Raj R. Makkar, MD Raj R. Makkar, MD Director, Interventional Cardiology & Cardiac Catheterization Laboratories Director, Interventional Cardiology & Cardiac Catheterization Laboratories Director, Interventional Cardiology & Cardiac Catheterization Laboratories Director, Interventional Cardiology & Cardiac Catheterization Laboratories Associate Director, Cedars Associate Director, Cedars-Sinai Heart Institute Sinai Heart Institute Professor of Medicine, University of California, Los Angeles Professor of Medicine, University of California, Los Angeles Stephen Corday Chair in Interventional Cardiology Stephen Corday Chair in Interventional Cardiology
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Raj R. Makkar, MD - Promedica International€¦ · SAVR: 27.5% Zhao ZG. et al. Nature Reviews in Cardiology 2015. Pivotal Randomized Trials Inoperable High Risk ... % or mean ±
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Associate Director, CedarsAssociate Director, Cedars--Sinai Heart InstituteSinai Heart InstituteProfessor of Medicine, University of California, Los AngelesProfessor of Medicine, University of California, Los AngelesProfessor of Medicine, University of California, Los AngelesProfessor of Medicine, University of California, Los Angeles
Stephen Corday Chair in Interventional CardiologyStephen Corday Chair in Interventional Cardiology
DisclosuresDisclosuresDisclosuresDisclosures
Consultant and research grant from EdwardsConsultant and research grant from Edwards LifeSciencesLifeSciences,,Medtronic, Abbott, Boston Scientific and Jena ValveMedtronic, Abbott, Boston Scientific and Jena ValveMedtronic, Abbott, Boston Scientific and Jena ValveMedtronic, Abbott, Boston Scientific and Jena Valve
Do we need a randomized trial of TAVR vs.Do we need a randomized trial of TAVR vs.Do we need a randomized trial of TAVR vs.Do we need a randomized trial of TAVR vs.SAVR in Bicuspid Aortic Stenosis?SAVR in Bicuspid Aortic Stenosis?
My 5 key arguments for a randomized trial forMy 5 key arguments for a randomized trial forBicuspid ASBicuspid ASBicuspid ASBicuspid AS
• Bicuspid AS will be encountered with greater frequency asTAVR use expands in the younger patients-50% of SAVRin young are bicuspidin young are bicuspid
• The available observational data are limited by treatmentbias..perhaps only favorable anatomies were treatedbias..perhaps only favorable anatomies were treated
• Surgical outcomes in young Bicuspid AS patients areexcellent; reasonable to expect robust evidence for TAVR toexcellent; reasonable to expect robust evidence for TAVR toreplace SAVR
• Anatomically heterogeneous group with frequentaortopathy-unlike what has been treated in previous IDEstudies
• The precedent for label expansion in TAVR in last decade• The precedent for label expansion in TAVR in last decadehas been IDE randomized clinical trials
• Low risk trials: (Mack et al, NEJM; Popma et al, NEJM)
TAVR equal/better than SAVR
• STS/ACC-TVT registry: (Makkar et al, JAMA 2019)
1 year Death/StrokeBicuspid AS =Tricuspid ASBicuspid AS =Tricuspid AS
Prevalence of Bicuspid Aortic ValvePrevalence of Bicuspid Aortic Valve
70
80
6064
69
6050
60
70
33
42
2820
30
40
28
0
10
20
20- 30- 40- 50- 60- 70- 80-
0
Age (years)
Roberts WC et al. Circulation. 2005;111:920-925
Age (years)
Prevalence of Bicuspid Aortic ValvePrevalence of Bicuspid Aortic Valve
Frequencies of Bicuspid Aortic ValveFrequencies of Bicuspid Aortic Valve
Fre
qu
ency
ofB
AV
(%)
646960
70
80
Fre
qu
ency
ofB
AV
(%)
33
6064
69
60
4230
40
50
60
Fedak P W et al. Circulation. 2002;106:900-904
Bicuspid aortic valve
20- 30- 40- 50- 60- 70- 80-F
req
uency
ofB
AV
(%)
3328
0
10
20
30
20- 30- 40- 50- 60- 70- 80-
Roberts WC et al. Circulation. 2005;111:920-925
Age (years)
• The most common congenital cardiac malformation (1-2%)• Serious complications occurred > 30%
Aortic Stenosis (the most common)Aortic RegurgitationAortic RegurgitationAortic dilation and dissection
Prevalence of bicuspid valve in patients undergoingPrevalence of bicuspid valve in patients undergoingisolated AVRisolated AVR--almost 50%!almost 50%!isolated AVRisolated AVR--almost 50%!almost 50%!
Operatively excised, stenotic aortic valves from 932 patientsOperatively excised, stenotic aortic valves from 932 patientsaged 26 to 91 years
Roberts WC. et al. Circulation 2005
Prevalence of bicuspid aortic valve in TAVRPrevalence of bicuspid aortic valve in TAVRstudies is less than SAVR studiesstudies is less than SAVR studiesstudies is less than SAVR studiesstudies is less than SAVR studies
• Less than 7% of patientswith bicuspid aortic valvewith bicuspid aortic valvein TAVR registries
First Large Series of TAVR for Bicuspid ASFirst Large Series of TAVR for Bicuspid ASFirst Large Series of TAVR for Bicuspid ASFirst Large Series of TAVR for Bicuspid AS
• A total of 139 patients (mean age 78.0±8.9 and STS score 4.9±3.4%)underwent TAVR with Sapien (n=48) or CoreValve (n=91)underwent TAVR with Sapien (n=48) or CoreValve (n=91)
• Type 1 68%, Type 0 27% (no central core laboratory)• Post-AR ≥ grade 2 in 28.4% • 30-day and 1-year mortality: 5% and 17.5%
Mylotte et al: J Am Colle Cardiol 2014;64:2330-9
Improved Outcomes TAVR with NewImproved Outcomes TAVR with New--generationgenerationDevices for Bicuspid ASDevices for Bicuspid ASDevices for Bicuspid ASDevices for Bicuspid AS
• A total of 301 patients (mean age 77.0±9.2 and STS score 4.7±5.2%)underwent TAVR with Sapien XT (n=87) or CoreValve (n=112), Sapien 3(n=91), Lotus (n=11)(n=91), Lotus (n=11)
• PVL ≥ moderate 0% vs 8.5% (new- vs early-generation devices)
Yoon et al: J Am Colle Cardiol 2016;68:1195-205
Outcomes of TAVR for Bicuspid vs Tricuspid ASOutcomes of TAVR for Bicuspid vs Tricuspid AS
• 546 pairs of patients with bicuspid and tricuspid AS were created with PS-matching
• Bicuspid had more frequent aortic root injury with Sapien XT and PVL withCoreValve, but no differences in complications with Sapien 3/Evolut R/LotusCoreValve, but no differences in complications with Sapien 3/Evolut R/Lotus
• No difference in 1-year mortality between bicuspid and tricuspid AS
Yoon et al: J Am Colle Cardiol 2017;69:2579-89
Contemporary TAVR for Bicuspid vs Tricuspid ASContemporary TAVR for Bicuspid vs Tricuspid ASSTS/ACC TVT RegistrySTS/ACC TVT RegistrySTS/ACC TVT RegistrySTS/ACC TVT Registry
• Of 81822 patients (2726 bicuspid; 79096 tricuspid), 2691 propensity-scorematched pairs of patients with bicuspid and tricuspid AS were analyzedmatched pairs of patients with bicuspid and tricuspid AS were analyzed
• Mean age 74 (66-81) years; STS 4.9% vs 5.1%• No difference in mortality at 30 days (2.6% vs 2.5%) and 1 year (10.5% vs 12.0%)• 30-day stroke rate was higher in bicuspid (2.5% vs 1.6%; HR 1.57 [95% CI, 1.06-
2.33])2.33])
Makkar et al: JAMA 2019;321:2193-202
Contemporary TAVR for Bicuspid vs Tricuspid ASContemporary TAVR for Bicuspid vs Tricuspid ASSTS/ACC TVT RegistrySTS/ACC TVT RegistrySTS/ACC TVT RegistrySTS/ACC TVT Registry
Makkar et al: JAMA 2019;321:2193-202
11--Year Mortality in Unmatched CohortYear Mortality in Unmatched Cohort11--Year Mortality in Unmatched CohortYear Mortality in Unmatched Cohort
11--Year Mortality in Matched CohortYear Mortality in Matched Cohort11--Year Mortality in Matched CohortYear Mortality in Matched Cohort
5 Reasons Why we need RCT for Bicuspid5 Reasons Why we need RCT for Bicuspid5 Reasons Why we need RCT for Bicuspid5 Reasons Why we need RCT for Bicuspid
1.1. Inherent limitation of observational studyInherent limitation of observational study1.1. Inherent limitation of observational studyInherent limitation of observational study
2.2. No central imaging core laboratory for diagnosis ofNo central imaging core laboratory for diagnosis ofbicuspid anatomy (CT is new standard)bicuspid anatomy (CT is new standard)bicuspid anatomy (CT is new standard)bicuspid anatomy (CT is new standard)
3.3. Various bicuspid phenotype and potential selectionVarious bicuspid phenotype and potential selectionbias (bias (ieie, TAVR for favorable anatomy), TAVR for favorable anatomy)
4.4. AortopathyAortopathy is poorly understood in TAVR populationis poorly understood in TAVR population
Outcomes of Transcatheter Aortic ValveReplacement with Balloon-Expandable Sapien3Replacement with Balloon-Expandable Sapien3Valve in Bicuspid Aortic Stenosis:An analysis of the STS/ACC TVT Registry
Raj R. Makkar, Sung-Han Yoon, Martin B. Leon, Tarun Chakravarty, SreekanthRaj R. Makkar, Sung-Han Yoon, Martin B. Leon, Tarun Chakravarty, Sreekanth
Vemulapalli, Michael Rinaldi, Pinak B. Shah, Eric R. Skipper, Vinod H. Thourani, Vasilis
Babaliaros, Wen Cheng, Alfredo Trento, Samir R. Kapadia, Susheel Kodali, Michael J.
Mack, Gilbert H. L. Tang, Tsuyoshi Kaneko
Study population
25 Covariates used for propensity matching
Age Chronic Lung Disease
92236 SAPIEN 3 Cases in TVT Registry(June 2015 − Nov 2018) Age Chronic Lung Disease
• No central CT core lab to diagnose bicuspid• No central CT core lab to diagnose bicuspidanatomy
• No central adjudication of events• No central adjudication of events• No data on aortopathy• Most importantly.. “Treatment bias-were there• Most importantly.. “Treatment bias-were there
anatomical factors as to why TAVR wasanatomical factors as to why TAVR waschosen rather than surgey? Only 3% of theentire cohort were bicuspid.entire cohort were bicuspid.
NYHA Class – Matched
[VALUE] [VALUE] [VALUE] [VALUE]
NYHA Class – Matched
p=0.93 p=0.80 p=0.70
38.4% 37.7% 32.3% 32.7%
6.3% 6.9% 6.8% 5.3%[VALUE] [VALUE]
[VALUE] [VALUE] [VALUE] [VALUE]
80%
100%
IV
59.7% 60.8%
38.4% 37.7%
59.9% 60.3%
40%
60%
IV
III
II
I
3.4% 3.5%
54.9% 54.7% 59.7% 60.8%
22.2% 22.4%
0%
20%
I
Bicuspid(n=2667)
Tricuspid(n=2664)
Bicuspid(n=1958)
Tricuspid(n=2015)
Biscuspid(n=752)
Tricuspid(n=804)
Baseline 30-day 1-year
29
Baseline 30-day 1-year
KCCQ – MatchedKCCQ – Matched
100
120
KC
CQ
Ov
era
llS
um
ma
ry
p=0.87 p=0.52 p=0.15
60
80
KC
CQ
Ov
era
llS
um
ma
ryS
co
re
Bicuspid
Tricuspid
20
40
KC
CQ
Ov
era
llS
um
ma
ryS
co
re
Tricuspid
n=2460 n=2463 n=1992 n=1990 n=732 n=776
0
Baseline 30-day 1-year
KC
CQ
Ov
era
llS
um
ma
ry
30
The “easy case”: Little calcium, No RapheThe “easy case”: Little calcium, No Raphe
TAVR with 23mm Sapien3 performedTAVR with 23mm Sapien3 performedTAVR with 23mm Sapien3 performedTAVR with 23mm Sapien3 performed
Trace paravalvular AR
The “ok case”: Little calcium, ModerateThe “ok case”: Little calcium, ModerateThe “ok case”: Little calcium, ModerateThe “ok case”: Little calcium, ModerateCalcified RapheCalcified Raphe
90 y/o male with severe AS referred for TAVR90 y/o male with severe AS referred for TAVRExtreme risk due to age, frailty and comorbiditiesExtreme risk due to age, frailty and comorbiditiesExtreme risk due to age, frailty and comorbiditiesExtreme risk due to age, frailty and comorbidities
BicuspidBicuspidvalvevalvevalvevalve
s/p successfuls/p successful transfemoraltransfemoral TAVR with 29TAVR with 29--mmmmSapienSapien--XT valveXT valveSapienSapien--XT valveXT valve
No significantNo significant paravalvularparavalvular ARAR
87 y/o male referred for TAVR87 y/o male referred for TAVRNYHA 3 heart failure, diastolicNYHA 3 heart failure, diastolicNYHA 3 heart failure, diastolicNYHA 3 heart failure, diastolic
Severely calcified aorticvalvevalve
Severe MR
Bicuspid valve with heavilycalcified raphe
Severe MR
Mean gradient 34mmHgMean gradient 34mmHgAVA 0.5cm2
PrePre--TAVR CTTAVR CTPlan for 29mm Sapien3Plan for 29mm Sapien3Plan for 29mm Sapien3Plan for 29mm Sapien3
Annular dimensions (28.9x32.8, meanAnnular dimensions (28.9x32.8, mean30.9mm), Area 722mm2
HighHigh--risk features on prerisk features on pre--TAVRTAVRHighHigh--risk features on prerisk features on pre--TAVRTAVR
Dilated ascending aortaDilated ascending aorta47.2x48.2mm, mean 47.7mm
Severe LVOT calcification
29mm Sapien 3 deployment29mm Sapien 3 deploymentPredilation with 23mm x 4cm ZPredilation with 23mm x 4cm Z--Med II BalloonMed II BalloonPredilation with 23mm x 4cm ZPredilation with 23mm x 4cm Z--Med II BalloonMed II Balloon
Eccentric deployment of Sapien3Eccentric deployment of Sapien3Well expanded valve, but eccentrically locatedWell expanded valve, but eccentrically locatedWell expanded valve, but eccentrically locatedWell expanded valve, but eccentrically located
Eccentric deployment of Sapien3Eccentric deployment of Sapien3
PVL closure performed immediately after postPVL closure performed immediately after post--dilation due to persistent moderate PVLdilation due to persistent moderate PVLdilation due to persistent moderate PVLdilation due to persistent moderate PVL
Step 1: Shuttle sheathacross the leak
Step 2: Amplatz wireremoved from the LV Final result s/p 10mm AVP 2 plug
deploymentdeployment
Leak crossed with Terumoglidewire with a MPA catheter;
wire exchanged for a Amplatz stiffwire
Step 3: 10mm AVP 2plug advanced
Step 4: 10mm AVP 2plug deployed
TEE guidance during the procedureTEE guidance during the procedureTEE guidance during the procedureTEE guidance during the procedure
Position of wire through the PVLconfirmed with TEE
Final result s/p TAVR and PVL closure
10mm AVP2plug
Difficult Anatomy: heavy calcium withDifficult Anatomy: heavy calcium withDifficult Anatomy: heavy calcium withDifficult Anatomy: heavy calcium withcalcified raphecalcified raphecalcified raphecalcified raphe
55 y/o male with severe AS, referred for TAVRPatient turned down for OHT/VAD or SAVR/CABGPatient turned down for OHT/VAD or SAVR/CABG
Mean gradient = 40 mmHg
Severely depressed EF (15-20%)
Baseline Coronary Angiogram
80% calcified stenosis in mid LAD Patent right coronary artery
Cardiac CT for aortic valve evaluationBicuspid aortic valveBicuspid aortic valve
RCAType 1 bicuspid
aortic valve
CalcifiedCalcifiedRaphe
Left Right
Left mainLeft main
Cardiac CT for aortic valve evaluation
STJ
Annulus Maximal aortic dimension
SOV mean = 30.5 mm
Pre TAVR TEE assessment
AnnulusArea; 474 cm2
STJ diameter 2.61 cm
Diameter 2.93 x 2.07 cm
Biventricular systolic dysfunction
TF TAVR – Preparation and valve deployment
Aortogram Valve deployment
Valvuloplasty with Z-MED 16 mm balloon
Aortogram Valve deployment
No contrast in the balloon…
Left main protection and secured venous access with stiff wire
Assessment immediately post valve deployment
Significant PVL after Valve deploymentPatent left main
AVP II positioning Persistent PVL after AVP plug positioning
Persistent diastolic flow reversal
Valve-in valve with Sapien XT 26 mm
Valve deployment Mild residual PVL
No diastolic flow reversal Improved diastolic gradient
Hemodynamics improvement post TAVR
Pre valve replacement Post valve replacement
Improved LV systolic function immediately post TAVR
Pre-valve replacement Post-valve replacement
Continuous improvement of LV systolic function post TAVR
Pre-TAVR (EF 15%) Day 1 post-TAVR (EF 40%)
PCI to mid LAD 5 days post TAVR
Baseline left coronary angiogramBaseline left coronary angiogram
2.5 mm balloonunable to cross theunable to cross the
lesion.
Rotationalatherectomy with 1.25
mm burr.mm burr.
Deployment ofDeployment ofXience 3.0 x 18 mm,
followed by postdilatation with 3.0 x 8
mm NC balloon.
PCI to mid LAD 5 days post TAVR
Final angiogramBaseline angiogram
2 years later: Severe paravalvular regurgitation in2 years later: Severe paravalvular regurgitation inthe presence of sinus of Valsalva aneurysmthe presence of sinus of Valsalva aneurysmthe presence of sinus of Valsalva aneurysmthe presence of sinus of Valsalva aneurysm
Repeat CT 2 years later revealedRepeat CT 2 years later revealedpseudoaneurysm of the sinus of Valsalvapseudoaneurysm of the sinus of Valsalvapseudoaneurysm of the sinus of Valsalvapseudoaneurysm of the sinus of Valsalva
Normal leaflet motionNormal leaflet motion
Patient underwent surgical repair of the pseudoaneurysm and bioprosthetic aortic valvePatient underwent surgical repair of the pseudoaneurysm and bioprosthetic aortic valvereplacement
Pseudoaneurysm
Surgical Outcomes for Bicuspid AorticSurgical Outcomes for Bicuspid AorticValveValveValveValve
Total No AgeMortality
30 days 1 year 5 years 10 years30 days 1 year 5 years 10 years
Borger at al 1 201 54±11 2.5% NA NA 19%
Girdauskas et al 2 153(aortopathy)
54±110.7%
(hospital death)NA NA 14%
(aortopathy) (hospital death)
Itagaki et al 3 2079 55.3±14.9 1.5% NA NA NA
Desai et al 4 1890 50±14 0.4% 1.0% 4.0% NADesai et al 4 1890 50±14 0.4% 1.0% 4.0% NA
Andrei et al 5
Total: 628Men: 478
Women: 150
Men: 56.3±13.6Women:
60.7±13.80.6%
Men: 3.2%Women: 6.0%
Men: 8.3%Women: 7.8%
NA
1 Borger et al: J Thorac Cardiovasc Surg 2004; 128: 677-832 Girdauskas et al: Eur J Cardiothorac Surg 2012; 42:832-8Girdauskas et al: Eur J Cardiothorac Surg 2012; 42:832-83 Itagaki et al: J Am Coll Cardiol 2015; 65: 2363-94 Desai et al: J Thorac Cardiovasc Surg 2016; 151: 1650-95 Andrei et al: Am J Cardiol 2015;116:250-255
• In the low risk trials the 1and 2 year death,stroke,and rehospitalization rates were verystroke,and rehospitalization rates were verylow and lower than surgerylow and lower than surgery
• Imaging has evolved to help better selectsuitable anatomical subsetssuitable anatomical subsets
Bicuspid Aortic Valve Morphologyand Outcomes After TAVRand Outcomes After TAVR
Sunghan Yoon, MDSunghan Yoon, MD
Raj R. Makkar, MDSmidt Heart Institute at Cedars-Sinai Medical CenterSmidt Heart Institute at Cedars-Sinai Medical Center
On Behalf of BAV TAVR Registry Investigators
Euro PCR 2019 LBCT Presentation
Baseline CharacteristicsBaseline Characteristics
Demographics & Overall Other Comorbidities & OverallDemographics &Risk Factors
Overall(n = 1115)
Other Comorbidities &Echo parameters
Overall(n = 1115)
Age, years 75.1 ± 9.4 Chronic lung disease 24.9%
Male 58.9% Atrial Fibrillation 19.8%
NYHA class III or IV 75.3% Permanent Pacemaker 7.6%
PVL ≥ moderate Aortic Root Injury Major VascularCompication
30-day MortalityCompication
All-cause Mortality and AortopathyAortopathy was not associated with All-causeMortality with Multivariate Analysis
4040 HR, 1.61 (95% CI, 1.13–2.32)
P = .009 by log-rank test
Mortality with Multivariate Analysis
30
cau
se
Mo
rtality
(%)
30
P = .009 by log-rank test
10
20
All-c
au
se
Mo
rtality
(%)
20
10
18.5
12.5
Aortopathy
0
10All
0
10
No Aortopathy
0 180 360 540 7200 180 720360 540
Days
Aortopathy
No. at Risk
509 302 147
No Aortopathy 606 380 192
ConclusionConclusion• BAV morphology such as calcified raphe and excess leaflet
calcification were independently associated with increasedcalcification were independently associated with increasedprocedural complications and 2-year all-cause mortality
• Highest risk BAV phenotype (both calcified raphe plus excess• Highest risk BAV phenotype (both calcified raphe plus excessleaflet calcification) was found in 26% of patients andassociated with 3-fold higher mortality
• The impact of BAV morphology on outcomes was consistent in• The impact of BAV morphology on outcomes was consistent inlow surgical risk patients as well as in patients who had TAVRwith newer generation devices
• Aortopathy was not independently associated with all-causemortality
Clinical Implications
• CT assessment of morphology in bicuspid aortic stenosis
Clinical Implications
• CT assessment of morphology in bicuspid aortic stenosishelps assess anatomical risk of TAVR
• In absence of randomized clinical trial data in treating• In absence of randomized clinical trial data in treatingBicuspid Aortic Stenosis, CT based anatomicalassessment may identify patients favorable for TAVR andin conjunction with surgical risk help triage patients toin conjunction with surgical risk help triage patients toTAVR vs. SAVR
Pivotal Randomized Trials have been the standardPivotal Randomized Trials have been the standardfor indication expansion for TAVRfor indication expansion for TAVR
Inoperable
High Risk
Intermediate Risk
Low Risk
Hierarchy of Evidence and Research Designs
Meta-Analysis
SystemicSystemicReviews
RandomizedControlled TrialControlled Trial
Cohort Studies
Case Control Studies
Case Report/ Case SeriesCase Report/ Case Series
Background Information & Expert Opinion
• Low risk trials: (Mack et al, NEJM; Popma et al, NEJM)
TAVR equal/better than SAVRWhy infer? Let us do the randomized clinical trial!
• STS/ACC-TVT registry: (Makkar et al, JAMA 2019)
1 year Death/StrokeBicuspid AS =Tricuspid ASBicuspid AS =Tricuspid AS
My 5 key arguments for a randomized trial forMy 5 key arguments for a randomized trial forBicuspid ASBicuspid ASBicuspid ASBicuspid AS
• Bicuspid AS will be encountered with greater frequency asTAVR expand in the younger patients-50% of SAVR inyoung are bicuspidyoung are bicuspid
• The available observational data are limited by treatmentbias..perhaps only favorable anatomies were treatedbias..perhaps only favorable anatomies were treated
• Surgical outcomes in young Bicuspid AS patients areexcellent; reasonable to expect robust evidence for TAVR toexcellent; reasonable to expect robust evidence for TAVR toreplace SAVR
• Anatomically heterogeneous group with frequentaortopathy-unlike what has been treated in previous IDEstudies
• The precedence for label expansion in last decade has been• The precedence for label expansion in last decade has beenIDE randomized clinical trials