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
Conflict of interest Lecture fees from AZ, BMS, BAYER, Boehringer-Ingelheim, Eli-Lilly, Merck, Pfizer, The Medicines Company. UNIVERSITY OF AARHUS 2
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
STEMI Fibrinolysis Primary PCI: IA ESC and other Guidelines Minimize delay
STEMI: classical prehospital therapy Aspirin: 250-300 mg orally (or i.v.) P2Y12 inhibitors: clopidogrel 600 mg Unfractionated heparin 5-10,000 IU i.v.
Treatments before PCI: Easy to administer Safe during transfer Needed anyway for PCI Beneficial on reperfusion
STEMI: prehospital therapy P2Y12 inhibitors GPI LMWH Bivalirudin New candidates?
Do we need studies on prehospital oral P2Y12 inhibition?
STEMI: prehospital therapy P2Y12 inhibitors CIPAMI, (ATLANTIC) GPI FINESSE, OnTIME2 LMWH ATOLL Bivalirudin (EUROMAX)
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 + 0.3 mg/kg SC) substudy only Abciximab Placebo Placebo Primary PCI with Abciximab Infusion (12 h) Follow up through 90 days and 1 year
FINESSE: Primary Composite Endpoint at 90 Days 15% p=0.55 10% 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
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=0.127 14,5% 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
Anti-trombotic therapy - ESC STEMI Guidelines 2008 Adjunctive therapy: primary PCI Not recommended: Upstream therapy with GPI, fibrinolytics or the combination.
ON-TIME 2 The Lancet 2008; 372: 537-46
Study Design On-TIME 2 STEMI diagnosed in ambulance or referral center ASA + 600 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):537-46. 18
Ongoing Tirofiban In Myocardial Infarction Evaluation Inclusion Site Ambulance 95% Referral Center 3% PCI center (ER) 2%
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)
Ongoing Tirofiban In Myocardial Infarction Evaluation Patient and system deay 60 min 76 20 25 19 16 d-t-b 35 min 0 60 120 180 Ischemic Time (min) SO-1st Contact Preparation Transportation Door-Angio Angio-Balloon [ Mean transport distance: 25 km/ 17 miles ]
Residual ST Deviation after PCI
Survival free from Major Adverse Clinical Events
All-Cause Mortality 30 Days open label & double-blind, n = 1398
On-TIME 2 Study Design STEMI diagnosed in ambulance or referral center ASA + 600 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):537-46. 25
% 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 12 8 8,6 p=0.043 5,8 p=0.051 5,8 p=0.078 4 4,1 2,2 3,7 0 n=662 n=677 n=662 n=677 n=656 n=670 30-Day MACE 30-Day Mortality 1-Year Mortality (Death, MI, or utvr) Ten Berg, et al. J Am Coll Cardiol. 2010;55(22):2446-55. 26
% 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, 0.31-0.82) 8 8,5 p=0.007 4 4,5 5,5 2,4 0 n=583 n=586 30-Day MACE n=515 n=477 1-Year Mortality Ten Berg, et al. J Am Coll Cardiol. 2010;55(22):2446-55. 27
GPI Primary PCI: metaanalysis
Early GPI: preprocedural TIMI 3 flow
Early GPI: preprocedural TIMI 3 flow
What about LMWH (enoxaparin)?
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 50-70 IU with GP IIbIIIa 70-100IU without GP IIbIIIa (Dose ACT-adjusted) UFH IV or SC 30-day results
% of patients Primary Endpoint Death, Complication of MI, Procedure Failure or Major Bleeding 40 35 30 33.7 RRR = 17% P = 0.07 25 28 20 15 UFH ENOX 10 5 0
Main secondary EP rate 0.00 0.05 0.10 0.15 Main Secondary Endpoint (ischemic) Death, Recurrent MI/ACS or Urgent Revascularization 30d rate (%) UFH ENOX Log-Rank Test p=0.01 11.3% i41% 6.7% 0 5 10 15 20 25 30 Days
Primary PCI in STEMI Aspirin + Clopidogrel + UFH
What should we add during PPCI? Change clopidogrel to prasugrel or ticagrelor? Bivalirudin? GPI?
K-M estimated rate (% per year) Primary endpoint: CV death, MI or stroke STEMI 12 11 Clopidogrel 11.0 10 9 8 7 6 5 4 3 2 1 Ticagrelor HR: 0.85 (95% CI = 0.74 0.97), p=0.02 9.3 0 0 1 2 3 4 5 6 7 8 9 10 11 12 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
STEMI Prasugrel and Ticagrelor work both very well in STEMI (substudies from TRITON and PLATO). We should implement it during/after PPCI
Incidence (%) Primary PCI: abciximab in cath lab 20 15 Placebo ReoPro 51% p=0.03 Death / MI / urg TVR at 30 days 53% p=0.04 58% p=0.02 36% 14,6 p=0.01 57% p=0.02 10 5 11,2 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)
GPI Intracoronary administration?
GPI Intracoronary administration? Logical First studies showed promising results
Study Design, Flow, and Compliance 2065 patients with suspected STEMI - STEMI with symptoms <12 h - Planned primary PCI - no contraindication for abciximab UFH 50-70 IU/kg Aspirin 500 mg, Clopidogrel 600 mg/prasugrel 60 mg Abciximab bolus 0.25 mg/kg plus 12 h infusion 0.125 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
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]
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)
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: 0.068 Aspiration lumen: 0.041 FDA approved for removal/aspiration of embolic material (thrombus/debris) from vessels In the single center TAPAS trial improved MBG, STR, survival
G Stone et al JAMA 2012
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)
Mortality (%) 1-Year All-Cause Mortality 5 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% 4 Δ = 1.4% 3 2 1 0 3.1% 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=0.029 0 1 2 3 4 5 6 7 8 9 10 11 12 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Time in Months 1800 1705 1684 1669 1520 1802 1678 1663 1646 1486 Mehran, TCT 2008
Cardiac Mortality (%) ' Time in Months 3-Year Cardiac Mortality Time in Months Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) 6 5 3-yr HR (95%CI) 0.56 (0.40, 0.80) P=0.001 5.1% 4 3 2 1 3.8% 2.1% 2.9% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Cardiac mortality (%) 3-Year Cardiac Mortality Landmark analysis 5 4 3 2 1 30 day HR (95% CI) 0.62 (0.40 0.96) p=0.03 2.9% 1.8% Heparin + GP IIb/IIIa (n=1802) Bivalirudin (n=1800) 3 year HR (95% CI) 0.49 0.28 0.86 p=0.01 2.2% 1.1% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
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.
ESC Myocardial Revascularization Guidelines 2010
ESC Myocardial Revascularization Updated 2012 Guidelines 2010
ESC Myocardial Revascularization Updated 2012 Guidelines 2010