ADAPT-DES
Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents
A Large-Scale, Prospective, Multicenter Registry
Examining the Relationship Between Platelet
Responsiveness and Stent Thrombosis
After DES Implantation
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation
Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial
interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
• Consulting Fees/Honoraria
• Abbott Vascular, Boston
Scientific, Medtronic,
Volcano, The Medicines
Company, Daiichi Sankyo,
Eli Lilly
ADAPT-DES: Background I
• Although prior studies have shown a correlation
between platelet hyporesponsiveness to ADP
antagonists and stent thrombosis, all have been small
to moderate in size. As such, several important
questions remain unanswered:

What proportion of the risk of ST at different times after stent
implantation can be attributed to platelet ADP antagonist
response, and how useful is this to reclassify the risk of ST?

What is the optimal cutoff for platelet reactivity to predict stent
thrombosis?

Is ADP antagonist hyporesponsiveness important in all pts?
(e.g. non-diabetics as well as diabetics; stable CAD vs. ACS)
ADAPT-DES: Background II
• Prior studies have emphasized the absolute level of
platelet activation/aggregation to ADP antagonists

The role of the baseline level of platelet activation and
% platelet inhibition to ADP antagonists have largely
been unstudied
• The impact of
1) platelet hyporesponsiveness to aspirin, and
2) overall platelet aggregation on DAPT
on the risk of ST has been incompletely studied
ADAPT-DES
Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents
Up to 11,000 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: DAPT Loading and GPI Washout for
VerifyNow Assessment Post-PCI
• Aspirin loading: Pre-PCI mandatory: ≥300 mg non EC oral
aspirin ≥6 hours prior to PCI or 324 mg chewed or ≥250 mg
IV aspirin at least 30 minutes prior to PCI.
• Clopidogrel loading: Pre-PCI recommended, but in all cases
600 mg ≥6 hours or 300 mg ≥12 hours prior to VerifyNow,
or ≥75 mg for ≥5 days prior to VerifyNow.
• GP IIb/IIIa inhibitor washout: GP IIb/IIIa inhibitors may be
used per standard of care. If used, eptifibatide or tirofiban
must have been discontinued for ≥24 hrs prior to VerifyNow,
and abciximab must have been discontinued for ≥10 days
prior to VerifyNow.
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
8,575 pts were enrolled at 11 sites between 1/7/2008 and
9/16/2010; 2,158 pts were enrolled in the IVUS substudy
Site
Principal investigator(s)
N enrolled
Charité Benjamin Franklin
Bernhard Witzenbichler
1,426
Columbia University Medical Center
Giora Weisz
1,369
Herz-Zentrum Bad Krozingen
Franz-Josef Neumann
1,035
Carolinas Medical Center
Mike Rinaldi
1,110
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=8,575)
Age (years)
Female
Non-caucasian
Diabetes mellitus
63.6 ± 10.9
25.9%
11.4%
32.4%
- Insulin-treated
11.6%
Hypertension
Hyperlipidemia
Cigarette smoking, current
Prior MI
Prior PCI
Prior CABG
Prior CHF
Prior PAD
History of renal insufficiency
- Dialysis
BMI
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=8,575)
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: Anti-platelet agents (n=8,575)
Aspirin
- Pre-admission
82.0%
- Loading dose pre-PCI
88.7%
- Discharge
99.2%
Thienopyridine
- Pre-admission
42.8%
- Loading dose pre-PCI
86.4%
- Discharge
99.7%
• Ticlopidine
• Clopidogrel
• Prasugrel
n=3 (0.04%)
n=8,541 (99.7%)
n=26 (0.3%)
ADAPT-DES: PCI procedure (n=8,575)
N = 10,091 vessels, 12,898 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
3.7%
46.0%
30.9%
37.0%
3.3%
1.8 ± 1.1
1.7 ± 1.0
32.4 ± 22.3
64.4% / 58.3%
16.5% / 14.4%
13.5% / 13.0%
6.2% / 5.2%
2.2% / 2.1%
0.2% / 0.2%
ADAPT-DES: Platelet function test results
(n=8,575)
Post-PCI to VerifyNow (hrs)
19.0 [16.3, 21.8]
VerifyNow Aspirin (ARU)
- ≥ 550 ARU*
VerifyNow P2Y12 (BASE)
VerifyNow P2Y12 (PRU)
- > 208 PRU*
- ≥ 230 PRU*
VerifyNow P2Y12 Inhibition (%)
VerifyNow IIb/IIIa PAU
*Pre-specified cut-off values
419 ± 55
5.6%
310 ± 58
188 ± 97
42.7%
35.0%
40.0 ± 28.3
193 ± 53
ADAPT-DES: Stent Thrombosis Within 30 Days
Stent thrombosis (ARC def/prob) occurred in 39 (0.46%) pts
6
Probable
Definite
Frequency
5
Definite or probable 0.46% (39)
- Definite
0.32% (27)
- Probable
0.14% (12)
4
3
2
1
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Days to definite or probable stent thrombosis
ADAPT-DES: Relationship between VerifyNow
platelet response to DAPT and subsequent
definite or probable stent thrombosis
VerifyNow test
Def/prob ST
(n=39)
425.6 ± 60.1
No def/prob ST
(n=8536)
419.2 ± 55.3
0.46
7.7%
5.6%
0.57
P2Y12 Base
301.7 ± 63.9
309.6 ± 58.1
0.41
P2Y12 PRU
249.4 ± 88.5
187.6 ± 96.7
0.0001
- PRU >208
74.4%
42.6%
0.0002
- PRU ≥230
64.1%
34.9%
0.0003
P2Y12 % Inhibition
19.8 ± 23.7
40.1 ± 28.2
<0.0001
- Inhibition ≤11%
51.3%
19.9%
<0.0001
188.2 ± 54.9
192.7 ± 53.4
0.60
Aspirin ARU
- ARU ≥550
IIb/IIIa PAU
Rates are KM estimates (n).
P
ADAPT-DES: ROC curve analysis of the relationship
between VerifyNow assessed platelet response to
DAPT and subsequent stent thrombosis
VerifyNow test
Def/prob ST
AUC Cut-off
Definite ST
AUC Cut-off
Aspirin ARU
0.563
403
0.626
403
P2Y12 Base
0.536
289
0.604
303
P2Y12 PRU
0.679
206
0.716
230
P2Y12 % Inhibition
0.720
25%
0.787
11%
IIb/IIIa PAU
0.542
195
0.587
181
ADAPT-DES: Relationship Between VerifyNow P2Y12
PRU and Stent Thrombosis within 30 Days
Definite or probable stent thrombosis
Definite/Probable ST (%)
2.0
P2Y12 PRU Q1 (≤94) (n=1691)
P2Y12 PRU Q2 (95-160) (n=1701)
P2Y12 PRU Q3 (161-216) (n=1705)
P2Y12 PRU Q4 (217-275) (n=1666)
P2Y12 PRU Q5 (≥276) (n=1691)
1.8
1.6
1.4
1.2
1.0
0.8
0.79%
0.78%
0.6
0.4
0.36%
0.24%
0.18%
0.2
0.0
0
Number at Risk
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
5
10
15
20
25
30
Days
1691
1688
1705
1666
1691
1665
1657
1677
1633
1662
1663
1657
1676
1631
1659
1640
1630
1656
1607
1635
ADAPT-DES: Relationship Between VerifyNow P2Y12
PRU and Stent Thrombosis within 30 Days
Definite or probable stent thrombosis
Definite/Probable ST (%)
2.0
P2Y12 PRU > 208 (n=3607)
P2Y12 PRU ≤ 208 (n=4834)
1.8
HR [95% CI]=
3.89 [1.90, 7.98]
P <0.001
1.6
1.4
1.2
1.0
0.81%
0.8
0.6
0.4
0.21%
0.2
0.0
0
5
10
20
25
30
Days
Number at risk
>208 PRU
≤208 PRU
15
3607
4834
3540
4754
3534
4752
3482
4686
ADAPT-DES: Relationship Between VerifyNow P2Y12
% Inhibition and Stent Thrombosis within 30 Days
Definite or probable stent thrombosis
P2Y12 % Q1 (≤11) (n=1694)
P2Y12 % Q2 (12-28) (n=1672)
P2Y12 % Q3 (29-46) (n=1676)
P2Y12 % Q4 (47-68) (n=1744)
P2Y12 % Q5 (≥69) (n=1626)
Definite/Probable ST (%)
2.0
1.8
1.6
1.4
1.2
1.19%
1.0
0.8
0.6
0.42%
0.42%
0.17%
0.12%
0.4
0.2
0.0
0
Number at Risk
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
5
10
15
20
25
30
Days
1694
1672
1676
1744
1653
1667
1647
1641
1712
1626
1663
1647
1639
1712
1624
1637
1627
1613
1692
1598
ADAPT-DES: Relationship Between VerifyNow P2Y12
% Inhibition and Stent Thrombosis within 30 Days
Definite or probable stent thrombosis
Definite/Probable ST (%)
2.0
VerifyNow P2Y12 % Lowest Quintile (≤11) (n=1694)
VerifyNow P2Y12 % Highest 4 Quintiles (>11) (n=6745)
1.8
1.6
1.4
1.19%
1.2
1.0
HR [95% CI]=
4.18 [2.23, 7.82]
P<0.001
0.8
0.6
0.4
0.29%
0.2
0.0
0
Number at risk
≤11%
>11%
5
10
15
20
25
30
Days
1694
6745
1667
6626
1663
6622
1637
6530
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
Definite or probable stent thrombosis
VerifyNow test
P2Y12
P2Y12 PRU
>208†
N
N
Adj. HR*
P
Attributable Attributable
at risk events [95%CI] value
events
percent
8439
39
3.00
0.005
[1.39, 6.49]
P2Y12 PRU
≥230†
8439
39
2.75
[8.1, 24.5]
0.005
[1.35, 5.60]
Inhibition ≤11%†
8437
39
2.78
19.3
15.9
[6.4, 20.5]
0.003
[1.43, 5.40]
12.8
[6.0, 16.3]
49.6%
[20.7%, 62.9%]
40.8%
[16.5%, 52.7%]
32.8%
[15.4%, 41.8%]
*Adjusted for non-ACS vs NSTEMI vs STEMI, diabetes vs no diabetes, and stent length
Model c-statistics = 0.609, 0.591, 0.623
†Pre-specified
measures
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
Definite or probable stent thrombosis
VerifyNow test
N
N
HR
at risk events [95%CI]
P
Attributable
value
events
P2Y12 PRU
8439
0.005
>208
39
3.00
[1.39, 6.49]
P2Y12 PRU
≥230
8439
39
2.75
[8.1, 24.5]
0.005
[1.35, 5.60]
Inhibition ≤11%
8437
39
2.78
8517
39
1.69
0.003
≥360
8436
39
1.18
0.39
0.70
[0.50, 2.80]
GPIIb/IIIa ≥238
8265
38
0.66
[0.27, 1.64]
12.8
[6.0, 16.3]
[0.51, 5.61]
P2Y12 Base
15.9
[6.4, 20.5]
[1.43, 5.40]
ARU ≥550
19.3
49.6%
[20.7%, 62.9%]
40.8%
[16.5%, 52.7%]
32.8%
[15.4%, 41.8%]
1.2
3.1%
[-2.9, 2.5]
[-7.4%, 6.3%]
1.4
3.6%
[-9.0, 5.8]
0.37
Attributable
percent
-3.1
[-16.5, 2.3]
[-23.0%, 14.8%]
-8.1%
[-43.5%, 6.1%]
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
Definite stent thrombosis
VerifyNow test
P2Y12
P2Y12 PRU
>208†
N
N
Adj. HR*
at risk events [95%CI]
P Attributable Attributable
value
events
percent
8439
0.002
27
5.36
[1.89, 15.21]
P2Y12 PRU
≥230†
8439
27
4.46
[10.4, 20.6]
0.001
[1.80, 11.03]
Inhibition ≤11%†
8437
27
4.60
17.9
14.7
[8.5, 17.3]
0.0003
[2.01, 10.55]
13.3
[8.5, 15.4]
66.3%
[38.3%, 76.1%]
54.6%
[31.4%, 64.0%]
49.3%
[31.6%, 57.0%]
*Adjusted for non-ACS vs NSTEMI vs STEMI, diabetes vs no diabetes, and stent length
Model c-statistics = 0.753, 0.721, 0.722
†Pre-specified
measures
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
Definite stent thrombosis
VerifyNow test
N
N
HR
at risk events [95%CI]
P
Attributable
value
events
P2Y12 PRU
8439
0.002
>208
27
5.36
[1.89, 15.21]
P2Y12 PRU
≥230
8439
27
4.46
[10.4, 20.6]
0.001
[1.80, 11.03]
Inhibition ≤11%
8437
27
4.60
8517
27
2.87
0.0003
≥360
8436
27
0.99
0.09
8265
27
0.43
[0.13, 1.49]
2.0
[-0.6, 2.7]
0.99
[0.33, 2.99]
GPIIb/IIIa ≥238
13.3
[8.5, 15.4]
[0.84, 9.82]
P2Y12 Base
14.7
[8.5, 17.3]
[2.01, 10.55]
ARU ≥550
17.9
0.0
[-10.2, 3.3]
0.18
-3.9
[-20.8, 1.0]
Attributable
percent
66.3%
[38.3%, 76.1%]
54.6%
[31.4%, 64.0%]
49.3%
[31.6%, 57.0%]
7.2%
[-2.1%, 10.0%]
-0.1%
[-37.7%, 12.3%]
-14.5%
[-77.0%, 3.7%]
ADAPT-DES: Predictive accuracy of
VerifyNow testing – all pts (n=8,575)
Definite or probable stent thrombosis by 30 days (n=39)
VerifyNow test
ASA ARU > 550
P2Y12 PRU > 208
P2Y12 PRU ≥ 230
P2Y12 % Inhibition ≤ 11%
IIb/IIIa PAU ≥ 238
Sensitivity Specificity
7.7%
94.4%
74.4%
57.4%
64.1%
65.1%
51.3%
15.8%
80.1%
80.2%
PPV
0.6%
0.8%
0.8%
NPV
99.6%
99.8%
99.7%
Accuracy
94.0%
57.5%
65.1%
1.2%
0.4%
99.7%
99.5%
79.9%
79.9%
Definite stent thrombosis by 30 days (n=27)
VerifyNow test
ASA ARU > 550
P2Y12 PRU > 208
P2Y12 PRU ≥ 230
P2Y12 % Inhibition ≤ 11%
IIb/IIIa PAU ≥ 238
Sensitivity Specificity
11.1%
94.4%
81.5%
57.4%
70.4%
65.1%
63.0%
80.1%
11.1%
80.1%
PPV
0.6%
0.6%
0.6%
1.0%
0.2%
NPV
99.7%
99.9%
99.9%
99.9%
99.6%
Accuracy
94.1%
57.5%
65.1%
80.0%
79.9%
ADAPT-DES: ADP Platelet Responsiveness in Pts
with and without Definite/Probable Stent
Thrombosis within 30 Days
100
600
P=0.0001
400
Median [IQR]
252 [206, 311]
300
200
Median [IQR]
188 [112, 260]
100
VerifyNow P2Y12 PERCENT (%)
VerifyNow P2Y12 (PRU)
500
P<0.0001
75
50
25
Median [IQR]
38 [16, 62]
Median [IQR]
11 [0, 36]
0
0
No Stent Thrombosis
N=8402
Stent Thrombosis
N=39
No Stent Thrombosis
N=8400
Stent Thrombosis
N=39
ADAPT-DES: Relationship between ACS and
stent thrombosis
P=0.002
9/4140
30/4435
10/2377
7/1246
13/812
ADAPT-DES: Relationship between ACS and
VerifyNow response to DAPT
VerifyNow test
ACS
(n=4435)
419.5 ± 54.4
No ACS
(n=4140)
419.0 ± 56.4
0.66
5.4%
5.8%
0.43
P2Y12 Base
304.6 ± 57.6
314.8 ± 58.1
<0.0001
P2Y12 PRU
193.8 ± 96.2
181.7 ± 97.0
<0.0001
- PRU >208
45.6%
39.7%
<0.0001
- PRU ≥230
37.6%
32.3%
<0.0001
P2Y12 % Inhibition
37.3 ± 28.2
42.9 ± 28.1
<0.0001
- Inhibition ≤11%
23.3%
16.6%
<0.0001
187.9 ± 52.3
197.8 ± 54.1
<0.0001
Aspirin ARU
- ARU ≥550
IIb/IIIa PAU
P
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
ACS: Definite or probable stent thrombosis
VerifyNow test
P2Y12
N
N
Adj. HR*
at risk events [95%CI]
P
Attributable
value
events
PRU >208†
4347
0.005
30
3.91
[1.51, 10.11]
PRU ≥230†
4347
30
2.95
[8.1, 21.6]
0.01
[1.29, 6.77]
Inhibition ≤11%† 4346
30
3.53
17.9
13.2
[4.5, 17.0]
0.001
[1.66, 7.52]
12.2
[6.8, 14.7]
*Adjusted for diabetes vs no diabetes and stent length
Model c-statistics = 0.541, 0.464, 0.524
†Pre-specified
measures
Attributable
percent
59.5%
[27.0%, 72.1%]
44.1%
[14.9%, 56.8%]
40.6%
[22.6%, 49.1%]
ADAPT-DES: Multivariable (Cox PHR) models of 30-day
stent thrombosis stratified by propensity quintiles
No ACS: Definite or probable stent thrombosis
VerifyNow test
P2Y12
N
N
Adj. HR*
at risk events [95%CI]
P
Attributable
value
events
PRU >208†
4092
0.59
9
1.49
[0.35, 6.36]
PRU ≥230†
4092
9
2.02
[-9.3, 4.2]
0.35
[0.46, 8.74]
Inhibition ≤11%† 4091
9
2.22
1.6
2.5
[-5.8, 4.4]
0.28
[0.53, 9.28]
1.6
[-2.7, 2.7]
*Adjusted for diabetes vs no diabetes and stent length
Model c-statistics = 0.704, 0.705, 0.760
†Pre-specified
measures
Attributable
percent
18.3%
[-103.0%, 46.8%]
28.0%
[-64.0%, 49.2%]
18.3%
[-29.6%, 29.7%]
ADAPT-DES: Conclusions and Implications
• The absolute and relative levels of platelet
inhibition to ADP antagonists as assessed by the
VerifyNow P2Y12 test are powerful independent
predictors of stent thrombosis within 30 days, with
a significant proportion of events independently
attributable to clopidogrel hyporesponsiveness.
• In contrast, the Base level of platelet P2Y12
response, as well as aspirin and overall platelet
responsiveness after DAPT loading as assessed
by VerifyNow were not shown to be related to the
30-day rate of stent thrombosis.
ADAPT-DES: Conclusions and Implications
• These data suggest that agents which more
effectively inhibit ADP-induced platelet activation
should reduce 30-day stent thrombosis when applied
to large patient populations (underlying the positive
findings of TRITON-TIMI 38 and PLATO).
• However, the modest sensitivity and specificity of
platelet function testing, coupled with the low
prevalence of events, implies that testing of platelet
ADP antagonist responsiveness is unlikely to provide
useful information to guide clinical decision-making
in most individual patients for the prevention of stent
thrombosis at 30 days.
ADAPT-DES: Conclusions and Implications
• The degree of platelet responsiveness to ADP
antagonist loading is useful to predict 30-day stent
thrombosis in diabetic and non-diabetic patients, as
well as those with ACS, but may have less clinical
utility in patients with stable CAD.
• The very low stent thrombosis rate in pts with stable
CAD, coupled with the poor prognostic utility of
platelet function testing in this setting suggests that
assessing DAPT response in pts without ACS
undergoing PCI is unlikely to provide incremental
clinical utility, and may explain the negative results of
trials such as GRAVITAS and TRIGGER-PCI.
ADAPT-DES: Conclusions and Implications
• The relationship between platelet responsiveness
testing and the occurrence of late and very late
stent thrombosis (in patients who have maintained
and discontinued DAPT) will be assessed during
the 2-year clinical follow-up phase of the ADAPTDES study.