Systematic review and meta-analysis of time-to-event long-term outcomes following the Ross procedure

Introduction

Management of aortic valve disease in young and middle-aged patients remains controversial. Historically, mechanical prostheses have long been the mainstay of choice for this population. Recently, bioprostheses have been increasingly used with the promise of valve-in-valve transcatheter aortic valve replacement (TAVR) within surgical bioprostheses to treat the expected structural valve deterioration, while avoiding lifelong anticoagulation (1,2). Mechanical and biological prostheses, however, have failed to restore life expectancy after aortic valve replacement (AVR) similar to the general population and are associated with excess mortality, particularly in young patients (3,4). The Ross procedure offers an alternative option to these conventional prosthetic valves. In this procedure, a non-functioning aortic valve is replaced with a patient’s pulmonary valve (pulmonary autograft), and a healthy donor valve (such as homograft) or prosthetic valve is implanted in the pulmonary valve position. The characteristic feature of the Ross procedure with a living substitute in the aortic valve position allows favorable hemodynamics and viability, is resistant to valve degeneration and does not require anticoagulation (5-10). However, despite these benefits and excellent outcomes reported by selected institutions or registry-based studies, its indication in the non-elderly adult patient population remains debated. The complexity of the Ross procedure, the perceived concern for reintervention on both the autograft and right ventricular outflow tract (RVOT), and the lack of prospective randomized controlled trials have contributed to these controversies. Therefore, the recent American College of Cardiology/American Heart Association (ACC/AHA) valve guideline only recommended the Ross procedure for the young population by experienced surgeons (class IIb) (11). In addition, long-term outcomes following the Ross procedure, including survival and freedom from valve reinterventions, remain mostly unknown (12,13). A large amount of contemporary data on the Ross procedure has recently accumulated (5-10). Hence, this study aimed to evaluate the long-term results of the Ross procedure using the meta-analysis of time-to-event outcomes. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-326/rc).

Methods

PRISMA flow diagram was shown in Figure 1. Studies were included if the following criteria were met: (I) the study design was retrospective or prospective, randomized or non-randomized, matched or unmatched populations; (II) the study included patients ≥16 years old with aortic valve disease who underwent the Ross procedure; (III) the study reported survival and/or reintervention at least one of autograft and/or homograft; (IV) the Kaplan-Meier curves were available beyond 20 years.

Figure 1 PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

The eligible studies were identified using a 2-level strategy. First, databases including MEDLINE, EMBASE, Cochrane Library, Web of Science, and Google Scholar were searched through June 2022 using Web-based search engines. Search terms were “pulmonary autograft” OR ‘Ross procedure” AND “outcome”. Second, relevant studies were identified through a manual search of secondary sources, including references to initially identified articles and a search of reviews and commentaries. The searched language was not limited to English. The extracted studies were carefully reviewed by two independent authors (Shimamura J and Kuno T). Abstracts or full manuscripts were screened to assess whether a study met the eligibility criteria. The risk of bias in individual studies was evaluated by two independent authors (Shimamura J and Kuno T) using the Newcastle-Ottawa Scale (Table S1).

Outcomes of interest

The primary outcome of this study was death from any cause. Secondary outcomes of interest included valve reinterventions on either autograft or RVOT. Reintervention was defined as surgical or percutaneous reintervention on any operated valves.

Statistical analysis

The meta-analysis of the time-to-event outcomes was performed as follows. Raw data (time, survival probability) were extracted from each Kaplan-Meier curve. Then, the data were processed in conjunction with the numbers at risk at given time point. Finally, the reconstructed time-to-event outcomes were merged to create the study dataset. The methodological details were described in the previous literature (14,15) (Appendix 1).

Results

Six studies were identified and analyzed, including 4,910 patients (3,601 males) (5-10). The summary of the included studies is shown in Table 1. Included studies are from single or multi-center studies from North or South America, Europe, and Australia. The mean/median age ranges from 39.0 to 47.7 years old. Mean/median follow-up period of these studies ranged from 9.2 to 17 years.

Regarding exclusion criteria, urgent/emergency surgery was excluded in most studies, but endocarditis was excluded in only one study. Regarding the valve etiology, the proportion of aortic insufficiency or mixed lesion (aortic stenosis and aortic insufficiency) varied among studies (aortic insufficiency: 19–36%, mixed lesion: 7–50%). In addition, the Ross procedure technique (sub-coronary, full root replacement with/without graft reinforcement, and the rate of annuloplasty) differed among studies.

Survival rate and freedom from any valve reintervention from each study are summarized in Table S1. Aggregated survival rate at 5, 10, 15, and 20 years was 99.9%±0.1%, 97.6%±0.5%, 94.3%±0.9%, and 87.4%±1.9% (Figure 2). Aggregated freedom from autograft reintervention at 5, 10, 15, and 20 years was 97.7%±0.5%, 95.3%±0.7%, 91.4%±1.2%, 84.8%±2.5% (Figure 3). Aggregated freedom from RVOT reintervention was 99.0%±0.3%, 99.0%±0.3%, 97.5%±0.7%, 93.3%±1.8% (Figure 4). Aggregated freedom from any valve reintervention at 5, 10, 15, and 20 years was 95.8%±0.6%, 92.6%±0.9%, 88.5%±1.2%, 80.8%±2.5% (Figure 5). The details of reinterventions, including indications and performed procedures, are shown in Table 2. Structural valve degeneration, non-structural valve degeneration, autograft dilatation, RVOT stenosis, and endocarditis were the main causes of reinterventions. The survival rate and freedom from reintervention of each study were summarized in Tables S2-S5. The causes of death in a late phase were described in Table S6.

Figure 2 Kaplan-Meier survival with 95% confidence intervals.

Figure 3 Freedom from pulmonary autograft reintervention. Kaplan-Meir curves with 95% confidence intervals.

Figure 4 Freedom from RVOT reintervention. Kaplan-Meir curves with 95% confidence intervals. RVOT, right ventricular outflow tract.

Figure 5 Freedom from any pulmonary autograft or homograft reintervention. Kaplan-Meir curves with 95% confidence intervals.

Discussion

In this study, we have reported 20-year survival and valve reintervention rates of 4,910 patients from six studies undergoing the Ross procedure using a meta-analysis of time-to-event data. The survival rate, freedom from autograft, RVOT, and any valve reintervention at 20 years were 87.4%, 84.8%, 93.3%, and 80.8%, respectively. Notably, freedom from any valve reintervention at 20 years in this relatively young population is excellent. Furthermore, Ross recipients experienced high survival outcomes despite the subset of patients requiring valve reinterventions.

Survival

The ultimate goal of aortic valve intervention for patients with aortic valve disease is to provide survival and quality of life that mirrors the healthy general population. The excellent short and long-term survival and quality of life following the Ross procedure have been repeatedly reported (5-10). For example, Aboud et al. reported that long-term survival was non-inferior to an age- and sex-matched general population with a median follow-up of 9.2 years (5). In contrast, both bioprosthetic and mechanical AVR for non-elderly patients have failed to provide comparable long-term survival (3,4). However, the Ross procedure tends to be performed in healthy individuals with fewer comorbidities, and selection bias cannot be easily eliminated compared to other valve substitute options.

From the hemodynamic and physiological point of view, an autograft is a living tissue that possesses a remodeling effect. However, mechanical or bioprosthetic valves have inevitable rigidities introduced by leaflet discs, stent frames, and fixed sewing rings that restrict the aortic root’s dynamic functional structure. The transvalvular gradient of the autograft is significantly lower than that of a conventional prosthetic valve (16). These benefits may result in the favorable long-term survival.

Interestingly, the causes of late death following the Ross procedure were mainly non-valve-related. Ryan et al. reported the clinical outcomes among 225 patients following the Ross procedure. There were 24 late deaths, but only three mortalities were valve-related (one death after the reoperation and two endocarditis-related deaths) (10). On the other hand, conventional AVR is often associated with valve-related complications. For example, structural valve degeneration requiring reintervention is inevitable in relatively young patients who choose to have a bioprosthetic AVR (8). In addition, mechanical AVR is associated with valve-related complication such as valve thrombosis or a bleeding event, and the annual risk of bleeding and thromboembolism were reported to be 0.7–3.5% (17,18). However, we need to consider that the Ross procedure is associated with higher perioperative risk compared with isolated AVR despite its long-term survival advantages (19).

Autograft reintervention

In the current analysis, autograft reintervention tended to be more common than reintervention on the RVOT, and autograft insufficiency was the most common form of autograft failure. It is well known that predominant preoperative aortic insufficiency and aortic annulus dilatation are associated with an increased risk of autograft failure and reintervention (20,21). However, in our series, the degree of preoperative aortic insufficiency and annulus size varied among studies. Because autograft failure can be more common in patients with primary aortic regurgitation, valve-sparing root replacement/remodeling with valve repair should be considered if a durable repair can be anticipated (10).

Autograft implantation has been modified to include specific technical elements: trimming off any excess muscle off the autograft; trimming off any excess autograft above the neo-sinotubular junction; placement of the autograft deep into the left ventricular outflow tract by meticulous attention to each suture (intra-annular implantation for external annulus support), and providing external supports of the autograft annulus and the neo-sinotubular junction using various materials, particularly in patients with aortic insufficiency and/or large aortic annulus (22,23). In the present study, the autograft implantation technique was different among studies, therefore comparing techniques was not possible. Most common autograft interventions were isolated valve replacement, redo root replacement, and valve-sparing operations. TAVR was performed in only four patients because the only failure mode of the autograft is regurgitation and TAVR is essentially an operation for stenosis (24).

RVOT reintervention

In the current study, RVOT reintervention was relatively rare and freedom from reintervention at 20 years was over 90%. Although detailed information for the RVOT was not available in these studies, stenosis was the primary cause of reintervention in the RVOT. Previous studies have reported that generous oversizing of the implanted homograft by removing RVOT muscle is an effective option to prevent homograft stenosis (25). Homograft dysfunction caused by immune response is another possible cause requiring homograft reintervention. The use of decellularized homograft has been thought to be effective in preventing robust immune responses (26). Homografts from older donors showed a lower peak transvalvular gradient during follow-up and might be considered in the future for homograft selection (27). Reintervention in the RVOT is one of the downsides of the Ross procedure, but the incidence of the reintervention is relatively rare despite 20 years follow-up period. Furthermore, the mortality associated with RVOT reintervention was relatively low in the present systematic review.

There has been a perception in our community that the Ross procedure introduces two-valve disease by harvesting a healthy pulmonary valve. In addition, autograft or RVOT reintervention following the Ross procedure is more complicated than redo AVR after prosthetic AVR (28-30). In our analysis, only approximately 20% of the patients experienced any valve reintervention over 20 years of follow-up. In previous reports, the Ross procedure was associated with a higher cumulative risk of autograft and/or RVOT reintervention than mechanical AVR (31). However, the incidence of the reintervention of the Ross procedure is still significantly lower than that of bioprosthetic AVR (8). El-Hamamsy et al. reported that the incidence of reintervention was 17.2%, 29.8%, and 7.4% after the Ross, biological, and mechanical AVR, respectively, at 15 years in a propensity-matched comparison (31).

Future directions

Our current study revealed that the long-term outcomes up to 20 years were excellent, but the indications and surgical techniques differ among studies. Generalization of the Ross procedure is essential for the education of surgeons who will start this procedure and potentially will bring even better outcomes. Discussion should include not only the advantages of the Ross but also the improvement in mechanical valves that may require less intense anticoagulation, and bioprosthetic valves with better durability (18). Advancement in the transcatheter approach may decrease the invasiveness and surgical risks of reintervention for autograft and RVOT following the Ross procedure, but more experience and newer devices are needed (23).

Limitations

This study has several limitations. First, the Ross procedure is still mainly performed at selected centers with experience, and generalization of our findings may be difficult. Second, our study shares the limitations of meta-analysis related to the inclusion of retrospective observational studies. Third, the described studies were different in terms of indication and technique of the Ross procedure. Fourth, there is a possible overlap of the patients among studies. Fifth, studies that did not report Kaplan-Meier curve were not included in the current study. Lastly, because the algorithm for reconstruction of individual patient data from the Kaplan-Meier curve is not able to reproduce informative censoring of competing risk, we could only calculate cause-specific Kaplan-Meier estimates in the outcome of reintervention. Despite these limitations, the present study represents the longest available meta-analysis analyzing long-term outcomes following the Ross procedure. Since life expectancy in the developed countries is around 80 years old, patients who undergo the Ross procedure at a younger age (approximately 40 years old on average in this study) will require extremely long-term follow-up and guidance regarding the reintervention since they may experience multiple valve reinterventions after very late follow-up.

Conclusions

In summary, the present meta-analysis of time-to-event outcomes revealed that the Ross procedure provides excellent freedom from valve reintervention and survival for up to 20 years. However, even longer follow-up and data from more centers are warranted to assess the clinical outcomes of the Ross procedure recipients.

Acknowledgments

This study was presented at the 72nd Annual Scientific Session of the American College of Cardiology Together with WCC (ACC.23/WCC), March 4–6, 2023, New Orleans, LA, USA.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-326/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-326/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-326/coif). SF serves as a consultant for Terumo Aortic, Artivion and Medtronic Inc. and has received speakers’ honoraria from Edwards Lifesciences and Medtronic Inc. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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