Paravalvular Regurgitation After TAVR: Time Heals, or Not?

We read with interest the study by Toggweiler et al in the September 2015 issue of the Journal of Invasive Cardiology,¹ which examined the natural course of paravalvular regurgitation (PAR) in 50 patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with the self-expanding CoreValve (Medtronic, Inc). The investigators performed transesophageal echocardiographic (TEE) imaging at 1-month (baseline) and 12-month intervals, and computed PAR perimeter and area in addition to conventional measurements. In the first month after TAVR, 48% of patients had mild-to-moderate PAR. Significant reductions in PAR perimeter and cross-sectional area by 43% and 45%, respectively, were observed at 12 months, as well as a non-significant trend toward reduced number and size of PAR jets. Notably, no patients without PAR at baseline developed new PAR at 1 year. 

We congratulate the investigators on their well-written manuscript and robustly designed study that illustrates the natural history of PAR. The study is, however, limited by its small size (n = 50) and single-center design. In addition, a large selection bias exists given that almost one-fourth of the study cohort, after excluding patients who died, did not undergo serial transthoracic echocardiographic measurements. The methodology for assessing PAR is also controversial and not standardized. 

Nevertheless, the findings by Toggweiler et al¹ lend support to the notion that, at least for the self-expanding CoreValve, PAR continues to improve over time, which corroborates the findings from the pivotal United States (US) CoreValve studies.^2,3 In the United States CoreValve high-risk study,² the majority of TAVR patients (76%) with significant PAR at discharge had mild or no regurgitation at 1 year. In the multicenter non-randomized cohort of extreme-risk AS patients,³ TAVR with the CoreValve was associated with a lower rate of significant PAR at 12 months (4.2% vs 10.7%; P=.01 for paired analysis).

PAR: Incidence and Clinical Impact

The great majority of aortic regurgitation (AR) post TAVR is attributable to PAR. Thus, many studies and operators use post-TAVR AR and PAR interchangeably. The incidence of significant PAR after TAVR, defined as moderate or severe PAR, is highly variable and ranges between 5%-15% with the first-generation devices. A systematic analysis⁴ of 45 studies reported a pooled estimate for significant post-TAVR AR of 11.7%. The pivotal US CoreValve study reported an even lower incidence of significant PAR of 6.1% at 1 year.² That particular study utilized an independent echocardiography core laboratory and implemented the Valve Academic Research Consortium (VARC) definitions.² Its salubrious outcomes (including a nearly 5% reduction in absolute mortality compared with SAVR) may be further attributable to other factors, such as the use of computed tomography (CT) assessment for valve sizing, higher valve placement, and the likely sustained expansion of the nitinol frame.   

The impact of significant PAR on post-TAVR outcomes is well established. In the PARTNER A trial,⁵ patients with mild and significant PAR had increased 1-year and 2-year mortality rates compared with those with no/trace PAR. A recent two-center comparative study from Germany⁶ showed that significant AR was associated with lower 1-year survival. The meta-analysis by Athappan et al⁴ demonstrated that the presence of significant AR post TAVR increased 30-day and 1-year mortality rates, and in that report, even mild AR was associated with increased hazard of long-term mortality. The pivotal US CoreValve study,² however, did not show an association between significant PAR and increased mortality. It is conceivable that the lack of association between PAR and outcomes in the CoreValve trial² can be explained by the improvement of PAR over time in these patients, as demonstrated in the study by Toggweiler et al.¹ 

On the other hand, the association of mild PAR with adverse outcomes is inconsistent across studies. This may be caused by imprecision in assessing PAR severity and the lack of standardized methodology and definitions. Notwithstanding, it is likely that mild AR post TAVR is simply a surrogate for higher-risk patients (eg, patients with severe valve calcification, advanced vascular disease) and not a causal predictor.

Given the impact of significant PAR on outcomes, an important question imposes itself: Is one transcatheter valve different from the other with respect to the occurrence of significant post-TAVR PAR? The answer is “yes” – at least for the two commercially-available transcatheter valves in the US. Significant post-TAVR AR occurred more commonly with the CoreValve compared with the Edwards valve in a large meta-analysis inclusive of 12,926 TAVR patients.⁴ In a study by Abdel-Wahab et al⁶ (394 TAVR procedures, predominantly transfemoral), significant AR was higher in the CoreValve group and adversely influenced device success. The CHOICE trial⁷ is the only randomized comparison of both transcatheter valves. CHOICE⁷ demonstrated more than four-fold frequency of significant PAR (18.3% vs 4.1%; P<.001) with the CoreValve, which largely drove its lower device success rate compared with the Edwards Sapien XT valve.

Assessment and Quantification of PAR

Identifying and accurately quantifying PAR is challenging. Multimodality imaging techniques coupled with hemodynamic data are often necessary. The Valve Academic Research Consortium (VARC) proposed stan-dardized definitions to report post-TAVR complications, and recommended a semi-quantitative assessment in the short-axis view of the proportion of prosthesis circumference involving the PAR. Overall, many grading schemes to measure PAR severity were proposed, but none are adequately validated. 

It is essential that operators possess in-depth understanding of the three-dimensional (3D) non-circular geometry of the aortic annulus. Acoustic shadowing from valve calcifications, reverberations of the stent frame, Doppler attenuation from the prosthesis, and the eccentricity, multiplicity, and irregularity of the regurgitant jets may make PAR assessment by echocardiography alone difficult. Invasive supraaortic angiography provides qualitative and semiquantitative assessment, but it is impractical for serial PAR follow-ups and depends on subjective interpretation of unidimensional images. It also cannot discern PAR from central AR and can cause contrast-induced nephropathy. Measurements of the aortic annulus by cross-sectional contrast CT are superior to conventional two-dimensional (2D)-TEE measurements and offer greater discriminatory value for PAR evaluation.⁸ A new method using 3D-TEE images closely approximates multidetector CT (MDCT) measurements, and both modalities predicted mild or significant PAR with equivalent accuracy.⁹ Its use is especially attractive if MDCT imaging is not feasible because of renal dysfunction (although the annular area may be slightly underestimated by 3D-TEE).¹⁰ Advances in CT imaging (eg, dual energy, high pitch, and helical methods) may, however, significantly reduce the volume of contrast required. 

How and When to Treat PAR?

The best way to treat PAR is to prevent its occurrence in the first place. 

It is important to recognize that PAR development is multifactorial and depends on several anatomical factors, including the shape and size of the annulus, degree of annular and leaflet calcification, and left ventricular outflow tract (LVOT) anatomy. Device-related factors may also have an impact, as previously outlined. In a large meta-analysis by Athappan et al,⁴ predictors of AR post TAVR included implantation depth, valve undersizing, and the Agatston calcium score. 

Precise annulus sizing by appropriate pre-TAVR imaging is critical. Undersizing of the prosthesis relative to the annulus size is the central etiology for most PAR events, and a low cover index was found to be an independent predictor of PAR. Actually, a certain degree of prosthesis oversizing (5%-30%) is needed for both types of commercially available valves to ensure adaptation of the prosthesis to the aortic annulus and create enough radial force for adequate anchoring and sealing. Exact assessment of the location, severity, and asymmetry of valve calcification is important, as aortic calcification hinders uniform valve expansion and tight sealing. The use of proper techniques during TAVR is also essential to obviate PAR. Accurate valve positioning, implantation depth, and correct plane are key factors. Increased aorta-LVOT angulation may be especially problematic with the self-expanding valve, as it reduces the ability of the nitinol stent to provide an adequate apposition. Increased angulation may sometimes require the use of stiffer wires that can be shaped to ensure adequate coaxiality.  

Study Implications

How do the findings of Toggweiler and colleagues¹ influence the treatment of PAR following TAVR? The current study suggests that PAR following TAVR with the self-expanding CoreValve continues to improve with time, and thus should be addressed taking this into account.

Mild PAR after TAVR with the CoreValve may be best left untreated. When significant PAR ensues, operators should examine its etiology and severity, and determine plausible strategies. We believe that severe PAR should generally be treated. For example, deep implantation usually results in severe AR as the covered skirt, situated below the annulus, allows blood to regurgitate through the holes of the uncovered portion of the stent frame. The snare technique (in the case of a deeply-implanted CoreValve) or a valve-in-valve is an appropriate therapy in this instance. If PAR is attrib-utable to valve underexpansion, balloon postdilation should be strongly considered in patients with severe PAR. Closure of significant PAR can also be undertaken several months after TAVR using vascular plugs, especially nowadays with the advent of the enhanced Amplatzer Vascular Plug 4 (St. Jude Medical, Inc). How-ever, if moderate PAR occurs, balloon postdilation should be individualized and weighed against its hazards. The latter include thromboembolism and neurological events, prosthetic valve leaflet injury, central AR from overstretched stent, and the infrequent but dreadful risk of aortic annular rupture. Balloon postdilation in the presence of asymmetric heavy calcification extending to the LVOT may be especially hazardous.

Importantly, the decision for further interventions after TAVR should be driven not only by angiographic and echocardiographic findings, but also by hemodynamic data, especially among patients with moderate PAR. Useful hemodynamic data that are readily measured include the LV end-diastolic pressure, aortic diastolic pressure, and the recently described AR index.

Future Directions 

Rapidly evolving valve platforms are emerging. These newer devices possess lower profile, better deliverability, the capability for retrievability and repositioning, and importantly salutary features that reduce PAR. 

The CoreValve Evolut (Medtronic, Inc) is the next generation of self-expanding TAVR system, and has a shorter height to optimize its fit in patients with angulated aortic anatomy and a 12 mm pericardial skirt that provides a tight seal to reduce PAR. The new Centera self-expanding TAVR system (Edwards Lifesciences) has a nitinol frame with a polyethylene terephthalate skirt that reduces PAR. The Sapien 3 valve (Edwards Lifesciences) incorporates an additional outer skirt to reduce PAR (a 3.7% rate of significant PAR was observed at 30 days in the PARTNER II trial),¹¹ and appears to need a lesser degree of oversizing. The Portico device (St Jude Medical) has a porcine pericardial sealing cuff (0% significant PAR at 12 months in a study of a 50 TAVR patients). The Direct Flow Medical aortic valve (Direct Flow Medical) has an inflatable ring cuff frame designed to anchor the bioprosthesis and minimize PAR (99% of patients had no/mild PAR in the DISCOVER trial).¹² The Colibri transcatheter valve (Colibri Heart Valve, LLC), the only prepackaged ready-to-use TAVR system, reported no PAR at 18 months in all 5 successfully implanted patients (personal communication). The Lotus Valve System (Boston Scientific) has an adaptive seal surrounding the ventricular portion of the device, which markedly reduces PAR.¹³ 

Overall, while the study by Toggweiler et al¹ is interesting and clinically useful, the new generation of transcatheter valves may make its findings obsolete and significant PAR a disease of the past.

References

1. Toggweiler S, van Schie B, Zuber M, et al. Natural course of paravalvular regurgitation after implantation of the self-expanding CoreValve: insights from serial TEE measurements. J Invasive Cardiol. 2015;27:435-440.
2. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370:1790-1798.
3. Popma JJ, Adams DH, Reardon MJ, et al; CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-1981. 
4. Athappan G, Patvardhan E, Tuzcu EM, et al. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. J Am Coll Cardiol. 2013;61:1585-1595.
5. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med. 2012;366:1686-1695.
6. Abdel-Wahab M, Comberg T, Büttner HJ, et al; Segeberg-Krozingen TAVI Registry. Aortic regurgitation after transcatheter aortic valve implantation with balloon- and self-expandable prostheses: a pooled analysis from a 2-center experience. JACC Cardiovasc Interv. 2014;7:284-292.
7. Abdel-Wahab M, Mehilli J, Frerker C, et al; CHOICE Investigators. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA. 2014;311:1503-1514.
8. Willson AB, Webb JG, Labounty TM, et al. 3-dimensional aortic annular assessment by multidetector computed tomography predicts moderate or severe paravalvular regurgitation after transcatheter aortic valve replacement: a multicenter retrospective analysis. J Am Coll Cardiol. 2012;59:1287-1294
9. Khalique OK, Kodali SK, Paradis JM, et al. Aortic annular sizing using a novel 3-dimensional echocardiographic method: use and comparison with cardiac computed tomography. Circ Cardiovasc Imaging. 2014;7:155-163.
10. Jilaihawi H, Kashif M, Fontana G, et al. Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation. J Am Coll Cardiol. 2012;59:1275-1286. 
11. Yang TH, Webb JG, Blanke P, et al. Incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3: a comparison with the Sapien XT. JACC Cardiovasc Interv. 2015;8:462-471. 
12. Schofer J, Colombo A, Klugmann S, et al. Prospective multicenter evaluation of the direct flow medical transcatheter aortic valve. J Am Coll Cardiol. 2014;63:763-768.
13. Meredith Am IT, Walters DL, Dumonteil N, et al. Transcatheter aortic valve replacement for severe symptomatic aortic stenosis using a repositionable valve system: 30-day primary endpoint results from the REPRISE II study. J Am Coll Cardiol. 2014;64:1339-1348.

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From the Division of Cardiology, Baylor College of Medicine and the Michael E. DeBakey VAMC, Houston, Texas.

Dedication: This editorial is dedicated to John, a friend, role model, and patient with a bioprosthetic aortic valve.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Paniagua is a founder and stockholder of the Colibri Heart Valve, LLC. The remaining authors report no conflicts of interest regarding the content herein.  

Address for correspondence: Hani Jneid, MD, Division of Cardiology, Baylor College of Medicine and the Michael E. DeBakey VAMC, 2002 Holcombe Blvd, Cardiology 3C-320C, Houston, TX 77030. Email: jneid@bcm.edu