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 to 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< 0.01). Overall survival (p = 0.93), freedom from
reintervention and valve dysfunction free survival (p = 0.91)
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 expertise, the
Ross procedure should be strongly considered in select patients
requiring aortic valve replacement.
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INTRODUCTION
The optimal type of aortic valve replacement for young and middle-aged
adults continues to serve as a challenging clinical judgement 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.1-3 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.4First 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 long-term outcomes with respect to operative mortality, freedom from
major complications, freedom from reintervention and overall
survival.5-7 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).8-11
Several recent studies have added further support to the use of the Ross
procedure in young and middle-aged adults. A propensity-matched analysis
from the University of Toronto including 208 pairs of patients who
underwent the Ross procedure or mechanical aortic valve replacement
(mAVR) demonstrated equivalent select perioperative outcomes, freedom
from valve deterioration and reintervention and overall
survival.12 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.13Neither 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.14-17 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.18-19 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.
METHODS
Data for all patients age 18 to 50 years of age who underwent either
mAVR (with or without root replacement) or the Ross procedure between
the years 2000 and 2016 at Indiana University affiliated hospitals were
retrospectively gathered following Institutional Review Board approval.
Demographics, perioperative, operative and postoperative variables were
collected from the electronic medical record. Primary endpoints included
overall survival and freedom from re-intervention of either aortic or
pulmonic valves. Valve dysfunction, defined as moderate insufficiency or
greater at the aortic or pulmonic valve, aortic valve gradient
> 20 mm Hg or pulmonic valve gradient > 40 mm
Hg, 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 anti-hypertensive, 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 follow-up of less than one year were excluded from the
study in order to accurately predict postoperative and long-term
complications. Prior to propensity score matching, there was significant
disparity appreciated between the two groups; however, this difference
became insignificant following matching (see Supplementary Figure 1).
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, operative outcomes
and late complications for the matched pairs were assessed using
conditional logistic regressions for binary variables and propensity
score weighted linear regressions for continuous variables. Log rank
tests were employed for time-to-event analyses regarding overall
survival and complication-free survival in order to compare the survival
function between Ross and mAVR over a ten-year follow-up period. All
analyses were performed using Stata MP 16.1 (StataCorp LLC; College
Station, TX).
RESULTS
Of the 32 matched pairs, the mean age was 37.1 years and 22 patients
(68.8)% were male. Mean body surface area of the cohort was 2.06
m2 with SD of 0.29 m2. The most
common cardiovascular risk factors observed for all included patients
were any tobacco use and hypertension at 53.1% and 48.4%,
respectively. Atrial flutter/fibrillation and transient ischemic
attack/stroke were the most commonly observed comorbidities but only at
17.2% and 10.9% of the cohort, respectively. Of the study population,
26.7% and 7.8% underwent previous surgical or catheter-based cardiac
interventions prior to their index Ross or mAVR, respectively
(Supplementary Table 1). 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 prior to 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 = 0.01) or
ascending aortic aneurysm (p = 0.02) being significantly more
common indications for the Ross procedure than mAVR.
The Ross procedure was associated with significantly longer
cardiopulmonary bypass and cross-clamp times (p <
0.01). The most common type of aortic prosthesis employed for mAVR was
St. Jude (St. Jude Medical Inc.; Saint Paul, MN) while the most frequent
type of pulmonic prosthesis utilized for the pulmonary autograft
technique was CryoLife SynerGraft (CryoLife Inc.; Kennesaw, GA).
Concomitant procedures at the time of Ross or mAVR included aortic arch
replacement (17.2%), 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 thirty 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 post-operative characteristics and outcomes can be
found in Table 2.
Of the matched Ross patients, three required reintervention of either
the aortic or pulmonic valves (Supplementary Table 2). One patient
developed aortic insufficiency as well as mitral regurgitation
necessitating aortic valve replacement and mitral valve repair. Another
patient acquired severe pulmonic insufficiency and ascending aortic
aneurysm requiring pulmonic valve and ascending aortic replacement. The
third underwent endovascular pulmonic valve repair for pulmonic
stenosis. Two mAVR patients required reintervention of the aortic valve.
The first developed severe aortic and mitral insufficiency requiring a
Bentall procedure and mitral valve replacement. This was ultimately
succeeded by repeat transcatheter aortic valve replacement fifteen years
later. The other patient acquired severe aortic insufficiency secondary
to endocarditis necessitating a Bentall procedure. One-, five- and
ten-year reintervention-free survival following Ross or mAVR was 100%
and 100%, 97% and 97% and 80% and 77%, respectively (Figure 1).
There was no statistically significant difference in reintervention free
survival between the two groups (p = 0.91).
Median time-to-follow-up was 7.3 (IQR 5.7-11.7) and 6.9 (IQR 5.6-10.0)
years for Ross and mAVR, respectively. For those patients who developed
complications, NYHA functional classification did not differ
significantly between the groups (Table 3). Peak and mean aortic valve
gradients at time of last follow-up were significantly lower for Ross
patients at -23.0 mm Hg and -12.5 mm Hg, respectively (p< 0.01). No statistically significant differences were
appreciated for the remaining echocardiographic variables at time of
last follow-up including left ventricular ejection fraction, peak and
mean pulmonic valve gradients, sinus of Valsalva and ascending aorta
diameters. One-, five- and ten-year freedom from valve dysfunction
following Ross or mAVR was 100% and 100%, 97% and 97% and 80% and
77%, respectively (Figure 2). There was no statistically significant
difference with respect to valve dysfunction free survival between the
two groups (p = 0.91). Major hemorrhage (intracranial,
gastrointestinal, genitourinary and nasal) requiring anticoagulation
reversal, blood product administration and/or hospitalization as well as
stroke events were significantly more frequent in the mAVR population
(p < 0.01). One-, five- and ten-year major hemorrhage
free survival following Ross or mAVR was 100% and 94%, 100% and 80%
and 83% and 61%, respectively (Figure 3). Similarly, one-, five- and
ten-year stroke free survival following Ross or mAVR was 100% and 97%,
100% and 80% and 83% an 45% (Figure 4). With respect to freedom from
all complications including endocarditis, arrhythmia, aortic root and
ascending aortic dilatation, no significant differences were appreciated
between the two groups (p = 0.46).
Late mortality amongst both Ross (n = 3) and mAVR (n = 4)
patients was rare (Table 4). Heart failure and ventricular
tachycardia/fibrillation were the cited causes of death for two of the
Ross subjects with unknown cause for the remaining patient. Cause of
death following mAVR included massive hemorrhage and aortic dissection
with septic shock, with unknown cause for the remaining two subjects.
The mAVR patient that sustained a lethal intracerebral hemorrhage had
experienced several prior cerebrovascular insults secondary to a
vegetative aortic valve thrombus. One-, five- and ten-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 = 0.93).
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
mechanical aortic valve replacement in the United
States.21,22 The technical complexity, longer
operative times and dual valve manipulation of the Ross procedure have
often been cited as its weaknesses, resulting in apprehension and
ultimately diminished use of this aortic valve replacement strategy in
recent years. Despite longer cardiopulmonary bypass and cross-clamp
times, this series demonstrated similar perioperative outcomes including
time to extubation, cardiovascular intensive care unit and hospital
length of stay, renal failure and readmission. Additionally, no early
mortality (within thirty days) was observed for either group, indicating
that the complex and lengthy nature of the Ross procedure does not
appear to translate into worse early postoperative outcomes. As has been
previously reported in the literature, the Ross procedure was also found
to offer equivalent freedom from reintervention and valve dysfunction
compared to mAVR at ten years.12 This finding was
extended to the pulmonary homograft with only one Ross patient requiring
replacement and another percutaneous balloon valvuloplasty. Furthermore,
this study demonstrated significantly lower peak and mean aortic valve
gradients at time of last follow-up for Ross patients with similar
overall pulmonic valve function, suggesting not only stability of the
pulmonary homograft but also superior aortic valve hemodynamics
following the Ross procedure.
In accordance with several prior studies, mechanical aortic valve
replacement was associated with significantly more major hemorrhage and
stroke events compared to the Ross procedure.12,22 It
is important to note that a St. Jude aortic valve prosthesis (St. Jude
Medical Inc.; Saint Paul, MN) was implanted into 66% of mAVR patients
included in this study. Interim results of the Prospective Randomized
On-X Anticoagulation Clinical Trial (PROACT) indicate that the Food and
Drug Administration (FDA)-approved On-X mechanical valve can be safely
managed with a reduced international normalized ratio (INR) goal of
1.5-2.0 when implanted in the aortic position.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 and colleagues
demonstrated equivalent bleeding and thromboembolic events with no
difference in overall survival at eight years when patients adhered to
optimal anticoagulation self-management.24,25 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 meta-analysis.12,13,22 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., 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 mechanical aortic valve replacement 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.
Acknowledgements: The authors wish to acknowledge the support
of the Riley Clinical Data and Outcomes Center.