广东省人民医院 广东省心血管病研究所 谭宁 何鹏程 抗血小板治疗进展 广东省人民医院 广东省心血管病研究所 谭宁 何鹏程

Antiplatelet Therapy What to use? How to use?

Route of Administration Comparison of P2Y12 Receptor Antagonists: Ticagrelor vs Thienopyridines Name Type of Molecule Route of Administration Mode of Action Ticagrelor Cyclo-pentyl-triazolo-pyrimidine Oral Direct, Reversible Clopidogrel Thienopyridine Prodrug, Irreversible Prasugrel 3

TIMI Major Non-CABG Bleeds Days After Randomization TRITON-TIMI 38: Prasugrel vs Clopidogrel in ACS Patients Treated With PCI 15 Clopidogrel HR 0.81 (95% CI, 0.73–0.90) P<0.001) 12.1 CV Death/MI/Stroke 10 9.9 Prasugrel* Endpoint (%) NNT=46 5 TIMI Major Non-CABG Bleeds HR 1.32 (95% CI, 1.03–1.68) P=0.03 Prasugrel TRITON-TIMI 38: Balance of Efficacy and Safety In addition to the efficacy data, shown here are the safety data for prasugrel. The key safety endpoint, TIMI major non-coronary artery bypass graft bleeding, occurred in 2.4% of prasugrel patients versus 1.8% of clopidogrel patients. Thus, for every patient treated with prasugrel, there were 35 additional bleeding events, but 138 fewer cardiac deaths, nonfatal myocardial infarctions, and nonfatal strokes. Wiviott SD, Braunwald E, McCabe CH, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. 2.4 1.8 Clopidogrel 30 60 90 180 270 360 450 NNH=167 Days After Randomization Wiviott SD et al. N Engl J Med. 2007;357(20):2001-2015.

PLATO: KM estimate of time to first primary efficacy event (CV death, MI or stroke) 13 12 Clopidogrel 11.7 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 HR 0.84 (95% CI 0.77–0.92), p=0.0003 3 2 1 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 Wallentin L et al, N Engl J Med. 2009;361(11):1045-1057

PLATO: Non-CABG and CABG-related major bleeding 9 NS Ticagrelor Clopidogrel 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 4 3.8 p=0.025 2.8 3 2.2 2 1 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

Antiplatelet Therapy What to use? How to use?

Prasugrel vs. Clopidogrel for Acute Coronary Syndromes Patients Managed without Revascularization — the TRILOGY ACS trial On behalf of the TRILOGY ACS Investigators NEJM 2012:on-line www.clinicaltrials.gov Identifier: NCT00699998

TRILOGY ACS Study Design With or w/o prior angiography; if with (42%), required CAD with DS ≥30% Medically managed UA or NSTEMI (68%) (n=9,326) Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years; n=7,243) Median Time to Enrollment = 4.5 Days Clopidogrel1 300 mg LD + 75 mg MD Prasugrel1 30 mg LD 5 or 10 mg MD Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Source: Q113, Q111, Q331 [Source: Figure 1 on page 19] Reference: Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1. Clopidogrel1 75 mg MD Prasugrel1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. Among pts <75 years, 7.9% underwent revascularization (median 113 [40-334] days) Pras00045111

Primary Efficacy Endpoint to 30 Months (Age < 75 years) HR (95% CI) ≤ 1 Year: 0.99 (0.84, 1.16) HR (95% CI) > 1 Year: 0.72 (0.54, 0.97) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Interaction P = 0.07 Median study FU 17 months

Efficacy Component Endpoints to 30 Months (Age < 75 years) CV Death All MI HR: 0.93 (0.75-1.15) HR: 0.89 (0.74-1.07) All Stroke HR (95% CI) ≤ 1 Year HR (95% CI) > 1 Year CV Death 1.00 (0.78, 1.28) 0.75 (0.49, 1.14) All MI 0.97 (0.78, 1.19) 0.68 (0.46, 0.99) All Stroke 0.86 (0.50, 1.47) 0.35 (0.14, 0.88) HR: 0.67 (0.42-1.06)

Primary Endpoint - Pre-Specified Sub-Groups (Age < 75 years)

TIMI Major Bleeding to 30 Months (Age < 75 years) HR (95% CI): 1.31 (0.81, 2.11) P = 0.27

Incidence of Bleeding Outcomes (Age < 75 years) P = 0.87 P = 0.06 TIMI Criteria P = 0.02 P = 0.39 P = 0.99 P = 0.88 P = 0.27 70 8 4 16 39 46 12 17 30 13 14 52 35 GUSTO Criteria

TRILOGY ACS: Need to be answered Currently, prasugrel is indicated only for pts with NSTE-ACS managed by PCI. What are the implications of TRILOGY ACS, if any, for pts with NSTE-ACS treated medically after angiography?

CURRENT OASIS-7: Low vs. High-Dose Clopidogrel And Aspirin in ACS Patients Managed Invasively Intended PCI < 24 hrs No restriction on GP IIb/IIIa inhibitors Clopidogrel 600 mg 150 mg from Day 2 to Day 7 75mg from Day 8 to 30 Clopidogrel 300 mg 75 mg from Day 2 to 30 CURRENT/OASIS-7 is a Phase III, multinational, multicenter, randomized, factorial design, parallel-group study comparing 2 regimens of clopidogrel (high vs. standard dose) in a double-blind fashion and 2 regimens of ASA (high vs. low dose) in an open-label fashion in patients with non-ST-segment elevation ACS managed with an early invasive strategy with intent for PCI as early as possible within 24 hours. Each patient will be treated and followed for 30 days. ASA 300 mg Day 1 75–100 mg from Day 2 to 30 ASA 300 mg Day 1 300 mg–325 mg from Day 2 to 30 ASA 300 mg Day 1 75–100 mg from Day 2 to 30 ASA 300 mg Day 1 300 mg–325 mg from Day 2 to 30 1o Outcome: Death / MI /stroke, 30 Days; 2o outcome: CURRENT bleeding Mehta SR et al. N Engl J Med. 2010;363(10):930-942

Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 0.95 0.84-1.07 0.370 MI 2.6 2.0 0.78 0.64-0.95 0.012 0.025 1.4 1.7 1.25 0.87-1.79 0.23 2.2 1.9 0.86 0.73-1.03 0.097 CV Death 0.96 0.77-1.19 0.68 1.0 2.8 2.7 0.74-1.26 0.77 2.1 0.81-1.14 0.628 Stroke 0.4 0.88 0.55-1.41 0.59 0.50 0.8 0.9 1.11 0.68-1.82 0.67 0.5 0.99 0.70-1.39 0.950

Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed) Clopidogrel Standard Dose 0.012 42% RRR 0.008 Cumulative Hazard Clopidogrel Double Dose 0.004 HR 0.58 95% CI 0.42-0.79 P=0.001 0.0 3 6 9 12 15 18 21 24 27 30 Days

ACCF/AHA Recommendations Regarding Thienopyridine Use to Support PCI in Patients with NSTEMI During PCI Drug Patient Received Initial Medical Treatment (with a thienopyridine) Patient Did Not Receive Initial Medical Treatment (with a thienopyridine) Comments All Patients to Receive ASA (162-325 mg) Clopidogrel* If 600 mg given orally, then no additional treatment. A second LD of 300 mg may be given orally to supplement a prior LD of 300 mg (Class I, LOE: C) LD of 300-600 mg (Class I, LOE; A) MD of 75 mg orally QD (Class I, LOE: A) An MD of 150 mg orally QD for initial 6 days may be considered (Class IIb, LOE: B) Optimum LD requires clinical consideration. Dose for patient >75 years of age has not been established There is a recommended duration of therapy for all post-PCI patients receiving a BMS or DES Period of withdrawal before surgery should be at least 5 days. (For full explanations, see footnote) Prasugrel** No data are available to guide decision making LD of 60 mg orally MD of 10 mg orally QD (Class I, LOE: B) There is no clear need for treatment with prasugrel before PCI MD of 5 mg orally QD in special circumstances Special dosing for patients >60 kg There is a recommended duration of therapy for all post-PCI patients receiving a DES Prasugrel is generally not recommended for patients ≥75 years of age because of increased bleeding risk and uncertain benefit compared with clopidogrel Contraindicated for use in patients with prior history of TIA or stroke (For full explanations, see footnote) Wright RS et al. J Am Coll Cardiol. 2011;57:1920-1959.

Time Relative to PCI Recommendation COR LOE Pre-PCI Aspirin 81-325 mg before PCI if already on aspirin therapy I B Nonenteric-coated aspirin 325 mg before PCI if not on aspirin therapy PCI Aspirin administered at time of PCI Post-PCI After PCI, aspirin continued indefinitely. A After PCI, use of 81 mg/d of aspirin in preference to higher maintenance doses. IIa

Recommendation COR LOE Administration of a loading dose** of a P2Y12 receptor to patients undergoing PCI with stenting I A Patients counseling on the need for and risks of DAPT before placement of intracoronary stents, especially a DES C P2Y12 inhibitor therapy for at least 12 months in patients receiving a stent (BMS or DES) during PCI for ACS B Clopidogrel for at least 12 months in patients treated with a DES for a non–ACS indication, if patients are not at high risk of bleeding Clopidogrel for a minimum of 1 month and ideally up to 12 months in patients receiving a BMS for a non-ACS indication (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks) Earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy after stent implantation if the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy IIa Continuation of DAPT beyond 12 months in patients undergoing DES implantation IIb Prasugrel administration in patients with a prior history of stroke or transient ischemic attack III – Harm

对于最佳DAPT时长，已有RCTs尝试进行分析 REAL-LATE&ZEST-LATE :Zotarolimus-Eluting Stent versus Sirolimus-Eluting Stent and Paclitaxel-Eluting Stent for Coronary Lesions Excellent 研究：比较Xience/promus和 Cypher支架植入后减少晚期失败的疗效的随机、多中心研究 PRODIGY:bare-metal, zotarolimus-eluting, paclitaxel-eluting,or everolimus-eluting stent 三个研究的结果并无统计学差异 Park SJ, Park DW, Kim YH, et al. N Engl J Med. 2010;362(15):1374-82. Gwon HC, Hahn JY, Park KW, et al. Circulation. 2012;125(3):505-13. Valgimigli M, Campo G, Monti M, et al. Circulation. 2012;125(16):2015-26.

EXCELLENT Trial DAT 6 months N=722 DAT 12 months N=721 1443 Patients Matching Enrollment Criteria EES N=540 SES N=182 EES N=539 SES N=182 Percutaneous Coronary Intervention 2x2 factorial design 1mo 3mo 9mo 12mo Clinical Angiographic 3yr 2yr 4yr 5yr Primary clinical endpoint evaluation Co-primary angiographic endpoint evaluation Am Heart J 2009 May;157:811-817.e1 Gwon HC et al ACC 2011

Cumulative incidence rate (%) Months after initial procedure EXCELLENT Trial Target Vessel Failure 6-mo DAT 12-mo DAT P=0.507 HR = 1.17 (95% CI 0.73-1.89) Non-inferiority p=0.0031 4.7% Cumulative incidence rate (%) 4.4% Months after initial procedure Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680 Am Heart J 2009 May;157:811-817.e1 Gwon HC et al ACC 2011

PRODIGY Trial : DAPT 6 versus 24 month 1970 Pts DES: 75% ACS: 75% Valgimigli M et al, ESC 2011

PRODIGY Trial : DAPT 6 versus 24 month Valgimigli M et al, ESC 2011

Ongoing Trials Dual Antiplatelet Therapy(DAPT) DES/BMS，12m vs. 30m  Stenting and Antithrombotic Regimen: Safety And EFficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) DES，6m vs. 12m http://www.clinicaltrials.gov/

COGENT TRIAL ACS – PCI 3627 PATIENTS CLOPIDOGREL + ASPIRIN + OMEPRAZOLE CLOPIDOGREL + ASPIRIN + PLACEBO GI EVENTS - 38 TREATMENT GROUP 67 PLACEBO ARM P=0.007 NO DIFFERENCE CLINICAL CARDIOVASCULAR END POINTS DEATH IN MI

The only available randomized trial showed no significant association of omeprazole with CV events A significant association between PPI use and increased CV events has been inconsistently demonstrated in observational studies, with the majority of studies show-ing no association Evidence remains weak for diminished antiplatelet activity associated with PPIs and thienopyridine coprescription.

Thank you for your attention!