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 - PowerPoint PPT Presentation

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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

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Title: 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


1
ADAPT-DES One-Year ResultsAssessment of Dual
AntiPlatelet Therapy with Drug-Eluting StentsA
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-Presbyt
erian Hospital Cardiovascular Research Foundation
2
Disclosures
  • Gregg W. Stone
  • Consultant to Eli Lilly, Daiichi Sankyo,
    AstraZeneca, Medtronic, Boston Scientific, Abbott
    Vascular, Volcano, The Medicines Company

3
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

4
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/12 matching
controls
clinicaltrials.gov NCT00638794
5
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
6
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 Col
umbia 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
7
ADAPT-DES Baseline features (n8,583)
Age (years) 63.6 10.9 Female 25.9 Caucasian
88.6 Diabetes mellitus 32.4 -
Insulin-treated 11.6 Hypertension 79.6 Hyperlipi
demia 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
8
ADAPT-DES Baseline features (n8,583)
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
9
ADAPT-DES PCI procedure (n8,583)
N 10,106 vessels, 12,940 lesions
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
10
ADAPT-DES Anti-platelet agents (n8,583)
Aspirin Thienopyridine Pre-admission 82.0 42.9
Loading dose pre-PCI 88.7 86.4 Discharge 99.2
gt99.9 - 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
11
ADAPT-DES Platelet function test results
(n8,583 8,527 with ARU, 8,449 with PRU)
Post-PCI to VerifyNow (hrs) 20.3
8.3 VerifyNow Aspirin (ARU) 419 55 - gt550
ARU 5.6 VerifyNow P2Y12 (BASE) 310
58 VerifyNow P2Y12 (PRU) 188 97 - gt208
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
12
ADAPT-DES Time to First Stent Thrombosis
70 patients (0.84) developed 74 ST events (ARC
def/prob)
N8,583
Definite ST Probable ST
Definite or probable 0.84 (70) -
Definite 0.63 (53) - Probable 0.20 (17)
Frequency
40 (57.1) of ST events occurred within 30 days
Days to definite or probable stent thrombosis
13
ADAPT-DES Relationship between VerifyNow
platelet response to DAPT and subsequent
1-year def/prob stent thrombosis (n8,583)
VerifyNow test Def/prob ST No def/prob ST
P (n70) (n8,513) 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 lt0.0001 - PRU gt208 65.2 42.5 0.0002 -
PRU 230 53.6 34.9 0.001 P2Y12
Inhibition 24.8 27.0 40.1 28.2 lt0.0001 -
Inhibition 11 44.9 19.9 lt0.0001 IIb/IIIa
PAU 194 56 193 54 0.92
14
ADAPT-DES Stent thrombosis (definite or
probable) according to post-PCI PRU
2
HR 95CI 2.54 1.55, 4.16 P0.0001
1.3
Stent thrombosis (def/prob) ()
1
0.5
0
0
3
6
9
12
Months
Number at risk
3610
3450
3420
3380
3152
PRU gt 208
4839
4688
4654
4631
4341
PRU 208
15
ADAPT-DES MI and major bleeding according to
post-PCI PRU
16
ADAPT-DES Mortality according
to post-PCI PRU
HR 95CI 1.62 1.18, 2.22 P0.002
Mortality ()
2.4
1.5
0
3
6
9
12
Months
Number at risk
3610
3475
3447
3408
3181
PRU gt 208
4839
4696
4664
4645
4365
PRU 208
17
ADAPT-DES Assessment of Propensity Score
Model to Adjust for 87 Baseline Predictors of
VerifyNow P2Y12 gt208 PRU
1.2
1.1
Model c-statistic 0.744
1.0
0.9
0.8
0.7
0.6
0.5
0.4
Log Odds Ratio
0.3
0.2
0.1
0.0
-0.1
-0.2
Open circles Plt0.05 Solid circles PNS
-0.3
-0.4
-0.5
-0.6
Includes Age Diabetes Prior MI NSTEMI STEMI Anemi
a Etc.
Graft
Anemia
BMIgt30
LAD
Male
Pre TIMI 0/1
Any Calcium
Caucasian
Killip Class 2-4
Hypertension
Any dissection
Hyperlipidemia
Previous CABG
Final TIMI 0/1
STEMI
Non-STEMI
Current smoking
Diabetes Insulin
3 vessels treated
Age gt Median (64)
Atypical chest pain
Positive stress test
Any Ostial
Aysmpomatic CAD
Closure device used
History of dialysis
Aspirin Loading dose
History of PAD
Patients with DES only
PPI Through Procedure
tPA Through Procedure
LMWH Through Procedure
Intra-aortic balloon pump
Any Lesion within a graft
Xience / Promus
VerifyNow P2Y12 (BASE)
Cardiopulmonary Support
Enrolled in Substudy
Previous MI (gt 7 Days PCI)
Retavase Through Procedure
NSAID Through Procedure
Bivalirudin Through Procedure
Amidorome Through Procedure
Diuretic Through Procedure
Platelet Count lt15000
IC Adenosine During PCI (IV)
GPIIb/IIIa Through Procedure
Atropine Through Procedure
Any Chronic Total Occlusion
Heparin though substudy
Diabetes
Cilostazol Through Procedure
History of renal insufficiency
TNK (rtPA) Through Procedure
IV Pressor Through Procedure
Coumadin Through Procedure
Aspirin Pre-hospital admission
Any previous brachytherapy
Amiodarone Through Procedure
ACE or ARB Through Procedure
Beta Blocker Through Procedure
History of CHD
CrCl lt60 ml/min
Black
Max Pre-stenosis gt Median (90)
Previous Coronary Brachytherapy
Cox-2 inhibitor Through Procedure
Anti Hypertensives Through Procedure
IC/IV Nitroprusside During PCI (IV)
Calcium blocker Through Procedure
Total stent length gt Median (24mm)
Thienopyridine Pre-hospital admission
Any bifurcation
Max balloon pressure gt Median (16atm)
Max device diameter gt Median (3.25mm)
Vascular Access Femoral
IVUS used to guide and optimize procedure
No variables remain significant in the adjusted
model
18
ADAPT-DES Multivariable propensity score
adjusted risk of VerifyNow PRU gt208 for
subsequent 1-year adverse events (n8,583)
Event Adj HR 95CI 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 gt208 (forced
in), ARU gt550 (forced in)
19
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 95CI P
value Definite ST No definite
ST N 53 8530 Deaths 5 (9.6) 156 (1.9) 5.47
2.25, 13.31 lt0.0001 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 lt0.0001 Major bleeding No
major bleeding N 531 8052 Deaths 45 (8.6) 116
(1.5) 5.97 4.23, 8.42 lt0.0001
1 year event rates (n8,583) Definite ST 53
(0.6) MI w/o def ST 224 (2.6) Major
bleeding 531 (6.2)
20
ADAPT-DES Multivariable propensity score Cox
model for all-cause mortality (n8,583),
including events during FU as
time-adjusted covariates
Baseline features Adj HR 95CI 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 lt0.0001
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 1 year 4.30 2.96, 6.26 lt0.0001
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 lt0.0001
Major bleeding 4.17 2.84, 6.13 lt0.0001
Other variables in model prior MI, NSTEMI/STEMI,
hypertension, platelet count, creatinine
clearance, MVD, VerifyNow P2Y12 gt 208 PRU and
VerifyNow Aspirin gt 550 ARU
21
Hypothetically Increasing Clopidogrel Response
in Pts with gt208
PRU ? Incremental Decrease in Stent Thrombosis
(from 1.3) vs. Increase in Bleeding (from 5.5)
18
16
14
12
10
NNT/NNH ( of ? Bleeding to Prevent One ST)
8
6
4
2
0
? 10 (to 6.1)
? 20 (to 6.6)
? 30 (to 7.2)
? 50 (to 8.2)
? 60 (to 8.8)
? 40 (to 7.7)
Safety treatment effect Major bleeding increase
(from MV HR 0.76)
22
ADAPT-DES Multivariable propensity score
adjusted risk of VerifyNow ARU gt550 for
subsequent 1-year adverse events (n8,583)
Event Adj HR95CI 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 gt208 (forced
in), ARU gt550 (forced in)
23
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

24
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
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