1. 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

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

3. 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

4. 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

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

6. 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

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

8. Stent Thrombosis in STEMI Patients
Lancet 2014;384:602

9. 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 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

10. 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 %

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

12. 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

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

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

15. 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

16. 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)

17. 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

18. 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

19. 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

20. 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

22. Bivalirudin vs Heparin in NSTE-ACS Randomised Trials
BAT Trial (Bittl et al NEJM 1995;33: 764-9)
4098 patients randomized
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
Composite endpoint NS including major bleeding
All randomized patients had femoral access
Majority of randomized patients were biomarker negative

23. 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)
<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

24. MACE Comparing Bivalirudin
Lancet 2014;394: