Abstract
BACKGROUND
Little is known about the incidence of prosthesis-patient mismatch (PPM) and its impact on outcomes after transcatheter aortic valve replacement (TAVR).
OBJECTIVES
The objectives of this study were: 1) to compare the incidence of PPM in the transcatheter and surgical aortic valve replacement (SAVR) randomized (RCT) arms of the PARTNER-I trial Cohort A; and 2) to assess the impact of PPM on regression of left ventricular (LV) hypertrophy and mortality in these 2 arms and in the TAVR nonrandomized continued access (NRCA) Registry cohort.
METHODS
The PARTNER trial Cohort A randomized patients 1:1 to TAVR or bioprosthetic SAVR. Postoperative PPM was defined as absent if indexed effective orifice area >0.85, moderate ≥0.65 but ≤0.85, or severe <0.65 cm2/m2. LV mass regression and mortality were analyzed using the SAVR-RCT (n = 270), TAVR-RCT (n = 304) and TAVR-NRCA (n = 1637) cohorts.
RESULTS
Incidence of PPM was 60.0% (severe: 28.1%) in SAVR-RCT versus 46.4% (severe: 19.7%) in TAVR-RCT (p < 0.001) and 43.8% (severe: 13.6%) in TAVR-NRCA. In patients with aortic annulus diameter < 20 mm, severe PPM developed in 33.7% undergoing SAVR compared to 19.0% undergoing TAVR (p = 0.002). PPM was an independent predictor of less LV mass regression at 1 year in SAVR-RCT (p = 0.017) and TAVR-NRCA (p = 0.012) but not in TAVRRCT (p = 0.35). Severe PPM was an independent predictor of 2-year mortality in SAVR-RCT (hazard ratio [HR]: 1.78; p = 0.041) but not in TAVR-RCT (HR: 0.58; p = 0.11). In the TAVRNRCA, severe PPM was not a predictor of 1-year mortality in the whole cohort (HR: 1.05; p = 0.60) but did independently predict mortality in the subset of patients with no post-procedural aortic regurgitation (HR: 1.88; p = 0.02).
CONCLUSIONS
In patients with severe aortic stenosis and high surgical risk, PPM is more frequent and more often severe following SAVR than TAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also has a significant impact on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation. TAVR may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM to avoid its adverse impact on LV mass regression and survival.
Keywords: Doppler echocardiography, aortic regurgitation, left ventricular mass regression, mortality
Prosthesis-patient mismatch (PPM) occurs when the effective orifice area (EOA) of a normally functioning prosthetic valve is too small in relation to patient body size. Several studies have reported that PPM is frequent (20% to 70%) and has a negative impact on short- and long-term outcomes following surgical aortic valve replacement (SAVR) for aortic stenosis (1). A recent meta-analysis reported that moderate and severe PPM are associated with a 1.2- and 1.8-fold increase in the risk of all-cause mortality, respectively (2). It thus appears important to implement preventive strategies to avoid PPM without increasing operative risk.
Transcatheter aortic valve replacement (TAVR) has emerged as a valid alternative to SAVR in selected patients (3,4). Previous nonrandomized studies suggested that TAVR could be associated with a lower incidence of PPM compared to SAVR (5,6). Some studies reported PPM is associated with less regression of left ventricular (LV) hypertrophy, less improvement in patient functional status, and increased mortality following TAVR (7,8), whereas others found no significant impact of PPM on outcomes (9,10). No randomized trial has published data comparing TAVR versus SAVR with respect to incidence and clinical impact of PPM.
The PARTNER (Placement of Aortic Transcatheter Valves) trial was a multicenter, randomized controlled trial (RCT) comparing TAVR with SAVR in high-risk patients with severe aortic stenosis (Cohort A) (3,4,11). Trial results showed that TAVR was noninferior to SAVR with no difference in 2-year all-cause mortality, cardiovascular mortality, or rehospitalization for heart failure (3,4). The objectives of this study were to: 1) compare the incidence of PPM in the TAVR- and SAVR-RCT arms of the PARTNER-I Cohort A trial; and 2) examine PPM's impact on regression of LV hypertrophy and on mortality in the RCT arms and in the TAVR-nonrandomized continued access (NRCA) Registry of PARTNER IA.
METHODS
STUDY DESIGN AND PATIENT POPULATION
In a 1:1 ratio, Cohort A of the PARTNER trial randomized 699 high surgical risk patients with severe, symptomatic aortic stenosis (AS) between SAVR and TAVR with the Edwards-SAPIEN heart valve system (Edwards Lifesciences, Irvine, California) (Online Figure) (3). The trial's design, inclusion and exclusion criteria, and primary results have been reported (3,11). These patients had severe AS with an aortic valve area <0.8 cm2 (or indexed aortic valve area <0.5 cm2/m2) and either resting or inducible mean gradient >40 mm Hg or peak jet velocity >4 m/s. They were symptomatic from AS (New York Heart Association functional class ≥2) and were at high surgical risk as defined by a predicted risk of death of 15% or higher by 30 days after conventional surgery. Exclusion criteria included bicuspid or noncalcified valve, coronary artery disease requiring revascularization, an LV ejection fraction ≤20%, an aortic annulus diameter <18 mm or > 25 mm, severe mitral regurgitation (MR) or aortic regurgitation (AR), and an aortic bioprosthesis. For patients assigned to SAVR, the study protocol strongly discouraged use of surgical valves other than Edwards bovine bioprostheses and excluded patients in whom the need for a root enlargement was recognized in advance. Nonetheless, for various reasons, 10% of the surgical valves were not Edwards valves, and intraoperative findings led to root enlargement in 2 patients and root replacement in 2 patients.
Patients assigned to the TAVR group underwent either transfemoral or transapical placement of the aortic valve on the basis of whether peripheral arteries could accommodate the large sheaths required (22 French for the 23-mm valve and 24 French for the 26-mm valve) (Online Figure). Furthermore, 1,776 patients were enrolled in the high-risk TAVR-NRCA cohort and the inclusion and exclusion criteria for this registry were the same as those for the Cohort A-RCT (Online Figure). In addition, given that paravalvular AR has been shown to be a powerful predictor of mortality in the TAVR arm of the PARTNER-I Cohort A (3) and that it may confound the association between PPM and outcomes, we also assessed the impact of PPM in the subset of TAVR-NRCA patients (n = 835) with none or trace post-procedural AR.
Echocardiograms were obtained at baseline and at 7 days, 30 days, 6 months, 1 year, and 2 years post-procedure. For this post-hoc analysis, we included patients of the SAVR- and TAVR-RCT groups and patients of the TAVR-NRCA group of the as-treated population with a post-implant echocardiogram available. This analysis included 270 SAVR-RCT patients, 304 TAVR-RCT, and 1,637 TAVR-NRCA (Online Figure). The first post-implant echocardiogram was the 7-day echocardiogram in 84.1% of the SAVR-RCT patients and 89.5 % of the TAVRRCT patients (p = 0.06).
DOPPLER-ECHOCARDIOGRAPHIC MEASUREMENTS
All baseline and follow-up echocardiograms were interpreted by an independent core laboratory housed at the Duke Clinical Research Institute. Study work flow, reproducibility testing, image acquisition and analysis, and quality assurance data have been published (12).
Ventricular size and function and valvular function were measured according to previously published guidelines (13,14). LV volumes and ejection fraction were measured using the biplane Simpson formula. LV mass was calculated using the formula recommended by the American Society of Echocardiography (13). The stroke volume was measured in the LV outflow tract (LVOT) with the use of the diameter and velocity measured just underneath the prosthesis stent for both surgical and transcatheter valves. The EOA was calculated as the LVOT stroke volume divided by the aortic jet velocity time integral and was indexed for body surface area (BSA). An integrative, semi-quantitative approach was used to assess the severity of central, paravalvular, and total regurgitation (12,14). The results of the comparison of the echocardiographic findings in the TAVR-RCT versus SAVR-RCT arms of the PARTNER-A trial have been previously published (15).
DEFINITION OF PPM
The first available post-implant (7 days, 30 days, or 6 months) echo showing EOA indexed for BSA was used to identify and quantify PPM. The severity of PPM was graded from the echocardiograms using the indexed EOA with absence defined as >0.85 cm2/m2, moderate ≥0.65 and ≤0.85 cm2/m2, and severe <0.65cm2/m2 (1,2).
STUDY ENDPOINTS
The study endpoints were regression of LV mass at 1 year and all-cause mortality at 2 years for the RCT cohort. For the TAVR-NRCA cohort, 1-year mortality was used as the endpoint because events were not adjudicated beyond this time point in the registry cohort.
STATISTICAL ANALYSIS
Continuous variables are presented as mean ± SD or median (IQR = interquartile range) for variables with a skewed distribution and compared with the use of the Student's t-test or the Wilcoxon Rank-Sum test. The normality of variables was assessed with the Kolmogorov-Smirnov test. Categorical variables were compared with the use of the Chi-square or the Fisher's exact tests. The Fisher's exact test was used when the expected cell frequency was <5.
Absolute and percent changes in LV mass were calculated using paired data at baseline and 1 year and were compared between PPM groups in each treatment arm (TAVR-RCT, SAVRRCT, TAVR-NRCA). Multivariable analysis was performed with linear regression. Survival curves for time-to-event variables were constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates and compared with the use of the log-rank test. Multivariable analysis was performed in each treatment arm with the Cox proportional hazards model. PPM was entered into the models in binary (PPM/no-PPM) or ternary (severe PPM/moderate PPM/no-PPM) format. Other variables entered into the multivariable models for adjustment were the univariable predictors of mortality and the variables that showed a statistically significant difference between the PPM and no-PPM groups. All statistical analyses were performed with the use of SAS® software, version 9.2.
The Cardiovascular Research Foundation (New York, NY) maintains the study's database, and independent analyses can be requested by investigators with statistical assistance provided. All of the analyses were performed with data from the as-implanted population. Data are based on an extract date of February 13, 2012.
RESULTS
COMPARISON OF THE INCIDENCE OF PPM IN TAVR-RCT VS. SAVR-RCT
The incidence of PPM assessed at first postoperative echocardiogram was significantly (p < 0.001) lower in the TAVR-RCT arm (overall PPM: 46.4% [n =141]; moderate: 26.6% [n = 81]; severe: 19.7% [n = 60]) than in the SAVR-RCT arm (overall: 60.0% [n = 162]; moderate: 31.9% [n = 86]; severe: 28.1% [n = 76]) (Figure 1A). Similar results were obtained if PPM was assessed at the 7-day echocardiogram (TAVR 47% vs. SAVR 61%; p < 0.001) or 30-day echocardiogram (TAVR 42% vs. SAVR 57%; p < 0.001).
FIGURE 1.
Incidence of Prosthesis-Patient Mismatch According to Treatment Type in the High-Risk Cohort of the PARTNER Trial Incidence of prosthesis-patient mismatch (PPM) at first post-implant echocardiogram according to treatment group (SAVR-RCT, TAVR-RCT, and TAVR-NRCA) in the as-treated population of the PARTNER trial (A) and in the subsets of patients with a small aortic annulus diameter (<20mm) (B). Incidence of PPM according to the implantation approach (transfemoral vs. transapical) in the TAVR-RCT and TAVR-NRCA cohorts (C). Incidence of PPM according to the utilization of post-dilation or intraprocedural valve-in-valve procedures in the TAVR-NRCA cohort (D).
NRCA = nonrandomized continued access; RCT = randomized clinical trial; SAVR = surgical aortic valve replacement; TAVR = transcatheter aortic valve replacement.
In the patients with an aortic annulus diameter <20 mm, the incidence of severe PPM was 19.0% (n = 24/126) in TAVR-RCT versus 33.7% (n = 35/104) in SAVR-RCT (p = 0.002; Figure 1B). The incidence of PPM was not significantly different between transfemoral vs. transapical approach in the TAVR-RCT cohort (Figure 1C).
Compared to SAVR-RCT patients, those in the TAVR-RCT group had significantly higher indexed aortic valve area (p = 0.0004) and lower transprosthetic gradients (p = 0.005) despite higher stroke volume (p < 0.0001) (Online Table 1).
INCIDENCE OF PPM IN TAVR-NRCA
In the TAVR-NRCA cohort, the incidence of overall, moderate, and severe PPM was 43.8% (n = 920), 30.2% (n = 495), and 13.6% (n = 222), respectively (Figure 1A), and it did not differ between transfemoral vs. transapical approach (Figure 1C). Forty-six (2.8%) of the patients in the TAVR-NRCA cohort underwent intraprocedural transcatheter valve-in-valve procedure for either valve malposition or dysfunction and the incidence of PPM was similar in this subset (overall: 47.8% [n = 22]; moderate: 30.4% [n = 14]; severe: 17.4% [n = 8]) compared to the patients who did not undergo this procedure (overall: 43.7% [n = 695]; moderate: 30.2% [n = 481]; severe: 13.5% [n = 214]) (Figure 1D). Patients who underwent post-dilation (n = 222; 14.2%) had significantly (p <0.001) less PPM (overall: 30.6% [n = 68]; moderate: 22.0% [n = 49]; severe: 8.6% [n = 19]) compared to the 1,415 patients in the TAVR-NRCA cohort who did not undergo post-dilation (overall: 45.8% [n = 647]; moderate: 31.5% [n = 445]; severe: 14.3% [n = 202]) (Figure 1D).
COMPARISON OF BASELINE CHARACTERISTICS ACCORDING TO PPM
In the SAVR-RCT arm, patients with PPM on their first postoperative echocardiogram had similar age, sex distribution, body mass index (BMI), and Society of Thoracic Surgeons (STS) score compared to those with no PPM (Table 1). However, SAVR-RCT patients with PPM had significantly larger BSA and higher prevalence of renal disease than those without PPM. The incidence of moderate or greater total prosthetic AR was respectively 3%, 0%, and 0% in the no-PPM, moderate PPM, and severe PPM groups of the SAVR-RCT (p = 0.13).
TABLE 1.
Baseline Clinical and Doppler Echocardiography Characteristics of Patients in the TAVR and SAVR Arms of the PARTNER - Cohort A Trial According to Presence or Absence of Prosthesis-Patient Mismatch
| SAVR-RCT n = 270 | TAVR-RCT n = 304 | TAVR-NRCA n = 1,637 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| No-PPM n = 108 (40%) | PPM n = 162 (60%) | p Value | No-PPM n = 163 (53.6%) | PPM n 141 (46.4%) | p Value | No-PPM n = 920 (56.2%) | PPM n = 717 (43.8%) | p Value | |
| Demographic and Clinical Data | |||||||||
| Age, yrs | 84 ± 7 | 85 ± 6 | 0.55 | 85 ± 6 | 83 ± 8 | 0.02 | 86 ± 6 | 84 ± 7 | <0.0001 |
| Female, % (n) | 44.4% (48) | 40.7% (66) | 0.55 | 39.9% (65) | 44.0% (62) | 0.47 | 48.2% (443) | 48.3% (346) | 0.97 |
| BSA, m2 | 1.79 ± 0.23 | 1.85 ± 0.22 | 0.04 | 1.77 ± 0.23 | 1.90 ± 0.26 | <0.001 | 1.75 ± 0.24 | 1.85 ± 0.25 | <0.0001 |
| BMI, kg/m2 | 26.6 ± 5.6 | 27.0 ± 5.7 | 0.44 | 25.7 ± 4.8 | 29.7 ± 8.5 | <0.001 | 25.5 ± 5.5 | 27.8 ± 6.4 | <0.0001 |
| Obesity, BMI ≥30 kg/m2 (n) | 23.0% (25) | 25.9% (42) | 0.67 | 16.2% (26) | 38.0% (54) | <0.001 | 14.9% (137) | 30.7% (220) | <0.001 |
| STS Score | 11[10-13] | 11[10-13] | 0.45 | 11[10-13] | 11[10-13] | 0.92 | 11[9-13] | 11[10-13] | 0.32 |
| Logistic EuroSCORE | 26[16-37] | 27[19-42] | 0.12 | 26[17-38] | 26[15-39] | 0.85 | 23[15-34] | 23[14-35] | 0.81 |
| Diabetes, % (n) | 40.7% (44) | 42.0% (68) | 0.84 | 40.5% (66) | 46.8% (66) | 0.27 | 32.6% (300) | 42.8% (307) | <0.0001 |
| Hyperlipidemia, % (n) | 80.6% (87) | 87.0% (141) | 0.15 | 79.1% (129) | 80.1% (113) | 0.83 | 85.1% (783) | 87.0% (624) | 0.27 |
| Smoking, % (n) | 48.1% (52) | 48.8% (79) | 0.92 | 48.5% (79) | 53.2% (75) | 0.41 | 47.1% (433) | 50.2% (360) | 0.21 |
| Hypertension, % (n) | 96.3% (104) | 93.8% (152) | 0.37 | 85.3% (139) | 93.6% (132) | 0.02 | 94.2% (867) | 93.6% (671) | 0.58 |
| NYHA class IV, 5 (n) | 55.6% (60) | 48.1% (78) | 0.23 | 53.4% (87) | 49.6% (70) | 0.52 | 43.9% (403) | 48.6% (348) | 0.056 |
| Angina, % (n) | 21.3% (23) | 19.1% (31) | 0.66 | 23.9% (39) | 27.0% (38) | 0.55 | 19.0% (175) | 19.2% (138) | 0.91 |
| Coronary artery disease, % (n) | 74.1% (80) | 79.0% (128) | 0.34 | 70.6% (115) | 79.4% (112) | 0.08 | 78.3% (720) | 82.1% (589) | 0.056 |
| Prior MI, % (n) | 25.9% (28) | 30.6% (49) | 0.40 | 27.0% (44) | 27.0% (38) | 0.99 | 25.0% (229) | 28.9% (206) | 0.07 |
| Prior PCI, % (n) | 29.6% (32) | 33.5% (54) | 0.50 | 29.4% (48) | 35.0% (49) | 0.30 | 44.8% (412) | 39.5% (283) | 0.03 |
| Prior CABG. % (n) | 39.8% (43) | 50.0% (81) | 0.10 | 39.9% (65) | 48.2% (68) | 0.15 | 42.3% (389) | 48.1% (345) | 0.02 |
| Stroke or TIA (lasting 6-12 mos), % (n) | 31.4% (32) | 25.7% (38) | 0.32 | 27.8% (42) | 32.8% (44) | 0.36 | 25.5% (232) | 25.9% (183) | 0.84 |
| Carotid disease, % (n) | 28.7% (29) | 23.9% (34) | 0.40 | 28.7% (43) | 31.8% (42) | 0.56 | 24.7% (223) | 28.2% (197) | 0.11 |
| Peripheral vascular disease, % (n) | 49.5% (53) | 39.9% (63) | 0.12 | 38.9% (63) | 42.4% (59) | 0.53 | 47.2% (431) | 45.5% (320) | 0.48 |
| Porcelain aorta, % (n) | 0.9% (1) | 0.0% (0) | 0.40 | 1.2% (2) | 0.0% (0) | 0.50 | 1.5% (14) | 0.6% (4) | 0.06 |
| Pulmonary hypertension, % (n) | 48.1% (52) | 50.6% (82) | 0.69 | 50.9% (83) | 51.1% (72) | 0.98 | 37.2% (337) | 38.7% (276) | 0.54 |
| Major arrhythmia, % (n) | 50.9% (55) | 53.4% (86) | 0.69 | 45.4% (74) | 47.5% (67) | 0.71 | 47.9% (440) | 56.2% (403) | 0.0008 |
| Permanent pacemaker, % (n) | 22.2% (24) | 24.1% (39) | 0.72 | 22.7% (37) | 17.7% (25) | 0.28 | 20.4% (188) | 23.9% (171) | 0.09 |
| Renal disease (Cr ≥2), % (n) | 13.0% (14) | 25.3% (41) | 0.01 | 17.3% (28) | 17.7% (25) | 0.92 | 15.8% (145) | 16.2% (116) | 0.81 |
| Liver disease, % (n) | 4.6% (5) | 1.2% (2) | 0.12 | 1.8% (3) | 2.8% (4) | 0.71 | 2.4% (22) | 2.0% (14) | 0.55 |
| COPD, % (n) | 45.4% (49) | 43.8% (71) | 0.80 | 39.9% (65) | 48.9% (69) | 0.11 | 39.8% (366) | 46.2% (331) | 0.01 |
| Oxygen dependent, % (n) | 5.6% (13) | 8.0% (19) | 0.44 | 8.6% (14) | 9.2% (13) | 0.85 | 6.3% (58) | 10.2% (73) | 0.004 |
| Baseline Doppler-Echo Data | |||||||||
| Aortic annulus diameter, mm | 20.3 ± 2.3 | 19.8 ± 2.2 | 0.12 | 19.8 ± 2.4 | 20.4 ± 2.4 | 0.18 | 18.9 ± 2.8 | 18.8 ± 2.6 | 0.61 |
| LV ejection fraction, % | 56 ± 13 | 53 ± 13 | 0.12 | 53 ± 15 | 50 ± 13 | 0.09 | 54 ± 12 | 51 ± 13 | 0.0001 |
| AV mean gradient, mm Hg | 45 ± 14 | 42 ± 15 | 0.053 | 44 ± 15 | 43 ± 14 | 0.39 | 45 ± 15 | 44 ± 14 | 0.22 |
| Moderate/Severe AR, % (n) | 10.8% (11) | 15.1% (24) | 0.48 | 10% (16) | 4.4% (6) | 0.12 | 10.3% (93) | 8.8% (61) | 0.40 |
| Moderate/Severe MR, % (n) | 13.7% (14) | 22.8% (36) | 0.16 | 22.4% (36) | 18.8% | 0.46 | 22.5% (196) | 22.9% (157) | 0.46 |
The continuous variables are reported as mean ± SD and compared with Student t test, except STS score and logistic EuroSCORE that are reported as median and [interquartile range] and compared with Wilcoxon Rank-Sum test. The values between parentheses indicate the number of patients.
AR: aortic regurgitation; AV = aortic valve; BSA = body surface area; BMI = body mass index; CABG = coronary artery bypass graft surgery; COPD = chronic obstructive pulmonary disease; Cr = creatinine; LV = left ventricular; MI = myocardial infarction; MR = mitral regurgitation; NRCA = nonrandomized continued access; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; RCT = randomized clinical trial; SAVR = surgical aortic valve replacement; STS = Society of Thoracic Surgeons; TAVR = transcatheter aortic valve replacement; TIA = transient ischemic attack.
In the TAVR-RCT arm, patients with PPM were significantly younger and had higher BSA and BMI and larger baseline LV mass compared to those with no PPM (Tables 1 and 2). In the TAVR-RCT cohort, the incidence of mild or greater total prosthetic AR at first post-implant echocardiography was 63.1%, 57.0%, and 63.2% (p = 0.42) in the no-PPM, moderate PPM, and severe PPM groups and the incidence of at least moderate total regurgitation was 11.5%, 10.1%, and 7.0% respectively (p = 0.63).
TABLE 2.
Impact of PPM on LV Mass Regression at 1 Year in the SAVR-RCT and TAVR-RCT Arms and the TAVR-NRCA Cohort
| LV Mass | |||
|---|---|---|---|
| Baseline (mean ± SD) | Absolute Change - Baseline to 1 year (mean ± SD) | Percent Change - Baseline to 1 year (median [IQR]) | |
| SAVR-RCT | |||
| No-PPM | 275 ± 80 g | −61 ± 51 g ) | −23 [−32, −12]% |
| PPM | 280 ± 88 g | −36 ± 68 g | −15 [−28, −3]% |
| p Value | 0.70 | 0.02 | 0.007 |
| TAVR-RCT | |||
| No-PPM | 275 ± 84 g | −27 ± 56 g | −9 [−19, 4]% |
| PPM | 295 ± 84 g | −44 ± 63 g | −10 [−24, −1]% |
| p Value | 0.05 | 0.07 | 0.27 |
| TAVR-NRCA | |||
| No-PPM | 237 ± 70 g | −40 ± 61g | −17 [−30, −4]% |
| PPM | 247 ± 73g | −32 ± 61 g | −13 [−24, 2]% |
| p Value | 0.01 | 0.24 | 0.09 |
The p value is for PPM versus no-PPM in each of the 3 cohorts. The text in bold underlines the differences that are statistically significant. Percent change in LV mass are presented as median and IQR]. IQR = interquartile range; SD = standard deviation; other abbreviations as in Table 1.
Table 1 shows the comparison of the baseline characteristics between the PPM and no PPM groups in the TAVR-NRCA arm. In this cohort, the incidence of mild or greater AR was 56.0%, 47.3%, and 43.4% (p < 0.001) and that of at least moderate AR was 10.6%, 8.3%, and 5.9% (p = 0.07) in the no-PPM, moderate PPM, and severe PPM groups, respectively.
IMPACT OF PPM ON THE REGRESSION OF LV HYPERTROPHY IN TAVR AND SAVR
In the SAVR-RCT arm, there was significantly less LV mass regression at 1 year in the PPM group compared to the no-PPM group (Figure 2; Table 2). However, LV mass regression was similar between PPM and no-PPM groups in the TAVR-RCT arm. Among the patients with no PPM, those in the SAVR-RCT group experienced significantly more LV mass regression than those in TAVR-RCT (p < 0.001), whereas among those with PPM the extent of LV mass regression was similar in both arms (p = 0.46). In the TAVR-NRCA cohort, there was a trend for lesser percent LV mass regression in patients with PPM versus those with no PPM in univariable analysis (Table 2).
FIGURE 2.
Left Ventricular Mass Regression over Time for the Groups of Patients with PPM versus no PPM.
LV mass (mean ± SEM) at baseline and different follow-up times according to the presence/absence of PPM in the SAVR-RCT arm (A), TAVR-RCT arm (B), and TAVR-NRCA cohort (C). *Significant difference (p < 0.05) between PPM and no-PPM groups. #Significant difference (p < 0.05) from baseline within each PPM group (green: No PPM; orange: PPM). LV = left ventricular; SEM = standard error of the mean. Other abbreviations as in Figure 1.
In multivariable analysis including age, sex, baseline LV mass, baseline MR, and post-procedural total AR, PPM independently predicted lower absolute LV mass regression at 1 year in SAVR-RCT (β coeff: -21 ± 9; p = 0.017) but not in TAVR-RCT (β coeff: 7 ± 8; p = 0.35). However, PPM was independently associated with less LV mass regression in TAVR-NRCA (β coeff: -13 ± 5; p = 0.012). Similar results were obtained when using percent LV mass regression in the multivariable analysis (SAVR-RCT: p = 0.016; TAVR-RCT: p = 0.38, TAVR-NRCA: p = 0.017). Higher “residual” mean gradient at first post-implant echocardiography also was associated with less LV mass regression in both TAVR-RCT (p = 0.014) and TAVR-NRCA (p < 0.001). On multivariable analysis, there was an independent association between higher mean gradient and less absolute LV mass regression in TAVR-NCRA (β coeff: -0.61±0.18; p < 0.001) but not in TAVR-RCT.
We found no significant association between PPM and change in LV ejection fraction from baseline to 1 year in the SAVR-RCT, TAVR-RCT, and TAVR-NRCA groups. Similar results were obtained when the analyses were restricted to the subsets of patients with LV ejection fraction <50% at baseline.
IMPACT OF PPM ON MORTALITY IN TAVR AND SAVR
Thirty-day mortality was similar in PPM vs. no PPM groups in SAVR-RCT (4.3 vs. 5.6%), TAVR-RCT (1.8 vs. 2.1%), and TAVR-NRCA (1.6 vs. 2.2%) (all p = NS). Figure 3 shows the curves of all-cause mortality according to PPM.
FIGURE 3.
All-Cause Mortality According to Presence and Severity of PPM Time-to-death curves for prosthesis-patient mismatch stratified in 2 groups (overall [i.e., moderate + severe] PPM vs. no-PPM) or in 3 groups (severe PPM, moderate PPM, no-PPM) for death from any cause in SAVR-RCT (A and B), TAVR-RCT (C and D), TAVR-NRCA (E and F), and TAVR-NRCA excluding patients with mild or greater total aortic regurgitation (G and H). For the panels B, D, F, E, the log-rank p values refer to the 3-group comparison. Abbreviations as in Figure 1.
In the SAVR-RCT arm, patients with any degree of PPM demonstrated significantly higher 2-year mortality (hazard Ratio [HR]: 1.64; 95% confidence interval [95% CI]: 1.01 to 2.67; p = 0.047) than patients with no PPM (Figure 3A and Table 3). Compared to patients with no PPM, those with severe PPM had an increased risk of 2-year mortality (HR: 1.79; 95% CI: 1.03 to 3.12; p = 0.04), but those with moderate PPM did not (HR: 1.51; 95% CI: 0.87 to 2.64; p = 0.14) (Figure 3B and Table 3). The other predictors of 2-year mortality in univariable analysis are presented in the Online Table 2. In multivariable analysis including age, sex, BMI, STS score, major arrhythmia, pulmonary arterial hypertension, renal disease, and post-procedural AR (Table 3), severe PPM independently predicted 2-year mortality (HR: 1.78; 95% CI: 1.02 to 3.11; p = 0.041) in the SAVR-RCT arm. There was also a trend toward an independent association between overall PPM and 2-year mortality (HR: 1.52; 95% CI: 0.93 to 2.48; p = 0.09). When restricting analysis of mortality rates to the 1-year time period, the univariable HR was 1.82, (95% CI: 0.96 to 3.45; p = 0.06) for severe PPM and 1.48 (95% CI: 0.78 to 2.83; p = 0.23) for moderate PPM.
TABLE 3.
Univariable and Multivariable Analyses of the Association Between PPM and 2-Year Mortality in the SAVR-RCT and TAVR-RCT arms
| 2-Year Mortality | ||||
|---|---|---|---|---|
| Univariable Analysis | Multivariable Analysis* | |||
| HR (95% CI) | p Value | HR (95% CI) | p Value | |
| SAVR-RCT (n = 270) | ||||
| PPM | 1.64 (1.01-2.67) | 0.047 | 1.52 (0.93-2.48) | 0.09 |
| Moderate PPM | 1.51 (0.87-2.64) | 0.14 | 1.44 (0.82-2.52) | 0.20 |
| Severe PPM | 1.79 (1.03-3.12) | 0.04 | 1.78 (1.02-3.11) | 0.041 |
| TAVR-RCT (n = 304) | ||||
| PPM | 0.74 (0.48-1.13) | 0.16 | 0.85 (0.55-1.31) | 0.46 |
| Moderate PPM | 0.92 (0.57-1.49) | 0.74 | 1.10 (0.67-1.80) | 0.70 |
| Severe PPM | 0.51 (0.27-0.98) | 0.045 | 0.58 (0.30-1.13) | 0.11 |
Adjusted for age, sex, BMI, STS score, pulmonary arterial hypertension, major arrhythmia, renal disease, and post-procedural AR. CI = confidence interval; HR = hazard ratio; other abbreviations as in Table 1. The text in bold underlines the differences that are statistically significant.
In the TAVR-RCT arm, overall PPM was not significantly (p = 0.16) associated with 2-year mortality (Figures 3C and 3D and Table 3), while severe PPM was associated with significantly lower mortality (HR: 0.51; 95% CI: 0.27 to 0.98; p = 0.041) in univariable analysis. (Other univariate predictors of mortality in TAVR-RCT are shown in the Online Table 2.) In multivariable analysis including age, sex, BMI, STS score, major arrhythmia, pulmonary arterial hypertension, renal disease, and post-procedural AR (Table 3), the association between severe PPM and 2-year mortality was no longer significant (p = 0.11).
When restricting the analysis of mortality rates to the 1-year time period, the univariable HR was 0.44 (95% CI: 0.19 to 1.06; p = 0.07) for moderate PPM and 1.08 (95% CI: 0.61 to 1.91; p = 0.80) for severe PPM.
The univariate predictors of 1-year mortality in the TAVR-NRCA cohort are presented in Online Table 2. PPM was not significantly associated with 1-year mortality in both univariable (HR: 1.05; 95% CI: 0.85 to 1.28, p = 0.60; Figures 3E and 3F) and multivariable analysis (Table 3). However, after excluding patients with mild or greater total prosthetic AR, severe PPM in TAVR-NRCA was independently associated with increased mortality (HR: 1.88, 95%CI: 1.09-3.22, p = 0.02) and there was a trend (p = 0.056) toward an independent association between overall PPM and mortality (Table 3).The impact of PPM on mortality was not statistically different in patients with transfemoral approach versus those with transapical approach (pint = 0.85).
DISCUSSION
The main findings of this study are: 1) PPM is more frequent and more often severe following SAVR than TAVR in Cohort A of the PARTNER-I trial; 2) PPM is associated with less regression of LV hypertrophy in the SAVR-RCT arm as well as in the TAVR-NRCA cohort but this association is not present in the TAVR-RCT arm; 3) PPM is associated with increased 2-year mortality in the SAVR-RCT arm but not in the TAVR-RCT arm; and 4) PPM is not associated with increased risk of 1-year mortality in the whole TAVR-NCRA cohort; however, severe PPM is independently associated with higher mortality in the subset of patients with no residual prosthetic AR.
INCIDENCE OF PPM IN TAVR VERSUS SAVR
The incidence of PPM was lower with TAVR than with SAVR, particularly in patients with a small aortic annulus. This difference may be related to the superior hemodynamic performance of transcatheter versus surgical valves (5,16) (Central Illustration). Although the transcatheter valves are stented valves, the stent is much thinner and no sewing ring occupies the annular space, which causes less obstruction to blood flow, a difference that would be more important when implanted in a small aortic annulus (5,16).
The present study reveals that post-dilation also may help to reduce the degree of PPM, most likely by achieving more complete valve expansion. Previous studies reported that balloon post-dilation also successfully reduced paravalvular regurgitation in the majority of patients, but may be associated with increased risk of cerebrovascular events (24,25). Further studies are needed to determine whether the benefits of post-dilation outweigh its risks.
IMPACT OF PPM ON OUTCOMES IN TAVR AND SAVR
Several previous studies and meta-analyses have reported that PPM, particularly severe PPM, negatively impacts outcomes following SAVR (1,2). However, this is the first prospective multicenter study with adjudication of events and central analyses of echocardiographic studies to examine the incidence and impact of PPM on outcomes in patients randomized to receive SAVR or TAVR. This also is the first large multicenter study to examine the impact of PPM on LV mass regression and survival in patients undergoing TAVR.
This study shows that PPM is associated with persistence of LV hypertrophy and increased 2-year mortality in high-risk patients with severe AS undergoing SAVR. The hazard ratio for severe PPM we reported is similar to that reported in the recent meta-analysis by Head et al. (2). One hypothesis to explain the increased mortality associated with PPM is that the persistence of residual LV afterload and greater hypertrophy impacts negatively on postoperative normalization of coronary flow reserve (1,17). Additionally, patients with PPM experience significantly less LV hypertrophy regression, as seen in the SAVR group of the present study.
However, as opposed to what was observed in the SAVR-RCT arm, PPM was not associated with lesser regression of LV hypertrophy or increased mortality in the TAVR-RCT arm. The differential impact of PPM on survival in TAVR-RCT versus SAVR-RCT is intriguing but may be explained, at least in part, by the following factors:
In the TAVR-RCT arm, patients with PPM were younger, had larger BMI, and higher prevalence of obesity compared to those with no PPM, whereas these differences between the PPM and non-PPM groups were not present in the SAVR-RCT arm. To this effect, Kodali et al. reported that larger BMI is a powerful independent predictor of better 2-year survival (i.e., obesity paradox) in the TAVR-RCT arm of the PARTNER-A trial (4). Furthermore, the indexation of the prosthetic valve EOA to the patient's BSA may overestimate PPM severity in obese individuals (18). This overestimation may have been more important in the severe PPM group of the TAVR-RCT since there was a high prevalence of obesity in this group. These 2 phenomena may have contributed to the absence of negative impact of PPM on LV mass regression and survival in TAVR-RCT.
Several studies have reported that moderate-severe AR is associated with increased mortality following TAVR (4,19). In the TAVR cohorts of the present study, patients with PPM had less post-procedural AR compared to those with non-PPM, whereas paravalvular regurgitation was extremely rare in SAVR, regardless of PPM status. Furthermore, no-PPM SAVR patients appeared to have better LV mass regression and survival than no-PPM TAVR patients. This finding may be explained by the fact that the former subset of patients has an optimal valve hemodynamic performance (i.e., no residual aortic stenosis and no paravalvular regurgitation), whereas the latter subset has no residual stenosis but often paravalvular regurgitation that may impair LV mass regression and adversely impact survival. Hence, paravalvular regurgitation may have confounded or masked the effect of PPM on LV mass regression and survival in TAVR. This hypothesis is supported by the fact that when excluding patients with post-procedural AR, severe PPM became an independent predictor of 1-year mortality in the TAVR-NRCA cohort with a hazard ratio very similar to that obtained in the SAVR-RCT arm.
The counter-intuitive association between severe PPM and improved survival observed on univariable analysis in the TAVR-RCT arm was not confirmed in TAVR-NRCA, which suggests that factors related to initial experience and learning curve might also have contributed to this association. To this effect, the analysis of the TAVR-NRCA patients with no post-procedural AR is important because, in this subset, the learning curve effect was likely less powerful than in the TAVR-RCT and, as in the SAVR-RCT, there was no confounding effect of paravalvular regurgitation. Interestingly, in this subset, the results with respect to impact of PPM on mortality were highly consistent with those observed in the SAVR-RCT.
STUDY LIMITATIONS AND STRENGTHS
In this study, we used the data from a large, randomized study with core laboratory echocardiographic data and adjudicated outcome data. However, this analysis was retrospective and subject to the limitations of an observational study. In addition, 2-year outcomes were unavailable in the NRCA cohort because events were not adjudicated in the registry beyond 1 year.
We chose a definition of PPM based on commonly-used indexed EOA criteria included in the guidelines; other cut-points might produce different results. Errors can occur in estimating prosthetic valve EOA by Doppler echocardiography, particularly in patients with transcatheter aortic valves where the measurement of stroke volume in the LV outflow tract is challenging. However, the stroke volume measured by Doppler in the LVOT was consistent with that measured by the 2-dimensional echocardiographic method.
Patients who died in the peri-procedural period and/or who did not have a post-procedural echocardiographic exam were excluded, possibly introducing a survival bias. Several previous studies have used the projected indexed EOA (i.e., the indexed EOA calculated by dividing the normal reference value of EOA of the prosthesis by the patient's BSA) to identify PPM and these studies have demonstrated that PPM significantly impacts operative mortality following SAVR (1,2)
In the TAVR-NRCA cohort, we did a sub-analysis after excluding patients with AR. Such analysis could not be performed in the TAVR-RCT arm due to the limited number of patients.
In the present study, small aortic annulus was defined as an annulus diameter <20 mm as measured by transthoracic echocardiography. This cut-point likely corresponds to a larger diameter value when measured by computed tomography prior to TAVR or by the surgeon during SAVR. However, comparing incidence of PPM between TAVR and SAVR in the small annulus subsets remains valid given that we used the same method and criteria to define small annulus in both arms.
It is important to emphasize that the protocol of the PARTNER-I Cohort A trial strongly discouraged use of valves other than the Edwards bioprostheses and excluded patients with a root enlargement planned in advance; therefore, the incidence of PPM in the SAVR arm of this randomized study may be higher than if other prosthetic valves with higher EOA had been used. We cannot extrapolate our results to patients who have alternative surgical procedures to prevent PPM (i.e., aortic annulus enlargement, implantation of a stentless bioprosthesis, insertion of a homograft, etc.) although these procedures are associated with their own perioperative risks.
CONCLUSIONS
In high-risk patients with severe AS, the incidence of PPM is reduced after TAVR compared to SAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also significantly impacted survival after TAVR in the subset of patients with no post-procedural AR. TAVR may be preferable to SAVR in patients with a small aortic annulus susceptible to PPM to enhance LV mass regression and reduce postoperative mortality.
Supplementary Material
Perspectives.
Competency in Patient Care and Procedural Skills: Transcatheter aortic valve replacement (TAVR) may be preferred over surgical aortic valve replacement (SAVR) in high-risk patients with severe aortic stenosis and small aortic annulus diameter susceptible to prosthesis-patient mismatch to enhance regression of left ventricular hypertrophy and reduce post-procedural mortality.
Translational Outlook: Longer follow-up of patients in clinical trials and studies of a wider variety of prostheses are needed to fully characterize differences in hemodynamic responses to TAVR vs. SAVR.
CENTRAL ILLUSTRATION.
Hemodynamic Sequelae Following Transcatheter or Surgical Aortic Valve Replacement In patients with severe AS and high surgical risk, PPM is less frequent and less often severe following TAVR than SAVR due to larger EOA for a given patient's annulus size; this hemodynamic sequel is associated with less LV mass regression and higher mortality. On the other hand, as shown in previous studies, PVR is much more frequent following TAVR than SAVR and it is associated with persistent LV hypertrophy and increased mortality. The hemodynamic benefit of TAVR over SAVR appears to be more important in the subset of patients with a small aortic annulus.
AS = aortic stenosis; EOA = effective orifice area; LV = left ventricular; PPM = prosthesis-patient mismatch; PVR = paravalvular regurgitation; SAVR = surgical aortic valve replacement; TAVR: transcatheter aortic valve replacement.
TABLE 4.
Impact of PPM on 1-Year Mortality in the TAVR-NRCA Cohort
| 1-Year Mortality | ||||
|---|---|---|---|---|
| Univariable Analysis | Multivariable Analysis* | |||
| HR (95% CI) | p Value | HR (95% CI) | p Value | |
| TAVR-NRCA – Whole Cohort (n = 1,637) | ||||
| PPM | 1.05 (0.85-1.28) | 0.60 | 1.05 (0.76-1.44) | 0.77 |
| Moderate PPM | 0.97 (0.72-1.31) | 0.85 | 0.94 (0.69-1.29) | 0.98 |
| Severe PPM | 1.23 (0.85-1.79) | 0.27 | 1.20 (0.81-1.78) | 0.35 |
| TAVR-NRCA – Subset with no AR† (n = 835) | ||||
| PPM | 1.38 (0.91-2.09) | 0.12 | 1.50 (0.99-2.29) | 0.056 |
| Moderate PPM | 1.22 (0.76, 1.95) | 0.41 | 1.36 (0.85-2.20) | 0.21 |
| Severe PPM | 1.74 (1.02-1.98) | 0.04 | 1.88 (1.09-3.22) | 0.02 |
Adjusted for age, sex, BMI, STS score, major arrhythmia, pulmonary arterial hypertension, renal disease, baseline mitral regurgitation, mean transaortic gradient, LV ejection fraction, and post-procedural AR.
Subset the TAVR-NCRA cohort with none or trace post-procedural total AR. In this subset, there was no adjustment for post-procedural AR in the models.
Acknowledgements
The authors would like to thank Maria Alu for her contribution in the preparation of the manuscript.
Funding sources: The PARTNER Trial was funded by Edwards Life Sciences. The current analysis was carried out by academic investigators and at the Cardiovascular Research Foundation under the auspices of the PARTNER Publications Office. P Pibarot holds the Canada research Chair in Valvular Heart Diseases, Canadian Institutes of Health research, Ottawa, Ontario, Canada. B Lindman was supported by K23 HL116660 from the NIH.
Author disclosures are as follows:
P Pibarot holds the Canada research Chair in Valvular Heart Diseases, Canadian Institutes of Health research, Ottawa, Ontario, Canada and has received research grant support from Edwards Lifesciences. B Lindman was supported by K23 grant # HL116660 from the National Institutes of Health, Washington, USA. N Weissman has received grant support from Boston Scientific Corporation. S Kodali is a member of the PARTNER Trial Steering Committee and consultant for Edwards Lifesciences, a member of the steering committee for the Portico Trial (St. Jude Medical), and a member of the scientific advisory board of Thubrikar Aortic Valve. M Mack has received travel reimbursements from Edwards Lifesciences relating to his participation as an unpaid member of the PARTNER Trial Executive Committee. V Thourani is a member of the PARTNER Trial Steering Committee and a consultant for Edwards Lifesciences, Sorin Medical, St. Jude Medical, and DirectFlow. DC Miller is supported by an R01 research grant from the NHLBI #HL67025, has received travel reimbursements from Edwards Lifesciences related to his work as an unpaid member of the PARTNER Trial Executive Committee, and has received consulting fees/honoraria from Abbott Vascular, St. Jude Medical, and Medtronic., L Svensson has received travel reimbursements from Edwards Lifesciences related to his work as an unpaid member of the PARTNER Trial Executive Committee, holds equity in Cardiosolutions and ValvXchange, and has Intellectual Property Rights/Royalties from Posthorax. H Herrmann has received grant support from Abbott Vascular, Boston Scientific Corporation, Edwards Lifesciences, Medtronic, Siemens, and W.L. Gore & Associates, and has received consulting fees/honoraria from Paieon and W.L. Gore & Associates. J Rodés-Cabau has received grant support from Boston Scientific Corporation and Edwards Lifesciences, and has received consulting fees/honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Janssen, Merck/Schering-Plough, and Regeneron. J Webb is a member of the PARTNER Trial Executive Committee and has received consulting fees from Edwards Lifesciences. S Lim has received consulting fees/honoraria from Boston Scientific Corporation, Guerbet, and St. Jude Medical. C Smith and M Leon have received travel reimbursements from Edwards Lifesciences related to their work as unpaid members of the PARTNER Trial Executive Committee.
ABBREVIATIONS
- EOA
effective orifice area
- NRCA
nonrandomized continued access
- PPM
prosthesis-patient mismatch
- RCT
randomized controlled trial
- SAVR
surgical aortic valve replacement
- TAVR
transcatheter aortic valve replacement
Footnotes
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