Should we Monitor Anti-Platelet Treatment? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular...
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Transcript of Should we Monitor Anti-Platelet Treatment? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular...
Should we Monitor Anti-Platelet Should we Monitor Anti-Platelet Treatment?Treatment?
Rabih R. Azar, MD, MSc, FACCRabih R. Azar, MD, MSc, FACC
Director of Cardiovascular ResearchDirector of Cardiovascular Research
Hotel Dieu de France HospitalHotel Dieu de France Hospital
Associate Professor of MedicineAssociate Professor of Medicine
Saint Joseph University School of MedicineSaint Joseph University School of Medicine
Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?
1. Is there a reliable test to measure platelet function?
2. Is there a variability in the response to anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
How to Measure Platelets Aggregation?
• Platelets function is measured in vitro by light transmission aggregometry
• This method is considered the gold standard
• Disadvantages:
– Limited reproducibility
– Complex sample preparation
– Cannot be routinely performed
WHAT ARE THE ALTERNATIVES WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION TO LIGHT TRANSMISSION
AGGREGOMETRY?AGGREGOMETRY?
Rapid Platelet Function AssayRapid Platelet Function AssayPlateletworksPlateletworks
An alternative to light transmission An alternative to light transmission aggregometryaggregometry
PlateletworksPlateletworks
Excellent Correlation Between Light Transmission Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test Aggregometry and Plateletworks Test ((Cathet Cardiovasc Intervent Cathet Cardiovasc Intervent
2001;53:346-351)2001;53:346-351)
VERIFYNOW Point of Care Test
It measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed
It thus mimics light transmission aggregometry
Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance
The VASP test: A Specific Test to Measure P2Y12 Inhibition
•VASP is not phosphorylated at basal state
•PGE1 activates VASP phosphorylation
•ADP inhhibits VASP phosphorylation via the P2Y12 receptor
•Thus high VASP = active form of P2Y12 receptor
•Low VASP (high VASP-P) = inhibition of P2Y12 receptor
Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?
1. Is there a reliable test to measure platelet function?
2. Is there a variability in the response to anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.
Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment
% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)
97.597.5
92.592.5
87.587.5
82.582.5
77.577.5
72.572.5
67.567.5
62.562.5
57.557.5
52.552.5
47.547.5
42.542.5
37.537.5
32.532.5
27.527.5
22.522.5
17.517.5
12.512.5
7.57.5
2.52.5
2020
1515
1010
55
00
Nu
mb
er
Nu
mb
er o
f o
f Pati
en
tsP
ati
en
ts
Bleeding riskBleeding risk Ischemic riskIschemic risk
Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days)48% inhibition at 30 days)
Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)aggregation compared to baseline)
ACC/AHA Guidelines (2005)ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Percutaneous Coronary Interventions:
Oral Antiplatelet TherapyOral Antiplatelet Therapy
Prevalence of inadequate response to Prevalence of inadequate response to clopidogrel 4% to 30%clopidogrel 4% to 30%
Nguyen et al. J Am Coll Cardiol 2005;45:1157-64Nguyen et al. J Am Coll Cardiol 2005;45:1157-64
Cellular FactorsCellular Factors• Accelerated platelet turnoverAccelerated platelet turnover
•• Reduced CYP3A metabolic activityReduced CYP3A metabolic activity•• Increased ADP exposure Increased ADP exposure •• UpUp--regulation of the P2Yregulation of the P2Y1212 pathwaypathway•• UpUp--regulation of the P2Yregulation of the P2Y11 pathway pathway •• UpUp--regulation of P2Yregulation of P2Y––independent pathwaysindependent pathways
(collagen, epinephrine, TXA(collagen, epinephrine, TXA22, thrombin), thrombin)
Clinical FactorsClinical Factors• Failure to prescribe/poor complianceFailure to prescribe/poor compliance
•• UnderUnder--dosing dosing •• Poor absorptionPoor absorption•• DrugDrug--drug interactions involving CYP3A4drug interactions involving CYP3A4•• Acute coronary syndromeAcute coronary syndrome•• Diabetes mellitus/insulin resistanceDiabetes mellitus/insulin resistance•• Elevated body mass indexElevated body mass index
Genetic FactorsGenetic Factors• Polymorphisms of CYPPolymorphisms of CYP
•• Polymorphisms of Polymorphisms of GPIaGPIa•• Polymorphisms of P2YPolymorphisms of P2Y1212
•• Polymorphisms of Polymorphisms of GPIIIaGPIIIa
Clopidogrel Response VariabilityClopidogrel Response Variability
Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .
Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?
1. Is there a reliable test to measure platelet function?
2. Is there a variability in the response to anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness
Clinical RelevanceFunctional ParameterN
Stent thrombosis↑shear-induced platelet aggregation49Ajzenberg et al.JACC 2005
Stent thrombosis↑P2Y12 reactivity ratio; ↑platelet
aggregation;
↑stimulated GPIIb/IIIa expression
120Gurbel et al.JACC 2005
Stent thrombosis↑P2Y12 reactivity ratio (VASP-levels)36Barragan et al. CCI 2003
Stent thrombosis↓inhibition of platelet aggregation105Mueller et al.
Thromb Haemost2003
Angiolillo DJ et al. Am J Cardiov Drugs. 2007.
Stent ThrombosisStent Thrombosis
Clinical RelevanceFunctional ParameterN
Post-PCI ischemic events (30 days)
↑ platelet aggregation292Cuisset et al.JACC 2006
Post-PCI ischemic events (30 days)
Post-PCI ischemic events (3 months)
Post-PCI ischemic events (12 months)
↑ platelet aggregation (3rd & 4th quartiles)
↓ platelet inhibition
↑ platelet aggregation
802
379
100
Hocholzer et al.JACC 2006
Geisler et al.Eur Heart J 2006
Bliden et al.JACC 2007
Post PCI-myonecrosis↑ clopidogrel/aspirin-resistant patients120Lev et al.JACC 2006
Post-PCI ischemic events (30 days)
↑ platelet aggregation106Cuisset et al.J Thromb Haemost2006
Myonecrosis and inflammation marker release
↑ periprocedrual platelet aggregation 120Gurbel et al.Circulation 2005
Post-PCI ischemic events(6 months)
↑ periprocedrual platelet aggregation 192Gurbel et al.JACC 2005
Post-primary PCI ischemic events (6 months)
↑ platelet aggregation (4th quartile)60Matezky et al.Circulation 2004
Angiolillo DJ et al. Am J Cardiov Drugs. 2007.
PostPost-- Stent Ischemic Events and Stent Ischemic Events and PeriproceduralPeriprocedural InfarctionInfarction
Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness
Platelet Reactivity And Early Drug-Eluting Stent Thrombosis
• 1608 consecutive patients with CAD and planned drug eluting stent implantation
• All received a loading of 600 mg of clopidogrel prior to stenting
• Blood was obtained directly prior to PCI
• ADP induced platelet aggregation was assessed with a point of care assay: Multiple Electrode Platelet Aggregometry (MEA) (principle of impedance aggregometry)
• Poor response to clopidogrel was prospectively defined by a cutoff point at the upper quintile of MEA measurments
Sibbing et al. JACC 2009;53:849-56
Clinical Characteristics Associated With Low Response to Cloopidogrel
normal response Low response p
n = 1285 n = 323
BMI 27.3 + 4.2 28.3 + 4.9 < 0.001
Ejection Fraction 54.9 + 10.9 53.2 + 12.6 0.03
Diabetes mellitus 27.4% 34.1% 0.02
Active smokers 12.1% 18.6% 0.002
ACS 31.4% 39.9% 0.001
Platelet count 213 + 62 236 + 64 < 0.001
Time from loading (h) 4 (2-15.5) 3 (2-7) < 0.001
Sibbing et al. JACC 2009;53:849-56
Clinical Outcome According to Clopidogrel Response
Sibbing et al. JACC 2009;53:849-56
P = < 0.001 0.07 0.02 0.005 0.03
Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?
1. Is there a reliable test to measure platelet function?
2. Is there a variability in the response to anti-platelet therapy?
3. Is a poor response to anti-platelet indicative of adverse cardiovascular outcome?
4. Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?
TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET
REACTIVITY MONITORING DECREASE EARLY STENT THROMBOSIS
L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli.
Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCELaboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCEService de cardiologie, Hôpital d’aubagne, Aubagne; FRANCEService de cardiologie, Clinique clairval, Marseille; FRANCEService de cardiologie, Clinique Bouchard, Marseille; FRANCEService de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCELaboratoire de statistique, Faculté de la Timone, Marseille; FRANCEService de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE
Am J Cardiol 2009;103:5-10
DESIGN
Non-emergent PCI : ACS and Stable angina (n= 1122)
Loading dose (LD) -ASA 250mg -Clopidogrel 600mg
VASP ≥ 50%
Randomization(n=429)
CONTROL (n =215) VASP-guided LD (n =214)
Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose -ASA 160 mg
-Clopidogrel 75 mg
1° endpoint: Definite stent thrombosis (ARC definition)
2° endpoints: MACE including CV death, MI and U-TVRTIMI major and minor bleeding at 30 days
Platelet reactivity monitoring
VASP after first LD 66 ± 11 67 ± 10
VASP after sensitization 37 ± 12†
17 patients (8%)
† p <0.01
Timing of early stent thrombosis
All early stent thrombosis occured during the first 7 days
Am J Cardiol 2009;103:5-10
Secondary end-point: MACE
Endpoint n, (%) Control (n= 214)
VASP-guided (n= 215)
p
Cardiovascular death 4 (1.8) 0 0.06
Myocardial infarction 10 (4.8) 1 (0.5) 0.01
Urgent revascularization 5 (2.3) 0 0.06
All MACE 19 (8.9) 1 (0.5) < 0.001
M. Valgimigli, MD, PhD
On behalf of 3T/2R
Investigators
Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel
Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel
< 40% platelet inhibition 600 mg clopidogrel LD at least 2 hours before 300 mg clopidgrel LD at least 6 hours before 75 mg clopidogrel MD for at least 7 days
Aspirin reaction units (ARU) >550 ASA orally ≥80 mg for at least 5 days i.v. 500 mg ASA 15 mins or more before
Response evaluationResponse evaluation
Aspirin Poor Response
Clopidogrel Poor Response
And/ Or
Or
Or
Valgimigli et al. Cardiovasc Drugs Ther. 2008 Aug;22(4):313-20
Aspirin + Clopidogrel UFH or Bivalirudin
Aspirin + Clopidogrel UFH or Bivalirudin
Tirofiban*Tirofiban*Tirofiban* PlaceboPlaceboPlacebo
Trial DesignTrial Design
1:11:1
*: 25 g/ kg in 3 mins, followed by an 14-24 hour infusion at 0.15 g/ kg/ min
Blood sampling: Hb, PLT, Tp; CK-MB mass @ 6, 12, 18 or 24 hrs Clinical F-UP: 30-d, 4, 8 and 12 months
Bail-out Tirofiban
Double Blind
Bail-out Placebo
30-Day OutcomesEfficacy Endpoints
(CEC adjudicated)
30-Day OutcomesEfficacy Endpoints
(CEC adjudicated)
-5
1 0
2 5
4 0
MACEMACE DeathDeath MIMI Definite STDefinite ST
P=0.006P=0.006
Placebo Tirofiban
40%
10%
25%
uTVRuTVR
P=0.006P=0.006
37%37%
21%21%
Tailored GP IIb/IIIa Receptor Blockade According to Clopidogrel Resistance
• 149 Clopidorel resistant patients
• Resistance defined by inhibition < 30% using light transmission aggregometry
• Elective PCI
• Randomized to :
– Conventional therapy: 600 mg Clopidogrel
– Active therapy: 600 mg Clopidogrel + GP IIb/IIIa blockade
• Combined end-point of: death, periprocedural MI, stent thrombosis and recurrent ACS at 1 month
Cuisset et al. JACC Interventions. 2008;1:649-53
Events According to GPIIb/IIIa Blockade in Clopidogrel Resistant Patients
P=0.006
Cuisset et al. JACC Interventions. 2008;1:649-53
How Can We Solve the Problem Caused by Clopidogrel Resistance?
Is the answer by increasing the dose?
P < 0.05 vs. 300 mg LD
A Faster Onset of Action Was Seen with Higher Clopidogrel Loading Regimens
A Faster Onset of Action Was Seen with Higher A Faster Onset of Action Was Seen with Higher ClopidogrelClopidogrel Loading RegimensLoading Regimens
The ALBION trial
0
10
20
30
40
50
1 2 3 4 5 6
300 mg LD600 mg LD900 mg LD
Maximum Inhibition of Platelet Aggregation (5 µM ADP)
Time (h)
(%) Inhibition
Shortened time to reach the highest level of inhibition of the 300 mg LD
Montalescot G et al. J Am Coll Cardiol 2006;48:931-8
11
CURRENT – OASIS-7 Study Design
Clopidogrel high-dose group600 mg LD Day 1 followed
by 150 mg from Day 2 to Day 7; 75 mg from Day 8 to 30
Clopidogrel standard-dose group300 mg LD Day 1 followed
by 75 mg from Day 2 to Day 7;75 mg from Day 8 to 30
RANDOMIZE RANDOMIZE
ASA low-dose groupAt least 300 mg Day 1;
75–100 mgfrom D2 to D30
ASA high-dose groupAt least 300mg Day 1;
300–325 mgfrom D2 to D30
ASA high-dose groupAt least 300 mg Day 1;
300–325 mgfrom D2 to D30
ASA low-dose groupAt least 300 mg Day 1;
75–100 mgfrom D2 to D30
14,000 patients with UA/NSTEMI planned for early invasivestrategy, i.e. intended for PCI as early as possible within 24 h
RANDOMIZE
Primary endpoint: CV death, MI, stroke at 30 days
ASA Dose ComparisonPrimary Outcome and Bleeding
ASA
75-100 mg
ASA
300-325 mg
HR 95% CI P
CV Death/MI/Stroke
PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76
No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44
Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47
Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37
TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71
CURRENT Major Bleed 2.3 2.3 0.99 0.84-1.17 0.90
CURRENT Severe Bleed 1.7 1.7 1.00 0.83-1.21 1.00
No other significant differences between ASA dose groups
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients
Day 30 Clopidogrel
StandardN=8684
%
Double N=8548
%
Hazard Ratio
95% CI P value
Stent Thrombosis 2.3 1.6 0.71 0.57-0.89 0.002
Definite 1.2 0.7 0.58 0.42-0.79 0.001
MI 2.6 2.0 0.78 0.64-0.95 0.012
MI or stent thrombosis 3.7 3.0 0.80 0.68-0.94 0.008
CV Death 1.9 1.9 0.96 0.77-1.19 0.68
Stroke 0.4 0.4 0.88 0.55-1.41 0.59
CV Death/MI/Stroke 4.5 3.9 0.85 0.74-0.99 0.036
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
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
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 0.31
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
Sanofi-aventis-BMS Confidential- For Internal Purposes Only- Not for Further Copying or Distribution
TRITON: Primary Efficacy and Safety Endpoints TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Monthsin Entire ACS Cohort at 15 Months
Wiviott SD, et al. N Engl J Med 2007;357:2001-15
0
5
10
15
0 30 60 90 180 270 360 450
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
Prasugrel
Clopidogrel1.82.4
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
HR 0.81(0.73-0.90)
P<0.001
138events
NNT = 46
HR 1.32(1.03-1.68)
P=0.03
35events
NNH = 167
Should we Monitor Anti-Platelet Treatment?Should we Monitor Anti-Platelet Treatment?
FACTS:
1- More potent anti-platelet therapy is associated with better outcome
2- But it is also associated with more bleeding !!!
WHAT TO DO IN PRACTICE:
1- Give all patients potent drugs: double dose clopidogrel, or better: prasugrel. Proven to be better, but risk of bleeding
2- Monitor platelet response and adjust therapy accordingly. Waiting confirmation in large clinical trials (GRAVITAS)