Νεώτερα στην αντιαιμοπεταλιακή αγωγή

Patras University Hospital Νεώτερα στην αντιαιμοπεταλιακή αγωγή Δημήτριος Αλεξόπουλος MD, FESC, FACC Καθηγητής Καρδιολογίας Παν/μίου Πατρών ΟΕ 2014

Patras University Hospital I, Dimitrios Alexopoulos, have received honoraria for lecturing and research grants from: Astra Zeneca Boeringer Ingelheim

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Kohli et al, Circ 2013;127:673

Kohli et al, Circ 2013;127:673

Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization: A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial Lars Wallentin, Daniel Lindholm, Agneta Siegbahn, Lisa Wernroth, Richard C. Becker, Christopher P. Cannon, Jan H. Cornel, Anders Himmelmann, Evangelos Giannitsis, Robert A. Harrington, Claes Held, Steen Husted, Hugo A. Katus, Kenneth W. Mahaffey, Ph. Gabriel Steg, Robert F. Storey and Stefan K. James for the PLATO study group Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization: Lars Wallentin, Daniel I nhibition Lindholm, and A Substudy Patient Agneta Outcomes From the Siegbahn, Lisa (PLATO) Prospective Wernroth, Trial Randomized Platelet Richard C. Becker, Christopher P. Cannon, Jan H. Cornel, Anders Himmelmann, Evangelos Giannitsis, Robert A. Harrington, Claes doi: Held, 10.1161/CIRCULATIONAHA.113.004420 Steen Husted, Hugo A. Katus, Kenneth W. Mahaffey, Ph. Gabriel Steg, Robert F. Storey and Stefan K. James for the PLATO study group Circulation. 2014;129:293-303; originally published online October 29, 2013; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 Circulation. 2014;129:293-303; originally published online October 29, 2013; doi: 10.1161/CIRCULATIONAHA.113.004420 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: The online version of this article, along http://circ.ahajournals.org/content/129/3/293 with updated information and services, is located on the

Wallentin, Circulation 2014:129:293

ACCOAST design NSTEMI + Troponin 1.5 i tl ames UN lo cal l Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 Double-blind b value n~4100 (event driven) Prasugrel 30 mg Placebo CABG or Medical Management (no more prasugrel) Coronary Angiography Prasugrel 30 mg Coronary Angiography Prasugrel 60 mg CABG or Medical Management (no prasugrel) PCI PCI Patras University Hospital Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days

Endpoint (%) 1 Efficacy End Point @ 7 + 30 days (All Patients) 15 Pre-treatment 10.0 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment 10.8 10 No Pre-treatment 10.8 No Pre-treatment 9.8 5 Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 No. at Risk, Primary Efficacy End Point: No pre-treatment Pre-treatment Patras University Hospital 0 0 5 10 15 20 25 30 1996 2037 1788 1821 Days From First Dose 1775 1809 1769 1802 1762 1797 1752 1791 1621 1616

Endpoint (%) All TIMI (CABG or non-cabg) Major Bleeding (All Treated patients) 5 4 Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006 Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002 3 Pre-treatment 2.6 Pre-treatment 2.9 2 All TIMI Major Bleeding 1 0 No Pre-treatment 1.4 No Pre-treatment 1.5 No. at Risk, All TIMI Major Bleeding: No pre-treatment Pre-treatment Patras University Hospital 0 5 10 15 20 25 30 1996 2037 1947 1972 Days From First Dose 1328 1339 1297 1310 1288 1299 1284 1297 1263 1280

Event Rate (%) Death/ MI/ IDR/ Stent Thrombosis within 48 Hours clopidogrel cangrelor 5.9% 4.7% Log Rank P Value = 0.006 Patient at Risk Hours from Randomization Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213 Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org Patras University Hospital

Patras University Hospital Cangrelor : CHAMPION PHOENIX and the pooled analysis of patient-level data from the CHAMPION trials Ph.Gabriel Steg *DHU-FIRE, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, INSERM U-698, Paris, France, French Alliance for Cardiovascular trials and NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK

CHAMPION Trials Study Designs Randomised, Double Blind, Controlled Trials of patients undergoing PCI CHAMPION PHOENIX n=10,942 mitt SA / NSTE-ACS / STEMI P2Y 12 naïve Placebo or clopidogrel before or after PCI Cangrelor bolus then infusion OR Clopidogrel 600 mg or 300 mg oral Clopidogrel 600 mg oral CHAMPION PCI n=8667 mitt SA / NSTE-ACS / STEMI Placebo or clopidogrel before PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral CHAMPION PLATFORM n=5301 mitt SA / NSTE-ACS P2Y 12 naïve Placebo or clopidogrel after PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral 0 1 2 hours Patras University Hospital PCI ~30

Patras University Hospital Event rate (%) Death/ MI/ IDR/ Stent Thrombosis within 48 Hours Clopidogrel Cangrelor 4.7% 3.8% Log-rank p value=0.0007 Hours from randomization No. patients at risk Cangrelor: 12,475 12,053 12,040 12,033 12,021 12,006 12,002 11,994 11,985 Clopidogrel: 12,435 11,903 11,897 11,891 11,882 11,874 11,866 11,853 11,843

Event rate (%) Patras University Hospital Stent Thrombosis within 48 Hours Clopidogrel Cangrelor 0.8% 0.5% Log-rank p value=0.0008 Hours from randomization No. patients at risk Cangrelor: 12,475 12,420 12,406 12,403 12,395 12,387 12,384 12,377 12,371 Clopidogrel: 12,435 12,327 12,319 12,318 12,308 12,306 12,304 12,297 12,291

Patras University Hospital

Stone GW et al. Lancet 2013 ;382:614 Patras University Hospital

Adj. Hazard Ratio Patras University Hospital ADAPT DES at 2 Years: MV Analysis of ST and Maj Bleeding by PRU 2.0 Q1 (<95) 1.45 * Q2 (95-159) Q3 (160-215) Maj Bleeding Def/Prob ST Q4 (216-275) Q5 (>275) 1.67 1.24 1.0 0.75 1.06 0.83 1.00 referent 0.88 0.87 Note: Bleeding occurred ~8x more frequently than ST 0.5 *p=0.001; all other p=ns

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. Alexopoulos D et al. Circ Cardiovasc Interv. 2012;5:797

Patras University Hospital Alexopoulos et al.

Subgroups: Death, MI, IDR, Stent Thrombosis OR [95% CI] P [Int] Overall 0.81 (0.71, 0.91) Age >=75 0.69 (0.52, 0.91) 0.219 Age <75 0.84 (0.73, 0.96) Male 0.85 (0.74, 0.99) 0.18 Female 0.71 (0.56, 0.89) Ethnicity: White 0.80 (0.70, 0.92) 0.683 Ethnicity: Non-white 0.87 (0.60, 1.28) United States 0.82 (0.68, 0.98) 0.816 ROW 0.80 (0.67, 0.94) Stable Angina 0.77 (0.64, 0.93) 0.866 NSTE-ACS 0.82 (0.68, 0.99) STEMI 0.84 (0.55, 1.27) Weight >=60 0.80 (0.71, 0.92) 0.927 Weight <60 0.82 (0.52, 1.30) Biomarker Positive 0.79 (0.62, 1.02) 0.962 Biomarker Negative 0.79 (0.68, 0.91) Diabetic Yes 0.87 (0.69, 1.09) 0.446 Diabetic No 0.78 (0.67, 0.91) Insulin-Dependent Diabetes: Yes 0.63 (0.41, 0.98) 0.247 Insulin-Dependent Diabetes: No 0.83 (0.72, 0.94) Prior MI 0.72 (0.57, 0.92) 0.25 No Prior MI 0.85 (0.74, 0.99) Cangrelor better Clopidogrel better Steg et al. Lancet Sep 3, 2013

Patras University Hospital P2Y12 inhibition and thrombolysis Platelet reactivity is heightened after thrombolytic therapy Role of prasugrel or ticagrelor is unclear. In TRITON TIMI-38, there was a very limited experience with co-administration of thrombolysis with prasugrel, mainly in the secondary PCI cohort. In PLATO, thrombolysis was an exclusion criterion.

Patras University Hospital Adjunctive Antithrombotic Therapy to Support PCI After Fibrinolytic Therapy ACCF/AHA STEMI guidelines 2013

Montalescot et al, Lancet 2009

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Int J Cardiol. 2013 Aug 15. doi:pii: S0167-5273(13)01532-5

Eligibility criteria for P2Y12 inhibitor selection

Appropriateness of overall P2Y12 inhibitor selection initially and at discharge.

Prevalence of at least 1 CON/SWP and the prescription rates at discharge for each P2Y12 inhibitor. At least 1 CON Clopidogrel 5(0.4%) Prasugrel 49(3.8%) Ticagrelor 12(0.9%) Patients with CON/SWP to all the 3 P2Y12 inhibitors were prescribed with descending frequency clopidogrel, ticagrelor and prasugrel

Patras University Hospital Distribution of patients according to the number of C/SWP for each P2Y12 inhibitor At least 1 CON/SWP for use was less prevalent for clopidogrel (45.8%) than prasugrel (49.1%) or ticagrelor (48.8%). Significantly more patients had a high number ( 3) CON/SWP for use of prasugrel than clopidogrel or ticagrelor.

Patras University Hospital

Platelet reactivity measurements reveal patient noncompliance during ticagrelor maintenance therapy. PR post ticagrelor maintenance dose. N=210 Median, (Q1-Q3) are indicated by dotted lines. Noncompliant patients are shown as red bars. PR=Platelet reactivity, PRU= Platelet reaction units. Alexopoulos D, Can J Cardiol 2013;29:1743e13

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Patras University Hospital

In the era of more potent P2Y12 receptor inhibitors, there is a heightened risk for bleeding. A therapeutic counterpoise may occur, with the absolute risk reduction in ischemic event occurrence and the absolute risk increase in bleedings approaching to the same magnitude A ceiling effect in reducing ischemic event occurrence even with new P2Y12 receptor inhibitors (i.e., 10% residual ischemic event occurrence)? Introduction of novel clinical endpoints such as the net: adverse clinical events The greater net clinical benefit of the more potent P2Y12 blockade may beobserved early after stenting when thrombotic risk is the highest Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Patras University Hospital

Patras University Hospital

ARCTIC-INTERRUPTION trial design Coronary angiogram Rd VerifyNow and drug adjustment Stent-PCI VerifyNow and drug adjustment Standard of care Stent-PCI Standard of care 12-month FU Rd #2 DAPT SAPT 6-18 more months of FU 1 EP: Death, MI, stroke, stent thrombosis, urg. revasc.

Event Probability Primary Endpoint up to 18 months Death, MI, stroke, stent thrombosis, urgent revascularization DAPT SAPT ----- HR = 1.17 [0.68-2.03] p= 0. 5750 4.3% 3.8% N at risks Follow-up (days) DAPT 635 633 613 593 513 440 SAPT 624 611 591 572 488 411

Patras University Hospital

Patras University Hospital

Study Design-OPTIMIZE Broad patient population undergoing PCI with Endeavor ZES RVD 2.5 mm 4.0 mm 3 Months DAPT N = 1560 N = 3120 patients 1:1 Randomization 33 Sites in Brazil 12 Months DAPT N = 1560 Clinical endpoints 30-d. 3-mo. 6-mo. 12-mo. 18-mo. 24-mo. 36-mo. Primary Endpoint: NACCE (Death / MI / Stroke / Major Bleeding) at 12 months Secondary Endpoints: ARC defined ST, TVR, TLR, MACE, DAPT compliance, and bleeding (REPLACE-2 & GUSTO definitions) NACCE = Net Adverse Clinical and Cerebral Events MACE is composed of Death, MI, Emergent CABG, TLR major Patras University Hospital Feres F. et al, Am Heart J. 2012;164:810-6

Cumulative Incidence of NACCE (%) Primary Endpoint: NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding) 15 10 3M DAPT 12M DAPT Log-Rank P = 0.84 HR 1.03 (0.77 1.38) Non-inferiority P-value = 0.002 6.0 5.8 5 0 0 3 6 9 12 Time After Initial Procedure (Months) Patras University Hospital Month 0 1 3 6 12 No. at risk 1563 1520 1504 1468 1384 No. events 18 25 11 18 21 No. at risk 1556 1514 1497 1466 1381 No. events 16 25 11 16 22

Patras University Hospital CE Mark approval for use with DAPT Xience Prime and Xience V (everolimus-eluting): Resolute Integrity (Zotarolimus-eluting): 3 months 1 month

Patras University Hospital

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Patras University Hospital

Discontinuation Patras University Hospital Modes of DAPT Cessation patients had discontinued DAPT as per recommendation of their physician who felt the patient no longer needed therapy Interruption patients had interrupted DAPT use on a voluntary basis and as guided by a physician due to (e.g. surgery) DAPT was then reinstituted within 14 days Disruption patients had disrupted DAPT use due to bleeding or noncompliance.

Patras University Hospital

Patras University Hospital

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

The What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) Dewilde et al, Lancet 2013; 381: 1107 15 Patras University Hospital Design DESIGN: randomized, placebo-controlled, openlabel, multi-center OBJECTIVE: to compare the safety and efficacy of clopidogrel alone with clopidogrel + ASA in patients taking OAK therapy and undergoing PCI 573 patients treated with OAK and undergoing PCI from November 2008 to November 2011 at 15 centers in Belgium and Netherlands Warfarin + Clopidogrel (The doubletherapy group) N = 284 ACS ~ 25% in both groups DES used in 65% in both groups randomization F/U: median 365 days Warfarin + ASA + Clopidogrel (The triple-therapy group) N=289 1 endpoint: any bleeding episode during 1 year 2 endpoint: death, MI, stroke, TVR, and ST

Patras University Hospital Lancet 2013; 381: 1107 15

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital Clinical studies STEMI Novel agents/real life use Bleeding risk Optimal duration Discontinuation Triple therapy Pleiotropic actions

Patras University Hospital

Study Design Day 0 Visit 1 Day 15 Visit 2 Day 30 NonSTEACS, PCI treated patient Eligible for the study Baseline LAD CBFV adequately recorded Informed consent R Ticagrelor 90mg bid Prasugrel 10mg od Ticagrelor 90mg bid Prasugrel 10 mg od Study procedure at Visit 1 and 2 10 min Resting Period Compliance with treatment assessment MACES, adverse events and bleeding events documentation BP, HR LAD bcbfv Patras University Hospital 2 min Adenosine infusion 50μg/kg/min BP, HR maxcbfv 2 min Adenosine infusion 80μg/kg/min BP, HR maxcbfv 2 min Adenosine infusion 110μg/kg/min BP, HR maxcbfv 5min Recovery periods between the infusions Adverse events monitoring throughout the procedure 2 min Adenosine infusion 140μg/kg/min BP, HR maxcbfv

An example of transthoracic Doppler echocardiography images in a single patient LAD baseline (A) and maximal at 110μg/kg/min adenosine infusion rate (B) CBFV recorded at Day 15 while under prasugrel. Same patient s images of baseline (C) and maximal at 110μg/kg/min adenosine infusion rate CBFV (D) on Day 30, while under ticagrelor. The respective ratios of maximalcbfv/baseline CBFV are shown (B, D).

AUC of LAD maxcbfv at gradually increasing doses of adenosine. Alexopoulos et al, Circ Cardiovasc Interv 2013;6:277

Varenhorst et al, JACC 2012;60:1623

Patras University Hospital

Patras University Hospital

Stone GW et al. Lancet 2013 Aug 17;382(9892):614-23 Patras University Hospital

Torngren et al, Cardiology 2013;124:252

Ticagrelor vs high dose of clopidogrel in ST elevation myocardial infarction patients with high residual platelet reactivity post thrombolysis: a pharmacodynamic comparison Prospective, 2-center, randomized study of parallel design. Patients with STEMI and HPR (defined as PRU 208) 3 to 48 hours post fibrinolysis and standard clopidogrel treatment [300mg loading dose (LD) 75mg maintenance dose (MD)] are randomized pre coronary angiography to: Ticagrelor 180mg LD 90mg bid MD or Clopidogrel 600mg LD 150mg MD. Platelet reactivity (PR) assessment at randomization (Hour 0) and at 2, 24 hours after randomization, as well as pre-discharge, using the VerifyNow assay, in platelet reactivity units (PRU). Primary endpoint is PR at Hour 2 between groups. Patras University Hospital ClinicalTrials.gov NCT01950416, Alexopoulos et al

Patras University Hospital

Patras University Hospital

Patras University Hospital Summary OPTIMIZE compared 3 vs. 12 months DAPT in a patient population from daily clinical practice treated with a single 2 nd generation DES. At 1 year, NACCE (Death / MI / Stroke / Major Bleeding) rate was noninferior in patients receiving 3 months DAPT compared with prolonged standard DAPT. 6.0% w/ 3-mo. vs. 5.8% w/ 12-mo. DAPT (P non-inf =0.002) Landmark analysis at 90 days demonstrated: Comparable rates of NACCE, ST, and TLR/TVR. A trend towards increased rate of any bleeding events with longer DAPT arm.