tavr has only a limited role in the treatment of patients with severe aortic...

TAVR has only a limited role in the treatment of patients with severe

aortic stenosis

D. Craig Miller, M.D.

Stanford University CV Surgery

Stanford CV SurgeryStanford CV SurgeryStanford CV SurgeryStanford CV Surgery

Affiliation/Financial Relationship Company

Grant/ Research Support: NHLBI RO1 HL67025

Consulting Fees/Honoraria:

•Stanford PI – The PARTNER Trial, Edwards Lifesciences •Consultant, Abbott Vascular Structural Heart (MitraClip)

Conflict of Interest Disclosure

•Consultant, Abbott Vascular Structural Heart (MitraClip)•Consultant, Medtronic CardioVascular Division•Consultant, St. Jude Medical •The PARTNER U.S. Pivotal Trial Executive Committee, Edwards Lifesciences (nonremunerative)

Major Stock Shareholder/Equity Interest:Royalty Income:Ownership/Founder:Salary:Intellectual Property Rights:Other Financial Benefit:


What’s in a Name?

Placement of AoRTic TraNscathetERValves


Rules of Engagement

PARTNER

CardiacSurgery

InterventionalCardiology


AORTIC VALVE REPLACEMENT SURGERY

Potential TAVR Patient Pool

High Risk Patients

How Do We

SEVERE AORTIC STENOSIS

SURGERY

~50,000/year

BALLOON AORTIC VALVULOPLASTY

TAVR

How Do We Identify Ideal Candidates?

adapted from Susheel Kodali

Aortic Valve Surgery in Germany2000-2010

2000 - 2010

2.198

921157

3.6291,3%

7,0%15,6%

23,9%

12.000

15.000

18.000konventionell chirurgisch kathetergeführt

+ 1200

unreported

9.691 9.545 10.104 10.18910.915 11.011 11.603 12.116 12.262 11.861 11.582

0

3.000

6.000

9.000

00 01 02 03 04 05 06 07 08 09 10

Position statements not always considered

Where Does Threshold for TAVR Belong?- Surgical Operative Risk

Low or Moderate High Inoperable

TAVR orAVRAVR TAVR

FutilityUtility

Surgical Risk > 15%

AVR

Surgical Risk 10-15%

AVR TAVR

ALSO CONSIDER: Age, co-morbidities, life expectancy, higher neurological event risk with TAVR (↑3x in P-1A “AT” TF stratum), adverse consequences of AR (PPL), unknown valve durability (Adapted from Susheel Kodali, TCT 2010)

ReasonableIrrational, reckless,

financially irresponsible

JTCVS 2009;137:82-90

100

80

60

Age >75

% Survival

Long-term survival after AVR by type of prosthesis> 75 years old

60

40

20

00 5 10 15

AllograftMechanicalPorcinePericardial

% Survival

Years After AVR

Anesthesia time - min 330

Total procedure time - min 230

Aborted procedure - no. (%) 0

Anesthesia time - min 236

Total procedure time - min 133

Aborted procedure - no. (%) 7 (2.0)

AVR TAVR

3 failed access2 new TEE findings

2 diedAborted procedure - no. (%)Aborted procedure - no. (%)

P1A Procedural OutcomesTAVR vs AVR

Reoperation for bleeding - no. (%) 12 (3.4)

Intra-procedural death - no. (%) 1 (0.3)

Aortic perforation - no. (%) 1 (0.3)

Aortic dissection - no. (%) 3 (0.9)

Median ICU stay (days) 5.0

Reoperation for bleeding - no. (%) 2 (0.6)

Intra-procedural death - no. (%) 3 (0.9)

Aortic perforation - no. (%) 0

Aortic dissection - no. (%) 3 (0.9)

Median ICU stay (days) 3.0

*Converted to transapical TAVR due to porcelain aorta

2 died


Sternal wound infection - no. (%) 7 (2.0)

Total cross clamp time - min 74

Pump time - min 105

Access site infection - no. (%) 7 (2.0)

Fluoroscopy time - min 31

Converted to AVR - no. (%) 9 (2.6)

P1A Procedural OutcomesTAVR vs AVR

AVR TAVR

5 valve embolization3 annulus size on TEE1 large sigmoid septum

Converted to AVR - no. (%)Converted to AVR - no. (%)

Multiple (≥2) valves - no. (%) 7 (2.0)

Valve embolization - no. (%) 9 (2.6)

*Converted to transapical TAVR due to porcelain aorta

1 large sigmoid septum

5 converted to AVR2 valve-in-valve2 not treated

Valve embolization - no. (%)Valve embolization - no. (%)


VARC Device Success – PARTNER 1A(Correct Valve Placement and Function)

Intraop failures = 33 (9.5%)Intraop failures = 33 (9.5%)

6 month Moderate / Severe AR = 10.5%

No AS or SVD


TAVR Trial Devices

SAPIEN>25,000 patients

CoreValve>30,000 patients

Higher neurological event risk with TAVR (↑3x in P-1A “AT” TF

stratum), more vascular complications (TF), adverse influence of AR (PPL) on survival, unknown valve durability, AGE, BICUSPID AORTIC VALVE

Inclusion Criteria

PARTNER A and B – Study Design

Cohort A and B

• Severe calcific aortic stenosis with echo derived valve area of <0.8 cm2 (EOA index <0.5cm2) or mean gradient >40 mmHg or jet velocity > 4.0 m/s

• NYHA functional class II or greater• NYHA functional class II or greater

Cohort A (TAVR vs. Surgical AVR)

• Predicted operative mortality of 15% and a minimum STS score of 10% (or 8% with “new” STS)

Cohort B (TAVR vs. best medical management)

• Risk of death or serious irreversible morbidity as assessed by cardiologist and two surgeons must exceed 50%


PARTNERTwice Weekly Case Reviews Calls

Mike Fischbein at Stanford defendinga cohort B PARTNER case


PARTNERSTS Scores (by Sites - means)

0

2

4

6

8

10

12

14

16

Barnes

Mass Gen

Brigham

Cedars

Cleveland

Columbia

Cornell

Dallas

Emory

Evanston

Intermnt

Laval

Leipzig

Mayo

Miami

Northwest

Ochsner

Upenn

Scripps

StLukes

Stanford

Uwash

Vancouver

Virginia

WHC

Cohort A

Barnes

Mass Gen

Brigham

Cedars

Cleveland

Columbia

Cornell

Dallas

Emory

Evanston

Intermnt

Laval

Leipzig

Mayo

Miami

Northwest

Ochsner

Upenn

Scripps

StLukes

Stanford

Uwash

Vancouver

Virginia

WHC

0

5

10

15

20

Barne

sMas

sGen

Brigh

amCed

ars

Cleve

land

Colum

bia

Dallas

Emory

Eva

nston

Interm

ntLa

val

May

oMiami

Northwes

tUpe

nnScripps

StLuk

esStanford

Toronto

Uwas

hSt. Lu

kes

Virg

inia

WHC

Cohort B


Aortic StenosisPotential TAVR Population

25th percentile =STS 3.8

10th percentile= STS 8%

Modified from Michael J. MackStanford CV SurgeryStanford CV SurgeryStanford CV SurgeryStanford CV Surgery

P1B- All Cause Mortality (ITT)Landmark Analysis

All Cause M

ortality (%

)

60%

80%

100%

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%

All Cause M

ortality

Months

0%

20%

40%

0 6 12 18 24

30.7%

35.1%

18.2%

Numbers at RiskNumbers at Risk

TAVRTAVR 179179 138138 124124 110110 8383

Standard RxStandard Rx 179179 121121 8585 6262 4242


∆Cost = $79,837 ∆∆∆∆ LE = 1.59 years

ICER = $50,212/LYG

∆Cost = $79,837 ∆∆∆∆ LE = 1.59 years

ICER = $50,212/LYG

$100,000 per LY$100,000 per LY

Cost-Effectiveness of TAVR vs. Control Lifetime Results

$50,000 per LY$50,000 per LY


Published U.S. Cost Effectiveness Estimates

$200

$250

$300

QA

LY (

$th

ou

san

ds)

$0

$50

$100

$150

aspirin MI

prevention

rosuvastatin

high-CRP

ICD prim prev CRT-D v.

medical Rx

dabigatran AF PARTNER

Cohort B

AF ablation vs.

AAD

dialysis PCI stable CAD LVAD

destination Rx

Do

lla

rs p

er

Life

Ye

ar

or

QA

LY (

$th

ou

san

ds)


U.S. Commercial TAVR Era

CMS National Coverage Decision (NCD) for TF TAVR in inoperable patients

(proposed, 2 February 2012)


U.S. Commercial TAVR Era


CMS TAVR NCD Physician and Institution Qualifying Requirements


CMS TAVR NCD outcome standards for continued certification (inoperable)


Local EconomicsU.S. Commercial TAVR Era

CMS National Coverage Decision (NCD) for TF TAVR in inoperable patients


At current CMS reimbursement rates and SAPIEN cost of $32,500, TF TAVR cases represent $2-3,000

loss and each TA TAVR case ~$6,000 (CCF and Penn)

High risk operable TAVR (P1A)

N Engl J Med 2011;364:2187-98Stanford CV SurgeryStanford CV SurgeryStanford CV SurgeryStanford CV Surgery

High risk operable TAVR (P1A) 2 year all cause mortality (AT)

30%

40%

50%

60%

70%HR [95% CI] =0.95 [0.74, 1.22]

p (log rank) = 0.692

25.2%

33.9%

Cause Mortality

TAVR

AVR

0%

10%

20%

30%

0 6 12 18 24 30 36

25.2%

23.7%

32.7%


TAVRTAVR 344344 291291 259259 232232 155155 7070 2929

AVRAVR 313313 243243 229229 211211 143143 6363 2828

Months Post Procedure

All-Cause Mortality

Neurological events at 30 daysand 1 year (AT, n= 657)

TF stratum (n= 461) TF TAVR vs. AVR

Types of Neurologic Events in P1A

As treated [AT] analysis (Sept 2010 datalock)

47 patients, 49 neuro eventsIschemic - 72%, hemorrhagic - 0%,

ischemic evolving to hemorrhagic - 4%, unknown - 24%

51% Procedural51% Procedural(<10 days)(<10 days)

Timing and Types of Neurologic Events (stroke and TIA)

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

AVR

AVR

TAVR

TAVR

00--22daysdays

33--55daysdays

3131--364364daysdays

1111--3030daysdays

66--1010daysdays

22--33yearsyears

11--22yearsyears

Risk FactorCoefficient ±

SDP

R (%)

Incremental risk factors for neurologic events (early)

Early high peaking hazard phase

Early hazard phase

TAVR 2.21±0.68 .001 59

Smaller AVA index in TAVR group

-11.8±5.1 .02 57

R(%) = bagging reliability

Atrial fibrillation not significant

in multivariable analysisStanford CV Surgery

90

120

150

TAVR

%/mo%/mo

TF Candidate

Early hazard of neurologic event

0

30

60

.25 .50 .75 1.0

AVR

%/mo%/mo

Months after ProcedureMonths after Procedure

Neurologic event incidence

%% 15

20

25

30TF Candidate

%%

0

5

10

15

6 12 18 24MosMos

TAVRAVR

5451

10699

179159

203170

242221

TAVRAVR

3.4

6.0

2.4

7.4

Neurologic event by 1 monthInfluence of smaller AVA index

%%CandidateCandidate

TAVR

10

15

20

%%

AVAI (cmAVAI (cm22/m/m22))

TF

TA

5

10

0.2 0.3 0.4 0.5 0.6

Neurologic events

15

20

25

%%

Considering

competing risk of death

AVR-TA

TAVR-TA11

0

5

10

6 12 18 24

%% TAVR-TA

AVR-TF

TAVR-TF6.9

2.62.2

5.8

9.1

67

59

1143210618

1796416062

2237617067

24210222192

TAVR-TFTAVR-TAAVR-TFAVR-TA

New Engl J Med (on line, March 26, 2012)


P1A 2 year aortic regurgitation (AT)

p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001

N = 279 N = 228 N = 231 N = 173 N = 217 N = 156 N = 145 N = 113

Total AR and MortalityTAVR Patients (AT)

Mortality

None - Trace

Mild

Moderate - Severe 50.7%

33.4%35.3%

26.2%

p (log rank) < 0.001

Months Post Procedure

Mortality


NoneNone--TrTr 135135 125125 115115 101101 6868 3131 1111

MildMild 165165 139139 121121 111111 7171 3333 1616

ModMod--SevSev 3434 2525 2222 1919 1515 66 22

26.3%

12.7%

26.2%

Where Does Threshold for TAVR Belong?- Surgical Operative Risk

Low or Moderate High Inoperable

TAVR orAVRAVR TAVR

FutilityUtility

Surgical Risk > 15%

AVR

Surgical Risk 10-15%

AVR TAVR

ALSO CONSIDER: Age, co-morbidities, life expectancy, higher neurological event risk with TAVR (↑3x in P-1A “AT” TF stratum), adverse consequences of AR (PPL), unknown valve durability (Adapted from Susheel Kodali, TCT 2010)

ReasonableIrrational, reckless,

financially irresponsible

PARTNER P1B inoperable CohortPrimary Endpoint: All-Cause Mortality

Standard Rx

TAVI

cause mortality

(%)

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

HR [95% CI] =0.54 [0.38, 0.78]

P (log rank) < 0.0001

Number at Risk

TAVITAVI 179179 138138 122122 6767 2626

Standard RxStandard Rx 179179 121121 8383 4141 1212

All-cause mortality

(%)

Months

30.7%

Leon et al, NEJM 2010; 363:1597-1607

Cohort “C” ???

P1B 2 year 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 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.

Raj R. Makkar, TCT November 2011


0.3

0.4

0.5TAVR

AVR

26.8

PARTNER P1A Primary Endpoint:All-Cause Mortality at 1 Year

HR [95% CI] =0.93 [0.71, 1.22]P (log rank) = 0.62

0

0.1

0.2

0 6 12 18 24

Months

348 298 260 147 67

351 252 236 139 65

No. at Risk

TAVR

AVR

24.2

Cohort “C” ???


How do you define debility or frailty?

Same age (90) and STS AVR risk (12%)

Frailty Index

7(Severely frail) 1 (Very fit)


Courtesy

Todd Dewey

How do you define debility or frailty?Texas “Eyeball Test”

95 years oldTexas tough


Courtesy

Todd Dewey

5m walk gait speed & STS risk scoreMortality or Major Morbidity

43.2

30

35

40

45

50

ality or Major

rbidity

rbidity

Normal gait speed (<6s)

Slow gait speed

(≥6s)

Slow gait speed Slow gait speed

((≥≥6s)6s)

5.9

18.921.7

0

5

10

15

20

25

30

Mort

Mortality or Major

Morbidity

rbidity

Low STS risk (<15%)

Low STS risk (<15%)

High STS risk (≥15%)

High STS risk (≥15%)

Afilalo J, J Am Coll Cardiol 56:1668-76, 2010

Normal gait speed (<6s)

(<6s) (≥6s)


Who possibly is a Cohort “C”?STS >15- 20

FEV1 < 40%

Long term O2 dependence with history cigarette smoking

Pulmonary hypertension, especially with right heart failure and severe TR, ± severe MR

Chronic kidney disease- Cr >3Chronic kidney disease- Cr >3

Liver disease with MELD > 15

Extreme obesity

Depressed affect, dementia, psychologically has “given up”

Frailty, impairment from previous CVA, neuromuscular disease

Immobile- wheel chair bound

Very slow 5M walk test- > 12 seconds or unable to walk


Medical Futility:

Its Meaning and Ethical Implications*

“In judging futility, physicians must distinguish between an effect, which is limited to some part of the patient’s body, and a benefit, which appreciably improves the person as a whole.”

“ futility is a professional judgment that takes

precedence over patient autonomy .”

*Schneiderman et al, Ann Int Med 1990;112:949-54

Stanford CV SurgeryStanford CV SurgeryStanford CV SurgeryStanford CV Surgery Craig R. Smith, AATS 2011

appreciably improves the person as a whole.”

TAVR Cohort C considerations

Wise tips to avoid futile treatment

Michael Mack:“it will be important in these inoperable patients to identify those who are cohort C- dying with aortic stenosis, but not from aortic stenosis”


aortic stenosis, but not from aortic stenosis”

John Webb:"It's becoming more and more our job not to do the patients we did earlier.”

PCR London Valve, October 2011


Can’t anybody in the USA die with dignity today?Just because we can treat with TAVR does not mean we should offer TAVR to all inoperable AS patients


“We've added years to life, not life to

years.”

George Carlin (2001)


Avoiding Futile Therapy

There are other ways to find AS patients with

an STS risk of 11-12%....

PARTNER 1B excluded: Renal failure, end-


PARTNER 1B excluded: Renal failure, end-

stage liver disease, endocarditis, severe LV

dysfunction, cardiomyopathy,

urgent/emergent cases, untreated CAD

With limited healthcare dollars in the future, we face difficult choices

concerning unrestricted patient access to

innovative but costly

September 21, 2009

innovative but costly new technologies


Economic Constraints

• Cost-effectiveness• Comparative effectivenessresearch (CER)? fewer procedures

Obama Health Economics

? fewer procedures? reduced access? increased regulation? innovation stagnation


tavr has only a limited role in the treatment of patients with severe aortic...

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