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Early and late effects of aortic root enlargement: Results from the Pericardial Surgical Aortic Valve Replacement Pivotal Trial: A multicenter, prospective clinical trial
Address for reprints: Vivek Rao, MD, PhD, Division of Cardiac Surgery, Toronto General Hospital, 200 Elizabeth St, 4PMB-464, Toronto, Ontario, Canada M5G 2C4.
During surgical aortic valve replacement, prosthesis–patient mismatch is avoided by implanting the largest possible valve, which sometimes requires annular enlargement (ARE). The effects of ARE on mortality remain controversial. We reviewed data from a multinational clinical trial evaluating a novel pericardial bioprosthesis to determine the influence of ARE 5 years postimplant.
Methods
Patients with aortic valve disease requiring surgical aortic valve replacement were prospectively enrolled at 25 centers in North America and 13 centers in Europe. Standardized follow-up was prescribed, including serial echocardiography assessed by a core lab. A composite 30-day end point of major morbidity or mortality was defined as death, reoperation for any cause, stroke, deep sternal wound infection, and acute kidney injury.
Results
Among 602 patients with detailed intraoperative data, 90 (15%) underwent ARE with similar rates in North America (17%) and Europe (12%; P = .11). Implanted valve size was similar in both groups (P = .18). The prevalence of moderate or severe prosthesis–patient mismatch at 12 months and at 5 years was comparable between groups, as was the average indexed effective orifice area (P = .3). Five-year survival (ARE, 91% vs no ARE, 89%) and freedom from 30-day major morbidity and mortality (ARE, 87% vs no ARE, 89%) were also similar.
Conclusions
In this analysis of a prospective, observational clinical trial, we observed that the performance of an aortic root enlargement procedure did not increase morbidity or mortality at 30 days. We found that survival at 5 years was similar between groups, suggesting that the performance of an ARE procedure restored survival to that observed in patients who did not require an ARE.
Aortic root enlargement is infrequently performed but can facilitate implantation of a larger valve to optimize hemodynamics and avoid prosthesis–patient mismatch.
Patch enlargement of the aortic root is a technique employed by surgeons to avoid prosthesis–patient mismatch when implanting a prosthetic valve. This study looks at regional differences in the performance of ARE and its influence on 5-year outcomes with data obtained from a prospective, observational clinical trial.
Despite the rapid proliferation of percutaneous therapies for aortic valve disease (eg, transcatheter aortic valve implantation [TAVI]), surgical aortic valve replacement (SAVR) remains commonly performed.
However, several studies have demonstrated a detrimental influence of PPM, especially in younger patients with obesity who present with mixed aortic valve disease and/or significant left ventricular dysfunction.
Impact of prosthesis-patient mismatch on long-term survival after aortic valve replacement: influence of age, obesity and left ventricular dysfunction.
In younger patients, valve durability and hemodynamic performance become even more important, particularly as we consider the lifetime management of aortic valve disease. Surgeons must consider the immediate hemodynamic performance of a valve in addition to the potential need for TAVI in the future. It is commonly believed that a 23-mm valve is the minimum size required for successful deployment of a valve-in-valve prosthesis. The Hancock II porcine valve (Medtronic) is a recognized durable bioprosthetic valve; however, compared with pericardial valves the early residual transvalvular gradients are higher.
TAVI prostheses have also demonstrated superior early hemodynamic status compared with stented surgical valves, yet their durability remains unknown.
The Avalus bovine pericardial valve (Medtronic) was introduced to provide a surgical solution that addresses both durability and hemodynamic performance. The early results of the Pericardial Surgical Aortic Valve Replacement (PERIGON) Pivotal Trial of the Avalus valve have demonstrated an excellent safety and hemodynamic profile.
Kiaii BB, Moront MG, Patel HJ, Ruel M, Bensari FN, Kress DC, et al. Outcomes of surgical bioprosthetic valve replacement in patients aged <65 and >65 years. Ann Thorac Surg. January 20, 2022 [Epub ahead of print].
Although mean gradients have remained stable and low over 5 years of follow-up, the predicted indexed effective orifice areas (iEOAs) have been lower than expected given the mean gradients observed after implant. We have previously demonstrated the fallacy in using predicted iEOA to classify PPM; however, surgeons still commonly utilize iEOA charts to determine the minimum acceptable valve size for a given patient.
When the measured annular size does not facilitate the implantation of an adequately sized prosthesis, surgeons will employ a variety of annular enlargement (ARE) procedures to enable the insertion of a larger valve.
Haunschild J, Scharnowski S, Mende M, von Aspern K, Misfeld M, Mohr F-W, et al. Aortic root enlargement to mitigate patient-prosthesis mismatch: do early adverse events justify reluctance? Eur J Cardiothorac Surg. February 20, 2019 [Epub ahead of print].
Haunschild J, Scharnowski S, Mende M, von Aspern K, Misfeld M, Mohr F-W, et al. Aortic root enlargement to mitigate patient-prosthesis mismatch: do early adverse events justify reluctance? Eur J Cardiothorac Surg. February 20, 2019 [Epub ahead of print].
We therefore reviewed clinical data from the PERIGON study to examine the rates of ARE, regional differences in the performance of ARE, and the influence of ARE on early and late (5-year) outcomes.
Methods
Study Design and Patient Eligibility
The PERIGON Pivotal Trial (ClinicalTrials.gov ID: NCT02088554) is a prospective, nonrandomized observational trial evaluating the safety and efficacy of the Avalus bioprosthesis. The trial was designed in accordance with the Declaration of Helsinki and Good Clinical Practice guidance. Institutional review board or ethics committee approval of the protocol was obtained at each center (see Table E1). Written informed consent was obtained from all enrolled patients. The trial was conducted at 25 centers in North America and 13 centers in Europe. The first implant occurred May 14, 2014, and the final implant was on July 26, 2017. Enrollment was reopened in April 2019 at selected sites in the United States and Canada for patients eligible to receive a 29-mm valve.
Patients with moderate or greater symptomatic aortic stenosis or chronic severe aortic regurgitation and a clinical indication for SAVR were eligible for enrollment. Exclusion criteria included the following: a preexisting prosthetic valve or annuloplasty device in another position, need for repair of another heart valve, active systemic infection, any anatomic abnormality that was perceived by the surgeon to increase surgical risk (eg, ascending aortic aneurysm or dissection repair requiring circulatory arrest, porcelain aorta, hostile mediastinum, or documented pulmonary hypertension [systolic >60 mm Hg], life expectancy <2 years, or renal failure [ie, dialysis therapy or glomerular filtration rate <30 mL/min/1.73 m2]). Patients who required left atrial appendage ligation, coronary artery bypass grafting, patent foramen ovale closure, ascending aortic aneurysm/dissection repair not requiring circulatory arrest, and subaortic membrane resection not requiring myectomy were eligible for enrollment. Patients found intraoperatively to require other procedures were treated with a commercially available valve and exited from the study. For this analysis, only patients with nonmissing values for aortic root, sinotubular junction, or annular enlargement (ARE) were included.
Safety outcomes were adjudicated by an independent clinical events committee, and study oversight was provided by an independent data safety and monitoring board (both from Baim Institute for Clinical Research). Echocardiograms were assessed by a core laboratory (MedStar Research Institute).
Valve Design and Implant Technique
The study device is a stented bovine pericardial bioprosthesis. It has a low profile, and the laser-cut leaflets are mounted on the interior of the stent. The leaflets are treated with alpha-amino oleic acid for anticalcification.
Implant technique, type and route of cardioplegia, and cardiopulmonary bypass strategies as well as postoperative anticoagulation regimen were left to the discretion of the surgeon. The valve was designed for supra-annular placement with sizes 17 to 29 mm available for use in the study.
Duration of Follow-up and Study End Points
Standardized visits that included serial echocardiography were performed at baseline, discharge up to 30 days, 3 to 6 months, 1 year, and annually thereafter through 5 years of follow-up. Clinical outcomes included all-cause mortality and valve-related thromboembolism, major bleeding, endocarditis, paravalvular regurgitation, structural valve deterioration (SVD), nonstructural valve dysfunction (NSVD), reintervention, and explant. An additional end point of severe hemodynamic dysfunction of indeterminate or evolving cause was used to categorize potential safety events with inconclusive information that did not meet the protocol-defined criteria for SVD or NSVD. The specific definitions of this end point, as well as SVD and NSVD, are included in the Appendix E1. Echocardiographic outcomes included mean aortic gradient, EOA, iEOA, PPM, and degree of paravalvular and transvalvular regurgitation. New York Heart Association (NYHA) class was used to assess functional status. We defined short-term major morbidity and mortality (MMOM) as a composite 30-day end point of all-cause mortality, stroke (adjudicated by a clinical events committee), acute kidney injury, deep sternal wound infection, and reoperation for any cause.
Statistical Analysis
Categorical variables are reported as frequencies and percentages and were compared using the χ2 or Fisher exact test, whereas the Cochran-Mantel-Haenszel test was used to compare ordinal variables. Continuous variables are expressed as the mean ± SD and were compared using the 2-sample t test. The Kaplan-Meier method was used to estimate the event rates of mortality and valve-related safety events through 5 years of follow-up and freedom from the MMOM composite end point through 30 days. Outcomes were compared using the log-rank test. Statistical analyses were performed using SAS software version 9.4 (SAS Institute).
Results
A total of 1288 patients were enrolled in the PERIGON Pivotal Trial, and 1118 received the study device. Among these patients, 602 had detailed intraoperative data regarding ARE; 90 of these 602 patients (15%) underwent an ARE procedure at the discretion of their surgeon. The rates of ARE were generally similar in North America (69 out of 419 [16.5%]) and in Europe (21 out of 183 [11.5%]; P = .11). Figure E1 shows the disposition of patients throughout 5 years of follow-up.
Baseline Characteristics and Procedural Data
The mean age at implant was 68 ± 7 and 69 ± 9 years in the ARE and no ARE groups, respectively (P = .10). There were more female patients in the ARE group (38% vs 22%; P = .001). Body surface area was similar between the two groups (ARE, 2.00 ± 0.21 mm2 vs no ARE, 2.00 ± 0.22 m2; P = .85), as was the Society of Thoracic Surgeons risk of mortality score (1.6% ± 1.0% vs 1.8% ± 1.2%; P = .16). The prevalence of coronary artery disease was lower in the ARE group than in the no ARE group (30% vs 47%; P = .002) as was the prevalence of dyslipidemia (53% vs 66%; P = .03). There were no significant differences between groups in the prevalence of hypertension (74% vs 75%; P = .88) or left ventricular hypertrophy (31% vs 38%; P = .21). One patient in the ARE group (1.1%) and 5 patients in the no ARE group (1.0%) had a previous aortic valve implanted (P > .99). A previous aortic valve repair had been performed in 0 patients in the ARE group and 2 patients in the no ARE group (0.4%) (P > .99). Mean aortic gradient at baseline was 46 ± 17 mm Hg in the ARE group and 42 ± 18 mm Hg in the no ARE group (P = .05). Baseline EOA was 0.81 ± 0.28 cm2 in the ARE group and 0.94 ± 0.60 cm2 in the no ARE group (P = .002). The proportion of patients in NYHA class III or IV was similar in the 2 groups (ARE vs no ARE: 51.1% vs 43.1%; P = .16). Table 1 presents additional baseline patient characteristics.
Table 1Baseline characteristics in patients who did and did not undergo aortic root, sinotubular junction, or ARE
Characteristic
ARE (n = 90)
No ARE (n = 512)
P value
Age (y)
67.9 ± 7.2
69.3 ± 8.9
.10
Sex
.001
Male
56 (62.2)
401 (78.3)
Female
34 (37.8)
111 (21.7)
Body surface area (m2)
2.00 ± 0.21
2.00 ± 0.22
.85
NYHA functional class
.13
I
7 (7.8)
60 (11.7)
II
37 (41.1)
231 (45.1)
III
44 (48.9)
210 (41.0)
IV
2 (2.2)
11 (2.1)
STS risk of mortality (%)
1.6 ± 1.0
1.8 ± 1.2
.16
Aortic aneurysm
3 (3.3)
57 (11.1)
.02
Atrial fibrillation
.93
None
83 (92.2)
456 (89.1)
Paroxysmal
4 (4.4)
31 (6.1)
Persistent
1 (1.1)
13 (2.5)
Long-standing persistent
1 (1.1)
7 (1.4)
Unknown
1 (1.1)
5 (1.0)
Congestive heart failure
17 (18.9)
92 (18.0)
.83
Coronary artery disease
27 (30.0)
242 (47.3)
.002
Dyslipidemia
48 (53.3)
336 (65.6)
.025
Hypertension
67 (74.4)
385 (75.2)
.88
Left ventricular hypertrophy
28 (31.1)
195 (38.1)
.21
Renal dysfunction/insufficiency
4 (4.4)
47 (9.2)
.16
Stroke/CVA
1 (1.1)
24 (4.7)
.15
TIA
5 (5.6)
29 (5.7)
.97
Percutaneous coronary intervention
7 (7.8)
92 (18.0)
.016
Implanted cardiac device (ie, pacemaker or defibrillator)
1 (1.1)
21 (4.1)
.23
Previous aortic valve implanted
1 (1.1)
5 (1.0)
>.99
Prior open-heart surgery
.16
0
89 (98.9)
491 (95.9)
1
1 (1.1)
21 (4.1)
2+
0 (0.0)
0 (0.0)
Values are presented as mean ± SD or n (%). ARE, Annular enlargement; NYHA, New York Heart Association; STS, Society of Thoracic Surgeons; CVA, cerebrovascular accident; TIA, transient ischemic attack.
Aortic stenosis was the primary indication for valve replacement in both groups (ARE 89% vs no ARE 82%; P = .12), followed by mixed stenosis and regurgitation (8.9% vs 10.4%; P = .67), regurgitation alone (2.2% vs 7.0%; P = .10), and a failed aortic prosthesis (0.0% vs 0.4%; P > .99). Median sternotomy was the most common surgical approach in each group (77% vs 82%; P = .14). Coronary artery bypass grafting was performed concomitantly in 27% of the ARE group and in 32% of the no ARE group (P = .31). Among patients who underwent ARE, only 27 underwent an annular enlargement with no regional differences (North America, 3.8% vs Europe, 6.1%; P = .2). However, patch enlargement of the aortic sinus and/or sinotubular junction was more common in North America (16.2% vs 7.7%; P = .005). The indication for patch enlargement of the sinus or sinotubular junction was not captured, but likely reflected the need to reduce tension on the aortic closure. The Nicks procedure was most commonly performed for annular enlargement (70%), followed by an “other” procedure (30%). The mean valve size implanted was 23.1 ± 1.9 mm in the ARE group and 23.7 ± 2.1 mm in the no ARE group (P = .03). Figure 1 shows the distribution of implanted valve sizes (see Table E2 for annular diameters as measured by the barrel end and replica end of the sizer). Additional procedural details are provided in Table 2.
Figure 1Valve size distribution in patients who did or did not undergo aortic root, sinotubular junction, or annular enlargement (ARE).
For example, pacemaker, coronary resynchronization therapy, or implantable cardioverter-defibrillator.
0 (0.0)
1 (0.2)
>.99
LAA closure
12 (13.3)
41 (8.0)
.10
PFO closure
2 (2.2)
4 (0.8)
.22
Resection of subaortic membrane not requiring myectomy
3 (3.3)
9 (1.8)
.40
Ascending aortic aneurysm not requiring circulatory arrest
3 (3.3)
54 (10.5)
.03
Dissection repair not requiring circulatory arrest
0 (0.0)
1 (0.2)
>.99
Other
22 (24.4)
52 (10.2)
.001
Total bypass time (min)
122.8 ± 52.7
105.7 ± 40.3
.004
Total aortic crossclamp time (min)
93.1 ± 38.8
80.0 ± 30.3
.003
Congenital bicuspid valve
37 (41.1)
179 (35.0)
.26
Annular enlargement
27 (30.7)
0 (0.0)
<.001
Nicks procedure
19 (21.6)
0 (0.0)
Manougian
4 (4.5)
0 (0.0)
Other
4 (4.5)
0 (0.0)
Aortic root/STJ enlargement
82 (91.1)
0 (0.0)
<.001
Patch closure
52 (57.8)
0 (0.0)
Aortic root replacement
3 (3.3)
0 (0.0)
Other
28 (31.1)
0 (0.0)
Valve size distribution (mm)
.18
17
0 (0.0)
0 (0.0)
19
3 (3.3)
15 (2.9)
21
24 (26.7)
96 (18.8)
23
32 (35.6)
174 (34.0)
25
27 (30.0)
167 (32.6)
27
3 (3.3)
53 (10.4)
29
1 (1.1)
7 (1.4)
Final implanted position of valve
.06
Intra-annular
15 (16.7)
45 (8.8)
Supra-annular/subcoronary
75 (83.3)
459 (89.6)
Subannular
0 (0.0)
8 (1.6)
Values are presented as mean ± SD or n (%). ARE, Annular enlargement; CABG, coronary artery bypass graft; LAA, left atrial appendage; PFO, patent foramen ovale; STJ, sinotubular junction.
∗ For example, pacemaker, coronary resynchronization therapy, or implantable cardioverter-defibrillator.
MMOM at 30 days was similar between groups (ARE, 13% vs no ARE, 11%; P = .55) (Figure 2). Table 3 provides the 30-day event rates for the composite end point and the individual components. All-cause mortality at 5 years was 9.1% (95% CI, 4.4%-18.2%) in the ARE group and 11.3% (95% CI, 8.6%-14.8%) in the no ARE group (P = .46) (Figure 3). There were no cases of SVD in either group. As shown in Table 4, 5-year safety outcomes between patients who did and did not undergo ARE were low and were not significantly different.
Figure 2Freedom from major morbidity or mortality in patients who did and did not undergo aortic root, sinotubular junction, or annular enlargement (ARE).
Table 3Kaplan-Meier (KM) freedom from event rates for major morbidity or mortality and the individual components of this end point through 30 days postimplant in patients who did and did not undergo aortic root, sinotubular junction, or ARE
The composite end point event rate was calculated based on the time to first event (any of the individual components). If a patient had >1 type of individual event, the patient was included in the KM event rates of all corresponding individual components.
12
14
86.7 (77.7-92.2)
57
64
88.9 (85.8-91.3)
.55
Death
2
2
97.8 (91.4-99.4)
3
3
99.4 (98.2-99.8)
.11
Stroke
2
2
97.7 (91.2-99.4)
3
4
99.4 (98.2-99.8)
.11
Reoperation
0
0
100.0 (100.0-100.0)
3
3
99.4 (98.2-99.8)
.47
Deep sternal wound infection
0
0
100.0 (100.0-100.0)
3
3
99.4 (98.2-99.8)
.47
Renal failure
8
10
91.0 (82.8-95.4)
48
51
90.6 (87.7-92.8)
.91
ARE, Annular enlargement; KM, Kaplan-Meier; CI, confidence interval.
∗ The composite end point event rate was calculated based on the time to first event (any of the individual components). If a patient had >1 type of individual event, the patient was included in the KM event rates of all corresponding individual components.
Table 4Mortality, permanent pacemaker implantation, and valve-related safety outcomes through 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular junction, or ARE
At 5 years, the mean aortic gradient was 14.2 ± 5.5 mm Hg and 13.1 ± 4.1 mm Hg in the ARE and no ARE groups, respectively (P = .30). EOA was 1.36 ± 0.27 cm2 and 1.42 ± 0.35 cm2, respectively (P = .37). Figure E2 shows the mean gradient and EOA from baseline to 5 years in each group; Tables E3 and E4 provides the gradient and EOA, respectively, by valve size. The prevalence of moderate or severe PPM at 1 year and 5 years was comparable between the ARE and the no ARE groups (Table E5).
PPM was defined using Valve Academic Research Consortium 3 criteria.E2
and indexed effective orifice area (iEOA) through 1 and 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular junction, or ARE
At 5 years, all patients in the ARE group (n = 33) and 90 of 91 patients (98.9%) in the no ARE group had no or trace paravalvular regurgitation. One patient in the no ARE group (1.1%) had mild paravalvular regurgitation. There were no cases of moderate or severe paravalvular regurgitation at 5 years in either group. Figure E3, A, shows the severity of paravalvular regurgitation from discharge through 5 years. Thirty-one of 33 patients in the ARE group (93.9%) had no or trace transvalvular regurgitation and 2 (6.1%) had mild transvalvular regurgitation at 5 years. In the no ARE group, 84 of 91 patients (92.3%) had no or trace transvalvular regurgitation, and 7 (7.7%) had mild transvalvular regurgitation at 5 years. There were no cases of moderate or severe transvalvular regurgitation in either group at the same time point. Figure E3, B, shows the severity of transvalvular regurgitation from discharge through 5 years of follow-up.
Functional Status
At 5 years, 36 of 38 patients in the ARE group (94.7%) were in NYHA functional class I, as were 115 of 119 patients in the no ARE group (96.6%) (P = .63). Two patients in the ARE group (5.3%) and 4 patients in the no ARE group (3.4%) were in NYHA functional class III at 5 years. No patients in either group were in NYHA functional class IV at 5 years. Figure E4 shows NYHA functional class from baseline through 5 years in each group.
Discussion
Despite the rapid penetration of percutaneous therapy for aortic valve disease, SAVR remains an important therapeutic option for selected patients. Currently, young patients (age <70 years), those with bicuspid valve pathology, and those with low perioperative risk are offered surgical valve replacement. In addition, the presence of acute infective endocarditis is a contraindication to percutaneous therapy. Thus, there remains a need for a durable prosthetic valve with excellent hemodynamic performance.
Percutaneous valves have been shown to result in better periprocedural hemodynamic status than stented surgical valves; however, this has not translated into better clinical outcomes in medium-term follow-up.
One criticism of prior randomized trials comparing TAVI to SAVR is the arguably suboptimal choice of bioprostheses. Both the Trifecta (Abbott Labs) and Mitroflow valves (Livanova) have been associated with early SVD. The Hancock and Mosaic porcine valves (Medtronic) have been associated with higher transvalvular gradients than similarly sized pericardial valves.
Whereas the Perimount pericardial valve (Edwards Lifesciences) was commonly used in the previous TAVI randomized trials, surgeons were permitted to use their surgical valve of choice.
The Avalus pericardial valve, evaluated in the ongoing PERIGON Pivotal Trial,
was introduced into the market after enrollment was complete in the TAVI randomized trials. The valve was designed to provide the early hemodynamic benefits observed with other pericardial valves while employing the anticalcification treatment believed to confer durability to the Mosaic porcine valve. Another important engineering design is the use of internally mounted leaflets (as in the Magna Perimount valve). This is in stark contrast to the Epic (Abbott Laboratories) and Mitroflow valves, which employ externally mounted leaflets to maximize EOAs.
Squiers JJ, Robinson NB, Audisio K, Ryan WH, Mack MJ, Rahouma M, et al. Structural valve degeneration of bioprosthetic aortic valves: a network meta-analysis. J Thorac Cardiovasc Surg. January 14, 2022 [Epub ahead of print].
The early hemodynamic results of this valve appear favorable; however, the investigators have reported a higher-than-expected rate of PPM considering the mean gradients. Although we have previously described the fallacy in employing iEOAs to predict PPM, we acknowledge that clinicians still commonly use this metric to evaluate the hemodynamic performance of artificial heart valves.
The purpose of this study was to investigate the rates of ARE within the PERIGON trial and its influence on early and late outcomes. Detailed intraoperative surgical data were available for more than 50% of trial participants, including the site of patch enlargement of the aortic annulus, the sinus, and/or the sinotubular junction.
We found that there were subtle regional differences in surgical techniques with ARE procedures being numerically more common in North America. Whereas true annular enlargement was relatively rare (27 out of 90 patients with ARE) in both North America and Europe, patch augmentation of the aortic sinus and/or sinotubular junction was more common in North America. This may be the reason why implanted valve size did not differ between groups.
Regardless of geographic region, the performance of an ARE did not influence early or late outcomes. Peterson and colleagues
have previously reported that ARE was historically associated with higher perioperative mortality and morbidity, but that the influence of ARE dissipated with increasing surgical experience. Unfortunately, even in prospective studies, intangible clinical factors that influence a surgical decision to defer an ARE are hard to capture. It is likely that ARE procedures were performed in patients believed to be less complex than those in the no ARE group, despite no major clinical differences in standard preoperative characteristics.
An analysis of Medicare patients who underwent aortic valve replacement with or without ARE demonstrated higher perioperative risk with ARE but better survival after 3 years.
This study employed the Society of Thoracic Surgeons database matched to Medicare-eligible patients and thus may include patients at higher risk for ARE than the present analysis. Nevertheless, even in this study the benefits of ARE were observable after 3 years.
Another study by the same authors utilized the Virginia Cardiac Surgery Quality Initiative to examine the influence of ARE on early mortality and subsequent candidacy for valve-in-valve TAVI.
These authors again found that ARE was associated with higher perioperative mortality but led to less PPM and a higher rate of candidacy for valve-in-valve TAVI.
A unique surgical consideration of the Avalus valve is intraoperative sizing. Whereas surgeons commonly select the largest possible valve size for a given annular measurement, this can be problematic with the generous sewing cuff of the Avalus valve. Thus, we recommend choosing the valve size determined by the barrel side of the sizer easily passing through the native annulus and the replica side fitting comfortably in the suprannular region.
Again, if this selected valve size is deemed to be inadequate, we would favor an ARE versus an attempt to “stuff” in a larger-sized valve.
We found that the rates of severe prosthesis–patient mismatch at 5 years were not different between those patients who received an ARE versus those who did not. This finding is supported by the fact that mean gradients remained stable and were similar between groups at all time points. Similarly, 5-year survival was excellent and did not differ between groups. One can speculate that without an ARE, 5-year survival may have been lower due to higher gradients and/or rates of PPM. Our interpretation of this trial data is that the performance of an ARE restored survival to that of patients who did not require an ARE and was not associated with higher perioperative morbidity and mortality. Therefore, we continue to support the increased use of ARE techniques to facilitate the implantation of a suitably sized bioprosthesis. We recognize that the technique of root enlargement (eg, Nicks, Manougian and Konno) is surgeon-specific and is commensurate to their training and surgical experience. This study demonstrates that ARE is safe and generalizable to the more than 100 surgeons who participated in the PERIGON study.
Limitations
The PERIGON study is a nonrandomized observational study. The use of root enlargement procedures was not dictated by trial protocol but was at the surgeon's discretion and likely incorporated several variables, not all of which were readily available for analysis. It is possible there could be disagreement between surgeons about the need for a root enlargement procedure in some patients. In addition, because of the way valve size data were collected, we were unable to report the degree of size increases (2 mm, 4 mm, etc). Although the case report forms required the documentation of “adjunctive” surgery, in this analysis we eliminated those patients whose exact site of root repair was unspecified. This limited our final analysis to just more than 50% of the study population. However, the early and late clinical outcomes of our study groups do not differ from the overall cohort reported previously.
In this analysis of a prospective, observational clinical trial, we observed that the performance of an aortic root enlargement procedure did not increase morbidity or mortality at 30 days. We found that survival at 5 years was similar between groups, suggesting that the performance of an ARE procedure restored survival to that observed in patients who did not require an ARE.
Dr Rao is a consultant for Medtronic, Abbott, and Gore; is a member of the Surgical Advisory Board for Medtronic, and holds equity in Medtronic. Ms Linick and Dr Liu are employees of Medtronic. Dr Reardon is a consultant to Medtronic with all payments going directly to his department. Dr Vriesendorp has received a research grant from Medtronic. Dr Ruel is a proctor for Medtronic and principal investigator of the Minimally Invasive Coronary Surgery Compared to Sternotomy Coronary Artery Bypass Grafting Trial. Dr Patel is a consultant and Surgical Advisory Board member for Medtronic. Prof Klautz has received a research grant from Medtronic, consulting and proctoring fees from Medtronic and LivaNova, and participates in speakers' bureaus for Medtronic, LivaNova, and Edwards Lifesciences.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
The authors thank the patients who agreed to participate in the Pericardial Surgical Aortic Valve Replacement Pivotal Trial and the study coordinators at each site who carefully collected clinical data for electronic submission.
Appendix E1. Supplemental methods
Definitions of Bioprosthetic Valve Dysfunction
Structural valve deterioration (SVD): Change to the function of a heart valve substitute resulting from an intrinsic abnormality that causes stenosis or regurgitation.
The diagnosis should be confirmed by examination of the explanted or damaged valve. It includes intrinsic changes such as wear, fatigue failure, stress fracture, calcification, leaflet tear, and stent creep. This definition excludes paravalvular leak infection or pannus overgrowth, or thrombosis of the heart valve substitute as determined by reoperation, autopsy, or in vivo investigation.
Nonstructural valve dysfunction (NSVD): Abnormality resulting in stenosis or regurgitation of the heart valve substitute that is not intrinsic to the valve itself. The diagnosis should be confirmed by examination of the explanted or damaged valve. Examples include entrapment by pannus (ingrowth of tissue into the heart valve substitute which may interfere with normal functioning) or suture, paravalvular leak (clinically or hemodynamically detectable defect between the heart valve substitute and the patient's annulus), inappropriate sizing, and significant hemolytic anemia. This dysfunction is exclusive of valve thrombosis, systemic embolus, or infection diagnosed at reoperation, autopsy, or in vivo investigation.
Severe hemodynamic dysfunction of indeterminate or evolving cause: Dysfunction of the bioprosthesis resulting in severe stenosis (mean transvalvular gradient >40 mm Hg) and/or severe transvalvular regurgitation not caused by study valve endocarditis or valvular thrombosis where any of the following apply: Root cause of the hemodynamic dysfunction is unable to be determined definitively as SVD or NSVD, or progressive severe hemodynamic dysfunction resulting from deterioration that does not meet definition criteria for NSVD or SVD, specifically the requirement that an SVD or NSVD diagnosis should be confirmed by examination of the explanted or damaged valve at reoperation, explant, or in vivo investigation (eg, an evolving or unresolved event). In the case where both severe stenosis and regurgitation are present, the event will be classified as stenosis. This dysfunction is exclusive of valve thrombosis, systemic embolus, infection, or definitive evidence of intrinsic SVD or NSVD from an extrinsic cause.
Figure E1Patient disposition through 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular, or annular enlargement (ARE). The denominators indicate the number of patients expected at the follow-up visit, and the numerators indicate the number who completed the visit. LTFU, Lost to follow-up.
Figure E2Mean aortic gradient (A) and effective orifice area (EOA) (B) through 5 years of follow-up among patients who did and did not undergo aortic root, sinotubular junction, or annular enlargement (ARE). Data are core lab reported. The boxes are centered at the median, with upper and lower bounds of the box being the 75th and 25th percentiles, respectively. The upper and lower ends of the whiskers are maximum and minimum values. The filled circles indicate the mean of the observations.
Figure E3Paravalvular (A) and transvalvular regurgitation (B) through 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular junction, or annular enlargement (ARE). ∗Discharge up to 30 days.
Figure E4New York Heart Association classification through 5 years of follow-up among patients who did and did not undergo aortic root, sinotubular junction, or annular enlargement (ARE).
Western IRB 1019 39th Ave, SE, Suite 120 Puyallup, WA 98374
Sept 10, 2014
20141211
University of Maryland Medical Center Baltimore, Md
Maryland School of Medicine IRB Human Research Protections Office 800 W. Baltimore St, Suite 100 Baltimore, MD 21201
April 30, 2015
HP-00063749
ProMedica Physicians Group Toledo, Ohio
Western IRB 1019 39th Ave SE Suite 120 Puyallup, WA 98374
Aug 28, 2014
20141211
Oklahoma Heart Hospital Oklahoma City, Okla
Western IRB 1019 39th Ave, SE, Suite 120 Puyallup, WA 98374
Oct 17, 2014
20141211
Aurora Medical Group Cardiovascular and Thoracic Surgery Milwaukee, Wis
Aurora Heath Care IRB Office 945 N 12th St PO Box 342, W310 Milwaukee, WI 53201
Aug 19, 2014
14-77
Maimonides Medical Center Brooklyn, NY
Maimonides Medical Center IRB/Research Committee 4802 Tenth Ave Brooklyn, NY 11219
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University of Michigan Cardiovascular Center Ann Arbor, Mich
University of Michigan, Office of Research University of Michigan Medical School 4107 Medical Science Building I, 1301 Catherine St, SPC 5624 Ann Arbor, MI 48109-5624
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Cardiothoracic and Vascular Surgeons Austin, Tex
St David's Health Care IRB St David's Medical Center 919 E 32nd St Austin, TX 78705
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University of Colorado Aurora, Colo
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University of Southern California Los Angeles, Calif
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University of Florida-Shands Gainesville, Fla
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June 3, 2014
Reference: 36/ 14Mf-AS EudaMed: CIV-14-01
Ospedale San Raffaele Milano, Italy
Comitato Etico dell’ Ospedale San Raffaele Via Olgettina, 60 20132 Milano, Italy
March 6, 2014
Approval number not specified in approval letter
Hôpital Bichat–Claude Bernard Paris, France
Comité de protection des personnes Sud-Ouest et outre mer III Service de pharmacologie clinique Groupe Hospitalier Pellegrin Bât. 1A Place Amélie Raba Léon 33076 Bordeaux Cedex, France
Jan 29, 2014
ANSM No: 2013-A00897-38/4
Universitäts Spital Zürich Zürich, Switzerland
Central EC: Kantonale Ethikkommission Bern Institut für Pathophysiologie Hörsaaltrakt Pathologie, Eingang 43A, Büro H372 Murtenstrasse 31 3010 Bern, Switzerland Local EC: Kantonale Ethikkommission Zürich Stampfenbachstrasse 121 8090 Zürich Switzerland
Hôpital Haut-Lévêque–CHU de Bordeaux Bordeaux, France
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2013-A000897-38
Leids Universitair Medisch Centrum Leiden, the Netherlands
Medisch-Ethische Toetsingscommissie Leiden Den Haag Delft PO Box 9600 2300 RC Leiden, The Netherlands
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Erasmus Medical Centre Rotterdam, the Netherlands
Medisch Ethische toetsings Commissie Erasmus MC Westzeedijk 353, Room Ae-337 3015 AA Rotterdam The Netherlands
June 5, 2014
MEC-2014-272/NL45419.058.13
Universitätsklinikum Frankfurt Klinik für Thorax-, Herz- und Thorakale Gefäβchirurgie Frankfurt, Germany
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Guy's & St Thomas' NHS Foundation Trust–St Thomas' Hospital London, United Kingdom
NRES Committee London–Dulwich Health Research Authority Skipton House 80 London Road London SE1 6LH, United Kingdom
Apr 28, 2014
REC reference: 14/LO/0353 IRAS project ID: 134481
Universitätsklinikum Köln Köln, Germany
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Deutsches Herzzentrum München Klinik an der TU München München, Germany
Ethikkommission der Fakultät für Medizin der Technischen Universität München Ismaninger Straβe 22 81675 München, Germany
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Table E3Mean aortic gradient by valve size through 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular junction, or ARE
Mean aortic gradient (mm Hg)
Visit
19 mm
21 mm
23 mm
25 mm
27 mm
29 mm
All sizes
Baseline
No ARE
48.6 ± 22.6 (14)
43.2 ± 16.8 (95)
42.8 ± 16.4 (173)
39.1 ± 18.7 (163)
42.0 ± 21.1 (51)
35.2 ± 14.2 (6)
41.7 ± 17.9 (502)
ARE
31.0 ± 21.2 (3)
49.6 ± 16.8 (24)
45.0 ± 16.8 (29)
45.0 ± 14.6 (27)
51.3 ± 29.3 (3)
22.0 ± (1)
45.7 ± 16.8 (87)
Discharge up to 30 d
No ARE
17.9 ± 7.7 (14)
15.1 ± 4.7 (94)
13.1 ± 4.8 (166)
11.7 ± 3.6 (160)
10.9 ± 3.7 (48)
9.7 ± 2.7 (6)
12.9 ± 4.7 (488)
ARE
17.0 ± 2.6 (3)
15.1 ± 5.8 (22)
13.0 ± 4.6 (29)
12.6 ± 4.6 (26)
14.0 ± 8.5 (2)
9.0 ± (1)
13.5 ± 5.0 (83)
1 y
No ARE
17.4 ± 5.7 (12)
16.2 ± 5.9 (85)
12.5 ± 3.8 (156)
12.3 ± 4.4 (149)
10.3 ± 3.6 (47)
10.6 ± 3.0 (5)
13.0 ± 4.8 (454)
ARE
14.7 ± 5.5 (3)
13.6 ± 5.5 (23)
12.2 ± 5.2 (29)
12.3 ± 3.1 (26)
9.7 ± 3.2 (3)
11.0 ± (1)
12.6 ± 4.6 (85)
2 y
No ARE
17.5 ± 4.3 (11)
16.4 ± 5.8 (77)
12.4 ± 4.3 (149)
11.9 ± 5.1 (144)
9.9 ± 3.2 (44)
7.8 ± 1.3 (4)
12.8 ± 5.2 (429)
ARE
15.3 ± 9.3 (3)
15.1 ± 5.4 (21)
12.4 ± 5.3 (26)
13.3 ± 4.1 (23)
12.3 ± 2.1 (3)
39.0 ± (1)
13.9 ± 5.8 (77)
3 y
No ARE
18.2 ± 5.5 (10)
16.0 ± 5.9 (75)
12.3 ± 3.8 (126)
11.7 ± 4.1 (118)
10.2 ± 3.9 (40)
8.5 ± 1.7 (4)
12.8 ± 4.9 (373)
ARE
11.0 ± 1.4 (2)
16.4 ± 8.1 (20)
12.4 ± 5.0 (26)
11.2 ± 3.6 (23)
12.0 ± 2.6 (3)
15.0 ± (1)
13.1 ± 5.8 (75)
4 y
No ARE
18.0 ± 6.1 (7)
14.6 ± 4.1 (49)
12.4 ± 3.5 (97)
11.1 ± 3.6 (95)
10.4 ± 6.2 (23)
7.3 ± 2.2 (4)
12.3 ± 4.3 (275)
ARE
9.0 ± (1)
16.5 ± 8.6 (13)
12.6 ± 4.8 (21)
11.5 ± 4.3 (18)
11.7 ± 2.5 (3)
14.0 ± (1)
13.1 ± 5.8 (57)
5 y
No ARE
16.5 ± 4.5 (4)
15.5 ± 4.4 (22)
12.6 ± 3.9 (20)
12.5 ± 3.3 (34)
10.0 ± 2.2 (8)
7.0 ± (1)
13.1 ± 4.1 (89)
ARE
NA
18.9 ± 6.2 (9)
12.3 ± 4.9 (14)
13.6 ± 3.2 (7)
10.0 ± 1.4 (2)
13.0 ± (1)
14.2 ± 5.5 (33)
Values are presented as mean ± SD (n). ARE, Annular enlargement; NA, not applicable.
Table E4Effective orifice area by valve size through 5 years of follow-up in patients who did and did not undergo aortic root, sinotubular junction, or ARE
Visit
Effective orifice area (cm2)
19 mm
21 mm
23 mm
25 mm
27 mm
29 mm
All sizes
Baseline
No ARE
0.75 ± 0.19 (14)
0.75 ± 0.31 (85)
0.89 ± 0.49 (163)
1.08 ± 0.70 (156)
1.11 ± 0.89 (49)
0.88 ± 0.27 (5)
0.94 ± 0.60 (472)
ARE
1.50 ± (1)
0.70 ± 0.17 (24)
0.77 ± 0.28 (29)
0.91 ± 0.29 (25)
1.17 ± 0.17 (3)
NA
0.81 ± 0.28 (82)
Discharge up to 30 d
No ARE
1.22 ± 0.32 (12)
1.29 ± 0.26 (84)
1.61 ± 0.37 (143)
1.69 ± 0.40 (147)
1.87 ± 0.39 (47)
2.02 ± 0.27 (6)
1.60 ± 0.41 (439)
ARE
1.12 ± 0.16 (3)
1.43 ± 0.43 (19)
1.49 ± 0.28 (25)
1.74 ± 0.28 (23)
2.15 ± 0.08 (2)
1.62 ± (1)
1.56 ± 0.36 (73)
1 y
No ARE
1.13 ± 0.25 (11)
1.25 ± 0.21 (83)
1.47 ± 0.33 (149)
1.60 ± 0.34 (144)
1.74 ± 0.30 (45)
1.99 ± 0.42 (5)
1.50 ± 0.35 (437)
ARE
1.06 ± 0.11 (3)
1.37 ± 0.35 (23)
1.59 ± 0.42 (29)
1.71 ± 0.48 (25)
1.74 ± 0.24 (3)
2.18 ± (1)
1.56 ± 0.44 (84)
2 y
No ARE
1.06 ± 0.16 (11)
1.21 ± 0.22 (73)
1.48 ± 0.31 (137)
1.64 ± 0.35 (136)
1.86 ± 0.42 (42)
2.01 ± 0.48 (3)
1.52 ± 0.38 (402)
ARE
1.24 ± 0.21 (2)
1.32 ± 0.31 (18)
1.60 ± 0.39 (25)
1.60 ± 0.35 (21)
1.53 ± 0.26 (3)
NA
1.51 ± 0.37 (69)
3 y
No ARE
0.98 ± 0.17 (10)
1.19 ± 0.24 (67)
1.44 ± 0.30 (115)
1.65 ± 0.39 (109)
1.78 ± 0.43 (36)
2.06 ± 0.37 (3)
1.48 ± 0.39 (340)
ARE
1.04 ± 0.21 (2)
1.25 ± 0.39 (18)
1.51 ± 0.37 (25)
1.80 ± 0.48 (21)
1.44 ± 0.36 (3)
1.14 ± (1)
1.51 ± 0.46 (70)
4 y
No ARE
1.03 ± 0.13 (7)
1.24 ± 0.20 (43)
1.44 ± 0.24 (75)
1.61 ± 0.34 (84)
1.71 ± 0.30 (18)
2.45 ± 0.42 (3)
1.49 ± 0.34 (230)
ARE
NA
1.24 ± 0.26 (11)
1.50 ± 0.40 (19)
1.64 ± 0.28 (17)
1.80 ± 0.08 (3)
NA
1.51 ± 0.35 (50)
5 y
No ARE
1.26 ± 0.37 (4)
1.21 ± 0.25 (20)
1.35 ± 0.30 (14)
1.57 ± 0.29 (24)
1.56 ± 0.26 (6)
2.58 ± (1)
1.42 ± 0.35 (69)
ARE
NA
1.14 ± 0.16 (9)
1.45 ± 0.29 (13)
1.36 ± 0.24 (7)
1.56 ± 0.30 (2)
1.59 ± (1)
1.36 ± 0.27 (32)
Values are mean ± SD (n). ARE, Annular enlargement; NA, not available.
Impact of prosthesis-patient mismatch on long-term survival after aortic valve replacement: influence of age, obesity and left ventricular dysfunction.
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