ADAPT-DES One-Year Results Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents

A Large-Scale, Multicenter, Prospective, Observational Study of the Impact of

Clopidogrel and Aspirin Hyporesponsiveness on Patient Outcomes

Gregg W. Stone, MD Columbia University Medical Center

NewYork-Presbyterian Hospital Cardiovascular Research Foundation

Disclosures

• Gregg W. Stone Consultant to Eli Lilly, Daiichi Sankyo,

AstraZeneca, Medtronic, Boston Scientific, Abbott Vascular, Volcano, The Medicines Company

• From the large-scale prospective, multicenter ADAPT-DES registry, we previously demonstrated a strong relationship between platelet hyporesponsiveness to clopidogrel, but not to aspirin, and subsequent stent thrombosis to 30 days

• With follow-up to 1-year, we now report the overall treatment implications of aspirin and clopidogrel hyporesponsiveness on patient outcomes

ADAPT-DES: Background

ADAPT-DES Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents

11,000 DES pts prospectively enrolled No clinical or anatomic exclusion criteria

11 sites in US and Germany

Clinical FU at 30 days, 1 year and 2 years Angio core lab assessment all STs w/1:2 matching controls

Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics VerifyNow Aspirin, VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded)

PCI with ≥1 non-investigational DES Successful and uncomplicated

(IVUS/VH substudy; Up to 3000 pts enrolled)

clinicaltrials.gov NCT00638794

ADAPT-DES: Study organization Principal investigator: Gregg W. Stone (& Chuck Simonton prior to joining AVD)

Co-principal investigators: Thomas Stuckey, Bruce Brodie, Mike Rinaldi

Pharmacology committee: Paul Gurbel and Steve Steinhubl

Sponsor (IDE): Cardiovascular Research Foundation

Site management & monitoring: R. Stuart Dickson Institute For Health Studies Michael Dulin, director, Sherry Laurent, consultant

Data management: R. Stuart Dickson Institute For Health Studies Susan Christopher, project lead

Event adjudication: Cardiovascular Research Foundation Roxana Mehran and Ecaterina Cristea, directors

Angio and IVUS core labs: Cardiovascular Research Foundation Ecaterina Cristea and Akiko Maehara, directors

Biostatistics: Cardiovascular Research Foundation Helen Parise, director

Financial support: Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, Accumetrics

ADAPT-DES: Sites and enrollment 8,583 pts were enrolled at 11 sites between 1/7/2008 and 9/16/2010; 2,143 pts were enrolled in the IVUS substudy

Site Principal investigator(s) N enrolled

Charité Benjamin Franklin Bernhard Witzenbichler 1,435

Columbia University Medical Center Giora Weisz 1,365

Herz-Zentrum Bad Krozingen Franz-Josef Neumann 1,035

Carolinas Medical Center Mike Rinaldi 1,113

Wellmont Holstein Valley Chris Metzger 790

Minneapolis Heart Institute Tim Henry and Ivan Chavez 788

Lehigh Valley Hospital David Cox 673

Firsthealth Moore Regional Peter Duffy 544

LeBauer CV Research Bruce Brodie, Tom Stuckey 534

Ohio State University Ernest Mazzaferri 304

Indiana Heart Institute Jim Hermiller 2

ADAPT-DES: Baseline features (n=8,583) Age (years) 63.6 ± 10.9 Female 25.9% Caucasian 88.6% Diabetes mellitus 32.4% - Insulin-treated 11.6% Hypertension 79.6% Hyperlipidemia 74.4% Cigarette smoking, current 22.6% Prior MI 25.2% Prior PCI 42.8% Prior CABG 17.1% Prior CHF 8.1% Prior PAD 10.2% History of renal insufficiency 7.7% - Dialysis 1.6% BMI 29.5 ± 5.7

Presentation during PCI - Stable CAD 48.3% - ACS 51.7% - UA, biomarker negative 27.7% - NSTEMI 14.5% - STEMI 9.5% Extent of CAD - 1 vessel disease 38.3% - 2 vessel disease 33.0% - 3 vessel disease 28.7% - Left main disease 3.0% LVEF (%) 55.0 ± 14.1 LVEDP (mmHg) 16.7 ± 9.3

ADAPT-DES: Baseline features (n=8,583)

ADAPT-DES: PCI procedure (n=8,583)

N vessels treated per pt 1.2 ± 0.4 - LM 3.1% - LAD 39.1% - LCX 26.2% - RCA 31.5% - Bypass graft 4.5% N lesions treated per pt 1.8 ± 1.1 N stents per pt 1.7 ± 1.0 Total stent length (mm) 32.4 ± 22.3 DES type used per pt / lesion - Xience V / Promus 64.5% / 58.5% - Taxus (Express, Liberté) 16.5% / 14.4% - Cypher 13.5% / 13.0% - Endeavor 6.2% / 5.2% - Resolute 2.2% / 2.1% - Other 0.2% / 0.2%

N = 10,106 vessels, 12,940 lesions

ADAPT-DES: Anti-platelet agents (n=8,583)

Aspirin Thienopyridine

Pre-admission 82.0% 42.9%

Loading dose pre-PCI 88.7% 86.4%

Discharge 99.2% >99.9%

- clopidogrel - 99.7%

- ticlopidine - 0.03%

- prasugrel - 0.3%

Days taken through 1 year 345 ± 120 334 ± 120

Daily through 1 yr w/o any d/c 87.2% 79.6%

Taking at 1 year 95.4% 83.9%

ADAPT-DES: Platelet function test results (n=8,583; 8,527 with ARU, 8,449 with PRU)

Post-PCI to VerifyNow (hrs) 20.3 ± 8.3

VerifyNow Aspirin (ARU) 419 ± 55 - >550 ARU* 5.6%

VerifyNow P2Y12 (BASE) 310 ± 58 VerifyNow P2Y12 (PRU) 188 ± 97 - >208 PRU* 42.7% - ≥230 PRU* 35.0% VerifyNow P2Y12 Inhibition (%) 40.0 ± 28.3

VerifyNow IIb/IIIa PAU 193 ± 53

*Pre-specified cut-off values

Days to definite or probable stent thrombosis

Freq

uenc

y

Definite or probable 0.84% (70) - Definite 0.63% (53) - Probable 0.20% (17)

40 (57.1%) of ST events occurred within 30 days

70 patients (0.84%) developed 74 ST events (ARC def/prob) ADAPT-DES: Time to First Stent Thrombosis

0

2

4

6

8

10

12

14

16

18

0 30 60 90 120 150 180 210 240 270 300 330 360

Definite ST Probable ST

N=8,583

VerifyNow test Def/prob ST No def/prob ST P (n=70) (n=8,513) Aspirin ARU 426 ± 58 419 ± 55 0.30 - ARU ≥550 7.2% 5.6% 0.54 P2Y12 Base 305 ± 60 310 ± 58 0.56 P2Y12 PRU 234 ± 97 188 ± 97 <0.0001 - PRU >208 65.2% 42.5% 0.0002 - PRU ≥230 53.6% 34.9% 0.001 P2Y12 % Inhibition 24.8 ± 27.0 40.1 ± 28.2 <0.0001 - Inhibition ≤11% 44.9% 19.9% <0.0001 IIb/IIIa PAU 194 ± 56 193 ± 54 0.92

ADAPT-DES: Relationship between VerifyNow platelet response to DAPT and subsequent 1-year def/prob stent thrombosis (n=8,583)

ADAPT-DES: Stent thrombosis (definite or probable) according to post-PCI PRU

HR [95%CI] = 2.54 [1.55, 4.16]

P=0.0001

PRU >208 (n=3610) PRU ≤208 (n=4839)

Sten

t thr

ombo

sis

(def

/pro

b) (%

)

0

1

2

Months 0 3 6 9 12

3610 3450 3420 3380 3152

4839 4688 4654 4631 4341

Number at risk:

PRU > 208

PRU ≤ 208

1.3%

0.5%

ADAPT-DES: MI and major bleeding according to post-PCI PRU

PRU >208 (n=3610) PRU ≤208 (n=4839)

0

5

10

Months 0 6 12

6.7%

5.6%

Major bleeding HR [95%CI] = 0.83 [0.69, 0.99]

P=0.04

Myocardial infarction HR [95%CI] = 1.47 [1.15, 1.87]

P=0.002

PRU >208 (n=3610) PRU ≤208 (n=4839)

0

5

10

Months 0 6 12

3.9%

2.7%

ADAPT-DES: Mortality according to post-PCI PRU

PRU >208 (n=3610) PRU ≤208 (n=4839)

Mor

talit

y (%

)

Months 0 3 6 9 12

3610 3475 3447 3408 3181

4839 4696 4664 4645 4365

Number at risk:

PRU > 208

PRU ≤ 208

2.4%

1.5%

HR [95%CI] = 1.62 [1.18, 2.22]

P=0.002

0

3

5

1

2

4

ADAPT-DES: Assessment of Propensity Score Model to Adjust for 87 Baseline Predictors of

VerifyNow P2Y12 >208 PRU

No variables remain significant in the adjusted model

Log

Odd

s R

atio

-0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2

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Model c-statistic = 0.744

Includes: Age Diabetes Prior MI NSTEMI STEMI Anemia Etc.

ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow PRU >208 for

subsequent 1-year adverse events (n=8,583)

Event Adj HR [95%CI] P value

ST, def/prob 2.49 [1.43, 4.31] 0.001

- Definite 3.05 [1.62, 5.75] 0.0006

MI 1.42 [1.09, 1.86] 0.01

Major bleeding 0.73 [0.61, 0.89] 0.002

Death, all-cause 1.20 [0.85, 1.70] 0.30

Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD,

premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)

ADAPT-DES: Relationship between adverse events and death at 1 year

Event type Event No event HR [95%CI] P value Definite ST No definite ST N 53 8530 Deaths 5 (9.6%) 156 (1.9%) 5.47 [2.25, 13.31] <0.0001 MI w/o ST No MI w/o ST N 224 8359 Deaths 21 (9.7%) 140 (1.7%) 5.78 [3.65, 9.14] <0.0001 Major bleeding No major bleeding N 531 8052 Deaths 45 (8.6%) 116 (1.5%) 5.97 [4.23, 8.42] <0.0001

- 161/8583 pts (1.9%) died within 1 year -

1 year event rates (n=8,583) Definite ST: 53 (0.6%); MI w/o def :ST 224 (2.6%);

Major bleeding: 531 (6.2%)

ADAPT-DES: Multivariable propensity score adjusted Cox model for all-cause mortality (n=8,583), including

events during FU as time-adjusted covariates Baseline features Adj HR [95%CI] P value

Age (years) 1.03 [1.01, 1.05] 0.001 Male gender 1.95 [1.32, 2.87] 0.0008 Diabetes mellitus 1.84 [1.30, 2.62] 0.0007 Current smoking 1.48 [0.96, 2.29] 0.08 Hyperlipidemia 0.59 [0.41, 0.85] 0.005 Creatinine clearance 0.99 [0.98, 1.00] 0.004 Hemoglobin (g/dL) 0.74 [0.66, 0.83] <0.0001 WBC (x103/mL) 1.03 [1.01, 1.05] 0.003 STEMI/NSTEMI (vs stable CAD) 1.38 [0.96, 2.00] 0.08 Premature DAPT D/C w/i 6 months 4.30 [2.96, 6.26] <0.0001 Adverse events (time-adjusted) Definite stent thrombosis 3.43 [1.48, 7.98] 0.004 MI (w/o definite ST) 4.52 [2.84, 7.17] <0.0001 Major bleeding 4.17 [2.84, 6.13] <0.0001

Other variables in model: prior MI, NSTEMI/STEMI, hypertension, platelet count, creatinine clearance, MVD, VerifyNow P2Y12 > 208 PRU and VerifyNow Aspirin > 550 ARU

Hypothetically Increasing Clopidogrel Response in Pts with >208 PRU → Incremental Decrease in Stent

Thrombosis (from 1.3%) vs. Increase in Bleeding (from 5.5%)

Safety treatment effect: Major bleeding increase (from MV HR 0.76)

NN

T/N

NH

(#

of ↑

Ble

edin

g to

Pre

vent

One

ST)

↑ 10% (to 6.1%)

0

2

4

6

8

10

12

14

16

18

↑ 20% (to 6.6%)

↑ 30% (to 7.2%)

↑ 50% (to 8.2%)

↑ 60% (to 8.8%)

↑ 40% (to 7.7%)

ST ↓ 15% (to 1.1%) ST ↓ 20% (to 1.0%) ST ↓ 25% (to 1.0%) ST ↓ 30% (to 0.9%) ST ↓ 35% (to 0.8%) ST ↓ 40% (to 0.8%) ST ↓ 45% (to 0.7%) ST ↓ 50% (to 0.7%) ST ↓ 55% (to 0.6%) ST ↓ 60% (to 0.6%) ST ↓ 65% (to 0.5%) ST ↓ 70% (to 0.4%)

Efficacy treatment effect

(from MV HR 2.51)

If max effect on ST and bleeding: ~4 bleeds caused

for each ST prevented

ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow ARU >550 for

subsequent 1-year adverse events (n=8,583)

Event Adj HR[95%CI] P value

ST, def/prob 1.46 [0.58, 3.64] 0.42

- Definite 1.60 [0.57, 4.48] 0.37

MI 0.81 [0.46, 1.42] 0.46

Major bleeding 0.65 [0.43, 0.99] 0.04

Death, all-cause 1.42 [0.83, 2.43] 0.20

Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD,

premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)

ADAPT-DES: Conclusions and Implications I

• In the large-scale, prospective ADAPT-DES study, on-treatment hyporesponsiveness to clopidogrel after DES was an independent predictor of 1-year ST and MI, but was also protective against major bleeding, both of which were strongly related to mortality

• As a result, on-treatment clopidogrel hypo-responsiveness was not independently predictive of 1-year mortality

ADAPT-DES: Conclusions and Implications II

• Overcoming clopidogrel hyporesponsiveness with more potent antiplatelet agents is therefore unlikely to improve survival unless the beneficial effects of reducing ST and MI can be uncoupled from the likely increase in bleeding with greater platelet inhibition

• Hyporesponsiveness to aspirin was unrelated to ST, MI or death, but may be related to bleeding, questioning the utility of aspirin in pts treated with DES