1. Bivalirudin is Superior to Heparin for ACS Patients
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation

2. Disclosures
None

3. Comparison 1
Bivalirudin
vs.
Heparin + routine GPI
in STEMI

4. Meta-analysis: UFH ± Abciximab in Primary PCI 8 RCTs, 3,949 pts with STEMI w/i 12 undergoing primary (7) or rescue (1) PCI randomized to UFH + abciximab vs. UFH alone
OR [95%CI] = 0.72 [0.55,0.94]
P=0.01
OR [95%CI] = 0.63 [0.54,0.73]
P<0.001
De Luca G et al. JAMA 2005;293:1759–1765

5. CADILLAC (n=2,082) Subacute thrombosis: Impact of abciximab
Stone GW et al. NEJM 2002;346:957–66 4

6. Kandzari DE et al. AHJ 2004;147:457–62
4 RCTs of Abciximab vs. Control in Primary PCI (N=3,266): Safety Events
OR [95%CI) =
1.45 (1.04–2.02)
OR [95%CI) =
1.74 (1.11–2.72)
OR [95%CI) =
2.13 (0.78–5.76)
OR [95%CI) =
0.75 (0.26–2.13)
Kandzari DE et al. AHJ 2004;147:457–62

7. HORIZONS-AMI + EUROMAX Pooled 30-day results (n=5,800)
Heparin ± GPI
(N=2911)
Bivalirudin
(N=2889)
Relative risk
(95% CI)
P Value
Death
90 (3.1%)
69 (2.4%)
0.77 ( )
0.10
Cardiac
85 (2.9%)
59 (2.0%)
0.70 ( )
0.03
Non‑cardiac
5 (0.2%)
10 (0.4%)
2.01 ( )
0.19
Reinfarction
42 (1.4%)
53 (1.8%)
1.27 ( )
0.24
Stent thrombosis (ARC)
40 (1.4%)
60 (2.1%)
1.51 ( )
0.04
Acute
6 (0.2%)
36 (1.2%)
6.04 ( )
<0.0001
Sub‑acute
34 (1.2%)
25 (0.9%)
0.74 ( )
MACE (death, MI, IDR, or stroke)
161 (5.5%)
163 (5.6%)
1.02 ( )
0.85
Protocol major bleeding
226 (7.8%)
120 (4.2%)
0.53 ( )
Blood transfusion
110 (3.8%)
62 (2.1%)
0.57 ( )
0.0002
Acquired thrombocytopenia
77 (2.9%)
37 (1.4%)
0.48 ( )
NACE (MACE or major bleeding)
346 (11.9%)
253 (8.8%)
0.74 ( )
Breslow-Day test for study heterogeneity non-significant: P ≥0.11 for all variables
Stone GW et al. JACC 2015;65:27–38 6

8. Comparison 2
Bivalirudin
vs.
Heparin + bailout GPI
in STEMI

9. Bivalirudin vs. Heparin Monotherapy During Primary PCI in STEMI: Three major RCTs
EUROMAX
HEAT PPCI
BRIGHT
N centers 65 1 82
N patients
2,198
1,812
2,194
- Bivalirudin
1,089
905
735
- Heparin
460
907
729
- Heparin + GPI
649 -
730
Heparin mono bolus
60 IU/kg
70 IU/kg
100 IU/kg
Bival infusion
Low or high dose
Median 4 hrs No
High dose
Median 3 hrs
GPI bailout, Biv vs. Hep
7.9% vs. 25.4%
13.5% vs. 15.5%
4.4% vs. 5.6%
Prasugrel/ticagrelor
59%
89% 0%
Radial
47%
81%
79%
non-rand
rand

10. EUROMAX: Treatment According to Routine GPI Use
1:1
UFH (91.3%*)/LMWH ± GPI
Per standard practice
(n=1,109)
BIVALIRUDIN
(provisional GPI only)
(n=1,089)
58.5% (n=649)
Routine GPI
41.5% (n=460)
No GPI
3.9% (n=42)
Routine GPI*
96% (n=1047)
No GPI
Note:
Non-randomized, non-stratified
* Median 60 U/kg received in both arms
* Protocol Deviation
25.4% (n=117)
Bailout GPI
7.9% (n=83)
Bailout GPI
Zeymer U et al. EHJ 2014:on-line

11. EUROMAX: Primary Endpoint Death or Major Bleeding
Log Rank P values
Overall:
A vs. B: 0.18
A vs. C: 0.04
B vs. C:
A. Heparin + Routine GPI
B. Heparin Only + Bailout GPI 12
C. Bivalirudin
9.8% 10 8
7.4%
major bleeding (%)
Death or 6
5.1% 4 2 5 10 15 20 25 30
Days from Randomization
Patients at risk:
A. Heparin + Routine GPI
649
598
588
586
577
563
445
B. Hep Only + Bailout GPI
460
426
415
412
407
395
320
C. Bivalirudin
1089
1038
1024
1020
1007
899
791
Zeymer U et al. EHJ 2014:on-line 10

12. EuroMax A prolonged high-dose bivalirudin infusion may safely reduce acute stent thrombosis
Heparin
± GPI
(n=1109)
Bivalirudin +
0.25 mg/kg/hr infusion*
(n=670)‡
Bivalirudin mg/kg/hr infusion*
(n=244)§
Acute ST
2 (0.2%)
11 (1.6%)
1 (0.4%)
Major bleeding
57 (6.0%)
16 (2.4%)
7 (2.9%)
Data on a post-PCI infusion is not available for 35 patients
* Median [95%CI] infusion duration was 4.5 [4.2, 4.9] hours
‡ 659 of these received at least 2 hours infusion post-PCI
§191 of these received at least 2 hours infusion post-PCI
Clemmensen P et al. JACC Int 2015;8:214–20

13. HEAT PPCI: 30-Day MACE (n=1,812)
Death, ReMI, CVA, TLR (%)
Days
Bivalirudin
Heparin
No. at risk
907
905 5 10 15 20 25 30
871
853
866
844
862
835
857
830
856
828 0% 1% 2% 3% 4% 5% 6% 7% 8% 9%
10%
Bivalirudin
Heparin P
MACE
8.7%
5.7%
0.01
The event curves demonstrate an early separation reflecting the substantial early hazard in the PPCI setting.
Shahzad A et al. Lancet 2014 12

14. HEAT PPCI: Stent Thrombosis
ARC definite or probable stent thrombosis
Bivalirudin (n=905)
Heparin (n=907)
Definite or probable
24 (3.4%)
6 (0.9%)
- Definite
23 (3.3%)
5 (0.7%)
- Probable
1 (0.1%)
- Acute
20 (2.9%)
- Subacute
4 (0.6%)
0 (0%)
Almost all of these events were - by ARC criteria - definite events occurring in the first 24 hours after stent implantation.
2-3x higher than in other trials
Shahzad A et al. Lancet 2014 13

15. Median activated clotting time post bolus
Why were the rates of acute stent thrombosis higher in HEAT PPCI than in any other bivalirudin STEMI trial?
Median activated clotting time post bolus
~239 secs
w/o GPI
ACT (seconds)
HEAT PPCI: Actalyke XL MAX‐ACT system
HORIZONS-AMI: Hemotec and Hemochron

16. HEAT PPCI: ACT* and GPI bailout Bivalirudin arm (n=915)
Measure
ACT 5-15 mins after bolus
806 (88%)
251 [229, 285] sec
ACT end-procedure
771 (84%)
246 [229, 270] sec
Bivalirudin rebolus anytime**
12.7%
GPI bailout
13.5%
~25% <229 seconds; rebolus rate should have been ~25%
*Actalyke XL MAX‐ACT system
**By protocol, rebolus for ACT <225 seconds
Shahzad A et al. Lancet 2014

17. Bellomo R et al. Crit Care Med 2009;37:3114-9
Limited external validity
Implausible effect size
Unequal allocation of resources
Lack of blinding
Numerous examples where single- center trials were “reversed” by multiple multicenter trials
“What works in one location may not in others due differences in baseline risk, intercurrent care, opportunity cost, and the fidelity with which the intervention can be delivered.”
“Single-center studies are valuable hypothesis-generating investigations. However, the evidence shows that.…they have typically not been confirmed by larger multicenter studies….the history of this field argues that two beneficial RCTs are necessary with at least one being a confirmatory trial. Accordingly, we should be very careful in taking single-center trials as a demonstration of a biological truth and should avoid giving them undue weight or value. .…practice guidelines should rarely, if ever, be based on evidence from single-center trials.”
Bellomo R et al. Crit Care Med 2009;37:3114-9

18. Limitations of HEAT PPCI
Suboptimal use of bivalirudin
PCI performed in only 82% of patients – not a typical primary PCI cohort
Study investigators did the data monitoring
CEC was at the study center – not independent
Data analysis was performed at the study center – not independent
Reinfarction diagnosed by a “common sense” definition – new thrombus qualifies!
Stent thrombosis not adjudicated by a core lab

19. BRIGHT: Study flow
2,194 pts with AMI randomized at 82 centers in China
Aspirin and clopidogrel
86.2 % STEMI
13.8% NSTEMI
79% radial
Randomization (1:1:1)
Bivalirudin alone
N=735
Biv 0.75 mg/kg bolus mg /kg/h infusion (0.3 mg/kg bolus if ACT< 225s). Bailout GPI permitted. Biv infusion (1.75 mg/kg/h) continued for at least 30 min post PCI (median 3h). 4.4% bailout tirofiban.
UFH alone
N=729
Heparin 100 U/kg bolus + additional dose if ACT <200 s. Bailout GPI permitted.
ACT goal =
5.6% bailout tirofiban.
UFH + Tirofiban
N=730
Heparin 60U/kg bolus .
Tirofiban 10μg/kg bolus μg/kg/min infusion for h.
ACT goal =
This is the study flowchart.
Bivalirudin, unfractionated Heparin, and Tirofiban were administrated according to the protocol.
Follow-up at 30 days, 6 months and 1 year
Primary endpoint: NACE, including MACCE (all-cause death, reMI, TVR or stroke) and bleeding events at 30 days.
Han Y et al. Submitted.

20. BRIGHT: Primary and Major Secondary Endpoint Events at 30 Days
Bivalirudin (n=735)
Heparin (n=729)
Heparin + Tirofiban (n=730)
Primary endpoint
Biv vs. Hep, p=0.009
RR (95%CI) 0.67 ( ), NNT=23.1
Biv vs. Hep+Tiro, p<0.001
RR (95%CI) 0.52 ( ), NNT=12.3
Hep vs. Hep+Tiro, p=0.04
RR (95%CI) 0.78 ( ), NNT=26.2 18
17.0
P<0.001 16
13.2 14
12.3 12
P<0.001
(%) 10
8.8
P=0.74
7.5 8
5.8
5.0 6
Primary events occurred in 8.8% of the patients receiving bivalirudin, which acquired 33% and 48% relative risk reductions compared with those of heparin monotherapy and heparin plus tirofiban, respectively, and the number need treatment were 23.1 and 12.3, respectively. The incidences of MACCE were similar among three treatment arms. Bivalirudin treatment was associated with a significantly reduced risk of overall bleeding events compared with heparin monotherapy and heparin plus tirofiban.
4.9
4.1 4 2
NACE
MACCE
Any Bleeding
Han Y et al. Submitted. 19

21. BRIGHT: Stent Thrombosis at 30 Days
Bivalirudin (n=735)
Heparin (n=729)
Heparin + Tirofiban (n=730)
P=0.77
1.2
1.0
0.9%
0.7%
0.8
0.6%
Stent thrombosis (%)
0.6
0.4
0.2
Stent thrombosis occurred in 0.6% of patients in bivalirudin group, similar to those of other two groups.
Thrombocytopenia was significantly lower for patients received bivalidrudin compared with those received heparin plus tirofiban, with a p value of The difference was significant when that of bivalirudin group compared with pooled populations in the other two heparin groups, with a p value of 0.04.
Bivalirudin
(n=735)
Heparin
(n=729)
Heparin + Tirofiban
(n=730)
Han Y et al. Submitted. 20

22. Comparison 3
Bivalirudin
vs.
Heparin GPI
in STEMI
in the “real world”

23. Impact of Bleeding Avoidance Strategies
NCDR CathPCI Registry : PCI in 1,522,935 pts
Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively.
Propensity-adjusted major bleeding
Adj OR (95%CI) =
0.77 (0.73 – 0.80)
NNT = 148
Adj OR (95%CI) =
0.67 (0.63 – 0.70)
NNT = 118
Adj OR (95%CI) =
0.38 (0.35 – 0.42)
NNT = 70
23%↓
33%↓
62%↓
Marso SP et al. JAMA. 2010;303:

24. Impact of Bivalirudin in Radial Procedures
NCDR CathPCI Registry : PCI in 501,017 pts
Femoral access with closure devices, radial access with heparin, and radial access with bivalirudin were used in 76%, 13%, 11%, and 18% of pts.
Major bleeding:
Propensity-adjusted
Non-access bleeding
Access bleeding
3.0
All pts
OR (95% CI)
NNT
2.7%
2.5%
Radial + heparin
0.96 ( )
1607
2.5
2190 (0.6)
P<0.0001
Radial + bival
0.79 ( )
138
168 (0.3)
2.0
1.8%
High bleeding risk pts
114 (0.2)
Radial + heparin
1.00 ( )
1393
1.5
Radial + bival
0.79 ( ) 68
1.0
0.4
0.6
0.8
1.0
1.2
Bival is AC of choice 2013
Adjusted OR
0.5
8186 (2.1)
1405 (2.2)
889 (1.6)
Lower than femoral + bivalirudin + VCD
Higher than femoral + bivalirudin + VCD
Radial access/bivalirudin combination was used less frequently in pts at highest risk for bleeding
Femoral access with VCD +
bivalirudin
Radial access
+ heparin
Radial access
+ bivalirudin
Baklanov DV et al. Circ Cardiovasc Interv. 2013;6:347-53 23

25. Anticoagulation Regimens During PCI
N = 458,448 PCI pts at 299 hosps
(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)
In-hospital events, propensity adjusted
Bleeding + Transfusion
Mortality OR
(95% CI) OR
(95% CI)
Comparator OR
(95% CI)
P Value
Comparator OR
(95% CI)
P Value
Bivalirudin
monotherapy
(n=156,064)
Bivalirudin monotherapy
(n=156,064)
0.51 (0.48, 0.55)
<0.0001
0.59 (0.54, 0.65)
<0.0001
Bivalirudin + GPI
(n=33,566)
Bivalirudin + GPI
(n=33,566)
0.96 (0.87, 1.06)
0.37
0.82 (0.72, 0.94)
0.004
Heparin alone
(n=85,870)
Heparin alone
(n=85,870)
0.71 (0.66, 0.76)
<0.0001
0.88 (0.82, 0.96)
0.003
Comparator Better 1
Heparin + GPI Better
(n=182,948) 2
Comparator Better 1
Heparin + GPI Better
(n=182,948) 2
Wise GR et al. J Interv Cardiol 2012;25:278–88

26. SCAAR (31,438 STEMIs) ARC Definite Stent Thrombosis
All primary PCI patients who received a stent in Sweden from January 2007 to July 2014
Bivalirudin alone
Heparin alone
Heparin + GPIIb/IIIa n
16,860
3,246
11,392
ST day 0-30
0.8% (n=142)
0.9% (n=30)
0.9% (n=103)
ST day 0-1
0.3% (n=55)
0.3% (n=9)
0.2% (n=25)
ST day 2-30
0.5% (n=87)
0.7% (n=21)
0.7% (n=78)
c/o David Erlinge

27. The MATRIX Trial (NCT01433627) ~8400 pts with STEMI and NSTEACS PCI
ACC Monday, March 16th
~8400 pts with STEMI and NSTEACS
Femoral access
Radial access
PCI
Bivalirudin
with or without a
4-hour post-PCI infusion
(low dose or high dose)
Unfractionated
heparin
+ bailout GPI
PI: Marco Valgimigli