Natural Course of Paravalvular Regurgitation After Implantation of the Self-Expanding CoreValve: Insights From Serial TEE Measurements

Abstract: This study investigates the natural course of paravalvular regurgitation (PAR) with serial transesophageal echocardiography (TEE) measurements. Methods. TEE studies were performed at 30 days and 1 year post TAVI with the self-expanding Core-Valve for the treatment of severe aortic valve stenosis in 50 patients. In addition to conventional measurements, PAR perimeter and orifice area were assessed in the cross-sectional short-axis view at the level of the native aortic annulus. Results. At 30 days, PAR was classified as none in 26 patients (52%), mild in 19 patients (38%) and moderate in 5 patients (10%). Between 30 days and 1 year, the number and size of PAR jets decreased and PAR was absent in 30 patients (60%) (P=.58 compared with 30-day results). Paravalvular regurgitation perimeter decreased from 8.2 ± 10.9% to 4.7 ± 7.7% (P<.01), a relative reduction of 43%. Cross-sectional area of regurgitation decreased from 0.22 ± 0.36 cm² to 0.12 ± 0.20 cm² (P=.01), a relative reduction of 45%. This improvement was observed in patients with mild and moderate PAR. No patient without PAR at 30 days developed PAR at 1-year follow-up. Conclusions. PAR perimeter and area as visualized by Color-Doppler TEE in the cross-sectional view decreased by about 45% between 30 days and 1 year post implantation of the self-expanding CoreValve.

J INVASIVE CARDIOL 2015;27(9):435-440

Key words: aortic stenosis, paravalvular regurgitation, transcatheter aortic valve implantation, transcatheter aortic valve replacement, transesophageal echocardiography

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Paravalvular regurgitation (PAR) is commonly seen after transcatheter aortic valve implantation (TAVI). Moderate or severe PAR has been reported in 5%-15% of patients after TAVI, and several studies have shown that survival is worse in such patients.^1-7 There is an ongoing debate regarding whether or not PAR may improve over time.⁸ However, follow-up examinations are usually performed with transthoracic echocardiography (TTE), and precise assessment of PAR is challenging. Due to the superior image quality, transesophageal echocardiography (TEE) may allow better quantification of PAR. Therefore, the purpose of this study was to investigate the natural course of PAR with serial TEE measurements.

Methods

Study population. Between March 2009 and March 2013, a total of 82 patients underwent TAVI with the self-expanding CoreValve (Medtronic, Inc) for treatment of severe aortic stenosis at the Luzerner Kantonsspital, Lucerne, Switzerland. A total of 16 patients (20%) died during the first year of follow-up (30-day mortality was 7.3%), and 16 patients (20%) did not undergo TEE either at 30 days or at 1 year. The remaining 50 patients (61%) underwent TEE at 30-day and 1-year follow-up exams and were included in this study. All TAVI candidates were discussed with the interdisciplinary heart team, which consisted of cardiologists, interventional cardiologists, and cardiac surgeons. All patients provided written informed consent for the TAVI procedure, and for the follow-up TEE examinations.

TAVI procedure. The procedure has been previously described in detail.⁹ For selection of valve size, all patients underwent preprocedural multidetector computed tomography to assess the native aortic valve annulus in a double-oblique plane.¹⁰ Femoral arterial access was the default transcatheter approach, with direct aortic access utilized in the presence of small or diseased iliofemoral arteries. Most transfemoral procedures were performed under local anesthesia. Balloon valvuloplasty was performed in a standard manner in all patients with a balloon smaller than the intended valve prosthesis (a 20 mm balloon was used for 26 mm valves, a 22 mm balloon for 29 mm valves, and a 24 mm balloon for 31 mm valves). Rapid right ventricular pacing was used for balloon valvuloplasty, but only rarely for prosthesis implantation. The CoreValve was implanted in all patients. 

Data analysis and echocardiography measurements. Clinical endpoints were defined according to the updated definitions of the Valve Academic Research Consortium (VARC).^11,12 TEE was performed at 30-day and 1-year follow-up by a single senior echocardiographer (MZ) with a Philips IE33 machine. PAR was visualized in the cross-sectional view (~30°-50°) at the level of the native aortic annulus. OsiriX Imaging Software (Pixmeo) was used for offline measurements of PAR perimeter and area (Figure 1). In patients with ≥2 jets, PAR perimeter and area were calculated as a summation of measurements of all jets. Very small PAR jets consisting of only a few pixels were not included. All offline measurements were performed by a single physician (BVS). For intraobserver and interobserver variability, 10 loops were randomly chosen and analyzed a second time by the same physician (BVS, for intraobserver variability) and by a second physician (ST, for interobserver variability), with both physicians blinded to the original measurements. 

Statistical analysis. If not indicated otherwise, data are presented as mean ± standard deviation for continuous variables and as number and percentage for categorical variables. Continuous parametric variables were compared using paired and unpaired Student’s t-tests. Categorical variables were compared using the chi-square test and the Fisher’s exact test, as appropriate. Paired non-parametric variables (perimeter and area of PAR at 30 days and 1 year post TAVI) were compared using the Wilcoxon signed rank sum test. Intraobserver and interobserver variability of PAR perimeter and area was measured using Pearson’s correlation. Statistical analyses were conducted using STATA v. 13 (StataCorp) and tested using 2-sided tests at a significance level of .05.

Results

A total of 50 patients (25 female, 25 male) with a mean age of 82 ± 6 years were studied. The self-expanding CoreValve was implanted in all patients. One patient (2%) had a second valve implanted due to low position of the first valve, and two valves (4% of patients) were postdilated. TTE was performed after a median of 3 days post TAVI (range, 1-6 days). Mean aortic valve area increased from 0.7 ± 0.2 cm² at baseline to 1.7 ± 0.3 cm² post TAVI (P<.01) and the mean transaortic gradient was reduced from 45 ± 17 mm Hg to 7 ± 4 mm Hg (P<.01). PAR was graded by conventional TTE measurements as none in 23 patients (46%), mild in 23 patients (46%), and moderate in the remaining 5 patients (10%). Mild transvalvular regurgitation was present in 2 patients (4%). Patients were discharged after a median of 10 days post TAVI (range, 4-29 days).

At 30-day follow-up exam, PAR was assessed using TEE and was present in 24 patients (48%). Table 1 summarizes baseline characteristics of the patient population for those with and without (or with very minimal) PAR at 30 days. Diabetes was more frequently present in patients without PAR. 

Procedural and 30-day outcomes in patients with and without PAR at 30 days are summarized in Table 2. Patients with PAR had a significantly higher left-ventricular end-diastolic diameter than those without PAR (46 ± 6 mm vs 51 ± 8 mm; P=.02). In addition, PAR was more frequently present in patients who required implantation of a permanent pacemaker. At 30-day and 1-year follow-up, PAR severity did not correlate with systolic or diastolic blood pressure.

Localization of paravalvular regurgitation. At both 30-day and 1-year follow-up, PAR was predominantly localized at the commissure of the non-coronary cusp and left coronary cusp, and in the middle of the left coronary cusp, and much less frequently at other parts of the native valve (Figure 2). 

Natural course of paravalvular regurgitation. At 30 days, 26 patients (52%) had no PAR, 15 patients (30%) had 1 jet, and 9 patients (18%) had 2 or more jets (a maximum of 4 jets). At 1 year, there were 30 patients (60%) without PAR (P=.58 compared with 30-day results), 16 patients (32%) had 1 jet, and the remaining 4 patients (8%) had 2 or more jets. Between 30 days and 1 year, regurgitation perimeter decreased from 8.2 ± 10.9% to 4.7 ± 7.7% (P<.01), a relative reduction of 43% (Figure 3). Cross-sectional area of regurgitation decreased from 0.22 ± 0.36 cm² to 0.12 ± 0.20 cm² (P=.01), a relative reduction of 45% (Figure 3). In the patient subgroup with mild PAR at 30 days (n = 19), PAR perimeter decreased from 13.2 ± 7.5% to 6.6 ± 1.3% (P<.01), a relative reduction of 50%. PAR cross-sectional area decreased from 0.31 ± 0.25 cm² to 0.17 ± 0.18 cm² (P<.01), a relative reduction of 45%. In the subgroup of patients with moderate PAR at 30 days (n = 5), PAR perimeter decreased from 27.8 ± 6.0% to 20.6 ± 4.9% (P=.02), a relative reduction of 26%. Cross-sectional area decreased from 0.82 ± 0.32 cm² to 0.50 ± 0.12 cm² (P=.18), a relative reduction of 39%. None of the patients without PAR at 30 days developed mild or moderate PAR at 1-year follow-up.

Reproducibility of measurements. Correlation coefficients for intraobserver and interobserver variability measurements of PAR perimeter and area were PAR perimeter, intraobserver r = 0.97 and interobserver r = 0.96; PAR area, intraobserver r = 0.98 and interobserver r = 0.98.

Discussion

To our knowledge, this is the first study to investigate the natural course of PAR with serial TEE measurements. The main finding of this study was that PAR significantly decreased between 30-day and 1-year follow-up exams. Circumferential extent and orifice area of PAR both decreased by about 45%. Some jets became smaller, and some jets completely disappeared. The reason for this improvement is unknown, but endothelialization of the CoreValve frame may result in better sealing and decreased paravalvular orifice area. Furthermore, the self-expanding CoreValve is made of nitinol, which may further improve apposition over time. The decrease in PAR was observed in both patients with mild PAR and moderate PAR at 30-day follow-up. However, patients with mild PAR improved more than those with moderate PAR, although the number of patients with moderate PAR was small in the present study. Furthermore, none of the patients without PAR at 30 days developed mild or moderate PAR at 1 year. 

Comparison with previous studies. PAR is frequently present after implantation of the self-expanding CoreValve and also after implantation of the Edwards Sapien or Sapien XT valves (Edwards Lifesciences, Inc).^13,14 Most trials and registries measured PAR with TTE, but angiographic supravalvular injection or hemodynamic measurements have been used.^15,16 However, these measurements are not always consistent. For instance, in the randomized CHOICE trial, moderate or severe PAR as assessed by angiography using the method of Sellers et al was present in 4.1% and 18.3% of patients undergoing implantation of the Edwards Sapien XT valve and the Medtronic CoreValve, respectively.^15,17 With echocardiography, these proportions were 1.6% and 5.8%, respectively. This inconsistency is also reflected by the wide range of PAR reported in different studies and registries.¹⁸

Some studies have suggested that PAR severity may decrease over time. In the United States CoreValve trial, the proportion of patients with moderate or severe PAR decreased from 9% at 30 days to 6% at 1 year.⁸ The proportion of patients with mild PAR decreased from 36% to 26%, whereas the proportion of no/trace PAR increased from 55% to 68%. In patients at extreme risk for surgery, the frequency of moderate or severe PAR was lower 12 months after TAVI (4.2%) when compared with discharge (10.7%).¹⁹ A reduction of PAR was also found after implantation of the balloon-expandable Edwards Sapien valve. In the PARTNER trial, moderate or severe PAR after TAVI was present in 12% and 7% at 30 days and 1 year, respectively.⁷ However, these data have to be interpreted with caution. The lower rate of PAR may be due to improvement in PAR, but may also be a result of survival bias since patients without PAR are more likely to be alive at 1-year follow-up. Indeed, the number of TAVI patients undergoing echocardiography in the PARTNER trial decreased from 287 at 30 days to 222 at 1 year.⁷ Therefore, in the present study, we analyzed PAR only in patients with survival beyond 1 year and used more quantitative measurements such as PAR circumferential extent and area.

The challenge to measure paravalvular regurgitation. Assessment of PAR is often challenging with conventional TTE measurements. Echocardiographic image quality may be suboptimal in some patients, and multiple, very eccentric jets may be present. It is now widely accepted that grading for PAR should be different than grading for prosthetic central aortic regurgitation.²⁰ For clinical grading of PAR into none, mild, moderate, or severe, the VARC recommends an integrative approach using different parameters including PAR perimeter and area, but also diastolic flow reversal in the descending aorta, regurgitation fraction, and regurgitation volume.^11,21,22 A recent study comparing PAR grading as recommended by the VARC criteria versus PAR measured with cardiac magnetic resonance imaging; it found that there was agreement in 82% of patients.²³ Since the focus of this study was on anatomy (ie, the extent of the effective orifice area) and not on hemodynamics, we focused on PAR perimeter and area. However, these parameters have not been validated in clinical routine.

Because of the “spray-effect,” it is important that the cross-sectional measurements are performed exactly at the level of the native annulus, and this may not always be possible with TTE. However, even with TEE, some jets may have been measured larger than they actually are due to suboptimal positioning of the probe, limited resolution of TEE, and extreme eccentric PAR jet anatomy. This may explain why some of the jet measurements were relatively large in the present study. TEE’s disadvantages are that it is more invasive and more time-consuming. PAR jets that are anterior may be more challenging to visualize since the frame of the transcatheter heart valve is then between the probe and the color Doppler jet.

Impact of postdilation. In the present study, only 2 patients (4%) underwent postdilation of a transcatheter heart valve, and therefore no meaningful analysis about its impact on PAR can be derived. However, postdilation is frequently performed to treat PAR in cases where the transcatheter valve appears underexpanded.^24,25 In the PARTNER trial, postdilation was performed in 12% of patients and resulted in larger effective orifica area of the valve at 30 days and 1 year. But despite postdilation, PAR remained greater in such patients when compared with patients not requiring postdilation.²⁵ Furthermore, there was a higher incidence of neurologic events during the first 7 days (but not at 30 days and 1 year). In a large Italian registry including patients undergoing TAVI with the CoreValve, postdilation was performed in 20% of cases and successfully reduced PAR to none or mild in 63%. In this analysis, the risk of stroke and the need for a permanent pacemaker was not significantly elevated in patients requiring postdilation.²⁴ Summarizing the existing evidence and the results of the present study, postdilation should be performed only in patients with hemodynamically relevant PAR, as PAR will spontaneously improve in many during the first year of follow-up.

Study limitations. For more precise jet measurements, images were zoomed, resulting in relatively large pixels. Furthermore, very small jets may have been missed in the cross-sectional view. Large calcifications and the frame of the transcatheter valve may interfere with PAR color-Doppler signals. The number of patients was too small to identify predictors of improvement.

Conclusion

PAR area as visualized by color-Doppler TEE in the cross-sectional view decreased by about 45% between 30 days and 1 year post procedure. The reason for this improvement is unknown, but improved valve apposition, annular remodeling, and endothelialization of the stent frame may play a role.

Impact on daily practice. Paravalvular regurgitation decreases by about 45% between 30 days and 1 year post procedure, and this improvement was greater in patients with mild PAR than in those with moderate PAR. According to our results, at least a subset of patients with relevant PAR may improve over time. 

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^*Joint first authors.

From the ¹Department of Cardiology, Heart Center Lucerne, Luzerner Kantonsspital, Lucerne, Switzerland; and the ²University Hospital Zurich, Zurich, Switzerland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Toggweiler reports speaker fees from Medtronic and Edwards Lifesciences. The remaining authors report no disclosures regarding the content herein.

Manuscript submitted August 11, 2014, provisional acceptance given October 20, 2014, final version accepted November 21, 2014.

Address for correspondence: Paul Erne, MD, FESC, Cardiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8000, Switzerland. Email: paul.erne@erne-net.ch