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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 Baseline TXB2 25 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 Point-of-Care Platelet Function Testing • 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. 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 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) 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. Secondary Comparison: High vs. Not High Reactivity Treated with Clopidogrel 75-mg daily Observed event rates are listed. P value by log-rank test. 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: 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. Primary Results of Testing 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 onclopidogrel platelet reactivity after elective PCI with drugeluting stents can be improved by switching from clopidogrel to prasugrel. Primary efficacy endpoint: Cardiovascular death or myocardial infarction Key safety endpoint: Non-CABG TIMI major bleeding TRIGGER-PCI 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 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. Early termination of TRIGGERPCI 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: High on-clopidogrel platelet reactivity (>208 PRU by VerifyNow P2Y12 test) was observed less frequently than expected. Compared with standard-dose clopidogrel 75 mg QD, prasugrel 10 mg QD substantially decreased platelet reactivity in patients with high on-clopidogrel platelet reactivity after elective PCI. Given the low event rate in elective PCI patients without peri-procedural complications it was not possible to assess the risk – benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility. ARCTIC Trial design: Patients undergoing drug-eluting stent implantation were randomized to a strategy of platelet function monitoring with antiplatelet dose adjustments as necessary (n = 1,213) vs. usual care without monitoring or drug adjustments (n = 1,227). Results (p = 0.10) 40 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 35 31 % 20 0 Conclusions MI, stroke, stent thrombosis, or urgent revascularization Platelet function monitoring Usual care • 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 Collet JP, et al. N Engl J Med 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