Transcript in ACS and PCI - Clinical Trial Results

Welcome
Ask The Experts
March 24-27, 2007
New Orleans, LA
AntiPlatelet Therapy in ACS
and PCI
Stephen D. Wiviott, MD
Associate Physician, Cardiovascular Division,
Brigham and Women's Hospital
Investigator, TIMI Study Group
Harvard Medical School
Boston, MA
Antiplatelet Therapy in ACS and
PCI: Challenges and Future
Directions
Stephen D. Wiviott
Cardiovascular Division
Brigham and Women’s Hospital
Harvard Medical School
TIMI Study Group
Disclosures
Speakers Bureau: Pfizer; CME
Honoraria: Eli Lilly, Merck, Pfizer,
Sankyo; Accumetrics.
Consultancies: Amgen, Transform
Pharmaceuticals, Forrest Labs,
Biogen-Idec, Sanofi-Aventis
Circ 102: 624,2000
Dual Antiplatelet Rx for PCI
12
12
OAC + ASA
Ticlopidine + ASA
11
10
10
% MACE
8.6
8
6.2
5.8
5.7
6
4
2.7
1.6
2
0.9
0.5
1.5
1.2
0
ISAR
FANTASTIC
STARS
MATTIS
CLASSICS
CURE
NSTEACS: Clopidogrel (300/75) vs Placebo
Primary End Point - MI/Stroke/CV
Death
Cumulative Hazard Rate
0.14
11.4%
Placebo
+ ASA*
0.12
9.3%
0.10
0.08
Clopidogrel
+ ASA*
0.06
0.04
20% RRR
P < 0.001
N = 12,562
0.02
0.00
0
3
6
9
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
12
Early Effects of Pre-treatment with
Clopidogrel – 28 Day Results
Death, MI, UTVR- PP Population
10
Combined Endpoint
Occurrence (%)
9
8
7
6
8.3%
18.5%
RRR
6.8%
P=0.23
5
4
3
2
No-PT - Placebo*
1
PT- Clopidogrel*
0
0
PT = Pre-treatment
7
14
21
Days From Randomization
*Plus ASA and other standard therapies
28
Steinhubl S, Berger P, Tift Mann III J et al.
JAMA. 2002;Vol 288,No 19:2411-2420.
CREDO: Clopidogrel Loading
Dose Timing and Risk of MACE
Placebo
-2
P=0.020
for treatment/timing
interaction
-3
-4
Clopidogrel
-5
-6
0
5
10
15
20
25
Hours Prior to PCI of Study Drug Loading Dose
Steinhubl, et al
30
Limitations of Current
thienopyridines
Slow onset: requires prolonged
pretreatment for PCI efficacy
Bleeding (especially related to
CABG)
Modest levels of platelet
inhibition
Variability of response
The First Clopidogrel Resistance Study (300 mg):
A “Fingerprint” of Clopidogrel Response Variability
2 Hours
Resistance = 63%
20
12
Resistance = 31%
10
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
 Aggregation (%)
5 Days
Resistance
 Aggregation (%)
30 Days
28
Resistance = 31%
Patients (%)
Patients (%)
22
Resistance
Patients (%)
Resistance
Patients (%)
24
24 Hours
11
≤ -10
(-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
 Aggregation (%)
Gurbel PA, et al. Circulation. 2003;107: 2908-2913.
Resistance = 15%
14
Resistance
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
 Aggregation (%)
Potential Mechanisms of Response
Variability
Extrinsic Mechanisms
•Non-compliance
•Under-dosing
•Drug-drug interactions
•Absorption and/or metabolism
•Patient Factors (DM, ACS, etc…)
Intrinsic Mechanisms
•P2Y12 receptor affinity (ADP or Drug) or number
•Variable response to agonist:
•Release
•GP IIb/IIIa receptor activation
Wiviott and Antman Circ 2004
CYP 3A4 Activity* Correlates
Inversely with Platelet Aggregation
Following Clopidogrel Loading
100
Platelet Aggregation (%)
90
80
70
60
50
40
30
r=–0.6
P=0.003
20
10
0
0
.5
1
1.5
14CO
2
*Erythromycin breath test.
Lau WC, et al. Circulation. 2004;109:166-171.
2
2.5
Exhaled/Hour (%)
3
3.5
4
Clinical Importance of
Response Variability ?
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Clopidogrel Resistance and
Increased Risk of Ischemic Events
N = 60 Prim PCI for STEMI
5 µM ADP induced plt agg
120
Clop resist
100
40
40
Q1
80
Q2
60
Q3
P=0.007
Percent
Baseline (%)
Death/ACS/CVA by 6 m
30
20
40
Q4
20
10
6.7
Quartiles of response
0
1
2
3
4
Days
5
Matetzky S, et al. Circulation. 2004;109:3171-3175.
Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067.
6
0
Q1
Q2
0
0
Q3
Q4
Platelet Reactivity* Correlates
with CK-MB Release:
CLEAR Platelet Study
100
P<0.001
Mean Platelet Reactivity
90
80
P<0.001
P=0.015
70
60
50
40
30
20
10
0
CK-MB
(NL)
*5 m ADP.
Gurbel PA, et al. Circulation. 2005;111:1153-1159.
CK-MB
(>1-3x ULN)
CK-MB
(>3x ULN)
The Clopidogrel REsistance and
Stent Thrombosis (CREST) Study
Platelet Reactivity in Patients with SAT(N=20) versus no SAT (N=50)
P<0.001 For
Each
LTA – 5 M ADP (%)
LTA – 20 M ADP (%)
70
70
60
60
50
49
65
46
50
40
40
26
30
30
20
20
10
10
0
0
SAT
No SAT
Gurbel PA, et al. J Am Coll Cardiol. 2005 (in press).
SAT
No SAT
Patients (%)
Increase the Dose:
(300 mg vs 600 mg)
33
30
27
24
21
18
15
12
9
6
3
0
300 mg Clopidogrel
600 mg Clopidogrel
Resistance = 28% (300 mg)
Resistance = 8% (600 mg)
≤-30
(-20,-10]
(0,10]
(20,30]
(40,50]
(60,70]
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
 Aggregation (5 µM ADP-induced Aggregation) at 24 Hours
Gurbel PA, et al. J Am Coll Cardiol. 2005;45:1392-1396.
> 70
ISAR - CHOICE
Platelet Aggregation
Metabolite
Concentrations
Von Beckenrath et al Circ 2005
ARMYDA-2 Trial: Primary endpoint
255 patients with stable
CAD or UA/NSTEMI
Primary Composite of death, MI, and
target vessel revascularization
p = 0.04
4-8 hours prior to PCI
13% received IIb/IIa
inhibitors and 20% drugeluting stents
14%
12%
12%
10%
8%
Primary Endpoint:
Composite of death,
MI, or target vessel
revascularization
(TVR) at 30 days
6%
4%
4%
2%
0%
Circulation 2005
600 mg
300 mg
CURRENT/OASIS 7
Clopidogrel optimal loading dose Usage to Reduce Recurrent
EveNTs/Optimal Antiplatelet Strategy for InterventionS
Patients with UA/NSTEMI planned for early invasive
Strategy; ie, intend for PCI as early as possible within 24 hrs
RANDOMIZE
Clopidogrel High-Dose Group
Clopidogrel 600 mg loading dose day 1 followed by
150 mg from days 2 to 7; 75 mg from days 8 to 30
RANDOMIZE
ASA low-dose group
At least 300 mg day 1;
75–100 mg
from days 2 to 30
ASA high-dose group
At least 300 mg day1;
300–325 mg
from days 2 to 30
PCI: Percutaneous coronary intervention
UA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction
Clopidogrel Standard-Dose Group
Clopidogrel 300 mg (+ placebo) day 1 followed
by 75 mg (+ placebo) from days 2 to 7;
75 mg from days 8 to 30
RANDOMIZE
ASA low-dose group
At least 300 mg day 1;
75–100 mg
from days 2 to 30
ASA high-dose group
At least 300 mg day 1;
300–325 mg
from days 2 to 30
Sem Vasc Med 3:113, 2003
Sankyo Ann Report 51:1,1999
Change the Agent?
O
O CH3
C
O
Pro-drug
N
S
O
Cl
N
O
C
S
CH3
Clopidogrel
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
N
O
S
O
C
O CH3
Oxidation
(Cytochrome P450)
N
S
F
Cl
O
O
C
N
S
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
N
F
Cl
Active Metabolite
Active Metabolite
100.0
60.0
40.0
20.0
0.0
Interpatient Variability
80.0
-20.0
Response to
Clopidogrel
*Responder =  25% IPA at 4 and 24
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
Inhibition of Platelet Aggregation
(IPA) at 24 Hours (Healthy Volunteers)
Clopidogrel Responder
Clopidogrel Nonresponder
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ
Inhibition of Platelet Aggregation
(Stable Atherosclerosis)
Maintenance dose (MD)
Loading dose (LD)
70
Mean IPA (%)
60
50
40
30
20
Prasugrel (40 mg LD/5 mg MD)
Prasugrel (40 mg LD/7.5 mg MD)
Prasugrel (60 mg LD/10 mg MD)
Prasugrel (60 mg LD/15 mg MD)
Clopidogrel(300 mg LD/75 mg MD)
10
0
-10
1/0
1/2
1/4
1/6
Jernberg, T et al EHJ 2006
7/1
7/2
28/0
Day/Hour Post Dosing
28/2
28/4
28/6
In Vitro Antiplatelet Effects of Active
Metabolites in PRP
(B) Human
(A) Rat
80
Platelet aggregation (%)
Platelet aggregation (%)
70
60
50
40
Prasugrel AM
30 (IC50 = 51 μM)
Clopidogrel AM
20
(IC50 = 41 μM)
10
0
**
**
**
0
**
100
1
10
Concentration (μM)
Ogawa, et al ESC 2005.
**
1000
60
*
** **
40 Prasugrel AM
(IC50 = 26 μM)
Clopidogrel AM
20 (IC50 = 21 μM)
**
**
**
**
0
**
1
10 100 1000
0
Concentration (μM)
* P < 0.05 ** P < 0.01 vs. control
Insights into Potency : Active Metabolite
Levels in Humans (Crossover Study)
Plasma Concentration
(ng/ml)
1000
Prasugrel 60 mg
Clopidogrel 300 mg
100
10
1
0.1
0
6
Time 12
in Hr 18
24
ISTH 2005 Payne et al, P0952
Wiviott et al Circ 2005
STUDY DESIGN
PCI with stenting
(N=900)
Study Drug in lab; Stratify for GP IIb/IIIa
PRASUGREL
LD 40 mg
MD 7.5 mg
N=200
PRASUGREL
LD 60 mg
MD 10 mg
N=200
PRASUGREL
LD 60 mg
MD 15 mg
N=250
CLOPIDOGREL
LD 300 mg
MD 75 mg
N=250
Maintenance Rx for 30 days
1o endpoint:
Significant (non-CABG) bleeding through 30 D
2o endpoints: CV MACE through 30 D, Major Bleeding,
Component Clinical Endpoints
Wiviott et al Circ 2005
10 EP: Significant Non-CABG Bleeding 30 D
Clop. vs Prasugrel
Dose Ranging
P = 0.77
Treatment Group
R/N
3/254 11/650
P= NS
Prasugrel LD/MD
3/199
4/200
4/251
Wiviott et al Circ 2005
MI at 30 D
RR=0.72 [0.4,1.2]
P = 0.23
R/N
P= NS
Treatment Group
Prasugrel LD/MD
20/254 37/650 14/199 13/200 10/251
Implications
In patients undergoing PCI, prasugrel:
• Demonstrated a similar safety profile to standard
dose clopidogrel
• Resulted in non-significant, but lower rates of
ischemic events compared to patients treated with
standard doses of clopidogrel
QUESTION: Would prasugrel, with higher and more
consistent levels of platelet inhibition, be superior to
clopidogrel in reducing ischemic events in a trial
powered to detect a clinically significant difference?
STUDY DESIGN
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
N= 13,000
Double-blind
CLOPIDOGREL
Enrollment Complete
PRASUGREL
300 mg LD/ 75 January
mg MD
60 mg LD/ 10 mg MD
2007
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR
Wiviott et al, AHJ 2006
Implications
•Establish the safety and efficacy of prasugrel
compared to clopidogrel in patients with ACS
undergoing PCI in this registry pathway trial
•Proof of Concept:
Does an agent that has higher inhibition of platelet
aggregation and less “thienopyridine resistance”
result in improved clinical outcomes in an
adequately powered clinical trial?
Wiviott et al, AHJ 2006
TIMI 38 C R
Hypotheses
In the follow up phase, beyond completion of TRITON – TIMI 38*:
1. Patients withdrawn from thienopyridine at study
completion will have a higher rate of stent
thrombosis than those continuing therapy in the
registry follow up period
2. Patients treated with DES will have higher rates of
stent thrombosis than those treated with BMS
over the entire treatment period (trial plus registry)
*Analyses adjusted for baseline, procedural features, and propensity for clopidogrel use
TIMI 38 C R
Trial Duration
Summary of Analytical Groups
and Trial/ Registry Timing
Registry Duration
24 M Following LPV in TRITON – TIMI 38
6-15 Months
TRITON – TIMI 38
DES
Continue
Clinical Trial
Prasugrel vs
Clopidogrel
Open Label
Thienopyridine
Discontinue
Continue
BMS
Discontinue
30 - 54 Months
Registry + Trial Duration
Inhibition of Platelet Aggregation (%)
Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD:
Higher IPA During Maintenance Dosing
Loading Dose
Maintenance Doses
100
*
80
*
*
†
†
Pras 10 mg
* * *
§
* *
Clop 75 mg
!
*
40
* *
Clop 600 mg†
Pras 60 mg
60
**
Clop 75 mg
!
Clop 300 mg
20
*p<0.001 vs. Clop 300 mg
mean ± SEM
20 μM ADP
0
0 0.25 0.5 1
Time
2
Hours
4 6 24 3 4
5
6
7 8
Days
9
or 600 mg LD
p<0.001 vs. Clop 300
!
p<0.05 vs. Clop 300
§p<0.05 vs Clop 300/75
†
PRINCIPLE – TIMI 44
Protocol Design
(PCI Subjects Only) – Phase I
PHASE I
Planned Elective PCI
Aggregometry*and Biomarkers√
N < 180
CLOPIDOGREL Naive
Planned GP IIb/IIIa Prohibited
Clopidogrel
600 mg
ASA
Prasugrel
60 mg
0.5, hour post-LD
Aggregometry* and Biomarkers√
Diagnostic Catheterization Anatomy Suitable for
PCI
Post Cath† aggregometry
N = 100
PCI
†Or 2 h whichever
is sooner
6, 18-24 h, Aggregometry*,
biomarkers
Primary Endpoint: Mean IPA (6h) in all treated
PRINCIPLE – TIMI 44
Protocol Design
Confidential
(PCI Subjects Only) – Phase II
PCI
PHASE II
Clopidogrel
150 mg
x14d
Prasugrel
10 mg x 14d
14 d clinical events, biomarkers
√, aggregometry*, CROSSOVER
Prasugrel
10 mg x 14
d
30 d clinical events,biomarkers
√, aggregometry*
Clopidogrel
150 mg
x14d
Primary Endpoint: Mean IPA (14d&30d) in all treated
subjects
√ Biomarkers (VASP, CD40L, P-selectin, LPA, Tn, CK-MB, CRP, MPO)
*Aggregometry: Primary (20 uM ADP), secondary (5 uM ADP), Accumetrics
Change the Agent?
AZD6140 Characteristics
•Class: CPTP* (non-thienopyridine)
•Reversible platelet P2Y12 receptor antagonist
•Orally active
•Rapid onset of action (2 h) with or without a
loading dose
•Acts directly (no metabolic activation
required)
•Plasma t½ ~12 h (BID Drug)
F
F
HN
N
N
N
HO
O
N
*cyclo-pentyl-triazolo-pyrimidine
HO
OH
N
S
AZD6140
Maximal and Final IPA on Day 1
Clopidogrel Naive Patients
IPA (%)
Mean ± SEM
Maximal Extent
Final Extent
100
100
75
75
50
50
25
25
0
0
0
2
4
8
12
Time, h
AZD6140 90 mg
AZD6140 180 mg
P<0.0176 for all AZD6140 groups vs
clopidogrel at 4 h
0
2
4
8
12
Time, h
AZD6140 270 mg
CLOP 300 mg
P<0.0002 for all AZD6140 groups vs
clopidogrel at 4 h
UA/NSTEMI (mod-high risk)
STEMI (if primary PCI)
All Receiving ASA
Clopidogrel Treated or Naïve
Clopidogrel
If pretreated, no additional load;
if naïve, standard 300 mg load,
then 75 mg od maintenance
(additional 300 mg allowed pre-PCI)
n=18,000 pts
AZD6140
180 mg load, then
90 mg bid maintenance
(additional 90 mg pre-PCI)
12 month maximum exposure
(Min=6 mo, max=12 mo, mean=11 mo)
Primary Endpoint: CV Death/MI/Stroke
Secondary EP: CV Death/MI/Stroke/Revascularization with PCI;
CV Death/MI/Stroke; Severe Recurrent Ischemia
ClinicalTrials.gov Identifier: NCT00391872
Change The Agent and the
Route: Cangrelor?
Low volume of distribution, extensively
protein bound
Short half-life (3-5 min), full recovery 20
min
Unlike thienopyridines, direct P2Y12
inhibition, independent of CYP 3A4
metabolism
? Competitive inhibition of clopidogrel
Clopidogrel Response
Variability: Change the Dose
and the Route of
Administration?
8
+ Placebo
+ Aspirin/heparin/GTN
7
80
6
5
60
4
40
20
3
Aggregation
2
Bleeding time
1
0
50
Fold Increase in Bleeding Time
Inhibition of Aggregation (%)
100
500
100
1000
Cangrelor (ng.kg-1.min-1)
Stepped infusion period
Nassim MA. J Am Coll Cardiol. 1999;33:225A.
2000 7
0
15 20 45 60 min
Recovery period
CHAMPION PCI (Phase III)
UA, MI, or ACS
n=9,000
Double-blind
CLOPIDOGREL
CANGRELOR
Primary Objective: Superiority or noninferiority of cangrelor
versus clopidogrel for PCI
1o endpoint: All-cause mortality, MI, and IDR in the 48 hours after
randomization
2o endpoints: All-cause mortality and MI at 48 hours
Accessed September25, 2006, at http://www.clinicaltrials.gov/ct/show/NCT00305162?order=1.
Summary
1. ADP induced platelet activation plays a central
role in ACS and PCI complications
2. Thienopyridines have become a key component
of therapy
3. Current thienopyridines have important
limitations including response variability
4. Agents in development offer improved
pharmacological profiles, and results of ongoing
trials will determine clinical efficacy
Question
&
Answer
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