Early and mid-term outcomes of 1904 patients undergoing transcatheter balloon-expandable valve implantation in Italy: results from the Italian Transcatheter Balloon-Expandable Valve Implantation Registry (ITER)^†

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is an established procedure for patients suffering from severe symptomatic aortic valve stenosis who are considered inoperable or with serious comorbidities that generate a high-risk surgical profile [1–9].

Clinical data are still needed to further support expansion of TAVI to moderate-risk patients [10]. Controlled trials and ‘real-world’ experience from single centres and multicentre registries are crucial to share results and complications to improve patient selection and outcomes.

ITER (Italian Transcatheter Balloon-Expandable Valve Implantation Registry) is a Latin word that stands for the new ‘path’ we are searching for in the treatment of stenotic aortic valve disease.

ITER is an ‘all-comers’, real-world, independent multicentre registry that virtually includes all TAVI procedures with a balloon-expandable prosthesis performed in Italy since the beginning of the activity in 2007. The study device is the only balloon-expandable transcatheter bioprosthesis available for clinical use so far, the Sapien (Edwards Lifesciences, Irvine, CA, USA) and all its following generations (Sapien XT and Sapien 3). The aim of this registry is ultimately to assess long-term clinical and haemodynamic results of patients undergoing TAVI with a balloon-expandable bioprosthesis in a real-world national scenario. However, in this first report of the ITER, we aim to evaluate patients' characteristics as well as to assess early and medium-term clinical and haemodynamic outcomes of all patients undergoing balloon-expandable TAVI in our country.

PATIENTS AND METHODS

The ITER includes 33 Italian centres performing balloon-expandable TAVI. All patients undergoing balloon-expandable TAVI in each centre between 2007 and 2012 were enrolled in this registry regardless of the access. Data were collected from each study site and then anonymously sent to the University of Torino for storage and analysis. Ethic committees from the partipating centres approved data collection, and patient informed consent was always collected. As this is a real-world, all-comers’ experience, patient selection and procedure strategies were done according to single-site policies, experience and protocols. All procedures were performed using the Edwards Sapien and Sapien XT prostheses with retrograde or antegrade approaches. The Sapien 3 valve was not yet available during the study period of this first ITER report.

Data and definitions

Preoperative risk factors were defined according to the EuroSCORE (ES) classification [11, 12].

The presence of preoperative coronary artery disease was considered according to the STS Score definitions as left anterior descending system, circumflex system and/or right system with greater than or equal to 50% narrowing of any vessel.

Postoperative outcomes were defined according to the updated Valve Academic Research Consortium (VARC-2) definitions [13].

In particular, ‘operative mortality’ is defined as all deaths that occurred within 30 days from the procedure or longer if the patient was not discharged from the treatment hospital or a secondary rehabilitation facility. The echocardiographic measurements were performed according to the current recommendations of the European and American Societies of Echocardiography. In particular, aortic regurgitation was classified as absent/trivial (0), mild (1+), moderate (2+) and severe (3+).

Follow-up

Patients underwent clinical and echocardiographic assessment at the study site before the operation, at hospital discharge and then according to each centre's protocol.

Follow-up time points were requested after 3–6 months, 1 year and every year thereafter.

Data on late mortality were collected in different ways according to the various centres. Mainly follow-up data were collected by direct contact with patients, telephone and registry office. Few centres had data linkage with regional registers for data on mortality. The last census date varies between centres, and it is between January and March 2014.

Statistical analysis

Data are presented as frequency and percentages as well as mean and standard deviation or median and first and third quartiles. A univariable analysis was performed to test which covariates would be considered in a further multivariable analysis: a hazard ratio and its 95% confidence interval were estimated for each variable; a log-rank test was used for categorical variables. Multivariable analysis was used to determine risk factors for the occurrence of total mortality.

A Cox proportional hazards regression model was fitted to determine the relative risk for death from the procedure until the end of follow-up: the results were expressed as hazard ratios with 95% confidence interval.

Clinical significant variables were then entered in the model; we chose the variables with a 0.2 significance level. Only variables missing for less than 5% of the records were considered for inclusion in the multivariable model and for these it was made imputation with the mean of the observed values. The logistic EuroSCORE was not included in the model because the individual factors had been already included.

The assumption of proportional hazards was assessed by including and testing time-dependent covariates defined as the interaction between the predictor and a function of survival time. All time-dependent covariates were not significant. A plot of the Kaplan–Meier estimator was performed for all patients. All data were analysed using SAS release 9.03 by SAS Institute Inc. (Cary, NC, USA).

RESULTS

Study population

The study population comprises 1904 patients enrolled in ITER from November 2007 to December 2012. Enrolment at each centre is summarized in supplementary Figure A. Mean age was 81.7 (SD:6.2) years; 1147 (60.2%) patients were female; mean Logistic EuroSCORE, EuroSCORE II and STS score were 21.1 (SD:13.7)%, 7.3 (SD:6.7)% and 9.2 (SD:7.6)%, respectively. The New York Heart Association (NYHA) functional class was III or IV in 1536 (80.7%) patients. Preoperative clinical variables of patients are listed in Table 1.

Baseline echocardiography

Indication for TAVI was severe symptomatic aortic stenosis, with or without concomitant insufficiency, in all patients. In particular, 47 (2.5%) patients suffered from concomitant severe aortic regurgitation. Mean aortic gradient was 50.2 (SD: 15.0) mmHg, and the aortic valve area index was 0.46 (SD: 0.14) cm²/m². Mean left ventricle ejection fraction was 53.5% (SD: 12.4). Detailed echocardiographic data are summarized in Table 2.

Procedural results

The antegrade transapical approach was used in 630 (33.1%) patients. Retrograde access was achieved in the remaining cases: 1252 (65.8%) underwent transfemoral, 18 (1.0%) transaortic and 4 (0.2%) transaxillary TAVI. The Sapien XT valve has been implanted in 1303 (68.4%) patients since mid-2010.

The 23- and 26-mm prostheses were equally used: 902 (47.3%) and 906 (47.6%), respectively. The 29-mm valve was used in 96 (5.1%) patients.

A total of 223 operative complications occurred in 143 (7.5%) patients. A detailed description of intraoperative complications is depicted in Table 3.

Perioperative outcomes

Outcomes according to VARC-2 definitions are summarized in Table 4.

Device success was 88.1%; life-threatening bleeding occurred in 186 (9.8%) patients and major vascular complications happened in 177 (9.3%) patients. Heart rhythm conduction disturbances occurred in 286 (15%) patients, 116 (6.1%) of whom needed a pacemaker (PM) implantation before discharge and 170 (8.9%) of whom had at least one episode of atrial fibrillation.

Acute kidney injury (AKI) occurred in 156 (8.2%) patients, 53 (2.8%) of whom needed dialysis support in the perioperative period. Operative mortality occurred in 137 (7.2%) patients. The 60-day and 90-day mortality rates, using the Kaplan–Meier estimator, were, respectively, 7.1 and 8.1%.

The early safety (at 30 days) composite end-point was reached in 1418 (74.5%) patients.

Echocardiographic outcomes

Peak and mean transvalvular gradients at discharge were 19.9 (SD: 7.8) and 10.8 (SD: 4.5) mmHg (P < 0.001), respectively, and after 1 year were 20.5 (SD: 8.4) and 10.9 (SD: 4.8) mmHg.

More than mild aortic regurgitation was detected in 99 (5.2%) patients, 8 (0.4%) of whom had severe insufficiency. Detailed echocardiographic measurements are summarized in Table 5.

Hospital and intensive care unit stay

After TAVI, 1153 patients (60.6%) were admitted into an intensive care unit: 618 (49.4% of all TF) transfemoral; 519 (82.5%) transapical; 16 (84.2%) transaortic. Average stay was 24 (IQR1 18; IQR3 48) h. The average length of in-hospital stay was 7 (IQR1 5; IQR3 11) days after the procedure.

Follow-up

Median follow-up was 773 days (IQR1 468; IQR3 1126; longest 2319). A total of 10 patients were lost to follow-up.

After hospital discharge, a total of 444/1767 (25.1%) deaths were reported: of these, 168 (37.8%) were classified as cardiac death. Figure 1 shows the Kaplan–Meier curve of all-cause mortality.

Figure 1:

Kaplan–Meier survival curve for all-cause mortality.

Open in new tabDownload slide

Two patients underwent late open-heart surgery for prosthetic failure: (i) aortic valve replacement (AVR) because of endocarditis 108 days after TAVI and (ii) AVR for severe perivalvular leak (PVL) on the 41st postoperative day.

Three other patients underwent transcatheter reintervention on the aortic prosthesis: (i) valve-in-valve for severe intraprosthetic regurgitation 10 months after the index procedure, (ii) valve-in-valve for moderate intraprosthetic regurgitation 7 months after the index procedure and (iii) prosthesis balloon expansion on the 18th postoperative day for severe circumferential periprosthetic regurgitation. All procedures resulted in a good final result. Six late endocarditic events on the implanted prosthesis were treated medically.

Three other patients underwent elective reintervention for mitral valve disease: (i) mitral valve annuloplasty 5 months after TAVI; (ii) mitral valve replacement after 7 months and (iii) Mitraclip (Abbott Vascular, Menlo Park, CA, USA) procedure 8 months after TAVI.

Hospital readmission for heart failure occurred in 252/1767 (14.3%) patients. At the last clinical assessment, 7.9% of patients were in NYHA class higher than II.

Clinical efficacy (after 30 days) composite end-point was observed in 1030 (54.1%) patients. After 1 year, a total of 286/1904 (15.0%) patients died.

Univariable analysis of all-cause mortality

Univariable analysis was performed to assess associations between preoperative risk factors and overall mortality. Patients who died were more frequently female, had lower body mass index, poorer renal function, and worse functional class and more frequently presented a critical preoperative state. In addition, patients who died had a history of diabetes, neurological dysfunction, peripheral vascular disease, previous cardiac surgery, previous coronary artery disease or previous balloon angioplasty. Lastly, also atrial fibrillation and pacemaker rhythm were associated with mortality. Owing to these dissimilarities in comorbidities, logistic EuroSCORE, logistic EuroSCORE II and STS were significantly higher in patients who died (Table 1).

Regarding preoperative echocardiographic parameters, left ventricle ejection fraction, systolic pulmonary artery pressure and mitral regurgitation were statistically different among patients who died or survived (Table 2).

Access and valve size seem also to influence the procedural outcomes (Table 3); in fact, quite often patients who died had a transapical approach.

The influences of procedural complications on mortality are given in Table 4. Device failure, acute myocardial infarction within 72 h, any stroke, life-threatening bleeding, major vascular complication and AKI Grade 2–3 were associated with higher mortality rates. Post-procedural echocardiographic variables are given in Table 5.

Multivariable analysis of all-cause mortality

In the multivariable analysis, the independent preoperative predictors of cumulative all-cause mortality were male gender (HR: 1.395; 95% CI: 1.052–1.849); overweight, BMI 25–30 kg/m² (HR: 0.775; 95% CI: 0.616–0.974); serum creatinine level (every 1 mg/dl increase; HR: 1.314; 95% CI: 1.167–1.480); haemoglobin level (every 1 g/dl increase HR: 0.905; 95% CI: 0.833–0.984); critical preoperative state (HR: 2.282; 95% CI: 1.384–3.761); neurological dysfunction (HR: 1.552; 95% CI: 1.060–2.272); atrial fibrillation (HR: 1.556; 95% CI: 1.213–1.995); pacemaker rhythm (HR: 1.948; 95% CI: 1.310–2.896); NYHA Class III or IV (HR: 1.800; 95% CI: 1.205–2.689 or HR: 2.331; 95% CI: 1.392–3.903, respectively). All data are listed in Table 6.

DISCUSSION

Several single-centre and multicentre studies have already evaluated early, mid-term and long-term outcomes of patients who underwent TAVI [3–9]. These reports are very important not only to understand the clinical outcome of patients who have been treated with TAVI, but also to clarify the behaviour of TAVI at long-term follow-up. This point is crucial to define the real possibility to extend TAVI to younger and intermediate-risk patients. Another important element is the identification of independent preoperative risk factors for poor outcome in this population to perform TAVI only in patients who will likely benefit from it.

The ITER is a voluntarily independent registry reporting the Italian experience of balloon-expandable TAVI. Its independence from industry allows an objective evaluation of ‘real-world’ outcomes excluding potential bias derived from patient selection. Different from many other single- and multicentre experiences, our registry collects data only from patients who received a balloon-expandable Sapien valve prosthesis.

This first ITER report includes the experience of 33 Italian centres that have implanted the Sapien aortic transcatheter prosthesis through 2012.

Table 7 summarizes and compares nine major registries. In our study, mean age, Logistic EuroSCORE, periprocedural complications as at least moderate PVL, life-threatening bleeding, PM implantation and strokes at 30 days were consistent with paravalvular leak results from previously published studies. Also, operative mortality and 1-year mortality rates were comparable. The rate of moderate to severe paravalvular leak was slightly lower than that in other reports. This difference might be explained by the use of only balloon-expandable prostheses in our registry compared to those that collect data about both self-expandable and balloon-expandable prostheses. The same reason could explain the minimal difference in PM implantation rate as well. PM was necessary in 116 patients (6.1%); most studies report a rate of PM implantation that ranges between 5 and 40%, with lower rates among patients who received a balloon-expandable bioprosthesis (5–22%) [14]. Described rates of PM implantation after TAVI with self-expandable prosthesis are higher than those using balloon-expandable valves probably because of the mechanical features of the device. Indeed, the radial force applied on the aortic annulus, adjacent to the conduction system, and the lower extension of the stent inside the left ventricle outflow tract could explain the difference in PM rate.

A similar distribution is described for PVL rates. The literature reports rates that vary between 10 and 40% regardless of prosthesis type [15, 16]. However, most authors report a lower incidence of at least moderate PVL after TAVI using a balloon-expandable bioprosthesis [15]. In our series, the rate of moderate-to-severe PVL was 5.2% (99 patients) at discharge, slightly lower than that reported in the literature. The explanation of this rate could be the exclusive employment of the Sapien prostheses.

Several studies and meta-analyses showed that sex seems to be related to the outcome after TAVI, despite baseline features [17]. Our registry confirmed that female sex has a protective role for all-cause mortality in TAVI patients.

Interestingly, our study supports the ‘obesity paradox’: patients with an increased body mass index have better outcomes, in particular, than those considered overweight (BMI ranging between 25 and 30 kg/m²). This was already demonstrated by several studies in conventional cardiac surgery patients, but only the FRANCE-2 registry supported this conclusion in the TAVI population [18].

Preoperative data analysis showed that chronic kidney disease (CKD) is a predictor of mortality. Several studies have demonstrated the negative impact of survival of CKD on the survival of patients who underwent surgical AVR for aortic disease. CKD is frequent in patients with AS, in particular in elderly high-risk patients screened for transcatheter treatment. Authors reported higher rates of acute kidney disease requiring temporary haemofiltration in patients with CKD [19–21]. Also early and long-term survival of patients undergoing AVR is negatively influenced by CKD. On the other hand, it is widely demonstrated that survival after TAVI is reduced by preoperative impaired renal function and consequent onset of acute kidney disease. Renal impairment is an independent risk factor for worse survival in most studies [19–21]. Nguyen et al. [20] described the association between different degrees of CKD and mortality after TAVI and AVR. They found increasing in-hospital mortality only in the AVR group with mild, moderate and severe renal dysfunction. Also mid-term and long-term mortalities were higher only in AVR patients with CKD. These contradictory findings suggest the need for an accurate preoperative evaluation of other risk factors besides CKD of each patient to identify the surgical strategy between TAVI and AVR.

Previous studies have shown a significant association between preprocedural anaemia and mortality [22]. This study confirms that a low haemoglobin level is significantly related to mortality and suggests that preprocedural haemoglobin levels should be carefully evaluated prior to the procedure.

Cockburn et al. [23] recently reported that poor mobility (defined as severe impairment of mobility secondary to musculoskeletal or neurological dysfunction) predicts adverse outcome better than other frailty indices in patients undergoing TAVI. Also in our study patients with poor mobility or else defined neurological dysfunction suffered a worse outcome.

Heart rhythm conduction disturbances (defined as patient with atrial fibrillation at the time of intervention or previous PM implantation) were also identified as predictors of mortality. They are already considered as risk factors in currently used risk scores, as for example the STS, and they have been just recently associated with the TAVI population [24]. The presence of a PM before the procedure is probably associated with higher mortality because it represents a sign of heart performance deterioration or pre-existing chronic ischaemic heart disease [14]. On the other hand, conduction disturbances such as atrial fibrillation or complete or incomplete bundle blocks should not be underestimated, in particular in patients with severe valve calcifications since there is a high risk of progression towards a complete A/V block [25].

Reported transprosthesis gradients are lower and the incidence of at least moderate PVL is 5.2%. This rate is inferior to that most reported in the literature, which is probably justified by the use of only balloon-expandable prostheses that are usually associated with a lower rate of significant PVL [5, 7, 13]. The analysis of post-procedural PVL is particularly important considering the large number of studies that report this complication as an independent risk factor for early and late death and worse clinical status [4–9].

We reported few cases of endocarditis or valve degeneration needing reoperation within follow-up. However, data reported in the literature are not conclusive about TAVI durability. Longer follow-up on larger series is needed to confirm these findings to extend the indication for TAVI also to younger or intermediate-risk patients and, on the other hand, to avoid futile procedures [26].

LIMITATIONS

Data were self-adjudicated, and there was no external event adjudication. The number of patients operated at each centre was heterogeneous, ranging from 1 to 358. Different physicians using different machines performed echocardiographic examinations. Clinical follow-up was done either by phone or clinical assessment depending on centre policies.

Because of the nature of the registry, several important variables (such as catheterization and CT-scan measurement) were not included, leading to an ‘omitted variable bias’.

Data on quality of life and geriatric assessment were collected only in a few centres.

CONCLUSIONS

According to ITER, the results of a real-world experience with only a balloon-expandable device, TAVI shows good early and mid-term outcomes in terms of survival, technical success, valve-related adverse events and haemodynamic performance. Male gender, preoperative renal function and haemoglobin level, lower BMI, critical preoperative state, neurological dysfunction, NYHA Classes III–IV and heart rhythm disturbances (atrial fibrillation and previously implanted PM) were independently associated with mortality.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

Conflict of interest: Augusto D'Onofrio, Marco Aiello and Davide Gabbieri report consulting fees from Edwards Lifesciences. Mauro Cassese reports consulting fees from Edwards Lifesciences and Medtronic, as well as lecture fees from Medtronic. Mauro Rinaldi reports consulting fees from Edwards Lifesciences and lecture fees from Edwards Lifesciences, Medtronic, and Novartis. Gino Gerosa reports consulting fees from AstraZeneca, lecture fees from HeartWare and St Jude Medical, and grant support from Edwards. Giuseppe Bruschi reports consulting for Medtronic and Direct Flow. Gian Luca Martinelli is a speaker for Edwards. Francesco Bedogni reports consulting for Medtronic, Boston Scientific and St. Jude Medical. Antonio Colombo is a minor shareholder in Direct Flow Medical. Corrado Tamburino receives speaker honorara from Abbott, Medtronic and St Jude Medical. All other authors none declared.

REFERENCES