Author + information
- Received September 21, 2016
- Revision received March 6, 2017
- Accepted March 9, 2017
- Published online May 15, 2017.
- G. Michael Deeb, MDa,∗ (, )
- Stanley J. Chetcuti, MDb,
- Michael J. Reardon, MDc,
- Himanshu J. Patel, MDa,
- P. Michael Grossman, MDb,
- Theodore Schreiber, MDd,
- John K. Forrest, MDe,
- Tanvir K. Bajwa, MDf,
- Daniel P. O’Hair, MDg,
- George Petrossian, MDh,
- Newell Robinson, MDi,
- Stanley Katz, MDj,
- Alan Hartman, MDk,
- Harold L. Dauerman, MDl,
- Joseph Schmoker, MDm,
- Kamal Khabbaz, MDn,
- Daniel R. Watson, MDo,
- Steven J. Yakubov, MDp,
- Jae K. Oh, MDq,
- Shuzhen Li, PhDr,
- Neal S. Kleiman, MDs,
- David H. Adams, MDt and
- Jeffrey J. Popma, MDu
- aDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan
- bDepartment of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan
- cDepartment of Cardiothoracic Surgery, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas
- dDepartment of Cardiology, Detroit Medical Center, Detroit, Michigan
- eDepartment of Cardiology, Yale University School of Medicine, New Haven, Connecticut
- fDepartment of Cardiology, Aurora Healthcare, Milwaukee, Wisconsin
- gDepartment of Cardiothoracic Surgery, Aurora Healthcare, Milwaukee, Wisconsin
- hDepartment of Cardiology, St. Francis Hospital, Roslyn, New York
- iDepartment of Cardiothoracic and Vascular Surgery, St. Francis Hospital, Roslyn, New York
- jDepartment of Cardiology, North Shore University Hospital, Manhasset, New York
- kDepartment of Cardiovascular and Thoracic Surgery, North Shore University Hospital, Manhasset, New York
- lDepartment of Cardiology, University of Vermont Medical Center, Burlington, Vermont
- mDepartment of Cardiothoracic Surgery, University of Vermont Medical Center, Burlington, Vermont
- nDepartment of Cardiac Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- oDepartment of Cardiothoracic Surgery, Riverside Methodist Hospital, Columbus, Ohio
- pDepartment of Cardiology, Riverside Methodist Hospital, Columbus, Ohio
- qDepartment of Cardiovascular Diseases, Mayo Clinic Foundation, Rochester, Minnesota
- rCoronary and Structural Heart Clinical Department, Medtronic, Mounds View, Minnesota
- sDepartment of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas
- tDepartment of Cardiovascular Surgery, Mount Sinai Medical Center, New York, New York
- uDepartment of Internal Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. G. Michael Deeb, University of Michigan Hospitals, Department of Cardiac Surgery, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-5864.
Objectives This study evaluated the safety and effectiveness of self-expanding transcatheter aortic valve replacement (TAVR) in patients with surgical valve failure (SVF).
Background Self-expanding TAVR is superior to medical therapy for patients with severe native aortic valve stenosis at increased surgical risk.
Methods The CoreValve U.S. Expanded Use Study was a prospective, nonrandomized study that enrolled 233 patients with symptomatic SVF who were deemed unsuitable for reoperation. Patients were treated with self-expanding TAVR and evaluated for 30-day and 1-year outcomes after the procedure. An independent core laboratory was used to evaluate serial echocardiograms for valve hemodynamics and aortic regurgitation.
Results SVF occurred through stenosis (56.4%), regurgitation (22.0%), or a combination (21.6%). A total of 227 patients underwent attempted TAVR and successful TAVR was achieved in 225 (99.1%) patients. Patients were elderly (76.7 ± 10.8 years), had a Society of Thoracic Surgeons Predicted Risk of Mortality score of 9.0 ± 6.7%, and were severely symptomatic (86.8% New York Heart Association functional class III or IV). The all-cause mortality rate was 2.2% at 30 days and 14.6% at 1 year; major stroke rate was 0.4% at 30 days and 1.8% at 1 year. Moderate aortic regurgitation occurred in 3.5% of patients at 30 days and 7.4% of patients at 1 year, with no severe aortic regurgitation. The rate of new permanent pacemaker implantation was 8.1% at 30 days and 11.0% at 1 year. The mean valve gradient was 17.0 ± 8.8 mm Hg at 30 days and 16.6 ± 8.9 mm Hg at 1 year. Factors significantly associated with higher discharge mean aortic gradients were surgical valve size, stenosis as modality of SVF, and presence of surgical valve prosthesis patient mismatch (all p < 0.001).
Conclusions Self-expanding TAVR in patients with SVF at increased risk for surgery was associated with a low 1-year mortality and major stroke rate, significantly improved aortic valve hemodynamics, and low rates of moderate and no severe residual aortic regurgitation, with improved quality of life.
Bioprosthetic surgical aortic valves (SAVs) are the predominant therapy in older patients with symptomatic aortic valve disease (1). Long-term survival in patients with surgical aortic bioprostheses has been excellent (2,3), but bioprosthetic valve degeneration over time is inevitable, resulting in more surgical patients who will require an additional procedure to treat symptomatic prosthesis dysfunction (4).
Reoperation for surgical bioprosthesis failure carries an operative mortality that ranges from 2% for purely elective surgery up to 30% for urgent or emergent surgery, depending on a multitude of factors (4–11); consequently, many patients are not ideal candidates for reoperation (4–6,12). Based on favorable results using transcatheter aortic valve replacement (TAVR) for native valve degenerative aortic stenosis (AS) in patients deemed to be at high (13,14) or extreme risk (15,16) for open surgery, the indications for use of self-expanding TAVR have been expanded for the treatment of patients with failed surgical bioprostheses who are at increased risk for open reoperation (17–20). TAVR may allow more rapid symptomatic relief in these patients without the attendant risks of a prolonged surgical recovery (21,22). Despite these benefits, the VIVID (Valve-in-Valve International Data) registry has demonstrated other associated challenges that include bioprosthesis malposition, left main coronary occlusion, and post-procedural high residual mean valve gradients (MVGs) in some patients (17,18).
The objectives of this study were to prospectively investigate safety and efficacy of self-expanding transcatheter aortic valve in surgical aortic valve (TAV in SAV), and in addition we performed an analysis to evaluate the predictors and prognostic importance of the residual MVG after TAV in SAV.
The findings of the U.S. CoreValve Pivotal Trial Extreme- and High-Risk Studies have been reported in detail elsewhere (15,23). The CoreValve U.S. Expanded Use Study was designed to prospectively evaluate self-expanding TAVR in patients with surgical valve failure (SVF) who were deemed at increased risk for surgery, defined as a 50% or greater risk for mortality or irreversible morbidity at 30 days. Patients with New York Heart Association (NYHA) functional class II or greater symptoms were eligible for the trial. Inclusion and exclusion criteria are summarized in the Online Appendix.
Patients were categorized according to the modality of SVF obtained from the baseline echocardiogram: AS was the categorization used for patients with an aortic valve area <1.2 cm2 and either MVG ≥20 mm Hg or peak velocity ≥3.0 m/s but with less than moderate aortic regurgitation (AR). AR was the categorization for patients with moderate or greater AR who did not meet criteria for AS, and combined disease was defined as at least moderate AS with an aortic valve area <1.2 cm2 and either MVG ≥20 mm Hg or peak velocity ≥3.0 m/s and at least moderate AR.
A manufacturer inner diameter for the failed surgical bioprosthesis between 17 and 29 mm rendered the patient eligible for treatment with a 23-, 26-, 29-, or 31-mm diameter CoreValve bioprosthesis (Medtronic, Minneapolis, Minnesota). The self-expanding bioprosthesis was implanted through the iliofemoral, axillary, or direct aortic access routes. The valve characteristics and implantation procedure have been previously described (13,15,23). Target implantation depth was 3 to 4 mm below the bioprosthetic valve annulus.
The primary endpoint for the study was the rate of all-cause mortality or major stroke at 1 year after TAVR in the attempted implant population. Major and minor stroke were defined using the Valve Academic Research Consortium-1 criteria (24). Secondary endpoints are detailed in the Online Appendix and previous publications (13,15,23). Symptom Status was assessed using the NYHA functional classification system. Quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. Device success and procedural success are defined in the Online Appendix and previous publications (24).
Serial echocardiograms were performed at baseline, at hospital discharge, and 1, 6, and 12 months after TAVR. Clinical site measurements were used for baseline studies, and independent echocardiographic core laboratory (Mayo Clinic, Rochester, Minnesota) readings were used for all follow-up studies.
For additional analyses, patients were classified according to SAVR or SVF modality, 1-month post-procedural MVG (low: <20 mm Hg; high: ≥20 mm Hg), surgical valve size (small: <23 mm; medium: 23 to 25 mm; large: >25 mm), and predicted surgical valve prosthesis-patient mismatch (SV-PPM) derived using the effective orifice area index (EOAi) based on the Instructions for Use from the Food and Drug Administration–approved product labeling (no SV-PPM: EOAi >0.85 cm2/m2; moderate SV-PPM: EOAi >0.65 cm2/m2 but ≤0.85cm2/m2; and severe SV-PPM: EOAi ≤0.65 cm2/m2).
Continuous variables were presented as mean ± SD. Comparisons between or across subgroups were evaluated using 2 sample t tests or analysis of variance F tests. Changes from baseline in continuous variables were evaluated using paired Student t tests. Categorical variables were compared using the chi-square or Fisher exact test, as appropriate. Ordinal variables were compared using the Cochran-Mantel-Haenszel test. Survival curves and other clinical outcomes are presented as Kaplan-Meier estimates. The log-rank test was used to assess possible differences between or among subgroups in time to event data. A 2-sided alpha level of 0.05 was used for all testing, and statistical analyses were performed using SAS version 9.2 software (SAS Institute, Cary, North Carolina).
Between March 2013 and May 2015, 233 patients were enrolled in the TAV-in-SAV study and 227 (97.4%) patients underwent attempted implantation: 3 patients expired after enrollment but before the procedure and 1 patient withdrew consent before the procedure. Two patients were not implanted due to the decision of the implanting physician. The self-expanding bioprosthesis was successfully implanted in 225 (99.1%) of the 227 attempted procedures. Two patients did not have valves implanted: 1 patient developed an access site complication before valve insertion resulting in an aborted procedure and subsequent patient expiration, and the other patient was found to have severe surgical prosthesis patient mismatch by transesophageal echocardiography that resulted in the implanting physician’s decision to terminate the procedure. Study disposition details are provided in Online Figure 1.
Patients were elderly (76.7 ± 10.8 years), commonly men (63.0%), severely symptomatic (86.8% NYHA functional class III or IV), and with a Society of Thoracic Surgeons Predicted Risk of Mortality score of 9.0 ± 6.7%. Clinical findings were similar among the different modalities of SVF other than male sex and diabetes mellitus (both p < 0.01). Complete baseline characteristic data are presented in Table 1.
Surgical valve characteristics
As summarized in Table 2, SVF occurred due to AS (56.4%), AR (22.0%), and combined disease (21.6%). The average surgical valve duration was 10.2 ± 4.3 years. Patients with combined disease had the longest duration, whereas patients with stenosis had the shortest duration (p < 0.001).
Device success was achieved in 210 (93.3%) patients. Of the 15 patients who had device failure, 11 had more than 1 bioprosthesis implanted, and 3 had isolated vascular access complications. There was 1 additional patient who experienced multiple complications, which included more than 1 bioprosthesis implanted, a vascular access complication, and a malposition, such that the total number of each of these events are 12, 4, and 1, respectively. Procedure success was attained in 203 (90.2%) patients. Of the 22 patients with procedural failure, 15 were due to device failure and 7 experienced in-hospital major adverse cardiovascular and cerebrovascular events.
Thirty-day clinical outcomes
At 30 days the all-cause mortality or major stroke rate was 2.6% and did not vary among the modalities of SVF. Six patients (2.7%) experienced neurological events within the first 30 days, including 1 major stroke, 1 minor stroke, 1 transient ischemic attack, and 3 with neuroencephalopathy. Thirty-day all-cause mortality was 2.2%, with no valve-related deaths. There were 4 procedural deaths, including 1 perforation, 1 tamponade from aortic dissection, 1 vascular complication, and 1 from coronary artery occlusion. There was an additional coronary artery obstruction successfully resolved with a percutaneous stent. One patient required surgical reintervention within 30 days. Two patients experienced a myocardial infarction (0.9%). Complete 30-day outcomes are presented in Table 3.
One-year clinical outcomes
Clinical outcomes for patients eligible for 1-year follow up are found in Table 4. The all-cause mortality or major stroke rate at 1 year was 15.8% (Figure 1A). All-cause mortality and cardiovascular mortality rates at 1 year were 14.6% and 7.7%, respectively (Figure 1B) and all-cause mortality did not vary by modality of SVF, SAV size, or presence of SV-PPM (Online Figure 2). There were 3 patients with major strokes, 2 with minor strokes, and 3 with transient ischemic attacks. One patient experienced cardiac perforation with tamponade 8 months after the initial procedure during placement of a plug for worsening paravalvular leak and subsequently expired. There were no additional myocardial infarctions. The rate of new permanent pacemaker implantation was 11.0%. Ninety-three percent of patients were in NYHA functional class I or II (Online Figure 3).
At 1 year, mean aortic valve gradients were reduced from 37.7 to 16.6 mm Hg and EOA improved from 1.02 to 1.41 cm2, as shown in Figure 2A and Online Table 1. In a corresponding paired analysis, these changes were statistically significant (both p < 0.001). The mean aortic valve gradient was significantly higher with smaller valve size at discharge (p < 0.001) and 1 month (p = 0.01) (Figure 2B). More severe SV-PPM (Figure 2C) and stenosis as modality of SVF (Figure 2D) were associated with significantly higher gradients through the first 6 months after the procedure (p < 0.01). Additionally, the percentage of patients with mean gradients ≥20 mm Hg at 1 month is elevated when stenosis is combined with either small surgical valves or severe SV-PPM, and when small surgical valves are combined with severe SV-PPM (Figure 3). There was no significant difference in the 1-year mortality rate (p = 0.64) between patients with 1-month MVG of <20 or ≥20 mm Hg (Figure 4). The impact of 1-month MVG on a composite outcome of mortality, rehospitalization, and reintervention for any reason except residual AR (Online Figure 4) revealed no significant difference between the 2 groups at 1 year. The degree of total aortic valve regurgitation is found in Online Figure 5 and Online Table 1 and shows 4.5% moderate and 0.6% severe regurgitation at 6 months and 7.4% moderate regurgitation at 1 year, with no severe regurgitation. In a separate paired analysis for 107 patients with data available at all follow-up time points, results were similar, with 2.8% moderate and 0.9% severe regurgitation at 6 months and 5.6% moderate and no severe regurgitation at 1 year. For the full cohort, regurgitation was predominantly paravalvular (2.8% moderate and 0.6% severe at 6 months; 4.1% moderate and 0.0% severe at 1 year) rather than transvalvular (1.1% moderate and 0.0% severe at 6 months; 0.8% moderate and 0.0% severe at 1 year).
Improvement in quality of life
The improvements in quality-of-life metrics assessed by the KCCQ overall summary score demonstrate a significant increase from baseline to 30 days (Δ = 28.7) that persisted at 6 months (Δ = 30.8) and 1 year (Δ = 29.9; p < 0.001) (Online Figure 6). When stratified by the modality of SVF, SV-PPM, SAV size, and residual gradient the results show that patients with smaller valves, SV-PPM, stenosis for modality of SVF, and an MVG ≥20 mm Hg have a smaller improvement in quality of life up to 6 months as assessed by the KCCQ, but are similar to the remaining patients at 1 year (Online Figure 7).
Mechanisms of SVF
Bioprosthetic aortic valve surgery is the standard therapy for older patients with symptomatic aortic valve disease. Longer survival and risk of SVF suggest that a number of patients will require a second procedure. Patients presenting with SVF are often elderly with multiple comorbidities, frailty, and disabilities, rendering them increased risk for surgical reoperation (4–6). In our series, the Society of Thoracic Surgeons Predicted Risk of Mortality score was 9.0 ± 6.7% and patients were deemed increased risk for surgery if their predicted operative risk of death or morbidity was 50% or greater at 30 days, determined by 2 clinical site cardiac surgeons and confirmed by a National Screening Committee.
Typically, SVF is due to stenosis, regurgitation, or a combination of both. We found more than one-half of our SVF cases were due to stenosis, and most were smaller stented surgical valves (<23 mm in diameter).
TAVR for SVF
A number of retrospective series have demonstrated the feasibility and safety of the use of TAVR for SVF (19–22,25–30). In the largest of these, the VIVID registry, 459 patients with SVF were treated with either a balloon-expandable or self-expanding TAVR. The 30-day mortality rate was 7.6% of patients and major stroke occurred in 1.7% of patients. Factors associated with mortality at 1 year were AS as the modality of SVF and small surgical valve size (18).
We examined the modality of SVF, surgical valve sizes, and the incidence of SV-PPM at the time of procedure with respect to their impact on post-procedural MVG. Similar to the VIVID registry, smaller surgical valve size and stenosis as modality of SVF had a significant association with higher residual MVG; and we observed that the magnitude of improvement in the KCCQ score was lower within the first 6 months after implantation. However, unlike the VIVID registry, we observed no significant impact on 1-year mortality from either of these factors. Additionally, we found higher gradients in patients with SV-PPM, but again, this had no impact on 1-year mortality.
Independent echocardiographic core lab analysis found a 30-day MVG of 17.0 ± 8.8 mm Hg and 16.6 ± 8.9 mm Hg at 1 year, which we attribute to a large percentage of the study population with stenosis as the modality of SVF, a small surgical valve size, or SV-PPM, which were shown to be associated with higher gradients. These mean gradients are higher than those seen with native aortic valve TAVR, because of the smaller effective aortic annulus with the surgical bioprosthesis. Although TAV in SAV is associated with higher MVG in comparison with TAV in a degenerative native aortic valve, a 1-month MVG ≥20 mm Hg was not associated with a higher mortality rate or with a composite outcome of mortality, readmission to the hospital, or reintervention for any reason other than post-procedural residual AR up to 1 year, and therefore is beneficial in patients at increased risk for reoperation. However, this analysis should not be interpreted as sufficient to expand TAV in SAV for the intermediate- or low-risk patient population because the impact of this higher gradient on medium- and long-term survival and valve durability with the need for reintervention is unknown. Clearly surgeons should make every effort to implant the largest size appropriate SAV and avoid PPM at the initial operation to help minimize the MVG for a subsequent TAV in SAV procedure.
Complications associated with TAVR in SVF
In the published data, numerous complications and other issues have been identified with the use of TAVR for SVF, including device malposition in 15.3% of patients, left main coronary artery occlusion of 3.5%, and a high post-procedural mean gradient of 15.8 ± 8.9 mm Hg (17,18). In our study, <5% of patients required implantation of more than 1 valve, 2.2% were implanted in the nonorthotopic position, and <1% experienced a coronary artery occlusion. We attribute these low complication rates to careful pre-procedural screening, including computed tomography angiography. In addition to the absolute aortic root diameter, the distance from the surgical frame to the origin of the coronary artery was considered for case screening.
This study was not a randomized trial, and no comparisons were pre-specified. Due to a relatively low number of patients in the study, subgroup analyses were somewhat limited. Pre-procedural echocardiography was site reported and not core lab reported similar to all post-procedural data.
The results of our study demonstrate that the use of self-expanding TAVR is safe and effective for SVF in patients unsuitable for SAV replacement. Self-expanding TAVR resulted in acceptable aortic valve hemodynamics and low rates of moderate residual AR, with no severe regurgitation at 1 or 12 months. Higher residual aortic valve gradients at 1 month are associated with small surgical valve size, stenosis as a modality of failure, and degree of PPM. A residual MVG ≥20 mm Hg at discharge appears to be associated with a poorer quality of life within the first 6 months after the procedure but is resolved at 1 year. Higher residual MVG did not significantly impact 1-year survival or a composite outcome of mortality, hospital readmission rate, or reintervention for any reason other than residual post-procedural AR. Longer-term follow-up is essential to determine the impact of the higher residual MVG.
WHAT IS KNOWN? Bioprosthetic surgical valves are the predominant therapy in patients with symptomatic aortic valve disease; however, these valves fail over time and many patients are not candidates for reoperation. Results with TAVR in this patient population have been favorable, and have led to the emergence of TAV in SAV as a less invasive option for patients at increased risk of reoperation.
WHAT IS NEW? Surgeons should avoid PPM at the time of primary surgery, because PPM causes post-procedural gradients at the time of secondary TAV in SAV. Our study demonstrates that TAV in SAV results in a higher residual gradient, which does not appear to negatively impact on early mortality, morbidity, or quality of life; this could possibly have an impact in the future on mid- or late-term mortality as well as durability of the TAV in SAV due to higher shear forces on the valve leaflets secondary to the higher residual gradient and flow velocity. Despite the potential for a higher resulting gradient, this therapy should be used in patients who are at increased surgical risk because of the low overall mortality and stroke rate and the marked increase in quality of life as shown by the KCCQ and NYHA functional class results (Online Appendix).
WHAT IS NEXT? Further studies should include determining the impact of the depth of implant on the gradient and studying the various types of surgical valves implanted to determine if a particular type of valve is more advantageous for TAV in SAV.
Jessica Dries-Devlin, PhD, of Medtronic, provided assistance with tables, figures, and editorial support. Julie Houle Rapp, MBA, Erin McDowell, and Mike Boulware, PhD, of Medtronic, provided overall study management support.
For an expanded Methods section as well as a supplemental table and figures, please see the online version of this article.
This work was funded by Medtronic (Minneapolis, Minnesota). Dr. Deeb has served on the advisory board, on screening committee, on steering committee, and as a principal investigator on the Pivotal trial for Medtronic. Dr. Chetcuti has served as a consultant and proctor for MDT and Edwards Lifesciences. Dr. Reardon has received fees from and served on the advisory board for Medtronic. Dr. Patel has served as a consultant for Medtronic and Edwards Lifesciences. Dr. Grossman has received grant support from Edwards Lifesciences, Medtronic, Blue Cross Blue Shield of Michigan, and the National Institutes of Health, and proctoring fees from Medtronic. Dr. Grossman has received research support from Medtronic and Edwards Lifesciences; and has served as a proctor for Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees from and served as a proctor for Edwards Lifesciences and Medtronic. Dr. Bajwa has served as a proctor for Medtronic. Dr. O’Hair has received grant support from Medtronic and Edwards Lifesciences; and has served as a proctor for Medtronic. Dr. Dauerman has received grant support from Medtronic and Boston Scientific; and has served as a consultant for Medtronic, Abbott Vascular, and Boston Scientific. Dr. Schmoker has received consulting fees from Medtronic. Dr. Watson has received grant support/research contracts and consulting fees from Edwards Lifesciences and Medtronic. Dr. Yakubov has received grant support from Medtronic, Boston Scientific, and Direct Flow Medical. Dr. Oh has received core laboratory and consulting funding from Medtronic. Dr. Li is an employee and shareholder of Medtronic. Dr. Kleiman has received fees from Medtronic. Dr. Adams has received grant support from Medtronic and has royalty agreements through the Mount Sinai School of Medicine with Medtronic and Edwards Lifesciences. Dr. Popma has received institutional grants from Medtronic, Boston Scientific, Direct Flow Medical, and Abbott Vascular; has served on the medical advisory board for Boston Scientific; and has served as a consultant for Direct Flow Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic regurgitation
- aortic stenosis
- effective orifice area index
- Kansas City Cardiomyopathy Questionnaire
- mean valve gradient
- New York Heart Association
- surgical aortic valve
- predicted surgical valve prosthesis-patient mismatch
- surgical valve failure
- TAV in SAV
- transcatheter aortic valve in surgical aortic valve
- transcatheter aortic valve replacement
- Received September 21, 2016.
- Revision received March 6, 2017.
- Accepted March 9, 2017.
- 2017 American College of Cardiology Foundation
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