Author + information
- Received August 21, 2018
- Revision received September 13, 2018
- Accepted September 14, 2018
- Published online December 3, 2018.
- Lars Søndergaard, MDa,∗ (, )@uni_copenhagen@Rigshospitalet,
- Josep Rodés-Cabau, MDb,
- Axel Hans-Peter Linke, MDc,
- Stephan Fichtlscherer, MDd,
- Ulrich Schäfer, MDe,
- Karl-Heinz Kuck, MDf,
- Joerg Kempfert, MDg,
- Dabit Arzamendi, MDh,
- Francesco Bedogni, MDi,
- Federico M. Asch, MDj,
- Stephen Worthley, MDk and
- Francesco Maisano, MDl
- aDepartment of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- bQuebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- cTechnical University Dresden, Heart Center Dresden, Dresden, Germany
- dKlinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany
- eUKE Hamburg (Universitatsklinik Eppendorf), Hamburg, Germany
- fAsklepios Klinik St. Georg, Lohmuehlenstrasse, Hamburg, Germany
- gDeutsches Herzzentrum Berlin, Berlin, Germany
- hHospital de la Santa Creu I Sant Pau, Sant Antoni Maria Claret, Barcelona, Spain
- iIRCCS Policlinico San Donato, Piazza E. Malan, San Donato Milanese, Italy
- jCardiovascular Core Laboratories, MedStar Health Research Institute at Washington Hospital Center, Washington, DC
- kRoyal Adelaide Hospital, Adelaide, South Australia, Australia
- lClinic for Heart and Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
- ↵∗Address for correspondence:
Dr. Lars Søndergaard, Department of Cardiology, Rigshospitalet, Rigshospitalet–University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Background The new self-expanding, repositionable transcatheter heart valve (THV) system was designed for treatment of severe, symptomatic aortic stenosis in patients with high surgical risk.
Objectives The purpose of this study was to report 1-year outcomes of transcatheter aortic valve replacement with the new THV system.
Methods This ongoing, international, multicenter study evaluated patients with severe, symptomatic aortic stenosis implanted with the THV via transfemoral access and follow-up at 30 days, 1 year, and annually through 5 years. The primary endpoint is all-cause mortality at 1 year; secondary endpoints include clinical outcomes and echocardiographic measurements, both adjudicated.
Results A total of 941 patients (82.4 ± 5.9 years; 65.7% female; Society of Thoracic Surgeons Predicted Risk of Operative Mortality score: 5.8%) were enrolled and underwent an implant at 61 sites in Europe, Australia, and Canada. At 1 year, Kaplan-Meier estimates for all-cause mortality, cardiovascular mortality, disabling stroke rates, and myocardial infarction were 12.1%, 6.6%, 2.2%, and 2.5%, respectively. Mean aortic transvalvular gradient and aortic valve area were 8.66 mm Hg and 1.75 cm2, respectively. Paravalvular leakage was moderate or higher in 2.6% of patients with no severe leakage. New pacemaker rates were 18.7% and 21.3% for pacemaker naïve patients at 30 days and 1 year, respectively. Functional class, exercise capacity, and quality of life improved significantly from baseline to 1 year.
Conclusions Transcatheter aortic valve replacement with the new THV in patients who are at increased surgical risk is associated with low 1-year mortality and stroke rates. Favorable hemodynamic results at 1 year are observed with low transvalvular pressure gradient and incidence of significant paravalvular leakage. (5 Year Observation of Patients With PORTICO Valves [PORTICO-I]; NCT01802788)
Safety and efficacy outcomes of transcatheter aortic valve replacement (TAVR) using the new self-expanding, repositionable transcatheter heart valve (THV) system (Figure 1) for treatment of severe, symptomatic aortic stenosis (AS) have been reported from relatively small studies and over limited follow-up periods (1–3). The PORTICO I study was initiated to collect comprehensive long-term, real-world experience from implanters’ early commercial experience with this device. This ongoing multicenter study enrolled a large population of patients at increased risk of surgical mortality and will follow this cohort for ≤5 years after valve implantation. Favorable 30-day safety and efficacy outcomes of this cohort have been reported (4). This paper reports on the primary study endpoint of 1-year all-cause mortality, provides 1-year secondary endpoint results on safety events and valve hemodynamic performance, and characterizes the clinical benefit of receiving a new THV system.
The prospective, single-arm, nonrandomized, multicenter PORTICO I study was conducted to assess acute and long-term clinical outcomes of the new self-expanding, repositionable Portico THV system (Abbott, Chicago, Illinois) for the treatment of severe, symptomatic AS. The design of the study and procedural aspects have been described in detail elsewhere (4). In brief, the study included patients with symptomatic, severe AS that were evaluated by the heart team and deemed to have high surgical risk according to the Society of Thoracic Surgeons Predicted Risk of Operative Mortality (STS) score, logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE), or other individual risk factors, such as frailty and comorbidities not captured by the risk scores. All patients underwent transfemoral TAVR using the THV system (5). The appropriate valve size was selected from the 4 available sizes (23, 25, 27, and 29 mm) covering an aortic annulus diameter between 19 and 27 mm based on pre-procedural multislice computed tomography (CT). It was recommended to perform balloon pre-dilatation, after which the valve could be deployed without rapid pacing. The valve could be resheathed and repositioned if indicated. Post-dilatation under rapid pacing was allowed to improve sealing and full device expansion if deemed necessary by the operator.
Post-procedural antithrombotic protocol was at the physician’s discretion. Follow-ups are scheduled at 30 days, 1 year, and annually through 5 years post-implant. This paper reports the primary and secondary outcomes of PORTICO I patients through 1 year.
The study was conducted in compliance with the Declaration of Helsinki and was approved by ethics committees and local authorities. All patients provided written informed consent prior to participation. This study was sponsored by Abbott (formerly St. Jude Medical).
The primary endpoint of the study was all-cause mortality at 1 year. Secondary clinical endpoints assessed at 1 year included cardiovascular mortality, myocardial infarction (MI), stroke, THV function, functional classification, 6-min walk test, and quality-of-life assessment. An independent clinical events committee adjudicated all safety endpoints according to Valve Academic Research Consortium-2 consensus (6). Valve hemodynamics were assessed by transthoracic echocardiography at baseline and at subsequent follow-ups. The 30-day and 1-year results were evaluated by an independent core laboratory (MedStar Health Research Institute, Washington, DC).
Continuous variables were summarized by mean ± SD or median (interquartile range). Categorical variables were summarized using frequencies and percentages. Paired Student’s t-tests (e.g., echocardiographic data, 6-min walk test, and so on) and the Wilcoxon sign rank test (e.g., New York Heart Association [NYHA] functional class) were used to compare outcomes at follow-up relative to baseline. Time to event variables were analyzed using the Kaplan-Meier method and Cox proportional hazard model. The 1-year Kaplan-Meier survival analyses used 365 days as a strict cut-off. For example, the patients who had a 1-year follow-up visit conducted on or before 365 days are not considered at risk at 1 year.
A 30-day landmark analysis for selected safety outcomes was performed by calculating Kaplan-Meier estimates over the period from day 31 to 1-year post-TAVR, excluding patients who experienced the safety event within the first 30 days.
Cox proportional hazard regression modeling was used to identify variables associated with 1-year mortality. Baseline, procedural, and limited event variables were included. Variables with univariate p values <0.20 were subsequently included in multivariable analysis. Statistical significance was indicated by a p value <0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
TAVR was attempted in 941 patients (age at implant: 82.4 ± 5.9 years; 65.7% women; STS score: 5.8 ± 4.8%). Approximately one-third of patients (33.7%) also had 2 frailty indexes. Demographics and baseline characteristics are presented in Table 1. Procedural data are summarized in Table 2. The 30-day outcomes of this cohort have been previously reported in detail (4) and are therefore only briefly summarized as follows. A single self-expanding, repositionable THV was successfully implanted in 903 of 941 patients (96.0%), while 2 valves were implanted in 19 patients (2.0%). In the remaining 19 patients (2.0%) no heart valve was implanted due to implantation of another commercial TAVR device (n = 12; 1.3%), conversion to surgery (n = 4; 0.4%) and procedural death (n = 3; 0.3%). The reasons for implanting another commercial valve include: a second THV was required to reduce paravalvular leakage (PVL), unstable or migrated self-expanding repositionable THV, Portico malpositioned, and annulus size not suitable for the patient. The 19 patients in whom a THV was attempted but not implanted were monitored for adverse events through 30 days post-TAVR and were then withdrawn. In the PORTICO I study, there was no screening committee. The selection of the patients and the annulus sizing was left to the standard of care at each institution. All sites were trained on the PORTICO I inclusion and exclusion criteria, and adherence to the criteria was monitored. The 30-day and 1-year assessments were completed for 828 and 717 patients, respectively, representing follow-up visits on more that 92% of active patients at each visit (Figure 2). At 1 year, there were 585 patients with echocardiographic assessments deemed suitable for evaluation by the core laboratory.
Adverse events rates at 30 days and at 1 year after TAVR are shown in Table 3. Kaplan-Meier event rates for all-cause mortality and cardiovascular death at 30 days were 2.7% (95% confidence interval [CI]: 1.8% to 3.9%) and 2.5% (95% CI: 1.6% to 3.7%), respectively. At 1 year, these were 12.1% (95% CI: 10.1% to 14.4%) and 6.6% (95% CI: 5.1% to 8.4%), respectively (Central Illustration, A).
Table 4 shows a 30-day landmark analysis conducted to further examine the safety rates solely after the periprocedural period (i.e., from 31 to 365 days). For this latter period, the Kaplan-Meier event rates were 9.7% (95% CI: 7.9% to 11.8%) and 4.2% (95% CI: 3.0% to 5.8%) for all-cause and cardiovascular mortality, respectively.
In total, 108 deaths were reported during the first year (cutoff at 365 days) after TAVR, of which, 58 were classified as cardiovascular deaths. The most common cause of cardiovascular deaths within the first 30 days were procedural complications. After 30 days, the most common causes of cardiovascular death were sudden cardiac death SCD (n = 12) and heart failure (n = 10) (Table 5).
Within the first year after TAVR disabling strokes occurred in 20 patients, resulting in a Kaplan-Meier 1-year estimate of 2.2% (95% CI: 1.4% to 3.4%). Through 1 year, 22 patients experienced an MI, resulting in a Kaplan-Meier estimate of 2.5% (95% CI: 1.7% to 3.8%). Most cases of disabling stroke or MI occurred within the first month after the index procedure, in 15 patients for each event.
Minor increases in other events rates (e.g., acute kidney injury, bleeding, new-onset AF, and pacemaker implantation) occurred between 30 days and 1 year. Among patients with no pacemaker at baseline, a pacemaker was implanted in 18.7% (n = 161) at 30 days, and in 21.3% (n = 178) at 1 year after TAVR.
Table 4 further shows the risk for a disabling stroke rate of 0.6%, an acute MI rate of 0.9%, and pacemaker implantation rate of 2.8% in the period after 30 days up to 1 year.
Five patients needed reintervention due to worsening of PVL severity. All of these had been prepared with a pre-balloon aortic valvuloplasty during their initial implant. One patient had the self-expanding, repositionable THV system replaced with a surgically implanted valve at 29 days post-implant; a valve-in-valve procedure was performed in 3 patients (at 15, 83, and 256 days post-procedure); and 1 patient (in whom post-dilatation was not performed during implant) required a post-balloon aortic valvuloplasty 160 days later. All treatments were successful.
After implant, there have been no reports of infective endocarditis, coronary occlusion, valve thrombosis, or structural valve failure that needed intervention through 1 year.
Predictors of all-cause mortality
Multivariate analysis identified pre-existing kidney disease, heart failure, history of MI, mitral regurgitation, NYHA functional class IV, and length of hospitalization after the index procedure as independent predictors of 1-year mortality (Online Table 1). Implantation of a pacemaker within 30 days post-TAVR had no effect on 1-year all-cause mortality (p = 0.30) (Figure 3). Moderate or higher PVL at discharge is not associated with a higher mortality risk at 1 year (p = 0.69).
Echocardiographic assessments of valve hemodynamics are summarized in Figure 4 (valve area, mean transvalvular gradient, unpaired data) and Figure 5 (PVL, unpaired data). Hemodynamic outcomes for patients with data available at all data points through 1 year are reported in the paired analysis (Central Illustration, B and C). In the paired analysis, TAVR was associated with a significant increase in valve area at 30 days over baseline (0.72 ± 0.37 cm2 to 1.79 ± 0.48 cm2; p < 0.0001), which remained stable through 1 year (1.74 ± 0.49 cm2; p = 0.058) (Central Illustration, B). Similarly, the mean aortic transvalvular gradient significantly decreased from 49.73 ± 15.80 mm Hg at baseline to 8.60 ± 3.80 mm Hg at 30 days (p < 0.0001) and remained stable through 1 year (8.75 ± 4.22 mm Hg; p = 0.325). Moderate or higher PVL was present in 2.6% of the patients at 1-year post-TAVR, with no severe PVL (Central Illustration, C). The paired PVL analysis (n = 524) (Table 6) shows that the majority of patients with mild PVL at 30 days remained mild at 1 year (287 of 358; 80.2%); 64 (17.9%) improved from mild to none/trace, and 7 (1.9%) patients changed from mild to moderate between 30 days and 1 year.
Compared with baseline, the study cohort showed an overall improvement in NYHA functional class at 30 days post-TAVR. The improvement was sustained through the 1-year assessment (Figure 6). The signed-rank test (p value <0.0001) showed a significant improvement in NYHA functional class at 1 year compared with baseline in the paired NYHA analysis (Central Illustration, D). Compared with baseline, the 6-min walk test improved significantly at 1 year (250.3 ± 117.0 m vs. 285.9 ± 112.2 m; p < 0.0001). Similar improvements were also seen in Euro Quality of Life-Visual Analogue Scale at 1 year (62.2 vs. 69.0; p < 0.0001; paired data).
With 941 attempted patients, the present study comprises the largest 1-year multicenter dataset from a cohort implanted with the self-expanding, repositionable THV. Overall, the study outcomes confirm the high safety, hemodynamic performance, and clinical improvement provided by the THV system at 1 year. Specifically, there has been a low mortality and disabling stroke rate given the higher-risk patients enrolled, low and stable transvalvular pressure gradients, and low rate of more than mild significant PVL through 1 year.
Procedural mortality (0.3%), and 30-day rates of all-cause mortality (2.7%) and disabling stroke (1.6%) were relatively low and similar to outcomes reported from other TAVR cohorts implanted with the self-expanding, repositionable valve (1,2) or other contemporary transcatheter aortic valves (7–10).
In this study, TAVR with the self-expanding, repositionable valve was associated with low 1-year all-cause and cardiovascular mortality rates of 12.1% and 6.6%, respectively. These rates compare well with those reported from smaller series with the self-expanding, repositionable valve (1,3) and larger studies with the CoreValve (Medtronic, Dublin, Ireland) and Sapien 3 (Edwards Lifesciences, Irvine, California) THV systems in comparable cohorts (7,10–12).
Only a few additional safety events occurred between 30 days and 1 year post-TAVR, as demonstrated in the landmark analysis set at 30 days. In this analysis, the probability for all-cause mortality between 30 days and 1 year is 9.7%, for cardiovascular death 4.2%, for disabling stroke 0.6%, for AMI 0.9%, and for new pacemaker implant 2.8%. With events occurring in only 5 patients after the 30-day post-procedural period, a relatively low rate (2.2%) of disabling stroke at 1 year was achieved. Stroke rates were similar to outcomes reported from the SURTAVI (SUrgical Replacement and Transcatheter Aortic Valve Implantation) (7), SOURCE 3 (Sapien Aortic Bioprosthesis European Outcome) Registry (13), and SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral access) Registry (14) studies, with similar overall risk scores. After the post-procedural period, 9.7% of the patients died, mainly SCD and deaths due to heart failure. While the univariate analysis identified multiple predictors of mortality at 1 year, the multivariate analysis confirmed 6 independent predictors: 5 were baseline risk factors common in the high surgical-risk population, and the sixth was a longer hospitalization period following the index procedure. Many of these associations are consistent with those reported from other studies (13).
TAVR with self-expanding, repositionable THV system was associated with functional improvement at 30 days, with 87% of the patients in NYHA functional class I/II versus 36% at baseline. This improvement was sustained through 1 year.
At 1 year post-TAVR, 19.5% of the population, regardless of pacemaker at baseline, received a new pacemaker, the vast majority of these being implanted by 30 days. This rate is higher than reported previously from other studies with the Portico THV (1,3) and is similar to the 1-year new pacemaker implant of 19.7% for Evolut R (Medtronic, Dublin, Ireland) in 1,040 patients with median STS score of 5.5% (10). The new pacemaker implantation at 1 year post-TAVR was 21.3% among the Portico-I patients without a pacemaker at baseline. This study previously confirmed that pre-existing conduction disturbances at baseline, RBBB, and AV block I/II and QRS >120 ms are significant predictors for pacemaker implantation post-implant (4). A new pacemaker implant within 30 days had no effect on mortality at 1 year.
Significantly improved hemodynamic performance, as reported from this cohort at 30 days (4) was sustained through 1 year after TAVR. In particular, the valve achieved low transvalvular pressure gradients, and the degree of PVL remained stable from 30 days to 1 year post-TAVR, with no severe PVL at either assessment. The PVL status of 458 of the 524 (87.4%) patients with paired echocardiography data remained the same or improved between 30 days and 1 year. As suggested by other authors (11,15), improving PVL outcomes over time suggest remodeling of the interface between the aortic annulus and the self-expanding valve. These outcomes compare well with those from other balloon-expandable and self-expanding valves (7,12,15). Aspects that may have promoted these favorable outcomes include accurate sizing using multislice CT; the resheathing and repositioning capability of the self-expanding, repositionable THV system; and that pre-dilatation was performed in the majority of the procedures. Pre-dilatation is commonly used and is not associated with further complications (13), but facilitates gradual and uniform valve deployment during implantation. While pre-dilatation has been suggested to affect the risk of early stroke (16), the frequent use of pre-dilatation in the present study does not allow testing of this relationship, because the self-expanding, repositionable THV achieved a relatively low rate of disabling stroke, both at 30 days and at 1 year post-TAVR. Finally, there was no evidence of moderate PVL impacting 1-year mortality in this cohort, although the low rate of clinically significant PVL in the present study did not allow to be fully evaluate this.
The predictor analysis showed that pre-existing comorbidities were the primary drivers for 1-year mortality. As expected, patients who are sicker at baseline have a higher risk of dying within 1 year. Interestingly, the only procedure-related factor reaching a level of significance after the multivariate analysis was the days from implant to discharge.
This study was conducted as a real-world post-approval study, involving a nonrandomized and possibly biased selection of patients to be treated with the self-expanding, repositionable TAVR system. Initial enrollment was relatively slow, due to only small valve sizes being commercially available. Data was obtained from centers with variable experience and patient load, providing a cross-section of centers performing TAVR and included the initial learning curve in most institutions.
The self-expanding, repositionable THV system is safe and significantly improves hemodynamic performance in patients experiencing severe, symptomatic AS. At 1 year after implant, relatively low mortality and stroke rates were observed, with single-digit transvalvular gradients and a low degree of greater than mild PVL. Clinical benefit is also demonstrated through an observed improvement in functional class, exercise capacity, and quality of life.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Deployment of a commercially available, resheathable THV device is associated with low 1-year mortality and stroke rates, low transvalvular pressure gradients, and low rates of paravalvular regurgitation in patients with severe aortic stenosis at increased surgical risk.
TRANSLATIONAL OUTLOOK: Data from randomized trials are needed to compare the safety and efficacy of various types of transcatheter valve prostheses and guide device selection based on individual patient characteristics.
The authors thank Mr. Bert Albers for assisting with the initial draft of this manuscript, and Qian Ren, PhD, Elizabeth Obinger, and Dmitry Rozhetskin for conducting all statistical analysis associated with this paper.
This study was funded by Abbott. Dr. Søndergaard has received consultant fees and an institutional research grant from Abbott (formerly St. Jude Medical). Dr. Rodés-Cabau has received institutional research grants from Abbott. Dr. Linke has received speaker honoraria as a consultant for and grant support from Abbott. Drs. Fichtlscherer, Schäfer, and Maisano have served as proctors for and have received travel/speaker’s honoraria and grant support from Abbott Vascular. Dr. Kuck has received research grants and is a consultant for Abbott; and has served as a consultant for Medtronic, Boston Scientific, Biosense Webster, and Edwards. Drs. Kempfert and Arzamendi have served as proctors for Abbott. Dr. Bedogni has served as a proctor and consultant for Abbott. Dr. Asch, as Director of MedStar Health, has received institutional contracts from Abbott, Edwards, Medtronic, Boston Scientific, JenaValve, Livanova, and Biotronik. Dr. Worthley has received research grants from Abbott and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute kidney injury
- aortic stenosis
- New York Heart Association
- paravalvular leakage
- transcatheter aortic valve replacement
- transcatheter heart valve
- Received August 21, 2018.
- Revision received September 13, 2018.
- Accepted September 14, 2018.
- 2018 American College of Cardiology Foundation
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