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
ADAPT-DES: Background
• 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
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
PCI with ≥1 non-investigational DES
Successful and uncomplicated
(IVUS/VH substudy; Up to 3000 pts enrolled)
Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics
VerifyNow Aspirin, VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded)
Clinical FU at 30 days, 1 year and 2 years
Angio core lab assessment all STs w/1:2 matching controls
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)
Female
Caucasian
Diabetes mellitus
- Insulin-treated
Hypertension
Hyperlipidemia
Cigarette smoking, current
Prior MI
Prior PCI
Prior CABG
Prior CHF
Prior PAD
History of renal insufficiency
- Dialysis
BMI
63.6 ± 10.9
25.9%
88.6%
32.4%
11.6%
79.6%
74.4%
22.6%
25.2%
42.8%
17.1%
8.1%
10.2%
7.7%
1.6%
29.5 ± 5.7
ADAPT-DES: Baseline features (n=8,583)
Presentation during PCI
- Stable CAD
- ACS
- UA, biomarker negative
- NSTEMI
- STEMI
Extent of CAD
- 1 vessel disease
- 2 vessel disease
- 3 vessel disease
- Left main disease
LVEF (%)
LVEDP (mmHg)
48.3%
51.7%
27.7%
14.5%
9.5%
38.3%
33.0%
28.7%
3.0%
55.0 ± 14.1
16.7 ± 9.3
ADAPT-DES: PCI procedure (n=8,583)
N = 10,106 vessels, 12,940 lesions
N vessels treated per pt
- LM
- LAD
- LCX
- RCA
- Bypass graft
N lesions treated per pt
N stents per pt
Total stent length (mm)
DES type used per pt / lesion
- Xience V / Promus
- Taxus (Express, Liberté)
- Cypher
- Endeavor
- Resolute
- Other
1.2 ± 0.4
3.1%
39.1%
26.2%
31.5%
4.5%
1.8 ± 1.1
1.7 ± 1.0
32.4 ± 22.3
64.5% / 58.5%
16.5% / 14.4%
13.5% / 13.0%
6.2% / 5.2%
2.2% / 2.1%
0.2% / 0.2%
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%
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%
Days taken through 1 year
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)
- >550 ARU*
419 ± 55
5.6%
VerifyNow P2Y12 (BASE)
VerifyNow P2Y12 (PRU)
- >208 PRU*
- ≥230 PRU*
VerifyNow P2Y12 Inhibition (%)
VerifyNow IIb/IIIa PAU
*Pre-specified cut-off values
310 ± 58
188 ± 97
42.7%
35.0%
40.0 ± 28.3
193 ± 53
ADAPT-DES: Time to First Stent Thrombosis
70 patients (0.84%) developed 74 ST events (ARC def/prob)
18
N=8,583
Definite ST
Definite or probable 0.84% (70)
- Definite
0.63% (53)
- Probable
0.20% (17)
Probable ST
16
14
Frequency
12
10
40 (57.1%) of ST events
occurred within 30 days
8
6
4
2
0
0
30
60
90
120
150
180
210
240
270
300
Days to definite or probable stent thrombosis
330
360
ADAPT-DES: Relationship between VerifyNow
platelet response to DAPT and subsequent
1-year def/prob stent thrombosis (n=8,583)
VerifyNow test
Def/prob ST
(n=70)
426 ± 58
No def/prob ST
(n=8,513)
419 ± 55
0.30
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
194 ± 56
193 ± 54
0.92
Aspirin ARU
- ARU ≥550
IIb/IIIa PAU
P
ADAPT-DES: Stent thrombosis (definite or
probable) according to post-PCI PRU
2
Stent thrombosis
(def/prob) (%)
PRU >208 (n=3610)
PRU ≤208 (n=4839)
HR [95%CI] =
2.54 [1.55, 4.16]
P=0.0001
1.3%
1
0.5%
0
0
3
6
9
12
Months
Number at risk:
PRU > 208
3610
3450
3420
3380
3152
PRU ≤ 208
4839
4688
4654
4631
4341
ADAPT-DES: MI and major bleeding
according to post-PCI PRU
Myocardial infarction
Major bleeding
HR [95%CI] = 1.47 [1.15, 1.87]
P=0.002
HR [95%CI] = 0.83 [0.69, 0.99]
P=0.04
10
10
PRU >208 (n=3610)
PRU ≤208 (n=4839)
PRU >208 (n=3610)
PRU ≤208 (n=4839)
6.7%
5.6%
5
5
3.9%
2.7%
0
0
0
6
Months
12
0
6
Months
12
ADAPT-DES: Mortality according
to post-PCI PRU
5
HR [95%CI] =
1.62 [1.18, 2.22]
P=0.002
PRU >208 (n=3610)
PRU ≤208 (n=4839)
Mortality (%)
4
3
2.4%
2
1.5%
1
0
0
3
6
9
12
Months
Number at risk:
PRU > 208
3610
3475
3447
3408
3181
PRU ≤ 208
4839
4696
4664
4645
4365
1.2
1.1
1.0
0.9
0.8
0.7
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
Includes:
Age
Diabetes
Prior MI
NSTEMI
STEMI
Anemia
Etc.
Intra-aortic balloon pump
Anemia
Diabetes
Diabetes Insulin
Retavase Through Procedure
BMI>30
IC/IV Nitroprusside During PCI (IV)
Killip Class 2-4
History of dialysis
History of renal insufficiency
TNK (rtPA) Through Procedure
Black
Bivalirudin Through Procedure
IV Pressor Through Procedure
Amidorome Through Procedure
Cox-2 inhibitor Through Procedure
PPI Through Procedure
Anti Hypertensives Through Procedure
Diuretic Through Procedure
STEMI
History of CHD
CrCl <60 ml/min
Calcium blocker Through Procedure
NSAID Through Procedure
Age >= Median (64)
Amiodarone Through Procedure
Coumadin Through Procedure
Graft
Any Lesion within a graft
Platelet Count <15000
Hypertension
Pre TIMI 0/1
ACE or ARB Through Procedure
Previous Coronary Brachytherapy
Non-STEMI
GPIIb/IIIa Through Procedure
IC Adenosine During PCI (IV)
Heparin though substudy
Enrolled in Substudy
History of PAD
Any dissection
Beta Blocker Through Procedure
tPA Through Procedure
Previous CABG
Atropine Through Procedure
IVUS used to guide and optimize procedure
LMWH Through Procedure
Hyperlipidemia
Xience / Promus
Closure device used
Atypical chest pain
Previous MI (> 7 Days PCI)
Max Pre-stenosis >= Median (90%)
VerifyNow P2Y12 (BASE)
Total stent length >= Median (24mm)
LAD
Aspirin Pre-hospital admission
Any previous brachytherapy
Any Ostial
Positive stress test
Vascular Access Femoral
Aspirin Loading dose
Max device diameter >= Median (3.25mm)
Aysmpomatic CAD
Any Calcium
Cardiopulmonary Support
Max balloon pressure >= Median (16atm)
Any bifurcation
Thienopyridine Pre-hospital admission
Patients with DES only
Caucasian
3+ vessels treated
Current smoking
Any Chronic Total Occlusion
Final TIMI 0/1
Cilostazol Through Procedure
Male
Log Odds Ratio
ADAPT-DES: Assessment of Propensity Score
Model to Adjust for 87 Baseline Predictors of
VerifyNow P2Y12 >208 PRU
Model c-statistic = 0.744
Open circles: P<0.05
Solid circles: P=NS
No variables remain significant in the adjusted model
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
- 161/8583 pts (1.9%) died within 1 year Event type
Event
No event
HR [95%CI]
P value
N
Deaths
Definite ST
53
5 (9.6%)
No definite ST
8530
156 (1.9%)
5.47 [2.25, 13.31]
<0.0001
N
Deaths
MI w/o ST
224
21 (9.7%)
No MI w/o ST
8359
140 (1.7%)
5.78 [3.65, 9.14]
<0.0001
N
Deaths
Major bleeding
531
45 (8.6%)
No major bleeding
8052
116 (1.5%)
5.97 [4.23, 8.42]
<0.0001
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 Cox
model for all-cause mortality (n=8,583), including
events during FU as time-adjusted covariates
Baseline features
Age (years)
Male gender
Diabetes mellitus
Current smoking
Hyperlipidemia
Creatinine clearance
Hemoglobin (g/dL)
WBC (x103/mL)
STEMI/NSTEMI (vs stable CAD)
Premature DAPT D/C w/i 1 year
Adverse events (time-adjusted)
Definite stent thrombosis
MI (w/o definite ST)
Major bleeding
Adj HR [95%CI]
P value
1.03 [1.01, 1.05]
1.95 [1.32, 2.87]
1.84 [1.30, 2.62]
1.48 [0.96, 2.29]
0.59 [0.41, 0.85]
0.99 [0.98, 1.00]
0.74 [0.66, 0.83]
1.03 [1.01, 1.05]
1.38 [0.96, 2.00]
4.30 [2.96, 6.26]
0.001
0.0008
0.0007
0.08
0.005
0.004
<0.0001
0.003
0.08
<0.0001
3.43 [1.48, 7.98]
4.52 [2.84, 7.17]
4.17 [2.84, 6.13]
0.004
<0.0001
<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%)
Efficacy
treatment effect
(from MV HR 2.51)
(# of ↑ Bleeding to Prevent One ST)
NNT/NNH
18
16
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%)
14
12
10
8
6
4
2
0
↑ 10%
(to 6.1%)
↑ 20%
(to 6.6%)
↑ 30%
(to 7.2%)
↑ 40%
(to 7.7%)
↑ 50%
(to 8.2%)
↑ 60%
(to 8.8%)
If max effect on
ST and bleeding:
~4 bleeds caused
for each ST
prevented
Safety treatment effect: Major bleeding increase (from MV HR 0.76)
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 hyporesponsiveness 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