Measurement of Antiplatelet Therapeutic Efficacy Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA Professor of Medicine Director, Interventional Cardiology Research St Vincent Hospital Worcester MA
Disclosure No conflicts relative to this presentation General Disclosures Ownership Imaging Core Lab Services AtheroMed Acclarent Stryker/Surpass/Cersys Consulting Boston Biomedical Associates Cormend Honoraria Atricure Atheromed 480 Biomedical Angiolight Creganna Cardiac Assist GI Dynamics SCAI FAAC Accreditation for Cardiovascular Excellence Board Chair Chief Medical Officer
Antiplatelet Drug Resistance / Response Variability An Emerging Clinical Problem?
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 Does laboratory identification and treatment of high platelet reactivity benefit the patient? What does high on-treatment platelet reactivity mean to the patient?
Tests of Aspirin Resistance Light transmission Aggregometry Arachadonic acid ADP Whole blood aggregometry PFA-100 (platelet function analyzer) VerifyNow Aspirin Urinary 11-dehydro-thromboxane B2 European Heart Journal (2007) 28, 1702 1708 doi:10.1093/eurheartj/ehm226
Comparison in Patients with Stable CAD
Aspirin Resistance Lack of correlation between the different tests Measure different aspects of platelet function
Aspirin Resistance
HOPE Trial Heart Outcomes Prevention Evaluation Urinary 11-dehydro thromboxane B2 levels 488 patients on aspirin who had CV events compared to case controlled patients without events
HOPE 30 P=0.01 P=0.003 NS P<0.001 25 Baseline TXB2 20 Cases Controls 15 10 5 0 Death/MI/Stroke MI Stroke CV Death
HOPE Odds ratio Death/MI/Stroke 2 1.8 1.8 1.6 1.2 1 1.4 1.3 1.4 1 0.8 0.6 0.4 0.2 0 TXB2 < 15.1 15.1-21.8 21.9-33.8 > 33.8
PCI and ASA Resistance Ultegra Rapid Platelet Function Assay (Accumetrics Inc., San Diego, California)
Risk of any cardiovascular event in aspirin resistant patients Krasopoulos, G. et al. BMJ 2008;336:195-198
t-of-care Platelet Function Testing t least 7 studies involving more than,000 patients have concluded that high esidual (on-clopidogrel) platelet reactivity easured by the VerifyNow P2Y12 test is ssociated with poor clinical outcomes after CI. treatment strategy for patients with high esidual platelet reactivity has not been ested in a large, randomized, clinical trial.
Baseline Platelet Reactivity* Determines Outcomes Following Coronary Stenting 1.0 0.9 Low Reactivity Group 0.8 0.7 High Reactivity Group 0.6 0.5 P = 0.01 P = 0.006 P = 0.043 0 100 200 300 Time (Days) * Fibrinogen binding in response to 0.2 M ADP
clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs VITAS 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 lopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel clopidogrel 75-mg daily X 6 months ary 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
AVITAS Patient Flow 5429 patients screened with VerifyNow P2Y12 12-24 hours post-pci 14 (41%) with high residual platelet reactivity (PRU 230) 3215 (59%) without high residual platelet reactivity (PRU < 230) pidogrel gh Dose =1109 Clopidogrel Standard Dose N=1105
mary Endpoint: CV Death, MI, Stent Thrombosis
condary Comparison: High vs. Not High Reactivity ated with Clopidogrel 75-mg daily
AVITAS: Possible Explanations nderpowered: 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 harmacodynamic effect of the intervention was o weak? Stronger intervention and/or goal-directed therapy with serial measurements merit study (TRIGGER-PCI; ARCTIC; TARGET-PCI)
AVITAS: Summary ompared with standard-dose therapy, high-dose lopidogrel achieved a modest harmacodynamic effect in patients with high esidual reactivity. n patients with high residual reactivity measured fter PCI, 6-months of high-dose clopidogrel did ot reduce the rate of cardiovascular death, nonatal MI, or stent thrombosis and did not increase USTO severe or moderate bleeding.
Primary Results of esting platelet Reactivity In patients undergoing elective stent placement on clopidogrel to Guide alternative therapy with prasugrel TRIGGER-PCI Study
Study objective to assess whether the outcome of patients with high onpidogrel platelet reactivity after elective PCI with drugting stents can be improved by switching from clopidogrel rasugrel. mary efficacy endpoint: Cardiovascular death or myocardial infarction y safety endpoint: Non-CABG TIMI major bleeding
TRIGGER-PCI uccessful PCI with DES without major complication and NO GPIIb/IIIa use 8800 Post-PCI VerifyNow P2Y12 Assay (PRU) 2-4 hours after 1 st MD of clopidogrel 75 mg at day 1 post-pci Non-Responder Yes PRU 208? No Responder PRU 140? N = 1075 grel arm el 60 mg LD el 10 mg MD ogrel placebo B N = 1075 N = 550 Clopidogrel arm Placebo LD Clopidogrel 75 mg MD + Prasugrel placebo Prasugrel arm Prasugrel 60 mg LD Prasugrel 10 mg MD + Clopidogrel placebo Random Selection D C N = 550 Clopidogrel arm Placebo LD Clopidogrel 75 mg MD + Prasugrel placebo E Standard Therapy Clopidogrel 75 mg Platelet function substudy: VerifyNow Assessment at day 2 (2 4 h after 1 st MD of study drug) Clinical Follow-up and VerifyNow Assessment at 90 days, 180 days
Sample size and power calculation 6-month incidence of the composite endpoint of cardiovascular death or MI (including minor infarctions with elevated troponin) expected as 4.7%. Randomization of 2,150 patients to provide 93% power to detect a 50 % relative risk reduction on prasugrel.
arly termination of TRIGGER- PCI 236 patients completed 6 months follow-up Only 1 clinical endpoint (peri-procedural MI) observed rate 0.4% Upper 95 %-confidence limit 1.25 %
Summary and conclusion: igh on-clopidogrel platelet reactivity (>208 PRU by erifynow P2Y12 test) was observed less frequently than xpected. ompared with standard-dose clopidogrel 75 mg QD, rasugrel 10 mg QD substantially decreased platelet eactivity in patients with high on-clopidogrel platelet eactivity after elective PCI. iven the low event rate in elective PCI patients without eri-procedural complications it was not possible to ssess the risk benefit ratio with prasugrel treatment. herefore, the study was terminated prematurely for utility.
ARCTIC design: Patients undergoing drug-eluting stent implantation were randomized to a egy of platelet function monitoring with antiplatelet dose adjustments as necessary (n = 3) vs. usual care without monitoring or drug adjustments (n = 1,227). (p = 0.10) 35 31 Results MI, stroke, stent thrombosis, or urgent revascularization: 35% of the monitoring group vs. 31% of the usual care group (p = 0.10) Death or myocardial infarction: 32% vs. 29% (p = 0.15), respectively Stent thrombosis: 1.0% vs. 0.7% (p = 0.51), respectively Major bleeding: 2.3% vs. 3.3% (p = 0.15), respectively I, stroke, stent thrombosis, or urgent revascularization Platelet function monitoring Usual care Conclusions Among a relatively high-risk cohort of patients undergoing drug-eluting stent implantation, a strategy to monitor platelet reactivity to guide antiplatelet dosing failed to improve clinical outcomes
ARCTIC
ARCTIC
Conclusions Variability in platelet function testing Focus has been on P2Y12 resistance Newer more potent agents appear to be beneficial No clear correlation with clinical events or that correcting the laboratory finding affects clinical endpoints May be a relationship between ASA resistance and events