Transcript Mohan C3 Talk - Clinical Trial Results

Mohan Sathyamoorthy, M.D., F.A.C.C.
Vice-Chief, Cardiovascular Division
Baylor All Saints Medical Center, Fort Worth, TX
Adjunct Assistant Clinical Professor of Medicine
Vanderbilt Medical Center, Nashville, TN
Cardiologist, HeartPlace, Fort Worth, TX
Learning Objectives
Understand the key clinical data related
to platelet function testing in clinical
cardiovascular medicine
 Understand the key controversies
related to these data
 Can one incorporate this data into your
day to day clinical practice

Disclosures

Speakers Bureau for:
 Lantheus Medical Imaging
 Gilead Biosciences

Consultant for:
 None

Active Research Grants:
 None
The Clinical Effectiveness of an
Antiplatelet Agent….
A Platelet’s Response to a Drug
vs. A Drug’s Bioavailability to a Platelet
DRUG
PLATELET
Platelet Function
Testing
What Key Questions Would You Ask about
Platelet Function Testing?
What is the anti-platelet
effect of clopidogrel, asa,
and emerging agents?
Can increasing anti-platelet agent
doses affect high platelet reactivity?
High platelet reactivity:
quantifiable and modifiable
risk factor
4) Does laboratory
identification and
treatment of high
platelet reactivity
benefit the patient?
What does high
on-treatment platelet
reactivity mean to
the patient?
ACS and “Coronary Injury” is a “Platelet-Centric Disease”
Restenosis
Hypercoagulability
Inflammation
Shear Stress, PCI
Plaque Rupture
Procoagulant
State
TF
Cytokine
Release
TF
PLT-WBC
Aggregation/
Microparticles
Growth
Factor
Release
Thrombin
Initial
Activation
P-selectin
CD-40L
Stent
Thrombosis
Clopidogrel
Granule
Secretion
ADP
Sustained Activation
Membrane
PL’s
X
GPIIb/IIIa
Activation
X
TxA
2
Aspirin
X
GP IIb/IIIa Inhibitor
Platelet
Aggregation
Microaggregates
Myocardiall Infarction
What Affects a Platelet’s Response to a Drug

Platelet Biology
 Surface Receptor Biology
○ P2Y12
○ TP (Thromboplastin)
○ VW (VonWillenbrand. i.e. 2b3a)
○ PAR (Protease Activated Receptors)
 Granule Biology

Levels of Circulating Receptor Agonists
Central Role of Platelets and Interaction With
Coagulation in the Genesis of Thrombosis
Fibrinogen
Shear, PCI
Plaque Rupture
Tissue Factor
Thrombin
Collagen
vWF
Amplification
Initial
Activation
Amplification
P2Y12
ADP
TxA2
PAR-1
X
Fibrin
X
TP
Granule
Secretion
+
GPIIb/IIIa
Activation
Activation
X Platelet
Aggregation
X COX-1
Amplification
Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-1834.
Platelet -Fibrin
Clot Formation
What Affects A Drug’s “Bio”Availability to A Platelet?

Absorption kinetics
 Gut

Pharmacokinetics and dynamics
 Initial and steady state

Concomitant Medications
 Drug-drug interactions

Metabolism, i.e. Pharmacogenetics
 Liver Cytochromes and SNPs
Clopidogrel Metabolism and Effect
Clopidogrel
Prasugrel
CYP P450
Conversion
Intestinal
Absorption
Active Thiol
Metabolite
X
Gq
G12
PLC
Gi
Rho
Kinase
Ca++
Mobilization
Adenylyl
Cyclase
PI3-K
Shape
Rap-1b
Change
Akt
cAMP
VASP-P
Granule
Secretion
ADP Release
GPIIb/IIIa Activation
Platelet Aggregation
Gurbel PA et al. Nat Clin Pract Cardiovasc Med. 2006;3:387-395.
So How Do These Factors Relate
to a Clinical Endpoint?
Both of these phenomenon ultimately DETERMINE…..
VARIABILITY OF RESPONSE
TO THERAPY
i.e. hyporesponsiveness or “resistance”
Antiplatelet Drug “Resistance” / “Response Variability”
An Emerging Clinical Problem
Healthy Volunteer Crossover Study
100
Interpatient
Variability
N=66
60
40
20
Interpatient
Variability
IPA at 24 hours (%)
80
Clopidogrel Responder
0
Clopidogrel Non-responder
-20
Response to
Clopidogrel 300 mg
From Brandt JT AHJ 153: 66e9,2007
Baylor All Saints CV Conference 2010: Advances in
CV Therapy, M. Sathyamoorthy, MD, FACC
Response to
Prasugrel 60 mg
Risk of any cardiovascular event in aspirin resistant
patients
Krasopoulos, G. et al. BMJ 2008;336:195-198
Baylor All Saints CV Conference 2010: Advances in
CV Therapy, M. Sathyamoorthy, MD, FACC
Risk of any cardiovascular event in aspirin or clopidrogel “resistant” patients
Krasopoulos, G. et al. BMJ 2008;336:195-198
Baylor All Saints CV Conference 2010: Advances in
CV Therapy, M. Sathyamoorthy, MD, FACC
Assessing Platelet Function to Maximize a
Therapeutic Response
BOTTOM LINE:
•
Aspirin and clopidrogrel inhibit platelet aggregation but patients
exhibit a variable response to both aspirin and clopidrogrel
CLINCIAL IMPLICATION:
•
Maximum anti-platelet effects of aspirin and clopidrogrel may not
be obtained with standard dosage
•
Up to 30% of patients may be resistant to the effects of these drugs
•
Patient assessment may be required prior to initiation of
procedures where clopidrogrel is given
•
Pre-surgical testing of platelet function may assess the risk of
bleeding
Adapted from H. Aboul-Enein, Benha Faculty of Medicine
So how do we assess
“Responsiveness” in 2011

We test PLATELET FUNCTION

We should now consider PHARMACOGENETIC
TESTING i.e. liver cytochrome genotypes
PLATELET FUNCTION TESTING in 2011
Test
Advantages
Disadvantages
ASA
Thienopyridines
2B3A
Turbidometric
PA (PFA-100)
“gold
Standard”
Reproducibility
Expense
Time
Sample
Yes
Yes
Yes
Impedance PA
(MEA)
Whole blood
Reproducibility
Expense
Time
Sample
Yes
Yes
Yes
VerifyNow
Simple
POC
Whole Blood
No instrument
adjustment
Yes
Yes
Yes
Plateletworks
Whole Blood
Not well studied
Yes
Yes
Yes
TXAB2
COX-1
Indirect
Yes
No
No
Urinary
2,3DHTb2
COX-1
Indirect
Renal fcn
Yes
No
No
Clin Cardiol (Suppl. 1) 31.3.I-10-1-16 (2008)
E Braunwald et al: Assessing the current role of platelet function testing
Baseline Platelet Reactivity* Determines
Outcomes Following Coronary Stenting
1.0
Low Reactivity Group
0.9
0.8
0.7
High Reactivity Group
0.6
P = 0.01
0.5
0
100
Kabbani SS et al. Am J Cardiol. 2003;91:876-878.
P = 0.006
200
Time (Days)
P = 0.043
300
* Fibrinogen binding in response to 0.2 M ADP
** Composite MI, UR, Revascularization
Studies Linking High Ex-Vivo Platelet Reactivity to ADP and Ischemic Events
Study
1. Barragan et al.
(Catheter Cardiovasc Interv. 2003;59:295)
2. Ajzenberg et al.
(J Am Coll Cardiol. 2005;45:1753)
3. Gurbel et al.
(CREST Study)
(J Am Coll Cardiol. 2005;46:1827)
4. Buonamici
(J Am Coll Cardiol. 2007;49:2312)
5. Matzesky et al.
(Circulation. 2005;109:3171)
6. Gurbel et al.
(Circulation. 2005;111:1153)
(J Am Coll Cardiol;2006;48:2186)
7. Bliden et al.
(J Am Coll Cardiol. 2007;49:657)
8. Cuisset et al.
(J Thromb Haemost. 2006;3:542)
9. Lev et al.
(J Am Coll Cardiol. 2006;47:27)
10. Cuisset et al.
(J Am Coll Cardiol. 2006;48:1339)
11. Hochholzer et al.
(J Am Coll Cardiol. 2006;48:1742)
Results
Clinical Relevance
 VASP-P levels
Stent thrombosis
 Shear-induced aggregation
Stent thrombosis
 VASP-P levels
 ADP-LTA
 Stimulated GP IIb/IIIa expression
Stent thrombosis
 ADP-LTA
Stent thrombosis
 ∆ ADP-LTA
Recurrent cardiac events
 ADP-LTA
Myonecrosis and
inflammation
 pre-PCI ADP-LTA on
chronic clopidogrel
1 year post-PCI events
 ADP-LTA
30-day post-PCI events
 ADP and AA-LTA
Post-PCI myonecrosis
 ADP-LTA
30-day post-PCI events
600 mg – less events
 ADP-LTA
30-day MACE
Prognostic significance of high on-clopidogrel platelet
reactivity after percutaneous coronary intervention:
systematic review and meta-analysis.

METHODS

CONCLUSIONS:
•
Systematic review and meta-analysis
on the clinical relevance of HPR ,
observation studies 2003-2010
Outcome measures : cardiovascular
(CV) death, definite/probable stent
thrombosis (ST), nonfatal myocardial
infarction (MI), and a composite end
point of reported ischemic events.

According to the meta-analysis,
patients with HPR had a 3.4-fold
higher risk for CV death compared
with patients with normal ADP
reactivity (odds ratio 3.35, 95% CI
2.39-4.70, P < .00001).
High on-clopidogrel platelet reactivity,
measured by an ADP-specific platelet
function assay, is a strong predictor of
CV death, MI, and ST in patients after
percutaneous coronary intervention.
•

RESULTS
•
Twenty studies , 9,187 patients
High on-clopidogrel platelet reactivity
•
MI:
3.00 [2.26-3.99,
STEMI:
4.14 [2.74-6.25]
Composite:
4.95 [3.34-7.34]
P < .00001 for all cases


ISSUES

Methodology
Definition of HPR between studies
Meta-analysis/Review


Aradi D , et al Am Heart J. 2010 Sep;160(3):543-51.
VerifyNow Assay
• Whole blood, closed-tube sampling with no pipetting required
• Assay results in less than 5 minutes (assay time)
• Good correlation with LTA and VASP
Mixing
Chamber
Agonists:
Aspirin Assay – AA
P2Y12 assay – ADP + PGE1
GpIIbIIIa assay – iso-TRAP
Light
Source
Agonist
+
Platelets in whole blood
maximally activated by
agonist in mixing chamber
Fibrinogen-coated beads
Agglutinated beads
aggregate in clusters
VerifyNow Point-of-Care Platelet Function Assay*
Correlates with Clinical Outcomes Post-DES Deployment
1.00
99.0%
Event-free Survival
0.95
P=0.004
91.5%
0.90
0.85
Not high platelet reactivity
High platelet reactivity
0.80
0
*pre-discharge
Price et al. Eur Heart J. 2008;29:992.
50
100
Time (days)
150
200
DES Thrombosis and Residual Platelet
Reactivity
Percent of patients free from
definite or probable ST (%)
100
98
98 1
96
94
92
Responders
Nonresponders*
90
88
91 3
86
84
Log rank P<0.001
82
80
0
30
60
90
120
150
180
Time(Days)
(days)
Time
Buonamici P et al. J Am Coll Cardiol. 2007;49:2312-2317.
*Residual platelet aggregation (10 µM ADP) ≥70%
OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)
Impact of high clopidogrel maintenance dosing on platelet
function in DM patients with suboptimal clopidogrel response
VerifyNow P2Y12 substudy
PRU
%IPA
300
p=0.009
P2Y12 Reactivity Units
Platelet inhibition (%)
80
60
40
20
p=0.007
250
200
150
100
50
0
0
75 mg
150 mg
Angiolillo DJ et al. Circulation. 2007;115:708-16.
Angiolillo DJ et al. Am J Cardiol. 2008;101:440-5.
75 mg
150 mg
Primary Results of The Gauging
Responsiveness with A VerifyNow
Assay - Impact on Thrombosis And
Safety Trial
GRAVITAS
AHA 2010
Matthew J. Price, MD
On behalf of the GRAVITAS Investigators
Point-of-Care Platelet Function Testing: Current Status
• At least 7 studies involving more than
3,000 patients have concluded that high
residual (on-clopidogrel) platelet reactivity
measured by the VerifyNow P2Y12 test is
associated with poor clinical outcomes after
PCI.
• A treatment strategy for patients with high
residual platelet reactivity has not been
tested in a large, randomized, clinical trial.
GRAVITAS: Primary Hypothesis
• High-dose clopidogrel for 6 months is
superior to standard-dose clopidogrel
for the prevention of adverse CV
events after PCI in patients with high
residual reactivity.
GRAVITAS Study Design
Elective or Urgent PCI with DES*
VerifyNow P2Y12 Test 12-24 hours post-PCI
PRU ≥ 230
R
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)
Inclusion and Exclusion Criteria
Major Inclusion Criteria
•DES for the treatment of stable or unstable
CAD*
Major Exclusion Criteria
• Bleeding event or other major complication
prior to platelet function testing
• Recent glycoprotein IIb/IIIa inhibitor
* STEMI pts were permitted after a protocol modification during the trial
GRAVITAS Patient Flow
5429 patients screened with VerifyNow P2Y12
12-24 hours post-PCI
2214 (41%) with high residual
platelet reactivity
(PRU ≥ 230)
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105
3215 (59%) without high
residual platelet reactivity
(PRU < 230)
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Bleeding Events: Safety Population
Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring
blood or fluid replacement, inotropic support, or surgical intervention
Moderate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding
P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose
Secondary Comparison: High vs. Not High Reactivity
Treated with Clopidogrel 75-mg daily
Observed event rates are listed. P value by log-rank test.
CV Events and Post-PCI PRU In Patients With High and
Not High Reactivity Treated With Clopidogrel 75-mg Daily
500
Red dots: patients with
CV death, MI, or ST
400
PRU
300
12 - 24 hrs
post-PCI
230 PRU
200
100
0
N=1105
High Residual
Reactivity
ITT population
N= 586
Not High
Residual Reactivity
GRAVITAS: Summary
• Compared with standard-dose therapy, high-dose
clopidogrel achieved a modest
pharmacodynamic effect in patients with high
residual reactivity.
• In patients with high residual reactivity measured
after PCI, 6-months of high-dose clopidogrel did
not reduce the rate of cardiovascular death, nonfatal MI, or stent thrombosis and did not increase
GUSTO severe or moderate bleeding.
GRAVITAS: Possible Explanations
• Underpowered: patients low-risk, low event rates?
• Given HR of 1.01 with more than 2,200 patients,
unlikely that a larger trial would show a clinically
meaningful benefit
• Pharmacodynamic effect of the intervention was
too weak?
• Stronger intervention and/or goal-directed
therapy with serial measurements merit study
(TRIGGER-PCI; ARCTIC; TARGET-PCI)
GRAVITAS does not support a
treatment strategy of high-dose
clopidogrel in patients with high
residual reactivity identified by a
single platelet function test after PCI.
TRIGGER-PCI
Courtesy of F.J. Neumann
Successful PCI with DES without major complication and NO GPIIb/IIIa use
Post-PCI VerifyNow P2Y12 Assay (PRU) 2 - 4 hours after 1st MD of
clopidogrel 75 mg at day 1 post-PCI
N ~ 8800
Non-Responder
Yes
PRU ≥ 208?
No
Responder
PRU ≥ 140?
Random Selection
A
N = 1075
B
N = 1075
C
N = 550
D
E
N = 550
“Prasugrel arm”
“Clopidogrel arm”
“Prasugrel arm”
“Clopidogrel arm”
Prasugrel 60 mg LD
Prasugrel 10 mg MD
+ Clopidogrel placebo
Placebo LD
Clopidogrel 75 mg MD
+ Prasugrel placebo
Prasugrel 60 mg LD
Prasugrel 10 mg MD
+ Clopidogrel placebo
Placebo LD
Clopidogrel 75 mg MD
+ Prasugrel placebo
“Standard Therapy”
Clopidogrel 75 mg
Platelet function substudy:
VerifyNow Assessment at day 2 (2 – 4 h after 1st MD of study drug)
Clinical Follow-up and VerifyNow Assessment at 90 days, 180 days
Primary Endpoint: 6 month CV Death and MI
ASCET (PFA-100)
AHA SS 11/2010
Primary Objective: Clinical outcome
(composite USA+MI+CVA+Death) over
2 years in patients with “stable”
symptomatic CAD on ASA therapy as
related to initial aspirin response via
PFA-100
 Secondary Objective: Investigate the
difference in composite event rate
between patients treated with ASA vs
Clopidrogel

ASCET (PFA-100)

Results

AHA SS 11/2010
Conclusions
 Composite Endpoint
 No difference in
when ASA no RPR
(n=373) 10.5% vs ASA
high RPR (n=130)
13.1% p=0.44
 Composite Endpoint
with RPR on ASA when
treated with ASA 13.1%
(n=130) or Clopidrogel
7.8% (n=129) p=0.16
 26% of patients had
RPR while on ASA by
PFA-100
composite endpoints
 RPR by PFA-100 did
NOT predict clinical
outcome
 Trend seems to
indicate fewer
endpoints using
clopidrogel in patients
with high RPR vs.
ASA
ASCET STUDY DESIGN FLOWCHART
ASA 160 mg QD
N=503
Angiographic
CAD w or w/o
PCI
N=1001
Composite
endpoint of
USA+MI+CVA
+Death
ASA 160
mg/d x 7
days then
PFA-100
Clopidrogel
75mg QD
N=503
ASA compliance was measured by TXAB2 levels
Platelet reactivity after clopidrogrel treatment assessed with point-ofcare analysis (MEA) and early drug-eluting stent thrombosis.
HYPOTHESIS:
Does platelet reactivity to clopidogrel
assessed with multiple electrode
platelet aggregometry (MEA) correlate
with the risk of early drug-eluting stent
thrombosis?
METHODS:



2/07-2/08, 1608 patients
Before PCI, all patients received 600
mg clopidogrel. The ADP-induced
platelet aggregation was assessed in
whole blood with a MEA.
The primary end point was definite ST
at 30 days.
CONCLUSIONS:
RESULTS:

Compared with normal responders (n
= 1,285), low responders (MEA upper
qunitile, n = 323) had a significantly
higher risk of:
 definite ST within 30 days (2.2%
vs. 0.2%; odds ratio [OR]: 9.4;
95% confidence interval [CI]: 3.1
to 28.4; p < 0.0001)
 Mortality rates were 1.2% in low
versus 0.4% in normal
responders (OR: 3.2; 95% CI: 0.9
to 11.1; p = 0.07).
 Composite of death or ST was
higher in low versus normal
responders (3.1% vs. 0.6%; OR:
5.1; 95% CI: 2.2 to 11.6; p <
0.001).
Low response to clopidogrel assessed with MEA is significantly associated with an
increased risk of ST. Further studies are warranted to evaluate the ability of MEA to
guide antiplatelet therapy in patients undergoing PCI.
Sibbing D et al, J Am Coll Cardiol. 2009 Mar 10;53(10):849-56.
Clopidogrel response status assessed with Multi-plate point-of-care
analysis (MEA) and the incidence and timing of stent thrombosis
over six months following coronary stenting.

6 Month followup data from Sibbing D et al, J Am Coll Cardiol. 2009
Mar 10;53(10):849-56.
Cumulative incidence of definite ST within six months was significantly
higher in low responders [2.5% vs. 0.4%; OR 6.5; 95% CI, 2.4-17.0;
P<0.001].
 The combined incidence of definite or probable ST was higher as well in low
vs. normal responders [4.1% vs. 0.7%; OR 5.8; 95% CI, 2.8-12.3;
P<0.0001].
 A significant inverse correlation of MEA values and the timing of definite or
probable ST (in days) was observed (Spearman coefficient = -0.45; P=0.04)
CONCLUSION
 MEA measurements are highly predictive for the occurrence of ST
during the first six months following coronary stenting.
 In the majority of clopidogrel low responders suffering ST, the ischemic
event occurs early in the course after the procedure.

Sibbing D, , et al Thromb Haemost. 2010 Jan;103(1):151-9.
Epub 2009 Oct 26.
VASP Guided PCI
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
Courtesy of Angiolillo
Bonello et al. J Am Coll Cardiol 2008
VASP and LTA: limitations
Not-user friendly
 Time consuming
 Require experienced lab personnel
 Require expensive equipment
 Not universally available
 Overall,….expensive

Courtesy of Angiolillo
Mechanism of Clopidogrel Response
Variability
Limited absorption capacity with ceiling effect at 600mg loading dose
Clopidogrel
Bisulfate
Intestinal
Absorption
?
P-glycoprotein
(MDR1 3435T genotype)2
Esterases
85%
Inactive Carboxylic Acid
Metabolite
15%
Hepatic P450
Cytochromes
CYP3A4
lipophilic statins
CYP3A5
Genetic polymorphisms
Genetic polymorphisms
CYP2C19
CYP1A2
Smoking, proton pump inhibitors
CYP2B6, 2C19
Multistep Conversion
Active Thiol Metabolite
P2Y12 Receptor
Inhibition of Platelet Aggregation (Wide Response Variability)1
~30%
75mg/day for 30days
Post-PCI
~30%-40%
75mg/day for 5-7days
volunteers
~30%-40%
300 mg load
Post-PCI
~30%-50%
600 mg load
Post-PCI
~1.4x
150mg/d vs. 75mg/d
for 30days Post-PCI3
1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9.
Residual Platelet Aggregation Stratified by
CYP2C19*2 Genotype
60
CYP2C19 *1/*1
CYP2C19 *1/*2
CYP2C19 *2/*2
40
20
0
Baseline
Trenk D et al. J Am Coll Cardiol. 2008:51:1925-1934.
Before PCI
Pre-discharge
Clopidogrel Non-Responsiveness
Correlation With CYP3A4 Enzyme Activity
Nonresponders (25%)
80 9
5.0
Responders (75%)
2.7 1.0
60
1.9 0.7
40
2.0
20
0
3.0
1.0
Platelet aggregation
4 hours post clopidogrel*
*450 mg PO (P=0.0002); **P=0.15
Lau WC et al. J Am Coll Cardiol. 2003;41:225A.
CYP3A4**
activity
0
exhaled/h (%)
37 20
4.0
2
80
14CO
Aggregation (%)
100
Pharmacogenetics of antiplatelet therapy
CYP2C19 and CVD, MI, or Stroke
PRASUGREL
CLOPIDOGREL
14
14
Carriers
CYP2C19 Reduced-Function Allele
Carriers
13
12.1
12
12
11
11
10
9
8.0
Non-carriers
8
7
6
5
4
Hazard Ratio 1.53
3
0
30
90
Carriers
8.5
CYP2C19
Reduced-Function
Allele Carriers
7
6
5
4
2
Hazard Ratio 0.89
(95% CI 0.60-1.31)
360
270
180
Days After Randomization
450
P=0.27
N=1,466
1
Number at Risk:
Non-Carrier
Carrier
8
P=0.014
0
9.8
9
3
N=1,477
Non-carriers
10
(95% CI 1.07-2.19)
2
1
CV Death, MI, or Stroke (%)
CV Death, MI, or Stroke (%)
13
0
0
30
90
1048 991
407 383
982
376
180
270
360
Days After Randomization
450
Number at Risk:
1064 1009
999
980
870
755
542
395 364
360
348
306
270
181
* Carriers ~30% of the population
Non-Carrier
Carrier
Courtesy of Angiolillo
951
364
849
320
750
276
541
188
Mega et al. NEJM 2009
Strategies to Improve/Overcome
Clopidogrel Response

Increase clopidogrel dose (What data do
we believe?? GRAVITAS implies NO!)

Prasugrel! New pharmacologic agents
coming….(ticagrelor, AZD6140, cangrelor)

Is there a role for CYP inducers (St. John’s
Wort, etc.) to enhance conversion?

Triple antiplatelet regimens (cilostazol,
dipirydamole)?
Learning Objectives

Understand the key clinical data related
to platelet function testing in guiding
clinical decision making
 OPTIMUS
 GRAVITAS
 TRIGGER-PCI
 ASCET
 MEA Studies (JACC 2010, TH 2010)
 Mega et al, NJEM 2009
Learning Objectives

Understand the key controversies
related to these data…
 Is there really a standard definition of
“responsiveness or resistance”
 Cut points matter, and we fundamentally DO
NOT have a consensus
 What is the best test? Do we combine
platelet function testing and Genotype
testing in a POC method?
Learning Objectives
Can one incorporate this data into your day
to day clinical practice and do we have
GUIDELINES supporting this?
 ISTH Consensus Statement:

Do not test ASA or clopidogrel resistance outside of clinical trials or to
change therapy based on such testing.
 Why? NO clinically meaningful, standardized definition of resistance based on
data linking therapy-dependent laboratory tests to clinical outcomes .
 Correct treatment of patients whose platelets are hyporesponsive to
antiplatelet agents is unknown.
Guidelines Continued

AHA/ACC/ASCI:

Daily ASA therapy after PCI for patients without ASA
‘‘resistance,’’ but no definition of resistance is offered.

Class IIb, level C recommendation
For clopidogrel, the guidelines state that ‘‘ . . .in patients
in whom stent thrombosis may be catastrophic or lethal.
. . 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.’’ What about GRAVITAS???

Method to assess platelet inhibition is not described.
HOW DO WE MOVE FORWARD?
We need adequately powered clinical trials to….
1. Determine what is the most simple, inexpensive, and rapid test of platelet
function and/or metabolism genotyping that best predicts clinical outcomes of
antiplatelet therapy for specific patient subgroups? AND STICK TO IT….results
in trials discussed seem to vary by assay!
2. Determine if individual outcomes are affected when treatment is
changed in response to the testing results. i.e. what is our “threshold” or
“cutoff” values
3. What the benefit of supplementary treatment with an agent having a different
mechanism of action in patients with known hypo-response to a given
antiplatelet agent?
4. With emerging agents, is any of this ultimately going to matter?
Adapted from H. Aboul-Enein, Benha Faculty of Medicine