myocardial infarction 1 year after TAVI was 4.3% (14 patients) and 3.1% (10 patients) respectively, with no differences between TF and TA groups. Mean follow-up of the entire cohort was 22.3 17.8 months (range, 1–74 months); mean follow up of patients in the TA group was significantly shorter than that in patients in the TF group (18.4 10.2 months versus 24.7 18.5 months; p ¼ 0.03). Overall survival rates at 1, 3, and 5 years were 85.5% 2.1%, 69.9% 3.2%, and 61% 4.3%, respectively (Fig 1). Survival rates at 1, 3, and 5 years
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were 84.4% 2.6%, 69.2% 3.8%, and 58.6% 4.9%, respectively, in the TF cohort and 92.8% 2.6%, 71.3% 6.6%, and 71.3% 6.6%, respectively, in the TA cohort (log-rank p ¼ 0.749) (Fig 1). Interestingly, as depicted in Figure 2, even mild paravalvular leak (PVL) had a significant impact on survival. In fact, the Kaplan-Meier survival analysis clearly shows that patients with mild (1þ/3þ) and moderate (2þ/3þ) postoperative AR had a significantly lower survival compared with patients with no AR (log-rank p ¼ 0.012; log-rank no PVL versus mild PVL, p ¼ 0.053; log-rank no PVL versus moderate/severe PVL, p ¼ 0.003). We observed a significant improvement in NYHA functional class during follow-up. In fact we observed a significant improvement of exercise capacity soon after TAVI, which remained stable with time. One year after TAVI, 77.9% of patients were in NYHA class I, 20.3% were in NYHA class II, and 1.8% were in NYHA class III. There were no patients in NYHA class IV (p < 0.05 compared with baseline) (Fig 3). One-year efficacy, according to VARC-2 definitions, was 69.2% (234 patients). In the TF and TA groups, 1-year efficacy was 70% (163 patients) and 67.6% (71 patients), respectively (p ¼ 0.15).
showed the need for reoperation on the transcatheter device for any reason during follow-up.
Hemodynamic Performance Figure 4 shows the variation of mean aortic gradient and aortic valve area before the operation and at follow-up. There is a significant reduction of transaortic gradients after TAVI and values remain stable over time. Mean aortic gradient at follow-up is 10.7 12 mm Hg. Looking at the aortic valve area, we observe the maximum increase 1 month after the operation, and subsequently a slight reduction of this value appears without reaching statistical significance. Mean effective orifice area index at follow-up was 1.1 0.9 cm2/m2. We have not observed any structural valve deterioration or endocarditis up to 5 years in this population. Furthermore, no patients
Fig 2. Kaplan-Meier survival of patients according to postoperative paravalvular leak (PVL).
Predictors of Mortality at Follow-Up The results of the multivariate analysis are shown in Table 3. Previous myocardial infarction (HR, 2.7; 95% CI, 1.1–7.1; p ¼ 0.03), AKI (HR, 3.1; 95% CI, 1.2–7.8; p ¼ 0.02), and any grade of PVL (HR, 2.5; 95% CI, 1.2–5.3; p ¼ 0.02) were identified as independent predictors of late mortality, in particular mild PVL versus no PVL (HR, 1.8; 95% CI, 1.0–2.8; p ¼ 0.051) and moderate/severe PVL versus no PVL (HR, 2.7; 95% CI, 1.3–6.2; p ¼ 0.002).
Comment This study shows that both TA and TF TAVI have good clinical and hemodynamic outcomes up to 5 years in high-risk or inoperable patients. Five-year survival was 61% with no differences between the TA and TF groups. Toggweiler and colleagues [8] found a lower long-term survival in their analysis based on 88 inoperable patients. In fact, they report a 35% survival 5 years after TAVI. There are many reasons to explain this difference: their experience started in 2005 and represents the first in human TAVI experience with first-generation prostheses; they evaluated only truly inoperable patients; and the mean patient age was 83 years. In our study, the mean age was 80 years; our population also included high-risk operable patients; and our experience started later and consequently many technical issues as well as issues related to patient selection had been resolved. In particular, the heart team approach is crucial to optimize patient selection, improve results, and reduce the incidence of complications and their impact on patient outcomes with a timely diagnosis and effective therapy. The heart team should always include at least a cardiac surgeon, an interventional cardiologist, a clinical cardiologist/ echocardiographer, and an anesthesiologist. Interestingly, although some authors describe better outcomes with TF TAVI compared with TA TAVI [9] regarding mortality, our data show that the only differences between the 2 forms of access were less AKI for TF TAVI and less access-related complications and less permanent pacemaker implantation for TA TAVI. However, the early safety end point is slightly in favor of TF TAVI mainly because of the nonsevere nature of access-related complications. Furthermore, the higher incidence of pacemaker implantation in patients belonging to the TF TAVI cohort is related to the use of CoreValve prostheses, which have been shown to produce more conduction disturbances compared with the SAPIEN valve [10]. Our finding that previous myocardial infarction is a predictor of late mortality seems to show that coronary artery disease (CAD) has a significant impact on survival after TAVI. The presence of CAD in patients undergoing TAVI has led many authors to look for the best therapeutic strategy in regard to timing and procedures in this specific population [11]. CAD is present in 40% to 75% of patients referred for TAVI [12]. If we look at long-term impact of severe CAD, there is conflicting evidence in
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Fig 3. Variation of New York Heart Association (NYHA) functional class in patients undergoing transcatheter aortic valve implantation (TAVI).
the literature. According to Dewey and coworkers [13], patients who have undergone previous coronary artery bypass or percutaneous coronary interventions had higher 30-day and 1-year mortality than did patients with no CAD. Conversely, other authors did not find significant differences in mortality in patients with and those without CAD undergoing TAVI [14–16]. PVL is often considered the Achilles’ heel of TAVI [17]. In our study, we observed that late survival decreases with worsening PVL and that PVL of any degree was independently associated with mortality at follow-up. Although it has been clearly demonstrated that moderate and severe PVL (2þ/3þ) has a significant impact on mortality after TAVI [18], there is no consensus about the impact of mild PVL (1þ/3þ). A recently published report by Kodali and associates [19] evaluating 2,434 patients from the Placement of Aortic Transcatheter Valve trial (PARTNER) shows
that 1-year all-cause mortality, cardiac-related mortality, and rehospitalization rates were significantly increased with worsening PVL and also that mild PVL was independently associated with late mortality. Opposite results are shown by the Medtronic CoreValve US Pivotal Trial, in which mild PVL did not seem to be associated with worse 1-year mortality [2]. Because the incidence of mild PVL in our study, as well as in other reports, is as high as 30%, a clear evaluation of its impact on longterm outcomes remains crucial before expanding TAVI indications to intermediate-risk patients. In fact, these patients are suitable for all currently available aortic valve procedures: AVR, TAVI, and sutureless aortic valve replacement (SU-AVR). Two studies that compared outcomes of AVR, TAVI, and SU-AVR showed that there were no differences in mortality among these procedures and that AVR was associated with a
Table 3. Predictors of Mortality at Follow-Up: Results of the Multivariate Cox Regression Analysis
Fig 4. Variation of transaortic gradients (peak and mean) and effective orifice area of patients undergoing transcatheter aortic valve implantation (TAVI).
Variable
HR
95% CI
p Value
Previous AMI PVL AKI LVEF Device diameter Device type Additive EuroSCORE Access (TA) Age
2.7 2.5 3.1 0.9 1.1 1.4 1.2 1.9 1.4
1.1–7.1 1.2–5.3 1.2–7.8 0.8–1.3 0.8–1.2 0.5–3.5 0.9–2.6 0.7–4.9 0.6–3.0
0.03 0.02 0.02 0.801 0.618 0.099 0.173 0.153 0.345
AKI ¼ acute kidney injury; AMI ¼ acute myocardial infarction; CI ¼ confidence interval; HR ¼ hazard ratio; LVEF ¼ left ventricular ejection fraction; PVL ¼ paravalvular leak; TA ¼ transapical.
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significantly lower incidence of postoperative AR compared with TAVI [20]. Furthermore, SU-AVR was also associated with a lower rate of postprocedural PVL [21] than was TAVI. Recently, new TAVI valves designed to reduce the incidence and the severity of postprocedural PVL have been introduced into clinical practice. Initial results are very promising and this may have a significant impact on patient outcomes. AKI is an independent predictor of mortality at follow-up after TAVI. We report an overall incidence of any degree of AKI of 17.2%, with a significantly higher incidence in patients who underwent TA TAVI. Even if baseline kidney function is not different between groups, this may result from the worse vascular condition of patients who undergo TA TAVI and to their higher incidence of bleeding. However, AKI requiring dialysis was 4.7% in the entire cohort, with no significant differences between groups. A recent meta-analysis reported an incidence of AKI after TAVI of 22.1% 11.2% irrespective of the approach. Furthermore, the authors showed a significant increase of all-cause and cardiovascular mortality of patients with AKI with an OR of 6.14 if compared with patients without AKI [22]. We did not observe any case of structural valve deterioration (SVD) or endocarditis up to 5 years. A recent report on very long-term outcomes after AVR with a pericardial bioprosthesis showed that freedom from SVD at 15 and 20 years was 78.6% and 48.5%, respectively [23]. The Kaplan-Meier curves of that study showed that SVD starts not earlier than 5 years after the procedure and that it reaches significant values after 10 to 15 years. Furthermore, Johnston and colleagues [24] found a significant relationship between age at implantation of a surgical bioprosthesis and risk of explantation because of SVD, and in particular they report a 0% risk for explantation in patients older than 80 years [24]. Thus if we consider that the mean age of our population was 80 years and that the number of patients at risk 5 years after TAVI was low, it is probably too early to draw conclusions about TAVI durability. Echocardiographic follow-up shows that transaortic gradients and effective orifice area are excellent and that they remain stable over time. Toggweiler and coworkers [8] described a decrease of aortic valve area from 1.67 cm2 postoperatively to 1.40 cm2 (p < 0.01) together with a slight increase of mean gradient. We did not observe this trend, maybe because different prostheses were used, but this clearly deserves attention and further investigation to be confirmed and to assess its impact on clinical and functional status.
the slightly different preoperative risk profile of the 2 cohorts.
Study Limitations The main limitations of this article are related to its retrospective nature. However, at our institution, all data from TAVI patients are prospectively collected in a dedicated database and follow-up is continuously updated. Clinical end points were self-adjudicated. No echocardiographic core laboratory was present. As is true of every retrospective study on heart valve prostheses, the risk of underestimation of SVD should be acknowledged. The comparison of TA and TF outcomes may be biased by
Conclusions According to our data, TAVI provides favorable early and up to 5-year clinical and hemodynamic outcomes. TA TAVI seems to be associated with fewer access site complications (especially minor ones) and less permanent pacemaker implantation, whereas TF TAVI demonstrates a lower incidence of postoperative kidney failure and better 30-day safety. However, early mortality and late survival are similar between the 2 techniques. PVL of any grade is directly associated with mortality. Further followup with more at-risk patients is needed to confirm these results.
References 1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. 2. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding prosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. 3. Leon MB, Smith CR, Mack MJ, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. 4. Zamorano JL, Badano LP, Bruce C, et al. EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. Eur Heart J 2011;32:2189–214. 5. Nashef SAM, Roques F, Michel P, et al. European System for Cardiac Operative Risk Evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16:9–13. 6. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32:205–17. 7. Kappetein AP, Head SJ, G en ereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J 2012;33:2403–18. 8. Toggweiler S, Humphries KH, Lee M, et al. 5-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61:413–9. 9. Di Mario C, Eltchaninoff H, Moat N, et al. The 2011-12 pilot European Sentinel Registry of transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients. EuroIntervention 2013;8:1362–71. 10. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA 2014;311:1503–14. 11. Gasparetto V, Fraccaro C, Tarantini G, et al. Safety and effectiveness of a selective strategy for coronary artery revascularization before transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;81:376–83. 12. Goel SS, Ige M, Tuzcu EM, et al. Severe aortic stenosis and coronary artery disease-implications for management in the transcatheter aortic valve replacement era. J Am Coll Cardiol 2013;62:1–10. 13. Dewey TM, Brown DL, Herbert MA, et al. Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation. Ann Thorac Surg 2010;89:758–67. 14. Masson JB, Lee M, Boone RH, et al. Impact of coronary artery disease on outcomes after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;76:165–73.
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15. Gautier M, Pepin M, Himbert D, et al. Impact of coronary artery disease on indications for transcatheter aortic valve implantation and on procedural outcomes. EuroIntervention 2011;7:549–55. 16. Wenaweser P, Pilgrim T, Guerios E, et al. Impact of coronary artery disease and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. EuroIntervention 2011;7:541–8. 17. Maisano F, Taramasso M, Nietlispach F. Prognostic influence of paravalvular leak following TAVI: is aortic regurgitation an active incremental risk factor or just a mere indicator? Eur Heart J 2015;36:413–5. 18. Athappan G, Patvarhan E, Tuzcu EM, et al. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement meta-analysis and systematic review of literature. J Am Coll Cardiol 2013;61: 1585–95. 19. Kodali S, Pibarot P, Douglas PS, et al. Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards SapienValve in the PARTNER trial: characterizing patients and impact on outcomes. Eur Heart J 2015;36:449–56.
20. D’Onofrio A, Rizzoli G, Messina A, et al. Conventional surgery, sutureless valves and transapical aortic valve replacement: what is the best option in patients with aortic valve stenosis? A multicenter, propensity-matched analysis. J Thorac Cardiovasc Surg 2013;146:1065–70. 21. D’Onofrio A, Messina A, Lorusso R, et al. Sutureless aortic valve replacement as an alternative treatment for patients belonging to the “gray zone” between transcatheter aortic valve implantation and conventional surgery: a propensitymatched, multicenter analysis. J Thorac Cardiovasc Surg 2012;144:1010–6. 22. Gargiulo G, Sannino A, Capodanno D, et al. Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic valve implantation: a meta-analysis of 5,971 patients. Catheter Cardiovasc Interv 2015;86: 518–27. 23. Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, et al. Very long-term outcomes of the Carpentier-Edwards Perimount Valve in aortic position. Ann Thorac Surg 2015;99:831–7. 24. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg 2015;99:1239–47.
DISCUSSION DR VINOD H. THOURANI (Atlanta, GA): Augusto, great presentation and a very important topic. You showed a pacemaker rate of 28% in transfemorals. Did that make an impact at five-year survival? I’ve seen it go both ways from different studies that if you have pacemaker postoperatively, it doesn’t affect your midterm mortality of 3 to 5 years. So, in your study, did you look at those people who had a pacemaker versus those who did not, and did it make a 3-year mortality difference or not or actually 5-year? DR D’ONOFRIO: Actually, we didn’t do this particular analysis, but the occurrence of AV block requiring pacemaker implantation was not associated with mortality at the multivariate analysis. And we also have to consider that this high incidence of pacemaker is mainly related to the CoreValve implantation, as has been demonstrated in many studies. And we mainly use the CoreValve implantation at the very early experience, very early part of our experience. And so if we consider the initial experience and we consider the device that has been used, putting all these things together, maybe this is why we have this incidence of the pacemaker and why maybe we haven’t observed an impact on mortality due to pacemaker implantation. DR CRAIG R. SAUNDERS (Newark, NJ): I appreciated your presentation, but in all the presentations here today nobody addressed the issue of concomitant mitral valve insufficiency, the choice of the patient and the outcomes of patients with that. Did you look at that at all? DR D’ONOFRIO: We haven’t looked at that in this particular study. However, we have already published our results from the Italian registry of transapical aortic valve implantation, and we have showed that, although patients with moderate to severe mitral valve insufficiency have significantly worse outcomes after TAVI compared with patients with no MR, the degree of mitral valve insufficiency seems to improve by 1 or 2 degrees after TAVI. Therefore we believe that TAVI is still a good procedure for patients with MR who cannot undergo conventional aortic valve replacement.
DR VINOD H. THOURANI (Atlanta, GA): I’m still not sure that, unless for really, really high-risk patients, that we should be advocating for those patients that have severe 4-plus MR in doing transcatheter valve. I think that we need to think twice about that. DR LAWRENCE H. COHN (Boston, MA): I was very impressed with your actuarial curves that show that any degree of aortic regurgitation led to decreased mortality. In view of that data, if you now encounter patients in your hospital that have AI after this procedure, do you then advocate an open operation to correct this or what do you do? DR THOURANI: You knew you were in trouble when he came up to the microphone. DR D’ONOFRIO: At our institution we still consider only highrisk or inoperable patients for TAVI. Having said that, if we have some degree of aortic insufficiency after TAVI we will try to fix it using all the possible techniques like postdilation and percutaneous closure of the leak. We do everything possible to go out from the OR with the least possible degree of aortic regurgitation. Unfortunately as you know, this is the Achilles’ heel of this procedure, and so far there is nothing we can do to completely eliminate it. DR VINOD H. THOURANI (Atlanta, GA): Professor Cohn, I would like to address that a little bit. I would tell you that we have operated on people who we have left early with moderate to severe. So if they’re operable patients, I think the right answer is in the sense of what to do for that patient, if they’re operable, they should have something done to them if you can’t do percutaneous closure of the paravalvular leaks. DR D’ONOFRIO: We followed the same strategy at the very beginning of this experience, but now I can honestly say that we don’t have patients with severe aortic regurgitation after TAVI.
Background. Concerns still exist regarding long-term results and freedom from valve-related adverse events in transcatheter aortic valve implantation (TAVI). The aim of this single-center retrospective study was to assess intermediate-term (up to 5-year) clinical and hemodynamic outcomes in patients undergoing TAVI. Methods. From 2007 through 2013, 338 consecutive patients underwent TAVI at our institution. Preoperative variables were defined according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) definitions, and outcomes were reported according to the Valve Academic Research Consortium (VARC)-2 definitions. Multivariate logistic regression analysis was performed to identify independent predictors of mortality at follow-up. Results. transfemoral (TF) and transapical (TA) TAVI were performed in 233 (69%) and 105 (31%) patients, respectively. All-cause 30-day mortality was 4.4%, with no differences between TA and TF procedures. Thirtyday cardiovascular death, stroke, and myocardial infarction were not different between groups. The acute kidney
injury (AKI) rate was higher in the TA group (30.5% versus 11.2%; p < 0.001). Access-related complications were more frequent in the TF group (36.1% versus 11.4%; p < 0.001). Mean follow-up was 22.3 ± 17.8 months (range, 1–74 months). Overall survival rates at 1, 3, and 5 years were 85.5% ± 2.1%, 69.9% ± 3.2%, and 61% ± 4.3%, respectively. Independent predictors of all-cause mortality at follow-up were previous myocardial infarction (odds ratio [OR], 2.7), any grade of paravalvular leak (PVL) (OR, 2.5), and AKI (OR, 3.1). Mean gradient and effective orifice area at follow-up were 10.7 ± 12.0 mm Hg and 1.1 ± 0.9 cm2/m2, respectively. Conclusions. Our data show that TAVI has good early and intermediate-term clinical and hemodynamic outcomes in high-risk or inoperable patients with severe symptomatic aortic valve stenosis. PVL of any grade has a significant impact on survival.
T
early and intermediate-term (up to 5 years) clinical data and hemodynamic performance of all patients who underwent TAVI at our institution.
ranscatheter aortic valve implantation (TAVI) is now a well-established therapeutic option in high-risk or inoperable patients with severe symptomatic aortic stenosis (AS) because it has been demonstrated to be noninferior to or even better than surgical aortic valve replacement (AVR) in high-risk operable patients [1, 2] and better than optimal medical therapy (including balloon aortic valvuloplasty) in inoperable patients [3]. However, the extension of TAVI indications for intermediate-risk as well as younger patients is somehow restrained by some concerns regarding TAVI late results. In fact, there are few data available about late clinical and hemodynamic outcomes of TAVI. Therefore, in this single-center retrospective study we aimed at reporting
Accepted for publication Aug 8, 2015.
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods We reviewed the entire TAVI experience of our institution since the first case in 2007. All patients underwent TAVI for severe symptomatic AS. Implanted devices were the self-expanding CoreValve (Medtronic, Minneapolis, MN) from June 2007 to November 2009 and the balloonexpandable Edwards SAPIEN, SAPIEN XT, and SAPIEN 3 (Edwards Lifesciences, Irvine, CA) from March 2009 until December 2013. All patients who received the CoreValve underwent a retrograde approach (transfemoral [TF] and transsubclavian), whereas SAPIEN valves were implanted in both antegrade (transapical
Presented at the Fifty-first Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 24–28, 2015. Address correspondence to Dr D’Onofrio, Division of Cardiac Surgery, Azienda Ospedaliera-University of Padova, Centro Gallucci, Via Giustiniani, 2, 35128, Padova, Italy; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
Drs D’Onofrio and Tarantini disclose a financial relationship with Edwards Lifesciences.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.08.032
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Table 1. Preoperative Clinical and Hemodynamic Characteristics of the Entire Population and of the Transfemoral and Transapical Cohorts
Baseline Age Male sex BMI Arterial hypertension Diabetes History of smoking Hypercholesterolemia Carotid artery disease Peripheral artery disease Chronic kidney failure Creatinine clearance, mL/min COPD Previous myocardial infarction Previous stroke Previous cardiac operation Previous PCI Atrial fibrillation Porcelain aorta, NYHA class I-II III-IV Angina Syncope Logistic EuroSCORE Additive EuroSCORE EDV (mL/m2) LVEF AVA (cm2/m2) Peak gradient (mm Hg) Mean gradient (mm Hg) Aortic regurgitation 1þ/4þ 2þ/4þ 3þ/4þ Mitral regurgitation 1þ/4þ 2þ/4þ 3þ/4þ Pulmonary pressure (mm Hg) Wedge pressure (mm Hg) Coronary artery disease Preoperative hemoglobin, g/dL
All N ¼ 338 n (%)
TF n ¼ 233 n (%)
TA n ¼ 105 n (%)
80.3 6.7 181 (53.6) 26.4 6.5 306 (90.5) 91 (27.0) 92 (27.2) 210 (62.2) 105 (31.1) 33 (9.8) 175 (51.8) 57.4 22.5 98 (29.2) 66 (19.5) 43 (12.7) 68 (20.1) 109 (32.3) 116 (34.3) 54 (16.3)
80.5 7.0 126 (54.1) 26.8 7.4 209 (89.7) 62 (26.6) 61 (26.2) 139 (59.7) 70 (30.0) 13 (5.6) 116 (49.8) 57.5 22.8 71 (30.6) 45 (19.3) 28 (12) 37 (15.9) 72 (30.9) 80 (34.3) 29 (12.4)
80.2 6.1 55 (52.4) 25.2 3.6 97 (92.4) 29 (27.6) 31 (29) 71 (67.6) 35 (33.3) 20 (19.0) 59 (56.2) 56.1 22.5 27 (25.7) 21 (20) 15 (14.3) 31 (29.5) 37 (35.2) 36 (34.3) 25 (23.8)
100 (29.6) 238 (70.4) 105 (31.2) 59 (17.5) 17.3 3.0 10.0 2.4 66.9 23.4 55.0 12.3 0.45 0.12 73.1 43.9 43.8 14.9
67 (28.8) 166 (71.2) 66 (28.6) 43 (18.5) 12.5 1.7 10.2 2.4 66.8 24.1 54.9 12.9 0.46 0.14 75.1 26.3 50.0 14.9
33 (31.4) 72 (68.6) 39 (37.1) 16 (15.2) 19.2 5.5 10.1 2.1 66.7 21.8 55.0 10.9 0.45 0.12 74.9 24.2 43.5 13.8
167 (49.4) 49 (14.5) 18 (5.3)
111 (47.6) 35 (15.0) 14 (6.0)
56 (53.3) 14 (13.3) 4 (3.8)
190 (56.2) 68 (20.1) 9 (2.7) 25.8 16.0 16.0 8.0 193 (57.1) 12.1 1.6
139 (59.7) 46 (19.7) 4 (1.7) 26.1 12.3 16.5 7.9 129 (55.4) 12.2 1.7
51 (48.6) 22 (21.1) 5 (4.8) 24.7 9.9 14.5 7.9 64 (61.0) 11.9 1.6
p Value 0.308 0.814 0.177 0.436 0.864 0.374 0.132 0.612 <0.001 0.275 0.856 0.387 0.725 0.572 0.005 0.167 0.215 0.003 0.089
0.031 0.260 0.050 0.237 0.206 0.179 0.653 0.337 0.240 0.291
0.726
0.413 0.975 0.358 0.253
AVA ¼ aortic valve area; BMI ¼ body mass index; COPD ¼ chronic obstructive pulmonary disease; EDV ¼ end-diastolic volume; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; TA ¼ transapical; TF ¼ transfemoral.
[TA]) and retrograde fashion (transaortic and TF). All patients gave informed consent for the procedure and for data collection; the local ethics committee approved data collection and analysis. Our institution follows a “TF first policy.” Data were prospectively collected in our TAVIdedicated database. Clinical and echocardiographic
evaluation was performed at hospital admission, before discharge, 1 to 3 months postoperatively, 6 to 9 months postoperatively, and on a yearly basis thereafter in a TAVI-dedicated outpatient clinic. In this setting, all patients underwent bidimensional and 3-dimensional transthoracic echocardiography using an iE33
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Table 2. Procedural and Hospital Results of the Entire Population and of the Transfemoral and Transapical Cohorts All N ¼ 338 n (%)
Results Device success (VARC-2) Conversion to surgical procedure Device embolization TAV in TAV Coronary obstruction Paravalvular leak None/trivial 1þ/3þ 2þ/3þ Access-related complications Minor Major Bleeding Minor Major Life-threatening AKI AKI needing dialysis Immediate procedural mortality 30-day mortality 30-day cardiovascular mortality Stroke Acute myocardial infarction Permanent pacemaker implantation 30-d safety 1-y efficacy AKI ¼ acute kidney injury; Consortium.
TA ¼ transapical;
TF n ¼ 233 n (%)
TA n ¼ 105 n (%)
322 6 6 12 1
(95.1) (1.8) (1.8) (3.6) (0.3)
224 3 4 9 1
(96.1) (1.3) (1.7) (3.9) (0.4)
98 3 2 3 0
(93.3) (2.9) (1.9) (2.9) (0)
210 100 28 96 58 38
(62.1) (29.6) (8.3) (28.4) (17.2) (11.2)
143 70 20 84 54 30
(61.4) (30.0) (8.6) (36.1) (23.2) (12.9)
67 30 8 12 4 8
(63.8) (28.6) (7.6) (11.4) (3.8) (7.6)
44 64 12 58 16 4 15 10 10 7 77 273 234
(12.9) (18.9) (3.6) (17.2) (4.7) (1.2) (4.4) (3) (3) (2.1) (22.8) (80.7) (69.2)
36 38 7 26 9 3 11 6 7 6 66 197 163
(15.5) (16.3) (3.0) (11.2) (3.9) (1.3) (4.7) (2.6) (3.0) (2.6) (28.3) (84.6) (70.0)
8 26 5 32 7 1 4 4 3 1 11 76 71
(7.1) (24.7) (4.8) (30.5) (6.7) (1.0) (4.0) (4.0) (3.0) (1.0) (10.5) (72.4) (67.6)
TAV ¼ transcatheter aortic valve;
echocardiography system (Philips Healthcare, the Netherlands), following the recommendations from the specific guidelines for echocardiography in transcatheter interventions for valvular heart disease [4]. If a more detailed evaluation was needed, transesophageal echocardiography was performed. For patients unable to come to our hospital for follow-up evaluation (<10%), we performed telephone interviews and asked for a copy of the most recent echocardiographic examination. Preoperative clinical variables were defined according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) definitions [5]. Postoperative outcomes and clinical end points were reported following the updated Valve Academic Research Consortium (VARC)-2 recommendations [6, 7]. Postoperative aortic regurgitation (AR) was graded as no or trivial AR, mild AR (1þ/3þ), moderate AR (2þ/3þ), and severe AR (3þ/3þ). In particular, the presence and severity of AR was based on the evaluation of both central and paravalvular components with a combined measurement of total AR. The assessment of AR was performed according to current guidelines [4, 6, 7] using quantitative (regurgitant volume, regurgitant fraction, and effective regurgitant orifice area) and semiquantitative (diastolic flow reversal in the
TF ¼ transfemoral;
p Value 0.185 0.105 0.908 0.639 0.500 0.506
<0.001 <0.001 0.113 0.063
<0.001 0.611 0.789 0.724 0.837 0.827 0.350 0.008 0.012 0.149
VARC ¼ Valve Academic Research
descending aorta, circumferential extent of prosthetic valve paravalvular regurgitation) methods. According to VARC-2, we analyzed the following composite end points: (1) early safety, defined as absence of procedural mortality and correct positioning of a single prosthetic heart valve into the proper anatomic location and intended performance of the prosthetic heart valve (no prosthesis/patient mismatch and mean aortic valve gradient <20 mm Hg or peak velocity <3 m/s and no moderate or severe prosthetic valve regurgitation); (2) 1-year efficacy, which includes all-cause mortality, all-stroke (disabling and nondisabling), requirment of hospitalization for valve-related symptoms or worsening congestive heart failure, New York Heart Association (NYHA) class III or IV, valve-related dysfunction (mean aortic valve gradient 20 mm Hg, effective orifice area 0.9–1.1 cm2 or dimensionless valve index <0. 35 (or both), or moderate or severe prosthetic valve regurgitation (or both). The incidence of mortality, stroke, and acute myocardial infarction at 1 year includes perioperative events.
Statistical Analysis For continuous variables, data are reported as mean with standard deviation. For categorical variables, data are
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reported as frequency (percentage). Comparison between groups for continuous variables was made using the t test or the Wilcoxon/Mann Whitney test as appropriate; comparison between groups for categorical variables was made using the c2 or the Fisher’s exact test as appropriate. Late results are expressed as percentage after the exclusion of patients who had died by 30 days after the procedure. Cox proportional hazard regression analysis was performed to identify independent predictors of mortality at follow-up, which are reported as hazard ratios (HRs), 95% confidence intervals (CIs), and p values. Preoperative and perioperative variables that were found significant at univariate analysis were included in the multivariate analysis. Cumulative survival was estimated using the KaplanMeier method. Survival rates were compared using the log-rank test. All statistical tests were 2-sided, and p values of 0.05 or less were considered statistically significant. Statistical analyses were conducted using IBM SPSS Statistics, version 19 (SPSS, Inc, Chicago, IL).
Results
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Early Results Procedural and early results are shown in Table 2. Overall all-cause 30-day mortality was 4.4% (15 patients); allcause 30-day mortality in the TF and TA groups was 4.7% (11 patients) and 3.8% (4 patients), respectively (p ¼ 0.72). Patients undergoing TA TAVI had a significantly higher incidence of AKI (30.5% versus 11.2%; p < 0.001), whereas patients undergoing TF TAVI had a higher incidence of access-related complications of any severity (36.1% versus 11.4%; p < 0.001) and permanent pacemaker implantation (28.3% versus 11%; p ¼ 0.008). The incidence of permanent pacemaker implantation in patients with CoreValve and SAPIEN devices was 41% (34 patients) and 16.9% (43 patients), respectively (p < 0.001). Overall VARC-2 early safety at 30 days was 78.4% (265 patients); 30-day safety in the TF and TA groups was 84.5% (197 patients) and 72.4% (76 patients), respectively (p ¼ 0.01). At discharge, aortic insufficiency was absent in 210 patients (62.1%), 1þ/3þ AR was present in 100 patients (39.6%), and 2þ/3þ AR was seen in 28 patients (8.3%). There were no patients with severe AR at discharge.
Study Population Between January 2007 and December 2013, 350 consecutive patients with severe symptomatic AS underwent TAVI at our institution. Transaortic and transsubclavian TAVI procedures were performed in 6 patients each, and because of this small number they were excluded from the analysis. In the remaining 338 patients, who represent the population of this study, TF and TA TAVI were performed in 233 (69%) and 105 (31%) patients, respectively. The implanted prostheses were CoreValve in 83 patients (24.6%) and SAPIEN with its evolutions in 255 (75.4%) patients. In particular, the new SAPIEN 3 valve was implanted in 34 patients. Preoperative variables of the entire cohort and of the 2 subgroups, TA and TF, are shown in Table 1. Unsurprisingly, patients who underwent TA TAVI had a higher logistic EuroSCORE (19% 5% versus 13% 2%; p ¼ 0.05) and they were also more likely to have peripheral vascular disease (19% versus 5.6%; p < 0.001). Fig 1. Kaplan-Meier overall survival in the entire population and in the transfemoral (TF) and transapical (TA) cohorts.
Late Results Overall mortality from all causes at 1 year was 13.9% (45 patients), and all-cause 1-year mortality in the TF and TA groups was 15.3% (34 patients) and 10.8% (11 patients), respectively (p ¼ 0.38). Cardiovascular death at one year in the entire cohort occurred in 27 patients (8.4%); 18 (8.1%) and 9 (8.9%) in TF and TA patients, respectively (p ¼ 0.72). The incidence of stroke and myocardial infarction 1 year after TAVI was 4.3% (14 patients) and 3.1% (10 patients) respectively, with no differences between TF and TA groups. Mean follow-up of the entire cohort was 22.3 17.8 months (range, 1–74 months); mean follow up of patients in the TA group was significantly shorter than that in patients in the TF group (18.4 10.2 months versus 24.7 18.5 months; p ¼ 0.03). Overall survival rates at 1, 3, and 5 years were 85.5% 2.1%, 69.9% 3.2%, and 61% 4.3%, respectively (Fig 1). Survival rates at 1, 3, and 5 years
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were 84.4% 2.6%, 69.2% 3.8%, and 58.6% 4.9%, respectively, in the TF cohort and 92.8% 2.6%, 71.3% 6.6%, and 71.3% 6.6%, respectively, in the TA cohort (log-rank p ¼ 0.749) (Fig 1). Interestingly, as depicted in Figure 2, even mild paravalvular leak (PVL) had a significant impact on survival. In fact, the Kaplan-Meier survival analysis clearly shows that patients with mild (1þ/3þ) and moderate (2þ/3þ) postoperative AR had a significantly lower survival compared with patients with no AR (log-rank p ¼ 0.012; log-rank no PVL versus mild PVL, p ¼ 0.053; log-rank no PVL versus moderate/severe PVL, p ¼ 0.003). We observed a significant improvement in NYHA functional class during follow-up. In fact we observed a significant improvement of exercise capacity soon after TAVI, which remained stable with time. One year after TAVI, 77.9% of patients were in NYHA class I, 20.3% were in NYHA class II, and 1.8% were in NYHA class III. There were no patients in NYHA class IV (p < 0.05 compared with baseline) (Fig 3). One-year efficacy, according to VARC-2 definitions, was 69.2% (234 patients). In the TF and TA groups, 1-year efficacy was 70% (163 patients) and 67.6% (71 patients), respectively (p ¼ 0.15).
showed the need for reoperation on the transcatheter device for any reason during follow-up.
Hemodynamic Performance Figure 4 shows the variation of mean aortic gradient and aortic valve area before the operation and at follow-up. There is a significant reduction of transaortic gradients after TAVI and values remain stable over time. Mean aortic gradient at follow-up is 10.7 12 mm Hg. Looking at the aortic valve area, we observe the maximum increase 1 month after the operation, and subsequently a slight reduction of this value appears without reaching statistical significance. Mean effective orifice area index at follow-up was 1.1 0.9 cm2/m2. We have not observed any structural valve deterioration or endocarditis up to 5 years in this population. Furthermore, no patients
Fig 2. Kaplan-Meier survival of patients according to postoperative paravalvular leak (PVL).
Predictors of Mortality at Follow-Up The results of the multivariate analysis are shown in Table 3. Previous myocardial infarction (HR, 2.7; 95% CI, 1.1–7.1; p ¼ 0.03), AKI (HR, 3.1; 95% CI, 1.2–7.8; p ¼ 0.02), and any grade of PVL (HR, 2.5; 95% CI, 1.2–5.3; p ¼ 0.02) were identified as independent predictors of late mortality, in particular mild PVL versus no PVL (HR, 1.8; 95% CI, 1.0–2.8; p ¼ 0.051) and moderate/severe PVL versus no PVL (HR, 2.7; 95% CI, 1.3–6.2; p ¼ 0.002).
Comment This study shows that both TA and TF TAVI have good clinical and hemodynamic outcomes up to 5 years in high-risk or inoperable patients. Five-year survival was 61% with no differences between the TA and TF groups. Toggweiler and colleagues [8] found a lower long-term survival in their analysis based on 88 inoperable patients. In fact, they report a 35% survival 5 years after TAVI. There are many reasons to explain this difference: their experience started in 2005 and represents the first in human TAVI experience with first-generation prostheses; they evaluated only truly inoperable patients; and the mean patient age was 83 years. In our study, the mean age was 80 years; our population also included high-risk operable patients; and our experience started later and consequently many technical issues as well as issues related to patient selection had been resolved. In particular, the heart team approach is crucial to optimize patient selection, improve results, and reduce the incidence of complications and their impact on patient outcomes with a timely diagnosis and effective therapy. The heart team should always include at least a cardiac surgeon, an interventional cardiologist, a clinical cardiologist/ echocardiographer, and an anesthesiologist. Interestingly, although some authors describe better outcomes with TF TAVI compared with TA TAVI [9] regarding mortality, our data show that the only differences between the 2 forms of access were less AKI for TF TAVI and less access-related complications and less permanent pacemaker implantation for TA TAVI. However, the early safety end point is slightly in favor of TF TAVI mainly because of the nonsevere nature of access-related complications. Furthermore, the higher incidence of pacemaker implantation in patients belonging to the TF TAVI cohort is related to the use of CoreValve prostheses, which have been shown to produce more conduction disturbances compared with the SAPIEN valve [10]. Our finding that previous myocardial infarction is a predictor of late mortality seems to show that coronary artery disease (CAD) has a significant impact on survival after TAVI. The presence of CAD in patients undergoing TAVI has led many authors to look for the best therapeutic strategy in regard to timing and procedures in this specific population [11]. CAD is present in 40% to 75% of patients referred for TAVI [12]. If we look at long-term impact of severe CAD, there is conflicting evidence in
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Fig 3. Variation of New York Heart Association (NYHA) functional class in patients undergoing transcatheter aortic valve implantation (TAVI).
the literature. According to Dewey and coworkers [13], patients who have undergone previous coronary artery bypass or percutaneous coronary interventions had higher 30-day and 1-year mortality than did patients with no CAD. Conversely, other authors did not find significant differences in mortality in patients with and those without CAD undergoing TAVI [14–16]. PVL is often considered the Achilles’ heel of TAVI [17]. In our study, we observed that late survival decreases with worsening PVL and that PVL of any degree was independently associated with mortality at follow-up. Although it has been clearly demonstrated that moderate and severe PVL (2þ/3þ) has a significant impact on mortality after TAVI [18], there is no consensus about the impact of mild PVL (1þ/3þ). A recently published report by Kodali and associates [19] evaluating 2,434 patients from the Placement of Aortic Transcatheter Valve trial (PARTNER) shows
that 1-year all-cause mortality, cardiac-related mortality, and rehospitalization rates were significantly increased with worsening PVL and also that mild PVL was independently associated with late mortality. Opposite results are shown by the Medtronic CoreValve US Pivotal Trial, in which mild PVL did not seem to be associated with worse 1-year mortality [2]. Because the incidence of mild PVL in our study, as well as in other reports, is as high as 30%, a clear evaluation of its impact on longterm outcomes remains crucial before expanding TAVI indications to intermediate-risk patients. In fact, these patients are suitable for all currently available aortic valve procedures: AVR, TAVI, and sutureless aortic valve replacement (SU-AVR). Two studies that compared outcomes of AVR, TAVI, and SU-AVR showed that there were no differences in mortality among these procedures and that AVR was associated with a
Table 3. Predictors of Mortality at Follow-Up: Results of the Multivariate Cox Regression Analysis
Fig 4. Variation of transaortic gradients (peak and mean) and effective orifice area of patients undergoing transcatheter aortic valve implantation (TAVI).
Variable
HR
95% CI
p Value
Previous AMI PVL AKI LVEF Device diameter Device type Additive EuroSCORE Access (TA) Age
2.7 2.5 3.1 0.9 1.1 1.4 1.2 1.9 1.4
1.1–7.1 1.2–5.3 1.2–7.8 0.8–1.3 0.8–1.2 0.5–3.5 0.9–2.6 0.7–4.9 0.6–3.0
0.03 0.02 0.02 0.801 0.618 0.099 0.173 0.153 0.345
AKI ¼ acute kidney injury; AMI ¼ acute myocardial infarction; CI ¼ confidence interval; HR ¼ hazard ratio; LVEF ¼ left ventricular ejection fraction; PVL ¼ paravalvular leak; TA ¼ transapical.
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significantly lower incidence of postoperative AR compared with TAVI [20]. Furthermore, SU-AVR was also associated with a lower rate of postprocedural PVL [21] than was TAVI. Recently, new TAVI valves designed to reduce the incidence and the severity of postprocedural PVL have been introduced into clinical practice. Initial results are very promising and this may have a significant impact on patient outcomes. AKI is an independent predictor of mortality at follow-up after TAVI. We report an overall incidence of any degree of AKI of 17.2%, with a significantly higher incidence in patients who underwent TA TAVI. Even if baseline kidney function is not different between groups, this may result from the worse vascular condition of patients who undergo TA TAVI and to their higher incidence of bleeding. However, AKI requiring dialysis was 4.7% in the entire cohort, with no significant differences between groups. A recent meta-analysis reported an incidence of AKI after TAVI of 22.1% 11.2% irrespective of the approach. Furthermore, the authors showed a significant increase of all-cause and cardiovascular mortality of patients with AKI with an OR of 6.14 if compared with patients without AKI [22]. We did not observe any case of structural valve deterioration (SVD) or endocarditis up to 5 years. A recent report on very long-term outcomes after AVR with a pericardial bioprosthesis showed that freedom from SVD at 15 and 20 years was 78.6% and 48.5%, respectively [23]. The Kaplan-Meier curves of that study showed that SVD starts not earlier than 5 years after the procedure and that it reaches significant values after 10 to 15 years. Furthermore, Johnston and colleagues [24] found a significant relationship between age at implantation of a surgical bioprosthesis and risk of explantation because of SVD, and in particular they report a 0% risk for explantation in patients older than 80 years [24]. Thus if we consider that the mean age of our population was 80 years and that the number of patients at risk 5 years after TAVI was low, it is probably too early to draw conclusions about TAVI durability. Echocardiographic follow-up shows that transaortic gradients and effective orifice area are excellent and that they remain stable over time. Toggweiler and coworkers [8] described a decrease of aortic valve area from 1.67 cm2 postoperatively to 1.40 cm2 (p < 0.01) together with a slight increase of mean gradient. We did not observe this trend, maybe because different prostheses were used, but this clearly deserves attention and further investigation to be confirmed and to assess its impact on clinical and functional status.
the slightly different preoperative risk profile of the 2 cohorts.
Study Limitations The main limitations of this article are related to its retrospective nature. However, at our institution, all data from TAVI patients are prospectively collected in a dedicated database and follow-up is continuously updated. Clinical end points were self-adjudicated. No echocardiographic core laboratory was present. As is true of every retrospective study on heart valve prostheses, the risk of underestimation of SVD should be acknowledged. The comparison of TA and TF outcomes may be biased by
Conclusions According to our data, TAVI provides favorable early and up to 5-year clinical and hemodynamic outcomes. TA TAVI seems to be associated with fewer access site complications (especially minor ones) and less permanent pacemaker implantation, whereas TF TAVI demonstrates a lower incidence of postoperative kidney failure and better 30-day safety. However, early mortality and late survival are similar between the 2 techniques. PVL of any grade is directly associated with mortality. Further followup with more at-risk patients is needed to confirm these results.
References 1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. 2. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding prosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. 3. Leon MB, Smith CR, Mack MJ, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. 4. Zamorano JL, Badano LP, Bruce C, et al. EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. Eur Heart J 2011;32:2189–214. 5. Nashef SAM, Roques F, Michel P, et al. European System for Cardiac Operative Risk Evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16:9–13. 6. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32:205–17. 7. Kappetein AP, Head SJ, G en ereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J 2012;33:2403–18. 8. Toggweiler S, Humphries KH, Lee M, et al. 5-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61:413–9. 9. Di Mario C, Eltchaninoff H, Moat N, et al. The 2011-12 pilot European Sentinel Registry of transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients. EuroIntervention 2013;8:1362–71. 10. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA 2014;311:1503–14. 11. Gasparetto V, Fraccaro C, Tarantini G, et al. Safety and effectiveness of a selective strategy for coronary artery revascularization before transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;81:376–83. 12. Goel SS, Ige M, Tuzcu EM, et al. Severe aortic stenosis and coronary artery disease-implications for management in the transcatheter aortic valve replacement era. J Am Coll Cardiol 2013;62:1–10. 13. Dewey TM, Brown DL, Herbert MA, et al. Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation. Ann Thorac Surg 2010;89:758–67. 14. Masson JB, Lee M, Boone RH, et al. Impact of coronary artery disease on outcomes after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;76:165–73.
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15. Gautier M, Pepin M, Himbert D, et al. Impact of coronary artery disease on indications for transcatheter aortic valve implantation and on procedural outcomes. EuroIntervention 2011;7:549–55. 16. Wenaweser P, Pilgrim T, Guerios E, et al. Impact of coronary artery disease and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. EuroIntervention 2011;7:541–8. 17. Maisano F, Taramasso M, Nietlispach F. Prognostic influence of paravalvular leak following TAVI: is aortic regurgitation an active incremental risk factor or just a mere indicator? Eur Heart J 2015;36:413–5. 18. Athappan G, Patvarhan E, Tuzcu EM, et al. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement meta-analysis and systematic review of literature. J Am Coll Cardiol 2013;61: 1585–95. 19. Kodali S, Pibarot P, Douglas PS, et al. Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards SapienValve in the PARTNER trial: characterizing patients and impact on outcomes. Eur Heart J 2015;36:449–56.
20. D’Onofrio A, Rizzoli G, Messina A, et al. Conventional surgery, sutureless valves and transapical aortic valve replacement: what is the best option in patients with aortic valve stenosis? A multicenter, propensity-matched analysis. J Thorac Cardiovasc Surg 2013;146:1065–70. 21. D’Onofrio A, Messina A, Lorusso R, et al. Sutureless aortic valve replacement as an alternative treatment for patients belonging to the “gray zone” between transcatheter aortic valve implantation and conventional surgery: a propensitymatched, multicenter analysis. J Thorac Cardiovasc Surg 2012;144:1010–6. 22. Gargiulo G, Sannino A, Capodanno D, et al. Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic valve implantation: a meta-analysis of 5,971 patients. Catheter Cardiovasc Interv 2015;86: 518–27. 23. Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, et al. Very long-term outcomes of the Carpentier-Edwards Perimount Valve in aortic position. Ann Thorac Surg 2015;99:831–7. 24. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg 2015;99:1239–47.
DISCUSSION DR VINOD H. THOURANI (Atlanta, GA): Augusto, great presentation and a very important topic. You showed a pacemaker rate of 28% in transfemorals. Did that make an impact at five-year survival? I’ve seen it go both ways from different studies that if you have pacemaker postoperatively, it doesn’t affect your midterm mortality of 3 to 5 years. So, in your study, did you look at those people who had a pacemaker versus those who did not, and did it make a 3-year mortality difference or not or actually 5-year? DR D’ONOFRIO: Actually, we didn’t do this particular analysis, but the occurrence of AV block requiring pacemaker implantation was not associated with mortality at the multivariate analysis. And we also have to consider that this high incidence of pacemaker is mainly related to the CoreValve implantation, as has been demonstrated in many studies. And we mainly use the CoreValve implantation at the very early experience, very early part of our experience. And so if we consider the initial experience and we consider the device that has been used, putting all these things together, maybe this is why we have this incidence of the pacemaker and why maybe we haven’t observed an impact on mortality due to pacemaker implantation. DR CRAIG R. SAUNDERS (Newark, NJ): I appreciated your presentation, but in all the presentations here today nobody addressed the issue of concomitant mitral valve insufficiency, the choice of the patient and the outcomes of patients with that. Did you look at that at all? DR D’ONOFRIO: We haven’t looked at that in this particular study. However, we have already published our results from the Italian registry of transapical aortic valve implantation, and we have showed that, although patients with moderate to severe mitral valve insufficiency have significantly worse outcomes after TAVI compared with patients with no MR, the degree of mitral valve insufficiency seems to improve by 1 or 2 degrees after TAVI. Therefore we believe that TAVI is still a good procedure for patients with MR who cannot undergo conventional aortic valve replacement.
DR VINOD H. THOURANI (Atlanta, GA): I’m still not sure that, unless for really, really high-risk patients, that we should be advocating for those patients that have severe 4-plus MR in doing transcatheter valve. I think that we need to think twice about that. DR LAWRENCE H. COHN (Boston, MA): I was very impressed with your actuarial curves that show that any degree of aortic regurgitation led to decreased mortality. In view of that data, if you now encounter patients in your hospital that have AI after this procedure, do you then advocate an open operation to correct this or what do you do? DR THOURANI: You knew you were in trouble when he came up to the microphone. DR D’ONOFRIO: At our institution we still consider only highrisk or inoperable patients for TAVI. Having said that, if we have some degree of aortic insufficiency after TAVI we will try to fix it using all the possible techniques like postdilation and percutaneous closure of the leak. We do everything possible to go out from the OR with the least possible degree of aortic regurgitation. Unfortunately as you know, this is the Achilles’ heel of this procedure, and so far there is nothing we can do to completely eliminate it. DR VINOD H. THOURANI (Atlanta, GA): Professor Cohn, I would like to address that a little bit. I would tell you that we have operated on people who we have left early with moderate to severe. So if they’re operable patients, I think the right answer is in the sense of what to do for that patient, if they’re operable, they should have something done to them if you can’t do percutaneous closure of the paravalvular leaks. DR D’ONOFRIO: We followed the same strategy at the very beginning of this experience, but now I can honestly say that we don’t have patients with severe aortic regurgitation after TAVI.