Selective use of platelet glycoprotein IIb/IIIa inhibition

Transcription

1 20 years clinical use of GP IIb/IIIa receptor antagonists: What have we learned and where to go? EBAC ACCREDITED EDUCATIONAL PROGRAMME HELD DURING THE ESC CONGRESS 2014 Selective use of platelet glycoprotein IIb/IIIa inhibition Jean-Philippe Collet Institut de Cardiologie Inserm 937 Pitié-Salpêtrière University Hospital Paris, France Presented September 1, 2014

2 Case presentation 1 55 year old male admitted to ER of large teaching hospital Chest pain and SOB (begun 8h before admission) History of previous MI 5 years earlier on BB/ASA/Statin Physical examination: BP 160/100 mmhg, HR 88 bpm S3 Crepitations at both lung bases (Killip II) Electrocardiogram: ST depression (1 mm) in I and avl + Q waves in II-III and avf Laboratory data at admission: TnI 200 Diagnosis of high risk NSTE-MI made. Pain and SOB resolve over 30 min with iv nitrates and frusemide 20 mg iv.

3 Question Planned coronary angio next morning. LMWH sc started. What antithrombotic Rx in the meantime? 1. Loading with P2Y 12 inhibitor 2. IIbIIIa blocker 3. Wait until angiogram

4 Thrombus in NSTE-ACS Angiographic Endpoints 30 days follow up Ischemic Endpoints 63.1% 13.0% p= % p=< for all 9.4% 21.6% 13.5% 5.5% 0.6% p= % 1.1% Goto K. et al. JACC Cardiovasc Intervention 2011

5 UPSTREAM VS DOWNSTREAM GP IIB-IIIA INHIBITORS IN ACS: A META-ANALYSIS OF RCTs (clopidogrel era) Major Bleeding Complications Upstream Gp Downstream Gp Study IIb-IIIa inhibitors IIb-IIIa inhibitors OR (fixed) Weight OR (fixed) n/n n/n 95% CI % 95% CI ACUITY 89/ / [0.89, 1.67] CLOTILDA 3/150 2/ [0.25, 9.17] EARLY ACS 73/ / [1.36, 3.03] ELISA 3/109 5/ [0.14, 2.57] EARLY Pilot 7/153 5/ [0.46, 4.73] Liu et al. 2/80 1/ [0.18, 22.80] ELISA 2 6/162 6/ [0.32, 3.19] Total (95% CI) 183/ / [1.14, 1.81] Test for heterogeneity: Chi² = 5.71, df = 6 (P = 0.46), I² = 0% Test for overall effect: Z = 3.12 (P = 0.002) Favours Upstream Gp IIb-IIIa inhibitors Favours Downstream Gp IIb-IIIa inhibitors Neutral effect on mortality Neutral effect on reinfarction De Luca G et al. AJC 2011

6 Endpoint (%) All TIMI (CABG or non-cabg) Major Bleeding (All Treated patients) Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006 Pre-treatment 2.6 Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002 Pre-treatment 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 Days From First Dose N Engl J Med Sep 12;369(11):

7 % with a primary EP Visible thrombus (21% in ACCOAST) Thrombus No thrombus GP Iib/IIIa use Primary Endpoint MI ST HR 2.61 [ ], p< Length of procedure (HR: 1 88 (1 49, 2 36) p<0 001, - number of lesions (HR: 1 24 (1 10, 1 39) p<0 001, - maximum length of stent (HR: 1 19 (1 04, 1 35) p=0 005), - and CRUSADE risk score (HR: 1 01 (1 00, 1 02) p=0 023; GPIIb/IIIa inhibitor use was very low in the PCI patients: Overall use: 14.9% prasugrel pretreatment, 16.0% prasugrel non-pretreatment GPIIb/IIIa bailout: 5.2% prasugrel pretreatment, 5.5% prasugrel non-pretreatment thru 7 days.

8 Coronary Angiogram LVEF 40% (inferior akinesia) Case presentation 1 Angios reviewed with interventionist and surgeon: CABG planned for same afternoon

9 Antiplatelet therapy for NSTE-ACS undergoing PCI Recommendations Class a Level b Ref c Antiplatelet therapy ASA is recommended for all patients without contraindications at an initial oral loading dose of mg (or mg i.v.), and at a maintenance dose of mg daily long-term regardless of treatment strategy. I A 778, 780, 798 A P2Y 12 inhibitor is recommended in addition to ASA, and maintained over 12 months unless there are contraindications such as excessive risk of bleeding. Options are: I A 337, 341, 829 Prasugrel (60-mg loading dose, 10-mg daily dose) in patients in whom coronary anatomy is known and who are proceeding to PCI if no contraindication. Ticagrelor (180-mg LD, 90 mg twice daily) for patients at moderate-to-high risk of ischaemic events, regardless of initial treatment strategy including those pretreated with clopidogrel if no contraindication. Clopidogrel (600-mg loading dose, 75 mg daily dose), only when prasugrel or ticagrelor are not available or are contraindicated. I B 337 I B 341 I B 816,829 GP IIb/IIIa antagonists should be considered for bailout situation or thrombotic complications. IIa C Pretreatment with prasugrel in patients in whom coronary anatomy is not known is not recommended. III B 830 Pretreatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not recommended. III A 361, European Heart Journal DOI /eurheartj/ehu278

10 NSTEMI Aspirin 500 mg IV Enox SQ Rapid transfer to cathlab (24h) with TNI+ or high-risk features NO YES Ticagrelor Cath Clopidogrel Cath In-lab loading if PCI

11 NSTE-ACS in the Real World of All-comers CABG >10% NSTEMI: normal angios >25% in women ANGIO-No PCI Med TT 20% 10% 35% No ANGIO-No PCI Med TT BENEFIT OF PRE-TTT? STEMI -PCI 90% -CABG 6-8% -Med 2-4% 35% SCAD -PCI 30-80% -Med 25-60% -CABG: 10% PCI Mandelzweig et al., Eur Heart J. 2006;27: O Donoghue et al; JAMA 2008; 300: Patel et al; Am Heart J 2006; 152:

12 Case 2 Mr F. a 55 yo, Active smoker, prior Hx, BMI=32kg/m2 Chest pain since 180 minutes SBP=150/90 mmhg; HR=92/min. Prior medications : statins and betablockers

13 Question 1: prehospital IIb/IIIa inh.? 1. YES 2. NO

14 Why?

15 IIb/IIIa-RA improves fibrinolysis Without GP IIb/IIIa inhibitors (A) With GP IIb/IIIa inhibitors (B) Collet JPh, Montalescot G: Circ. Res. 2002; 90: 428

16 Relative proportion (%) Antithrombotic therapy in STEMI must combine fast acting and effective antiplatelet and anticoagulant treatment Thrombus composition varies with time in acute myocardial infarction: platelets are key in the initiation of arterial thrombosis A. Typical early thrombus (ischaemic time* 1 h) Mainly platelet aggregates with a few cholesterol crystals (yellow asterisks). Scanning Electron Micrograph ( 3000) A Increase in the relative proportion of fibrin to platelets over time p=0.053 p=0.02 Fibrin Platelets B. Typical late thrombus (ischaemic time* >3 h) Mainly erythrocytes (b) trapped in fibrin mesh (c) with only a few platelet aggregates (d) and rare white cells (a). B p=0.09 p= <3 hours (reference) 3 6 hours 6 12 hours Ischaemic time* Silvain J et al. J Am Coll Cardiol 2011;57: * Time from symptom onset to thrombus retrieval 16

17 Thrombus STEMI p= % 1,342 (80.5%) angiograms of STEMI patients enrolled in ASSENT-4 PCI. % 13.4% POST-PCI THROMBUS BURDEN Residual TIMI thrombus grade 2 and/or distal embolization and/or slow flow OR 2.43 for 90-day mortality (95% CI , p=0.0052) ASSENT-4 PCI. Lancet 2006;367: Zalewski J et al. JACC 2011;57:

18 Angiography

19 Angiography

20 Abciximab for Primary PCI in STEMI Long-Term* Significant Mortality Reduction (but most trials antedate modern oral antiplatelet therapy) No. of Deaths/Total (%) Abciximab Control Control (n-14,145) Abciximab (n=12,297) Better Better P Value RAPPORT 11/242(4.5) 10/241(4.1).83 ISAR-2 17/200(8.5) 12/201(6.0).33 ADMIRAL 11/151(7.3) 5/149(3.4).13 CADILLAC 45/ /1052(4.2).83 Petronio et al 6/45(13.3) 2/44(4.5).15 Zorman et al 7/51(13.7) 5/112(4.5).04 ACE 21/197(10.5) 10/197(5.0).04 Primary PCI 118/1916(6.2) 88/1996(4.4).01 RRR 29% * 6 and 12 Month De Luca G et al. JAMA 2005;293:

21 GP IIb/IIIa inhibitors in primary PCI substantially increase bleeding Study Major bleeding complications Treatment n/n Control n/n OR (fixed) 95% CI Weight % OR (fixed) 95% CI ACE 7/200 6/ [0.39, 3.55] ADMIRAL 1/149 0/ [0.12, 75.73] APE 0/29 0/30 Not estimable ASSIST 19/201 11/199 B [0.83, 3.85] BRAVE-3 7/401 7/ [0.35, 2.86] CADILLAC 6/1052 4/ [0.41, 5.23] Ernst et al. 8/89 2/ [0.28, 6.90] HORIZONS MI 90/ / [1.15, 2.25] ISAR 7/201 9/ [0.28, 2.10] ON-TIME 2 9/473 7/ [0.48, 3.53] Petronio et al. 0/17 0/14 Not estimable Petronio et al. 0/30 0/60 Not estimable Petronio et al. 0/43 2/ [0.01, 3.90] RAPPORT 40/241 23/ [1.10, 3.28] Total (95% CI) 194/ / [1.19, 1.89] Test for heterogeneity: Chi 2 = 5.63, df = 10 (P = 0.85),I 2 = 0% Test for overall effect: Z = 3.47 (P = ) Total (95% CI)* 104/ / [1.04, 1.93] Test for heterogeneity: Chi 2 = 5.38, df = 9 (P = 0.80),I 2 = 0% Test for overall effect: Z = 2.18 (P = 0.03) De Luca et al. European Heart Journal 2009: 30; Favours Gp IIb-IIIa inh Favours control 21

22 When?

23 POST-PCI PRE-PCI Procedural TIMI 3 Flow Metanalysis on individual data of 7 randomized studies ( )(n=722) Study or Sub-category EARLY (n/n) LATE (n/n) ERAMI 7/40 5/40 PETRONIO et Al 9/55 7/55 Rakowski et al. 8/25 3/30 RELAx-MI 25/105 11/105 REOMOBILE 11/48 8/52 ReoPro-BRIDGING 8/28 2/27 Zorman et al. 9/56 1/56 Total (95% CI) 77/357 37/365 Weight (%) OR (Fixed) (95% CI) (0.43, 5.174) (0.46, 3.90) (0.98, 18.22) (1.24, 5.76) (1.60, 4.49) (0.95, 26.23) (1.29, 86.21) (1.61, 3.77) Test for heterogeneity: Chi² = 5.62, df = 6 (P = 0.47), I² = 0% Test for overall effect: Z = 4.16 (P < ) ERAMI 37/40 31/ (0.89, 14.39) PETRONIO et Al 49/55 49/ (0.30, 3.32) Rakowski et al. 22/25 26/ (0.23, 5.59) RELAx-MI 97/105 97/ (0.36, 2.77) REOMOBILE 40/48 40/ (0.55, 4.46) ReoPro-BRIDGING 25/28 20/ (0.67, 12.75) Zorman et al. 46/51 45/ (0.65, 6.45) Total (95% CI) 316/ / (1.02, 2.53) Test for heterogeneity: Chi² =3.69, df = 6 (P = 0.72), I² = 0% Test for overall effect: Z = 4.16 (P < 0.04) Favours Late GP IIb-IIIa inhibitors Favours Early GP IIb-IIIa inhibitors De Luca et al. J Thromb Haemost 2011; 12;

24 Early and late Mortality Benefit Early Abciximab (n=357) Late Abciximab (n=365) HR [95%CI] = 0.49[ ] P=0.04 HR [95%CI] = 0.98[ ] P= Mo Years Early vs late : 20% vs. 24.6%; HR 95% (CI) = 0.65 ( ) P = 0.02, Phet = 0.6]. Major Bleed (TIMI) : 3.3% vs. 2.3%, P = 0.4 Adapted from De Luca et al. J Thromb Haemost 2011; DOI: /j x. 24

25 In whom not to use it?

26 Efficacy according to time from SO and to risk profil Patient risk profil High risk and short delay High Intermediate EUROTRANSFER FINESSE ss grpe RELAX-AMI On Time FINESSE High risk and long delay Low MISTRAL BRAVE-3 Low risk and long delay Low Risk and short delay Ischemic time(min) (Symptom onset- TTT) Benefit of upstream tx No benefit of uspstream tx

27 Primary PCI on abciximab

28 Antiplatelet therapy for STEMI undergoing PCI Recommendations Class a Level b Antiplatelet therapy ASA is recommended for all patients without contraindications at an initial oral loading dose of mg (or mg i.v.) and at a maintenance dose of mg daily long-term regardless of treatment strategy. I A A P2Y 12 inhibitor is recommended in addition to ASA and maintained over 12 months unless there are contraindications such as excessive risk of bleeding. Options are: I A Prasugrel (60-mg loading dose, 10-mg daily dose) if no contraindication I B Ticagrelor 180-mg loading dose, 90 mg twice daily if no contraindication I B Clopidogrel (600-mg loading dose, 75 mg daily dose), only when prasugrel or ticagrelor are not available or are contraindicated. I B P2Y 12 inhibitors should be given at time of first medical contact. I B GP IIb/IIIa inhibitors should be considered for bailout or evidence of no-reflow or a thrombotic complication. IIa C Upstream use of a GP IIb/IIIa antagonists (vs. in-lab use) may be considered in high ischemic and low bleeding risk patients presenting <3 hours and undergoing transfer for primary PCI - Abciximab : 0.25mg/kg iv bolus and then 0.15µg/kg/min - Tirofiban: 25µg/kg iv bolus and then 0.15µg/kg/min (decrease by 50% if CrCl <30mL/min) - Eptifibatide: 180µg/kg and then 2µg/kg/min. A bolus of 180µg/kg/min is administered 10 min after first bolus ( decreased by 50% if CrCl <50mL/min). IIb B

29 STEMI (PRIMARY PCI) <24 h Aspirin 500 mg IV IV anticoagulation Bleeding Risk Stratification Prior STROKE/TIA, ACTIVE BLEEDS, RECENT IVASIVE PROCEDURE VKA or NOAC, Thrombopénia (< ) NO Prasugrel 60 mg OD (irrespective of weight and age) If <3h and <75 yo YES clopidogrel (LD according to risk) NO KT YES abciximab KT KT P. Ecollan, G. Montalescot 02/2010

30 Conclusion

31 Modes of Action of Platelet Antagonist ADHESION ACTIVATION AGGREGATION GP VI and GP Ib-VWF? no FDA or EMEA approved agents are designed specifically to target platelet adhesion Cox-1 Membran Receptors ASPIRIN P2Y 12 Inhibitors GP IIbIIa IIbIIIa Inhibitors