Research

JAMA Cardiology | Original Investigation Ross Procedure vs Mechanical Replacement in Adults A Systematic Review and Meta-analysis

Amine Mazine, MD, MSc; Rodolfo V. Rocha, MD; Ismail El-Hamamsy, MD, PhD; Maral Ouzounian, MD, PhD; Bobby Yanagawa, MD, PhD; Deepak L. Bhatt, MD, MPH; Subodh Verma, MD, PhD; Jan O. Friedrich, MD, DPhil

Invited Commentary IMPORTANCE The ideal aortic valve substitute in young and middle-aged adults remains page 988 unknown. Supplemental content

OBJECTIVE To compare long-term outcomes between the Ross procedure and mechanical aortic in adults.

DATA SOURCES The Ovid versions of MEDLINE and EMBASE classic (January 1, 1967, to April 26, 2018; search performed on April 27, 2018) were screened for relevant studies using the following text word search in the title or abstract: (“Ross” OR “autograft”) AND (“aortic” OR “mechanical”).

STUDY SELECTION All randomized clinical trials and observational studies comparing the Ross procedure to the use of mechanical prostheses in adults undergoing were included. Studies were included if they reported any of the prespecified primary or secondary outcomes. Studies were excluded if no clinical outcomes were reported or if data were published only as an abstract. Citations were screened in duplicate by 2 of the authors, and disagreements regarding inclusion were reconciled via consensus.

DATA EXTRACTION AND SYNTHESIS This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. Data were independently abstracted by 3 reviewers and pooled using a random-effects model.

MAIN OUTCOMES AND MEASURES The prespecified primary outcome was all-cause mortality.

RESULTS The search identified 2919 reports, of which 18 studies (3516 patients) met inclusion

criteria, including 1 randomized clinical trial and 17 observational studies, with a median Author Affiliations: Division of average follow-up of 5.8 (interquartile range, 3.4-9.2) years. Analysis of the primary outcome , Department of showed a 46% lower all-cause mortality in patients undergoing the Ross procedure Surgery, University of Toronto, compared with mechanical aortic valve replacement (incidence rate ratio [IRR], 0.54; 95% CI, Toronto, Ontario, Canada (Mazine, Rocha); Department of Cardiac 2 0.35-0.82; P = .004; I = 28%). The Ross procedure was also associated with lower rates of Surgery, Montreal Institute, stroke (IRR, 0.26; 95% CI, 0.09-0.80; P =.02;I2 = 8%) and major bleeding (IRR, 0.17; 95% Montreal, Quebec, Canada CI, 0.07-0.40; P < .001; I2 = 0%) but higher rates of reintervention (IRR, 1.76; 95% CI, (El-Hamamsy); Department of 2 Cardiac Surgery, Toronto General 1.16-2.65; P =.007;I = 0%). Hospital, Toronto, Ontario, Canada (Ouzounian); Department of Cardiac CONCLUSIONS AND RELEVANCE Data from primarily observational studies suggest that the Surgery, St Michael’s Hospital, Ross procedure is associated with lower all-cause mortality compared with mechanical aortic Toronto, Ontario, Canada (Yanagawa, Verma); Brigham and Women’s valve replacement. These findings highlight the need for a large, prospective randomized Hospital Heart & Vascular Center, clinical trial comparing long-term outcomes between these 2 interventions. Harvard Medical School, Boston, Massachusetts (Bhatt); Department of Critical Care Medicine, St Michael’s Hospital, Toronto, Ontario, Canada (Friedrich). Corresponding Author: Jan O. Friedrich, MD, DPhil, St Michael’s Hospital, 30 Bond St, Toronto, ON JAMA Cardiol. 2018;3(10):978-987. doi:10.1001/jamacardio.2018.2946 M5B 1W8, Canada (j.friedrich Published online August 25, 2018. @utoronto.ca).

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ortic valve replacement remains the only therapy that has been shown to improve the natural history in pa- Key Points tients with severe symptomatic aortic valve disease.1,2 A Question What is the optimal aortic valve substitute in young and However, young and middle-aged adults with diseased aortic middle-aged adults undergoing aortic valve replacement? valves constitute a challenging population. Owing to a longer Findings This meta-analysis included 3516 adults who underwent life expectancy, these patients present a higher cumulative life- the Ross procedure and found a 46% lower incidence of all-cause time risk of prosthesis-related complications. Because of their mortality compared with patients undergoing mechanical aortic proven durability and ease of implantation, mechanical pros- valve replacement, indicating a significant difference. theses are the most frequently used option in this patient Meaning In carefully selected young and middle-aged adults, the group.3 Recent evidence suggests better long-term survival in Ross procedure is associated with lower all-cause mortality young and middle-aged adults who undergo aortic valve re- compared with mechanical aortic valve replacement. placement with mechanical prostheses compared with bio- logic prostheses.4,5 However, mechanical valves are throm- bogenic and require lifelong anticoagulation, exposing prostheses in adults undergoing aortic valve replacement. Stud- the patient to a continuous hazard of bleeding and thrombo- ies were included if they reported the primary outcome embolic events. Recent studies have reported excess mortal- (ie, all-cause mortality) or any of the prespecified secondary ity in young adults undergoing mechanical aortic valve re- clinical outcomes: operative mortality, perioperative compli- placement compared with the age- and sex-matched general cations, late complications (reoperation, stroke, major bleed- population.6 ing, endocarditis), echocardiographic outcomes at follow-up Replacement of the aortic valve with a pulmonary auto- (mean aortic valve gradient, left ventricular ejection frac- graft and placement of a homograft in the pulmonary posi- tion), or quality of life. Studies were excluded if no clinical out- tion (Ross procedure) was first described by Donald Ross in comes were reported or if data were published only as an ab- 1967.7 In addition to alleviating the need for anticoagulation, stract. Citations were screened in duplicate by 2 of the authors this procedure remains the only aortic valve replacement op- (A.M. and R.V.R.), and full text review, also in duplicate, was eration that provides continued long-term viability of the aor- performed to determine eligibility when either screening re- tic valve substitute, thus allowing adaptive remodeling and viewer felt a citation potentially met inclusion criteria. Dis- conferring a hemodynamic profile similar to that of the na- agreements regarding inclusion were reconciled via consen- tive aortic valve.8 After an initial wave of enthusiasm in the sus. When there was overlap between 2 or more studies, we early 1990s, use of the Ross procedure has declined markedly included only the report with the larger sample size, the lon- over the last 2 decades owing to concerns over the perceived ger duration of follow-up, and/or the most complete descrip- complexity of this operation, which is felt by many to in- tion of the data. crease surgical risk and lead to high rates of reintervention due to autograft failure.9,10 In addition, patients who undergo the Data Analysis Ross procedure are also at risk of late homograft failure, al- Three reviewers (A.M., R.V.R., and J.O.F.) independently ab- though this problem is increasingly managed using percuta- stracted data including details of the publication (ie, study au- neous approaches in the current era.11-13 Thus, there is equi- thors, enrollment period, year of publication, study design), poise regarding the ideal aortic valve substitute in young and inclusion/exclusion criteria, demographics of the enrolled pa- middle-aged adults. Our aim was to compare early and late out- tients, description of the interventions used, and outcome defi- comes in adult patients who undergo the Ross procedure vs nitions and events. Risk of bias in randomized clinical trials mechanical aortic valve replacement. (including blinding of participants, method of sequence gen- eration and allocation concealment, intention-to-treat analy- sis, early trial stoppage for efficacy before planned enroll- Methods ment completion, and loss to follow-up) and cohort studies (including retrospective vs prospective data collection, con- Search Strategy and Selection Criteria current vs historical controls, and comparable baseline char- We conducted a systematic review and meta-analysis in ac- acteristics of cases and controls) were formally assessed using cordance with the Preferred Reporting Items for Systematic re- the Cochrane Collaboration’s Risk of Bias tool for randomized views and Meta-Analyses and Meta-analysis of Observa- clinical trials and the Newcastle-Ottawa Scale for nonrandom- tional Studies in Epidemiology guidelines (eTable 1 in ized studies,16,17 respectively, with disagreements resolved by Supplement 1).14,15 We systematically searched Ovid versions consensus. of MEDLINE (January 1, 1967, to April 26, 2018) and EMBASE All analyses were performed using Review Manager classic (January 1, 1967, to April 26, 2018; search performed on (RevMan version 5.2; Cochrane Collaboration) and the April 27, 2018) for relevant studies using the following text word DerSimonian and Laird random-effects method, which incor- search in the title or abstract: (“Ross” OR “autograft”) AND porates between-trial heterogeneity.18 We assessed statisti- (“aortic” OR “mechanical”). We also searched bibliographies cal heterogeneity among studies using I2, defined as the per- of included studies. We imposed no language restrictions. We centage of total variability across studies attributable to included all randomized clinical trials and observational stud- heterogeneity rather than chance, and used published guide- ies comparing the Ross procedure to the use of mechanical lines for low (I2 = 25% to 49%), moderate (I2 = 50% to 74%),

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and high (I2 > 75%) heterogeneity.19 For perioperative out- with a short duration of follow-up (1 year in all patients). Risk comes, relative risks were used to pool binary outcomes. When of bias in this randomized clinical trial was rated as high ow- necessary, we applied a continuity correction factor of 0.5 to ing to the absence of blinding and relatively stringent exclu- allow inclusion of studies with no events in one of the com- sion criteria (eTable 2 in Supplement 1). Risk of bias in the ob- parator groups but excluded studies with no events in either servational studies is summarized in the eTable 3 in comparator group.20 Weighted mean differences were used to Supplement 1. Five of 17 studies (29.4%) scored higher than pool continuous data. For skewed continuous data, means and 7 of 9 (denoting low risk of bias) on the Newcastle-Ottawa Scale SDs were estimated from medians and interquartile ranges or for nonrandomized studies. Inadequate comparability of the ranges as described by Wan et al.21 Imbalances in baseline char- 2 study groups (12 of 17 studies [70.6%]) and insufficient length acteristics were also assessed using standardized differences,22 of follow-up (<5 years in 7 of 17 studies [41.2%]) were the 2 most including correction for small sample bias.23 common sources of potential bias. Comparisons of baseline For long-term outcomes with potentially different fol- characteristics and intraoperative data between the groups are low-up between groups, we pooled incidence rate ratios (IRRs) presented in eTable 4 in Supplement 1. on the logarithmic scale using the generic inverse variance Compared with patients who underwent mechanical aor- method. When hazard ratios (assumed to be equivalent to IRRs) tic valve replacement, patients in the Ross group had a statis- were not provided, IRRs for each study were calculated in 1 of tically significant 46% reduction in the primary outcome of all- 2 ways: (1) using Kaplan-Meier survival curve estimates for each cause mortality (IRR, 0.54; 95% CI, 0.35-0.82; P = .004; group and the log-rank survival curve P value to estimate the I2 = 28%; 0.05%/y vs 0.10%/y) (Figure 1). Similarly, the inci- standard error of the logarithm-transformed IRR or other- dence of valve- or cardiac-related mortality was significantly wise (2) using absolute events divided by patient-years of fol- lower in the Ross group (IRR, 0.42; 95% CI, 0.18-0.97; P = .04; low-up (estimated as number of patients per group multi- I2 = 34%; 0.04%/y vs 0.09%/y) (eFigure 2 in Supplement 1). plied by group-specific mean duration of follow-up in years) There was no difference in the rate of perioperative mor- when group-specific mean follow-up durations were pro- tality between the groups (risk ratio [RR], 0.73; 95% CI, vided, as previously described.24,25 Individual study and 0.37-1.44; P = .36; I2 = 0%; 17 of 2085 [0.8%] vs 25 of 1766 pooled summary results are reported with 95% CIs. [1.4%]) (eFigure 3 in Supplement 1). Similarly, no significant Study results were subgrouped by study type: random- differences were noted in the incidence of the following peri- ized clinical trials vs propensity-score matched or risk- operative complications (eTable 5 in Supplement 1): acute myo- adjusted observational data vs unmatched/unadjusted obser- cardial infarction (RR, 1.96; 95% CI, 0.48-7.97; P = .35; I2 = 0%), vational data. In cases where observational studies reported stroke or transient ischemic attack (RR, 0.36; 95% CI, both matched/risk-adjusted and unmatched/unadjusted data, 0.10-1.32; P = .12; I2 = 0%), reoperation for bleeding (RR, 1.07; the matched or risk-adjusted outcomes were preferentially 95% CI, 0.66-1.75; P = .78; I2 = 14%), acute kidney injury (RR, used in calculating the overall pooled result, if available. Oth- 1.79; 95% CI, 0.30-10.49; P = .52; I2 = 40%), atrial fibrillation erwise, the unmatched/unadjusted outcomes were used. This (RR, 1.39; 95% CI, 0.73-2.66; P = .32; I2 = 22%), and sternal means that studies that report matched or risk-adjusted out- wound infection (RR, 1.49; 95% CI, 0.26-8.48; P =.65;I2 = 0%). comes for some but not all outcomes appear in the matched/ The Ross procedure was associated with lower rates of heart adjusted subgroup for some outcomes and the unmatched/ block requiring permanent pacemaker implantation (RR, 0.40; unadjusted subgroup for other outcomes. 95% CI, 0.17-0.94; P = .04; I2 = 0%). Freedom from any operated valve reintervention was com- pared between groups. In the Ross group, this included any Results percutaneous or surgical reintervention on the pulmonary au- tograft and/or pulmonary homograft. We noted a signifi- Our search strategy identified 2919 citations, of which 69 were cantly higher rate of reintervention in the Ross group (IRR, 1.76; retrieved for more detailed assessment. Fifty-one studies were 95% CI, 1.16-2.65; P = .007, I2 = 0%; 0.12%/y vs 0.06%/y) com- excluded following full text review. A total of 18 studies were pared with mechanical aortic valve replacement (Figure 2). included in the analysis: 1 randomized clinical trial (5.6%),26 The Ross procedure was associated with significantly lower 10 matched/adjusted observational studies (55.6%),27-36 and rates of stroke (IRR, 0.26; 95% CI, 0.09-0.80; P = .02; I2 =8%; 7 unmatched/unadjusted observational studies (38.9%) 0.04%/y vs 0.10%/y) (Figure 3) and major bleeding (IRR, 0.17; (eFigure 1 in Supplement 1).37-43 95% CI, 0.07-0.40; P < .001; I2 = 0%; 0.01%/y vs 0.11%/y) The selected studies included a total of 3516 patients, of (Figure 4) at follow-up, compared with mechanical aortic valve whom 1552 (44.1%) underwent a Ross procedure, and 1964 replacement. The incidence of endocarditis was low and (55.9%) underwent mechanical aortic valve replacement. Char- not significantly different between the groups (P = .35) acteristics of the included studies are presented in the Table. (eTable 5 in Supplement 1). Study size ranged from 11 to 692 patients. One study Echocardiographic data were reported in 7 studies. At last followed up patients only to hospital discharge. The median follow-up (median average study follow-up, 2.4 years; range: (interquartile range) average follow-up in the remaining stud- hospital discharge, 5.4 years), patients in the Ross group had ies was 5.8 (3.4 to 9.2) years (range, 11 months to 14.8 years). significantly lower mean transaortic valve gradients (mean dif- The single unblinded randomized clinical trial in this meta- ference, 9.8 mm Hg; 95% CI, 8.0-11.7; P < .001; I2 = 82%) analysis included a small number of patients (20 per group) (eFigure 4 in Supplement 1). There was high heterogeneity

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Table. Characteristics of Studies Included in the Meta-Analysis

No. of No. of Age, Follow-up, Source Country Centers Design Group Patients Mean (SD), y Men, % Mean (SD), y Retrospective Ross 39 40 (7) 69 6.1 (2.6) Aicher et al,40 2011 Germany 1 observational; unadjusted mAVR 41 40 (7) 86 6.5 (2.4) Retrospective Ross 18 38 (9) 72 3.2 (1.8) Akhyari et al,39 2009 Germany 1 observational; unadjusted mAVR 20 42 (7) 75 4.2 (2.2) Retrospective Ross 159 35 (8) 80 9.9 (6.0) Andreas et al,32 2014 Austria 1 observational, adjusted mAVR 173 41 (7) 75 7.9 (5.4) Retrospective Ross 3 20 (14-32)b 0 9 (9-16)b 42 a Basude et al, 2014 United Kingdom 1 observational; b b unadjusted mAVR 8 25 (7-33) 0 13 (6-20) c Propensity score Ross 70 52 (45-59) 77 Hospital stay Bouhout et al,35 2017 Canada 1 matching mAVR 70 52 (45-59)c 67 Hospital stay

1 Propensity score Ross 275 43 (11) 71 10 (7) Buratto et al,36 2018 Australia 31matching mAVR 275 44 (11) 73 10 (7) Retrospective Ross 63 35 (8) 78 2.5 (1.6) Concha et al,30 2005 Spain 1 observational; adjusted mAVR 62 38 (7) 76 2.5 (1.6) Randomized clinical Ross 20 49 (8) 60 1 (0) Doss et al,26 2005 Germany 1 trial mAVR 20 48 (7) 55 1 (0) Retrospective Ross 18 22 (7) 0 NR Heuvelman et al,41 Netherlands 1 observational; 2013a unadjusted mAVR 9 31 (9) 0 NR Retrospective Ross 22 38 (11) 77 0.9 (NR) Jaggers et al,27 1998 United States 1 observational; adjusted mAVR 27 41 (11) 63 2.5 (NR) Retrospective Ross 81 31 (9) 63 7.7 (2.3) Klieverik et al,37 2006 Netherlands 1 observational; unadjusted mAVR 204 45 (8) 73 6.2 (3.2) Propensity score Ross 208 37 (10) 64 13.6 (5.8) Mazine et al,33 2016 Canada 1 matching mAVR 209 37 (11) 63 14.8 (7.2)

Germany/ 12 Propensity score Ross 253 47 (9) 76 5.1 (NR) Mokhles et al,31 2011 Netherlands 1matching mAVR 253 48 (11) 73 6.3 (NR) Retrospective Ross 40 26 (6) 73 2.2 (1.3) Nötzold et al,28 2001 Germany 1 observational; adjusted mAVR 40 27 (5) 73 1.9 (0.7) Retrospective Ross 20 57 (9) 70 1.9 (0.9) Schmidtke et al,29 2001 Germany 1 observational; adjusted mAVR 40 58 (9) 70 2.1 (1.1) Propensity score Ross 224 Sharabiani et al,34 2016 United Kingdom 37 NR NR NR matching mAVR 468 Retrospective Ross 22 38 (12) 83 1.75 (NR) Zacek et al,43 2016 Czech Republic 1 observational; unadjusted mAVR 29 40 (7) 69 1.75 (NR) Retrospective Ross 17 26 (6) 59 5.9 (2.3) Zsolt et al,38 2008 Hungary 1 observational; unadjusted mAVR 17 27 (5) 88 4.8 (2.1) Abbreviations: mAVR, mechanical aortic valve replacement; NR, not reported. b Reported as median (range). a These studies included only pregnant women. c Reported as median (interquartile range).

between studies regarding the magnitude but not the direc- group for the subcomponents of bodily pain (P < .001), social tion of this difference in mean gradients. A clinically and sta- functioning (P = .03), and mental health (P = .002) (eFigures tistically insignificant improvement in left ventricular ejec- 5and6inSupplement 1). All other subcomponents were not tion fraction at follow-up (median average study follow-up, statistically different between the groups. 2.2 years; range, 1.0-5.4 years) was also noted in the Ross group (mean difference, 3%; 95% CI, −2% to 8%; P = .20; I2 =78%) (eTable 5 in Supplement 1). Discussion Four studies compared quality of life following the Ross procedure vs mechanical aortic valve replacement using the To our knowledge, this is the first systematic review and meta- 36-Item Short Form Survey. Our meta-analysis showed sig- analysis to compare the Ross procedure with mechanical nificantly higher scores (ie, improved quality of life) in the Ross aortic valve replacement in adults. This study included

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Figure 1. All-Cause Mortality

Mean Ross AVR IRR IV, Random Favors Favors Weight, Study or Subgroup Follow-up, y log (IRR) SE Total Total (95% CI) Ross Autograft Mechanical AVR % Randomized trial Doss et al,26 2005 1.0 0.6931 1.2247 20 20 2.00 (0.18-22.05) 3.0 Subtotal (95% CI) 20 20 2.00 (0.18-22.05) 3.0 Heterogeneity: not applicable Test for overall effect: z = 0.57 (P =.57) Matched/adjusted observational Jaggers et al,27 1998 1.7 –0.4185 1.5492 22 27 0.66 (0.03-13.71) 1.9 Concha et al,30 2005 2.5 –1.4023 1.1180 63 62 0.25 (0.03-2.20) 3.5 Andreas et al,32 2014 8.9 –0.9555 0.4019 159 173 0.38 (0.17-0.85) 16.4 Mazine et al,33 2016 14.0 –0.4415 0.3498 208 208 0.64 (0.32-1.28) 18.9 Sharabiani et al,34 2016 5.3 –0.8544 0.5380 224 468 0.43 (0.15-1.22) 11.4 Buratto et al,36 2018 10.0 –1.0986 0.4644 275 275 0.33 (0.13-0.83) 13.8 Subtotal (95% CI) 951 1213 0.45 (0.30-0.67) 65.9 Heterogeneity: τ2 = 0.00; χ2 = 1.97, df = 5 (P = .85); I2 = 0% Test for overall effect: z = 3.88 (P <.001) Unmatched/unadjusted observational Akhyari et al,39 2009 3.7 –0.7742 1.6330 18 20 0.46 (0.02-11.32) 1.7 Klieverik et al,37 2006 7.0 –1.4250 0.6567 81 204 0.24 (0.07-0.87) 8.5 Zsolt et al,38 2008 5.4 –1.8140 1.5492 17 17 0.16 (0.01-3.40) 1.9 Mokhles et al,31 2011 6.0 0.3706 0.3469 925 408 1.45 (0.73-2.86) 19.0 Subtotal (95% CI) 1041 649 0.53 (0.15-1.91) 31.2 Heterogeneity: τ2 = 0.88; χ2 = 7.30, df = 3 (P = .06); I2 = 59% Test for overall effect: z = 0.97 (P =.33) Total (95% CI) 2012 1882 0.54 (0.35-0.82) 100.0 Heterogeneity: τ2 = 0.13; χ2 = 13.95, df = 10 (P = .18); I2 = 28% Test for overall effect: z = 2.85 (P = .004) Test for subgroup differences: χ2 = 1.47; df = 2 (P = .48); I2 = 0% 0.01 0.1 1 10 100 IRR IV, Random Effects, (95% CI)

Forest plot comparing all-cause mortality following the Ross procedure vs unmatched/unadjusted observational studies. The pooled incidence rate ratios mechanical aortic valve replacement (AVR). Individual study and pooled with 95% CIs were calculated using random-effects models. IV indicates inverse incidence rate ratios (IRRs) are also presented separately for the randomized variance weighting; SE, standard error. clinical trial, and subgroups of matched/adjusted observational studies, and

3516 patients who underwent either the Ross procedure or me- Second, because the pulmonary autograft is a living struc- chanical aortic valve replacement. The main finding is that the ture, it has the potential to reproduce the sophisticated func- Ross procedure is associated with improved freedom from all- tions of the normal aortic root. Thus, the enhanced survival cause mortality, largely driven by superior freedom from car- observed in patients who have undergone the Ross proce- diac- and valve-related mortality. Secondary findings are that dure may reflect the beneficial effects of improved hemody- perioperative mortality and morbidity are not significantly dif- namics on left ventricular health, particularly in this young ac- ferent between the groups, with the exception of permanent tive patient population. These 2 hypotheses are supported by pacemaker implantation, which is higher after mechanical aor- the observation of a significantly better freedom from car- tic valve replacement. Furthermore, the Ross procedure is as- diac- and valve-related mortality in the Ross group, as well as sociated with lower rates of stroke and major bleeding at fol- lower rates of stroke and bleeding, improved quality of life, and low-up at the cost of a higher rate of reintervention. Quality lower mean aortic gradients at follow-up. These findings are of life and were enhanced after the Ross pro- also in keeping with the results of several contemporary co- cedure. Finally, our systematic review highlighted the pau- hort studies with long-term follow-up that have demon- city of randomized data addressing this question. strated excellent survival well into the second postoperative The superior freedom from all-cause mortality in pa- decade after the Ross procedure.44-50 The majority of these tients undergoing the Ross procedure may be explained by 2 studies have reported a survival that was similar to that of the main factors. First, in contrast to mechanical aortic valve re- age- and sex-matched general population. In contrast, large co- placement, the Ross procedure alleviates the need for life- hort studies have demonstrated that mechanical valves are as- long anticoagulation through the avoidance of prosthetic valve sociated with excess long-term mortality compared with the material. This advantage is particularly significant in young and matched general population when implanted in young and middle-aged adults who, because of their longer anticipated middle-aged adults.4,6 life expectancy and active lifestyle, present a higher cumula- While the superior survival observed in patients who have tive lifetime risk of prosthesis-related complications. undergone Ross procedure is in large part attributable to the

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Figure 2. Any Operated Valve Reintervention

Mean Ross AVR IRR IV, Random Favors Favors Weight, Study or Subgroup Follow-up, y log (IRR) SE Total Total (95% CI) Ross Autograft Mechanical AVR % Randomized clinical trial Doss et al,26 2005 1.0 1.6094 1.5492 20 20 5.00 (0.24-104.14) 1.8 Subtotal (95% CI) 20 20 5.00 (0.24-104.14) 1.8 Heterogeneity: not applicable Test for overall effect: z = 1.04 (P =.30) Matched/adjusted observational Jaggers et al,27 1998 1.7 0.1095 1.1547 22 27 1.12 (0.12-10.73) 3.3 Concha et al,30 2005 2.5 1.3196 1.1180 62 58 3.74 (0.42-33.48) 3.5 Mokhles et al,31 2011 6.0 3.0831 1.4552 253 253 21.83 (1.26-378.13) 2.1 Mazine et al,33 2016 14.0 0.6206 0.4775 207 207 1.86 (0.73-4.74) 19.2 Sharabiani et al,34 2016 5.3 –0.0953 0.4246 224 468 0.91 (0.40-2.09) 24.3 Subtotal (95% CI) 768 1013 1.70 (0.79-3.68) 52.4 Heterogeneity: τ2 = 0.22; χ2 = 5.71, df = 4 (P = .22); I2 = 30% Test for overall effect: z = 1.35 (P =.18) Unmatched/unadjusted observational Klieverik et al,37 2006 7.0 0.9163 0.5733 79 200 2.50 (0.81-7.69) 13.3 Zsolt et al,38 2008 5.4 0.8941 1.6330 17 17 2.45 (0.10-60.02) 1.6 Akhyari et al,39 2009 3.7 1.4231 1.6330 18 20 4.15 (0.17-101.87) 1.6 Andreas et al,32 2014 8.9 0.5592 0.3873 156 171 1.75 (0.82-3.74) 29.2 Subtotal (95% CI) 270 408 2.03 (1.11-3.71) 45.8 Heterogeneity: τ2 = 0.00; χ2 = .48, df = 3 (P = .92); I2 = 0% Test for overall effect: z = 2.28 (P =.02) Total (95% CI) 1058 1441 1.76 (1.16-2.65) 100.0 Heterogeneity: τ2 = 0.00; χ2 = 7.18, df = 9 (P = .62); I2 = 0% Test for overall effect: z = 2.69 (P = .007) Test for subgroup differences: χ2 = .50; df = 2 (P = .78); I2 = 0% 0.01 0.1 1 10 100 IRR IV, Random Effects, (95% CI)

Forest plot comparing reintervention on any operated valve following the Ross unmatched/unadjusted observational studies. The pooled incidence rate ratios procedure vs mechanical aortic valve replacement (AVR). In the Ross group, this with 95% CIs were calculated using random-effects models. Data from the includes any percutaneous or surgical reintervention on the pulmonary study by Sharabiani et al34 were extracted from the graphs using a plot autograft and/or pulmonary homograft. Individual study and pooled incidence digitization software. IV indicates inverse variance weighting; SE, standard rate ratios (IRRs) are also presented separately for the randomized clinical trial, error. and the subgroups of matched/adjusted observational studies, and

unique adaptive and hemodynamic characteristics of the liv- dilated aortic annulus and/or aortic/pulmonary annular mis- ing pulmonary autograft, there is no doubt that careful pa- match, a standard Ross procedure is associated with higher tient selection is equally important to achieve optimal out- rates of autograft dilatation and need for reoperation.52 Nev- comes with this operation. Although findings from this meta- ertheless, a number of technical modifications and adjunct analysis suggest better outcomes after a Ross procedure, this measures have been proposed to mitigate the risk of late fail- is not to say that, as a surgical approach, it is definitively su- ure, which are thought to improve the durability of the Ross perior to a mechanical aortic valve replacement. Instead, they procedure in these patients.53,54 However, the Ross proce- should be seen as 2 treatment options providing very differ- dure is contraindicated in patients with familial aortopathy and ent outcomes, each offering unique opportunities to a given connective tissue disorder—owing to a prohibitive risk of au- patient depending on their clinical profile and personal pref- tograft dilatation and failure—and certain autoimmune disor- erences. Achieving optimal outcomes therefore requires tai- ders (eg, lupus erythematosus, rheumatoid arthritis) as well loring the appropriate surgical approach to the individual pa- as in the presence of any associated condition that may limit tient, based on shared decision making and consideration of life expectancy (eg, radiation-induced mediastinal disease, patient values and preferences.51 end-stage renal disease).55 From a technical standpoint, the ideal candidate for the It is widely held that the Ross procedure is a technically com- Ross procedure is a young or middle-aged adult with aortic plex operation and that this increased complexity may translate valve disease (ideally aortic stenosis), a small or nondilated aor- into greater operative risk. Nevertheless, our meta-analysis sug- tic annulus (<25-27 mm), normal aortic dimensions, and a pro- gested equivalent rates of perioperative mortality and morbid- jected life expectancy of 10 to 15 years or longer. The opera- ity between the Ross procedure and mechanical aortic valve re- tion is of particular benefit to patients with high levels of placement. The only significant difference observed in early out- physical activity, those at risk of patient-prosthesis mis- comes was a higher rate of permanent pacemaker implantation match, and women contemplating pregnancy. In contrast, for in the mechanical aortic valve replacement group. This differ- patients presenting with preoperative aortic insufficiency, a ence may be explained by the potential impingement on the

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Figure 3. Stroke at Follow-up

Mean Ross AVR IRR IV, Random Favors Favors Weight, Study or Subgroup Follow-up, y log (IRR) SE Total Total (95% CI) Ross Autograft Mechanical AVR % Randomized clinical trial Doss et al,26 2005 1.0 1.0986 1.633 20 20 3.00 (0.12-73.64) 11.4 Subtotal (95% CI) 20 20 3.00 (0.12-73.64) 11.4 Heterogeneity: not applicable Test for overall effect: z = 0.67 (P =.50) Matched/adjusted observational Jaggers et al,27 1998 1.7 0.0924 1.633 22 27 1.10 (0.04-26.92) 11.4 Concha et al,30 2005 2.5 –1.1651 1.633 62 58 0.31 (0.01-7.66) 11.4 Mazine et al,33 2016 14.0 –1.7579 0.810 207 207 0.17 (0.04-0.84) 40.1 Subtotal (95% CI) 291 292 0.26 (0.07-0.95) 62.8 Heterogeneity: τ2 = 0.00; χ2 = 1.05, df = 2 (P = .59); I2 = 0% Test for overall effect: z = 2.04 (P =.04) Unmatched/unadjusted observational Andreas et al,32 2014 8.9 –2.4364 1.0488 156 171 0.09 (0.01-0.68) 25.8 Subtotal (95% CI) 156 171 0.09 (0.01-0.68) 25.8 Heterogeneity: not applicable Test for overall effect: z = 2.32 (P =.02) Total (95% CI) 467 483 0.26 (0.09-0.80) 100.0 Heterogeneity: τ2 = 0.14; χ2 = 4.37, df = 4 (P = .36); I2 = 8% Test for overall effect: z = 2.35 (P = .02) Test for subgroup differences: χ2 = 3.32; df = 2 (P = .19); I2 = 39.8% 0.01 0.1 1 10 100 IRR IV, Random Effects, (95% CI)

Forest plot comparing the incidence of stroke following the Ross procedure vs unmatched/unadjusted observational studies. The pooled incidence rate ratios mechanical aortic valve replacement (AVR). Individual study and pooled with 95% CIs were calculated using random-effects models. IV indicates inverse incidence rate ratios (IRRs) are also presented separately for the randomized variance weighting; SE, standard error. clinical trial, and subgroups of matched/adjusted observational studies, and

conduction system by the rigid sewing ring of mechanical pros- patient-year.44,45 These technical refinements and improved theses, which is not present on a pulmonary autograft. Thus, our outcomes notwithstanding, a subset of patients who un- findings suggest that in dedicated centers, the long-term benefits dergo the Ross procedure will invariably require reoperation, of the Ross operation do not come at the cost of increased early particularly after 15 to 20 years,46 and it is reasonable to as- risk. However, it should be mentioned that as with any complex sume this operation will always carry a risk of reintervention procedure, outcomes of the Ross procedure are closely correlated that is greater than that of mechanical valves. Our data sug- with surgical volumes.56,57 It follows that this operation should gest that this increased risk of reintervention is not enough to not be carried out sporadically and that an adequate annual vol- counterbalance the potential long-term benefits of the Ross ume of root replacement and Ross procedures is required to procedure, resulting in an associated net survival advantage. achieve and maintain competence. The higher rate of reintervention observed in the Ross group Strengths and Limitations can be explained by the risk of late dilatation of the pulmonary The strength of this study is the use of rigorous methodology,in- autograft, as well as by the potential long-term failure of 2 valves cluding a reproducible and comprehensive literature search, rather than 1, which is considered by many to be the Achilles’ heel clearly defined inclusion criteria, duplicate citation review, data of the Ross procedure. Fortunately, homograft failure—and the abstraction, and quality assessment of individual studies. Our ensuing right ventricular volume and/or pressure overload—is systematic review highlights the limited number of published usually tolerated for a long time before requiring reintervention. studies and enrolled patients per study. In contrast to the large Furthermore, in the current era, homograft failure is increasingly number of case series describing medium- and long-term out- treated percutaneously using transcatheter valves, therefore ob- comes of the Ross procedure and mechanical aortic valve replace- viating the need for open reinterventions.11-13 ment, there is a paucity of comparative data and only a single There is wide variability in the reported durability of the small randomized clinical trial directly comparing the 2 ap- Ross operation, and certain early series have reported con- proaches. Of note, risk of bias in this randomized clinical trial was cerning rates of reintervention.10 However, proponents of the rated as high, and while its results are presented separately in this Ross procedure argue that the risk of reintervention may be meta-analysis, they should be interpreted cautiously in light of largely mitigated by subtle technical refinements based on a the small number of patients included (20 per group) and short thorough understanding of aortic and pulmonary root physi- duration of follow-up (1 year in all patients). Thus, the results of ology and mechanisms of valve failure.58,59 Supporting this this meta-analysis are based almost exclusively on observational notion, several large recently published series have reported studies, most of which had baseline differences between low rates of reintervention ranging from 0.5% to 1.0% per the groups. Potential hidden confounders and known patient

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Figure 4. Major Bleeding at Follow-up

Mean Ross AVR IRR IV, Random Favors Favors Weight, Study or Subgroup Follow-up, y log (IRR) SE Total Total (95% CI) Ross Autograft Mechanical AVR % Randomized clinical trial Doss et al,26 2005 1.0 –1.0986 1.6330 20 20 0.33 (0.01-8.18) 7.5 Subtotal (95% CI) 20 20 0.33 (0.01-8.18) 7.5 Heterogeneity: not applicable Test for overall effect: z = 0.67 (P =.50) Matched/adjusted observational Jaggers et al,27 1998 1.7 0.0924 1.6330 22 27 1.10 (0.04-26.92) 7.5 Concha et al,30 2005 2.5 –2.2637 1.4907 62 58 0.10 (0.01-1.93) 9.0 Mokhles et al,31 2011 6.0 –0.8487 0.8165 253 253 0.43 (0.09-2.12) 30.1 Mazine et al,33 2016 14.0 –3.7656 1.4292 207 207 0.02 (0.00-0.38) 9.8 Subtotal (95% CI) 544 545 0.21 (0.05-0.93) 56.4 Heterogeneity: τ2 = .75; χ2 = 4.36, df = 3 (P = .23); I2 = 31% Test for overall effect: z = 2.06 (P =.04) Unmatched/unadjusted observational Klieverik et al,37 2006 7.0 –2.3327 1.4475 79 200 0.10 (0.01-1.66) 9.6 Zsolt et al,38 2008 5.4 –1.3032 1.6330 17 17 0.27 (0.01-6.67) 7.5 Andreas et al,32 2014 8.9 –3.0242 1.0274 156 171 0.05 (0.01-0.36) 19.0 Subtotal (95% CI) 252 388 0.08 (0.02-0.36) 36.1 Heterogeneity: τ2 = 0.00; χ2 = 0.81, df = 2 (P = .67); I2 = 0% Test for overall effect: z = 3.33 (P <.001) Total (95% CI) 816 953 0.17 (0.07-0.40) 100.0 Heterogeneity: τ2 = 0.00; χ2 = 6.52, df = 7 (P = .48); I2 = 0% Test for overall effect: z = 4.02 (P <.001) Test for subgroup differences: χ2 = 1.01; df = 2 (P = .60); I2 = 0% 0.01 0.1 1 10 100 IRR IV, Random Effects, (95% CI)

Forest plot comparing the incidence of major bleeding following the Ross studies, and unmatched/unadjusted observational studies. The pooled procedure vs mechanical aortic valve replacement (AVR). Individual study and incidence rate ratios with 95% CIs were calculated using random-effects pooled incidence rate ratios (IRRs) are also presented separately for the models. IV indicates inverse variance weighting; SE, standard error. randomized clinical trial, and subgroups of matched/adjusted observational

selection factors therefore undoubtedly contributed to the ob- who undergo the Ross procedure could not be assessed in this served differences. Although we prioritized data from matched/ meta-analysis. In addition, the included studies did not report adjusted studies that attempted to correct for these baseline dif- adequacy of anticoagulation (ie, adherence to treatment and time ferences, only an adequately powered randomized clinical trial in therapeutic range) in the mechanical aortic valve replacement would be able to definitively eliminate residual confounding in- group, which could have an impact on rates of and herent in nonrandomized studies. As a result, this meta-analysis bleeding. Only 7 of 18 included studies specified the type of me- is by no means prescriptive, nor is it intended to demonstrate the chanical valve models used, and none stratified reported out- superiority of one approach over the other in absolute terms. Fur- comes by type, making it impossible to assess differences in valve- thermore, the median average follow-up in the included stud- related complications between different models of mechanical ies was 5.8 years, which is insufficient to adequately address the prostheses. The recent introduction of less thrombogenic me- long-term impact of structural valve deterioration following the chanical valves requiring a lower target international normalized Ross procedure, which predominantly manifests into the second ratio (eg, On-X valve)63 may affect comparisons with the Ross pro- decade after surgery.Of note, the 2 studies with an average follow- cedure in the future. It is also unclear how closely outcomes up longer than 10 years included in this meta-analysis demon- within each study might have been associated with individual strated superior survival in the Ross group.33,36 Nonetheless, surgeons’ experience and level of comfort with each of the 2 tech- given the wide variability in published rates of reintervention fol- niques. Finally, the large number of statistical tests conducted lowing the Ross procedure,44,46,60,61 further comparative stud- in this analysis increases the risk of type I errors. As a result, out- ies with long-term follow-up are required to conclusively deter- comes with P values that are only slightly lower than the thresh- mine whether some of the benefits of the Ross operation over me- old of .05 should be considered as hypothesis-generating only chanical aortic valve replacement (eg, living substitute, optimal because P values have not been adjusted for multiple testing. hemodynamics, avoidance of anticoagulation) are offset by an increased risk of late structural valve deterioration and reinter- vention. Recent evidence suggests that the root replacement tech- Conclusions nique may provide superior long-term survival and freedom from reintervention compared with the subcoronary implantation In summary, data from this meta-analysis suggest long-term technique.62 However, the effect of the technique used in patients benefits of the Ross procedure in terms of association with

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better survival, freedom from thromboembolic and hemor- suggesting improved long-term outcomes with the Ross rhagic complications, and quality of life. These findings are in procedure,65 make it important for clinicians to discuss the pul- stark contrast with clinical practice, where the use of the Ross monary autograft when considering options for aortic valve procedure remains extremely limited and confined to only a replacement in young and middle-aged adults. Findings from handful of centers worldwide.9,64 The suboptimal outcomes this meta-analysis highlight the urgent need for a large, pro- associated with the use of prosthetic valves in young and spective randomized clinical trial comparing long-term out- middle-aged adults,4 as well as the accumulating evidence comes between these 2 interventions.

ARTICLE INFORMATION aortic valve disease. Lancet. 2016;387(10025):1312- 14. Moher D, Liberati A, Tetzlaff J, Altman DG; Accepted for Publication: August 2, 2018. 1323. doi:10.1016/S0140-6736(16)00586-9 PRISMA Group. Preferred reporting items for 2. Carabello BA, Paulus WJ. Aortic stenosis. Lancet. systematic reviews and meta-analyses: the PRISMA Published Online: August 25, 2018. Statement. Open Med. 2009;3(3):e123-e130. doi:10.1001/jamacardio.2018.2946 2009;373(9667):956-966. doi:10.1016/S0140-6736 (09)60211-7 15. Stroup DF, Berlin JA, Morton SC, et al. Author Contributions: Drs Mazine and Friedrich Meta-analysis of observational studies in had full access to all of the data in the study and 3. Isaacs AJ, Shuhaiber J, Salemi A, Isom OW, Sedrakyan A. National trends in utilization and epidemiology: a proposal for reporting. take responsibility for the integrity of the data and Meta-analysis Of Observational Studies in the accuracy of the data analysis. in-hospital outcomes of mechanical versus bioprosthetic aortic valve replacements. J Thorac Epidemiology (MOOSE) group. JAMA. 2000;283 Concept and design: El-Hamamsy, Ouzounian, (15):2008-2012. doi:10.1001/jama.283.15.2008 Yanagawa, Verma, Friedrich. Cardiovasc Surg. 2015;149(5):1262-1269. doi:10 Acquisition, analysis, or interpretation of data: .1016/j.jtcvs.2015.01.052 16. Higgins JP, Green S. Cochrane Handbook for Mazine, Rocha, Yanagawa, Bhatt, Verma, Friedrich. 4. Goldstone AB, Chiu P, Baiocchi M, et al. Systematic Reviews of Interventions Version 5.1.0 Drafting of the manuscript: Mazine, El-Hamamsy. Mechanical or biologic prostheses for aortic-valve [updated March 2011]. The Cochrane Collaboration. Critical revision of the manuscript for important and mitral-valve replacement. N Engl J Med.2017; http://handbook-5-1.cochrane.org/. Accessed August intellectual content: All authors. 377(19):1847-1857. doi:10.1056/NEJMoa1613792 8, 2018. Statistical analysis: Mazine, Friedrich. 5. Glaser N, Jackson V, Holzmann MJ, 17. Wells GA, Shea B, O’Connell D, et al. The Administrative, technical, or material support: Franco-Cereceda A, Sartipy U. Aortic valve Newcastle–Ottawa Scale (NOS) for assessing the Rocha. replacement with mechanical vs. biological quality of nonrandomised studies in meta-analyses. Supervision: El-Hamamsy, Ouzounian, Yanagawa, prostheses in patients aged 50-69 years. Eur Heart http://www.ohri.ca/programs/clinical Verma, Friedrich. J. 2016;37(34):2658-2667. doi:10.1093/eurheartj _epidemiology/oxford.htm. Accessed November 15, Conflict of Interest Disclosures: All authors have /ehv580 2017. completed and submitted the ICMJE Form for 6. Bouhout I, Stevens LM, Mazine A, et al. 18. DerSimonian R, Laird N. Meta-analysis in clinical Disclosure of Potential Conflicts of Interest. Dr Long-term outcomes after elective isolated trials. Control Clin Trials. 1986;7(3):177-188. doi:10 Bhatt reports grants from Amarin, AstraZeneca, mechanical aortic valve replacement in young .1016/0197-2456(86)90046-2 Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, adults. J Thorac Cardiovasc Surg. 2014;148(4):1341- 19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Sanofi-Aventis, Medicines Company, Roche, Pfizer, 1346. doi:10.1016/j.jtcvs.2013.10.064 Measuring inconsistency in meta-analyses. BMJ. Forest Laboratories/AstraZeneca, Ischemix, Amgen, 7. Ross DN. Replacement of aortic and mitral valves 2003;327(7414):557-560. doi:10.1136/bmj.327.7414 Eli Lilly and Company, Chiesi, Ironwood .557 Pharmaceuticals, Abbott, Regeneron with a pulmonary autograft. Lancet. 1967;2(7523): Pharmaceuticals, PhaseBio, Idorsia, and Synaptics; 956-958. doi:10.1016/S0140-6736(67)90794-5 20. Friedrich JO, Adhikari NK, Beyene J. Inclusion personal fees from Duke Clinical Research Institute, 8. Rabkin-Aikawa E, Aikawa M, Farber M, et al. of zero total event trials in meta-analyses maintains Mayo Clinic, Population Health Research Institute, Clinical pulmonary autograft valves: pathologic analytic consistency and incorporates all available American College of Cardiology, Belvoir evidence of adaptive remodeling in the aortic site. data. BMC Med Res Methodol. 2007;7:5. doi:10.1186 Publications, Slack Publications, WebMD, Elsevier, J Thorac Cardiovasc Surg. 2004;128(4):552-561. /1471-2288-7-5 Society of Cardiovascular Patient Care, HMP Global, doi:10.1016/j.jtcvs.2004.04.016 21. Wan X, Wang W, Liu J, Tong T. Estimating the Harvard Clinical Research Institute (now Baim 9. Reece TB, Welke KF, O’Brien S, Grau-Sepulveda sample mean and standard deviation from the Institute for Clinical Research), Journal of the MV, Grover FL, Gammie JS. Rethinking the ross sample size, median, range and/or interquartile American College of Cardiology, Cleveland Clinic, procedure in adults. Ann Thorac Surg. 2014;97(1): range. BMC Med Res Methodol. 2014;14:135. doi:10 Mount Sinai School of Medicine, TobeSoft, 175-181. doi:10.1016/j.athoracsur.2013.07.036 .1186/1471-2288-14-135 Boehringer Ingelheim, and Bayer; nonfinancial 22. Austin PC. Balance diagnostics for comparing support from American College of Cardiology, 10. Klieverik LM, Takkenberg JJ, Bekkers JA, Roos-Hesselink JW, Witsenburg M, Bogers AJ. The the distribution of baseline covariates between Society of Cardiovascular Patient Care, and treatment groups in propensity-score matched American Heart Association; and other support Ross operation: a Trojan horse? Eur Heart J.2007; 28(16):1993-2000. doi:10.1093/eurheartj/ehl550 samples. Stat Med. 2009;28(25):3083-3107. doi:10 from Flowco Solutions, PLx Pharma, Takeda, .1002/sim.3697 Medscape Cardiology, Regado Biosciences, Boston 11. Alassas K, Mohty D, Clavel MA, et al. VA Research Institute, Clinical Cardiology, Veterans Transcatheter versus surgical valve replacement for 23. Friedrich JO, Adhikari NK, Beyene J. The ratio of Affairs, St Jude Medical (now Abbott), Biotronik, a failed pulmonary homograft in the Ross means method as an alternative to mean Cardax, American College of Cardiology, Boston population. J Thorac Cardiovasc Surg. 2018;155(4): differences for analyzing continuous outcome Scientific, Merck, Svelte, and Boehringer Ingelheim 1434-1444. doi:10.1016/j.jtcvs.2017.10.141 variables in meta-analysis: a simulation study. BMC outside the submitted work. No other disclosures Med Res Methodol. 2008;8:32. doi:10.1186/1471 12. Gillespie MJ, McElhinney DB, Kreutzer J, et al. -2288-8-32 were reported. Transcatheter replacement for Meeting Presentation: This paper was presented right ventricular outflow tract conduit dysfunction 24. Parmar MK, Torri V, Stewart L. Extracting at the European Society of Cardiology Congress after the Ross procedure. Ann Thorac Surg. 2015; summary statistics to perform meta-analyses of the 2018; August 25, 2018; Munich, Germany. 100(3):996-1002. doi:10.1016/j.athoracsur.2015.04 published literature for survival endpoints. Stat Med. .108 1998;17(24):2815-2834. doi:10.1002/(SICI)1097-0258 Data Sharing Statement: See Supplement 2. (19981230)17:24<2815::AID-SIM110>3.0.CO;2-8 13. Wilson WM, Benson LN, Osten MD, Shah A, REFERENCES Horlick EM. Transcatheter pulmonary valve 25. Tierney JF, Stewart LA, Ghersi D, Burdett S, replacement with the Edwards Sapien system: the Sydes MR. Practical methods for incorporating 1. Bonow RO, Leon MB, Doshi D, Moat N. summary time-to-event data into meta-analysis. Management strategies and future challenges for Toronto experience. JACC Cardiovasc Interv. 2015;8 (14):1819-1827. doi:10.1016/j.jcin.2015.08.016 Trials. 2007;8:16. doi:10.1186/1745-6215-8-16

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26. Doss M, Wood JP, Martens S, adults [in Hungarian]. Magy Seb. 2008;61(suppl): 53. Mazine A, Ghoneim A, El-Hamamsy I. The Ross Wimmer-Greinecker G, Moritz A. Do pulmonary 23-27. doi:10.1556/MaSeb.61.2008.Suppl.7 procedure: how I teach it. Ann Thorac Surg. 2018; autografts provide better outcomes than 39. Akhyari P, Bara C, Kofidis T, Khaladj N, Haverich 105(5):1294-1298. doi:10.1016/j.athoracsur.2018.01 mechanical valves? a prospective randomized trial. A, Klima U. Aortic root and ascending aortic .048 Ann Thorac Surg. 2005;80(6):2194-2198. doi:10 replacement. Int Heart J. 2009;50(1):47-57. doi:10 54. David TE. Aortic valve replacement with .1016/j.athoracsur.2005.06.006 .1536/ihj.50.47 pulmonary autograft: subcoronary and aortic root 27. Jaggers J, Harrison JK, Bashore TM, Davis RD, 40. Aicher D, Holz A, Feldner S, Köllner V, Schäfers inclusion techniques. Oper Tech Thorac Cardiovasc Glower DD, Ungerleider RM. The Ross procedure: HJ. Quality of life after aortic valve surgery: Surg. 2012;17(1):27-40. doi:10.1053/j.optechstcvs shorter hospital stay, decreased morbidity, and cost replacement versus reconstruction. J Thorac .2011.09.002 effective. Ann Thorac Surg. 1998;65(6):1553-1557. Cardiovasc Surg. 2011;142(2):e19-e24. doi:10.1016/j 55. Mazine A, El-Hamamsy I, Ouzounian M. The doi:10.1016/S0003-4975(98)00288-4 .jtcvs.2011.02.006 Ross procedure in adults: which patients, which 28. Nötzold A, Hüppe M, Schmidtke C, Blömer P, 41. Heuvelman HJ, Arabkhani B, Cornette JM, et al. disease? Curr Opin Cardiol. 2017;32(6):663-671. Uhlig T, Sievers HH. Quality of life in aortic valve Pregnancy outcomes in women with aortic valve doi:10.1097/HCO.0000000000000449 replacement: pulmonary autografts versus substitutes. Am J Cardiol. 2013;111(3):382-387. 56. Bashir M, Harky A, Fok M, et al. Acute type A mechanical prostheses. J Am Coll Cardiol. doi:10.1016/j.amjcard.2012.09.035 aortic dissection in the United Kingdom: Surgeon 2001;37(7):1963-1966. volume-outcome relation. J Thorac Cardiovasc Surg. doi:10.1016/S0735-1097(01)01267-0 42. Basude S, Trinder J, Caputo M, Curtis SL. Pregnancy outcome and follow-up cardiac outcome 2017;154(2):398-406.e1. doi:10.1016/j.jtcvs.2017.02 29. Schmidtke C, Hüppe M, Berndt S, Nötzold A, in women with aortic valve replacement. Obstet Med. .015 Sievers HH. [Quality of life after aortic valve 2014;7(1):29-33. doi:10.1177/1753495X13514382 57. Hughes GC, Zhao Y, Rankin JS, et al. Effects of replacement: self-management or conventional institutional volumes on operative outcomes for anticoagulation therapy after mechanical valve 43. Zacek P, Holubec T, Vobornik M, et al. Quality of life after is similar to Ross aortic root replacement in North America. J Thorac replacement plus pulmonary autograft]. Z Kardiol. Cardiovasc Surg. 2013;145(1):166-170. doi:10.1016 2001;90(11):860-866. doi:10.1007/s003920170084 patients and superior to mechanical valve replacement: a cross-sectional study. BMC /j.jtcvs.2011.10.094 30. Concha M, Aranda PJ, Casares J, et al. Cardiovasc Disord. 2016;16:63. doi:10.1186/s12872 58. El-Hamamsy I, Poirier NC. What is the role of Prospective evaluation of aortic valve replacement -016-0236-0 the Ross procedure in today’s armamentarium? Can in young adults and middle-aged patients: 44. David TE, David C, Woo A, Manlhiot C. The J Cardiol. 2013;29(12):1569-1576. doi:10.1016/j.cjca mechanical prosthesis versus pulmonary autograft. .2013.08.009 J Dis. 2005;14(1):40-46. Ross procedure: outcomes at 20 years. J Thorac Cardiovasc Surg. 2014;147(1):85-93. doi:10.1016/j 59. Forcillo J, Cikirikcioglu M, Poirier N, 31. Mokhles MM, Körtke H, Stierle U, et al. Survival .jtcvs.2013.08.007 El-Hamamsy I. The Ross procedure: total root comparison of the Ross procedure and mechanical 45. Sievers HH, Stierle U, Charitos EI, et al. A technique. Multimed Man Cardiothorac Surg. 2014; valve replacement with optimal self-management 2014:mmu018. doi:10.1093/mmcts/mmu018 anticoagulation therapy: propensity-matched multicentre evaluation of the autograft procedure cohort study. Circulation. 2011;123(1):31-38. doi:10 for young patients undergoing aortic valve 60. Mokhles MM, Rizopoulos D, Andrinopoulou .1161/CIRCULATIONAHA.110.947341 replacement: update on the German Ross Registry. ER, et al. Autograft and pulmonary allograft Eur J Cardiothorac Surg. 2016;49(1):212-218. performance in the second post-operative decade 32. Andreas M, Wiedemann D, Seebacher G, et al. doi:10.1093/ejcts/ezv001 after the Ross procedure: insights from the The Ross procedure offers excellent survival 46. Martin E, Mohammadi S, Jacques F, et al. Rotterdam Prospective Cohort Study. Eur Heart J. compared with mechanical aortic valve 2012;33(17):2213-2224. doi:10.1093/eurheartj/ehs173 replacement in a real-world setting. Eur J Clinical outcomes following the Ross procedure in Cardiothorac Surg. 2014;46(3):409-413. doi:10 adults: a 25-year longitudinal study. J Am Coll Cardiol. 61. Sievers HH, Stierle U, Petersen M, et al. Valve .1093/ejcts/ezt663 2017;70(15):1890-1899. doi:10.1016/j.jacc.2017.08 performance classification in 630 subcoronary Ross .030 patients over 22 years. J Thorac Cardiovasc Surg. 33. Mazine A, David TE, Rao V, et al. Long-term 47. Mastrobuoni S, de Kerchove L, Solari S, et al. 2018;156(1):79-86.e2. doi:10.1016/j.jtcvs.2018.03 outcomes of the Ross procedure versus mechanical .015 aortic valve replacement: propensity-matched The Ross procedure in young adults: over 20 years cohort study. Circulation. 2016;134(8):576-585. of experience in our Institution. Eur J Cardiothorac 62. Berdajs DA, Muradbegovic M, Haselbach D, doi:10.1161/CIRCULATIONAHA.116.022800 Surg. 2016;49(2):507-512. doi:10.1093/ejcts/ezv053 et al. Ross procedure: is the root replacement 48. Skillington PD, Mokhles MM, Takkenberg JJ, technique superior to the sub-coronary 34. Sharabiani MT, Dorobantu DM, Mahani AS, implantation technique? Long-term results. Eur J et al. Aortic valve replacement and the Ross et al. The Ross procedure using autologous support of the pulmonary autograft: techniques and late Cardiothorac Surg. 2014;46(6):944-951. doi:10 operation in children and young adults. JAmColl .1093/ejcts/ezu176 Cardiol. 2016;67(24):2858-2870. doi:10.1016/j.jacc results. J Thorac Cardiovasc Surg. 2015;149(2) .2016.04.021 (suppl):S46-S52. doi:10.1016/j.jtcvs.2014.08.068 63. Puskas J, Gerdisch M, Nichols D, et al; PROACT Investigators. Reduced anticoagulation after 35. Bouhout I, Noly PE, Ghoneim A, et al. Is the 49. da Costa FD, Takkenberg JJ, Fornazari D, et al. Long-term results of the Ross operation: an 18-year mechanical aortic valve replacement: interim Ross procedure a riskier operation? perioperative results from the prospective randomized on-X valve outcome comparison with mechanical aortic valve single institutional experience. Eur J Cardiothorac Surg. 2014;46(3):415-422. doi:10.1093/ejcts/ezu013 anticoagulation clinical trial randomized Food and replacement in a propensity-matched cohort. Drug Administration investigational device Interact Cardiovasc Thorac Surg. 2017;24(1):41-47. 50. Yacoub MH, Klieverik LM, Melina G, et al. An exemption trial. J Thorac Cardiovasc Surg. 2014;147 doi:10.1093/icvts/ivw325 evaluation of the Ross operation in adults. J Heart (4):1202-1210. doi:10.1016/j.jtcvs.2014.01.004 Valve Dis. 2006;15(4):531-539. 36. Buratto E, Shi WY, Wynne R, et al. Improved 64. Yacoub MH, El-Hamamsy I, Sievers HH, et al. survival after the Ross procedure compared with 51. Treasure T, King A, Hidalgo Lemp L, Under-use of the Ross operation: a lost opportunity. mechanical aortic valve replacement. JAmColl Golesworthy T, Pepper J, Takkenberg JJ. Lancet. 2014;384(9943):559-560. doi:10.1016 Cardiol. 2018;71(12):1337-1344. doi:10.1016/j.jacc.2018 Developing a shared decision support framework /S0140-6736(14)61090-4 .01.048 for aortic root surgery in Marfan syndrome. Heart. 65. El-Hamamsy I, Eryigit Z, Stevens LM, et al. 37. Klieverik LM, Noorlander M, Takkenberg JJ, 2018;104(6):480-486. doi:10.1136/heartjnl-2017 -311598 Long-term outcomes after autograft versus et al. Outcome after aortic valve replacement in homograft aortic root replacement in adults with young adults: is patient profile more important than 52. David TE, Woo A, Armstrong S, Maganti M. aortic valve disease: a randomised controlled trial. prosthesis type? J Heart Valve Dis. 2006;15(4): When is the Ross operation a good option to treat Lancet. 2010;376(9740):524-531. doi:10.1016/S0140 479-487. aortic valve disease? J Thorac Cardiovasc Surg. -6736(10)60828-8 38. Zsolt N, Watterson KG. Ross procedure versus 2010;139(1):68-73. doi:10.1016/j.jtcvs.2009.09.053 mechanical aortic valve replacement in young

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