Is Bivalirudin the ideal anticoagulant therapy in high risk PCI and following ACS?

1. Controversies in antithrombotic therapy
Bivalirudin is the ideal anticoagulant therapy in high risk PCI and following ACS
G. Montalescot
www.action-coeur.org
COI DISCLOSURE FOR DR. MONTALESCOT: Gilles Montalescot reports: research grants to the institution or consulting/lecture
fees from Abbott Vascular, Accumetrics, AstraZeneca, Bayer, Biotronik, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Duke
Institute, Eli Lilly and Company, Europa, Fédération Française de Cardiologie, Fondation de France, GSK, INSERM, Institut de
France, Iroko, Lead-up, Menarini, Medtronic, Nanospheres, Novartis, Pfizer, Roche, Sanofi-Aventis, Stentys, Société Française de
Cardiologie, Springer, The Medicines Company, The TIMI group, WebMD, and Wolters.

2. Bivalirudin is the ideal anticoagulant therapy in
high risk PCI and following ACS

3. Is bivalirudin more effective than UFH and
IIb/IIIa inh. In REPLACE-2?
Secondary EP
10
Death, MI, Urg Rev (%)
Odds Ratio = 1.088
(0.895 - 1.322)
8
6
p = 0.40
7.1
7.6
Primary EP
Death, MI, URev, Maj Bld (%)
12
10
Odds Ratio = 0.917
(0.772 - 1.089)
10.0
p = 0.32
9.2
8
6
4
4
2
0
2
Heparin+
GP IIb/IIIa
(n=3008)
Bivalirudin
(n=2994)
0
Heparin+
GP IIb/IIIa
(n=3008)
Bivalirudin
(n=2994)
Lincoff AM et al. JAMA 2003

4. Is bivalirudin safer than UFH and IIb/IIIa
inh. In REPLACE-2?
UFH + GP IIb/IIIa
Bivalirudin
Heparin protocol:
p <0.001
•If ACT < 225 seconds, additional 20 U/kg administered
4.1
2.4
• NET RESULT = Median ACT 320s with UFH+GP IIb-IIIa RA
Major
much higher than:
- recommended by Guidelines
- recommended in PDR of GP IIb/IIIa RA
- recommended in modern GP IIb/IIIa RA studies
- used by practicing interventionalists
Bleeding
ACC/AHA guidelines, JACC 2001
Tolleson TR et al., JACC 41:386-93, 2003

5. Is bivalirudin superior to UFH?
• In a randomized comparison, bivalirudin was not superior to
UFH in thrombus containing lesions
Heparin (n=266)
Bivalirudin (n=301)
Incidence (%)
15
14,6
12,4
10
4,9 5,3
5
1,9 2,0
0,4 1,0
0
6,8 7,0
Death
MI
Emergency
CABG
Death, MI,
Bypass Surgery
Abrupt
Closure
*Shah, et al. J Am Coll Cardiol 1997:1264-1269.

6. Is bivalirudin superior to UFH?
(without IIb/IIIa)
ISAR
REACT 3
Cumulative incidence of Primary EP of Death, MI, UR, MB(%)
10
RR=0.94 [95% CI, 0.77-1.15], P=0.57
UFH
8
Bivalirudin
8.7%
8.3%
6
P=0.008
)
%
(
4
e
id
c
n
I
2
UFH =
140 IU/kg
0
0
5
10
15
20
Days after randomization
25
30
Kastrati A et al. NEJM 2008

7. ACUITY PCI
Is bivalirudin superior to UFH?
(with GP IIbIIIa inh.)
Stone GW et al. Lancet 2007;369:907-19

8. In high risk PCI
1. In head-to head comparisons, bivalirudin is
never more effective or safer than UFH at the
dose recommended by the guidelines
2. In asymetrical comparisons (with
inappropriate use of GPIs in control patients)
bivalirudin is safer in studies with femoral
access only.

9. Bivalirudin is the ideal anticoagulant therapy in
high risk PCI and following ACS

10. A cath lab drug that costs a lot and
cannot be used alone…
Ambulance
Fondaparinux
LMWH
UFH
ER
Cath Lab
Bivalirudin
Ward
Fondaparinux
LMWH
UFH

11. Bivalirudin is the ideal anticoagulant therapy in
high risk PCI and following ACS
Meaning primary PCI?

12. HORIZONS : primary PCI
STEMI ≤12 hours
Aspirin, thienopyridine, UFH
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG – Primary PCI – Medical Rx
NACE and MB at 30 days
Stone GW et al. N Engl J Med. 2008;358:2218-30

13. The dazzling effect of mortality reduction
(« p values are no substituent for a brain »)
30d Mortality (all cause): 2.1% vs 3.1%
– Low risk population
– 3.1% in the control arm, absolute difference for death of
1%  power: 48%
 Blinding effect of mortality reduction?

14. A cath lab drug that costs a lot
and should not be used alone!
Dangas GD et al. Circulation. 2011;123:1745-1756

15. HORIZONS
The study was powered to demonstrate superiority of
bivalirudin without GPIIbIIIa over UFH with GPIIbIIIa, on
major bleeding and NACE at 30 days.

16. Hematomas of at least 5 cm and
outcomes in patients undergoing PCI
« Hematomas > 5 cm have no effect on 30day ischemic outcome and 1-year
mortality in patients undergoing PCI» !
HD White et al. Am Heart J 2010;159:110-6

17. A cath lab drug that costs a lot for nothing
if you use radials!
Transradial: n=200 !

18. In primary PCI
1. In the real world, GPIs are used selectively in
high risk patients (not systematically as in the
controls of HORIZONS)
2. Bivalirudin does not protect your patients well
against ischemic events
3. Bivalirudin safety claim is not appropriate for
radial centers

19. One poorly convincing trial  wait for the next
Please wait for TCT 2013

20. … and the next!
N=6800

21. If you already use bivalirudin…
check the dose with your nurses!
Needs an IV infusion
No antidote
Complex dosing
• Elective: Bolus 0.75 mg/kg and
infusion of 1.75 mg/kg/h
• NSTE-ACS pre-lab: Bolus 0.1
mg/kg and infusion of 0.25
mg/kg/h
• NSTE-ACS in-lab: Bolus of 0.5
mg/kg and infusion of 1.75
mg/Kg/h
• Primary PCI: Bolus 0.75 mg/kg
and infusion of 1.75 mg/kg/h
• Post-primary PCI: infusion of
0.25 mg/kg/h

22. Conclusions
1. If you do not use GPIIbIIIa inhibitors  bivalirudin is not
for you
2. If you do not use UFH  bivalirudin is not for you
3. If you still use UFH and IIbIIIa inhibitors and you want to
reduce bleeding  think radial first
4. If you still use UFH and IIbIIIa inhibitors and you want to
replace GPIIbIIIa inhibitors  think prasugrel/ticagrelor
first
5. If you still use UFH and IIbIIIa inhibitors and you want to
replace UFH  think of less expensive options
Finally, do not forget that bivalirudin is a cath lab drug but
patients just cross the cath lab
Slides available at www.action-coeur.org

23. Controversies in antithrombotic therapy
Bivalirudin is the ideal anticoagulant therapy in high risk PCI and following ACS
G. Montalescot
www.action-coeur.org

24. God we trust.
Others bring your own data!

25. The reality is that nobody uses bivalirudin in Europe!
• ACCOAST presented tomorrow at 2.00pm at the
hotline II session
• NSTEMI undergoing PCI in Europe (19 countries)
• Anticoagulants:
Antithrombin Use
UFH
LMWH
Fondaparinux
Bivalirudin
%
65
30
4.3
0.7

26. Meta-analysis enoxaparin vs. UFH
 34%
 48%
J. Silvain et al. BMJ 2012

27. ATOLL : primary PCI
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
UFH IV
ENOXAPARIN IV
0.5 mg/kg
50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa
(Dose ACT-adjusted)
with or without GPIIbIIIa
Primary PCI
UFH IV or SC
ENOXAPARIN SC
30 days
1° EP: Death, Complication of MI, Procedure Failure, Major Bleeding
Main 2° EP: Death, recurrent MI/ACS, Urgent Revascularization
Montalescot G, et al. Lancet. 2011;378:693-703

28. ATOLL: enox IV vs. UFH IV in pPCI
Primary Endpoint
Death, Complication of MI, Procedure Failure or Major
Bleeding
Main Secondary Endpoint (ischemic)
Death, Recurrent ACS or Urgent Revascularization
Montalescot G, et al. Lancet. 2011;378:693-703

29. ATOLL: Primary end point
Death, Complication of MI, Procedure Failure or Major Bleeding
Intent-To-Treat
Per-protocole
RRR = 23%
P = 0.01
Montalescot G, et al. Lancet. 2011
Collet JP et al. Am J cardiol 2013

30. Mortality in ATOLL
Per-protocole
Intent-To-Treat
RRR = 40%
P = 0.08
Montalescot G, et al. Lancet. 2011;378:693-703
RRR = 64%
P = 0.003
Collet JP et al. ESC 2012