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Perioperative and long‐term outcomes of Ross versus mechanical aortic valve replacement

Abstract Background The ideal aortic valve replacement strategy in young‐ and middle‐aged adults remains up for debate. Clinical practice guidelines recommend mechanical prostheses for most patients less than 50 years of age undergoing aortic valve replacement. However, risks of major hemorrhage and thromboembolism associated with long‐term anticoagulation may make the pulmonary autograft technique, or Ross procedure, a preferred approach in select patients. Methods Data were retrospectively collected for patients 18–50 years of age who underwent either the Ross procedure or mechanical aortic valve replacement (mAVR) between January 2000 and December 2016 at a single institution. Propensity score matching was performed and yielded 32 well‐matched pairs from a total of 216 eligible patients. Results Demographic and preoperative characteristics were similar between the two groups. Median follow‐up was 7.3 and 6.9 years for Ross and mAVR, respectively. There were no early mortalities in either group and no statistically significant differences were observed with respect to perioperative outcomes or complications. Major hemorrhage and stroke events were significantly more frequent in the mAVR population (p < .01). Overall survival (p = .93), freedom from reintervention and valve dysfunction free survival (p = .91) were equivalent. Conclusions In this mid‐term propensity score‐matched analysis, the Ross procedure offers similar perioperative outcomes, freedom from reintervention or valve dysfunction as well as overall survival compared to traditional mAVR but without the morbidity associated with long‐term anticoagulation. At specialized centers with sufficient expertize, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement.

K E Y W O R D S replacement, valve repair

| INTRODUCTION
The optimal type of aortic valve replacement for young and middleaged adults continues to serve as a challenging clinical judgment for cardiothoracic surgeons. Mechanical prostheses generally exhibit longer durability but require long-term anticoagulation which carries elevated risks of bleeding and thromboembolic events at approximately 1% per patient-year. [1][2][3] While bioprosthetic valves do not require long-term anticoagulation on the basis of their tissue substrate, they exhibit shorter durability particularly amongst younger patients. An alternative to traditional aortic valve replacement is the pulmonary autograft technique, or Ross procedure. 4 First described in 1967, the Ross procedure involves excising a patient's dysfunctional aortic valve and replacing it with their native pulmonic valve which, in turn, is replaced with a separate bioprosthesis. Thus, the major advantage of the Ross procedure includes avoidance of long-term anticoagulation and durability of the autograft in the aortic position. Longitudinal follow-up of adults who have undergone the Ross procedure at our institution has shown excellent mid-and longterm outcomes with respect to operative mortality, freedom from major complications, freedom from reintervention and overall survival. [5][6][7] The Ross procedure may also confer comparable survival to age-and sex-matched controls in the general population, a finding that has consistently not been extended to mechanical aortic valve replacement (mAVR). [8][9][10][11][12] Several recent studies have added further support to the use of the Ross procedure in young and middle-aged adults. A propensitymatched analysis from the University of Toronto including 208 pairs of patients who underwent the Ross procedure or mAVR demonstrated equivalent select perioperative outcomes, freedom from valve deterioration and reintervention and overall survival. 13 Most notably, the Ross procedure exhibited superior freedom from stroke and major hemorrhage as well as cardiac-and valve-related mortality.
Similarly, an Australian propensity-score matched study of 275 pairs revealed superior survival at 20 years following the Ross procedure compared to mAVR. 14 Neither study thoroughly addressed early morbidity associated with the Ross procedure and cited that the vast majority of Ross procedures were performed by a single surgeon, limiting generalizability.
Despite these advantages, the technical complexity, longer operative times and concern for future complications involving two, replaced valves has limited utilization of the Ross procedure. In earlier experiences with the Ross procedure, neo-aortic root dilatation was observed, possibly a result of exposure of the native pulmonary valve to left-sided systemic pressures. [15][16][17][18] Accordingly, many centers (including our own) have adopted strategies involving external reinforcement of the autograft root and replacement of the ascending aorta, if dilated, to mitigate this. 7,19 Moreover, according to the most recent AHA/ACC guidelines, mechanical prostheses are recommended for most patients less than 50 years of age undergoing aortic valve replacement. 20 While a randomized trial to evaluate these two aortic valve replacement strategies is largely unfeasible secondary to patient and/or surgeon preference, we sought to employ propensity score matching order to generate a matched cohort of patients to compare both perioperative and long-term outcomes of the Ross procedure compared to mAVR in young and middle-age adults at a single institution. As previously reported in the literature, we hypothesized that the Ross procedure offers superior overall survival and equivalent durability without increased perioperative or long-term morbidity. Valve dysfunction, defined as moderate insufficiency or greater at the aortic or pulmonic valve, aortic valve gradient >20 mmHg or pulmonic valve gradient >40 mmHg, as well as perioperative and long-term complications including bleeding, stroke, endocarditis and arrhythmia served as secondary endpoints.
One-to-one propensity score weight bivariate analysis was performed using a caliper width of 0.05. Variables for propensity score matching at the time of index operation (mAVR or Ross) included: age, sex, year of surgery, previous cardiac intervention, clinical presentation (chest pain/angina, presyncope/syncope, dyspnea, fatigue and congestive heart failure), New York Heart Association (NYHA) functional classification, cardiovascular risk factors (obesity, any tobacco use, hypertension, hyperlipidemia, and diabetes mellitus), total number of comorbidities, prescribed antihypertensive, statin or aspirin medications and total number of concomitant procedures performed in addition to aortic valve replacement. This yielded 32 well-matched pairs from a total database of 216 eligible patients (Ross = 125, mAVR = 91). A total of 19 subjects with inadequate clinical follow-up of less than 1 year were excluded from the study to accurately predict postoperative and long-term complications. However, patients were otherwise included in the study including four mechanical aortic valve patients who were seen in follow-up but did not have echocardiography performed postoperatively. Before propensity score matching, there was significant disparity appreciated between the two groups; however, this difference became insignificant following matching (see Table S1 and Figure S1). Thus, any difference between the two groups after matching are assumed to be the result of treatment differences, i.e., type of index operation (mAVR or Ross).
Bivariate analyses were performed using the matched pairs of data. Mean (standard deviation) and frequency (percentage) were employed for continuous and discrete variables as appropriate.
The test of significance between the two groups was evaluated for these variables using conditional logistic regressions. Similarly,

| RESULTS
Of the 32 matched pairs, the mean age was 37.  (Table S2). The most common clinical presentations were dyspnea, fatigue and chest pain/angina at 46.9%, 37.5%, and 29.7%, respectively. Furthermore, of those patients for whom NYHA stages could be deduced from the electronic medical record, 65% were classified as either functional class I or II before surgery. The most frequently observed indication for surgery was the presence of a bicuspid aortic valve at 54.7% followed closely by aortic insufficiency at 50%, although it should be noted that these were not mutually exclusive. There were no statistically significant differences between those patients who underwent the Ross procedure and mAVR with respect to the demographic and preoperative characteristics discussed here and found in Table 1. The only exception to this was with respect to indication, with the presence of either a bicuspid aortic valve (p = .01) or ascending aortic aneurysm (p = .02) being significantly more common indications for the Ross procedure than mAVR. mitral valve replacement (n = 8; 12.5%) and root replacement (Bentall procedure, n = 8; 12.5%). There were no statistically significant differences with respect to time to extubation, cardiovascular intensive care unit or hospital length of stay between the two groups. No early mortality (within 30 days) was observed for either group and there were no statistically significant differences between the groups regarding early complications including arrhythmia (approaching significance), acute renal failure (documented by nephrology or requiring dialysis) or readmission. Additional operative and early postoperative characteristics and outcomes can be found in Table 2.

Late mortality amongst both Ross (n = 3) and mAVR (n = 4)
patients was rare ( Note: Variables expressed as mean (SD) with p values from generalized regression on matched data with robust standard error, unless otherwise specified.
F I G U R E 2 Kaplan-Meier freedom from valve dysfunction F I G U R E 3 Kaplan-Meier freedom from major hemorrhage hemorrhage had experienced several prior cerebrovascular insults secondary to a vegetative aortic valve thrombus. 1-, 5-, and 10-year survival following Ross or mAVR was 100% and 100%, 100% and 97% and 83% and 83%, respectively ( Figure 5). No significant difference regarding overall survival was observed (p = .93).

| CONCLUSIONS
To the best of our knowledge, this is the first study in over two decades documenting the experience of the Ross procedure compared to mAVR in the United States. 21 23 This resulted in significantly fewer major and minor bleeding events without associated increase in thromboembolism.
Additionally, a propensity-matched cohort study performed by Mokhles 24 and colleagues demonstrated equivalent bleeding and thromboembolic events with no difference in overall survival at 8 years when patients adhered to optimal anticoagulation selfmanagement. 25 This highlights the importance of discussing valve replacement options with patients as well as appropriate patient selection by surgeons.
Despite the significantly reduced major hemorrhage and stroke free survival observed amongst mAVR patients, this did not translate into a significant difference in overall survival between the two groups, an observation that is at odds with similar propensity-matched studies and a recent metaanalysis. 13,14,22 Given that survival benefits in those studies were reported at 20 years, our negative finding is likely the result of an inadequate median follow-up period of 7.33 (IQR: 5.7-11.7) and 6.89 (IQR: 5.6-10.0) years for Ross and mAVR, respectively. Additional limitations of this study include its small sample size that is presumably insufficiently powered to detect survival differences. While randomization was successfully conducted in one clinical trial by Doss et al., 26 these profoundly distinct aortic valve replacement strategies do not easily lend themselves to random treatment allocation secondary to surgeon and patient preferences. 26 Nevertheless, this is another limitation of the current study for which propensity score weight bivariate analysis was a practical alternative. Even with these limitations, our results may be more generalizable than other studies as multiple surgeons (four) performed the Ross procedures.
In conclusion, the current study demonstrates that the Ross procedure offers equivalent perioperative outcomes, freedom from reintervention, freedom from valve dysfunction and overall survival compared to traditional mAVR in young and middle-aged adults but without the need for long-term anticoagulation. Thus, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement at specialized centers.