Transcatheter Aortic Valve Replacement for Mixed Aortic Valve Disease: A Propensity Score-Adjusted Analysis From the RISPEVA Registry

Abstract

Background. The differential outcomes between pure/predominant aortic stenosis (AS) and mixed aortic valve disease (MAVD) in patients undergoing transcatheter aortic valve implantation (TAVI) are still debated. Objective. To evaluate the comparative clinical outcomes of patients with MAVD and AS undergoing TAVI using data from the RISPEVA registry. Methods. A total of 3263 patients were included. Of the 3263 patients, 656 with concomitant moderate/severe aortic regurgitation constituted the MAVD group and 2607 constituted the AS cohort. Primary endpoints were 30-day mortality and 1-year survival. Postprocedural paravalvular regurgitation (PPVR), cerebrovascular events, bleeding, and vascular complications were assessed at 30 days. Results. In the overall population, 30-day mortality in the MAVD group was higher than in AS patients (4.3% vs 2.6%;P=.02); however, no differences were detected after propensity-score matching (4.1% vs 3.5%; P=.62). One-year survival was comparable between MAVD and AS patients in both unmatched and matched cohorts. Left ventricular ejection fraction, pulmonary artery systolic pressure, and PPVR, but not baseline MAVD, were predictors of 30-day mortality. The incidence of PPVR was higher in the MAVD group vs the AS group; this difference was not confirmed in patients implanted with a balloon-expandable device. Conclusion. MAVD per se did not negatively affect patients’ prognoses, but appears to identify a more complex cohort of patients with a worse clinical and functional status, probably referred to TAVI in a later stage of the disease. Patients with MAVD had a greater propensity to develop PPVR, which is a known predictor of worse outcome; this tendency seems to be mitigated by the implantation of balloon-expandable valves.

Keywords: mixed aortic valve disease, paravalvular regurgitation, propensity score, transcatheter aortic valve replacement

Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of patients with severe aortic stenosis (AS) at increased risk for surgical aortic valve replacement (SAVR) and is expanding to lower-risk categories as a result of the iterative refinements in valve design and delivery systems and the improvement in operator expertise.^1,2

In routine clinical practice, a nonnegligible number of AS patients have concomitant aortic regurgitation (AR) of variable severity.³ Mixed aortic valve disease (MAVD), defined as moderate or severe AR coexisting with severe AS, represents a peculiar anatomical and functional entity among the degenerative aortic valve disease spectrum. Compared with isolated AS or AR, MAVD carries a combination of both pressure and volume overload on the left ventricle.^4-6

Current literature is indefinite about the prognostic value of MAVD in TAVR referrals, as it is an exclusion criterion for most of the pivotal randomized clinical trials on TAVR vs SAVR.^7-10 The only available data are derived from small and single-center observational registries and a few national databases. Moreover, reported results are often contradictory.^11-17

Because the incidence of valvular aortic diseases is increasing owing to the population aging^18,19 and TAVR indications are expanding to include more complex anatomical and clinical scenarios,² the number of MAVD patients referred to TAVR is expected to rise. Clarifying the impact of concomitant AR on the outcome of patients with severe AS referred to TAVR, therefore, is of paramount importance. In this study, we sought to analyze the short- to mid-term prognosis after TAVR in patients with MAVD, relative to those with pure/predominant AS.

Methods

This was a retrospective analysis of data accrued in the prospective, multicenter Registro Italiano GISE sull’impianto di Valvola Aortica Percutanea (RISPEVA) registry. The study is an ongoing Italian observational registry approved by all ethics committees of participating centers and registered at clinicaltrials.gov (NCT02713932). All patients provided written informed consent. Details of the RISPEVA registry have been reported elsewhere.^20-25 Briefly, all patients in whom TAVR is attempted at participating centers and willing to provide consent are offered inclusion in the registry, without any additional selection criteria. Accordingly, patient selection, preprocedural management, and procedural technique were at physician discretion and largely guided by contemporary best-practice recommendations from national and European scientific societies.

For the current analysis, patients with available follow-up data treated from March 2008 to October 2019 and included in the RISPEVA registry were considered. The only exclusion criterion was pure AR as the indication for TAVR (Supplemental Figure S1).

Baseline and postprocedural AR grade were evaluated through transthoracic or transesophageal echocardiography imaging and graded according to the European Association of Echocardiography guidelines: 0/3+ absent; 1+/3+ mild; 2+/3+ moderate; or 3+/3+ severe.²⁶ The AS group included patients with pure or predominant severe AS, defined as severe AS coupled with absent or mild AR. The MAVD group comprised patients with severe AS and greater than moderate AR.

Severe chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate ≤30 mL/min calculated using the Cockcroft-Gault formula. New- and old-generation devices were defined according to the latest evidence in literature. Evolut Pro/R (Medtronic), Sapien 3 (Edwards Lifesciences), and Acurate prostheses (Boston Scientific) were intended as new-generation devices.²⁷ The most frequently implanted devices were also distinguished into balloon-expandable valves (BEVs) (Sapien XT and Sapien 3) and self-expanding valves (SEVs) (CoreValve [Medtronic] and Evolut Pro/R), according to the classification reported in randomized trials and large observational registries.^28,29

Primary endpoints were death from any cause occurring within the first 30 days and survival rate at 1 year. Secondary endpoints included moderate/severe paravalvular regurgitation (PVR) assessed at the end of the procedure and cerebrovascular events, myocardial infarction, bleeding (major or disabling and minor), vascular complications (major or disabling and minor), acute renal failure, pacemaker implantation, and surgical aortic repair assessed at 30 days and defined on the basis of the current Valve Academic Research Consortium recommendations.³⁰

Statistical analysis. The database was built using Excel software. Data were analyzed by IBM SPSS Statistics, version 26 (IBM Inc) and R, version 3.5.3 (R Foundation). The study population was divided into 2 groups: MAVD patients and AS patients. Furthermore, 2 subgroups were identified according to the type of implanted transcatheter aortic valve: the BEV (Sapien XT and Sapien 3) and SEV (CoreValve and Evolut Pro/R) groups. Among MAVD patients, a head-to-head comparison between new-generation devices (Sapien 3, Evolut Pro/R, Portico, and Acurate) with postprocedural moderate/severe PVR was also performed. Baseline characteristics, procedural findings, and adverse events were presented according to the presence of preprocedural AR. Continuous variables were expressed as medians with standard deviations and were compared using the Student’s t test, while categorical variables were expressed as percentages and were compared using the Pearson's Chi-square test or Fisher's exact test, when appropriate.

For 30-day mortality, the association with several clinical characteristics and procedural findings (known from the literature as predictors of poor outcome after TAVR) was tested in the general population with a univariate logistic regression model. A multivariate logistic regression model was subsequently built using as determinants the parameters associated with the single outcome in the simple linear regression.

Because of the observational nature of the study, propensity-score matching (PSM) was used to adjust for differences in patients’ baseline characteristics. Adjustment was performed for variables associated with worse survival (known from previous literature and/or our regression analysis) and included New York Heart Association (NYHA) class, arterial hypertension, severe CKD, prior aortic valve surgery, mitral regurgitation, left ventricular ejection fraction (LVEF), pulmonary artery systolic pressure, and femoral access. The 1:1 nearest-neighbor matching without replacement method with a propensity caliber of 0.1 was used.

Kaplan-Meier (KM) analysis was used to evaluate the 1-year survival in the overall and matched populations and the log-rank test was used to evaluate the differences between the 2 groups. For all tests, significance was set at a 2-tailed value of P<.05.

Results

A total of 3263 patients undergoing TAVR from March 2008 through October 2019 included in the RISPEVA registry were considered for the present analysis (Supplemental Figure S1). The study population was stratified according to the preprocedural AR. Of the cohort, 2607 (79.9%) and 656 (20.1%) patients were included in the AS and MAVD groups, respectively. The baseline demographic and clinical characteristics of the 2 groups are presented in Table 1, Part 1 and Table 1, Part 2. Although younger, patients in the MAVD cohort were more symptomatic (as expressed by the NYHA class and the higher rate of prior acute pulmonary edema episodes) and presented more frequently with renal insufficiency, arterial hypertension, and prior aortic valve surgery or valvuloplasty. Relative to echocardiographic characteristics, MAVD patients showed more dilated left ventricle with lower ejection fraction, higher pulmonary artery systolic pressure, and higher rate of mitral regurgitation and aortic valve calcifications. Procedural features are described in Table 2. The MAVD group received SEVs more frequently and were more often implanted via a transfemoral access.

After PSM, a population of 1026 patients (513 per group) was selected. Baseline clinical and procedural findings are shown in Supplemental Table S1, Part 1, Supplemental Table S1, Part 2 and Supplemental Table S2. Moreover, according to the implanted prosthesis, the BEV and SEV groups were generated and resulted in 1059 and 1146 patients, respectively.

Data on 1-month follow-up are shown in Table 3. In the overall population analysis, the MAVD group compared with the AS group showed higher rates of 30-day mortality (4.3% vs 2.6%; P=.02), major vascular complications (6.6% vs 3.8%; P<.01), and renal failure (11.7% vs 9.2%; P=.047), respectively. On the contrary, cerebrovascular events were lower (0.5% vs 1.7%; P= .02). After PSM, 30-day survival was comparable between the MAVD and AS groups, whereas the MAVD group still showed a higher rate of major vascular complications (7.4% vs 3.9%; P=.02) and demonstrated lower rates of pacemaker implantation (12.9% vs 17.7%; P=.03), respectively.

At the multivariate logistic regression, LVEF, pulmonary artery systolic pressure, and postprocedural moderate/severe PVR were predictors of 30-day mortality in the overall population (Table 4). Postprocedural PVR data were available for 2340 and 822 patients in the overall population and in the matched cohort, respectively. In the overall population, the rate of moderate/^­severe PVR was higher in the MAVD group (9.3% vs 6.3%; P=.02) (Figure 1); in the PSM population, although the same trend was noticed, the threshold for significance was not reached (9.4% vs 7.6%; P=.35) (Supplemental Table S2).

Clinical outcomes of MAVD and AS patients divided according to the implanted device (BEV or SEV) are described in Supplemental Table S3 and Supplemental Table S4). Among the SEV subpopulation, a higher frequency of postprocedural moderate/severe PVR and a lower 30-day survival rate were detected in the MAVD group (Supplemental Table S2 and Figure 1). Conversely, in the BEV group, there were no differences in moderate/severe PVR and 30-day mortality between MAVD and AS patients, although higher rates of vascular complications and bleeding were observed in the MAVD group (Supplemental Table S3 and Figure 1). The performance of new-generation devices in postprocedural moderate/severe PVR among MAVD patients is shown in Supplemental Table S5 and in Supplemental Figure 2. The Sapien 3 BEV continued to show the lowest rate of postprocedural moderate/severe PVR. However, in the pairwise comparison, the threshold for significance was reached only in the comparison between the Sapien 3 and Evolut Pro/R valves (P=.01). Despite the small sample sizes, relative to the Evolut Pro/R, the rates of moderate/severe PVR in the Portico and Acurate groups were lower and led to nonsignificant differences compared with the Sapien 3 valve. In the 1-year Kaplan-Meier curves, the MAVD and AS groups had similar survival rates, both in the unmatched and matched populations (Figure 2).

Discussion

The aim of this study was to evaluate the clinical outcomes of patients with MAVD undergoing TAVR. The main findings can be summarized as follows: (1) 30-day mortality was higher in the MAVD cohort compared with AS patients; however, no differences were detected between the 2 groups after PSM adjustment; (2) 1-year survival was comparable between the MAVD and AS groups in both the unmatched and matched populations; (3) LVEF, pulmonary artery systolic pressure, and postprocedural moderate/severe PVR, but not baseline MAVD, were shown as predictors of 30-day mortality in the overall population; and (4) the incidence of postprocedural moderate/severe PVR was higher in the MAVD cohort compared with the AS group; this difference was not confirmed in patients implanted with a BEV.

The natural history of MAVD, if conservatively managed, is characterized by a significantly lower event-free survival than AS.^4,6 The worse clinical evolution is attributed to the combination of both volume and pressure overload that impairs the function and anatomy of the left ventricle.⁵ The currently available data on the outcome of MAVD patients undergoing TAVR are contradictory. Some studies report higher cardiovascular or all-cause mortality than AS patients,^11,16 some a similar prognosis,^12,13 and some a better survival rate.^14,17 Remarkably, nonunivocal results are reported by both small single-center reports^12-15 and large national registries.^16,17 Different definitions of MAVD, which in some studies also included patients with mild AR,^11,15,17 make available data more unreliable, since mild AR is known to have no additional significant hemodynamic effect beyond that caused by pure AS.

In our cohort, which is larger than most of the above-mentioned registries, 30-day mortality rate was higher in the MAVD group compared with the AS counterpart. This difference was not confirmed after PSM adjustment (Table 3). The worse 30-day prognosis of MAVD patients could be explained by the worse clinical and functional status at the time of the intervention. Although younger, MAVD patients presented with more comorbidities and more advanced heart–failure-related symptoms coupled with worse left ventricular remodeling. The impact of these factors on patient prognosis is supposed to go beyond the effect of the sole concomitant AR. In support of this hypothesis, when tested, LVEF, pulmonary artery systolic pressure, and postprocedural moderate/severe PVR, but not baseline MAVD, resulted in independent predictors of 30-day mortality (Table 4).

The similar 30-day survival rates between MAVD and AS after PSM adjustment aligns with other smaller registries^12,13 and confirms that MAVD, rather than representing a relevant prognostic factor per se, may identify a more “diseased” cohort of patients undergoing TAVR in a later stage of valve disease. We could hypothesize that, due to the exclusion of MAVD patients from randomized pivotal trials, in the first decade of experience heart teams have referred MAVD patients to TAVR intervention when heart failure symptoms and left ventricular remodeling were more advanced. As expected, in the matched population, MAVD and AS patients also demonstrated comparable mid-term (1-year) mortality, as a confirmation of a negligible impact of MAVD on prognosis in patients with otherwise similar risk profile.

Most literature identifies postprocedural PVR as one of the most powerful outcome determinants after TAVR.³¹ This evidence was confirmed in our analysis, since postprocedural moderate/severe PVR was one of the strongest predictors of 30-day mortality (Table 4). Moreover, as previously described,^11,12,14 MAVD patients in our registry were more likely to develop postprocedural moderate/severe PVR, relative to the AS group. Even after PSM, although the threshold for significance was not reached, this trend was still observed. Of note, after splitting the population according to the implanted device, the higher frequency of postprocedural moderate/severe PVR seen in the MAVD group was not confirmed among patients implanted with BEVs, suggesting an influence of the type of prosthesis on PVR rate. Considering only MAVD patients implanted with new-generation devices, the Sapien 3 BEV continued to show a better performance in moderate/severe PVR compared with the same generation of SEV. When viewed on its own, among the new SEVs, the Portico prosthesis showed the lowest rate of moderate/severe PVR in absolute terms.

This finding is relevant but not new, since some studies already described higher rates of moderate/severe PVR following SEV implantation.^28,32,33 Furthermore, in line with our results, Van Belle et al reported that baseline AR grade ≥2 was a main predictor of PVR only if an SEV was implanted.³¹ The findings from the study suggest that the use of BEVs in MAVD patients might mitigate their higher propensity to develop moderate/severe PVR. This hypothesis is of remarkable interest considering the established link between PVR and prognosis.

Study limitations. Given the nonrandomized nature of the registry, data may be affected by selection bias. However, our dataset was large and prospectively collected from high-volume centers. We observed differences in baseline clinical and procedural characteristics between the 2 groups. Although we sought to reduce potential biases using the PSM analysis, we were not able to correct for unmeasured variables. Additionally, the type of device implanted as well as the entire procedural strategy were at physician discretion. Also, an accurate assessment of AR could be challenging in the presence of severe AS. Accordingly, our findings should be regarded as hypothesis generating and require further confirmation from a large, pragmatic, randomized trial.

Conclusion

In our study, MAVD per se did not negatively affect patient prognosis but seems to identify a more complex cohort of patients with a worse clinical and functional status, probably referred to TAVR in a later stage of the disease. Nonetheless, MAVD patients have a higher propensity to develop postprocedural PVR, a known predictor of worse outcomes. This tendency seems mitigated by the implantation of BEVs.

Affiliations and Disclosures

From the ¹Division of Cardiology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy; ²Invasive Cardiology Unit, “Pineta Grande” Hospital, Castel Volturno, Caserta, Italy; ³Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; ⁴Fondazione C.N.R.G. Monasterio Ospedale del Cuore, Massa, Italy; ⁵UOSA Cardiologia Interventistica, Dipartimento di Scienze Cardiache, Toraciche e Vascolari, Azienda Ospedaliera Universitaria, Siena, Italy; ⁶Centro Cardiologico Monzino, IRCCS, Milan, Italy; ⁷Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy; ⁸Department of Invasive Cardiology, Casa di Salute “Santa Lucia”, San Giuseppe Vesuviano, Napoli, Italy; ⁹Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; ¹⁰Cardiovascular Research Center, Magna Graecia University, Catanzaro, Italy; ¹¹Department of Cardiovascular Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy; ¹²Department of Mathematics, University of Bari “Aldo Moro”, Bari, Italy; ¹³Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; and ¹⁴Mediterranea Cardiocentro, Napoli, Italy.

Funding: The RISPEVA study was supported by unrestricted grants from Edwards Lifesciences and Medtronic to the Società Italiana di Cardiologia Invasiva (SICI-GISE).

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sardella has received proctor fees from Edwards Lifesciences, Boston Scientific, and Biosensors; speaker fees from AstraZeneca, Terumo, OrbusNeich, Biosensors, Boston Scientific, Abbott Vascular, Stentys, and Alvimedica. Dr Biondi-Zoccai has consulted for InnovHeart and Replycare. Dr Giordano was a proctor for Abbott. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted July 16, 2021.

Address for correspondence: Martino Pepe, MD, PhD, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari Piazza G. Cesare 11, Bari, Italy. Email: drmartinopepe@gmail.com

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