Optimal antithrombotic therapy:

Transcription

1 Optimal antithrombotic therapy: upstream and during primary PCI. Steen D Kristensen, MD, DMSc, FESC Professor and Consultant Interventional Cardiologist Aarhus University, Denmark UNIVERSITY OF AARHUS 1

2 Conflict of interest Lecture fees from AZ, BMS, BAYER, Boehringer-Ingelheim, Eli-Lilly, Merck, Pfizer, The Medicines Company. UNIVERSITY OF AARHUS 2

3 STEMI Fibrinolysis Primary PCI Earlier treatment => improved prognosis Boersma E et al, Lancet 1996; 348:771-5 De Luca G et al, Circulation 2004; 109:1223-5

4 STEMI Fibrinolysis Primary PCI: IA ESC and other Guidelines Minimize delay

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7 STEMI: classical prehospital therapy Aspirin: mg orally (or i.v.) P2Y12 inhibitors: clopidogrel 600 mg Unfractionated heparin 5-10,000 IU i.v.

8 Treatments before PCI: Easy to administer Safe during transfer Needed anyway for PCI Beneficial on reperfusion

9 STEMI: prehospital therapy P2Y12 inhibitors GPI LMWH Bivalirudin New candidates?

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11 Do we need studies on prehospital oral P2Y12 inhibition?

12 STEMI: prehospital therapy P2Y12 inhibitors CIPAMI, (ATLANTIC) GPI FINESSE, OnTIME2 LMWH ATOLL Bivalirudin (EUROMAX)

13 FINESSE: Study Design Acute ST Elevation MI (or New LBBB) within 6h pain onset Presenting at Hub or Spoke with estimated time to Cath between 1 & 4h Double Blind Double Dummy Randomize 1:1:1 2,400 patients *Only 5U if 75 yr Placebo Placebo Placebo Abciximab Reteplase (5U+5U)* Abciximab Transfer To Cath Lab ASA, unfractionated heparin 40U/kg (max 3000U) or enoxaparin (0.5 mg/kg IV mg/kg SC) substudy only Abciximab Placebo Placebo Primary PCI with Abciximab Infusion (12 h) Follow up through 90 days and 1 year

14 FINESSE: Primary Composite Endpoint at 90 Days 15% p= % 10,7% 10,5% 9,8% 5% 0% )n=806(primary PCI with in lab Abciximab )n=818(abciximab Facililated PCI )n=828(reteplase/abciximab Facilitated PCI S. Ellis et al, ESC 2007

15 FINESSE: TIMI Major or Minor Bleeding (nonintracranial) through Discharge/Day7 Percentage 30% 25% 20% 15% 10% 5% 0% TIMI Bleeding through Discharge/Day 7 p<0.001 p<0.001 p=0.025 p=0.008 p=0.006 p=0.547 p=0.141 p=0.025 p= ,5% 9,7% 10,1% 6,0% 6,9% 4,1% 4,8% 4,3% 2,6% TIMI Major TIMI Minor TIMI Major or Minor )n=795(primary PCI with In Lab Abciximab )n=805(abciximab Facililated PCI )n=814(abciximab/reteplase Facilitated PCI Ellis et al, ESC Vienna 2007

16 Anti-trombotic therapy - ESC STEMI Guidelines 2008 Adjunctive therapy: primary PCI Not recommended: Upstream therapy with GPI, fibrinolytics or the combination.

17 ON-TIME 2 The Lancet 2008; 372:

18 Study Design On-TIME 2 STEMI diagnosed in ambulance or referral center ASA mg clopidogrel + UFH N=984 Jun 2006 Nov 2007 Placebo HDB Tirofiban Bolus: 25 µg/kg 0.15 µg/kg/min infusion Transportation Angiogram PCI center Angiogram Provisional HDB Tirofiban PCI Tirofiban cont d van t Hof AWJ, et al. Lancet 2008;16;372(9638):

19 Ongoing Tirofiban In Myocardial Infarction Evaluation Inclusion Site Ambulance 95% Referral Center 3% PCI center (ER) 2%

20 Ongoing Tirofiban In Myocardial Infarction Evaluation Endpoints Primary Residual ST segment deviation (>3mm) 1 hour after PCI Key Secondary Combined occurrence of death, recurrent MI, urgent TVR or thrombotic bailout at 30 days follow-up Safety ( major bleeding)

21 Ongoing Tirofiban In Myocardial Infarction Evaluation Patient and system deay 60 min d-t-b 35 min Ischemic Time (min) SO-1st Contact Preparation Transportation Door-Angio Angio-Balloon [ Mean transport distance: 25 km/ 17 miles ]

22 Residual ST Deviation after PCI

23 Survival free from Major Adverse Clinical Events

24 All-Cause Mortality 30 Days open label & double-blind, n = 1398

25 On-TIME 2 Study Design STEMI diagnosed in ambulance or referral center ASA mg clopidogrel + UFH N=984 Jun 2006 Nov 2007 Placebo HDB Tirofiban Bolus: 25 µg/kg 0.15 µg/kg/min infusion Transportation Angiogram PCI center Angiogram Provisional HDB Tirofiban PCI Tirofiban cont d van t Hof AWJ, et al. Lancet 2008;16;372(9638):

26 % of Patients Results of the pooled analysis confirm the findings of the double-blind study On-TIME 2 Pooled Total Pooled Cohort (n=1398) 16 Placebo/No Tirofiban HDB Tirofiban ,6 p= ,8 p= ,8 p= ,1 2,2 3,7 0 n=662 n=677 n=662 n=677 n=656 n= Day MACE 30-Day Mortality 1-Year Mortality (Death, MI, or utvr) Ten Berg, et al. J Am Coll Cardiol. 2010;55(22):

27 % of Patients 30 Day-MACE and 1 Year-Mortality in On-TIME 2 Pooled Patients Undergoing Primary PCI (86%) Primary PCI Subgroup (n=1203) 16 Placebo/No Tirofiban HDB Tirofiban 12 OR = 0.50 (95% CI, ) 8 8,5 p= ,5 5,5 2,4 0 n=583 n= Day MACE n=515 n=477 1-Year Mortality Ten Berg, et al. J Am Coll Cardiol. 2010;55(22):

28 GPI Primary PCI: metaanalysis

29 Early GPI: preprocedural TIMI 3 flow

30 Early GPI: preprocedural TIMI 3 flow

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32 What about LMWH (enoxaparin)?

33 ATOLL Trial design Randomization as early as possible (MICU +++) Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before Rx Similar antiplatelet therapy in both groups STEMI Primary PCI ENOXAPARIN IV 0.5 mg/kg with or without GPIIbIIIa ENOXAPARIN SC IVRS Primary PCI UFH IV IU with GP IIbIIIa IU without GP IIbIIIa (Dose ACT-adjusted) UFH IV or SC 30-day results

34 % of patients Primary Endpoint Death, Complication of MI, Procedure Failure or Major Bleeding RRR = 17% P = UFH ENOX

35 Main secondary EP rate Main Secondary Endpoint (ischemic) Death, Recurrent MI/ACS or Urgent Revascularization 30d rate (%) UFH ENOX Log-Rank Test p= % i41% 6.7% Days

36 Primary PCI in STEMI Aspirin + Clopidogrel + UFH

37 What should we add during PPCI? Change clopidogrel to prasugrel or ticagrelor? Bivalirudin? GPI?

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39 K-M estimated rate (% per year) Primary endpoint: CV death, MI or stroke STEMI Clopidogrel Ticagrelor HR: 0.85 (95% CI = ), p= No. at risk Months Ticagrelor 4,201 3,887 3,834 3,732 3,011 2,297 Clopidogrel 4,229 3,892 3,823 3,730 3,022 2,333 G Steg et al 1,891 1,868

40 STEMI Prasugrel and Ticagrelor work both very well in STEMI (substudies from TRITON and PLATO). We should implement it during/after PPCI

41 Incidence (%) Primary PCI: abciximab in cath lab Placebo ReoPro 51% p=0.03 Death / MI / urg TVR at 30 days 53% p= % p= % 14,6 p= % p= ,2 5,8 10,5 5,0 6,1 6,7 4,3 10,5 4,5 0 RAPPORT (n=483) ISAR-2 (n=401) ADMIRAL (n=300) CADILLAC (n=2082) ACE (n=400)

42 GPI Intracoronary administration?

43 GPI Intracoronary administration? Logical First studies showed promising results

44 Study Design, Flow, and Compliance 2065 patients with suspected STEMI - STEMI with symptoms <12 h - Planned primary PCI - no contraindication for abciximab UFH IU/kg Aspirin 500 mg, Clopidogrel 600 mg/prasugrel 60 mg Abciximab bolus 0.25 mg/kg plus 12 h infusion µg/kg/min 1032 patients randomized to IC abciximab 1033 patients randomized to IV abciximab 1002 patients PCI started 1001 patients PCI started 995 patients abciximab bolus given; PCI completed 993 patients abciximab bolus given; PCI completed 935 patients with 90 day follow-up 932 patients with 90 day follow-up

45 Cumulative event free survival from death, reinfarction and congestive heart failure [%] H. Thiele et al. Results Combined Clinical Endpoint p=0.54 Intracoronary Abciximab Intravenous Abciximab Time from randomization [days]

46 INFUSE-AMI Trial 452 pts with anterior STEMI Anticipated Sx to PCI <5 hrs, TIMI 0-2 flow in prox or mid LAD Primary PCI with bivalirudin anticoagulation Pre-loaded with aspirin and clopidogrel 600 mg or prasugrel 60 mg Manual aspiration R 1:1 Stratified by symptoms to angio <3 vs 3 hrs, and prox vs mid LAD occlusion No aspiration R 1:1 R 1:1 IC Abcx No Abcx IC Abcx No Abcx Primary endpoint: Infarct size at 30 days (cmri) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30d, 1 yr)

47 INFUSE-AMI: Devices ClearWay RX Catheter (Atrium Medical) Export Catheter (Medtronic) Microporous PTFE balloon mounted on a 2.7Fr Rx catheter Fluid weeps through the pores no high pressure jets Vessel occlusion site-specific infusion without systemic drug dilution from preferential flow to the LCX or aorta (blowback) FDA approved for localized infusion of diagnostic and therapeutic agents Guide catheter compatibility: 6F (min ID 0.070") Crossing profile: Aspiration lumen: FDA approved for removal/aspiration of embolic material (thrombus/debris) from vessels In the single center TAPAS trial improved MBG, STR, survival

48 G Stone et al JAMA 2012

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51 Primary Endpoint Net adverse clinical events (%)* HORIZONS - bivalirudin: 30 Day Net Adverse Clinical Events Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin (n=1800) 12.2% 9.3% HR [95%CI] = 0.75 [0.62, 0.92] P=0.006 R. Mehran, G. Stone Time in Days *MACE or major bleeding (non CABG)

52 Mortality (%) 1-Year All-Cause Mortality 5 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% 4 Δ = 1.4% % 2.1% Δ = 1.0% P=0.049 Diff [95%CI] = 3.4% -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P= Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Time in Months Mehran, TCT 2008

53 Cardiac Mortality (%) ' Time in Months 3-Year Cardiac Mortality Time in Months Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) yr HR (95%CI) 0.56 (0.40, 0.80) P= % % 2.1% 2.9% Months Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

54 Cardiac mortality (%) 3-Year Cardiac Mortality Landmark analysis day HR (95% CI) 0.62 ( ) p= % 1.8% Heparin + GP IIb/IIIa (n=1802) Bivalirudin (n=1800) 3 year HR (95% CI) p= % 1.1% Months Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

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56 Gaps in knowledge (opportunities) Effect of new anti-thrombotic in the prehospital setting. New intravenous anti-platelet and anticoagulant drugs Local drug delivery at site of thrombus.

57 ESC Myocardial Revascularization Guidelines 2010

58 ESC Myocardial Revascularization Updated 2012 Guidelines 2010

59 ESC Myocardial Revascularization Updated 2012 Guidelines 2010