The Landscape of Oral Antiplatelet Agents 2009 George D. Dangas, MD, PhD, FSCAI, FACC Associate...
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Transcript of The Landscape of Oral Antiplatelet Agents 2009 George D. Dangas, MD, PhD, FSCAI, FACC Associate...
The Landscape of Oral The Landscape of Oral Antiplatelet Agents 2009Antiplatelet Agents 2009
George D. Dangas, MD, PhD, FSCAI, FACCGeorge D. Dangas, MD, PhD, FSCAI, FACC
Associate Professor of MedicineAssociate Professor of Medicine
Columbia University Medical CenterColumbia University Medical Center
DisclosuresDisclosures
• Advisory Board: Accumetrics, Astra-Advisory Board: Accumetrics, Astra-ZenecaZeneca
• Consultant: Lilly, Daichi-SankyoConsultant: Lilly, Daichi-Sankyo
• Speaker honoraria: Sanofi-Aventis, Speaker honoraria: Sanofi-Aventis, BMSBMS
EPISTENT: IV vs po Anti-Platelet RxEPISTENT: IV vs po Anti-Platelet Rx
IV placebo/abciximab & po ticlopidine preRx/no-preRxIV placebo/abciximab & po ticlopidine preRx/no-preRx
Steinhubl SR, Steinhubl SR, CirculationCirculation 1998;98:I-573 1998;98:I-573
0
5
10
15
% MACE% MACE(Death, MI,(Death, MI,
Urgent Urgent Revasc)Revasc)
Placebo/Placebo/No PreRxNo PreRx
N=343N=343
Abciximab/Abciximab/No PreRxNo PreRx
N=328N=328
Abciximab/Abciximab/ PreRxPreRxN=466N=466
Placebo/Placebo/PreRxPreRxN=466N=466
13.413.4
8.98.9
5.55.5 5.25.2
33% 33% P=0.033P=0.033
38% 38% P=0.028P=0.028
Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBCCurrently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC
Pro
po
rtio
n E
ven
t-F
ree
Benefit of Clopidogrel Therapy at Early and Late Time Intervals
Months
0.90
0.92
0.94
0.96
0.98
1.00
1 4 6 8 10 12Weeks
Pro
po
rtio
n E
ven
t-F
ree
0.90
0.92
0.94
0.96
0.98
1.00
0 1 2 3 4
RRR 21%RRR 21%95% CI 0.67–0.92 P=0.003P=0.003
Clopidogrel + ASA
Placebo + ASA
MI, stroke, CV Death: 0–30 days
Yusuf S et al for the CURE Trial Investigators. Yusuf S et al for the CURE Trial Investigators. CirculationCirculation. 2003;107:966-972.. 2003;107:966-972.
MI, stroke, CV Death: 31 d - 1 y
RRR 18%RRR 18%95% CI 0.70–0.95 P=0.009P=0.009
Clopidogrel + ASA
Placebo + ASA
CUREACS pts
CLARITY trial of APT in STEMI:CLARITY trial of APT in STEMI:Occluded Artery Occluded Artery (or D/MI thru Angio/HD)(or D/MI thru Angio/HD)
15.0
21.7
0
5
10
15
20
25
Occ
lud
ed A
rter
y o
r D
eath
/MI
(%
)
PlaceboPlaceboClopidogrelClopidogrel
P=0.00000036P=0.00000036P=0.00000036P=0.00000036
Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)
Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)
1.00.4 0.6 0.8 1.2 1.6
ClopidogrelClopidogrelbetterbetter
PlaceboPlacebobetterbetter
n=1752 n=1739
36%Odds Reduction
36%Odds Reduction
Safety of Long-Term Clopidogrel3 Placebo Controlled Trials3 Placebo Controlled Trials
3.7%
8.8%
3.8%2.7%
6.7%
2.6%
0%
2%
4%
6%
8%
10%
CURE CREDO CHARISMA
Sig
nif
ica
nt
ble
edin
g (
%) ASA + Clopidogrel
ASA + Placebo
3.7%
8.8%
3.8%2.7%
6.7%
2.6%
0%
2%
4%
6%
8%
10%
CURE CREDO CHARISMA
Sig
nif
ica
nt
ble
edin
g (
%) ASA + Clopidogrel
ASA + Placebo
P=0.001P=0.001
NEJM 2006;354:1706-17NEJM 2006;354:1706-17
N=15,603N=15,6032.5 year FU2.5 year FU
GUSTO major GUSTO major + moderate bleed+ moderate bleed
N=12,563N=12,5631 year FU1 year FU
CURE major bleedCURE major bleedNEJM 2001;345;494-502NEJM 2001;345;494-502
N=2,116N=2,1161 year FU1 year FU
TIMI major bleedTIMI major bleedJAMA 2002;288:2411-20JAMA 2002;288:2411-20
P=0.07P=0.07
P<0.001P<0.001
Placebo+ ASA*
Clopidogrel+ ASA*
Major Bleeding by ASA DoseMajor Bleeding by ASA Dose
<100 mg<100 mg 2.6% 2.6% 2.0%2.0%
100–200 mg 100–200 mg 3.5% 3.5% 2.3% 2.3%
>200 mg>200 mg 4.9% 4.9% 4.0% 4.0%
ASA Dose
CURE
Mean ±SD Control VASP-guided p
VASP after first LD, % 68 ±11 69 ±10 0.4
VASP after adjustment, % 38 ±14* *<0.001
Bonello et al. J Am Coll Cardiol 2008
MACE: CV death, MI, revascularization
Log rank p =0.007
Step-wise reloading increased % Inhibition and % responders
After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target.
Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769(99%)
Angio 24,769(99%) No PCI 7,855
(30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Clop in 1st 7d (median) 7d 7 d 2 d 7d
Complete Followup
99.8%
Complete Followup
99.8%
Compliance:Compliance:
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR15% RRR
CV Death, MI or StrokeCV Death, MI or Stroke
Clopidogrel Double vs Standard DoseBleeding PCI Population
Clopidogrel
Standard
N= 8684
Double
N=8548
Hazard
Ratio
95% CI P
TIMI Major1 0.5 0.5 1.06 0.70-1.61 0.79
CURRENT Major2 1.1 1.6 1.44 1.11-1.86 0.006
CURRENT Severe3 0.8 1.1 1.39 1.02-1.90 0.034
Fatal 0.15 0.07 0.47 0.18-1.23 0.125
ICH 0.035 0.046 1.35 0.30-6.04 0.69
RBC transfusion ≥ 2U 0.91 1.35 1.49 1.11-1.98 0.007
CABG-related Major 0.1 0.1 1.69 0.61-4.7 0.311ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
Definite Stent Thrombosis in 4 Groups (Angiographically Proven)
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
C Standard, A Low
C Standard, A High
C Double, A Low
C Double, A High
Standard Clop
Double Clop
HR PP
Intn
High ASA 1.2 0.6 0.49 0.003
Low ASA 1.2 0.8 0.6 0.058 0.35
45.4
61.9
0
20
40
60
80
100
30.8
64.574.8
69.3
4.9 20.3
31.8
32.6
0
20
40
60
80
100
0 4 8 12 16 20 24 28
PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel
P<0.0001 for eachP<0.0001 for each
IPA (%; 20 M ADP)
Hours 14 Days
IPA (%; 20 M ADP)
P<0.0001P<0.0001
Prasugrel 10 mg
Clopidogrel 150 mg
Wiviott et al Circ 2007
N=201
Prasugrel 60 mg
Clopidogrel 600 mg
Balance of Efficacy and Safety
0
5
10
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03P=0.03
Prasugrel
Clopidogrel1.82.4
138 events
35 events
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
15
TIMI-38 STENT ANALYSISTIMI-38 STENT ANALYSISDefinite/Probable ST: DES Only (N=5743)Definite/Probable ST: DES Only (N=5743)
% o
f S
ub
jec
ts
HR 0.29 [0.15-0.56]P=0.0001P=0.0001
HR 0.46 [0.22-0.97]P=0.04P=0.04
DAYS
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 450
EARLY ST LATE ST
1.44%
0.42%
71% 0.91%
0.42%
54%
CLOPIDOGREL
PRASUGREL
Wiviott et al, SCAI-ACCi2 2008
TIMI-38 STENT ANALYSISTIMI-38 STENT ANALYSISDefinite/Probable ST: BMS Only (N=6461)Definite/Probable ST: BMS Only (N=6461)
% o
f S
ub
jec
ts
HR 0.45 [0.28-0.73] P=0.0009P=0.0009
HR 0.68 [0.35-1.31]P=0.24P=0.24
DAYS
0
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 4500
0.5
1
1.5
2
2.5
0 5 10 15 20 25 30
EARLY ST LATE ST
1.66%
0.75%
55% 0.78%
0.53%
32%
CLOPIDOGREL
PRASUGREL
Wiviott et al, SCAI-ACCi2 2008
AZD6140: Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS
Patients (DISPERSE-2)Inhibition of platelet aggregation after initial doses
Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6
*P<0.05
Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry).
PLATO study design
Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding
6–12-month exposure
ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)
Ticagrelor180 mg loading dose, then
90 mg bid maintenance;(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;
randomised within 24 hours of index event (N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
121110
9876543210
13
Cu
mu
lati
ve in
cid
ence
(%
)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cu
mu
lati
ve i
nci
de
nce
(%
)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death
Cu
mu
lati
ve i
nci
de
nce
(%
)
Secondary efficacy endpoints over time
Non-CABG and CABG-related major bleeding
p=0.026
p=0.025
NS
NS
9K
-M e
stim
ated
rat
e (
% p
er y
ear)
Non-CABGPLATO major
bleeding
8
7
6
5
4
3
2
1
0Non-CABGTIMI major bleeding
CABGPLATO major
bleeding
CABG TIMI major bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
TicagrelorClopidogrel
Safety of New DAPT Regimens3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)
2.0%3.8% 3.8% 3.2%
7.9%
2.5%
5.0% 4.5%
13.4%
7.4%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO TRITONCABG
PLATOCABG
Sign
ifica
nt b
leed
ing
(%)
ASA + ClopidogrelNew Regimen
2.0%3.8% 3.8% 3.2%
7.9%
2.5%
5.0% 4.5%
13.4%
7.4%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO TRITONCABG
PLATOCABG
Sign
ifica
nt b
leed
ing
(%)
ASA + ClopidogrelNew Regimen
P=0.001P=0.001
N=25,087N=25,0871-month FU1-month FUCURRENT CURRENT major bleedmajor bleedNEJM 2009NEJM 2009
P<0.001P<0.001 P=0.32P=0.32
N=13,608N=13,60815-month FU15-month FU
TIMI major+minor TIMI major+minor bleedbleed
NEJM 2007NEJM 2007
N=18,864N=18,86412-month FU12-month FU
PLATOPLATOMajor bleedMajor bleedNEJM 2009NEJM 2009
TIMI major+minor TIMI major+minor bleedbleed
NEJM 2007NEJM 2007
PLATOPLATOMajor bleedMajor bleedNEJM 2009NEJM 2009
P=0.03P=0.03P=0.002P=0.002
Non-CABG related bleedingNon-CABG related bleeding
Efficacy of New DAPT Rx in ACS3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)
4.4%
12.1% 11.7%
2.3% 2.4% 2.8%
4.2%
9.9% 9.8%
1.6% 1.1%2.1%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST
Sign
ifica
nt E
vent
s (%
)
ASA + Clopidogrel
New Regimen
4.4%
12.1% 11.7%
2.3% 2.4% 2.8%
4.2%
9.9% 9.8%
1.6% 1.1%2.1%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST
Sign
ifica
nt E
vent
s (%
)
ASA + Clopidogrel
New Regimen
P=0.37P=0.37
N=25,087N=25,0871-month FU1-month FUD/MI/CVAD/MI/CVAESC 2009ESC 2009
P=0.02P=0.02
N=13,608N=13,60815-month FU15-month FU
D/MI/CVAD/MI/CVANEJM 2007NEJM 2007
Def/ProbDef/ProbESC 2009ESC 2009
Def/ProbDef/ProbNEJM 2007NEJM 2007
Def/ProbDef/ProbNEJM 2009NEJM 2009
P=0.0003P=0.0003
P=0.002P=0.002 P<0.001P<0.001
P<0.001P<0.001
N=18,864N=18,8641- Year FU1- Year FUD/MI/CVAD/MI/CVANEJM 2009NEJM 2009
Efficacy of New DAPT Rx: ACS+PCI3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)
4.5%
12.1%
0.0%
2.3% 2.4% 2.8%3.9%
9.9%
0.0%
1.6% 1.1%2.1%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST
Sign
ifica
nt E
vent
s (%
)
ASA + Clopidogrel
New Regimen
4.5%
12.1%
0.0%
2.3% 2.4% 2.8%3.9%
9.9%
0.0%
1.6% 1.1%2.1%
0%
3%
6%
9%
12%
15%
CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST
Sign
ifica
nt E
vent
s (%
)
ASA + Clopidogrel
New Regimen
P=0.04P=0.04
N=17,232N=17,2321-month FU1-month FUD/MI/CVAD/MI/CVA
ESC 2009ESC 2009
P<0.001P<0.001 P=0.02P=0.02
N=13,608N=13,60815-month FU15-month FU
D/MI/CVAD/MI/CVANEJM 2007NEJM 2007
Def/ProbDef/Prob
ESC 2009ESC 2009
Def/ProbDef/Prob
NEJM 2007NEJM 2007
Def/ProbDef/Prob
NEJM 2009NEJM 2009
P=0.0P=0.0
P=0.002P=0.002
P<0.001P<0.001
N=11,289N=11,2891-year FU1-year FUD/MI/CVAD/MI/CVATCT 2009TCT 2009
ACC/AHA/SCAI Guideline Update for PCIOral Antiplatelet Adjunctive Therapies
In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.
I IIa IIb III
C
Antiplatelet Therapy SummaryAntiplatelet Therapy Summary
• Major recent advances in clinical research have Major recent advances in clinical research have established the value of early + sustained therapy with established the value of early + sustained therapy with combination oral antiplatelet agents for CADcombination oral antiplatelet agents for CAD
• More complex combination regimens are under More complex combination regimens are under investigations that address the different clinical investigations that address the different clinical situations situations
• Prasugrel: newest addition as an FDA approved agent. Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk Improved efficacy. Drawback bleeding. Need for risk stratificationstratification
• Ticagrelor: newest clinical results with improved Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG efficacy. Reversibility likely related to less CABG bleeding. bleeding.
• CilostazolCilostazol 3ple combination therapy investigational3ple combination therapy investigational