Heparin Should be the First-line Therapy for Patients with ACS/AMI Cindy L. Grines MD, FACC, SCAI Detroit Medical Center Heart Hospital, Wayne State University, Detroit, MI

Disclosures Consultant / Advisory Board < 10k Salary Abbott Vascular, Inc. Merck Medicines Company Volcano Corp. Salary Editor-in-Chief: Journal of Interventional Cardiology

Why Heparin Should be used as First Line Inexpensive No reduction in bleeding with bivalirudin (compared to heparin alone) Reduced bleeding does not translate into reduced mortality Significant increase in early stent thrombosis in STEMI patients Data from DMC Pharmacy Feb 2015

Cost of Heparin vs Bivalirudin Heparin 10,000 units = $1.83 Bivalirudin 250mg/5mL single-use vial = $180.61 Based on a 100 kg patient PCI bolus & infusion (1.7mg/kg/hour) x 1 hour: Total: 250mg = $180.61 PCI bolus & infusion (1.7mg/kg/hour) x 1 hour, followed by reduced dose (0.25mg/kg/hours) x 4 hours: Total: 350mg 2 vials = $361.22 PCI bolus & infusion (1.75mg/kg/hour) x 5 hours: Total: 950mg 4 vials = $722.44 Data from DMC Pharmacy Feb 2015

Bivalirudin vs Heparin +/- GP IIb/IIIa Meta-analysis Lancet 2014;384:599-606

Meta-analysis:Bleeding comparing bivalirudin and heparin Reduced Bleeding: Heparin + GPIIb/IIIa trials No Reduction in Bleeding: Heparin alone (provisional GPIIb/IIIa in both arms) Planned GPIIb/IIIa in both arms

Meta-analysis of 16 Rand Trials (33,958 patients) Lancet 2014;384:599-606

Stent Thrombosis in STEMI Patients Lancet 2014;384:602

Bright Trial Design 2194 patients with STEMI (90%) and NSTEMI Clopidogrel in 100% R Bilvalirudin alone Biv 0.75mg/kg bolus (0.3mg/kg bolus if ACT<225s) during PCI 1.75mg/kg/h infusion PCI (0.2mg/kg/h) continued 234+ 117 min Heparin alone Heparin 100U/kg bolus Heparin plus tirobiban Heparin 60U/kg bolus. Tirofibiban 10µg/kg/min infusion for 18-36h. Clinical follow-up at 30 days and one year Yaling Han, MD

Bright Trial: Safety Endpoints at 30 Days no Elevated ST with Prolonged Bivalirudin Infusion 2.1 P=.07 1.5 P=.07 1.1 0.9 0.7 0.7 0.6 0.5 0.1 %

Bright Trial: Who cares about a reduction in bleeding if it does not affect mortality? All p value = NS

Euromax Acute Stent Thrombosis Ticagrelor or Prasugrel used in 50% ________ Bivalirudin (post PCI 0.25mg/kg/hr x 4 hrs) ------- Heparins + GPI JACC: Cardiovascular Interventions 2015;8:214-20

Euromax: Outcomes based on Post-PCI Infusion Dose of Bivalirudin Death REMI Definite ST NACE JACC: Cardiovascular Interventions 2015;8:214-20

Prolonged Infusion of Higher dose Bivalirudin is NOT superior to Heparin – Similar bleeding and outcomes

Increase in Acute Stent Thrombosis with Bivalirudin Remains a problem Observed in 3 of 4 randomized STEMI trials Not alternated with use of Prasugrel or Ticagrelor (high utilization in Euromax and HEAT) May not be improved with pre hospital use of oral antiplatelet agents Prasugrel (ACCOAST Trial - NSTEM patients) no benefit, increased bleeding Ticagrelor (ATLANTIC Trial – STEMI patients) primary endpoint negative, but ↓ST Trend for higher mortality May not be improved with 4 hr infusion of low dose bivalirudin post PCI (EUROMAX) Prolonged higher dose infusion – more bleeding

Bivalirudin Treatment of Choice in NSTE-ACS ? ESC NSTE-ACS Guidelines 2011 Bivalirudin plus provisional GP IIb/IIIa receptor inhibitors are recommended as an alternative to UFH plus GP IIb/IIIa receptor inhibitors in patients with an intended urgent or early invasive strategy, particularly in patients with a high risk of bleeding. I B ACC/AHA NSTE-ACS Guidelines Class IIa For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit administration of an IV GP IIb/IIIa inhibitor if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier than planned catheterization or PCI (57, 76, 77). (Level of Evidence: B)

SCAAR Heparin vs Bivalirudin 51,549 consecutive patients with NSTE-ACS in SCAAR not receiving GPIIb/IIIa inhibitors 5,395 patients with missing data Complete case analysis Heparin alone 35,167 patients Bivalirudin 10,985 patients Multiple imputation, adjusted for baseline and procedural differences Heparin alone 39,296 patients Bivalirudin 12,253 patients Imputed data set

SCAAR NSTEMI Results Complete case Imputed dataset 1.56 Complete case 1.40 Imputed dataset Instrumental variable 1.08 0.5 1.0 1.5 2.0 Favours bivalirudin Favours heparin

SCAAR Conclusion Our large observational study questions the superiority of bivalirudin over heparin (in the absence of GP IIb/IIIa blockade) in patients with NSTE-ACS undergoing PCI The randomized trial VALIDATE-SWEDEHEART comparing bivalirudin to heparin in patients pretreated with novel ADP-receptor blockers (n=6000) is under way

Why Heparin Should be used as First Line Inexpensive No reduction in bleeding with bivalirudin (compared to heparin alone) Reduced bleeding does not translate into reduced mortality Significant increase in early stent thrombosis in STEMI patients – not improved with more potent oral antiplatelet agents

Bivalirudin vs Heparin in NSTE-ACS Randomised Trials BAT Trial (Bittl et al NEJM 1995;33: 764-9) 4098 patients randomized 1993-1994 Composite endpoint NS Bivalirudin reduced major bleeding Trend for higher mortality in the bivalirudin group (p=0.08)! ISAR-REACT 3 (Kastrati et al NEJM 2008;359:688-96) 4570 biomarker negative patients randomized 2005-2008 Composite endpoint NS including major bleeding All randomized patients had femoral access Majority of randomized patients were biomarker negative

SCAAR Baseline and PCI Characteristics UH/LMWH (n=39,298) Bivalirudin (n=12,252) P-value P-value after ps-score adjustment Age (mean+SD) 67.6 + 11 68.3 + 11 <0.001 0.56 Female (%) 28 30 0.004 0.90 Prior MI (%) 26 0.70 Ex-smokers (%) 40 37 Active smoker (%) 20 0.53 Diabetes (%) 21 0.02 0.94 ASA (%) 97 0.008 0.74 Clopidogrel/Ticagrelor/Prasugrel (%) 94 92 0.29 Pretreated with UH/LMWH/ Fondaparinux (%) 54 55 0.08 0.91 Positive biomarkers (%) 74 80 Radial (%) 53 0.45 0.80 Use of stent (%) 0.59 Use of DES (%) 48 41 0.43

MACE Comparing Bivalirudin Lancet 2014;394:599-606