The Role of New Antiplatelet Agents and Antiplatelet Testing Kathleen A. Lusk, Pharm.D., BCPS Department of Pharmacy Practice University of the Incarnate Word Feik School of Pharmacy April 12, 2014
The Role of New Antiplatelet Agents and Antiplatelet Testing
Kathleen A. Lusk, Pharm.D., BCPS Department of Pharmacy Practice University of the Incarnate Word
Feik School of Pharmacy April 12, 2014
Pharmacist Learning Objectives
• List the adverse effects, monitoring parameters, and contraindications for the available antiplatelet agents.
• Describe the role of the new antiplatelet agents in the treatment of ischemic heart disease.
• Discuss the role of antiplatelet testing and determine its potential place in therapy.
• Determine appropriate therapeutic recommendations for patients with platelet nonresponsiveness.
Technician Learning Objectives
• List the generic and brand names for the available antiplatelet agents.
• Identify the indications for the available antiplatelet agents.
• List the contraindications for the available antiplatelet agents.
Patient Case MM is a 85 yo female who presents to the ED complaining of chest pain that occurred while she was sleeping. She describes the chest pain as “tightness” in the center of her chest. The pain radiates to her left arm and back. She rates the pain as 9/10 . In the ED she is diagnosed with an NSTEMI and is taken to the cardiac catheterization lab for PCI with a DES.
PMH: HTN x 40 years (home BP 140-150s)
HLD x 35 years
CAD s/p PCI with DES to LAD (6 months ago)
GERD x 2 years
Meds: Aspirin 81 mg PO daily
Atorvastatin 40 mg PO daily
Clopidogrel 75 mg PO daily
Lisinopril 20 mg PO daily
Metoprolol succinate 50 mg PO daily
NTG 0.4 mg SL q5 minutes prn CP
Omeprazole 40 mg PO daily
Vitals: BP 170/98 mmHg HR 108 RR 23 Temp 35.2oC SaO2 94% (RA) Ht 166 cm Wt 65 kg
Platelet Biology
• Platelet = thrombocyte
• Normal range: 150,000-350,000 cells/µL
• Principle function: prevent bleeding
– Involved in hemostasis
– Ischemic complications in CV disease
N Engl J Med 2008. 359(9):938-49. Clinical Medicine: Cardiology 2009;3:77-91. Department of Biostatistics & Epidemiology: College of Public Health, OUHSC; 2007 [18 Feb 2011; 3 Mar 2014].
Plaque Rupture and Thrombus Formation
1. Disruption of endothelial lining
Blood vessels lined with endothelial cells
↓
Blood flow ± vascular trauma exposes endothelial lining
↓
Exposure of thrombogenic substances to the circulating blood
J Biol Chem 1992; 267:13795-813. N Engl J Med 2008. 359(9):938-49.
Plaque Rupture and Thrombus Formation
2. Platelet Adhesion
Plaque rupture exposes circulating platelets to
adhesive proteins
↓
Platelets bind to adhesive proteins
J Biol Chem 1992; 267:13795-813. N Engl J Med 2008. 359(9):938-49.
Plaque Rupture and Thrombus Formation
3. Platelet Activation/Secretion
TXA2 and ADP secreted by platelets
↓
Activation of secondary messenger system
↓
Stimulation of neighboring platelets
↓
Secretion of additional TXA2 and ADP
J Biol Chem 1992; 267:13795-813. N Engl J Med 2008. 359(9):938-49.
Plaque Rupture and Thrombus Formation
4. Platelet shape change
Loss of discoid shape
↓
Conformational change in the platelet GP IIb/IIIa receptor
↓
GP IIb/IIIa receptor exposed and active
J Biol Chem 1992; 267:13795-813. N Engl J Med 2008. 359(9):938-49.
Inactive Platelet
Activated Platelet
http://biomed.brown.edu/Courses/BI108/BI108_2005_Groups/10/webpages/plateletslink.htm
Plaque Rupture and Thrombus Formation
5. Platelet aggregation
Fibrinogen binds to GP IIb/IIIa receptors on platelets
↓
Thrombus growth
J Biol Chem 1992; 267:13795-813. N Engl J Med 2008. 359(9):938-49.
Harrison's Principles of Internal Medicine, 18e. New York: McGraw-Hill; 2012. http://www.nottingham.ac.uk/nursing/practice/resources/cardiology/acs/platelet.php
P2Y12 Inhibitors
• Ticlopidine (Ticlid®)
• Clopidogrel (Plavix®)
• Prasugrel (Effient®)
• Ticagrelor (Brilinta®)
Psychosomatic Medicine 2001; 62(3):326-36.
P2Y12 Inhibitors Clopidogrel Prasugrel Ticagrelor
Active metabolite 2-oxo-clopidogrel R-138727 AR-C12490XX
Onset of action 300-600 mg: 6 hours
600 mg: 2 hours 75 mg: 48 hours
30 minutes 180 mg: 30 minutes
Metabolism Hepatic via CYP450
2C19
Rapid intestinal and serum to inactive
intermediate
Hepatic via CYP450 to active metabolite
Hepatic via CYP 3A4/5
Peak effect (time to max IPA)
300-600 mg: 20-37% at 6 hours
75 mg: 50-60% at 5-7 days
60 mg: 41% at 30 min
78-84% at 4 hours
180 mg: 88% at 2 hours
Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership;2013 December. Effient [package insert]. Eli Lilly and Co. Indianapolis, IN. 2012 November. Brilinta [package insert]. AstraZeneca LP. Wilmington, DE. 2013 March. J Am Coll Cardiol 2007;50: 1844-51. Eur Heart J 2006;27:1038-47.
P2Y12 Inhibitors Clopidogrel Prasugrel Ticagrelor
Loading dose 300-600 mg 60 mg 180 mg
Maintenance dose 75 mg daily 10 mg daily 90 mg BID
CI Active bleed Active bleed h/o stroke
Active bleed Hepatic impairment
Cautions CYP2C19 inhibitors Weight < 60 kg Age ≥ 75 years
Strong CYP 3A4 inducers/inhibitors ASA dose > 100 mg
ADRs Bleeding
Bleeding Hypertension
Headache Hyperlipidemia
Back pain
Bleeding Dyspnea
Ventricular pauses Bradycardia
Increased SCr Cough
Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership;2013 December. Effient [package insert]. Eli Lilly and Co. Indianapolis, IN. 2012 November. Brilinta [package insert]. AstraZeneca LP. Wilmington, DE. 2013 March. J Am Coll Cardiol 2007;50: 1844-51. Eur Heart J 2006;27:1038-47.
P2Y12 Inhibitors
Clopidogrel Prasugrel Ticagrelor
Monitoring Bleeding: every office visit and daily by patient Hemoglobin/hematocrit: baseline, q6-12 months, if bleed suspected
Monitoring (drug specific)
--- ---
Uric acid Serum creatinine
Dyspnea Ventricular pauses
Cost (30 days) $208.80 $297.36 $293.27
Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership;2013 December. Effient [package insert]. Eli Lilly and Co. Indianapolis, IN. 2012 November. Brilinta [package insert]. AstraZeneca LP. Wilmington, DE. 2013 March. J Am Coll Cardiol 2007;50: 1844-51. Eur Heart J 2006;27:1038-47.
TRITON-TIMI 38 Trial Population ACS + PCI (N=13,608)
Treatments Prasugrel 60 mg x 1, 10 mg daily Clopidogrel 300 mg x 1, 75 mg daily
1o endpoint/ Results
Composite: CV death, nonfatal MI, nonfatal stroke • Prasugrel 9.9% vs. clopidogrel 12.1% (p<0.001)
Safety endpoint/ Results
TIMI Major and Minor Bleeding • Prasugrel 5.0% vs. clopidogrel 3.8% (p=0.002)
Additional Safety Data
Previous stroke or TIA • More bleeding in patients with previous CVD and less benefit
> 75 years of age and weight < 60 kg • More bleeding in patients > 75 yo and < 60kg
Conclusion Prasugrel is a agent to consider; however, thorough patient assessment necessary.
N Engl J Med 2007. 357;20:2001-15.
TRILOGY ACS Trial
Population UA/NSTEMI without revascularization (N=9326)
Treatments Prasugrel 10 mg daily (>75 yo: 5 mg daily)
Clopidogrel 75 mg daily
1o endpoint/ Results
Composite: CV death, MI, stroke • All patients: prasugrel 18.7% vs. clopidogrel 20.3% (p=0.45) • < 75 yo: prasugrel 13.9% vs. clopidogrel 16.0% (p=0.21)
Safety endpoint/ Results
GUSTO severe /life threatening bleeding and TIMI major bleeding • No difference between groups or in age > 75 yo
Conclusions Prasugrel provided no benefit over clopidogrel No difference in bleeding
N Engl J Med 2012. 367;14:1297-309.
PLATO Trial
Population ACS (N=18,624)
Treatments Ticagrelor 180 mg x 1, 90 mg BID
Clopidogrel 300-600 mg x 1, 75 mg daily
1o endpoint/ Results
Composite: CV death, MI, stroke • Ticagrelor 9.8% vs. clopidogrel 11.7% (p<0.001)
2o endpoint/ Results
Stent thrombosis (definite) • Ticagrelor 1.3% vs. clopidogrel 1.9% (p=0.009)
Safety endpoint/ Results
Major Bleeding • Ticagrelor 11.6% vs. clopidogrel 11.2% (p=0.43) ADRs more common with ticagrelor • Dyspnea (13.8%), bradycardia (4.4%), ↑ uric acid, ↑ SCr
Conclusions Ticagrelor is an agent to consider, but thorough patient assessment necessary.
N Engl J Med 2009. 361;11:1045-57.
Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with ACS
Int J Cardiol 2011. 150(3):325-31.
Population ACS receiving ticagrelor or prasugrel
1o endpoint/ Results
Death, non-fatal MI, non-fatal stroke • No difference between groups
2o endpoint/ Results
Definite/probable stent thrombosis • Lower with prasugrel (OR 0.64 (0.43-0.93), p=0.020)
Safety endpoint/ Results
TIMI major bleeding • Higher with prasugrel (OR 1.43 (1.10-1.85), p=0.007)
Conclusions Similar efficacy between ticagrelor and prasugrel Weigh risk vs. benefit of prasugrel in regards to stent thrombosis and bleeding
Clopidogrel “Resistance”
• Persistent platelet activation despite clopidogrel use
Cardiovasc Res 2009;84(2): 309-16. Thrombosis Research 2007;120: 311-21.
Laboratory Endogenous mechanism preventing clopidogrel from
exerting full antithrombotic effects (Platelet reactivity)
Clinical Ongoing thrombotic events despite clopidogrel
(Vascular events)
Clopidogrel “Resistance”
• Incomplete blockade of the P2Y12 receptor
– Residual post-treatment P2Y12 activity with IPA
• Numerous signaling pathways mediate thrombotic complications
J Am Coll Cardiol 2005;45: 1157-69. Cardiovasc Res 2009;84(2): 309-16. Thrombosis Research 2007;120: 311-21.
Nonresponsiveness = failure to inhibit target
Nonresponsiveness ≠ treatment failure
Treatment failure vascular event
Clopidogrel Nonresponsiveness
Study # of
patients Pop-
ulation Loading
dose Maintenance
dose Non-responsiveness
prevalence
Angiolillo, et al Thromb Res
2005;115:101-8. 48 PCI 300 mg 75 mg 44%
Gurbel, et al. Circulation
2003;107:2908-13. 92 PCI 300 mg 75 mg 31-35%
Jaremo, et al. J Intern Med
2002;252:233-8. 18 PCI 300 mg 75 mg 28%
Lepantalo, et al. Eur Heart J
2004;25:476-83. 50 PCI 300 mg 75 mg 40%
Lev El, et al. J Am Coll Cardiol
2006;47:476-83. 150 PCI 300 mg --- 24%
Clopidogrel Nonresponsiveness
Study # of
patients Pop-
ulation Loading
dose Maintenance
dose Non-responsiveness
prevalence
Mobely, et al. Am J Coll Cardiol
2004;93:456-8. 50 PCI 300 mg 75 mg 30%
Mueller, et al. Thromb Haemost
2003;89:783-7. 115 PCI 600 mg 75 mg 5-11%
Dziewierz, et al. J Am Coll Cardiol
2007;49(24):2312-7.
31 CAD 300 mg --- 23%
Matetzky, et al. Kardil Pol
2006;62:108-17. 60 STEMI 300 mg 75 mg 25%
Angiolillo, et al. Diabetes
2005;54:2430-5. 52 Diabetes 300 mg 75 mg
Diabetes: 38% No diabetes: 8%
Mechanism of Nonresponsiveness
• Reduction in bioavailability
• Drug interactions
• Enhance platelet turnover
• Variable platelet response
Reduction in Bioavailability
• Noncompliance
– CHD and CVA: 22% of patients noncompliant
– CVD: up to 38% noncompliant
• Inadequate dose
• Poor absorption
– Intestinal defect or disease
Clinical Medicine: Cardiology 2009;3: 77-91. Psychosomatic Medicine 2001; 62(3):326-36. Thrombosis Research 2007;120: 311-21.
Drug Interactions
• Hepatic conversion to active metabolite
• 2C19 inhibition prevents conversion to active metabolite
2C19 Clopidogrel 2-oxo-clopidogrel
Clinical Medicine: Cardiology 2009;3: 77-91. Thrombosis Research 2007;120: 311-21.
Enhanced Platelet Turnover
• Increased production in bone marrow
• Introduction of new platelets not exposed to antiplatelet agents
– Transfusions
• Cigarette smoking
Clinical Medicine: Cardiology 2009;3: 77-91.
Variable Platelet Response
• Interpatient variability in platelet response to clopidogrel
– 83% of individual variance in response to clopidogrel
• Genetic variability may lead to suboptimal platelet response
– Increased number of P2Y12 receptors
– Polymorphisms of platelet receptors
Psychosomatic Medicine 2001; 62(3):326-36. Thrombosis Research 2007;120: 311-21.
Clopidogrel CYP2C19 Polymorphisms
Metabolism Genotype
Frequency (%)
White African
American Chinese
Extensive CYP2C19 *1/*1
(wild type) 74 66 38
Immediate CYP2C19 *1/*2 CYP2C19 *1/*3
26 29 50
Poor CYP2C19 *2/*2 CYP2C19 *2/*3 CYP2C19 *3/*3
2 4 14
Annu Rev Pharmacol Toxicol 2001;41:815-50.
Clinical Effects of Nonresponsiveness
• High platelet reactivity may increase CV event risk
• Limited data linking nonresponsiveness to CV events
Study
# of patients
Treatment Population 1o
endpoint Clinical implication
Matetzky, et al. Circulation 2004.
109; 3171-5. 60
Clopidogrel 300 mg x 1, 75 mg daily
STEMI + PCI MACE CV events:
Reduced IPA
Geisler, et al. Eur Heart J 2006. 27;
2420-5. 363
Clopidogrel 600 mg x 1, 75 mg daily
Symptomatic CAD +
intervention CV death
Adequate response 2.9% vs. low
response 18.2% (p=0.006)
J Am Coll Cardiol 2007; 49 (24):
2312-7. 804
Clopidogrel 600 mg x 1, 75 mg daily
ACS + PCI with DES
Stent thromb-
osis
Responders 2.3% vs. nonresponders 8.6%
(p<0.001)
EXCELSIOR Trial
Population CAD + elective stent placement (N=802)
Treatments Clopidogrel 600 mg x 1, 75 mg daily
1o endpoint/ Results
Composite: death, MI, or urgent target lesion revascularization
Safety endpoint/ Results
Composite: bleeding complications (TIMI major bleeding)
Conclusion Level of platelet aggregation before PCI in patients pre-treated with clopidogrel correlated with early outcome following procedure
J Am Coll Cardiol 2006; 48 (9): 1742-50.
1st Quartile (%)
2nd Quartile (%)
3rd Quartile (%)
4th Quartile (%)
P value
0.5 0.5 3.1 3.5 0.03
1st Quartile (%)
2nd Quartile (%)
3rd Quartile (%)
4th Quartile (%)
P value
1.4 1.0 1.0 0.5 0.83
Platelet Function Tests
• Single, standardized laboratory method lacking
• Prevalence of antiplatelet nonresponsiveness varies
– Laboratory method used
– Drug studied
– Dose prescribed
– Concomitant disease states
Clinical Medicine: Cardiology 2009;3: 77-91. Thrombosis Research 2007;120: 311-21.
Platelet Function Tests
• Light Transmittance Aggregometry (LTA)
• Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis
• Multiple electrode platelet aggregometry (MEA)
• Platelet Function Assay
• Image Analysis, Monitoring, Platelet, Adhesion, Cone & Plate Technology (IMPACT-R)
• Plateletworks
• VerifyNow P2Y12 test
Light Transmittance Aggregometry
Vasodilator-Stimulated Phosphoprotein
Phosphorylation Analysis
Abbreviation LTA VASP Analysis
Point of Care No No
Measurement P2Y12 platelet receptor
inhibition P2Y12 platelet receptor
inhibition
Results Inhibition of platelet
aggregation (IPA) Index of platelet reactivity
to ADP (PRI %)
Whole Blood Use No No
Blood Sample Volume +++ ++
Use in Thrombocytopenia No Yes
Use with GP IIa/IIIb Inhibitors
No Yes
Studies Supporting Use +++ ++
Technical Skill Needed +++ +++
Speed of Results + +
Clinical Medicine: Cardiology 2009;3: 77-91. Biomarkers Med 2011;5(1):43-51. Thrombosis Research 2007;120: 311-21.
Multiple Electrode Platelet
Aggregometry
Platelet Function Assay
Image Analysis, Monitoring, Platelet,
Adhesion, Cone & Plate Technology
Abbreviation MEA PFA IMPACT-R Point of Care Yes Yes Yes
Measurement Platelet accumulation
on electrodes
Platelet adhesion and aggregation under
high shear conditions
Platelet adhesion and aggregation under
arterial flow
Results Arbitrary aggregation
units (AU) plotted against time
Time needed to form a clot to block a membrane slit
Percentage of the well surface covered
by platelet aggregates (percentage SC)
Whole Blood Use Yes Yes Yes Blood Sample Volume + + +
Use in Thrombocytopenia
No Yes No
Use with GP IIa/IIIb Inhibitors
Yes No No
Studies Supporting Use ++ ++ + Technical Skill Required ++ ++ ++
Speed of Results ++ +++ ++
Clinical Medicine: Cardiology 2009;3: 77-91. Biomarkers Med 2011;5(1):43-51. Thrombosis Research 2007;120: 311-21.
Plateletworks VerifyNow P2Y12 Test
Abbreviation --- --- Point of Care Yes Yes
Measurement Single platelet
disappearance (SPD) ADP-induced platelet
aggregation
Results Percentage of IPA P2Y12 reaction units
(PRU) Whole Blood Use Yes Yes
Blood Sample Volume + + Use in
Thrombocytopenia No No
Use with GP IIa/IIIb Inhibitors
Yes No
Studies Supporting Use + ++ Technical Skill Required ++ +
Speed of Results +++ +++
Clinical Medicine: Cardiology 2009;3: 77-91. Biomarkers Med 2011;5(1):43-51. Thrombosis Research 2007;120: 311-21.
VerifyNow P2Y12 Test
Advantages • Point-of-care
• Automated
• Cartridge-based
• Mobility
• Whole blood used
• Results in minutes
• NPV > 95%
• Meta-analysis concluded risk of CV events increases with higher PRU
Disadvantages
• Cannot be used in patients with recent exposure to GP IIb/IIIa inhibitors
• No validation in diverse populations
• Only small studies correlating results to CV events
Clinical Medicine: Cardiology 2009;3: 77-91. Biomarkers Med 2011;5(1):43-51.
POPULAR Trial
JAMA 2010; 303 (8): 754-62.
Population CAD + schedule PCI with BMS or DES (N=1069)
Treatments
Clopidogrel 300-600 mg x 1, 75 mg daily Platelet function tests: LTA, IMPACT-R, VerifyNow P2Y12, Plateletworks, Dade PFA collage/ADP test cartridge, Innovance PFA P2Y PFA 100
1o endpoint/ Results
Composite: death, nonfatal MI, stent thrombosis, ischemic stroke Assessed platelet function tests’ ability to distinguish between patient with or without ischemic events • Able to distinguish between patients ± ischemic events
o LTA, VerifyNow P2Y12, Plateletworks, • Unable to discriminate between patients ± ischemic events
o IMPACT-R, Dade PFA collagen/ADP, Innovance PFA P2Y
Conclusions/ Comments
Only modest predictive accuracy of tests None of tests provided accurate prognostic information to identify low-risk patients at higher bleed risk following stent implantation
Treatment Options
• Increase doses
– Additional loading doses
– Higher daily doses
• Change the P2Y12 antagonist
– Prasugrel and ticagrelor proven efficacious • Not associated with genetic polymorphisms
– Cost difference
– Review side effect profiles and cautions/contraindications
N Eng J Med 2009;361:1045-57. N Engl J Med 2007;357(20):2001-15. N Engl J Med 2010;375:283-93. JACC Cardiovasc Interv 2010;3(10):1008-10.
GRAVITAS Trial
JAMA 2011; 305 (11): 1097-105.
Population Stable CAD or ACS s/p PCI (N=2800)
Treatments
Clopidogrel 300-600 mg x 1, 75 mg daily Patients assessed for presence of high on-treatment reactivity
1o endpoint/ Results
Composite: CV death, nonfatal MI, stent thrombosis in patient with high on-treatment reactivity
High Dose Standard Dose
Loading dose 600 mg Placebo
Maintenance dose
150 mg daily 75 mg daily
High Dose (%) Standard Dose (%) p value
2.3 2.3 0.97
GRAVITAS Trial
JAMA 2011; 305 (11): 1097-105.
2o endpoint/ Results
Composite: CV death, nonfatal MI, stent thrombosis in patients with standard clopidogrel dose ± high residual platelet activity
Safety endpoint/ Results
Moderate and severe bleeding
High On-Treatment Reactivity (%)
Without High On-Treatment Reactivity (%)
p value
2.3 1.4 0.20
High On-Treatment Reactivity (%)
Without High On-Treatment Reactivity (%)
High dose Standard dose p value Standard dose p value
1.4 2.3 0.10 1.2 0.12
GRAVITAS Trial
JAMA 2011; 305 (11): 1097-105.
Additional endpoint/ Results
Pharmacodynamics
Conclusions No benefit of high dose clopidogrel in patients with high on-treatment platelet reactivity
Questions remaining
Low event rate Clinical effect lacking Consider further dose increases? Level of platelet inhibition needed for efficacy?
PRU High Dose Standard Dose P value
30 days ↓ 80 PRU ↓ 37 PRU <0.001
6 months ↓ 85 PRU ↓ 44 PRU <0.001
BOCLA-Plan Trial
BMC Medicine 2011; 9 (3): 1-12.
Population Stable CAD or ACS s/p PCI (N=504)
Treatments
Clopidogrel 600 mg x 1, 75 mg daily Patients determined to be clopidogrel responder or nonresponder
Protocol
Steps 1 2
1 Clopidogrel 600 mg x 1,
150 mg daily Clopidogrel 600 mg x 1,
150 mg daily
2 Ticlopidine 500 mg x 1,
250 mg BID Prasugrel 60 mg x 1,
10 mg daily
3 ADP receptor defect
testing, then return to high dose clopidogrel
Prasugrel 20 mg daily
BOCLA-Plan Trial
1o endpoint/ Results
Effective treatment
Conclusions Using “test and treat” strategy, the prevalence of clopidogrel low response can be significantly reduced
Questions remaining
What cut-off values should be used to determine nonresponsiveness Clinical effect lacking
BMC Medicine 2011; 9 (3): 1-12.
Clopidogrel Therapeutic Plan Effective Treatment (%)
Standard dose clopidogrel 69.2
High dose clopidogrel 69.0
Ticlopidine 12.7
Standard dose prasugrel 92.0
High dose prasugrel 100.0
TRIGGER-PCI Trial
Population Stable CAD with high on-treatment platelet reactivity with clopidogrel + PCI with DES (N=273)
Treatments Prasugrel 10 mg daily Clopidogrel 75 mg daily
1o endpoint/ Results
Composite: CV death, MI • Prasugrel 0.0% vs. clopidogrel 0.5% (p=NE)
Additional endpoint/Results
Platelet reactivity (PRU) (3 months) • Prasugrel 245 80 vs. clopidogrel 249 241
Safety endpoint/ Results
Non-CABG related TIMI major bleeding • Prasugrel 1.4% vs. clopidogrel 0.5% (p=NE)
Conclusions Switching from clopidogrel to prasugrel increased level of effective platelet inhibition
Comments Discontinued early due to low incidence of 1o endpoint Clinical effect lacking
JACC 2012. 59;24:2159-64.
RESPOND Trial
Population Stable CAD (N=98)
Treatments
Clopidogrel 600 mg x 1, 75 mg daily Ticagrelor 180 mg x 1, 90 mg BID
Characterized as clopidogrel responder vs. nonresponder After 14 days, nonresponders switched groups and responders either continued current therapy or switched groups
1o endpoint/ Results
Clopidogrel nonresponders who respond to ticagrelor • IPA higher in nonresponders treated with ticagrelor (p<0.05)
Additional outcomes
Platelet aggregation • Clopidogrel to ticagrelor 59.9% to ± 9% 35% ± 11% • Ticagrelor to clopidogrel 36% ± 14% 56% to ± 9% Platelet reactivity below cut points associated with ischemic risk • Ticagrelor 98-100% vs. clopidogrel 44-76%
Conclusions Ticagrelor provided greater platelet inhibition, but clinical benefit cannot be determined
Circulation 2010. 121:1188-99.
Randomized Assessment of Ticagrelor vs. Prasugrel Antiplatelet Effects in Patients with Diabetes
Population Type 2 diabetes + ACS + PCI with DES (N=30)
Treatments Ticagrelor 90 mg BID Prasugrel 10 mg daily
After 15 days, patients switched to opposite group
1o endpoint/ Results
Platelet reactivity (PRU) • Ticagrelor 45.2 vs. prasugrel 80.8 (p=0.001)
2o endpoint/ Results
High platelet reactivity (PRU > 230 PRU) • Ticagrelor 0% vs. prasugrel 3.3% (p=1.0)
Additional outcomes
No major bleeds or MACE occurred in either group
Conclusions Ticagrelor provided greater platelet inhibition, but clinical benefit cannot be determined
Diabetes Care 2013. 36:2211-6.
Summary
• P2Y12-mediated platelet reactivity is a risk factor for CV events
• Currently no large trial has found that on-treatment platelet reactivity is a modifiable risk factor
• Current strength of platelet function testing lies with its use to predict patient risk
• Greater and more consistent P2Y12 inhibition seems promising
– Antiplatelet regimens that improve IPA
N Eng J Med 2009;361:1045-57. N Engl J Med 2007;357(20):2001-15. N Engl J Med 2010;375:283-93. JACC Cardiovasc Interv 2010;3(10):1008-10.
Summary
• Evidence for tailoring antiplatelet regimens for high on-treatment reactivity
– Pharmacodynamic studies
– Small, nonrandomized clinical trials
• Questions remaining
– How does laboratory effects translate to clinical effects
N Eng J Med 2009;361:1045-57. N Engl J Med 2007;357(20):2001-15. N Engl J Med 2010;375:283-93. JACC Cardiovasc Interv 2010;3(10):1008-10.
Review Questions
1. True/False. Clopidogrel nonresponsiveness increases a patient’s risk of CV events.
a. True
b. False
2. True/False. Clopidogrel nonresponsiveness is synonymous with treatment failure.
a. True
b. False
Patient Case MM is a 85 yo female who presents to the ED complaining of chest pain that occurred while she was sleeping. She describes the chest pain as “tightness” in the center of her chest. The pain radiates to her left arm and back. She rates the pain as 9/10 . In the ED she is diagnosed with an NSTEMI and is taken to the cardiac catheterization lab for PCI with a DES.
PMH: HTN x 40 years (home BP 140-150s)
HLD x 35 years
CAD s/p PCI with DES to LAD (6 months ago)
GERD x 2 years
Meds: Aspirin 81 mg PO daily
Atorvastatin 40 mg PO daily
Clopidogrel 75 mg PO daily
Lisinopril 20 mg PO daily
Metoprolol succinate 50 mg PO daily
NTG 0.4 mg SL q5 minutes prn CP
Omeprazole 40 mg PO daily
Vitals: BP 170/98 mmHg HR 108 RR 23 Temp 35.2oC SaO2 94% (RA) Ht 166 cm Wt 65 kg
Patient Case
1. Which of the following platelet function test would be most appropriate for use in this patient?
a. IMPACT-R
b. Innovance PFA P2Y
c. VerifyNow P2Y12 test
d. None of the above
2. Which of the following regimens is most appropriate for this patient to prevent future CV events?
a. Clopidogrel 600 mg x 1, then 75 mg daily
b. Clopidogrel 600 mg x 1, then 150 mg daily
c. Prasugrel 60 mg x 1, then 10 mg daily
d. Ticagrelor 180 mg x 1, then 90 mg BID