New Drugs and Technologies
`
`Paravalvular Aortic Leak After Transcatheter
`Aortic Valve Replacement
`Current Knowledge
`
`Stamatios Lerakis, MD; Salim S. Hayek, MD; Pamela S. Douglas, MD
`
`Transcatheter aortic valve replacement (TAVR) is now
`
`well-established as the standard of care for patients with
`severe symptomatic aortic stenosis who are deemed inoper-
`able,1 and is seen as an alternative treatment option to surgical
`aortic valve replacement (SAVR) in a subset of patients with
`high postoperative mortality.2 The native valve is typically not
`removed but instead crushed by the superimposed bioprosthe-
`sis, which can result in an incomplete seal of the bioprosthetic
`valve and aortic annulus, with subsequent occurrence of para-
`valvular leak (PVL). Two types of Transcatheter Heart Valves
`(THV) that have been widely used, the balloon-expandable
`Edwards valve (Cribier-Edwards, Edwards SAPIEN and
`Edwards SAPIEN XT) by Edwards Lifesciences, and the self-
`expandable CoreValve by Medtronic, have been described in
`detail elsewhere.3,4 Despite the evolving technology of trans-
`catheter valves, PVL post-TAVR is common, with a wide
`range of reported incidences (Table 1). Most importantly, PVL
`has been associated with increased short- and long-term mor-
`tality post-TAVR, and is seen as a barrier to more widespread
`use of this promising technique.5–13 This article describes the
`incidence, causes, and predictors of PVL, as well as its impact
`on clinical outcomes. Methods of prevention, diagnosis, and
`treatment of PVL are also reviewed.
`
`Definition and Incidence
`Aortic regurgitation is characterized as either central or para-
`valvular. Pathological central regurgitation occurs in diseased
`native valves or damaged prosthetic valves, whereas minor
`central regurgitation is often a physiological feature of some
`bioprosthetic valves by virtue of their design. On the other
`hand, PVL is a complication only of aortic valve prostheses
`and occurs more commonly post-TAVR (Figure 1) than after
`SAVR.
`Various multicenter registries and trials have reported
`data on incidence of PVL post-TAVR at different time points
`(Table 1). The overall incidence of PVL post-TAVR ranges
`between 50% and 85%, which is significantly higher than
`what has been observed in SAVR, reported between 1% and
`47.6%, with only 4.2% consisting of more than mild PVL.14
`Although the majority of post-TAVR PVL is mild (7.8–
`40.8%), moderate (5–37.9%) and severe (0.5–13.6%) PVL
`occur frequently.1,2,6,8,10,11,13,15–26 The largest meta-analysis of
`
`TAVR outcomes estimates the incidence of residual moder-
`ate or severe aortic regurgitation after TAVR to be 7.4%.27
`The UK TAVR registry suggests moderate-severe PVL
`occurred more commonly with CoreValve implants (17.3%,
`versus 9.6% with the Edwards implants).13 This finding has
`not been replicated in other studies. One study by Ewe et
`al21 did not find a statistically significant difference in inci-
`dence of PVL between transfemoral and transapical TAVR
`at 30 days and 6 months. The wide range of PVL incidence
`reported is not surprising and is likely a result of the lack of
`standardization across centers in the TAVR technique, dif-
`ferences in operator experience, types and sizes of valves
`used, in addition to the different imaging modalities used
`and challenges in grading PVL. Unbehaun et al6 used a mod-
`ified TAVR procedure after which no patient had severe PVL
`and only 2 had moderate PVL, of a relatively large cohort of
`358 patients.
`It is unclear whether PVL progresses in severity with time.
`The studies reporting the rate of PVL for multiple follow-up
`time points show decreasing incidences of moderate–severe
`PVL. Although the decrease could be attributed to the death
`of patients with higher-grade PVL who are at higher mortality
`risk, a reduction of severity from moderate to mild may also
`relate to geometric remodeling of the annulus2,5,20,21 (Table 1).
`Rates of mild PVL generally remained stable; there was no
`evidence of an increase in PVL over time.
`
`Clinical Impact of Paravalvular Leak
`Despite the difficulties in accurately characterizing PVL,
`the wide range of incidences reported, and the relative
`short period of follow-up, its impact on short- and long-
`term mortality has been consistently reported across studies
`(Table 2). Data from a large cohort of 3201 SAVR patients
`with a mean follow-up of 4.5±3.4 years confirm that patients
`with moderate–severe aortic regurgitation (AR>1/4) had
`lower survival at 1, 5, and 10 years (91.4 versus 96.7%,
`77.5 versus 82.4%, and 44.1 versus 54.5%; P<0.01).14 Other
`data on clinical outcomes related to PVL extend from the
`postoperative period to up to 2 years. Moderate–severe PVL
`is an independent predictor of mortality in the postoperative
`period to 30 days, at 1 year, and at 2 years5–11,13 (Table
`2). Recently, Kodali et al from the Placement of AoRTic
`
`From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (S.L., S.S.H.); and the Duke University
`Medical Center, Duke Clinical Research Institute, Durham, NC (P.S.D.).
`Correspondence to Stamatios Lerakis, MD, Emory University Hospital, 1365 Clifton Rd NE, Suite AT-503, Atlanta, GA 30322. E-mail:sleraki@emory.edu
`(Circulation. 2013;127:397-407.)
`© 2013 American Heart Association, Inc.
`Circulation is available at http://circ.ahajournals.org
`
`DOI: 10.1161/CIRCULATIONAHA.112.142000
`
`397
`
`Downloaded from
`
`http://circ.ahajournals.org/
`
` by guest on January 18, 2017
`
`Page 1 of 13
`
`Edwards Lifesciences v. Boston Scientific Scimed
`IPR2017-01293 U.S. Patent 8,992,608
`Exhibit 2004
`
`

`

`New Drugs and Technologies
`
`Paravalvular Aortic Leak After Transcatheter
`Aortic Valve Replacement
`Current Knowledge
`
`Stamatios Lerakis, MD; Salim S. Hayek, MD; Pamela S. Douglas, MD
`
`Transcatheter aortic valve replacement (TAVR) is now
`
`well-established as the standard of care for patients with
`severe symptomatic aortic stenosis who are deemed inoper-
`able,1 and is seen as an alternative treatment option to surgical
`aortic valve replacement (SAVR) in a subset of patients with
`high postoperative mortality.2 The native valve is typically not
`removed but instead crushed by the superimposed bioprosthe-
`sis, which can result in an incomplete seal of the bioprosthetic
`valve and aortic annulus, with subsequent occurrence of para-
`valvular leak (PVL). Two types of Transcatheter Heart Valves
`(THV) that have been widely used, the balloon-expandable
`Edwards valve (Cribier-Edwards, Edwards SAPIEN and
`Edwards SAPIEN XT) by Edwards Lifesciences, and the self-
`expandable CoreValve by Medtronic, have been described in
`detail elsewhere.3,4 Despite the evolving technology of trans-
`catheter valves, PVL post-TAVR is common, with a wide
`range of reported incidences (Table 1). Most importantly, PVL
`has been associated with increased short- and long-term mor-
`tality post-TAVR, and is seen as a barrier to more widespread
`use of this promising technique.5–13 This article describes the
`incidence, causes, and predictors of PVL, as well as its impact
`on clinical outcomes. Methods of prevention, diagnosis, and
`treatment of PVL are also reviewed.
`
`Definition and Incidence
`Aortic regurgitation is characterized as either central or para-
`valvular. Pathological central regurgitation occurs in diseased
`native valves or damaged prosthetic valves, whereas minor
`central regurgitation is often a physiological feature of some
`bioprosthetic valves by virtue of their design. On the other
`hand, PVL is a complication only of aortic valve prostheses
`and occurs more commonly post-TAVR (Figure 1) than after
`SAVR.
`Various multicenter registries and trials have reported
`data on incidence of PVL post-TAVR at different time points
`(Table 1). The overall incidence of PVL post-TAVR ranges
`between 50% and 85%, which is significantly higher than
`what has been observed in SAVR, reported between 1% and
`47.6%, with only 4.2% consisting of more than mild PVL.14
`Although the majority of post-TAVR PVL is mild (7.8–
`40.8%), moderate (5–37.9%) and severe (0.5–13.6%) PVL
`occur frequently.1,2,6,8,10,11,13,15–26 The largest meta-analysis of
`
`TAVR outcomes estimates the incidence of residual moder-
`ate or severe aortic regurgitation after TAVR to be 7.4%.27
`The UK TAVR registry suggests moderate-severe PVL
`occurred more commonly with CoreValve implants (17.3%,
`versus 9.6% with the Edwards implants).13 This finding has
`not been replicated in other studies. One study by Ewe et
`al21 did not find a statistically significant difference in inci-
`dence of PVL between transfemoral and transapical TAVR
`at 30 days and 6 months. The wide range of PVL incidence
`reported is not surprising and is likely a result of the lack of
`standardization across centers in the TAVR technique, dif-
`ferences in operator experience, types and sizes of valves
`used, in addition to the different imaging modalities used
`and challenges in grading PVL. Unbehaun et al6 used a mod-
`ified TAVR procedure after which no patient had severe PVL
`and only 2 had moderate PVL, of a relatively large cohort of
`358 patients.
`It is unclear whether PVL progresses in severity with time.
`The studies reporting the rate of PVL for multiple follow-up
`time points show decreasing incidences of moderate–severe
`PVL. Although the decrease could be attributed to the death
`of patients with higher-grade PVL who are at higher mortality
`risk, a reduction of severity from moderate to mild may also
`relate to geometric remodeling of the annulus2,5,20,21 (Table 1).
`Rates of mild PVL generally remained stable; there was no
`evidence of an increase in PVL over time.
`
`Clinical Impact of Paravalvular Leak
`Despite the difficulties in accurately characterizing PVL,
`the wide range of incidences reported, and the relative
`short period of follow-up, its impact on short- and long-
`term mortality has been consistently reported across studies
`(Table 2). Data from a large cohort of 3201 SAVR patients
`with a mean follow-up of 4.5±3.4 years confirm that patients
`with moderate–severe aortic regurgitation (AR>1/4) had
`lower survival at 1, 5, and 10 years (91.4 versus 96.7%,
`77.5 versus 82.4%, and 44.1 versus 54.5%; P<0.01).14 Other
`data on clinical outcomes related to PVL extend from the
`postoperative period to up to 2 years. Moderate–severe PVL
`is an independent predictor of mortality in the postoperative
`period to 30 days, at 1 year, and at 2 years5–11,13 (Table
`2). Recently, Kodali et al from the Placement of AoRTic
`
`From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (S.L., S.S.H.); and the Duke University
`Medical Center, Duke Clinical Research Institute, Durham, NC (P.S.D.).
`Correspondence to Stamatios Lerakis, MD, Emory University Hospital, 1365 Clifton Rd NE, Suite AT-503, Atlanta, GA 30322. E-mail:sleraki@emory.edu
`(Circulation. 2013;127:397-407.)
`© 2013 American Heart Association, Inc.
`Circulation is available at http://circ.ahajournals.org
`
`DOI: 10.1161/CIRCULATIONAHA.112.142000
`
`397
`
`Downloaded from
`
`http://circ.ahajournals.org/
`
` by guest on January 18, 2017
`
`Page 1 of 13
`
`

`

`398
`
` Circulation
`
` January 22, 2013
`
`Table 1.
`
` TAVR Studies and Registries Reporting Incidence of PVL in >100 Patients
`
`Valve
`
`Registry/Trial
`
`Diagnostic Modality
`
`Postprocedure/30 Days
`
`6 Months
`
`1 Year
`
`2 Years
`
`3 Years
`
`Edwards
`
`Rodes-Cabau et al15
`Canadian, 2010
`
`Echocardiography
`
`Echocardiography
`
`Echocardiography
`
`Thomas et al16
`SOURCE, 2010
`
`Leon et al1
`PARTNER
`nonoperable
`cohort, 2010
`
`—
`
`—
`
`—
`
`n=339
`Mild: 78%
`Moderate: 5%
`Severe: 1%
`n=1038
`Moderate–Severe: 1.9%
`n=144
`None: 14%
`Mild: 68%
`Moderate–Severe: 12%
`
`Smith et al2
`PARTNER high-risk
`cohort, 2011
`
`Echocardiography
`
`n=287
`None: 22.6%
`
`n=240
`None: 26.3%
`
`—
`
`—
`
`n=98
`None: 23%
`Mild: 59%
`Moderate–Severe:
`11%
`n=222
`None: 32.9%
`
`—
`
`—
`
`—
`
`n=143
`Moderate–
`Severe: 6.9%
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`Mild: 62.5%
`Moderate–Severe:
`11.3%
`—
`
`Mild: 60.4%
`Moderate–Severe:
`6.8%
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`…
`
`…
`
`None–Mild: 77%
`Moderate:
`“Unchanged”
`Severe: 0%
`
`None–Mild: 66% …
`Moderate:
`“Unchanged”
`Severe: 0%
`
`…
`
`TF, n=26
`TF, n=33
`None: 57.7%
`None: 51.5%
`Mild: 38.5%
`Mild: 36.4%
`Moderate: 51.5% Moderate: 3.8%
`Severe: 0%
`Severe: 0%
`TA, n=39
`TA, n=23
`None: 64.1%
`None: 73.9%
`Mild: 33.3%
`Mild: 26.1%
`Moderate: 2.6%
`Moderate: 0%
`Severe: 0%
`Severe:0%
`
`(Continued)
`
`Nombela-Franco
`et al,17 2012
`
`Echocardiography
`
`Gripari et al,18 2012 Echocardiography
`
`Unbehaun et al,6
`2012
`
`Echocardiography,
`Angiography
`
`Walther et al,19
`2012
`
`Echocardiography
`
`Webb et al,20 2009
`
`Echocardiography
`
`Ewe et al,21 2011
`
`Echocardiography
`
`Mild: 65.2%
`Moderate–Severe:
`12.2%
`n=211
`Mild: 30.8%
`Moderate: 37.9%
`Severe: 11.3%
`n=135
`None: 31.1%
`Mild: 48.1%
`Moderate: 18.5%
`Severe: 2.2%
`n=358
`None: 51.6%
`Mild: 47%
`Moderate: 0.6%
`Severe: 0%
`n=150
`None: 36%
`Mild: 30.7%
`Moderate: 22.8%
`Severe: 7%
`n=168
`Mild: 58%
`
`Moderate: 37%
`Severe: 5%
`TF, n=45
`None: 8.9%
`Mild: 26.7%
`Moderate: 53.3%
`Severe: 11.1%
`TA, n=59
`None: 3.4%
`Mild: 25.4%
`Moderate: 57.6%
`Severe:13.6%
`
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`
`http://circ.ahajournals.org/
`
` by guest on January 18, 2017
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`Page 3 of 13
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`

`

`Lerakis et al
`
` Paravalvular Leak After TAVR
`
` 399
`
`Table 1.
`
` Continued
`
`Valve
`
`Registry/Trial
`
`Diagnostic Modality
`
`Postprocedure/30 Days
`
`6 Months
`
`1 Year
`
`2 Years
`
`3 Years
`
`—
`
`n= N/A
`None: 55%
`Mild: 39%
`Moderate: 6%
`Severe: 0%
`—
`
`n=129
`Mild: 48.1%
`Moderate: 17.8%
`Severe: None
`n= N/A
`None: 63%
`Mild: 34%
`Moderate: 3%
`Severe: 0%
`—
`
`—
`
`n= N/A
`None: 63%
`Mild: 34%
`Moderate: 3%
`Severe: 0%
`—
`
`n=89
`Mild: 42%
`Moderate: 9%
`Severe: None
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`n=178
`Mild: 52.8%
`Moderate: 15.2%
`Severe: None
`n=126
`None: 59%
`Mild: 32%
`Moderate: 9%
`Severe: 0%
`n=146
`None: 36.3%
`Mild: 48.6%
`Moderate: 12.3%
`Severe: 2.7%
`n=244
`
`Absent/Mild: 90.5%
`Moderate: 9%
`Severe: 0.5%
`n=1846
`
`CoreValve
`
`Ussia et al22 Italian
`3-years, 2012
`
`Echocardiography
`
`Buellesfeld et al,23
`2011
`
`Echocardiography
`
`Sinning et al,8
`2012
`
`Echocardiography,
`Angiography
`
`Mixed
`
`Eltchaninoff et al24
`FRANCE, 2011
`
`Echocardiography,
`Angiography
`
`Edwards 68%
`CoreValve 32%
`
`Gilard et al25
`FRANCE2, 2012
`Edwards 66.9%
`CoreValve 33.1%
`
`Abdel-Wahab
`et al11,12 Germany,
`2011
`Edwards 15.6%
`CoreValve 88.4%
`
`Echocardiography
`
`Angiography
`
`Angiography
`
`Moat et al13 UK,
`2011
`Edwards 47.1%
`CoreValve 52.9%
`
`Echocardiography
`
`Echocardiography
`
`Fraccaro et al,26
`2012
`
`Hayashida et al,10
`2012
`Edwards 85.4%
`
`CoreValve 14.6%
`
`Downloaded from
`
`http://circ.ahajournals.org/
`
` by guest on January 18, 2017
`
`n=983
`
`n=426
`
`—
`
`Mild: 47.4%
`Moderate: 16.3%
`Severe: 0.8%
`n=689
`
`Mild: 47.2%
`Mild: 46%
`Moderate: 16.1% Moderate: 18.5%
`Severe: 0.8%
`Severe: 1.2%
`—
`—
`
`—
`
`None: 27.6%
`Mild: 54.9%
`Moderate: 15.2%
`Severe: 2.3%
`n=870
`None: 39%
`Mild: 47.4%
`Moderate–Severe:
`13.6%
`(Edwards 9.6%,
`CoreValve 17.3%)
`n=384
`Moderate–Severe: 4%
`n=260
`
`Moderate–Severe:
`30.8%
`Severe: 4.2%
`
`—
`
`—
`
`…
`
`Moderate–Severe:
`12.3%
`
`—
`
`—
`
`…
`
`—
`
`…
`
`—
`
`—
`
`—
`
`—
`
`…
`
`PARTNER indicates Placement of AoRTic TraNscathetER valve trial; TA, transapical; and TF, transfemoral.
`
`TraNscathetER (PARTNER) valve trial high-risk cohort
`suggested that any PVL regurgitation (mild–moderate–
`severe) was associated with increased mortality at 2 years,
`although this association was not analyzed in multivariate
`fashion. So far, most other studies have not reported worse
`outcomes with mild/trace PVL5(Table 2).
`
`Causes and Predictors of
`Paravalvular Regurgitation
`During SAVR the positioning of the prosthesis is performed
`under direct anatomic observation, allowing excision of the
`calcified valve, followed by optimal placement and alignment
`
`Page 4 of 13
`
`

`

`400
`
` Circulation
`
` January 22, 2013
`
`Figure 1. Parasternal longitudinal axis transthoracic echo-
`cardiography view showing mild paravalvular leak post–trans-
`catheter heart valve deployment. Arrow indicates the site of
`paravalvular leak.
`
`of the prosthetic valve within the aortic annulus. The mini-
`mally invasive nature of TAVR precludes removal of the heav-
`ily calcified native valve and direct observation of the annulus.
`It entails using preprocedural imaging to estimate the size of
`the aortic root, and indirectly implanting a circular bioprosthe-
`sis in a dynamic, oval-shaped aortic annulus. The technique
`
`relies on fluoroscopy and intraprocedural echocardiography
`for positioning. Thus, it is not surprising to expect a higher
`frequency of PVL in TAVR as a result of the risks of inap-
`propriate sizing of the prosthesis, its malpositioning, and the
`hindrance of the old calcified valve (Table 3).
`The diameter of the aortic annulus is measured before
`and during the procedure to determine the choice and size
`of the THV. To assess valve-annulus congruence, a cover
`index integrating aortic annulus diameter (A) and prosthetic
`diameter (P; 100×[A−P]/P) was used. Moderate-severe regur-
`gitation was not seen with a cover index >8% in this study
`of 74 patients. These findings were reproducible in a study
`using intraprocedural 3D tranesesophageal echocardiography
`(TEE) in addition to transthoracic echocardiography (TTE)
`to evaluate the THV.18 In another prospective study, annulus–
`prosthesis mismatch was defined as a native annulus diameter
`larger than normal on label diameter limit for the prosthesis
`and was associated with higher grade PVL.28 Larger aortic
`annulus size measured by MRI and computed tomography
`(CT) but not TTE was also predictive of PVL.29 These stud-
`ies suggest a certain amount of oversizing is indeed necessary
`to prevent PVL. Indeed, Detaint et al30 reported that patients
`with aortic annulus <22 mm by echocardiography had no
`moderate–severe PVL after TAVR. Although echocardiogra-
`phy is the most widely used method for measuring the annu-
`lus, multi-detector computed tomography (MDCT) allows
`
`Table 2. PVL as a Predictor of Outcomes: Reported Mortality/Survival Rates and Hazard Ratios in Studies With >100 Patients
`
`Valve
`
`Registry/Trial
`
`Severity
`
`Edwards
`
`Unbehaun et al,6 2012, n=358
`
`None, Trace, Mild–Moderate
`
`Outcome
`
`Survival
`
`Time
`
`2-year
`
`HR/Survival/Mortality
`
`None: 66%
`Trace: 72%
`
`Kodali et al5; PARTNER high risk cohort,
`2012 n=699
`Gotzmann et al,7 2012 n=198
`
`CoreValve
`
`Mild–Moderate–Severe
`
`Mortality
`
`2-year
`
`HR 2.11 [1.43–3.10]
`
`None–Mild, Moderate–Severe
`
`Mortality
`
`30 day
`
`1 yr
`
`30 day
`1 yr
`
`None–Mild: 6%, Moderate–Severe 21%; HR
`3.81 [1.384–10.482]
`None–Mild: 16%, Moderate–Severe 57%;
`HR 5.48 [2.807–10.683]
`None–Mild: 4%, Moderate–Severe: 22.7%
`None–Mild: 25%. Moderate–Severe 63.6%
`HR 3.9 [2.0–7.5]
`30 days – 1 yr HR 3.785 [1.57–9.10]
`6 mo
`HR 1.97 [1.19–3.28]
`
`Sinning et al,8 2012 n=146
`
`None–Mild, Moderate–Severe
`
`Mortality
`
`Mixed
`
`Tamburino et al9 Italian, 2011 n=661 Moderate–Severe
`Hayashida et al,10 2011, n=260
`Moderate–Severe
`
`Mortality
`Mortality
`
`Edwards 85.4%
`CoreValve 14.6%
`Abdel-Wahab et al11,12 German, 2011
`Edwards 15.6%
`CoreValve 88.4%
`n=689
`
`Moat et al13 UK, 2011
`Edwards 47.1%
`CoreValve 52.9%
`n=870
`
`None, Mild, Moderate, Severe
`
`Mortality
`
`In-Hospital
`
`Moderate–Severe
`
`Mortality
`
`1 yr
`
`None: 4.9%
`Mild: 6.1%
`Moderate 15.5%
`Severe: 12.5%
`Moderate–Severe: 2.43 [1.22–4.85]
`HR 1.49 [1.00–2.21]
`
`HR indicates hazard ratio; and PARTNER, Placement of AoRTic TraNscathetER valve trial.
`
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`
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`
` by guest on January 18, 2017
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`Page 5 of 13
`
`

`

`Table 3. Risk Factors and Predictors of Postprocedural PVL
`
`Valve
`
`Registry/Trial
`
`Diagnostic Modality
`
`Predictors
`
`Comments
`
`Lerakis et al
`
` Paravalvular Leak After TAVR
`
` 401
`
`Edwards
`
`Gripari et al,18 2012
`
`2D/3D Transesophageal
`Echocardiography
`n=135
`
`Nombela-Franco
`et al,17 2012
`
`Transesophageal
`Echocardiography
`
`Area Cover Index* 0.95
`
`—
`
`Calcification of commissure between right
`and NCC (OR 2.66)
`Valvular Calcium Volume per 500 mm3
`increase (OR 1.26 [1.11–1.44])
`
`Volume cutoff of 3,874 mm3 predicted the
`occurrence of AR (≥2) that did not respond to
`BPD, with a sensitivity of 82% and specificity of
`60% (area under the ROC curve: 0.71, 95% CI:
`0.54 to 0.88, P=0.033).
`Volume cutoff of 2,242 mm3 predicted the need
`for BPD with a sensitivity of 78% and specificity
`of 65% (area under the ROC curve: 0.74, 95%
`CI; 0.65 to 0.84, P<0.0001).
`Patients with previous AVR had less risk of PVL
`
`THV oversized to MDCT mean annular diameter
`by at least 1 mm area and annular area by at
`least 10% have significantly reduced risk of
`moderate-severe PVR
`
`Aortic annulus <22 mm, cover index >8%, had
`no AR≥2
`
`…
`
`2 ×∠LVOT-AO + (depth to NCC - 10)² ≥ 50, the
`likelihood of occurrence of significant AR could
`be predicted with a sensitivity of 85% and a
`specificity of 87%.
`
`n=211
`
`Transfemoral approach (OR: 2.49
`[1.03–5.97])
`
`Unbehaun et al,6
`2012
`
`Transesophageal
`Echocardiography,
`Angiography, MDCT
`n=358
`
`Willson et al,32 2012
`
`Transesophageal
`Echocardiography, MDCT
`n=109
`
`Détaint et. al,30 2009
`
`Echocardiography n=74
`
`CoreValve
`
`Takagi et al,28 2011
`
`Echocardiography
`
`n=79
`
`Sherif et al,36 2010
`
`Echocardiography,
`Angiography
`
`n=50
`
`Male sex (OR 1.66 [1.06–2.58])
`
`NYHA IV (OR 1.58 [1.04–2.42])
`Previous AVR(OR AVR 0.12 [0.03–0.51])
`Annular size (on TEE) (OR 1.18 [1.03–1.37])
`THV diameter - mean diameter by MDCT
`(AUC 0.81 [0.68–0.88])
`THV diameter - mean diameter by TEE (AUC
`0.70 [0.51–0.88])
`THV area/annula area by MDCT (AUC 0.80
`[0.65–0.90)
`Older age
`Male sex
`Greater height
`Larger aortic annulus
`Operator’s experience
`Low cover index† (OR 1.22 [1.03–1.51])
`Peripheral vascular disease (OR 2.57
`[0.99–6.69]
`
`History of heart failure (OR 2.89 [1.10–7.61]
`Chronic renal insufficiency (OR 2.62
`[1.02–6.71])
`Larger aortic annulus size (OR 1.66
`[1.21–2.29])
`Prosthesis mismatch (valve <annulus) (OR
`5.19 [0.98–27.63])
`Low implantation(OR3.11 [1.00–9.68])
`High implantation (OR 0.34 [0.12–0.98])
`Increasing angle of LVOT to ascending aorta
`(OR 1.24)
`
`Depth of device in relation to NCC (minimum
`chance of significant AR corresponding to
`depth = 9.5 mm)
`Depth of the device in relation to LCC
`(minimum chance of significant AR
`corresponding to depth = 10.42 mm)
`
`Downloaded from
`
`http://circ.ahajournals.org/
`
` by guest on January 18, 2017
`
`AR indicates aortic regurgitation; AUC, area under the curve; AVR, aortic valve replacement; BPD, balloon postdilation; CI, confidence interval; LCC, left coronary
`cusp; ∠LVOT-AO, angle of left ventricular outflow tract to ascending aorta; MDCT, multi-detector computed tomography; NCC, Non-coronary cusp; NYHA, New York Heart
`Association; OR, odds ratio; PVL, paravalvular leak; PVR, paravalvular regurgitation; and TEE, transesophageal echocardiography.
`*Area Cover Index (1−Annulus area/Prosthesis nominal area).
`†Cover Index=(100 × ([prosthesis diameter – TEE annulus diameter]/prosthesis diameter).
`
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`

`402
`
` Circulation
`
` January 22, 2013
`
`3-dimensional reconstruction of the annulus and multi-planar
`measurements of annular diameter, area, and circumference.31
`THV oversized by at least 1 mm relative to the mean annu-
`lar diameter, or by ≥10% of the annular area, as measured
`by MDCT, have a reduced risk of moderate to severe PVL.32
`The same study suggests that the difference between annu-
`lar perimeter measurement and THV size by MDCT was a
`slightly better predictor of PVL when compared with TEE,32
`although this may be partially attributable to differences in the
`type of measurement obtained (circumference by MDCT ver-
`sus sagittal diameter by TEE) rather than the imaging modal-
`ity used. The current TAVR technique systematically oversizes
`the THV ≈2 to 5 mm larger than the native valve. However,
`oversizing is not without risks and may cause annular rupture,
`coronary artery occlusion, and arrhythmias, underscoring the
`importance of accurately measuring the aortic annulus.
`Appropriate positioning of the bioprosthesis is essential to
`preventing PVL but is challenging in the setting of a beat-
`ing heart and catheter-guided deployment. The incidence of
`CoreValve dislocation ranged from 3% to 10% depending on
`the series.33 Similar results have been reported for the Edwards
`valve34,35 (4% to 11%). Sherif et al36 set out to identify anatomic
`predictors of PVL using angiography in patients undergoing
`TAVR with the CoreValve: the angle of the left ventricular
`outflow tract to the ascending aorta as well as the depth of the
`device in relation to the noncoronary cusps were found to be
`independent predictors of PVL.36 For all THV, the greater the
`angle the more likely the device incompletely seals the para-
`valvular space. Further, if implanted too low, the covered skirt
`may be situated below the native annulus, allowing blood to
`regurgitate through the holes of the uncovered portion of the
`stent frame, whereas high implantation allows blood to flow in
`the space between prosthesis and annulus. In addition to PVL,
`malposition and potential valvular dislocation is a serious
`complication of TAVR, which may cause coronary ischemia,
`arrhythmias requiring pacemaker implantation, and is asso-
`ciated with excess 30-day mortality (21.5% versus 9.9%).33
`Newer devices in development have an improved ability to
`reposition the valve during deployment and should reduce the
`incidence of PVL.
`The extent of native aortic valve calcification and its loca-
`tion has been repeatedly shown to be predictive of PVL post-
`TAVR with both the Edwards and CoreValve THV,17,18,37–41
`because it impairs apposition and complete expansion of the
`THV by imposing an asymmetrical shape to the valve deploy-
`ment area. Different studies have quantified calcification of
`the aortic root using different imaging techniques and scor-
`ing systems. The Agatston Score is derived from ECG-gated
`multislice contrast-enhanced computed tomography and has
`been used to characterize total valve and individual cusp cal-
`cification.42 High Agatston Score was correlated with higher
`degrees of PVL as well as the need for repeat maneuvers dur-
`ing implantation.38,40,41 Cusp calcification at the aortic wall was
`strongly predictive of PVL at the corresponding site.38,39 TEE
`has also been used to assess aortic root calcification semi-
`quantitatively using an echocardiographic calcification score
`devised by Corciu et al18,37,43 Application of this score yields
`results consistent with the MDCT findings, such that valvular
`calcification and annular size are strongly predictive of PVL
`
`as well as the need for additional maneuvers.18,37,43 Newer
`devices with more flexible cuffs allowing more complete seal
`over the retained native valve should mitigate this problem.
`Clinical characteristics associated, such as male sex, New
`York Heart Association functional class IV, and no previous
`aortic valve replacement, were suggested to be predictive
`of PVL.6
`
`The Role of Imaging in Assessing
`Paravalvular Regurgitation
`Identifying and accurately characterizing paravalvular regur-
`gitation in prosthetic valves is challenging. The shielding and
`reverberations of the valvular frame as well as the eccentricity
`of the jets render accurate localization and quantification of
`PVL difficult. Echocardiography, both TTE and TEE, angiog-
`raphy, MDCT, as well as MRI are modalities that have been
`used across studies to characterize PVL (Table 1).
`
`Intra-Procedural Imaging
`TEE is particularly useful for the detection and assessment
`of acute aortic regurgitation post-TAVR because it can be
`performed immediately on deployment.44 Immediately after
`valve deployment, stent positioning, shape, leaflet motion, and
`aortic regurgitation can rapidly be assessed with TEE imaging
`in biplane mode or a single plane short-axis view. For PVL,
`the short-axis plane of imaging should be just below the valve
`stent and skirt and just within the left ventricular outflow tract
`(LVOT); if the imaging plane is above the stent, regurgitation
`may not be visualized or color flow just above the annulus
`but contained within the sinuses of Valsalva may be mistaken
`for regurgitant jets into the left ventricle. Lower cross sec-
`tions may erroneously view jet spray rather than vena con-
`tracta. Confirmation of the severity of AR should always be
`performed from multiple echocardiographic views. Because
`of acoustic shadowing of the anterior THV annulus with mid-
`esophageal TEE, imaging just below the stent (within the
`LVOT) avoids most shadowing issues. The deep gastric view
`also allows imaging of the LVOT without acoustic shadowing.
`Imaging the entire annulus is mandatory and requires rotating
`180 degrees while centered on the valve.
`Aortography post-TAVR can provide accurate PVL evalu-
`ation and correlate it immediately with the simultaneous
`TEE evaluation under the same hemodynamic conditions.
`Hemodynamic data obtained immediately post-TAVR that
`include measurement of LV end-diastolic pressure and dia-
`stolic pressure and compare them with pre-TAVR values can
`provide additional information about grading the severity of
`PVL and has recently been shown to be of prognostic value.45
`
`Post-Procedural Imaging
`Transthoracic echocardiograms can identify the presence,
`location, and severity of the PVL and are the most common
`form of imaging because of availability and low cost. The
`optimal views for detection of regurgitant jets include the
`parasternal long-axis, short-axis, the apical long-axis, and
`the 5-chamber views, although as a result of eccentric jets,
`off-axis views should also be used to ensure accurate deter-
`mination of the location and severity of regurgitation. Para-
`valvular jets usually travel along the natural curvature of the
`
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`
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`

`prosthesis-annular interface, thus imaging in multiple planes
`is necessary. The transthoracic short-axis view offers the best
`visualization of the true orifice of PVL and helps prevent the
`overestimation of AR severity, which can occur when relying
`solely on apical views.
`integrated
`In quantifying PVL, a comprehensive
`approach must always be used.The American Society of
`Echocardiography (ASE) criteria for assessing PVL sever-
`ity by echocardiography have emphasized describing the jet
`anatomy (ie, location, circumferential extent, and width46;
`Table 4), particularly when visualized by color Doppler in
`the aortic short-axis view. These criteria have not been vali-
`dated in post-TAVR patients, and despite the adoption of these
`recommendations by the VARC (Valve Academic Research
`Consortium)47,48 they have not been uniformly adopted by
`the different registries and trials. Most commonly, PVL is
`assessed qualitatively by estimating the proportion of the cir-
`cumference of the sewing ring occupied by the jet: <10% of
`the sewing ring suggests mild, 10% to 20% suggests moder-
`ate, and >20% suggests severe.49 Overall aortic regurgitation
`is classified as absent (0), trace (<I), mild (I), moderate (II),
`and severe (III or IV).
`In addition, quantitative assessments of regurgitant frac-
`tion and volume can also be helpful in determining the sever-
`ity of PVL. These methods rely on the comparison of stroke
`volumes across the aortic valve and a nonregurgitant valve.
`Although total stroke volume can be measured by subtracting
`LV end-systolic volume from end-diastolic volume, the more
`common method is to calculate the stroke volume across the
`LVOT.
`Three-dimensional echocardiography may become the
`method of choice for assessing aortic regurgitant volume.
`
`Lerakis et al
`
` Paravalvular Leak After TAVR
`
` 403
`
`Three-dimensional TTE is an additional tool that can be used
`to evaluate the severity of PVL. Vena-contracta planimetry by
`3-dimensional TTE correlates better with regurgitant volume
`than vena contracta width with 2-dimensional TTE.50
`Cardiac MRI may be a useful supplement to echocar-
`diography and may be the modality of choice when there is
`discordance in grading from different echocardiographic win-
`dows. Quantified regurgitant volume and fraction by cardiac
`MRI appears to correlate better with qualitative angiographic
`evaluation and less with echocardiographic assessment.
`Qualitative evaluation by echo may underestimate the sever-
`ity of PVL when compared with quantitative cardiac MRI
`measurements.51
`
`Percutaneous Approaches to
`Treat Paravalvular Leak
`The pathophysiologic consequences of acute valvular regur-
`gitation occurring after valve deployment as well as the clini-
`cal impact of chronic moderate-severe PVL warrant early and
`effective remediation to avoid conversion to open surgery as
`well as prevent progression into heart failure. Thus far there
`are no universally established indications or algorithm for the
`procedural managemen