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Long-Term Outcomes for Patients With Severe Symptomatic Aortic Stenosis Treated With Transcatheter Aortic Valve Implantation
Long-Term Outcomes for Patients With Severe Symptomatic Aortic Stenosis Treated With Transcatheter Aortic Valve Implantation Pablo Codner, MDa,b, Katia Orvin, MDa,b, Abid Assali, MDa,b, Ram Sharony, MDb,c, Hanna Vaknin-Assa, MDa,b, Yaron Shapira, MDa,b, Shmuel Schwartzenberg, MDa,b, Tamir Bental, MDa,b, Alexander Sagie, MDa,b, and Ran Kornowski, MDa,b,* Transcatheter aortic valve implantation (TAVI) is an established technique for the treatment of severe symptomatic aortic stenosis. Data on long-term TAVI outcomes, both hemodynamic and clinical, in real-world practice settings are limited. We aim to explore the long-term clinical results in patients with severe symptomatic aortic stenosis using multiple catheter-based options: 360 TAVI-treated patients were followed up for £5 years. The Medtronic CoreValve was used in 71% and the Edwards SAPIEN in 26%. The primary end point was all-cause mortality during follow-up. Outcomes were assessed based on the Valve Academic Research Consortium 2 criteria. The mean – SD patient age was 82.1 – 6.9 years (56.4% women). The Society of Thoracic Surgeons score was 7.5 – 4.7. The clinical efficacy end point and time-related valve safety at 3 years was 50% and 81.7%, respectively. The calculated 3- and 5-year survival rates were 71.6% and 56.4%, respectively. Five-year follow-up data were obtained for 54 patients alive; 96.2% of alive patients were in the New York Heart Association class I and II, 4 years after TAVI. No gender differences in allcause mortality rates were observed (p [ 0.58). In multivariate analysis, hospitalization 6 months previous to TAVI (hazard ratio [HR] 1.92, 95% confidence interval [CI] 1.17 to 3.15, p [ 0.01), frailty (HR 1.89, 95% CI 1.11 to 3.2, p [ 0.02), acute kidney injury (HR 1.93, 95% CI 1.03 to 3.61, p [ 0.04), and moderate or more paravalvular aortic regurgitation after TAVI (HR 4.26, 95% CI 2.54 to 7.15, p <0.001) were independent predictors for all-cause mortality. In conclusion, long-term outcomes of TAVI are encouraging. Prevention and early identification of paravalvular leak and acute renal failure after the procedure would improve short- and long-term outcomes. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-)
Transcatheter aortic valve implantation (TAVI) is a wellestablished therapeutic option for severe symptomatic aortic stenosis (AS) in patients at high surgical risk and is the treatment of choice in nonsurgical candidates.1e3 In the present study, we report our long-term experience in treating patients with AS using the TAVI technique. Patients were followed for up to 5 years. We also assessed potential differences in outcomes based on gender differences. Methods From November 2008 to March 2015, 1,003 patients with severe symptomatic AS were referred to a dedicated consultation “heart team” forum and clinic in our medical center. This forum includes a multidisciplinary team of clinical cardiologists, cardiac imaging specialists, interventional cardiologists, cardiac surgeons, and geriatricians. To determine the most a
Cardiology Department and cCardiothoracic Surgery Department, Rabin Medical Center, Petah Tikwa, Israel; and b“Sackler” School of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received June 12, 2015; revised manuscript received and accepted August 1, 2015. See page 7 for disclosure information. *Corresponding author: Tel: (þ972) 3-9377108; fax: (þ972) 39249850. E-mail address: [email protected] (R. Kornowski). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.004
appropriate treatment, each patient underwent a rigorous assessment process. Severe AS was defined as a valvular orifice area <1.0 cm2 or <0.6 cm2/m2 and/or mean pressure gradient >40 mm Hg and/or jet velocity >4.0 m/s. Selected patients with discordant echocardiographic findings underwent dobutamine echocardiographic stress test and were classified into 3 groups: (1) low-flow, low-gradient, low left ventricular ejection fraction (LVEF%) severe AS (8%), (2) low-flow, low-gradient, preserved LVEF% severe AS (2.2%), and (3) low-flow, low-gradient, low LVEF% without AS. All patients considered for valve replacement were assessed by coronary angiography, and 88.6% and 45.6% of those selected for TAVI underwent transesophageal echocardiography and gated cardiac computed tomography (CT), respectively, for valve sizing and calcium burden assessment. Vascular access was assessed by multislice CT and peripheral angiography. Both the logistic European System for Cardiac Operative Risk Evaluation score (log-EuroScore) and Society of Thoracic Surgeons (STS) score were calculated. Patients with an estimated life expectancy shorter than 1 year or mental impairment were referred for palliative medical treatment and/or balloon aortic valvuloplasty. Patients who were deemed to be suitable candidates for valve replacement with a low operative risk, defined as a logEuroScore <15% and/or an STS score <8%, without www.ajconline.org
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Table 1 Baseline characteristics of transcatheter aortic valve implantation (TAVI) treated patients (n ¼ 360) Variable Age (years) Female Body mass index (kg/m2) Diabetes mellitus type 2 Hypertension Dyslipidemia * Mean glomerular filtration rate† Glomerular filtration rate <90 ml/min/1.73 m2 60-89 30-59 15-29 <15 Previous stroke or transient ischemic attack Peripheral vascular disease Anemia z Chronic obstructive lung disease “Porcelain” Aorta Pacemaker Atrial fibrillation Previous coronary bypass surgery Previous coronary angioplasty Previous myocardial infarction Society of Thoracic Surgeons score European System for Cardiac Operative Risk Evaluation Score New York Heart Association Functional Class III - IV Hospitalization in previous 6 months to TAVI Peak aortic valve gradient (mmHg) Mean aortic valve gradient (mmHg) Mean Aortic Valve Area (cm2) Coronary and Peripheral Angiography Trans-esophageal Echocardiography Cardiac Computed Tomography Mean Peak to Peak gradient (mmHg) Left Ventricular Dysfunction >Moderate
Value 82.1 6.9 203 (56.4%) 27.8 14.6 122 (34%) 332 (92.2%) 312 (86.7%) 65.6 16.4 299 (83%) 138 (38.3%) 134 (37.2%) 18 (5%) 9 (2.5%) 66 (18.3%) 59 (16.4%) 234 (65%) 76 (21%) 21 (5.8%) 30 (8.3%) 113 (31.4%) 71 (19.7%) 140 (39%) 30 (8.3%) 7.5 4.7 19.5 11.2 343 (95.3%) 198 (55%) 78.5 24.4 49.4 16.8 0.6 0.2 356 (99%) 319 (88.6%) 164 (45.6%) 53 21 29 (9.9%)
Data are presented as mean SD or n (%). * Dyslipidemia was defined as total cholesterol >200 mg/dl, low-density lipoprotein >130 mg/dl, high-density lipoprotein <40 mg/dl, and/or triglycerides >200 mg/dl. † Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. z Anemia was defined as hemoglobin <12 mg/dl for women and <13 mg/dl for men.
contraindications for surgery, were assigned to surgical aortic valve replacement. Patients with a log-EuroScore >15% and an STS score >8% were evaluated individually and referred for TAVI. Starting from 2013, patients >75 years, with STS score from 4% to 8% and multiple co-morbidities and/or frailty, were also considered for TAVI treatment by the heart team. The following parameters are considered to define frailty in our practice: gait speed, ability to perform activities of daily living, albumin levels, need for oxygen replacement therapy, cognitive status, patient’s general appearance, and the impression of the treating clinician. Patients with >6-mm iliac-femoral inner artery diameter were considered for transfemoral procedure. In patients in whom the transfemoral access was inappropriate, the
transaxillar, transapical, transaortic, and or retroperitoneal accesses were chosen according to patients’ characteristics. Our institution used both the Edwards SAPIEN system (Edwards Lifesciences, Irvine, California) and the Medtronic CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) starting from 2008. In 2010, the Edwards SAPIEN XT replaced the Edwards SAPIEN valve. In 2014, the Corevalve Evolut and Corevalve Evolut R (Medtronic), the Lotus Valve System (Boston Scientific Corporation, Marlborough, Massachusetts), and the Edwards SAPIEN 3 (Edwards Lifesciences) were added. The characteristics favoring one device over the other overlapped in most of the cases. However, the presence of electrical conduction abnormalities and transapical approach favored the implantation of an Edwards device, whereas large aortic valve annulus, transaxillar access, and borderline femoral size favored the implantation of a Corevalve device. In our practice, TAVI candidates are hospitalized 36 hours before the planned procedure in the clinical cardiology or the geriatrics departments. During this preprocedure hospitalization, patients underwent a comprehensive social, functional, and cognitive assessment. TAVI procedures were performed in our catheterization suite. Initial balloon valvuloplasty was frequently performed during the first 3 years of our TAVI program and abandoned as a routine practice afterward. At present, this is performed only in selected cases. Rapid right ventricular pacing was performed during deployment of the Edwards SAPIEN valve and only occasionally during Medtronic CoreValve implantation. The TAVI procedure was considered successful if a single implanted valve was in the appropriate location and functioning properly in the absence of any major complications, according to the Valve Academic Research Consortium 2 definition.4 The institutional review board approved this study (i.e., RECORD TAVI Database). The primary end point of the present study was all-cause mortality after TAVI. The secondary end points were death from cardiovascular causes, changes in the New York Heart Association (NYHA) functional class, the immediate and long-term valve gradients performance of the valve, the presence of residual aortic paravalvular leak (PVL), and stroke after the TAVI procedure. We also report the results of an analysis between the outcomes of patients stratified by gender. All patients were prospectively followed up at 30 days, 6 and 12 months, and yearly thereafter, after TAVI. A 100% follow-up rate was achieved during the assigned period. All TAVI-related data were registered in an electronic file and analyzed using the SPSS, version 20.0, software (SPSS, Chicago, Illinois). Data are presented as mean SD for continuous variables. Continuous variables were compared using the Student’s t test, and categorical variables were compared using the chi-square statistics with the Fisher’s exact test, as appropriate. All tests were 2 tailed, and a p value <0.05 was considered significant. All-cause and cardiac mortality were analyzed using the KaplanMeier procedure. Survival analysis stratified by gender comparison was performed using the log-rank test. Univariate and multivariate Cox regression analyses were applied to assess the dependent and independent predictors of all-cause mortality, respectively. The variables included in the present analysis were all clinical, laboratory, and
Valvular Heart Disease/TAVI Long-term Follow-up Table 2 Procedural details and outcomes according to Valve Academic Research Consortium 2 criteria (n ¼ 360) Variable Safety and efficacy end points Death At 30 days From non-cardiac cause From cardiovascular cause At 1 year From non-cardiac cause From cardiovascular cause At 2 years From non-cardiac cause From cardiovascular cause At 3 years From non-cardiac cause From cardiovascular cause At 4 years From non-cardiac cause From cardiovascular cause At 5 years From non-cardiac cause From cardiovascular cause Periprocedural Myocardial Infarction Ischemic Stroke Any at 30 days Major Ischemic Stroke at 30 days Minor Ischemic Stroke at 30 days Life-Threatening Bleeding Major bleeding Minor Bleeding Acute Kidney Injury AKIN Classification Stage I Acute Kidney Injury AKIN Classification Stage II Acute Kidney Injury AKIN Classification Stage III Vascular Complications Any Minor Vascular Complication Major Vascular Complication Prosthetic Valve Performance Aortic Stenosis Mild at 30 days Aortic Stenosis Moderate / Severe at 30 days Aortic Stenosis Mild at 4 years Aortic Stenosis Moderate / Severe at 4 years Prosthetic Valve Associated Complications Conduction Disturbances New onset left bundle branch block Need for pacemaker implantation Coronary Obstruction Clinical benefit end-points Hospitalization for symptoms of cardiac decompensation Therapy-specific endpoints Conversion to open surgery Ventricular perforation with tamponade Post-dilatation balloon valvuloplasty Need for a second valve Valve snaring in Corevalve implantations Composite endpoints Device success (single valve) Device success (including a 2nd valve) Early safety endpoint at 30 days Clinical efficacy endpoint at 3 years Time related valve safety at 3 years Hospital stay (days) Anesthesia type Conscious sedation General anesthesia
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Table 2 (continued) Variable
Value
Value
14 1 13 31 12 19 46 23 23 67 41 26 76 49 27 80 53 27 2
(3.9%) (0.3%) (3.6%) (8.6%) (3.3%) (5.3%) (12.8%) (6.4%) (6.4%) (18.6%) (11.4%) (7.2%) (21.1%) (13.6%) (7.5%) (22.2%) (14.2%) (7.5%) (0.5%)
5 7 16 43 5 11 68 61 7
(1.4%) (1.9%) (4.4%) (11.9%) (1.4%) (3%) (18.9%) (16.9%) (1.9%)
1 0 5 2
(0.3%) (0%) (8.9%) (3.5%)
62 (19.7%) 58 (16.1%) 2 (0.5%) 13 (5.2%) 3 6 65 18 10
(0.8%) (1.7%) (18.1%) (5%) (3.9%)
325 (90.3%) 343 (95.3%) 268 (74.4%) 89 (50%) 85 (81.7%) 5 4.1 282 (78.3%) 78 (21.7)
Implanted valve type Medtronic Corevalve Edwards-Sapien Boston Scientific Lotus Valve Medtronic Corevalve Evolut R Edwards-Sapien 3 Access type Transfemoral Transapical Transaxillary Retroperitoneal Transaortic
256 94 5 2 3
(71%) (26%) (1.4%) (0.5%) (0.8%)
308 31 19 1 1
(86.4%) (8.6%) (5.3%) (0.3%) (0.3%)
Data are presented as mean SD or n (%).
Figure 1. Kaplan-Meier curve of overall survival. At 1, 3, and 5 years, 89.9%, 71.6%, and 56.4% of patients were free from all-cause mortality, respectively.
echocardiographic parameters that can affect the prognosis before and after TAVI. The multivariate analysis was performed using the predictors found to be significant on the univariate analysis. Results From November 2008 to March 2015, 402 patients were treated with the percutaneous implantation of a valve device in our institution; 41 valve-in-valve implantations were performed for the treatment of bioprosthetic valve deterioration and 1 direct implantation in a native mitral valve. The present report focused on the outcomes of the 360 patients assigned to TAVI for the treatment of severe symptomatic AS. The mean follow-up was 681 441 days. Patient characteristics and echocardiographic findings are listed in Table 1.
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Figure 2. Echocardiographic findings. Large box: Maximum (blue) and mean (red) transaortic valve gradients at baseline, 30 days, and at 1, 2, 3, 4, and 5 years after TAVI. Error bars represent 1 SD. Small box: aortic valve area (cm2) at baseline and during the follow-up period after transcutaneous aortic valve implantation.
Table 3 Multivariate Cox regression model analysis Variable
Hospitalization in the 6 months pre-TAVI Frailty Diabetes Mellitus Glomerular Filtration Rate Baseline Hemoglobin Chronic obstructive pulmonary disease Society of Thoracic Surgeons Score LV EF% Acute Kidney Injury Moderate or Severe Aortic Regurgitation post-TAVI
Hazard 95% P value Ratio Confidence Interval 1.92 1.89 1.54 1.00 0.91 1.16 1.01 1.04 1.93 4.26
1.17 1.11 0.93 0.99 0.78 0.68 0.96 0.88 1.03 2.54
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3.15 <0.01 3.20 0.02 2.56 0.10 1.01 0.71 1.07 0.26 2.00 0.58 1.06 0.72 1.23 0.61 3.61 0.04 7.15 <0.001
Procedural details and outcomes are presented in Table 2. Pacemaker implantation after TAVI was required in 58 patients (17.6%) because of high-grade electrical conduction abnormalities: 20% and 4.3% of patients treated with the Medtronic CoreValve and Edwards SAPIEN valve, respectively. Of the 360 patients initially included in our study, 81 died during the 5-year follow-up period. Cardiovascular cause of death, including heart failure and procedure-related events, was noted in 27 patients (33%), the majority of these deaths, 19 (70%) occurred in the first year after the procedure. The calculated 1-, 3- and 5-year survival rates were 89.9%, 71.6%, and 56.4%, respectively. The overall Kaplan-Meier survival curve is depicted in Figure 1. There were no significant differences in all-cause mortality nor in cardiovascular mortality rates between patients in
whom the transfemoral route was used in comparison with those in whom a nonfemoral access was used (20.1% vs 37.2%, p ¼ 0.2, and 30.6% vs 42.1%, p ¼ 0.1, respectively). After TAVI, a prominent decrease in the peak pressure gradient and MPG was noted, and at 30 days after valve deployment (from 78.3 24.2 to 15.4 7.6 mm Hg [p >0.01] and from 49.2 16.7 to 8.4 2.7 mm Hg [p >0.01], respectively), this difference was stable at 5-year follow-up (Figure 2). Moderate and severe PVL was present in 16.4%, 13.4%, and 3.8% of patients at 1-month, 2-year, and 5-year follow-up, respectively. On multivariate analysis, moderate or more paravalvular AR was found to be a strong independent predictor of all-cause mortality (hazard ratio [HR] 4.26, 95% confidence interval [CI] 2.54 to 7.15, p 0.001; Table 3). This finding explains the stepwise decrease in the rates of significant AR over the follow-up period (Figure 3). Mild PVL was not found to be a predictor of all-cause mortality in univariate analysis (HR 1.03, 95% CI 0.64 to 1.63, p ¼ 0.931). After TAVI, the patients reported sustained symptomatic improvement (Figure 4). Gender differences in baseline characteristics: female (203 [56.4%]) in comparison with male patients had a lower prevalence of coronary artery bypass graft surgery (8.9% vs 34%, p 0.001) and a trend toward lower prevalence of diabetes mellitus (29% vs 40.1%, p ¼ 0.07) without statistically significant differences in the prevalence of peripheral vascular disease, chronic obstructive pulmonary disease, hypertension, previous cerebrovascular accident, and other co-morbidities. The mean age, mean STS score, mean glomerular filtration rate, and mean hemoglobin were similar between the 2 genders (82.4 5.8
Valvular Heart Disease/TAVI Long-term Follow-up
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Figure 3. Rates and severity of paravalvular aortic regurgitation after transcutaneous aortic valve implantation.
vs 81.1 6.7 years, p ¼ 0.9, 7.5 4.5 vs 7.2 4.9, p ¼ 0.72, 67.1 26.7 vs 63.7 25.8 ml/min, p ¼ 0.09, and 11.6 1.4 vs 12 1.6 g/dl, p ¼ 0.4, for women and men, respectively). No significant differences in all-cause mortality rates were observed in female compared with male patients (p ¼ 0.58; Figure 5) and gender was not found as a dependent predictor of mortality in univariate analysis (HR 1.004, 95% CI 0.96 to 1.04, p ¼ 0.84). On univariate analysis, the parameters associated with increased all-cause mortality were baseline NYHA functional class (HR 1.54, 95% CI 1.02 to 2.34, p ¼ 0.04), hospitalization in the 6 months before the TAVI procedure (HR 1.91, 95% CI 1.20 to 3.04, p ¼ 0.006), frailty (HR 2.7, 95% CI 1.76 to 4.41, p 0.01), chronic obstructive pulmonary disease (HR 1.67, 95% CI 1.05 to 2.65, p ¼ 0.029), Log-Euroscore and STS score (HR 1.02, 95% CI 1.00 to 1.04, p ¼ 0.014, and HR 1.04, 95% CI 1.00 to 1.09, p ¼ 0.018, respectively), acute kidney injury (HR 2.9, 95% CI 1.77 to 4.9, p 0.001), and moderate or more AR or PVL after TAVI (HR 3.4, 95% CI 2.19 to 5.54, p <0.001). Age, gender, body mass index, atrial fibrillation, diabetes mellitus, baseline aortic valve area, device type, anesthesia type, need for a second valve device, and need for inhospital pacemaker implantation after TAVI were not found to be predictors for all-cause mortality. On multivariate analysis, hospitalization in the 6 months before the procedure, frailty, acute kidney injury, and moderate or severe aortic regurgitation after TAVI
persisted as independent predictors for all-cause mortality (Table 3). Discussion Our cohort of patients has been followed prospectively over the years. The long-term follow-up results of our all-comers patients with severe symptomatic patients with AS treated with TAVI, using different devices, accesses, and anesthesia techniques demonstrated low rates of overall mortality. Most of the long-term deaths were unrelated to cardiac causes and most survivor patients were in NYHA class I or II. No clinically significant variation in transaortic valve pressure gradients during the 5-year follow-up period was present. This finding reflects bioprosthetic valve integrity and hemodynamic preservation over the years. Independent predictors of mortality were hospitalization in the 6 months before the TAVI procedure, moderate or more AR/PVL, frailty, and acute kidney injury after valve implantation. Data on long-term TAVI outcomes, both hemodynamic and clinical, in real-world practice settings are limited. Mack et al5 recently published the 5-year outcomes of patients included in the cohort B of the Partner trial. In this randomized control trial, all-cause mortality at 1 and 5 years was 24.2% and 62.4%, respectively. It should be noted that patients included in the Partner trial were extremely ill (mean STS score 12%) and were treated with first-generation Edwards devices and that this trial was the first TAVI
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Figure 4. NYHA functional status. Before TAVI, 57% of patients were in NYHA class III (yellow) and 35% were in NYHA class IV (red). During follow-up, the vast majority of patients were in NYHA class I (blue) and II (green).
Figure 5. Kaplan-Meier curves of overall survival after TAVI stratified by gender.
experience of most sites in the United States, which might account for the more adverse outcomes than expected in contemporary patients with TAVI.5,6
Two similar, albeit smaller single-center TAVI experiences were published. In the Vancouver report, patients were treated exclusively using Edwards devices (56% Cribier-Edwards), and all-cause mortality rate at 5 years was 65%.7 Bouleti et al8 reported the long-term outcomes of 122 patients with TAVI (90% implanted with an Edwards device), and similar to our findings, most late follow-up deaths were not cardiovascular related. We attribute our relatively low mortality rates to a rigorous patient selection process, comprehensive pre-TAVI assessment, meticulously planned procedures performed only by highly experienced operators, and individualized post-TAVI follow-up visit program. From analysis of the pretreatment baseline characteristics, we found previous hospitalizations and frailty to be independent predictors for long-term mortality. These 2 predictors are related to one another and highlight the importance of early recognition and referral of severe symptomatic patients with AS to a dedicated heart valve center.9e11 We found that a preprocedure hospitalization of TAVI candidates in a clinical geriatrics department contributed to accurately determining the functional and cognitive status, frailty index, and special needs of patients with TAVI.12 After implantation, moderate and/or severe AR/PVL was a strong predictor of short- and long-term mortality in our TAVI-treated patients (HR 3.4, 95% CI 2.19 to 5.54, p <0.001). This correlates with the previously published data.2,13,14 The treatment of post-TAVI PVL begins with its
Valvular Heart Disease/TAVI Long-term Follow-up
prevention, and accurate device sizing guided by gated cardiac CT and 3-dimensional echocardiography has been shown to correlate with lower rates of paravalvular AR.15,16 After dilation balloon valvuloplasty has the potential to reduce leakage after valve deployment.17 Finally, novel second-generation TAVI devices have been specially designed to reduce PVL after TAVI; the Edwards SAPIEN 3 valve device possess an outer skirt to improve valve sealing and apposition.18 The Corevalve Evolut R and the Lotus Valve System have repositionable features, which contribute to optimize valve positioning and, therefore, to reduce paravalvular AR.19,20 Acute kidney injury is a known predictor of poor prognosis after TAVI, and the results of our analysis are in accordance with previous reported experiences.21 Patients at risk for this complication should be identified in the pretreatment period and adequately hydrated and carefully managed before and during the procedure. The use of contrast agents and hemodynamic abrupt changes (e.g., rapid pacing) during the implantation should be minimized. Acute kidney injury should be promptly diagnosed and treated, nephrotoxic drugs should be stopped, and patients whom will benefit from renal replacement therapy should be identified.22 The usefulness of renal protection devices (e.g., Renal guard; RenalGuard Solutions, Inc., Milford, Massachusetts) is currently at most uncertain.23 Female gender has been found to be a positive predictor for survival in some TAVI cohorts and neutral in others.24,25 In our experience, the female and male groups were very well balanced for most demographic and baseline clinical parameters. No differences in all-cause mortality were found between the groups, and gender was not a dependent predictor for mortality in univariate analysis. Currently, the role of gender in the risk stratification process of TAVI candidates is unknown. Structural valve deterioration was an odd phenomenon in our cohort.26 Nonclinically significant variation in valve area or in the transvalvular gradients was observed 5 years after TAVI. This finding is in accordance with previous studies.27 Longer follow-up periods of larger cohorts of patients are required to establish the incidence and timing of valve deterioration after TAVI, before this therapeutic technique could be recommended to younger patients at lower surgical risk. Limitations The present study is a single-center investigation, and clinical and echocardiographic outcomes were self-reported with inherent limitations and potential bias. However, data were prospectively collected in a dedicated database, outcomes were rigorously assessed and reported based on the Valve Academic Research Consortium 2 criteria definitions, and data completeness was adequate and carefully validated, although not adjudicated by an independent clinical research organization. Data on patients’ diuresis during postprocedure hospitalization are lacking; therefore, an underestimation of acute kidney injury after TAVI rates might be present. Patient frailty was not assessed strictly based on a pre-established definition and included patient appearance and clinical status, although objective parameters were used, that is,
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assessment of activities of daily living, albumin level, and gait speed.
Disclosures The authors have no conflicts of interest to disclose. 1. Reardon MJ, Adams DH, Coselli JS, Deeb GM, Kleiman NS, Chetcuti S, Yakubov SJ, Heimansohn D, Hermiller J Jr, Hughes GC, Harrison JK, Khabbaz K, Tadros P, Zorn GL III, Merhi W, Heiser J, Petrossian G, Robinson N, Maini B, Mumtaz M, Lee JS, Gleason TG, Resar J, Conte J, Watson D, Chenoweth S, Popma JJ; CoreValve US Clinical Investigators. Self-expanding transcatheter aortic valve replacement using alternative access sites in symptomatic patients with severe aortic stenosis deemed extreme risk of surgery. J Thorac Cardiovasc Surg 2014;148:2869e2876. 2. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB; PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686e1695. 3. Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS, Thourani VH, Babaliaros VC, Webb JG, Herrmann HC, Bavaria JE, Kodali S, Brown DL, Bowers B, Dewey TM, Svensson LG, Tuzcu M, Moses JW, Williams MR, Siegel RJ, Akin JJ, Anderson WN, Pocock S, Smith CR, Leon MB; PARTNER Trial Investigators. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366:1696e1704. 4. Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, RodésCabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Valve Academic Research Consortium-2. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg 2013;145:6e23. 5. Mack MJ, Leon MB, Smith CR, Miller DC, Moses JW, Tuzcu EM, Webb JG, Douglas PS, Anderson WN, Blackstone EH, Kodali SK, Makkar RR, Fontana GP, Kapadia S, Bavaria J, Hahn RT, Thourani VH, Babaliaros V, Pichard A, Herrmann HC, Brown DL, Williams M, Davidson MJ, Svensson LG, PARTNER 1 trial investigatorsAkin J. 5year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477e2484. 6. Kapadia SR, Leon MB, Makkar RR, Tuzcu EM, Svensson LG, Kodali S, Webb JG, Mack MJ, Douglas PS, Thourani VH, Babaliaros VC, Herrmann HC, Szeto WY, Pichard AD, Williams MR, Fontana GP, Miller DC, Anderson WN, Smith CR, PARTNER Trial InvestigatorsAkin JJ, Davidson MJ. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2485e2491. 7. Toggweiler S, Humphries KH, Lee M, Binder RK, Moss RR, Freeman M, Ye J, Cheung A, Wood DA, Webb JG. 5-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61: 413e419. 8. Bouleti C, Himbert D, Iung B, Alos B, Kerneis C, Ghodbane W, Messika-Zeitoun D, Brochet E, Fassa AA, Depoix JP, Ou P, Nataf P, Vahanian A. Long-term outcome after transcatheter aortic valve implantation. Heart 2015;101:936e942. 9. Forman JM, Currie LM, Lauck SB, Baumbusch J. Exploring changes in functional status while waiting for transcatheter aortic valve implantation. Eur J Cardiovasc Nurs 2014 pii: 1474515114553907. 10. Puls M, Sobisiak B, Bleckmann A, Jacobshagen C, Danner BC, Hünlich M, Beißbarth T, Schöndube F, Hasenfuß G, Seipelt R, Schillinger W. Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living. EuroIntervention 2014;10: 609e619.
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11. Green P, Woglom AE, Genereux P, Daneault B, Paradis JM, Schnell S, Hawkey M, Maurer MS, Kirtane AJ, Kodali S, Moses JW, Leon MB, Smith CR, Williams M. The impact of frailty status on survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-center experience. JACC Cardiovasc Interv 2012;5: 974e981. 12. Orvin K, Dvir D, Weiss A, Assali A, Vaknin-Assa H, Shapira Y, Gazit O, Sagie A, Kornowski R. Comprehensive prospective cognitive and physical function assessment in elderly patients undergoing transcatheter aortic valve implantation. Cardiology 2014;127:227e235. 13. Gotzmann M, Korten M, Bojara W, Lindstaedt M, Rahlmann P, Mügge A, Ewers A. Long-term outcome of patients with moderate and severe prosthetic aortic valve regurgitation after transcatheter aortic valve implantation. Am J Cardiol 2012;110:1e7. 14. Athappan G, Patvardhan E, Tuzcu EM, Svensson LG, Lemos PA, Fraccaro C, Tarantini G, Sinning JM, Nickenig G, Capodanno D, Tamburino C, Latib A, Colombo A, Kapadia SR. Incidence, predictors and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. J Am Coll Cardiol 2013;61:1585e1595. 15. Jilaihawi H, Kashif M, Fontana G, Furugen A, Shiota T, Friede G, Makhija R, Doctor N, Leon MB, Makkar RR. Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation. J Am Coll Cardiol 2012;59:1275e1286. 16. Jilaihawi H, Doctor N, Kashif M, Chakravarty T, Rafique A, Makar M, Furugen A, Nakamura M, Mirocha J, Gheorghiu M, Stegic J, Okuyama K, Sullivan DJ, Siegel R, Min JK, Gurudevan SV, Fontana GP, Cheng W, Friede G, Shiota T, Makkar RR. Aortic annular sizing for transcatheter aortic valve replacement using cross-sectional 3-dimensional transesophageal echocardiography. J Am Coll Cardiol 2013;61:908e916. 17. Schultz C, Rossi A, van Mieghem N, van der Boon R, Papadopoulou SL, van Domburg R, Moelker A, Mollet N, Krestin G, van Geuns RJ, Nieman K, de Feyter P, Serruys PW, de Jaegere P. Aortic annulus dimensions and leaflet calcification from contrast MSCT predict the need for balloon post-dilatation after TAVI with the Medtronic CoreValve prosthesis. EuroIntervention 2011;7:564e572. 18. Murray MI, Geis N, Pleger ST, Kallenbach K, Katus HA, Bekeredjian R, Chorianopoulos E. First experience with the new generation Edwards Sapien 3 aortic bioprosthesis: procedural results and short term outcome. J Interv Cardiol 2015;28:109e116. 19. Piazza N, Martucci G, Lachapelle K, de Varennes B, Bilodeau L, Buithieu J, Mylotte D. First-in-human experience with the Medtronic CoreValve Evolut R. EuroIntervention 2014;9:1260e1263.
20. McCormick LM, Gooley R, Lockwood S, Meredith IT. First reported use of the repositionable lotus valve system for a failing surgical aortic bioprosthesis. JACC Cardiovasc Interv 2015;8:e19ee20. 21. Bagur R, Webb JG, Nietlispach F, Dumont E, De Larochelliere R, Doyle D, Masson JB, Gutierrez MJ, Clavel MA, Bertr OF, Pibarot P, Rodes-Cabau J. Acute kidney injury following transcatheter aortic valve implantation: predictive factors, prognostic value, and comparison with surgical aortic valve replacement. Eur Heart J 2010;31: 865e874. 22. Gargiulo G, Sannino A, Capodanno D, Perrino C, Capranzano P, Barbanti M, Stabile E, Trimarco B, Tamburino C, Esposito G. 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;86:518e527. 23. Arbel Y, Ben-Assa E, Halkin A, Keren G, Schwartz AL, Havakuk O, Leshem-Rubinow E, Konigstein M, Steinvil A, Abramowitz Y, Finkelstein A, Banai S. Forced diuresis with matched hydration in reducing acute kidney injury during transcatheter aortic valve implantation (Reduce-AKI): study protocol for a randomized shamcontrolled trial. Trials 2014;15:262. 24. Hayashida K, Morice MC, Chevalier B, Hovasse T, Romano M, Garot P, Farge A, Donzeau-Gouge P, Bouvier E, Cormier B, Lefèvre T. Sexrelated differences in clinical presentation and outcome of transcatheter aortic valve implantation for severe aortic stenosis. J Am Coll Cardiol 2012;59:566e571. 25. Conrotto F, D’Ascenzo F, Salizzoni S, Presbitero P, Agostoni P, Tamburino C, Tarantini G, Bedogni F, Nijhoff F, Gasparetto V, Napodano M, Ferrante G, Rossi ML, Stella P, Brambilla N, Barbanti M, Giordana F, Grasso C, Biondi Zoccai G, Moretti C, D’Amico M, Rinaldi M, Gaita F, Marra S. A gender based analysis of predictors of all cause death after transcatheter aortic valve implantation. Am J Cardiol 2014;114:1269e1274. 26. Kornowski R, Codner P, Vaknin-Assa H, Assali A. Self-expandable valve implantation within a failed balloon-expandable valve. EuroIntervention 2014;10:1001. 27. Rodés-Cabau J, Webb JG, Cheung A, Ye J, Dumont E, Osten M, Feindel CM, Natarajan MK, Velianou JL, Martucci G, DeVarennes B, Chisholm R, Peterson M, Thompson CR, Wood D, Toggweiler S, Gurvitch R, Lichtenstein SV, Doyle D, DeLarochellière R, Teoh K, Chu V, Bainey K, Lachapelle K, Cheema A, Latter D, Dumesnil JG, Pibarot P, Horlick E. Long-term outcomes after transcatheter aortic valve implantation: insights on prognostic factors and valve durability from the Canadian multicenter experience. J Am Coll Cardiol 2012;60: 1864e1875.
Transcatheter aortic valve implantation (TAVI) is a wellestablished therapeutic option for severe symptomatic aortic stenosis (AS) in patients at high surgical risk and is the treatment of choice in nonsurgical candidates.1e3 In the present study, we report our long-term experience in treating patients with AS using the TAVI technique. Patients were followed for up to 5 years. We also assessed potential differences in outcomes based on gender differences. Methods From November 2008 to March 2015, 1,003 patients with severe symptomatic AS were referred to a dedicated consultation “heart team” forum and clinic in our medical center. This forum includes a multidisciplinary team of clinical cardiologists, cardiac imaging specialists, interventional cardiologists, cardiac surgeons, and geriatricians. To determine the most a
Cardiology Department and cCardiothoracic Surgery Department, Rabin Medical Center, Petah Tikwa, Israel; and b“Sackler” School of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received June 12, 2015; revised manuscript received and accepted August 1, 2015. See page 7 for disclosure information. *Corresponding author: Tel: (þ972) 3-9377108; fax: (þ972) 39249850. E-mail address: [email protected] (R. Kornowski). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.004
appropriate treatment, each patient underwent a rigorous assessment process. Severe AS was defined as a valvular orifice area <1.0 cm2 or <0.6 cm2/m2 and/or mean pressure gradient >40 mm Hg and/or jet velocity >4.0 m/s. Selected patients with discordant echocardiographic findings underwent dobutamine echocardiographic stress test and were classified into 3 groups: (1) low-flow, low-gradient, low left ventricular ejection fraction (LVEF%) severe AS (8%), (2) low-flow, low-gradient, preserved LVEF% severe AS (2.2%), and (3) low-flow, low-gradient, low LVEF% without AS. All patients considered for valve replacement were assessed by coronary angiography, and 88.6% and 45.6% of those selected for TAVI underwent transesophageal echocardiography and gated cardiac computed tomography (CT), respectively, for valve sizing and calcium burden assessment. Vascular access was assessed by multislice CT and peripheral angiography. Both the logistic European System for Cardiac Operative Risk Evaluation score (log-EuroScore) and Society of Thoracic Surgeons (STS) score were calculated. Patients with an estimated life expectancy shorter than 1 year or mental impairment were referred for palliative medical treatment and/or balloon aortic valvuloplasty. Patients who were deemed to be suitable candidates for valve replacement with a low operative risk, defined as a logEuroScore <15% and/or an STS score <8%, without www.ajconline.org
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Table 1 Baseline characteristics of transcatheter aortic valve implantation (TAVI) treated patients (n ¼ 360) Variable Age (years) Female Body mass index (kg/m2) Diabetes mellitus type 2 Hypertension Dyslipidemia * Mean glomerular filtration rate† Glomerular filtration rate <90 ml/min/1.73 m2 60-89 30-59 15-29 <15 Previous stroke or transient ischemic attack Peripheral vascular disease Anemia z Chronic obstructive lung disease “Porcelain” Aorta Pacemaker Atrial fibrillation Previous coronary bypass surgery Previous coronary angioplasty Previous myocardial infarction Society of Thoracic Surgeons score European System for Cardiac Operative Risk Evaluation Score New York Heart Association Functional Class III - IV Hospitalization in previous 6 months to TAVI Peak aortic valve gradient (mmHg) Mean aortic valve gradient (mmHg) Mean Aortic Valve Area (cm2) Coronary and Peripheral Angiography Trans-esophageal Echocardiography Cardiac Computed Tomography Mean Peak to Peak gradient (mmHg) Left Ventricular Dysfunction >Moderate
Value 82.1 6.9 203 (56.4%) 27.8 14.6 122 (34%) 332 (92.2%) 312 (86.7%) 65.6 16.4 299 (83%) 138 (38.3%) 134 (37.2%) 18 (5%) 9 (2.5%) 66 (18.3%) 59 (16.4%) 234 (65%) 76 (21%) 21 (5.8%) 30 (8.3%) 113 (31.4%) 71 (19.7%) 140 (39%) 30 (8.3%) 7.5 4.7 19.5 11.2 343 (95.3%) 198 (55%) 78.5 24.4 49.4 16.8 0.6 0.2 356 (99%) 319 (88.6%) 164 (45.6%) 53 21 29 (9.9%)
Data are presented as mean SD or n (%). * Dyslipidemia was defined as total cholesterol >200 mg/dl, low-density lipoprotein >130 mg/dl, high-density lipoprotein <40 mg/dl, and/or triglycerides >200 mg/dl. † Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. z Anemia was defined as hemoglobin <12 mg/dl for women and <13 mg/dl for men.
contraindications for surgery, were assigned to surgical aortic valve replacement. Patients with a log-EuroScore >15% and an STS score >8% were evaluated individually and referred for TAVI. Starting from 2013, patients >75 years, with STS score from 4% to 8% and multiple co-morbidities and/or frailty, were also considered for TAVI treatment by the heart team. The following parameters are considered to define frailty in our practice: gait speed, ability to perform activities of daily living, albumin levels, need for oxygen replacement therapy, cognitive status, patient’s general appearance, and the impression of the treating clinician. Patients with >6-mm iliac-femoral inner artery diameter were considered for transfemoral procedure. In patients in whom the transfemoral access was inappropriate, the
transaxillar, transapical, transaortic, and or retroperitoneal accesses were chosen according to patients’ characteristics. Our institution used both the Edwards SAPIEN system (Edwards Lifesciences, Irvine, California) and the Medtronic CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) starting from 2008. In 2010, the Edwards SAPIEN XT replaced the Edwards SAPIEN valve. In 2014, the Corevalve Evolut and Corevalve Evolut R (Medtronic), the Lotus Valve System (Boston Scientific Corporation, Marlborough, Massachusetts), and the Edwards SAPIEN 3 (Edwards Lifesciences) were added. The characteristics favoring one device over the other overlapped in most of the cases. However, the presence of electrical conduction abnormalities and transapical approach favored the implantation of an Edwards device, whereas large aortic valve annulus, transaxillar access, and borderline femoral size favored the implantation of a Corevalve device. In our practice, TAVI candidates are hospitalized 36 hours before the planned procedure in the clinical cardiology or the geriatrics departments. During this preprocedure hospitalization, patients underwent a comprehensive social, functional, and cognitive assessment. TAVI procedures were performed in our catheterization suite. Initial balloon valvuloplasty was frequently performed during the first 3 years of our TAVI program and abandoned as a routine practice afterward. At present, this is performed only in selected cases. Rapid right ventricular pacing was performed during deployment of the Edwards SAPIEN valve and only occasionally during Medtronic CoreValve implantation. The TAVI procedure was considered successful if a single implanted valve was in the appropriate location and functioning properly in the absence of any major complications, according to the Valve Academic Research Consortium 2 definition.4 The institutional review board approved this study (i.e., RECORD TAVI Database). The primary end point of the present study was all-cause mortality after TAVI. The secondary end points were death from cardiovascular causes, changes in the New York Heart Association (NYHA) functional class, the immediate and long-term valve gradients performance of the valve, the presence of residual aortic paravalvular leak (PVL), and stroke after the TAVI procedure. We also report the results of an analysis between the outcomes of patients stratified by gender. All patients were prospectively followed up at 30 days, 6 and 12 months, and yearly thereafter, after TAVI. A 100% follow-up rate was achieved during the assigned period. All TAVI-related data were registered in an electronic file and analyzed using the SPSS, version 20.0, software (SPSS, Chicago, Illinois). Data are presented as mean SD for continuous variables. Continuous variables were compared using the Student’s t test, and categorical variables were compared using the chi-square statistics with the Fisher’s exact test, as appropriate. All tests were 2 tailed, and a p value <0.05 was considered significant. All-cause and cardiac mortality were analyzed using the KaplanMeier procedure. Survival analysis stratified by gender comparison was performed using the log-rank test. Univariate and multivariate Cox regression analyses were applied to assess the dependent and independent predictors of all-cause mortality, respectively. The variables included in the present analysis were all clinical, laboratory, and
Valvular Heart Disease/TAVI Long-term Follow-up Table 2 Procedural details and outcomes according to Valve Academic Research Consortium 2 criteria (n ¼ 360) Variable Safety and efficacy end points Death At 30 days From non-cardiac cause From cardiovascular cause At 1 year From non-cardiac cause From cardiovascular cause At 2 years From non-cardiac cause From cardiovascular cause At 3 years From non-cardiac cause From cardiovascular cause At 4 years From non-cardiac cause From cardiovascular cause At 5 years From non-cardiac cause From cardiovascular cause Periprocedural Myocardial Infarction Ischemic Stroke Any at 30 days Major Ischemic Stroke at 30 days Minor Ischemic Stroke at 30 days Life-Threatening Bleeding Major bleeding Minor Bleeding Acute Kidney Injury AKIN Classification Stage I Acute Kidney Injury AKIN Classification Stage II Acute Kidney Injury AKIN Classification Stage III Vascular Complications Any Minor Vascular Complication Major Vascular Complication Prosthetic Valve Performance Aortic Stenosis Mild at 30 days Aortic Stenosis Moderate / Severe at 30 days Aortic Stenosis Mild at 4 years Aortic Stenosis Moderate / Severe at 4 years Prosthetic Valve Associated Complications Conduction Disturbances New onset left bundle branch block Need for pacemaker implantation Coronary Obstruction Clinical benefit end-points Hospitalization for symptoms of cardiac decompensation Therapy-specific endpoints Conversion to open surgery Ventricular perforation with tamponade Post-dilatation balloon valvuloplasty Need for a second valve Valve snaring in Corevalve implantations Composite endpoints Device success (single valve) Device success (including a 2nd valve) Early safety endpoint at 30 days Clinical efficacy endpoint at 3 years Time related valve safety at 3 years Hospital stay (days) Anesthesia type Conscious sedation General anesthesia
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Table 2 (continued) Variable
Value
Value
14 1 13 31 12 19 46 23 23 67 41 26 76 49 27 80 53 27 2
(3.9%) (0.3%) (3.6%) (8.6%) (3.3%) (5.3%) (12.8%) (6.4%) (6.4%) (18.6%) (11.4%) (7.2%) (21.1%) (13.6%) (7.5%) (22.2%) (14.2%) (7.5%) (0.5%)
5 7 16 43 5 11 68 61 7
(1.4%) (1.9%) (4.4%) (11.9%) (1.4%) (3%) (18.9%) (16.9%) (1.9%)
1 0 5 2
(0.3%) (0%) (8.9%) (3.5%)
62 (19.7%) 58 (16.1%) 2 (0.5%) 13 (5.2%) 3 6 65 18 10
(0.8%) (1.7%) (18.1%) (5%) (3.9%)
325 (90.3%) 343 (95.3%) 268 (74.4%) 89 (50%) 85 (81.7%) 5 4.1 282 (78.3%) 78 (21.7)
Implanted valve type Medtronic Corevalve Edwards-Sapien Boston Scientific Lotus Valve Medtronic Corevalve Evolut R Edwards-Sapien 3 Access type Transfemoral Transapical Transaxillary Retroperitoneal Transaortic
256 94 5 2 3
(71%) (26%) (1.4%) (0.5%) (0.8%)
308 31 19 1 1
(86.4%) (8.6%) (5.3%) (0.3%) (0.3%)
Data are presented as mean SD or n (%).
Figure 1. Kaplan-Meier curve of overall survival. At 1, 3, and 5 years, 89.9%, 71.6%, and 56.4% of patients were free from all-cause mortality, respectively.
echocardiographic parameters that can affect the prognosis before and after TAVI. The multivariate analysis was performed using the predictors found to be significant on the univariate analysis. Results From November 2008 to March 2015, 402 patients were treated with the percutaneous implantation of a valve device in our institution; 41 valve-in-valve implantations were performed for the treatment of bioprosthetic valve deterioration and 1 direct implantation in a native mitral valve. The present report focused on the outcomes of the 360 patients assigned to TAVI for the treatment of severe symptomatic AS. The mean follow-up was 681 441 days. Patient characteristics and echocardiographic findings are listed in Table 1.
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Figure 2. Echocardiographic findings. Large box: Maximum (blue) and mean (red) transaortic valve gradients at baseline, 30 days, and at 1, 2, 3, 4, and 5 years after TAVI. Error bars represent 1 SD. Small box: aortic valve area (cm2) at baseline and during the follow-up period after transcutaneous aortic valve implantation.
Table 3 Multivariate Cox regression model analysis Variable
Hospitalization in the 6 months pre-TAVI Frailty Diabetes Mellitus Glomerular Filtration Rate Baseline Hemoglobin Chronic obstructive pulmonary disease Society of Thoracic Surgeons Score LV EF% Acute Kidney Injury Moderate or Severe Aortic Regurgitation post-TAVI
Hazard 95% P value Ratio Confidence Interval 1.92 1.89 1.54 1.00 0.91 1.16 1.01 1.04 1.93 4.26
1.17 1.11 0.93 0.99 0.78 0.68 0.96 0.88 1.03 2.54
-
3.15 <0.01 3.20 0.02 2.56 0.10 1.01 0.71 1.07 0.26 2.00 0.58 1.06 0.72 1.23 0.61 3.61 0.04 7.15 <0.001
Procedural details and outcomes are presented in Table 2. Pacemaker implantation after TAVI was required in 58 patients (17.6%) because of high-grade electrical conduction abnormalities: 20% and 4.3% of patients treated with the Medtronic CoreValve and Edwards SAPIEN valve, respectively. Of the 360 patients initially included in our study, 81 died during the 5-year follow-up period. Cardiovascular cause of death, including heart failure and procedure-related events, was noted in 27 patients (33%), the majority of these deaths, 19 (70%) occurred in the first year after the procedure. The calculated 1-, 3- and 5-year survival rates were 89.9%, 71.6%, and 56.4%, respectively. The overall Kaplan-Meier survival curve is depicted in Figure 1. There were no significant differences in all-cause mortality nor in cardiovascular mortality rates between patients in
whom the transfemoral route was used in comparison with those in whom a nonfemoral access was used (20.1% vs 37.2%, p ¼ 0.2, and 30.6% vs 42.1%, p ¼ 0.1, respectively). After TAVI, a prominent decrease in the peak pressure gradient and MPG was noted, and at 30 days after valve deployment (from 78.3 24.2 to 15.4 7.6 mm Hg [p >0.01] and from 49.2 16.7 to 8.4 2.7 mm Hg [p >0.01], respectively), this difference was stable at 5-year follow-up (Figure 2). Moderate and severe PVL was present in 16.4%, 13.4%, and 3.8% of patients at 1-month, 2-year, and 5-year follow-up, respectively. On multivariate analysis, moderate or more paravalvular AR was found to be a strong independent predictor of all-cause mortality (hazard ratio [HR] 4.26, 95% confidence interval [CI] 2.54 to 7.15, p 0.001; Table 3). This finding explains the stepwise decrease in the rates of significant AR over the follow-up period (Figure 3). Mild PVL was not found to be a predictor of all-cause mortality in univariate analysis (HR 1.03, 95% CI 0.64 to 1.63, p ¼ 0.931). After TAVI, the patients reported sustained symptomatic improvement (Figure 4). Gender differences in baseline characteristics: female (203 [56.4%]) in comparison with male patients had a lower prevalence of coronary artery bypass graft surgery (8.9% vs 34%, p 0.001) and a trend toward lower prevalence of diabetes mellitus (29% vs 40.1%, p ¼ 0.07) without statistically significant differences in the prevalence of peripheral vascular disease, chronic obstructive pulmonary disease, hypertension, previous cerebrovascular accident, and other co-morbidities. The mean age, mean STS score, mean glomerular filtration rate, and mean hemoglobin were similar between the 2 genders (82.4 5.8
Valvular Heart Disease/TAVI Long-term Follow-up
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Figure 3. Rates and severity of paravalvular aortic regurgitation after transcutaneous aortic valve implantation.
vs 81.1 6.7 years, p ¼ 0.9, 7.5 4.5 vs 7.2 4.9, p ¼ 0.72, 67.1 26.7 vs 63.7 25.8 ml/min, p ¼ 0.09, and 11.6 1.4 vs 12 1.6 g/dl, p ¼ 0.4, for women and men, respectively). No significant differences in all-cause mortality rates were observed in female compared with male patients (p ¼ 0.58; Figure 5) and gender was not found as a dependent predictor of mortality in univariate analysis (HR 1.004, 95% CI 0.96 to 1.04, p ¼ 0.84). On univariate analysis, the parameters associated with increased all-cause mortality were baseline NYHA functional class (HR 1.54, 95% CI 1.02 to 2.34, p ¼ 0.04), hospitalization in the 6 months before the TAVI procedure (HR 1.91, 95% CI 1.20 to 3.04, p ¼ 0.006), frailty (HR 2.7, 95% CI 1.76 to 4.41, p 0.01), chronic obstructive pulmonary disease (HR 1.67, 95% CI 1.05 to 2.65, p ¼ 0.029), Log-Euroscore and STS score (HR 1.02, 95% CI 1.00 to 1.04, p ¼ 0.014, and HR 1.04, 95% CI 1.00 to 1.09, p ¼ 0.018, respectively), acute kidney injury (HR 2.9, 95% CI 1.77 to 4.9, p 0.001), and moderate or more AR or PVL after TAVI (HR 3.4, 95% CI 2.19 to 5.54, p <0.001). Age, gender, body mass index, atrial fibrillation, diabetes mellitus, baseline aortic valve area, device type, anesthesia type, need for a second valve device, and need for inhospital pacemaker implantation after TAVI were not found to be predictors for all-cause mortality. On multivariate analysis, hospitalization in the 6 months before the procedure, frailty, acute kidney injury, and moderate or severe aortic regurgitation after TAVI
persisted as independent predictors for all-cause mortality (Table 3). Discussion Our cohort of patients has been followed prospectively over the years. The long-term follow-up results of our all-comers patients with severe symptomatic patients with AS treated with TAVI, using different devices, accesses, and anesthesia techniques demonstrated low rates of overall mortality. Most of the long-term deaths were unrelated to cardiac causes and most survivor patients were in NYHA class I or II. No clinically significant variation in transaortic valve pressure gradients during the 5-year follow-up period was present. This finding reflects bioprosthetic valve integrity and hemodynamic preservation over the years. Independent predictors of mortality were hospitalization in the 6 months before the TAVI procedure, moderate or more AR/PVL, frailty, and acute kidney injury after valve implantation. Data on long-term TAVI outcomes, both hemodynamic and clinical, in real-world practice settings are limited. Mack et al5 recently published the 5-year outcomes of patients included in the cohort B of the Partner trial. In this randomized control trial, all-cause mortality at 1 and 5 years was 24.2% and 62.4%, respectively. It should be noted that patients included in the Partner trial were extremely ill (mean STS score 12%) and were treated with first-generation Edwards devices and that this trial was the first TAVI
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Figure 4. NYHA functional status. Before TAVI, 57% of patients were in NYHA class III (yellow) and 35% were in NYHA class IV (red). During follow-up, the vast majority of patients were in NYHA class I (blue) and II (green).
Figure 5. Kaplan-Meier curves of overall survival after TAVI stratified by gender.
experience of most sites in the United States, which might account for the more adverse outcomes than expected in contemporary patients with TAVI.5,6
Two similar, albeit smaller single-center TAVI experiences were published. In the Vancouver report, patients were treated exclusively using Edwards devices (56% Cribier-Edwards), and all-cause mortality rate at 5 years was 65%.7 Bouleti et al8 reported the long-term outcomes of 122 patients with TAVI (90% implanted with an Edwards device), and similar to our findings, most late follow-up deaths were not cardiovascular related. We attribute our relatively low mortality rates to a rigorous patient selection process, comprehensive pre-TAVI assessment, meticulously planned procedures performed only by highly experienced operators, and individualized post-TAVI follow-up visit program. From analysis of the pretreatment baseline characteristics, we found previous hospitalizations and frailty to be independent predictors for long-term mortality. These 2 predictors are related to one another and highlight the importance of early recognition and referral of severe symptomatic patients with AS to a dedicated heart valve center.9e11 We found that a preprocedure hospitalization of TAVI candidates in a clinical geriatrics department contributed to accurately determining the functional and cognitive status, frailty index, and special needs of patients with TAVI.12 After implantation, moderate and/or severe AR/PVL was a strong predictor of short- and long-term mortality in our TAVI-treated patients (HR 3.4, 95% CI 2.19 to 5.54, p <0.001). This correlates with the previously published data.2,13,14 The treatment of post-TAVI PVL begins with its
Valvular Heart Disease/TAVI Long-term Follow-up
prevention, and accurate device sizing guided by gated cardiac CT and 3-dimensional echocardiography has been shown to correlate with lower rates of paravalvular AR.15,16 After dilation balloon valvuloplasty has the potential to reduce leakage after valve deployment.17 Finally, novel second-generation TAVI devices have been specially designed to reduce PVL after TAVI; the Edwards SAPIEN 3 valve device possess an outer skirt to improve valve sealing and apposition.18 The Corevalve Evolut R and the Lotus Valve System have repositionable features, which contribute to optimize valve positioning and, therefore, to reduce paravalvular AR.19,20 Acute kidney injury is a known predictor of poor prognosis after TAVI, and the results of our analysis are in accordance with previous reported experiences.21 Patients at risk for this complication should be identified in the pretreatment period and adequately hydrated and carefully managed before and during the procedure. The use of contrast agents and hemodynamic abrupt changes (e.g., rapid pacing) during the implantation should be minimized. Acute kidney injury should be promptly diagnosed and treated, nephrotoxic drugs should be stopped, and patients whom will benefit from renal replacement therapy should be identified.22 The usefulness of renal protection devices (e.g., Renal guard; RenalGuard Solutions, Inc., Milford, Massachusetts) is currently at most uncertain.23 Female gender has been found to be a positive predictor for survival in some TAVI cohorts and neutral in others.24,25 In our experience, the female and male groups were very well balanced for most demographic and baseline clinical parameters. No differences in all-cause mortality were found between the groups, and gender was not a dependent predictor for mortality in univariate analysis. Currently, the role of gender in the risk stratification process of TAVI candidates is unknown. Structural valve deterioration was an odd phenomenon in our cohort.26 Nonclinically significant variation in valve area or in the transvalvular gradients was observed 5 years after TAVI. This finding is in accordance with previous studies.27 Longer follow-up periods of larger cohorts of patients are required to establish the incidence and timing of valve deterioration after TAVI, before this therapeutic technique could be recommended to younger patients at lower surgical risk. Limitations The present study is a single-center investigation, and clinical and echocardiographic outcomes were self-reported with inherent limitations and potential bias. However, data were prospectively collected in a dedicated database, outcomes were rigorously assessed and reported based on the Valve Academic Research Consortium 2 criteria definitions, and data completeness was adequate and carefully validated, although not adjudicated by an independent clinical research organization. Data on patients’ diuresis during postprocedure hospitalization are lacking; therefore, an underestimation of acute kidney injury after TAVI rates might be present. Patient frailty was not assessed strictly based on a pre-established definition and included patient appearance and clinical status, although objective parameters were used, that is,
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assessment of activities of daily living, albumin level, and gait speed.
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