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Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients
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Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients Jeremy Y. Levett , Sarah B. Windle MPH , Kristian B. Filion PhD , Vanessa C. Brunetti MSc , Mark J. Eisenberg MD MPH PII: DOI: Reference:
S0002-9149(20)30058-8 https://doi.org/10.1016/j.amjcard.2020.01.017 AJC 24398
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
16 October 2019 14 January 2020 17 January 2020
Please cite this article as: Jeremy Y. Levett , Sarah B. Windle MPH , Kristian B. Filion PhD , Vanessa C. Brunetti MSc , Mark J. Eisenberg MD MPH , Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients, The American Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.amjcard.2020.01.017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
HIGHLIGHTS
TAVI was associated with a reduction in all-cause mortality at 30 days versus SAVR
TAVI patients had increased risk of pacemaker implantation at 30 days and 12 months
Results were inconclusive at 30 days and 12 months for major cardiovascular events
TAVI may be appropriate first-line therapy for aortic stenosis in low risk patients
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Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients Short Title: TAVI in Low Surgical Risk Patients Jeremy Y. Levetta,b, Sarah B. Windle MPHa, Kristian B. Filion PhDa,b,c, Vanessa C. Brunetti MSca,c, Mark J. Eisenberg MD MPHa,b,c,d a
Division of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital/McGill University, Montreal, QC b Department of Medicine, McGill University, Montreal, QC c Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC d Division of Cardiology, Jewish General Hospital/McGill University, Montreal, QC Word count – Introduction to Disclosures: 2,496
Corresponding Author: Mark J. Eisenberg, MD MPH Professor of Medicine Divisions of Cardiology and Clinical Epidemiology Jewish General Hospital/McGill University 3755 Côte Ste-Catherine Road, Suite H-421.1 Montreal, Quebec, Canada H3T 1E2 Telephone: (514) 340-8222 Ext.23564 Fax: (514) 340-7564 E-Mail: [email protected]
Mr. Levett is supported by a Mach-Gaensslen Foundation of Canada Student Grant, funded through the McGill University Faculty of Medicine Research Bursary Program. Dr. Filion is supported by a Junior 2 Research Scholar award from the Fonds de recherche du Québec – Santé and a William Dawson Scholar award from McGill University. Ms. Brunetti is supported by a doctoral bursary from the Fonds de recherche du Québec – Santé and the David G. Guthrie award from the Faculty of Medicine of McGill University. Conflicts of interest: none
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ABSTRACT Current guidelines recommend transcatheter aortic valve implantation (TAVI) for patients with severe aortic stenosis at elevated surgical risk, but not for patients at low surgical risk. Our objective is to compare major clinical outcomes and procedural complications with TAVI versus surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis at low surgical risk. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), identified through a systematic search of the PubMed, Embase, and Cochrane databases. Count data were pooled across trials using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). Three RCTs (n=2,629) were included. At 30 days, TAVI was associated with a substantial reduction in all-cause mortality (RR: 0.27, 95% CI: 0.17-0.41), atrial fibrillation (RR: 0.45, 95% CI: 0.20-0.99), life threatening/disabling bleeding (RR: 0.29, 95% CI: 0.12-0.69), and acute kidney injury (RR: 0.28, 95% CI: 0.14-0.57). The reduction in atrial fibrillation persisted at 12 months (RR: 0.32, 95% CI: 0.21-0.49). However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days (RR: 3.13, 95% CI: 1.36-7.21) and 12 months (RR: 2.99, 95% CI: 1.19-7.51). Due to the low absolute numbers of events, results were inconclusive at 30 days and 12 months for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction. In conclusion, while some outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients.
Keywords: aortic stenosis, transcatheter aortic valve implantation, surgical aortic valve replacement, low surgical risk, meta-analysis
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INTRODUCTION The 2017 American College of Cardiology and American Heart Association (ACC/AHA) guidelines recommend the use of transcatheter aortic valve implantation (TAVI) for the treatment of severe symptomatic aortic stenosis in patients with prohibitive (strength of recommendation: Class I), high (Class I), and intermediate (Class IIa) surgical risk.1 Until recently, little was known concerning TAVI outcomes in individuals at low surgical risk, who constitute the majority of patients with severe aortic stenosis. The ACC/AHA guidelines currently recommend SAVR as a Class I treatment for low-risk patients, without making mention of TAVI.1,2 Two large randomized controlled trials (RCTs) have now provided data on TAVI versus SAVR in low surgical risk patients.3,4 Because the absolute number of clinical events in each trial remains small, we conducted a systematic review and meta-analysis to compare major clinical outcomes and procedural complications for TAVI versus SAVR in patients at low surgical risk. METHODS Our systematic review and meta-analysis was conducted using a pre-specified protocol, with reporting as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.5 We performed a systematic search of PubMed, Embase (via Ovid), and the Cochrane Library’s Central Register of Controlled Trials from inception through May 28, 2019. No restrictions were placed on language of publication. Keywords (title/abstract) searched were TAVI, TAVI, transcatheter aortic valve implant*, or transcatheter aortic valve implantation. The Cochrane Collaboration’s search hedges were used to restrict results to RCTs in PubMed and Embase6. The complete search strategies can be found in Supplemental Information A.
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Following the removal of duplicate citations, 2 independent reviewers screened the titles and abstracts of the database search results using pre-specified inclusion criteria. Any article considered potentially relevant by either reviewer was retrieved and similarly screened in duplicate for inclusion, with disagreements resolved by consensus or a third reviewer. Included articles were RCTs published in English or French which compared TAVI to SAVR in patients with severe aortic stenosis. Studies had to self-identify as including at least 75% low surgical risk patients to be considered eligible, and report at least one of the major clinical outcomes of interest (see below) at 30 days or 12 months post-procedure. Observational studies were excluded to reduce potential bias. Abstracts, editorials, conference proceedings, and clinical trial registrations without results were also excluded, as were studies which performed TAVI via the transapical access route. All data were abstracted independently by 2 reviewers, including study and baseline characteristics. Major clinical outcomes (30 days and 12 months) abstracted were all-cause mortality, cardiovascular mortality, all stroke, transient ischemic attack, atrial fibrillation, myocardial infarction, and rehospitalization for heart failure. Procedural complications abstracted were life threatening or disabling bleeding, major vascular complications, acute kidney injury (stage II or III), permanent pacemaker implantation, coronary artery obstruction, endocarditis, valve thrombosis, and aortic reintervention. Characteristics of valve function abstracted were aortic valve gradient post-procedure and effective aortic orifice area. Change in quality of life measures abstracted were the New York Heart Association (NYHA) classification and the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Our statistical analysis protocol specified that we would abstract data from the intention-to-treat analyses. However, if intention-to-treat data were not available, as-treated data were abstracted.
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The risk of bias for all included RCTs was assessed in duplicate using the Cochrane Collaboration’s tool for assessing risk of bias in randomised trials (RoB 2).7 All eligible RCTs were included regardless of quality. Count data for clinical endpoints were pooled across RCTs using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). The amount of heterogeneity that was present was estimated using the I2 statistic. Analyses were performed using Stata version 15.8 RESULTS Our systematic search retrieved 4,370 citations, of which 3,142 remained after removing duplicates (Figure 1). Three RCTs3,4,9 met our inclusion criteria (n=2,629) and were sufficiently homogenous to be included in our meta-analysis (Table 1). Evolut Low Risk (n=1,403) and PARTNER 3 (n=950) restricted inclusion to patients with low surgical risk. The NOTION trial (n=276) included “all-comers”, with 82% defined as low risk. Valve generations and types used in TAVI varied between trials. All trials were multicenter and enrolled participants exclusively in high income countries (baseline demographic and clinical characteristics of randomized participants are described in Table 2). Patient characteristics were well-balanced between the 2 treatment arms within each RCT. The overall quality of included studies was high, as there was a low risk of bias in all domains (Supplemental Information B). Only as-treated count data were available for 2 of the 3 included trials, therefore as-treated data were abstracted from all trials to allow pooling of comparable data. All 3 trials reported clinical outcomes at 30 days and 12 months (Table 3). At 30 days (Figure 2), TAVI reduced all-cause mortality compared to SAVR (RR: 0.45, 95% CI: 0.20-0.99). Due to the low absolute numbers of events, results were inconclusive at 30 days for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction, although
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point estimates favored TAVI. Importantly, however, TAVI was associated with a substantial reduction in atrial fibrillation at 30 days (RR: 0.27, 95% CI: 0.17-0.41). At 12 months (Figure 3), results were inconclusive for all-cause mortality, cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction, although all point estimates except transient ischemic attack (RR: 1.00) favored TAVI. Atrial fibrillation remained reduced in TAVI patients at 12 months (RR: 0.32, 95% CI: 0.21-0.49). Data concerning hospitalization for heart failure were not able to be pooled, as they were not reported by NOTION and definitions between trials were heterogeneous. Evolut Low Risk defined rehospitalization for heart failure as any readmission following the index procedure which included a pre-specified list of signs and symptoms, whereas PARTNER 3 defined rehospitalization as valve- or procedure-related hospitalization. However, findings from both trials suggest reduced incidence of rehospitalization with TAVI at 30 days (Evolut Low Risk: 1.3% difference, 95% credible interval [CrI]: -2.8, 0.1; PARTNER 3: hazard ratio[HR]: 0.53, 95% CI: 0.29-0.97) and 12 months (Evolut Low Risk: -3.4% difference, 95% CrI: -5.9, -1.0; PARTNER 3: HR 0.65, 95% CI: 0.42-1.00). Procedural complications were reported for all trials at 30 days (Table 4, Figure 4). At 30 days, life threatening/disabling bleeding and acute kidney injury were reduced in TAVI compared to SAVR patients (RR: 0.29, 95% CI: 0.12-0.69 and RR: 0.28, 95% CI: 0.14-0.57, respectively). The risk of major vascular complications at 30 days was inconclusive (RR: 1.36, 95% CI: 0.87-2.14). At 12 months, data concerning life threatening/disabling bleeding, acute kidney injury, or major vascular complications could not be pooled, as NOTION did not report these outcomes. However, the Evolut Low Risk trial reported a decreased incidence of life threatening/disabling bleeding (-5.7% difference, 95% CrI: -8.4,-3.1) and acute kidney injury (-
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1.8% difference, 95% CrI: -3.4,-0.5). The PARTNER 3 trial also reported a decreased incidence of life threatening/disabling bleeding (HR: 0.20, 95% CI: 0.11-0.36), but did not report 12-month data for acute kidney injury. The risk of major vascular complications at 12 months remained inconclusive in both trials (Evolut Low Risk: 0.3% difference, 95% CrI: -1.7,2.3; PARTNER 3: HR: 1.83, 95% CI: 0.74-4.55). Importantly, TAVI was associated with increased permanent pacemaker implantation at 30 days (RR:3.13, 95% CI: 1.36-7.21; Figure 5) and 12 months (RR: 2.99, 95% CI: 1.19-7.51; Figure 5). In particular, NOTION had a high rate of permanent pacemaker implantation in TAVI compared to SAVR patients at 30 days. The trend was similar but attenuated in Evolut Low Risk and PARTNER 3. Coronary artery obstruction, valve thrombosis, aortic reintervention, and endocarditis occurred in a small proportion of participants (<1%) when reported (data not shown). All 3 trials reported information on valve function and quality of life (Table 5). Some trials found minor differences in aortic valve gradient and effective orifice area at 30 days and 12 months, which were of unclear clinical significance. Evolut Low Risk was the only trial to examine the difference in NYHA class change from baseline to 12 months. This trial found no differences between groups. Using the KCCQ scale, TAVI was associated with greater increases in quality of life at 30 days relative to SAVR in Evolut Low Risk and PARTNER 3. A small difference in quality of life favoring TAVI was present at 12 months post-procedure in PARTNER 3, but not in Evolut Low Risk. DISCUSSION Our study was designed to compare major clinical outcomes and procedural complications of TAVI versus SAVR in low surgical risk patients at 30 days and 12 months. We
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found that TAVI decreased all-cause mortality at 30 days compared to SAVR, a finding that was not definitive in any individual trial. Atrial fibrillation was also substantially reduced in TAVI patients, but the incidence of permanent pacemaker implantation was increased. Valve function appeared to be similar in TAVI and SAVR patients. Change in quality of life was better in TAVI patients at 30 days, but appeared to be comparable to SAVR patients at 12 months. Overall, these results suggest that TAVI should be considered as a first-line therapy for severe aortic stenosis in low-risk patients. Other previous meta-analyses of TAVI versus SAVR RCTs have studied high10 and intermediate11 surgical risk patients. Our findings in low-risk patients were consistent with the results of these meta-analyses, which showed a decreased risk of all-cause mortality and stroke at 30 days and 12 months post-procedure. Our point estimates for these outcomes followed similar trends, although relatively low event rates (due to lower surgical risk patients) decreased the precision of our estimates. Likewise, TAVI in higher surgical risk classifications was also associated with a decreased risk of life threatening/disabling bleeding and acute kidney injury, as well as an increased need for post-procedural permanent pacemaker implantation. Based on these findings, the benefits of TAVI appear to be similar across surgical risk categories. The incidence of conduction anomalies following TAVI has remained a concern across patient risk groups.12 While this complication has not been associated with increased mortality or rehospitalization for heart failure, it does increase the risk of permanent pacemaker implantation.13 Within the trials included in our systematic review, almost all permanent pacemaker implantations occurred within 30 days of the procedure, suggesting they are procedural complications. Previous studies found the incidence of conduction abnormalities to be associated with the self-expanding valve deployment strategy, as opposed to the balloon-
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expandable valve deployment strategy.14 Self-expanding valves exert greater radial force which, combined with first generation stent designs, may contribute to inflammation of cardiac tissue.15 However, second and third generation Evolut R and PRO self-expanding valves reduced the incidence of permanent pacemaker implantations by more than one-third.16 This is consistent with our finding of reduced incidence of permanent pacemaker implantations between the NOTION trial, which used a first generation CoreValve model, and the Evolut Low Risk trial, which predominantly used the second and third generation Evolut R and Evolut PRO valve implantation models. Long-term data are consistent with these findings, showing a greater incidence of permanent pacemaker implantations with self-expanding valves (58% versus 42% in balloon-expandable valves).13 These findings lead to the expectation that as valve technology improves further, the incidence of conduction anomalies and associated permanent pacemaker implantation will continue to decrease. The long-term durability of transcatheter valves remains unclear, and currently, the only long-term data available for low-risk patients are from the NOTION trial’s 6-year results.17 Across all time points, the effective orifice area was greater in the first-generation CoreValve transcatheter valves compared to surgical valves, which correlates with lower aortic valve gradients and improved left ventricular flow.18 The surgical valves also had a higher incidence of structural valve defects compared to the transcatheter valves. Data from observational studies19,20 suggest that long-term transcatheter valve function is excellent, with low incidence of clinically relevant structural valve defects and overall hemodynamics stable over time. While individual RCTs have found statistically significant differences in aortic valve gradient (with mixed directionality) between TAVI and SAVR, the differences were small and of uncertain clinical significance.
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Given the relatively long life expectancy of low surgical risk patients receiving TAVI, questions remain regarding the long-term management of these patients. Many implanted valves will eventually require either surgical re-intervention or valve-in-valve TAVI, however data concerning the optimal approach for re-intervention are as yet unavailable.21 Patients with aortic stenosis are also likely to either have or develop concomitant coronary artery disease. While patients receiving SAVR may have coronary artery bypass grafting at the time of their valve replacement, the optimal timing of PCI relative to TAVI remains unclear.21-23 The treatment of other long-term complications in patients with TAVI will likewise require additional study over time. For example, prothesthetic valve endocarditis is rare, but appears to occur at similar rates in patients who undergo TAVI or SAVR.24 Additional long-term clinical trial and observational data are needed to establish the optimal management of low-risk patients who undergo TAVI. Our study had several potential limitations. First, the absolute number of clinical events was small for some outcomes, which limited our ability to detect differences between groups. Ongoing RCTs25,26 (e.g., DEDICATE, NOTION-2) will contribute additional events to future meta-analyses. Second, our findings were based on data from 30 days and 12 months. The included RCTs all have planned 10-year follow-up and will eventually be able to provide additional long-term data. However, our meta-analysis constitutes the best available evidence to date, with important clinical implications. Third, we included data from patients who received first generation valves, which may have resulted in an underestimation of the benefits of TAVI using later generation valves compared to SAVR (particularly for procedural complications and valve function). Fourth, the clinical endpoints for all 3 trials were reported for as-treated rather than intention-to-treat groups. While this is reflective of the real-world occurrence of changes in treatment decisions, it is an inherent limitation which may have imbalanced unknown
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confounders between groups. The authors of the RCTs report that sensitivity analyses using intention-to-treat data were similar to the as-treated analyses. Our study was designed to compare major clinical outcomes and procedural complications of TAVI versus SAVR in low surgical risk patients with severe aortic stenosis. At 30 days, TAVI decreased all-cause mortality, atrial fibrillation, life threatening/disabling bleeding, and acute kidney injury. The reduction in atrial fibrillation persisted at 12 months. However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days and 12 months. While other outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients. Nevertheless, additional long-term data are needed. Author credit statement Jeremy Y. Levett: Conceptualization, Methodology, Investigation, Writing – Original Draft Sarah B. Windle: Methodology, Writing – Review & Editing, Project Administration Kristian B. Filion: Methodology, Supervision Vanessa C. Brunetti: Software, Formal Analysis, Data Curation Mark J. Eisenberg: Conceptualization, Supervision
AUTHOR DECLARATION FORM – THE AMERICAN JOURNAL OF CARDIOLOGY Manuscript Title: Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials List of all Authors: Jeremy Y. Levett; Sarah B. Windle MPH; Kristian B. Filion PhD; Vanessa C. Brunetti MSc; Mark J. Eisenberg MD MPH* We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. [OR] We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there
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are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author. On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. Any changes to the list of authors, including changes in order, additions or removals will require the submission of a new author agreement form approved and signed by all the original and added submitting authors.
ACKNOWLEDGMENTS The authors would like to thank Mr. Amir Razaghizad for his assistance with screening and data abstraction. FUNDING Mr. Levett is supported by a Mach-Gaensslen Foundation of Canada Student Grant, (McGill University). Dr. Filion is supported by a Junior 2 Research Scholar award (Fonds de recherche du Québec – Santé) and a William Dawson Scholar award (McGill University). Ms. Brunetti is supported by a doctoral bursary (Fonds de recherche du Québec – Santé) and the David G. Guthrie award (McGill University). DISCLOSURES The authors have no conflicts of interest to declare.
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REFERENCES 1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, Rigolin VH, Sundt TM, Thompson A. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135:e1159-e1195. 2. Thourani VH, Suri RM, Gunter RL, Sheng S, O’Brien SM, Ailawadi G, Szeto WY, Dewey TM, Guyton RA, Bavaria JE, Babaliaros V, Gammie JS, Svensson L, Williams M, Badhwar V, Mack MJ. Contemporary Real-World Outcomes of Surgical Aortic Valve Replacement in 141,905 Low-Risk, Intermediate-Risk, and High-Risk Patients. Ann Thorac Surg 2015;99:55-61. 3. Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, Kapadia SR, Malaisrie SC, Cohen DJ, Pibarot P, Leipsic J, Hahn RT, Blanke P, Williams MR, McCabe JM, Brown DL, Babaliaros V, Goldman S, Szeto WY, Genereux P, Pershad A, Pocock SJ, Alu MC, Webb JG, Smith CR. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in LowRisk Patients. N Engl J Med 2019;380:1695-1705. 4. Popma JJ, Deeb GM, Yakubov SJ, Mumtaz M, Gada H, O'Hair D, Bajwa T, Heiser JC, Merhi W, Kleiman NS, Askew J, Sorajja P, Rovin J, Chetcuti SJ, Adams DH, Teirstein PS, Zorn GL, 3rd, Forrest JK, Tchetche D, Resar J, Walton A, Piazza N, Ramlawi B, Robinson N, Petrossian G, Gleason TG, Oh JK, Boulware MJ, Qiao H, Mugglin AS, Reardon MJ. Transcatheter AorticValve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med 2019;380:1706-1715. 5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009;6:e1000097.
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6. Higgins J, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org. 7. Higgins JPT, Savović J, Page MJ (editors). Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) [updated July 9, 2019]. The Cochrane Collaboration, 2019. Available
from
https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-
version-of-rob-2. 8. StataCorp, Stata Statistical Software: Release 15. 2017, StataCorp LLC: College Station, TX. 9. Thyregod HG, Steinbruchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, Chang Y, Franzen OW, Engstrom T, Clemmensen P, Hansen PB, Andersen LW, Olsen PS, Sondergaard L. Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis: 1-Year Results From the All-Comers NOTION Randomized Clinical Trial. J Am Coll Cardiol 2015;65:2184-2194. 10. Carnero-Alcazar M, Maroto LC, Cobiella-Carnicer J, Vilacosta I, Nombela-Franco L, Alswies A, Villagran-Medinilla E, Macaya C. Transcatheter Versus Surgical Aortic Valve Replacement in Moderate and High-Risk Patients: A Meta-Analysis. Eur J Cardiothorac Surg 2017;51:644-652. 11. Lazkani M, Singh N, Howe C, Patel N, Colón MJ, Tasset M, Amabile O, Morris M, Fang HK, Pershad A. An Updated Meta-Analysis of TAVR in Patients at Intermediate Risk for SAVR. Cardiovasc Revasc Med 2019;20:57-69. 12. Bob-Manuel T, Nanda A, Latham S, Pour-Ghaz I, Skelton WPt, Khouzam RN. Permanent Pacemaker Insertion in Patients with Conduction Abnormalities Post Transcatheter Aortic Valve Replacement: A Review and Proposed Guidelines. Ann Transl Med 2018;6:11.
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13. Chamandi C, Barbanti M, Munoz-Garcia A, Latib A, Nombela-Franco L, Gutierrez-Ibanez E, Veiga-Fernandez G, Cheema AN, Cruz-Gonzalez I, Serra V, Tamburino C, Mangieri A, Colombo A, Jimenez-Quevedo P, Elizaga J, Lee DH, Garcia Del Blanco B, Puri R, Cote M, Philippon F, Rodes-Cabau J. Long-Term Outcomes in Patients With New-Onset Persistent Left Bundle Branch Block Following TAVR. JACC Cardiovasc Interv 2019;12:1175-1184. 14. Erkapic D, De Rosa S, Kelava A, Lehmann R, Fichtlscherer S, Hohnloser SH. Risk for Permanent Pacemaker After Transcatheter Aortic Valve Implantation: A Comprehensive Analysis of the Literature. J Cardiovasc Electrophysiol 2012;23:391-397. 15. Abdel-Wahab M, Mehilli J, Frerker C, Neumann FJ, Kurz T, Tolg R, Zachow D, Guerra E, Massberg S, Schafer U, El-Mawardy M, Richardt G. Comparison of Balloon-Expandable vs Self-Expandable Valves in Patients Undergoing Transcatheter Aortic Valve Replacement: The CHOICE Randomized Clinical Trial. JAMA 2014;311:1503-1514. 16. Barbanti M. Early Outcomes of the Evolut R Transcatheter Aortic Valve: A New Technology Between Achieved Goals and Desirable Improvements. JACC Cardiovasc Interv 2017;10:283285. 17. Sondergaard L, Ihlemann N, Capodanno D, Jorgensen TH, Nissen H, Kjeldsen BJ, Chang Y, Steinbruchel DA, Olsen PS, Petronio AS, Thyregod HGH. Durability of Transcatheter and Surgical Bioprosthetic Aortic Valves in Patients at Lower Surgical Risk. J Am Coll Cardiol 2019;73:546-553. 18. Gorlin R, Gorlin SG. Hydraulic Formula for Calculation of the Area of the Stenotic Mitral Valve, Other Cardiac Valves, and Central Circulatory Shunts. I. Am Heart J 1951;41:1-29. 19. Blackman DJ, Saraf S, MacCarthy PA, Myat A, Anderson SG, Malkin CJ, Cunnington MS, Somers K, Brennan P, Manoharan G, Parker J, Aldalati O, Brecker SJ, Dowling C, Hoole SP,
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Dorman S, Mullen M, Kennon S, Jerrum M, Chandrala P, Roberts DH, Tay J, Doshi SN, Ludman PF, Fairbairn TA, Crowe J, Levy RD, Banning AP, Ruparelia N, Spence MS, HildickSmith D. Long-Term Durability of Transcatheter Aortic Valve Prostheses. J Am Coll Cardiol 2019;73:537-545. 20. Guimarães LdFC, Urena M, Wijeysundera HC, Munoz-Garcia A, Serra V, Benitez LM, Auffret V, Cheema AN, Amat-Santos IJ, Fisher Q, Himbert D, Blanco BGd, Dager A, Breton HL, Paradis J-M, Dumont E, Pibarot P, Rodés-Cabau J. Long-Term Outcomes After Transcatheter Aortic Valve-in-Valve Replacement. Circ Cardiovasc Interv 2018;11:e007038. 21. Siddique S, Gada H, Mumtaz MA, Vora AN. Should All Low-risk Patients Now Be Considered for TAVR? Operative Risk, Clinical, and Anatomic Considerations. Curr Cardiol Rep 2019;21:161. 22. Voudris KV, Petropulos P, Karyofillis P, Charitakis K. Timing and Outcomes of PCI in the TAVR Era. Curr Treat Options Cardiovasc Med 2018;20:22. 23. Perez S, Thielhelm TP, Cohen MG. To Revascularize or Not Before Transcatheter Aortic Valve Implantation? J Thorac Dis 2018;10:S3578-s3587. 24. Moriyama N, Laakso T, Biancari F, Raivio P, Jalava MP, Jaakkola J, Dahlbacka S, Kinnunen EM, Juvonen T, Husso A, Niemela M, Ahvenvaara T, Tauriainen T, Virtanen M, Maaranen P, Eskola M, Rosato S, Makikallio T, Savontaus M, Valtola A, Anttila V, Airaksinen J, Laine M. Prosthetic Valve Endocarditis After Transcatheter or Surgical Aortic Valve Replacement with a Bioprosthesis: Results from the FinnValve Registry. EuroIntervention 2019;15:e500-e507. 25. Seiffert M, Walther T, Hamm C, Falk V, Frey N, Thiele H, Hagl C, Landmesser U, Borger M, Massberg S, Reichenspurner H, Baumgartner H, Blankenberg S, Cremer J. The DEDICATE Trial: An Independent All-Comers Trial of Transcatheter Aortic Valve Implantation vs. Surgical
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Aortic Valve Replacement in Patients at Low to Intermediate Operative Risk is Recruiting Patients. Eur Heart J 2019;40:331-333. 26. Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in Younger Low Surgical
Risk
Patients
With
Severe
https://clinicaltrials.gov/ct2/show/NCT02825134.
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Aortic
Stenosis
(NOTION-2).
FIGURE LEGENDS
Figure A.
PRISMA flow diagram of study selection. Abbreviations: PRISMA=Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT=Randomized Controlled Trial; SAVR=Surgical Aortic Valve Replacement; TAVI= Transcatheter aortic valve implantation.
19
Figure B.
Forest plot of the relative risks of 30-day major clinical outcomes in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
20
Figure C.
Forest plot of the relative risks of 12-month major clinical outcomes in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
21
Figure D.
Forest plot of the relative risks of 30-day procedural complications in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
22
Figure E.
Forest plot of the relative risks of 30-day and 12-month post-procedural permanent pacemaker implantation in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
23
Table 1: Study Characteristics of Transcatheter versus Surgical Aortic Valve Replacement Trials in Low Surgical Risk Patients Duration Definition of Countries of Variable
Sample Size
Femoral
Valve Model
of Follow-
Approach
Used
Up
Low Surgical Enrollment Risk
(years)†
United States, 74% Evolut R, Australia, Predicted risk Evolut Low
22% Evolut
Canada, of mortality for
Risk4
1,403
(2019)
France, Japan,
PRO, 4% 99%
1
surgery <3% at
CoreValve Self-
30 days
Expanding
Netherlands, New Zealand, Valves Switzerland Society of United States, Thoracic
100% SAPIEN
Australia, PARTNER 33
Surgeons 950
Canada,
(2019)
3 Balloon 100%
1
Predicted Risk
Expandable
of Mortality
Valves
Japan, New Zealand score <4% Society of Thoracic NOTION9
Denmark,
Surgeons
276 (2015)
CoreValve Self97%
Sweden
6
Predicted Risk
Expanding
of Mortality
Valves
score <4%
†
100%
All studies have a planned follow-up of 10 years.
24
Table 2: Baseline Demographic and Clinical Characteristics of Transcatheter versus Surgical Aortic Valve Replacement Trials in Low Surgical Risk Patients*† Prior
Societ Europe
y of
an
Thora
System
cic
for
Surge
Percutan
Cardia
ons
Myocar
eous
c
Predic
Chroni c Diabe Age Variab
M
tes
en
Melli
(me le an)
Systemic
Atrial
Obstru
Hyperte
Fibrilla
ctive
Stro
dial
Coronar
Operat
ted
nsion
tion
Pulmon
ke
Infarcti
y
ive
Risk
on
Interven
Risk
of
tion
Evalua
Morta
tion
lity
score
score
(mean)
(mean
tus ary Disease
) Evolut Low
65 74
Risk4
31%
84%
15%
16%
NR
6%
14%
NR
1.9
31%
NR
17%
6%
4%
6%
NR
1.5
1.9
19%
74%
27%
12%
17%
5%
8%
1.9
3.0
%
(2019) PART 69 NER 33
73 %
(2019) NOTI 53 ON9
79 %
(2015)
25
* †
Denominators varied within trial characteristics. Abbreviations: NR=Not Reported
26
Table 3: Major Clinical Outcomes at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*† Rehospitali Varia
Sample
ble
Size
Cardiovas
All
Transient
Atrial
Myocardia
cular
Strok
Ischemic
Fibrillati
l
Mortality
e
Attack
on
Infarction
All-Cause
zation for
Mortality
Heart Failure
TA
SA
TA
SAV
TA
SAV TAV SAV TA
VI
VR
VI
R
VI
R
I
R
4
9
4
9
25
23
SAV
TA
SA
TA
SAV
VI
R
VI
VR
VI
R
4
5
240
7
9
TAVI
SAVR
30 Days Evolut Low
72
Risk4
5
56 678
(0.6
(1.3
(0.6
%)
%)
%)
2
5
2
(1.3 (3.4 (3.4 (0.6 %) %)
%)
%)
11
0
17 9
(0.7
(35.4% (1.0 (7.7%) %) ) %)
(1.3
(2.5% (1.2%)
%)
)
(2019%) PART NER
4
3
3
21
145
5
6
49 33
29 17
454
(0.4
(1.1
(0.4
(0.9 (0.6 (2.4 (0%
(0.7 (4.2%) (31.9§ (1.0
(1.3
(6.4% (3.4%)¶
6 (2019
%) %)
%)
)
%)
§
%)
%)
%)
4
2
0
24
77
4
8
%)
%)
%)
3
5
3
(2.1
(3.7
(2.1
(3.7 (1.4 (3.0 (1.4
%)
%)
%)
%) %)
10
11
7
)¶
%) NOTI ON9
134 (2015
5
2
14 (0% (16.9 (57.5|| (2.8
(6.0
-
-
14
23
2 %)
%)
)
%)||
%)
%)
%)
15
7
6
42
135
7
6
%) 12 Month s Evolut
43
352
9
18
27
Low
2
Risk4
(2.3
(3.1
(1.6
(2.6 (4.2 (4.3 (1.6
(1.7 (9.7%)(38.4% (1.6
(1.7 (3.2%) (6.5%
%)
%)
%)
%) %)
5
11
4
%)
%)
%)
14
5
5
)
%)
%)
150
6
10
)
(2019%) PART NER
9
6
29
49 33
49 36
454
(1.0
(2.4
(0.8
(2.0 (1.2 (3.1 (1.0
(1.1 (5.8%)(33.0% (1.2
(2.2
(10.8 (7.3%)¶
6 (2019
%) %)
%)
%)
%)
§
)§
%)
%)
6
3
2
30
79
5
8
%)
%)
%)
7
10
6
(4.9
(7.5
(4.2
(7.5 (2.8 (4.5 (2.1
(1.5 (21.1 (59.0% (3.5
%)
%)
%)
%) %)
%)
%)¶
%) NOTI ON9
14
(2015
2
134
10
4
%)
%)
%)||
)||
%)
(6.0
-
-
%)
%)
* †
Denominators varied within clinical endpoints. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation; §
Defined as new onset atrial fibrillation.
||
Defined as new onset or worsening atrial fibrillation.
¶
Defined rehospitalization as being valve-related or procedure related, and including heart failure.
28
Table 4: Procedural Complications at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*†
Variable
Life Threatening or
Major Vascular
Disabling Bleeding
Complication
Sample Size
TAVI
SAVR
725
678
Acute Kidney
Permanent
Injury (stage II
Pacemaker
or III%)
Implantation
TAVI
SAVR
TAVI
SAVR
TAVI
SAVR
17
51
28
22
7
19
(2.3%)
(7.5%)
(3.9%)
(3.2%)
(1.0%)
(2.8%)
6
54
11
7
2
8
(1.2%)
(11.9%)
(2.2%)
(1.5%)
(0.4%)
(1.8%)
16
28
8
2
1
9
(11.3§‡%)
(20.9%)§‡
(5.6%)‡
(1.5%)‡
(0.7%)‡
(6.7%)‡
14
31
16
12
4
10
(3.2%)
(8.8%)
(3.7%)
(3.4%)
(0.9%)
(2.8%)
14
58
14
7 -
-
TAVI SAVR
30 Days Evolut Low Risk4
126
41
(17.4%) (6.0%)
(2019%) PARTNER 33 496 (2019%) NOTION9 142
32
18
454
134
(2015%)
(6.5%) (4.0%) 46
2
(32.4%) (1.5%)
12 Months Evolut Low Risk4
432
84
24
352 (19.4%) (6.8%)
(2019%) PARTNER 33 496
454
(2019%)
(2.8%)
(12.8%)
(2.8%)
(1.5%)
-
-
-
-
36
(7.3%) (5.3%)
NOTION9
51 142
134
(2015%) * †
§
-
3
(35.9%) (2.2%)
Denominators varied within complication outcomes. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation ‡
24
Reported for index hospitalization only. Also included major, but non-life threatening/disabling bleeding.
29
Table 5: Characteristics of Valve Function and Quality of Life at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*† Characteristics of Valve Function
Quality of Life Measures Kansas City New York Heart Cardiomyopathy
Aortic Valve
Effective Orifice
Association Class
Variable 2
Gradient (mmHg)
Area (cm )
Questionnaire‡
Change From Change From Baseline Baseline
TAVI
SAVR
TAVI
SAVR
TAVI
SAVR
8.4 3.5
10.5 4.0
2.2 0.6
2.0 0.6
-
-
TAVI
SAVR
30 Days Evolut Low Risk4
20.0
9.1 22.3
21.1 (2019) PARTNER 33
12.8 4.4
11.2 4.5
1.7 0.4
1.8 0.4
18.5 -
-
2.5 22.4
18.5 (2019) NOTION9 -
-
-
-
-
-
8.6 3.7
11.2 4.9
2.3 0.7
2.0 0.6
0.9 0.7
1.0 0.7
-
-
22.2
20.9
20.3
21.0
19.4
17.4
19.4
21.1
-
-
(2015) 12 Months Evolut Low Risk4 (2019) PARTNER 33
13.7 5.8
11.6 5.3
1.7 0.4
1.8 0.4
-
-
(2019) NOTION9 8.6
12.5
1.7
1.3
(2015)
30
-
-
*
†
Values are mean standard deviation. Denominators varied within outcomes. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation. ‡
The Kansas City Cardiomyopathy Questionnaire (KCCQ) scale is a 23-item self-administered questionnaire on the
Likert scale, where higher scores correlate with greater quality of life.
31
Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients Jeremy Y. Levett , Sarah B. Windle MPH , Kristian B. Filion PhD , Vanessa C. Brunetti MSc , Mark J. Eisenberg MD MPH PII: DOI: Reference:
S0002-9149(20)30058-8 https://doi.org/10.1016/j.amjcard.2020.01.017 AJC 24398
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
16 October 2019 14 January 2020 17 January 2020
Please cite this article as: Jeremy Y. Levett , Sarah B. Windle MPH , Kristian B. Filion PhD , Vanessa C. Brunetti MSc , Mark J. Eisenberg MD MPH , Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients, The American Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.amjcard.2020.01.017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
HIGHLIGHTS
TAVI was associated with a reduction in all-cause mortality at 30 days versus SAVR
TAVI patients had increased risk of pacemaker implantation at 30 days and 12 months
Results were inconclusive at 30 days and 12 months for major cardiovascular events
TAVI may be appropriate first-line therapy for aortic stenosis in low risk patients
1
Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients Short Title: TAVI in Low Surgical Risk Patients Jeremy Y. Levetta,b, Sarah B. Windle MPHa, Kristian B. Filion PhDa,b,c, Vanessa C. Brunetti MSca,c, Mark J. Eisenberg MD MPHa,b,c,d a
Division of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital/McGill University, Montreal, QC b Department of Medicine, McGill University, Montreal, QC c Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC d Division of Cardiology, Jewish General Hospital/McGill University, Montreal, QC Word count – Introduction to Disclosures: 2,496
Corresponding Author: Mark J. Eisenberg, MD MPH Professor of Medicine Divisions of Cardiology and Clinical Epidemiology Jewish General Hospital/McGill University 3755 Côte Ste-Catherine Road, Suite H-421.1 Montreal, Quebec, Canada H3T 1E2 Telephone: (514) 340-8222 Ext.23564 Fax: (514) 340-7564 E-Mail: [email protected]
Mr. Levett is supported by a Mach-Gaensslen Foundation of Canada Student Grant, funded through the McGill University Faculty of Medicine Research Bursary Program. Dr. Filion is supported by a Junior 2 Research Scholar award from the Fonds de recherche du Québec – Santé and a William Dawson Scholar award from McGill University. Ms. Brunetti is supported by a doctoral bursary from the Fonds de recherche du Québec – Santé and the David G. Guthrie award from the Faculty of Medicine of McGill University. Conflicts of interest: none
2
ABSTRACT Current guidelines recommend transcatheter aortic valve implantation (TAVI) for patients with severe aortic stenosis at elevated surgical risk, but not for patients at low surgical risk. Our objective is to compare major clinical outcomes and procedural complications with TAVI versus surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis at low surgical risk. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), identified through a systematic search of the PubMed, Embase, and Cochrane databases. Count data were pooled across trials using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). Three RCTs (n=2,629) were included. At 30 days, TAVI was associated with a substantial reduction in all-cause mortality (RR: 0.27, 95% CI: 0.17-0.41), atrial fibrillation (RR: 0.45, 95% CI: 0.20-0.99), life threatening/disabling bleeding (RR: 0.29, 95% CI: 0.12-0.69), and acute kidney injury (RR: 0.28, 95% CI: 0.14-0.57). The reduction in atrial fibrillation persisted at 12 months (RR: 0.32, 95% CI: 0.21-0.49). However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days (RR: 3.13, 95% CI: 1.36-7.21) and 12 months (RR: 2.99, 95% CI: 1.19-7.51). Due to the low absolute numbers of events, results were inconclusive at 30 days and 12 months for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction. In conclusion, while some outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients.
Keywords: aortic stenosis, transcatheter aortic valve implantation, surgical aortic valve replacement, low surgical risk, meta-analysis
3
INTRODUCTION The 2017 American College of Cardiology and American Heart Association (ACC/AHA) guidelines recommend the use of transcatheter aortic valve implantation (TAVI) for the treatment of severe symptomatic aortic stenosis in patients with prohibitive (strength of recommendation: Class I), high (Class I), and intermediate (Class IIa) surgical risk.1 Until recently, little was known concerning TAVI outcomes in individuals at low surgical risk, who constitute the majority of patients with severe aortic stenosis. The ACC/AHA guidelines currently recommend SAVR as a Class I treatment for low-risk patients, without making mention of TAVI.1,2 Two large randomized controlled trials (RCTs) have now provided data on TAVI versus SAVR in low surgical risk patients.3,4 Because the absolute number of clinical events in each trial remains small, we conducted a systematic review and meta-analysis to compare major clinical outcomes and procedural complications for TAVI versus SAVR in patients at low surgical risk. METHODS Our systematic review and meta-analysis was conducted using a pre-specified protocol, with reporting as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.5 We performed a systematic search of PubMed, Embase (via Ovid), and the Cochrane Library’s Central Register of Controlled Trials from inception through May 28, 2019. No restrictions were placed on language of publication. Keywords (title/abstract) searched were TAVI, TAVI, transcatheter aortic valve implant*, or transcatheter aortic valve implantation. The Cochrane Collaboration’s search hedges were used to restrict results to RCTs in PubMed and Embase6. The complete search strategies can be found in Supplemental Information A.
4
Following the removal of duplicate citations, 2 independent reviewers screened the titles and abstracts of the database search results using pre-specified inclusion criteria. Any article considered potentially relevant by either reviewer was retrieved and similarly screened in duplicate for inclusion, with disagreements resolved by consensus or a third reviewer. Included articles were RCTs published in English or French which compared TAVI to SAVR in patients with severe aortic stenosis. Studies had to self-identify as including at least 75% low surgical risk patients to be considered eligible, and report at least one of the major clinical outcomes of interest (see below) at 30 days or 12 months post-procedure. Observational studies were excluded to reduce potential bias. Abstracts, editorials, conference proceedings, and clinical trial registrations without results were also excluded, as were studies which performed TAVI via the transapical access route. All data were abstracted independently by 2 reviewers, including study and baseline characteristics. Major clinical outcomes (30 days and 12 months) abstracted were all-cause mortality, cardiovascular mortality, all stroke, transient ischemic attack, atrial fibrillation, myocardial infarction, and rehospitalization for heart failure. Procedural complications abstracted were life threatening or disabling bleeding, major vascular complications, acute kidney injury (stage II or III), permanent pacemaker implantation, coronary artery obstruction, endocarditis, valve thrombosis, and aortic reintervention. Characteristics of valve function abstracted were aortic valve gradient post-procedure and effective aortic orifice area. Change in quality of life measures abstracted were the New York Heart Association (NYHA) classification and the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Our statistical analysis protocol specified that we would abstract data from the intention-to-treat analyses. However, if intention-to-treat data were not available, as-treated data were abstracted.
5
The risk of bias for all included RCTs was assessed in duplicate using the Cochrane Collaboration’s tool for assessing risk of bias in randomised trials (RoB 2).7 All eligible RCTs were included regardless of quality. Count data for clinical endpoints were pooled across RCTs using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). The amount of heterogeneity that was present was estimated using the I2 statistic. Analyses were performed using Stata version 15.8 RESULTS Our systematic search retrieved 4,370 citations, of which 3,142 remained after removing duplicates (Figure 1). Three RCTs3,4,9 met our inclusion criteria (n=2,629) and were sufficiently homogenous to be included in our meta-analysis (Table 1). Evolut Low Risk (n=1,403) and PARTNER 3 (n=950) restricted inclusion to patients with low surgical risk. The NOTION trial (n=276) included “all-comers”, with 82% defined as low risk. Valve generations and types used in TAVI varied between trials. All trials were multicenter and enrolled participants exclusively in high income countries (baseline demographic and clinical characteristics of randomized participants are described in Table 2). Patient characteristics were well-balanced between the 2 treatment arms within each RCT. The overall quality of included studies was high, as there was a low risk of bias in all domains (Supplemental Information B). Only as-treated count data were available for 2 of the 3 included trials, therefore as-treated data were abstracted from all trials to allow pooling of comparable data. All 3 trials reported clinical outcomes at 30 days and 12 months (Table 3). At 30 days (Figure 2), TAVI reduced all-cause mortality compared to SAVR (RR: 0.45, 95% CI: 0.20-0.99). Due to the low absolute numbers of events, results were inconclusive at 30 days for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction, although
6
point estimates favored TAVI. Importantly, however, TAVI was associated with a substantial reduction in atrial fibrillation at 30 days (RR: 0.27, 95% CI: 0.17-0.41). At 12 months (Figure 3), results were inconclusive for all-cause mortality, cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction, although all point estimates except transient ischemic attack (RR: 1.00) favored TAVI. Atrial fibrillation remained reduced in TAVI patients at 12 months (RR: 0.32, 95% CI: 0.21-0.49). Data concerning hospitalization for heart failure were not able to be pooled, as they were not reported by NOTION and definitions between trials were heterogeneous. Evolut Low Risk defined rehospitalization for heart failure as any readmission following the index procedure which included a pre-specified list of signs and symptoms, whereas PARTNER 3 defined rehospitalization as valve- or procedure-related hospitalization. However, findings from both trials suggest reduced incidence of rehospitalization with TAVI at 30 days (Evolut Low Risk: 1.3% difference, 95% credible interval [CrI]: -2.8, 0.1; PARTNER 3: hazard ratio[HR]: 0.53, 95% CI: 0.29-0.97) and 12 months (Evolut Low Risk: -3.4% difference, 95% CrI: -5.9, -1.0; PARTNER 3: HR 0.65, 95% CI: 0.42-1.00). Procedural complications were reported for all trials at 30 days (Table 4, Figure 4). At 30 days, life threatening/disabling bleeding and acute kidney injury were reduced in TAVI compared to SAVR patients (RR: 0.29, 95% CI: 0.12-0.69 and RR: 0.28, 95% CI: 0.14-0.57, respectively). The risk of major vascular complications at 30 days was inconclusive (RR: 1.36, 95% CI: 0.87-2.14). At 12 months, data concerning life threatening/disabling bleeding, acute kidney injury, or major vascular complications could not be pooled, as NOTION did not report these outcomes. However, the Evolut Low Risk trial reported a decreased incidence of life threatening/disabling bleeding (-5.7% difference, 95% CrI: -8.4,-3.1) and acute kidney injury (-
7
1.8% difference, 95% CrI: -3.4,-0.5). The PARTNER 3 trial also reported a decreased incidence of life threatening/disabling bleeding (HR: 0.20, 95% CI: 0.11-0.36), but did not report 12-month data for acute kidney injury. The risk of major vascular complications at 12 months remained inconclusive in both trials (Evolut Low Risk: 0.3% difference, 95% CrI: -1.7,2.3; PARTNER 3: HR: 1.83, 95% CI: 0.74-4.55). Importantly, TAVI was associated with increased permanent pacemaker implantation at 30 days (RR:3.13, 95% CI: 1.36-7.21; Figure 5) and 12 months (RR: 2.99, 95% CI: 1.19-7.51; Figure 5). In particular, NOTION had a high rate of permanent pacemaker implantation in TAVI compared to SAVR patients at 30 days. The trend was similar but attenuated in Evolut Low Risk and PARTNER 3. Coronary artery obstruction, valve thrombosis, aortic reintervention, and endocarditis occurred in a small proportion of participants (<1%) when reported (data not shown). All 3 trials reported information on valve function and quality of life (Table 5). Some trials found minor differences in aortic valve gradient and effective orifice area at 30 days and 12 months, which were of unclear clinical significance. Evolut Low Risk was the only trial to examine the difference in NYHA class change from baseline to 12 months. This trial found no differences between groups. Using the KCCQ scale, TAVI was associated with greater increases in quality of life at 30 days relative to SAVR in Evolut Low Risk and PARTNER 3. A small difference in quality of life favoring TAVI was present at 12 months post-procedure in PARTNER 3, but not in Evolut Low Risk. DISCUSSION Our study was designed to compare major clinical outcomes and procedural complications of TAVI versus SAVR in low surgical risk patients at 30 days and 12 months. We
8
found that TAVI decreased all-cause mortality at 30 days compared to SAVR, a finding that was not definitive in any individual trial. Atrial fibrillation was also substantially reduced in TAVI patients, but the incidence of permanent pacemaker implantation was increased. Valve function appeared to be similar in TAVI and SAVR patients. Change in quality of life was better in TAVI patients at 30 days, but appeared to be comparable to SAVR patients at 12 months. Overall, these results suggest that TAVI should be considered as a first-line therapy for severe aortic stenosis in low-risk patients. Other previous meta-analyses of TAVI versus SAVR RCTs have studied high10 and intermediate11 surgical risk patients. Our findings in low-risk patients were consistent with the results of these meta-analyses, which showed a decreased risk of all-cause mortality and stroke at 30 days and 12 months post-procedure. Our point estimates for these outcomes followed similar trends, although relatively low event rates (due to lower surgical risk patients) decreased the precision of our estimates. Likewise, TAVI in higher surgical risk classifications was also associated with a decreased risk of life threatening/disabling bleeding and acute kidney injury, as well as an increased need for post-procedural permanent pacemaker implantation. Based on these findings, the benefits of TAVI appear to be similar across surgical risk categories. The incidence of conduction anomalies following TAVI has remained a concern across patient risk groups.12 While this complication has not been associated with increased mortality or rehospitalization for heart failure, it does increase the risk of permanent pacemaker implantation.13 Within the trials included in our systematic review, almost all permanent pacemaker implantations occurred within 30 days of the procedure, suggesting they are procedural complications. Previous studies found the incidence of conduction abnormalities to be associated with the self-expanding valve deployment strategy, as opposed to the balloon-
9
expandable valve deployment strategy.14 Self-expanding valves exert greater radial force which, combined with first generation stent designs, may contribute to inflammation of cardiac tissue.15 However, second and third generation Evolut R and PRO self-expanding valves reduced the incidence of permanent pacemaker implantations by more than one-third.16 This is consistent with our finding of reduced incidence of permanent pacemaker implantations between the NOTION trial, which used a first generation CoreValve model, and the Evolut Low Risk trial, which predominantly used the second and third generation Evolut R and Evolut PRO valve implantation models. Long-term data are consistent with these findings, showing a greater incidence of permanent pacemaker implantations with self-expanding valves (58% versus 42% in balloon-expandable valves).13 These findings lead to the expectation that as valve technology improves further, the incidence of conduction anomalies and associated permanent pacemaker implantation will continue to decrease. The long-term durability of transcatheter valves remains unclear, and currently, the only long-term data available for low-risk patients are from the NOTION trial’s 6-year results.17 Across all time points, the effective orifice area was greater in the first-generation CoreValve transcatheter valves compared to surgical valves, which correlates with lower aortic valve gradients and improved left ventricular flow.18 The surgical valves also had a higher incidence of structural valve defects compared to the transcatheter valves. Data from observational studies19,20 suggest that long-term transcatheter valve function is excellent, with low incidence of clinically relevant structural valve defects and overall hemodynamics stable over time. While individual RCTs have found statistically significant differences in aortic valve gradient (with mixed directionality) between TAVI and SAVR, the differences were small and of uncertain clinical significance.
10
Given the relatively long life expectancy of low surgical risk patients receiving TAVI, questions remain regarding the long-term management of these patients. Many implanted valves will eventually require either surgical re-intervention or valve-in-valve TAVI, however data concerning the optimal approach for re-intervention are as yet unavailable.21 Patients with aortic stenosis are also likely to either have or develop concomitant coronary artery disease. While patients receiving SAVR may have coronary artery bypass grafting at the time of their valve replacement, the optimal timing of PCI relative to TAVI remains unclear.21-23 The treatment of other long-term complications in patients with TAVI will likewise require additional study over time. For example, prothesthetic valve endocarditis is rare, but appears to occur at similar rates in patients who undergo TAVI or SAVR.24 Additional long-term clinical trial and observational data are needed to establish the optimal management of low-risk patients who undergo TAVI. Our study had several potential limitations. First, the absolute number of clinical events was small for some outcomes, which limited our ability to detect differences between groups. Ongoing RCTs25,26 (e.g., DEDICATE, NOTION-2) will contribute additional events to future meta-analyses. Second, our findings were based on data from 30 days and 12 months. The included RCTs all have planned 10-year follow-up and will eventually be able to provide additional long-term data. However, our meta-analysis constitutes the best available evidence to date, with important clinical implications. Third, we included data from patients who received first generation valves, which may have resulted in an underestimation of the benefits of TAVI using later generation valves compared to SAVR (particularly for procedural complications and valve function). Fourth, the clinical endpoints for all 3 trials were reported for as-treated rather than intention-to-treat groups. While this is reflective of the real-world occurrence of changes in treatment decisions, it is an inherent limitation which may have imbalanced unknown
11
confounders between groups. The authors of the RCTs report that sensitivity analyses using intention-to-treat data were similar to the as-treated analyses. Our study was designed to compare major clinical outcomes and procedural complications of TAVI versus SAVR in low surgical risk patients with severe aortic stenosis. At 30 days, TAVI decreased all-cause mortality, atrial fibrillation, life threatening/disabling bleeding, and acute kidney injury. The reduction in atrial fibrillation persisted at 12 months. However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days and 12 months. While other outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients. Nevertheless, additional long-term data are needed. Author credit statement Jeremy Y. Levett: Conceptualization, Methodology, Investigation, Writing – Original Draft Sarah B. Windle: Methodology, Writing – Review & Editing, Project Administration Kristian B. Filion: Methodology, Supervision Vanessa C. Brunetti: Software, Formal Analysis, Data Curation Mark J. Eisenberg: Conceptualization, Supervision
AUTHOR DECLARATION FORM – THE AMERICAN JOURNAL OF CARDIOLOGY Manuscript Title: Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials List of all Authors: Jeremy Y. Levett; Sarah B. Windle MPH; Kristian B. Filion PhD; Vanessa C. Brunetti MSc; Mark J. Eisenberg MD MPH* We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. [OR] We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there
12
are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author. On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. Any changes to the list of authors, including changes in order, additions or removals will require the submission of a new author agreement form approved and signed by all the original and added submitting authors.
ACKNOWLEDGMENTS The authors would like to thank Mr. Amir Razaghizad for his assistance with screening and data abstraction. FUNDING Mr. Levett is supported by a Mach-Gaensslen Foundation of Canada Student Grant, (McGill University). Dr. Filion is supported by a Junior 2 Research Scholar award (Fonds de recherche du Québec – Santé) and a William Dawson Scholar award (McGill University). Ms. Brunetti is supported by a doctoral bursary (Fonds de recherche du Québec – Santé) and the David G. Guthrie award (McGill University). DISCLOSURES The authors have no conflicts of interest to declare.
13
REFERENCES 1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, Rigolin VH, Sundt TM, Thompson A. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135:e1159-e1195. 2. Thourani VH, Suri RM, Gunter RL, Sheng S, O’Brien SM, Ailawadi G, Szeto WY, Dewey TM, Guyton RA, Bavaria JE, Babaliaros V, Gammie JS, Svensson L, Williams M, Badhwar V, Mack MJ. Contemporary Real-World Outcomes of Surgical Aortic Valve Replacement in 141,905 Low-Risk, Intermediate-Risk, and High-Risk Patients. Ann Thorac Surg 2015;99:55-61. 3. Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, Kapadia SR, Malaisrie SC, Cohen DJ, Pibarot P, Leipsic J, Hahn RT, Blanke P, Williams MR, McCabe JM, Brown DL, Babaliaros V, Goldman S, Szeto WY, Genereux P, Pershad A, Pocock SJ, Alu MC, Webb JG, Smith CR. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in LowRisk Patients. N Engl J Med 2019;380:1695-1705. 4. Popma JJ, Deeb GM, Yakubov SJ, Mumtaz M, Gada H, O'Hair D, Bajwa T, Heiser JC, Merhi W, Kleiman NS, Askew J, Sorajja P, Rovin J, Chetcuti SJ, Adams DH, Teirstein PS, Zorn GL, 3rd, Forrest JK, Tchetche D, Resar J, Walton A, Piazza N, Ramlawi B, Robinson N, Petrossian G, Gleason TG, Oh JK, Boulware MJ, Qiao H, Mugglin AS, Reardon MJ. Transcatheter AorticValve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med 2019;380:1706-1715. 5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009;6:e1000097.
14
6. Higgins J, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org. 7. Higgins JPT, Savović J, Page MJ (editors). Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) [updated July 9, 2019]. The Cochrane Collaboration, 2019. Available
from
https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-
version-of-rob-2. 8. StataCorp, Stata Statistical Software: Release 15. 2017, StataCorp LLC: College Station, TX. 9. Thyregod HG, Steinbruchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, Chang Y, Franzen OW, Engstrom T, Clemmensen P, Hansen PB, Andersen LW, Olsen PS, Sondergaard L. Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis: 1-Year Results From the All-Comers NOTION Randomized Clinical Trial. J Am Coll Cardiol 2015;65:2184-2194. 10. Carnero-Alcazar M, Maroto LC, Cobiella-Carnicer J, Vilacosta I, Nombela-Franco L, Alswies A, Villagran-Medinilla E, Macaya C. Transcatheter Versus Surgical Aortic Valve Replacement in Moderate and High-Risk Patients: A Meta-Analysis. Eur J Cardiothorac Surg 2017;51:644-652. 11. Lazkani M, Singh N, Howe C, Patel N, Colón MJ, Tasset M, Amabile O, Morris M, Fang HK, Pershad A. An Updated Meta-Analysis of TAVR in Patients at Intermediate Risk for SAVR. Cardiovasc Revasc Med 2019;20:57-69. 12. Bob-Manuel T, Nanda A, Latham S, Pour-Ghaz I, Skelton WPt, Khouzam RN. Permanent Pacemaker Insertion in Patients with Conduction Abnormalities Post Transcatheter Aortic Valve Replacement: A Review and Proposed Guidelines. Ann Transl Med 2018;6:11.
15
13. Chamandi C, Barbanti M, Munoz-Garcia A, Latib A, Nombela-Franco L, Gutierrez-Ibanez E, Veiga-Fernandez G, Cheema AN, Cruz-Gonzalez I, Serra V, Tamburino C, Mangieri A, Colombo A, Jimenez-Quevedo P, Elizaga J, Lee DH, Garcia Del Blanco B, Puri R, Cote M, Philippon F, Rodes-Cabau J. Long-Term Outcomes in Patients With New-Onset Persistent Left Bundle Branch Block Following TAVR. JACC Cardiovasc Interv 2019;12:1175-1184. 14. Erkapic D, De Rosa S, Kelava A, Lehmann R, Fichtlscherer S, Hohnloser SH. Risk for Permanent Pacemaker After Transcatheter Aortic Valve Implantation: A Comprehensive Analysis of the Literature. J Cardiovasc Electrophysiol 2012;23:391-397. 15. Abdel-Wahab M, Mehilli J, Frerker C, Neumann FJ, Kurz T, Tolg R, Zachow D, Guerra E, Massberg S, Schafer U, El-Mawardy M, Richardt G. Comparison of Balloon-Expandable vs Self-Expandable Valves in Patients Undergoing Transcatheter Aortic Valve Replacement: The CHOICE Randomized Clinical Trial. JAMA 2014;311:1503-1514. 16. Barbanti M. Early Outcomes of the Evolut R Transcatheter Aortic Valve: A New Technology Between Achieved Goals and Desirable Improvements. JACC Cardiovasc Interv 2017;10:283285. 17. Sondergaard L, Ihlemann N, Capodanno D, Jorgensen TH, Nissen H, Kjeldsen BJ, Chang Y, Steinbruchel DA, Olsen PS, Petronio AS, Thyregod HGH. Durability of Transcatheter and Surgical Bioprosthetic Aortic Valves in Patients at Lower Surgical Risk. J Am Coll Cardiol 2019;73:546-553. 18. Gorlin R, Gorlin SG. Hydraulic Formula for Calculation of the Area of the Stenotic Mitral Valve, Other Cardiac Valves, and Central Circulatory Shunts. I. Am Heart J 1951;41:1-29. 19. Blackman DJ, Saraf S, MacCarthy PA, Myat A, Anderson SG, Malkin CJ, Cunnington MS, Somers K, Brennan P, Manoharan G, Parker J, Aldalati O, Brecker SJ, Dowling C, Hoole SP,
16
Dorman S, Mullen M, Kennon S, Jerrum M, Chandrala P, Roberts DH, Tay J, Doshi SN, Ludman PF, Fairbairn TA, Crowe J, Levy RD, Banning AP, Ruparelia N, Spence MS, HildickSmith D. Long-Term Durability of Transcatheter Aortic Valve Prostheses. J Am Coll Cardiol 2019;73:537-545. 20. Guimarães LdFC, Urena M, Wijeysundera HC, Munoz-Garcia A, Serra V, Benitez LM, Auffret V, Cheema AN, Amat-Santos IJ, Fisher Q, Himbert D, Blanco BGd, Dager A, Breton HL, Paradis J-M, Dumont E, Pibarot P, Rodés-Cabau J. Long-Term Outcomes After Transcatheter Aortic Valve-in-Valve Replacement. Circ Cardiovasc Interv 2018;11:e007038. 21. Siddique S, Gada H, Mumtaz MA, Vora AN. Should All Low-risk Patients Now Be Considered for TAVR? Operative Risk, Clinical, and Anatomic Considerations. Curr Cardiol Rep 2019;21:161. 22. Voudris KV, Petropulos P, Karyofillis P, Charitakis K. Timing and Outcomes of PCI in the TAVR Era. Curr Treat Options Cardiovasc Med 2018;20:22. 23. Perez S, Thielhelm TP, Cohen MG. To Revascularize or Not Before Transcatheter Aortic Valve Implantation? J Thorac Dis 2018;10:S3578-s3587. 24. Moriyama N, Laakso T, Biancari F, Raivio P, Jalava MP, Jaakkola J, Dahlbacka S, Kinnunen EM, Juvonen T, Husso A, Niemela M, Ahvenvaara T, Tauriainen T, Virtanen M, Maaranen P, Eskola M, Rosato S, Makikallio T, Savontaus M, Valtola A, Anttila V, Airaksinen J, Laine M. Prosthetic Valve Endocarditis After Transcatheter or Surgical Aortic Valve Replacement with a Bioprosthesis: Results from the FinnValve Registry. EuroIntervention 2019;15:e500-e507. 25. Seiffert M, Walther T, Hamm C, Falk V, Frey N, Thiele H, Hagl C, Landmesser U, Borger M, Massberg S, Reichenspurner H, Baumgartner H, Blankenberg S, Cremer J. The DEDICATE Trial: An Independent All-Comers Trial of Transcatheter Aortic Valve Implantation vs. Surgical
17
Aortic Valve Replacement in Patients at Low to Intermediate Operative Risk is Recruiting Patients. Eur Heart J 2019;40:331-333. 26. Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in Younger Low Surgical
Risk
Patients
With
Severe
https://clinicaltrials.gov/ct2/show/NCT02825134.
18
Aortic
Stenosis
(NOTION-2).
FIGURE LEGENDS
Figure A.
PRISMA flow diagram of study selection. Abbreviations: PRISMA=Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT=Randomized Controlled Trial; SAVR=Surgical Aortic Valve Replacement; TAVI= Transcatheter aortic valve implantation.
19
Figure B.
Forest plot of the relative risks of 30-day major clinical outcomes in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
20
Figure C.
Forest plot of the relative risks of 12-month major clinical outcomes in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
21
Figure D.
Forest plot of the relative risks of 30-day procedural complications in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
22
Figure E.
Forest plot of the relative risks of 30-day and 12-month post-procedural permanent pacemaker implantation in patients randomized to TAVI compared to SAVR. Abbreviations: CI=Confidence Interval; RR=Relative Risk; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter aortic valve implantation.
23
Table 1: Study Characteristics of Transcatheter versus Surgical Aortic Valve Replacement Trials in Low Surgical Risk Patients Duration Definition of Countries of Variable
Sample Size
Femoral
Valve Model
of Follow-
Approach
Used
Up
Low Surgical Enrollment Risk
(years)†
United States, 74% Evolut R, Australia, Predicted risk Evolut Low
22% Evolut
Canada, of mortality for
Risk4
1,403
(2019)
France, Japan,
PRO, 4% 99%
1
surgery <3% at
CoreValve Self-
30 days
Expanding
Netherlands, New Zealand, Valves Switzerland Society of United States, Thoracic
100% SAPIEN
Australia, PARTNER 33
Surgeons 950
Canada,
(2019)
3 Balloon 100%
1
Predicted Risk
Expandable
of Mortality
Valves
Japan, New Zealand score <4% Society of Thoracic NOTION9
Denmark,
Surgeons
276 (2015)
CoreValve Self97%
Sweden
6
Predicted Risk
Expanding
of Mortality
Valves
score <4%
†
100%
All studies have a planned follow-up of 10 years.
24
Table 2: Baseline Demographic and Clinical Characteristics of Transcatheter versus Surgical Aortic Valve Replacement Trials in Low Surgical Risk Patients*† Prior
Societ Europe
y of
an
Thora
System
cic
for
Surge
Percutan
Cardia
ons
Myocar
eous
c
Predic
Chroni c Diabe Age Variab
M
tes
en
Melli
(me le an)
Systemic
Atrial
Obstru
Hyperte
Fibrilla
ctive
Stro
dial
Coronar
Operat
ted
nsion
tion
Pulmon
ke
Infarcti
y
ive
Risk
on
Interven
Risk
of
tion
Evalua
Morta
tion
lity
score
score
(mean)
(mean
tus ary Disease
) Evolut Low
65 74
Risk4
31%
84%
15%
16%
NR
6%
14%
NR
1.9
31%
NR
17%
6%
4%
6%
NR
1.5
1.9
19%
74%
27%
12%
17%
5%
8%
1.9
3.0
%
(2019) PART 69 NER 33
73 %
(2019) NOTI 53 ON9
79 %
(2015)
25
* †
Denominators varied within trial characteristics. Abbreviations: NR=Not Reported
26
Table 3: Major Clinical Outcomes at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*† Rehospitali Varia
Sample
ble
Size
Cardiovas
All
Transient
Atrial
Myocardia
cular
Strok
Ischemic
Fibrillati
l
Mortality
e
Attack
on
Infarction
All-Cause
zation for
Mortality
Heart Failure
TA
SA
TA
SAV
TA
SAV TAV SAV TA
VI
VR
VI
R
VI
R
I
R
4
9
4
9
25
23
SAV
TA
SA
TA
SAV
VI
R
VI
VR
VI
R
4
5
240
7
9
TAVI
SAVR
30 Days Evolut Low
72
Risk4
5
56 678
(0.6
(1.3
(0.6
%)
%)
%)
2
5
2
(1.3 (3.4 (3.4 (0.6 %) %)
%)
%)
11
0
17 9
(0.7
(35.4% (1.0 (7.7%) %) ) %)
(1.3
(2.5% (1.2%)
%)
)
(2019%) PART NER
4
3
3
21
145
5
6
49 33
29 17
454
(0.4
(1.1
(0.4
(0.9 (0.6 (2.4 (0%
(0.7 (4.2%) (31.9§ (1.0
(1.3
(6.4% (3.4%)¶
6 (2019
%) %)
%)
)
%)
§
%)
%)
%)
4
2
0
24
77
4
8
%)
%)
%)
3
5
3
(2.1
(3.7
(2.1
(3.7 (1.4 (3.0 (1.4
%)
%)
%)
%) %)
10
11
7
)¶
%) NOTI ON9
134 (2015
5
2
14 (0% (16.9 (57.5|| (2.8
(6.0
-
-
14
23
2 %)
%)
)
%)||
%)
%)
%)
15
7
6
42
135
7
6
%) 12 Month s Evolut
43
352
9
18
27
Low
2
Risk4
(2.3
(3.1
(1.6
(2.6 (4.2 (4.3 (1.6
(1.7 (9.7%)(38.4% (1.6
(1.7 (3.2%) (6.5%
%)
%)
%)
%) %)
5
11
4
%)
%)
%)
14
5
5
)
%)
%)
150
6
10
)
(2019%) PART NER
9
6
29
49 33
49 36
454
(1.0
(2.4
(0.8
(2.0 (1.2 (3.1 (1.0
(1.1 (5.8%)(33.0% (1.2
(2.2
(10.8 (7.3%)¶
6 (2019
%) %)
%)
%)
%)
§
)§
%)
%)
6
3
2
30
79
5
8
%)
%)
%)
7
10
6
(4.9
(7.5
(4.2
(7.5 (2.8 (4.5 (2.1
(1.5 (21.1 (59.0% (3.5
%)
%)
%)
%) %)
%)
%)¶
%) NOTI ON9
14
(2015
2
134
10
4
%)
%)
%)||
)||
%)
(6.0
-
-
%)
%)
* †
Denominators varied within clinical endpoints. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation; §
Defined as new onset atrial fibrillation.
||
Defined as new onset or worsening atrial fibrillation.
¶
Defined rehospitalization as being valve-related or procedure related, and including heart failure.
28
Table 4: Procedural Complications at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*†
Variable
Life Threatening or
Major Vascular
Disabling Bleeding
Complication
Sample Size
TAVI
SAVR
725
678
Acute Kidney
Permanent
Injury (stage II
Pacemaker
or III%)
Implantation
TAVI
SAVR
TAVI
SAVR
TAVI
SAVR
17
51
28
22
7
19
(2.3%)
(7.5%)
(3.9%)
(3.2%)
(1.0%)
(2.8%)
6
54
11
7
2
8
(1.2%)
(11.9%)
(2.2%)
(1.5%)
(0.4%)
(1.8%)
16
28
8
2
1
9
(11.3§‡%)
(20.9%)§‡
(5.6%)‡
(1.5%)‡
(0.7%)‡
(6.7%)‡
14
31
16
12
4
10
(3.2%)
(8.8%)
(3.7%)
(3.4%)
(0.9%)
(2.8%)
14
58
14
7 -
-
TAVI SAVR
30 Days Evolut Low Risk4
126
41
(17.4%) (6.0%)
(2019%) PARTNER 33 496 (2019%) NOTION9 142
32
18
454
134
(2015%)
(6.5%) (4.0%) 46
2
(32.4%) (1.5%)
12 Months Evolut Low Risk4
432
84
24
352 (19.4%) (6.8%)
(2019%) PARTNER 33 496
454
(2019%)
(2.8%)
(12.8%)
(2.8%)
(1.5%)
-
-
-
-
36
(7.3%) (5.3%)
NOTION9
51 142
134
(2015%) * †
§
-
3
(35.9%) (2.2%)
Denominators varied within complication outcomes. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation ‡
24
Reported for index hospitalization only. Also included major, but non-life threatening/disabling bleeding.
29
Table 5: Characteristics of Valve Function and Quality of Life at 30 Days and 12 Months Post Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients*† Characteristics of Valve Function
Quality of Life Measures Kansas City New York Heart Cardiomyopathy
Aortic Valve
Effective Orifice
Association Class
Variable 2
Gradient (mmHg)
Area (cm )
Questionnaire‡
Change From Change From Baseline Baseline
TAVI
SAVR
TAVI
SAVR
TAVI
SAVR
8.4 3.5
10.5 4.0
2.2 0.6
2.0 0.6
-
-
TAVI
SAVR
30 Days Evolut Low Risk4
20.0
9.1 22.3
21.1 (2019) PARTNER 33
12.8 4.4
11.2 4.5
1.7 0.4
1.8 0.4
18.5 -
-
2.5 22.4
18.5 (2019) NOTION9 -
-
-
-
-
-
8.6 3.7
11.2 4.9
2.3 0.7
2.0 0.6
0.9 0.7
1.0 0.7
-
-
22.2
20.9
20.3
21.0
19.4
17.4
19.4
21.1
-
-
(2015) 12 Months Evolut Low Risk4 (2019) PARTNER 33
13.7 5.8
11.6 5.3
1.7 0.4
1.8 0.4
-
-
(2019) NOTION9 8.6
12.5
1.7
1.3
(2015)
30
-
-
*
†
Values are mean standard deviation. Denominators varied within outcomes. Abbreviations: NR=Not Reported; SAVR=Surgical Aortic Valve Replacement; TAVI=Transcatheter Aortic Valve
Implantation. ‡
The Kansas City Cardiomyopathy Questionnaire (KCCQ) scale is a 23-item self-administered questionnaire on the
Likert scale, where higher scores correlate with greater quality of life.
31