types of avr examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a...
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Types of AVRTypes of AVR
Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a xenograft, d) shows a ball and
cage valve, e) shows a tilting-disk valve, f) shows a bi-leaflet valve
Elderly PatientsElderly PatientsPts >80years, operative mortality as high
as 30%.
Percutaneous aortic balloon valvuloplasty is an alternative to valve replacement introduced in ‘80s.
Inflating one or more large balloons across the aortic valve from a percutaneous route, a modest decrease in gradient and improvement in symptoms
Balloon ValvuloplastyBalloon ValvuloplastyFollow-up has demonstrated a high rate
of re-stenosis (>60% at 6 months and nearly 100% at 2 years), with no decrease in mortality rate after procedure
Therefore, now only has a role in critically ill elderly pts who are not candidates for surgery or as a “bridge” in critically ill pts before AV replacement
Building on 50 Years of Proven Building on 50 Years of Proven Valve ExpertiseValve Expertise
Aortic stenosis is life threatening and progresses rapidly
– Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1
– “Surgical intervention [for severe AS] should be performed promptly once even…minor symptoms occur”1
Helping to Solve a Grave Helping to Solve a Grave Problem Problem
Latent Period(Increasing Obstruction,Myocardial Overload)
Su
rviv
al, %
100
80
60
40
20
0 40 50 60 70 80Age, y
Onset Severe Symptoms
AnginaSyncope
Average Survival, y
Failure
0 2 4 6
At least 40% of patients with severe aortic stenosis (AS) do not have an AVR2-8
Addressing a Serious Addressing a Serious Unmet NeedUnmet Need
1999 2006 2006 20092005 2010
Pati
ents
, %
Aortic Valve Replacement (AVR) No AVR
2009
4657
40 39
26
48
31
54 43 60 61 74 52 69
0
20
40
60
80
100
Boum
a
Pellikk
a
Charls
on
Varad
araja
n Jan
Bach
Freed
For inoperable patients with severe symptomatic native aortic valve stenosis
Edwards SAPIEN Transcatheter Edwards SAPIEN Transcatheter Heart Valve Heart Valve With the RetroFlex 3 Transfemoral With the RetroFlex 3 Transfemoral System System
Patient-Focused Patient-Focused Multidisciplinary Multidisciplinary Heart Team ApproachHeart Team Approach
Multidisciplinary in all aspects:Patient selectionProcedure planningPatient treatmentPost-operative care
The PARTNER Trial The PARTNER Trial ProtocolProtocol
Not in StudyNot in Study
AssessmentTransfemoral Access
AssessmentTransfemoral AccessYesYes NoNo
Primary Endpoint: All-Cause Mortality OverLength of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
Primary Endpoint: All-Cause Mortality OverLength of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
TFTAVR
(n = 179)
TFTAVR
(n = 179)
Standard Therapy(Control)(n = 179)
Standard Therapy(Control)(n = 179)
vsvs
1:1 Randomization
AssessmentTransfemoral Access
AssessmentTransfemoral Access
TF(n = 492)
TF(n = 492)
TA(n = 207)
TA(n = 207)
YesYes NoNo
Primary Endpoint: All-Cause Mortality (1 yr)(Non-inferiority)
Primary Endpoint: All-Cause Mortality (1 yr)(Non-inferiority)
TFTAVR
(n = 244)
TFTAVR
(n = 244)
AVR(Control)(n = 248)
AVR(Control)(n = 248)
vsvs
1:1 Randomization
TATAVR
(n = 104)
TATAVR
(n = 104)
AVR(Control)(n = 103)
AVR(Control)(n = 103)
vsvs
1:1 Randomization
Cohort ACohort ACohort A(n = 699)
Cohort B(n = 358)
2 CohortsIndividually Powered
(N = 1,057)
2 CohortsIndividually Powered
(N = 1,057)
TA, transapical; TF, transfemoral.
AssessmentOperability
AssessmentOperability
NoNoYesYes
Severe Symptomatic Native Aortic Valve StenosisSevere Symptomatic Native Aortic Valve Stenosis
A Seminal Date in A Seminal Date in Cardiovascular Medicine Cardiovascular Medicine
September 22, 2010 on NEJM.org
Absolute Reduction in Mortality Absolute Reduction in Mortality Continues to Diverge at 2 YearsContinues to Diverge at 2 Years
∆ at 1 yr = 20.0%
NNT = 5.0 pts
All-
Cause
Mort
alit
y, %
50.7%
30.7%
HR [95% CI] = 0.57 [0.44, 0.75]P (log rank) < .0001
Numbers at Risk
Edwards SAPIEN THV
179 138 124 110 83
Standard Therapy 179 121 85 67 51
Months
0
20
40
60
80
100Edwards SAPIEN THV
Standard Therapy
67.6%
∆ at 2 yr = 24.3%
NNT = 4.1 pts
43.3%
Edwards SAPIEN THV Edwards SAPIEN THV Delivered Delivered QOL BenefitsQOL Benefits
MCID, minimum clinically important difference.
60
40
20
0
80
100
0 4 6 8 10 122
Standard Therapy
Edwards SAPIEN THV
∆ = 13.9P < .001
∆ = 24.5P < .001
KC
CQ
Sco
re (
Mean)
MCID = 5 points
Months
Improvement in quality
of life
At 30 days, TAVR resulted in more frequent strokes, major vascular complications, and bleeding events than standard therapyAll strokes, 7.3% vs 1.7%, P = .02
Major vascular complications, 16.8% vs 1.1%, P < .0001
Bleeding events, 16.2% vs 2.2%, P < .0001
Peri-procedural Peri-procedural HazardsHazards
Sobering PerspectiveSobering Perspective
* National Institutes of Health. National Cancer Institute. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets.http://seer.cancer.gov/statfacts/. Accessed November 16, 2010. † Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu.
5-Year Survival
Surv
ival, %
†**
* * *
23
4
12
3028
30
5
10
15
20
25
30
35
BreastCancer
Lung Cancer ColorectalCancer
ProstateCancer
OvarianCancer
SevereInoperable
AS
Advancing the Science Advancing the Science of TAVR of TAVR
TCT 2011 | San Francisco, CA | November 10, 2011TCT 2011 | San Francisco, CA | November 10, 2011
Two-Year Outcomes of Transcatheter Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe “Inoperable” Patients With Severe Aortic Stenosis: Aortic Stenosis: The PARTNER The PARTNER TrialTrial
Raj R. Makkar, MDRaj R. Makkar, MDOn behalf of The PARTNER Trial On behalf of The PARTNER Trial InvestigatorsInvestigators
Background (1)Background (1)Transcatheter aortic valve replacement (TAVR)
is the recommended treatment for “inoperable” patients with severe aortic stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated reduced mortality and improved quality of life.
However, whether clinical benefit and valve performance are sustained beyond one year is unknown and longer term outcomes will importantly alter clinical practice decisions.
ObjectivesObjectivesTo evaluate the clinical outcomes of TAVR
compared to standard therapy at 2 years in “inoperable” aortic stenosis patients.
To assess valve hemodynamics and durability using echocardiography.
To perform subgroup analyses to better define the impact of co-morbidities on outcomes.
Inclusion CriteriaInclusion CriteriaSevere calcific aortic stenosis defined as echo
derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s.
NYHA functional class II or greater.Risk of death or serious irreversible morbidity
of AVR as assessed by cardiologist and two surgeons must exceed 50%.
Surgeons must agree and attest that before PARTNER these patients would not have received AVR treatment!
Key End-Points for 2 Year Key End-Points for 2 Year AnalysisAnalysisAll cause mortalityAll cause mortalityCardiac mortalityCardiac mortalityRehospitalizationRehospitalizationStrokeStrokeNYHA functional classNYHA functional classDays alive and out of hospitalDays alive and out of hospitalEcho-derived valve areas, transvalvular Echo-derived valve areas, transvalvular
gradients, paravalvular aortic regurgitationgradients, paravalvular aortic regurgitationMortality outcomes stratified by STS scoreMortality outcomes stratified by STS score
n = 358Randomized Inoperable
n = 358Randomized Inoperable
n = 179TAVR
n = 179TAVR
n = 179Standard therapy
n = 179Standard therapy
124/124 patients100% followed at 1
Yr
124/124 patients100% followed at 1
Yr
85/85 patients100% followed at 1 Yr
85/85 patients100% followed at 1 Yr
99/102 patients*97.1% followed at 2
Yr
99/102 patients*97.1% followed at 2
Yr
56/56 patients100% followed at 2 Yr
56/56 patients100% followed at 2 Yr
Study Flow - Study Flow - Inoperable Inoperable CohortCohort
• 5 withdrawals in the first year in Standard Rx arm• *3 patients followed outside of protocol window in TAVR group• No patients were lost to follow-up
Patient Characteristics Patient Characteristics (1)(1)
CharacteristicCharacteristic TAVRTAVRn = 179n = 179
Standard RxStandard Rxn = 179n = 179
p valuep value
Age – yrAge – yr 83.1 ± 8.683.1 ± 8.6 83.2 ± 8.383.2 ± 8.3 0.950.95
Male sex (%)Male sex (%) 45.845.8 46.946.9 0.920.92
STS ScoreSTS Score 11.2 ± 5.811.2 ± 5.8 12.1 ± 6.112.1 ± 6.1 0.140.14
NYHANYHA I or II (%)I or II (%) III or IV (%)III or IV (%)
7.87.892.292.2
6.16.193.993.9
0.680.680.680.68
CAD (%)CAD (%) 67.667.6 74.374.3 0.200.20
Prior MI (%)Prior MI (%) 18.618.6 26.426.4 0.100.10
Prior CABG (%)Prior CABG (%) 37.437.4 45.645.6 0.170.17
Prior PCI (%)Prior PCI (%) 30.530.5 24.824.8 0.310.31
Prior BAV (%)Prior BAV (%) 16.216.2 24.424.4 0.090.09
CVD (%)CVD (%) 27.427.4 27.527.5 1.001.00
Patient Characteristics Patient Characteristics (2)(2)
CharacteristicCharacteristic TAVRTAVRn = 179n = 179
Standard RxStandard Rxn = 179n = 179
p valuep value
PVD (%)PVD (%) 30.330.3 25.125.1 0.290.29
COPDCOPD Any (%)Any (%) OO2 2 dependent (%)dependent (%)
41.341.321.221.2
52.552.525.725.7
0.040.040.380.38
Creatinine > 2 mg/dL (%)Creatinine > 2 mg/dL (%) 5.65.6 9.69.6 0.230.23
Atrial fibrillation (%)Atrial fibrillation (%) 32.932.9 48.848.8 0.040.04
Perm. pacemaker (%) Perm. pacemaker (%) 22.922.9 19.519.5 0.490.49
Pulmonary HTN (%)Pulmonary HTN (%) 42.442.4 43.843.8 0.900.90
Frailty (%)Frailty (%) 18.118.1 28.028.0 0.090.09
Porcelain aorta (%)Porcelain aorta (%) 19.019.0 11.211.2 0.050.05
Chest wall radiation (%)Chest wall radiation (%) 8.98.9 8.48.4 1.001.00
Chest wall deformity (%)Chest wall deformity (%) 8.48.4 5.05.0 0.290.29
Liver disease (%)Liver disease (%) 3.43.4 3.43.4 1.001.00
All Cause Mortality All Cause Mortality (ITT)(ITT)Crossover Patients Followed
Numbers at RiskNumbers at Risk
TAVRTAVR 179179 138138 124124 110110 8383 Standard Standard RxRx 179179 121121 8585 6767 5151
All
Cause
Mort
alit
y (
%)
Standard Rx
TAVR
∆ at 2 yr = 24.3%NNT = 4.1 pts
67.6%
43.3%
∆ at 1 yr = 20.0%NNT = 5.0 pts
50.7%
30.7%
Months
HR [95% CI] =0.57 [0.44, 0.75]
p (log rank) < 0.0001
All Cause Mortality (ITT)All Cause Mortality (ITT)Landmark AnalysisLandmark Analysis
All
Cause
Mort
alit
y (
%)
Months
Mortality 0-1 yr Mortality 1-2yr
Standard Rx TAVR
HR [95% CI] =0.57 [0.44, 0.75]
p (log rank) < 0.0001
HR [95% CI] =0.58 [0.37, 0.92]
p (log rank) = 0.019450.7%
30.7%
35.1%
18.2%
Numbers at RiskNumbers at Risk
TAVRTAVR179179 138138 124124 110110 88
33 Standard Standard RxRx 179179 121121 8585 6262 44
22
Cardiovascular Mortality Cardiovascular Mortality (ITT)(ITT)Crossover Patients CensoredCrossover Patients Censored
Numbers at RiskNumbers at Risk
TAVRTAVR 179179 138138 124124 110110 8383 Standard Standard RxRx 179179 121121 8585 6262 4242
Card
iovasc
ula
r M
ort
alit
y (
%) Standard Rx
TAVR
∆ at 2 yr = 31.4%NNT = 3.2 pts
62.4%
31.0%
∆ at 1 yr = 24.1%NNT = 4.1 pts 44.6%
20.5%
Months
HR [95% CI] =0.44 [0.32, 0.60]
p (log rank) < 0.0001
Repeat Hospitalization Repeat Hospitalization (ITT)(ITT)
Numbers at RiskNumbers at Risk
TAVRTAVR 179179 115115 100100 8989 6464 Standard Standard RxRx 179179 8686 4949 3030 1717
Repeat
Hosp
italiz
ati
on (
%) Standard Rx
TAVR
∆ at 2 yr = 37.5%NNT = 2.7 pts
72.5%
35.0%
∆ at 1 yr = 26.9%NNT = 3.7 pts
53.9%
27.0%
Months
HR [95% CI] =0.41 [0.30, 0.58]
p (log rank) < 0.0001
Hospitalization Through Hospitalization Through 2 Years2 Years
TAVRTAVR Standard Standard TxTx p valuep value
Repeat Hospitalizations Repeat Hospitalizations (No.)(No.) 7878 151151 <.0001<.0001
Repeat Hospitalizations Repeat Hospitalizations (%)(%) 35.0%35.0% 72.5%72.5% <.0001<.0001
Days Alive Out of Days Alive Out of Hospital Median [IQR]Hospital Median [IQR]
699 [201-699 [201-720]720] 355 [116-712]355 [116-712] .0003.0003
Perc
ent
Treatment Treatment VisitVisit
Baseline 1 Year 2 Year
p = 0.61 p < 0.0001 p < 0.0001
92.2%
57.5%
16.9%23.7%
60.8%
93.9%
NYHA Class Over TimeNYHA Class Over TimeSurvivorsSurvivors
All Stroke (ITT)All Stroke (ITT)
Numbers at RiskNumbers at Risk
TAVRTAVR 179179 128128 116116 105105 7979 Standard Standard RxRx 179179 118118 8484 6262 4242
Inci
dence
(%
)
Months
Standard Rx
TAVR
∆ at 2 yr = 8.3%
5.5%
13.8%
∆ at 1 yr = 5.7%
5.5%
11.2%
HR [95% CI] =2.79 [1.25, 6.22]
p (log rank) = 0.009
All Cerebrovascular All Cerebrovascular Events (%)Events (%)
≤ ≤ 30 Days30 Days 31 Days – 1 Year31 Days – 1 Year 1 Year – 2 Years1 Year – 2 Years
All CVA p = 0.010 p = 0.387 p = 0.028
Ischemic Stroke p = 0.017 p = 0.155 p = 0.083
Hemorrhagic Stroke p = 0.316 p = 0.121 p = 0.415
Even
ts
Note: Percents are of patients in the trial (n/179).
Mortality or Stroke (ITT)
Numbers at RiskNumbers at Risk
TAVRTAVR 179179 128128 116116 105105 7979 Standard Standard RxRx 179179 118118 8484 6262 4242
All
Cause
Mort
alit
y o
r Str
oke
(%
)
Months
Standard Rx
TAVR
∆ at 2 yr = 21.9%NNT = 4.6 pts
68.0%
46.1%
∆ at 1 yr = 16.1%NNT = 6.2 pts 51.3%
35.2%
HR [95% CI] =0.64 [0.49, 0.84]
p (log rank) = 0.0009
1 Year1 Yearn = 179n = 179
OutcomeOutcomeTAVRTAVR StandarStandar
d Rxd Rx P valueP value
2 Year 2 Year n = 179n = 179
TAVRTAVR Standard Standard RxRx P valueP value
Acute kidney injuryAcute kidney injury
Creatinine > 3 mg/dL, % Creatinine > 3 mg/dL, % (n)(n) 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449
Renal failure (CEC), % (n)Renal failure (CEC), % (n) 2.3 (4)2.3 (4) 4.7 (7)4.7 (7) 0.2570.257 3.2 (5)3.2 (5) 7.6 (9)7.6 (9) 0.1490.149
Cardiac re-interventionCardiac re-intervention
BAV, % (n)BAV, % (n) 1.1 (2)1.1 (2) 82.3 (138)82.3 (138) <.0001<.0001 2.8 (4)2.8 (4) 85.3 85.3 (140)(140) <.0001<.0001
Re-TAVR, % (n)Re-TAVR, % (n) 1.7* (3)1.7* (3) NANA -- 1.7* (3)1.7* (3) NANA --
AVR, % (n)AVR, % (n) 0 (0)0 (0) 7.6 (10)7.6 (10) 0.0020.002 0.9 (1)0.9 (1) 8.9 (11)8.9 (11) 0.0050.005Endocarditis, % (n)Endocarditis, % (n) 1.4 (2)1.4 (2) 0.8 (1)0.8 (1) 0.6180.618 2.3 (3)2.3 (3) 0.8 (1)0.8 (1) 0.3160.316
Bleeding – major, % (n)Bleeding – major, % (n) 24.2 24.2 (42)(42) 14.9 (21)14.9 (21) 0.0380.038 28.9 (48)28.9 (48) 20.1 (25)20.1 (25) 0.0930.093
New pacemaker, % (n)New pacemaker, % (n) 4.7 (8)4.7 (8) 8.6 (14)8.6 (14) 0.1490.149 6.4 (10)6.4 (10) 8.6 (14)8.6 (14) 0.4690.469
Myocardial infarctionMyocardial infarction
All, % (n)All, % (n) 0.8 (1)0.8 (1) 0.7 (1)0.7 (1) 0.9060.906 1.6 (2)1.6 (2) 2.5 (2)2.5 (2) 0.6940.694
Clinical Outcomes1 Year and 2 Year (ITT)
Mean G
radie
nt
(mm
Hg)
Error bars = ± 1 Std DevError bars = ± 1 Std Dev
EOA
Mean Gradient
N = 158
N = 162
N = 137
N = 143
N = 84
N = 89
N = 65
N = 65
N = 9
N = 9
AV
A (cm
²)
Mean Gradient & Valve Mean Gradient & Valve AreaArea
Numbers at RiskNumbers at Risk
None to MildNone to Mild 147147 118118 107107 9595 7272 Moderate or Moderate or SevereSevere 1717 1212 1111 1010 88
Death
Inci
dence
(%
)
Months
Moderate or Severe
None to Mild
41.2%
40.5%
35.3%
27.2%
Mortality Stratified by Paravalvular Mortality Stratified by Paravalvular Leak (ITT)Leak (ITT)Starting at DischargeStarting at Discharge
p (log rank) = 0.891
2828 2626 2525 2424 1616108108 8080 7676 6767 5252
4343 3232 2323 1919 1515
Death
Inci
dence
(%
)
Months
STS <5STS <5 STS 5-STS 5-14.914.9
Months
STS ≥15STS ≥15
p value (log rank) = 0.012
p value (log rank) = 0.676
1212 88 77 66 55119119 8484 5959 4242 2929
4747 2929 1919 1414 88
Mortality Stratified by STS Mortality Stratified by STS Score (ITT)Score (ITT)
TAVRTAVRStandard RxStandard Rx
Numbers at RiskNumbers at Risk
Conclusions (1)Conclusions (1)At 2 years, in patients with symptomatic
severe ASwho are not suitable candidates for surgery…TAVR remained superior to standard therapy
with incremental benefit from 1 to 2 years, markedly reducing the rates of… All cause mortality Cardiovascular mortality Repeat hospitalization• TAVR improved NYHA functional status and
decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001).
Conclusions (2)Conclusions (2)At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…
There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.
After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients.
A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities.
Conclusions (3)Conclusions (3)At 2 years, in patients with symptomatic At 2 years, in patients with symptomatic severe AS who are not suitable candidates for severe AS who are not suitable candidates for surgery…surgery…
TAVR hemodynamics by echo showed durable TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to improvements in AVA and mean gradients up to 3 years after implantation.3 years after implantation.
Moderate or severe paravalvular AR in the TAVR Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR was a trend towards reduced paravalvular AR between 1 and 2 years.between 1 and 2 years.
Clinical Implications Clinical Implications • Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.
The ultimate value of TAVR in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile.
QUESTIONS?QUESTIONS?