Anticoagulation and PCI: evidence still favors bivalirudin

1. The Data Still Favor
Bivalirudin – Even in Radial
Patients
Ajay J. Kirtane, MD, SM
Center for Interventional Vascular Therapy
Columbia University Medical Center /
New York Presbyterian Hospital

2. Financial Conflict of Interest Disclosure
• Ajay J. Kirtane
 Personal: None
 Institutional (Columbia University): Research
grants from Medtronic, Boston Scientific,
Abbott Vascular, St. Jude Medical, Abiomed,
Eli Lilly, Vascular Dynamics

3. Heparin: A Disgusting Product?
• Combine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform,
and 5 gallons toluene. Hold at 90°F for 17 hours.
• Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to
adjust pH, and 235
gallons water. Bring to
a boil; then filter.
• Add 200 gallons hot water
to filtrate and allow to
stand overnight, then
skim off the fat.
• Keep pancreatic extract at
100°F for three days, then
bring to boil.
• Filter solids and assay for
heparin content.

4. Unfractionated Heparin (UFH)
• 5,000-30,000 Daltons
• Heterogeneous mixture of polysaccharide chains
with varying effects on anticoagulant activity
• Accelerates the action of circulating antithrombin
(AT), a proteolytic enzyme which inactivates factors
IIa (thrombin), IXa, Xa, XIa, XIIa
• Prevents thrombus propagation, but does not lyse
existing thrombi
UFH
bound
to
AT

5. Limitations of Heparins
Attribute UFH Enox Impact
Active moieties in substance 30-35% 40-60% Unpredictable
Action independent of AT No No Unpredictable
Non-specific protease binding Yes Partial Unpredictable
Variable PK-PD Yes Less Unpredictable
Inhibits fibrin-bound thrombin No No Need ↑ dose
Activates/aggregates platelets Yes +/- Need IIb/IIIa
T0.5 in minutes 60-90’ 270’ ↑ Bleeding
PF-4 complexing & risk of HIT Yes Reduced Very bad

6. Bivalirudin
Bivalent Synthetic Direct Thrombin Inhibitor
• Specifically inhibits
 Fluid phase thrombin
 Clot-bound thrombin
 Thrombin-mediated
platelet aggregation
• Reversible
• T0.5 25 minutes
Bivalirudin
Topol EJ: Textbook of Interventional Cardiology

7. 30 Day Primary Endpoint
6,012 Patients Undergoing PCI
p <0.001
p = 0.32
p = 0.44
p = 0.23
p = 0.26
Triple ischemic
endpoint
Lincoff AM et al. JAMA 2003;289:853–63

8. 10
8
6
4
2
0
5.9%
5.0%
Bivalirudin
UFH
n=4570
RR=1.16 [95% CI, 0.91-1.49]
P=0.23
0 5 10 15 20 25 30
Days after randomization
Death, MI, UTVR (%)
ISAR-REACT 3
Bivalirudin vs. UFH in Biomarker Negative ACS pts
3.1
12
10
8
6
4
2
Kastrati et al. N Engl J Med 2008;359:688-96.
6.8
Bivalirudin
UFH
1.3
4.6
9.9
1.8
0
Major
bleeding
Minor
bleeding
Transfusion
P=0.008
P=0.0001
P=0.15
* UFH Dose: 140 U/Kg

9. ISAR-REACT 3A
Bivalirudin vs. UFH in Biomarker Negative Pts
UFH (140 U/Kg) UFH (100 U/Kg) Bivalirudin
0.75 (0.60–0.92) 0.82 (0.62–1.08) 0.71 (0.53–0.97)
p < 0.001*
8.7
5 4.6
7.3
4.4
3.6
8.3
5.9
3.1
12
9
6
3
0
Quadruple
Endpoint
Death, MI, UTVR Major Bleeding
* Non-inferiority between Bivalirudin
and low-dose UFH
Schulz S et al. Eur Heart J. 2010:2482-91
n=2281
Patients (%)
Adjusted HR

10. ACUITY: Ischemic Composite Endpoint
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
15
10
5
0
Estimate P
UFH/Enoxaparin + IIb/IIIa (N=4603) 7.4% (log rank)
Bivalirudin + IIb/IIIa (N=4604) 7.9% 0.37
Bivalirudin alone (N=4612) 8.0% 0.30
0 5 10 15 20 25 30 35
Cumulative Events (%)
Days from Randomization
Stone GW et al. NEJM 2006;355:2203-16

11. ACUITY: Major Bleeding Endpoint
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
15
10
5
0
Estimate P
UFH/Enoxaparin + IIb/IIIa (N=4603) 5.7% (log rank)
Bivalirudin + IIb/IIIa (N=4604) 5.3% 0.41
Bivalirudin alone (N=4612) 3.1% <0.0001
0 5 10 15 20 25 30 35
Cumulative Events (%)
Days from Randomization
Stone GW et al. NEJM 2006;355:2203-16

12. ISAR-REACT-4
1,721 Pts with NSTEMI (CK-MB or troponin+)
undergoing PCI
Pre-treated with aspirin and 600 mg of clopidogrel
R
Double-blind
(double-dummy drug)
UFH + Abciximab
Bolus UFH 70 U/kg
Bolus Abcx 0.25 mg/kg + infusion
0.125 μg/kg/min x12h
N=861
Bivalirudin
Bolus 0.75 mg/kg +
infusion 1.75 mg/kg/hr for
duration of PCI
N=860
Primary endpoint = death, large MI, urgent TVR, or major bleeding at 30d
Powered for superiority of UFH/Abcx over bivalirudin
Kastrati A et al. NEJM 2011

13. ISAR-REACT-4: Composite ischemia
UFH + Abciximab (n=861)
Days
Kastrati A et al. NEJM 2011
20
15
10
5
0
13.4%
0 5 10 15 20 25 30
Death, MI, or urgent TVR (%)
RR (95%CI) = 1.04 (0.80–1.35)
P=0.76
Bivalirudin (n=860)
12.8%

14. ISAR-REACT-4: Major bleeding
UFH + Abciximab (n=861)
Days
Kastrati A et al. NEJM 2011
20
15
10
5
0
*Intracranial, intraocular,
or RP hemorrhage; hgb
>4 g/dL with overt
bleeding or ≥2U RBC Rx
0 5 10 15 20 25 30
Major bleeding* (%)
RR (95%CI) = 0.54 (0.33 – 0.91)
P=0.02
Bivalirudin (n=860)
4.6%
2.6%

15. HORIZONS: 30 Day Adverse Events
*Not related to CABG
** Plat cnt <100,000 cells/mm3
P = 0.002
P<0.001
P = 0.90
Stone GW et al. NEJM 2008;358:2218-30

16. 30 Day and 1-Year All-Cause Mortality
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
5
4
3
2
1
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 4.8%
Δ = 1.0%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
0 1 2 3 4 5 6 7 8 9 10 11 12
1800 1705 1684 1669 1520
1802 1678 1663 1646 1486
Mortality (%)
0
Time in Months
3.4%
HR [95%CI] =
0.69 [0.50, 0.97]
P=0.029
3.1%
2.1%
Δ = 1.4%
Stone GW et al. NEJM 2008;358:2218-30
Mehran R et al. Lancet 2009;374:1149-59.

17. 3 Most Common Criticisms of the
Bivalirudin Data
• The deck was stacked against heparin!
 Routine GPI Use explains the
bleeding advantage of bivalirudin
• Vascular Closure Devices could
mitigate the bleeding advantage of
bivalirudin!
• Transradial access could mitigate the
bleeding advantage of bivalirudin!

18. “Contemporary” Bivalirudin Trials
Study N Comparator Setting
Ischemic
Events
Bleeding
REPLACE-2 6002 UFH + GPI Elective PCI -

ISAR REACT 3 4570 UFH (140 u/kg) Elective PCI - 
ACUITY 13800 UFH/LMWH + GPI NSTEACS - 
ISAR REACT 4 1721 UFH + GPI NSTEACS - 
BRIGHT 2100 UFH or UFH + GPI
STEMI &
NSTEMI
-

HORIZONS 3602 UFH + GPI STEMI
(-) MACE
 Death
 Stent thromb

EUROMAX 2218 UFH ± GPI STEMI
(-) MACE
 Stent thromb

HEAT PPCI 1829 UFH STEMI  MACE -
adapted from S. Rao

19. Bivalirudin vs UFH Monotherapy Meta-analysis
16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:
Major Bleeding
Bivalirudin
Heparin
4
1
2
23
10
26
5
6
101
12
38
0.52 [0.18, 1.47]
0.55 [0.05, 6.12]
0.30 [0.07, 1.31]
0.97 [0.49, 1.90]
0.52 [0.21, 3.17]
0.32 [0.21, 0.49]
1.21 [0.23, 6.33]
0.39 [0.16, 0.95]
0.87 [0.65, 1.16]
0.82 [0.39, 1.74]
0.47 [0.32, 0.70]
0.57 [0.42, 0.78]
335
54
216
566
79
1207
267
503
1771
2289
1511
8798
35
2
14
14
20
101
2
26
89
16
78
Wolfram 2003
Rha 2005
Chu 2006
Bonello 2009
Lemesle 2009
Lemesle 2009-b
Delhaye 2010
Lindsey 2010
Lopes 2010
Schultz 2010
Bangalore 2011
Subtotal (95% CI)
Total
1543
60
456
333
92
1559
129
861
1365
2505
1551
10414
Total Events 228 397
Test for heterogeneity: Tau2=0.11, Chi2=20.84, df=10 (P=0.02),I2=52%
Test for overall effect: Z=3.55 (P=0.0004)
12
3
1
0.50 [0.25, 0.99]
0.31 [0.08, 1.19]
0.51 [0.05, 5.67]
0.45 [0.25, 0.82]
2289
363
198
2850
24
8
2
2281
308
203
2792
Total Events 16 34
Test for heterogeneity: Tau2=0.00, Chi2=0.37, df=2 (P=0.83),I2=0%
Test for overall effect: Z=2.60 (P=0.009)
11648 13206
0.55 [0.43, 0.72]
Bertrand OF et al. Am J Cardiol 2012;110:599–606
Study
or subgroup Events
Odds Ratio M-H,
Random, 95% CI
Odds Ratio M-H,
Total Events
Random, 95% CI
0.01
0.1 1 10 100
Favors Bivalirudin
Favors Heparin
Observational
Randomized
Kastrati 2008
Parodi 2010
Patti 2011
Subtotal (95% CI)
Total (95% CI)
Total Events 244 431
Test for heterogeneity: Tau2=0.08, Chi2=21.99, df=13 (P=0.06),I2=41%
Test for overall effect: Z=4.38 (P<0.0001)
Test for subgroup differences: Chi2=0.47, df=1 (P=0.49),I2=0%
45%↓

20. Anticoagulation Regimens During PCI
N = 458,448 PCI pts 2004-2008 at 299 hosps
(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)
In-hospital events, propensity adjusted
Bleeding + Transfusion
Mortality
0.71 (0.66, 0.76)
0 1 2
0.88 (0.82, 0.96)
0 1 2
Wise GR et al. J Interv Cardiol 2012;25:278–88
Comparator
Better
Heparin + GPI
Better
(n=182,948)
Heparin alone
(n=85,870)
<0.0001
0.96 (0.87, 1.06)
Bivalirudin + GPI
(n=33,566)
0.37
0.51 (0.48, 0.55)
Bivalirudin
monotherapy
(n=156,064)
<0.0001
OR
Comparator (95% CI) P Value
Comparator
Better
Heparin + GPI
Better
(n=182,948)
Heparin alone
(n=85,870)
0.003
0.82 (0.72, 0.94)
Bivalirudin + GPI
(n=33,566)
0.004
0.59 (0.54, 0.65)
Bivalirudin
monotherapy
(n=156,064)
<0.0001
OR
Comparator (95% CI) P Value
OR
(95% CI)
OR
(95% CI)

21. Impact of Bleeding Avoidance Strategies
NCDR CathPCI Registry 2004-2008: 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 bleeding
Adj OR (95%CI) =
0.77 (0.73 – 0.80)
NNT = 148
2.7 2.5
1.9
Marso SP et al. JAMA. 2010;303:2156-64
1.0
8
6
4
2
0
All pts
Major bleeding (%)
Manual compression (n=508,455) Vascular closure devices (n=205,606)
Bivalirudin (n=172,471) Bivalirudin + VCD (n=130,378)
23%↓
Adj OR (95%CI) =
0.67 (0.63 – 0.70)
NNT = 118
Adj OR (95%CI) =
0.38 (0.35 – 0.42)
NNT = 70
33%↓
62%↓

22. Impact of Access and Non-Access
Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS
925 pts (5.3%) had TIMI major or minor bleeding within 30 days
357
145
(15.7%)
142 (38.6%)
(15.4%)
281
(30.4%)
Access site only (2.1%)
Indeterminate (1.6%)
Non access site (0.8%)
Access + non access site (0.8%)
568
(61.4%)
non access
site related
Source of bleeding (absolute rate)
Indeterminate – most likely
intraprocedural (catheter
exchanges) or baseline anemia
with lower transfusion threshold
Verheugt FWA et al. JACC Int 2011;4;191-197

23. Impact of Access and Non-Access
Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS
925 pts (5.3%) had TIMI major or minor bleeding within 30 days
Time-updated multivariable risk of death within 1-year
TIMI Bleed - All
TIMI Bleed – Non Access Site
TIMI Bleed – Access Site Only
0.1 1 8
Adjusted risk of 1-year mortality
HR [95%CI] P
3.17 [2.51, 4.00] <0.0001
3.94 [3.07, 5.15] <0.0001
1.82 [1.17, 2.83] 0.008
Verheugt FWA et al. JACC Int 2011;4;191-197

24. Bivalirudin vs. Heparin During Primary PCI in
STEMI: Three major RCTs
EUROMAX BRIGHT HEAT PPCI
N centers 65 82 1
N patients 2,198 2,194 1,812
- Bivalirudin 1,089 735 905
- Heparin 460 729 907
- Heparin + GPI 649 730 -
Heparin mono bolus 60 IU/kg 100 IU/kg 70 IU/kg
Bival infusion
non-rand rand
None, low or
high dose
Mean 4.5 hrs
Low dose
Mean 4 hrs
No
GPI bailout, Biv vs. Hep 7.9% vs. 25.4% 4.4% vs. 5.6% 13.5% vs. 15.5%
Prasugrel/ticagrelor 59% 0% 89%
Radial 47% 79% 81%

25. EUROMAX: Treatment
According to Routine GPI Use
UFH (91.3%*)/LMWH
± GPI
Per standard practice
(n=1,109)
BIVALIRUDIN
(provisional GPI only)
(n=1,089)
41.5%
(n=460)
No GPI
25.4%
(n=117)
Bailout GPI
7.9%
(n=83)
Bailout GPI
3.9% (n=42)
Routine GPI*
96%
(n=1047)
No GPI
N = 2,198
R
1:1
Note: * Protocol Deviation
Non-randomized, non-stratified
* Median 60 U/kg received
in both arms
Zeymer U et al. EHJ 2014:on-line
58.5%
(n=649)
Routine GPI

26. EUROMAX: Primary Endpoint
Death or Major Bleeding
A. Heparin + Routine GPI
B. Heparin Only + Bailout GPI
C. Bivalirudin
Log Rank P values
Overall: 0.003
A vs. B: 0.18
A vs. C: 0.04
B vs. C: 0.0006
Days from Randomization
Death or
major bleeding (%)
9.8%
12
10
Patients at risk:
7.4%
Zeymer U et al. EHJ 2014:on-line
8
6
4
2
0
0 5 10 15 20 25 30
5.1%
A. Heparin + Routine GPI
B. Hep Only + Bailout GPI
C. Bivalirudin
649
460
1089
598
426
1038
588
415
1024
586
412
1020
577
407
1007
563
395
899
445
320
791
2,198 pts
at 65 centers

27. 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)‡
Clemmensen P et al. ACC 2014
Bivalirudin +
1.75 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

28. BRIGHT: Study flow
2,194 pts with AMI randomized at 82 centers in China
Bivalirudin alone
N=735
Randomization (1:1:1)
Biv 0.75 mg/kg bolus + 1.75 mg
/kg/h infusion (0.3 mg/kg bolus
if ACT< 225s). Bailout GPI
permitted. Biv infusion (0.2
mg/kg/h) continued for at least
30 min post PCI (mean 4h).
4.4% bailout tirofiban.
UFH alone
N=729
Heparin 100 U/kg bolus +
additional dose if ACT
<200 s. Bailout GPI
permitted.
ACT goal = 250-300.
5.6% bailout tirofiban.
UFH + Tirofiban
N=730
Heparin 60U/kg bolus .
Tirofiban 10μg/kg bolus +
0.15 μg/kg/min infusion for
18-36 h.
ACT goal = 200-250.
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. TCT 2014
86.2 % STEMI
13.8% NSTEMI
79% radial
Aspirin and clopidogrel

29. BRIGHT: Primary and Major
Secondary Endpoint Events at 30 Days
Bivalirudin (n=735) Heparin (n=729) Heparin + Tirofiban (n=730)
Biv vs. Hep, p=0.009
RR (95%CI) 0.67 (0.50-0.90), NNT=23.1
Biv vs. Hep+Tiro, p<0.001
RR (95%CI) 0.52 (0.39-0.69), NNT=12.3
Hep vs. Hep+Tiro, p=0.04
RR (95%CI) 0.78 (0.61-0.99), NNT=26.2
Han Y. TCT 2014.
P<0.001
P<0.001
P=0.74
(%)
Primary endpoint
NACE
8.8
18
16
14
12
10
8
6
4
2
0
13.2
17.0
5.0
5.8
4.9 4.1
7.5
12.3
MACCE Any Bleeding
2,194 pts
at 82 centers

30. BRIGHT: Stent Thrombosis at 30 Days
STEMI Only
0.8 0.8
0.2
Han Y. TCT 2014.
P=0.59
P=0.49
P=1.00
P=0.81
P=0.71
(%)
1.2
1.0
0.8
0.6
0.4
0.2
0
0.5
1.0
0.8
Bivalirudin (N=629)
Heparin (N=620)
Heparin+Tirofiban (N=609)
0.3
Definite
Probable
0.2
0.3
Acute
0.6
0.5
Subacute
0.2
0
0.3 0.3
Def/prob

31. HEAT PPCI: Design and enrollment
1917 STEMI pts scheduled for emergency angiography at a single
center between Feb 2012–Nov 2013*
29 (1.5%) already randomized in the trial
59 (3.0%) met one or more other exclusion criteria
Exclusion Criteria
• Active bleeding at presentation
• Factors precluding oral DAPT
• Intolerance or contraindication
to trial medications
• Previous enrolment in this trial
1829 eligible for recruitment were
randomized 1:1
Assigned to
Heparin* (n=914)
Assigned to
Bivalirudin (n=915)
17 (1%) refused post procedure
*70 U/kg consent and were withdrawn
Assigned to
Assigned to
Heparin* (n=907)
Bivalirudin (n=905)
Shahzad A et al. Lancet 2014

32. HEAT PPCI: MACE Outcomes
Bivalirudin
(n=905)
Heparin
(n=907)
Any MACE 79 (8.7%) 52 (5.7%)
- Death 46 (5.1%) 39 (4.3%)
- CVA 15 (1.6%) 11 (1.2%)
- Reinfarction 24 (2.7%) 8 (0.9%)
- TLR 24 (2.7%) 6 (0.7%)
Shahzad A et al. Lancet 2014

33. HEAT PPCI: Safety Outcomes
Bivalirudin
(n=905)
Heparin
(n=907)
P
BARC 2-5 115 (12.7%) 126 (13.9%) 0.54
- BARC 3-5 32 (3.5%) 28 (3.1%) 0.59
- BARC 2 83 (9.2%) 98 (10.8%) 0.25
Thrombocytopenia
(moderate/severe)
6 (0.8%) 6 (0.8%) 0.99
Shahzad A et al. Lancet 2014

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

35. So Where Does this Leave Us Now?
• The bleeding benefit of bivalirudin has
been called into question
 Absent GPI, how great is the benefit?
 With other bleeding avoidance strategies
(e.g. transradial PCI), how great is the
benefit?
• But are we really optimizing our use of
bivalirudin?
 Prolonged infusion
 Targeting usage to highest risk patients

36. Patients at High-Risk for Non-Access Site Bleeding
≥2 risk factors among: Age>70, Female sex, CKD, Recent GI/Organ
Bleeding, Anemia, Diabetes, Prior GPI/TNK, Current Anticoagulation
Transradial PCI
R
1:1
HEPARIN BIVALIRUDIN
Bail-out GPI Permitted
Primary Study Endpoint:
Death, MI, Urgent Revascularization, Major Bleeding at 30 days

37. MATRIX Trial NCT01433627
NSTEACS or STEMI with invasive management
Aspirin+P2Y12 blocker
1:1
1:1
Trans-Femoral
Access
Heparin
±GPI
Trans-Radial
Access
Bivalirudin
Mono-Tx
Stop
Infusion
Prolong≥ 6 hs
infusion
1:1
http://matrixstudy.ospfe.it/web/

38. Ongoing RCTs in Swedish Registry
Planned RRCTs in SCAAR
REAL-SWEDEHEART
STEMI
N=3450
Radial
N=1725
Femoral
N=1725
R
Primary outcome: death at
180 days
VALIDATE-SWEDEHEART
STEMI N=3000
NSTEMI N=3000
Heparin
alone
N=3000
Bivalirudin
N=3000
R
Primary outcome: death,
MI or major bleedning at
180 days
SCAAR Study Group, ESC 2013

39. Conclusions
• Just because there are weaknesses to
the bivalirudin data doesn’t mean that
heparin is better or even equivalent
 We need a historical perspective
 Cost cannot dictate everything…
• One size DOES NOT fit all!
 Titrating antithrombotics to patient risk is a
concept that we desparately need to
embrace in our daily practices…