Bivalirudin for all

1. Bivalirudin for All!
Sunil V. Rao MD

2. Disclosures

Consultant, Honoraria

The Medicines Company, Terumo
Corporation, Astra Zeneca

Research funding


Ikaria
Off-label uses

May be discussed in this presentation

3. The case for bivalirudin

PCI – goals of therapy

Role of anticoagulation

Interaction between access site and
antithrombotic strategies

Can we select patients for different
approaches?

Summary

4. The case for bivalirudin

PCI – goals of therapy

Role of anticoagulation

Interaction between access site and
antithrombotic strategies

Can we select patients for different
approaches?

Summary

5. PCI and Thrombosis:
An Obligatory Event
Thrombin
Tissue Factor
Generation
Platelet
Activation
Adhesion Molecules
Vessel Wall Injury
and Inflammation

6. Goals of PCI

Procedure success

Minimize ischemic sequelae


Large MI

Stent thrombosis


Atherothrombotic emboli
Side branch occlusion
Minimize bleeding risk

7. Twenty-five year trends in PCI outcomes
N=24,410 procedures at the Mayo Clinic
Singh M., et. al. Circulation 2007

8. Bleeding & Outcomes
N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
log rank p-value for all four categories <0.0001
log-rank p-value for no bleeding vs. mild bleeding = 0.02
log-rank p-value for mild vs. moderate bleeding <0.0001
log-rank p-value for moderate vs. severe <0.001
Rao SV, et al. Am J Cardiol. 2005

9. Impact of MI and Major Bleeding (non-CABG) in the First
30 Days on Risk of Death Over 1 Year
1 year
Estimate
Both MI and Major Bleed (N=94)
Major Bleed only (without MI) (N=551)
MI only (without Major Bleed) (N=611)
No MI or Major Bleed (N=12,557)
28.9%
12.5%
8.6%
3.4%
30
28.9%
Mortality (%)
25
20
15
12.5%
10
8.6%
5
3.4%
0
0
30
60
90
120 150
180 210 240 270
300 330 360
390
Days from Randomization
Mehran R, et. al. Lancet 2010

10. The case for bivalirudin

PCI – goals of therapy

Role of anticoagulation

Interaction between access site and
antithrombotic strategies

Can we select patients for different
approaches?

Summary

11. Sites of action for anticoagulants
Factor Xa
Fondaparinux
Otamixaban
Apixaban
Factor IIa (thrombin)
Unfractionated
Heparin
Enoxaparin
Bivalirudin

12. Role of anticoagulants in PCI
TRANSRADIAL PCI

Minimize thrombus on the equipment

Minimize platelet activation

Minimize atherothrombotic emboli

Minimize bleeding risk

Reduce radial artery occlusion

13. Quadruple Endpoin (N=6010)t
30 Day Primary Endpoint Components
p <0.001
Lincoff AM, et. al. JAMA 2003

14. ACUITY Trial Design

Moderate- and high-risk UA or NSTEMI patients undergoing an
invasive strategy
Prospective, randomized, active-controlled trial
Heparin(s)†
+ GP IIb/IIIa
(n=4,603)
Moderateand highrisk ACS
Bivalirudin
R*
+ GP IIb/IIIa
(n=4,604)
(N=13,819)
Aspirin in all;
clopidogrel
dosing and timing
per local practice
Bivalirudin
alone
(n=4,612)
Medical
Angiography within 72 h

management
PCI
CABG
*Stratified by preangiography thienopyridine use or administration.
†UFH
or enoxaparin.
Stone GW, et. al. NEJM 2007

15. ACUITY: Net Clinical Outcome Composite Endpoint
UFH/enoxaparin+GPI vs bivalirudin+GPI vs bivalirudin alone
Cumulative Events (%)
15
10
Estimate
5
UFH/enoxaparin+GPI (N=4603)
Bivalirudin+GPI (N=4604)
Bivalirudin alone (N=4612)
P
(log rank)
11.7%
11.8% 0.89
10.1% 0.014
0
0
5
10
15
20
25
30
35
Days from Randomization
UFH, unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitor.
Stone GW. NEJM 2007.

16. HORIZONS- MI Trial Design
≥3400* pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
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
3000 pts eligible for stent randomization
Bare metal stent
R
1:3
TAXUS paclitaxel-eluting stent
Clinical FU at 30 days, 6 months,
1 year, and then yearly through 5 years
Stone GW et al. NEJM 2008.

17. HORIZONS-MI Primary Endpoints at 30 Days
Diff = -2.9% [-4.9, -0.8]
Diff = -3.3% [-5.0, -1.6]
Diff = 0.0% [-1.6, 1.5]
RR = 0.76 [0.63, 0.92]
RR = 0.60 [0.46, 0.77]
RR = 0.99 [0.76, 1.30]
PNI ≤ 0.0001
PNI ≤ 0.0001
Psup = 0.95
Psup = 0.005
Psup ≤ 0.0001
1° endpoint
1° endpoint
Major 2° endpoint
Stone GW et al. NEJM 2008;358:2218-30

18. HORIZONS-MI: 30-day mortality
Death (%)
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
3.1%
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Time in Days
1800
1802
1758
1764
1751
1748
1746
1736
1742
1728
1729
1707
1666
1630
Stone GW et al. NEJM 2008.

19. HORIZONS MI - Three-Year All-Cause Mortality
Bivalirudin alone (n=1800)
All-Cause Mortality (%)
10
Heparin + GPIIb/IIIa (n=1802)
9
7.7%
8
7
6
4.8%
5
3-yr HR [95%CI]=
0.75 [0.58, 0.97]
P=0.03
4
3
3.4%
2
1-yr HR [95%CI]=
0.71 [0.51, 0.98]
P=0.04
1
0
0
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
5.9%
3
6
9
12
15
18
21
24
27
30
33
36
Months
1800
1802
1689
1670
1660
1643
1633
1593
1611
1568
1574
1525
1098
1043
Stone GW, et. al. Lancet 2011

20. Comparison of Bivalirudin with UFH
Bertrand OF, et. al. AJC 2012

21. The case for bivalirudin

PCI – goals of therapy

Role of anticoagulation

Interaction between access site and
antithrombotic strategies

Can we select patients for different
approaches?

Summary

22. ACUITY: Protocol Non-CABG Major
Bleeding by access site & drug strategy
30 day events (%)
Radial (n=798)
P = 0.01!
Femoral (n=11,988)
P = 0.06!
5.8%
2.2%
UFH/enox + GPI
Slide courtesy of M. Hamon
5.4%
2.7%
Biv + GPI
P = 0.29!
4.2%
3.0%
Biv Alone

23. Radial access & Bivalirudin in HORIZONS MI
N=3602 STEMI pts undergoing primary PCI
123 Centers in 11 countries; 6% TRI (N=200)
17 centers treated ≥ 1 patient with TRI
Genereux PG, et. al. Eurointervention 2011

24. Combining radial approach and bivalirudin
N=501,017 pts from NCDR CathPCI
Baklanov D, et. al. Circ Intv. 2013

25. What about costs??

26. 26
OP Medication Reimbursement
• Separate APC codes for each of these medications
• Reimbursement rates updated on a quarterly
basis.
• Current Medicare reimbursement rates:
Drug
HCPCS
Code
Q3 2012 Reimbursement Rate
Bivalirudin
J0583
$2.93 per mg ($732.50 per vial)
Abciximab
J0130
$556.57 per 10 mg ($556.57 per vial)
Eptifibitide
J1327
$23.52 per 5 mg ($352.80 for 75mg infusion vial)
PLEASE SEE ACCOMPANYING FULL PRESCRIBING INFORMATION FOR ANGIOMAX
Medicare Hospital Outpatient Prospective Payment System, July 2012 Addendum B,
https://www.cms.gov/HospitalOutpatientPPS/AU/list.asp, accessed August 8, 2012.
Slide courtesy of Adhir Shroff, MD, MPH
Associate Professor of Medicine

27. MATRIX
1:1
N>6,800
Angiography
Radial Access
PCI
Femoral Access
1:1
UFH±GPI
Post-PCI
Discontinue
Slide courtesy of Marco Valgimigli MD
1:1
Bivalirudin
1:1
N~6,800
UFH±GPI
N~3,400
≥6 h Bivalirudin infusion

28. Slide courtesy of Olivier Bertrand

29. The case for bivalirudin

PCI – goals of therapy

Role of anticoagulation

Interaction between access site and
antithrombotic strategies

Can we select patients for different
approaches?

Summary

30. Models to predict bleeding in ACS/PCI



REPLACE-2
ACUITY
OASIS-5

Pooled ISAR Trials

CHARISMA

GUSTO

REACH Registry

GRACE

CRUSADE

NCDR CathPCI
Registry

31. Why risk stratify…?

Because sometimes
we see what we want
to see…

32. Baseline Major Bleeding and Mortality Risk in
CRUSADE N=68,270
Mortality Risk Tertiles
1%
7.6%
23.5%
(5,199)
(16,044)
9.4%
15.1%
8.4%
(6,403)
(10,320)
(5,762)
23.4%
9.9%
2%
High
(706)
Mod
Low
(15,974)
Low
(6,748)
(1,114)
Mod
High
Bleeding Risk Tertiles
Alexander KA, et. al. ACC 2008

33. GRACE Risk score: Bleeding
N=20,078 patients from the OASIS 5 trial
Major Bleeding in 9 days
0.07
Enoxaparin
0.06
0.05
0.04
Fondaparinux
0.03
0.02
80
100
120
140
160
180
200
GRACE Mortality Score
Joyner CD, et. al. AHJ 2009

34. Bleeding – Can we discriminate appropriately?

Yes

Identification of patients at risk for adverse
outcomes is possible with currently available
models

But, there is significant overlap in covariates
across outcome models

35. Bivalirudin for all - Summary


Bleeding is the most common complication of PCI
Radial access and bivalirudin are associated with
reduced bleeding over femoral access and UFH



There may be an interaction between the two that
augments the safety of PCI
While we can identify patients at increased
bleeding risk, we cannot separate this risk from
ischemic risk
Since bivalirudin maintains ischemic efficacy while
reducing bleeding, it is the preferred antithrombin
agent

36. Thank you
Radialist