Transcript The Detrimental Impact of Chronic Renal Insufficiency

The Landscape of Oral
Antiplatelet Agents 2009
George D. Dangas, MD, PhD, FSCAI, FACC
Associate Professor of Medicine
Columbia University Medical Center
Disclosures
• Advisory Board: Accumetrics, AstraZeneca
• Consultant: Lilly, Daichi-Sankyo
• Speaker honoraria: Sanofi-Aventis,
BMS
EPISTENT: IV vs po Anti-Platelet Rx
IV placebo/abciximab & po ticlopidine preRx/no-preRx
15
33% 
P=0.033
38% 
P=0.028
13.4
% MACE 10
(Death, MI,
Urgent
Revasc)
5
0
8.9
5.5
Placebo/
No PreRx
N=343
Placebo/
PreRx
N=466
Abciximab/
No PreRx
N=328
5.2
Abciximab/
PreRx
N=466
Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC
Steinhubl SR, Circulation 1998;98:I-573
CURE
ACS pts
Benefit of Clopidogrel Therapy at
Early and Late Time Intervals
MI, stroke, CV Death: 31 d - 1 y
0.92
0
1
0.98
0.96
Placebo +
ASA
RRR 18%
95% CI 0.70–
0.95 P=0.009
0.90
RRR 21%
95% CI 0.67–
0.92 P=0.003
0.94
Placebo +
ASA
Clopidogrel +
ASA
0.92
Proportion Event-Free
0.94
0.96
0.98
Clopidogrel +
ASA
0.90
Proportion Event-Free
1.00
1.00
MI, stroke, CV Death: 0–30 days
2
3
Weeks
4
1
4
6
8
Months
Yusuf S et al for the CURE Trial Investigators.
Circulation. 2003;107:966-972.
10
12
CLARITY trial of APT in STEMI:
Occluded Artery or Death/MI (%)
Occluded Artery (or D/MI thru Angio/HD)
25
36%
21.7
Odds Ratio 0.64
(95% CI 0.53-0.76)
Odds Reduction
20
P=0.00000036
15.0
15
10
5
0
n=1752
n=1739
Clopidogrel
Placebo
0.4
0.6
0.8 1.0 1.2
Clopidogrel
better
1.6
Placebo
better
Safety of Long-Term Clopidogrel
Significant bleeding (%)
3 Placebo Controlled Trials
10%
8.8%
8%
6%
4%
P=0.07
6.7%
P=0.001
ASA + Clopidogrel
ASA + Placebo
P<0.001
3.8%
3.7%
2.7%
2.6%
2%
0%
CURE
CREDO
CHARISMA
N=12,563
1 year FU
CURE major bleed
N=2,116
1 year FU
TIMI major bleed
NEJM 2001;345;494-502
JAMA 2002;288:2411-20
N=15,603
2.5 year FU
GUSTO major
+ moderate bleed
NEJM 2006;354:1706-17
CURE
Major Bleeding by ASA Dose
ASA Dose
Clopidogrel
+ ASA*
Placebo
+ ASA*
<100 mg
2.6%
2.0%
100–200 mg
3.5%
2.3%
>200 mg
4.9%
4.0%
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.
Mean ±SD
VASP after first LD, %
VASP after adjustment, %
Control
VASP-guided
p
68 ±11
69 ±10
0.4

38 ±14*
*<0.001
Log rank p =0.007
MACE: CV death, MI,
revascularization
Bonello et al. J Am Coll Cardiol 2008
Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
 Planned Early (<24 h) Invasive Management with intended PCI
 Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
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)
PCI
17,232
(70%)
Compliance:
Clop in 1st 7d (median) 7d
7d
Efficacy Outcomes:
Safety Outcomes:
Key Subgroup:
Angio
24,769
(99%)
No Sig. CAD 3,616
7d
No PCI 7,855
(30%)
CABG 1,809
CAD 2,430
2d
CV Death, MI or stroke at day 30
Complete
Stent Thrombosis at day 30
Followup
Bleeding (CURRENT defined Major/Severe and TIMI Major)
99.8%
PCI v No PCI
Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
0.02
0.03
Clopidogrel Double
0.01
HR 0.85
95% CI 0.74-0.99
P=0.036
0.0
Cumulative Hazard
0.04
15% RRR
0
3
6
9
12
15
Days
18
21
24
27
30
Clopidogrel Double vs Standard Dose
Bleeding PCI Population
Clopidogrel
Standar Double
d
N=8548
Hazard
95% CI
P
Ratio
N= 8684
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
0.31
Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
1ICH,
2Severe
Definite Stent Thrombosis in 4 Groups
(Angiographically Proven)
0.008
C Standard, A High
C Double, A Low
0.004
C Double, A High
Standar Double
d Clop
Clop
0.0
Cumulative Hazard
0.012
C Standard, A Low
0
3
6
9
HR
P
High ASA
1.2
0.6
0.49 0.003
Low ASA
1.2
0.8
0.6
12
15
Days
18
21
0.058
24
P
Intn
0.35
27
30
PRINCIPLE-TIMI 44: Comparison of Prasugrel
with Higher Dose Clopidogrel
IPA (%; 20 mM ADP)
100
74.8
80
Prasugrel 60 mg
64.5
61.9
60
69.3
60
45.4
Clopidogrel 600 mg
40
4.9
40
32.6
31.8
30.8
20
IPA (%; 20 mM ADP)
P<0.0001
P<0.0001 for each
N=201
80
100
20
20.3
0
0
0
4
8
12
16
20
24
28
Hours
Wiviott et al Circ 2007
Clopidogrel
150 mg
Prasugrel
10 mg
14 Days
Balance of Efficacy and Safety
15
138
events
Clopidogrel
12.1
Endpoint (%)
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46
Prasugrel
5
TIMI Major
NonCABG Bleeds
35
events
Prasugrel
2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
0
0 30 60 90
180
270
Days
360
450
P=0.03
NNH = 167
TIMI-38 STENT ANALYSIS
Definite/Probable ST: DES Only (N=5743)
EARLY ST
LATE ST
HR 0.29 [0.15-0.56]
HR 0.46 [0.22-0.97]
% of Subjects
P=0.0001
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
90
150
DAYS
Wiviott et al, SCAI-ACCi2 2008
210
270
330
390
450
TIMI-38 STENT ANALYSIS
Definite/Probable ST: BMS Only (N=6461)
EARLY ST
LATE ST
HR 0.45 [0.28-0.73]
HR 0.68 [0.35-1.31]
% of Subjects
P=0.0009
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75%
0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
90
150
DAYS
Wiviott et al, SCAI-ACCi2 2008
210
270
330
390
450
AZD6140: Inhibition of Platelet aggregation
Compared With Clopidogrel in NSTEMI ACS
Patients (DISPERSE-2)
Inhibition of platelet aggregation after initial doses
*P<0.05
Mean % inhibition of platelet aggregation derived from maximum
aggregation response after addition of ADP 20 mol/l (optical
aggregometry).
Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6
PLATO study design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack
Cumulative incidence (%)
K-M estimate of time to first primary efficacy
event (composite of CV death, MI or stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
9.8
Ticagrelor
HR 0.84 (95% CI 0.77–0.92), p=0.0003
0
No. at risk
Ticagrelor
11.7
Clopidogrel
60
120
180
240
300
360
Days after randomisation
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel 9,291
8,521
8,362
8,124
6,743
5,096
4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Secondary efficacy endpoints over time
Cardiovascular death
Myocardial infarction
7
6
6
5.8
5
Ticagrelor
4
3
2
1
Cumulative incidence (%)
Cumulative incidence (%)
7
6.9
Clopidogrel
Clopidogrel
5
5.1
4.0
4
Ticagrelor
3
2
1
HR 0.84 (95% CI 0.75–0.95), p=0.005
HR 0.79 (95% CI 0.69–0.91), p=0.001
0
0
0
60
120
180
240
300
360
0
120
180
240
300
360
Days after randomisation
Days after randomisation
No. at risk
60
Ticagrelor
9,333
8,678
8,520
8,279
6,796
5,210
4,191
9,333
8,294
8,822
8,626
7119
5,482
4,419
Clopidogrel
9,291
8,560
8,405
8,177
6,703
5,136
4,109
9,291
8,865
8,780
8,589
7079
5,441
4,364
Non-CABG and CABG-related major bleeding
K-M estimated rate (% per year)
9
Ticagrelor
Clopidogrel
NS
7.9
8
7.4
7
NS
5.8
6
5.3
p=0.026
5
4
4.5
3.8
p=0.025
2.8
3
2.2
2
1
0
Non-CABG
PLATO major
bleeding
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
Safety of New DAPT Regimens
Significant bleeding (%)
3 Active Controlled Trials (vs Standard Clop)
15%
ASA + Clopidogrel
New Regimen
13.4%
P<0.001
12%
9%
Non-CABG related bleeding
P=0.001
7.9%7.4%
P=0.03
5.0%
3.8%
4.5%
3.8%
CURRENT TRITON
PLATO
6%
3%
P=0.002
2.0%2.5%
P=0.32
3.2%
0%
TRITON
CABG
PLATO
CABG
N=25,087
N=13,608
N=18,864
1-month FU 15-month FU 12-month FU
CURRENT TIMI major+minor
PLATO TIMI major+minor
PLATO
major bleed
bleed
bleed
Major bleed
Major bleed
NEJM 2009
NEJM 2007
NEJM 2009
NEJM 2007
NEJM 2009
Efficacy of New DAPT Rx in ACS
Significant Events (%)
3 Active Controlled Trials (vs Standard Clop)
15%
ASA + Clopidogrel
New Regimen
P<0.001 P=0.0003
12.1%
11.7%
12%
9.9%
9.8%
9%
P=0.37
6%
P=0.002
P<0.001 P=0.02
2.3%
1.6%
2.4%
1.1%
4.4%4.2%
3%
2.8%
2.1%
0%
CURRENT
TRITON
PLATO
N=18,864
N=13,608
N=25,087
1-month FU 15-month FU 1- Year FU
D/MI/CVA
D/MI/CVA
D/MI/CVA
ESC 2009
NEJM 2007
NEJM 2009
CURR. ST TRITON ST PLATO ST
Def/Prob
Def/Prob
Def/Prob
ESC 2009
NEJM 2007
NEJM 2009
Efficacy of New DAPT Rx: ACS+PCI
Significant Events (%)
3 Active Controlled Trials (vs Standard Clop)
15%
ASA + Clopidogrel
New Regimen
P<0.001 P=0.0
12.1%
12%
9.9%
9%
P=0.04
6%
P=0.002
P<0.001 P=0.02
2.3%
1.6%
2.4%
1.1%
4.5%
3.9%
3%
2.8%
2.1%
0.0%0.0%
0%
CURRENT
TRITON
PLATO
N=17,232
N=13,608 N=11,289
1-month FU 15-month FU 1-year FU
D/MI/CVA
D/MI/CVA D/MI/CVA
CURR. ST TRITON ST PLATO ST
Def/Prob
Def/Prob
Def/Prob
ESC 2009
NEJM 2007
NEJM 2009
ACC/AHA/SCAI Guideline Update for PCI
Oral Antiplatelet Adjunctive Therapies
I IIa IIb III
C
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.
Antiplatelet Therapy Summary
• Major recent advances in clinical research have
•
•
•
•
established the value of early + sustained therapy with
combination oral antiplatelet agents for CAD
More complex combination regimens are under
investigations that address the different clinical
situations
Prasugrel: newest addition as an FDA approved agent.
Improved efficacy. Drawback bleeding. Need for risk
stratification
Ticagrelor: newest clinical results with improved
efficacy. Reversibility likely related to less CABG
bleeding.
Cilostazol
 3ple combination therapy investigational