Bivalirudin: dead and buried

1. Bivalirudin
Dead and Buried
Dr Rod Stables
The Liverpool Heart and Chest Hospital

2. The Truman Show 1998 (Director Peter Weir)

3. The Truman Show 1998 (Director Peter Weir)

4. My ‘British’ View of the World

5. A ‘British’ View of the World

6. A Distortion of Reality

7. A Distortion of Reality

8. Africa and Greenland - Land Surface Area

9. A Bivalirudin View of the World
• Anti-thrombotic agent of choice in STEMI PPCI
• New (?)
• Has proven efficacy - better than heparin (?)
• Obviates the need for routine GPI use (?)
• Reduced bleeding (?)
• Better outcomes (?)
• Expensive but cost effective (?)

10. Heparin Does not Have to be Better to Win !
• Heparin does not need to be better
• Much cheaper to purchase
• € 1 versus € 400 - 1600
• Easier and cheaper to administer (nursing time)
• Does not need reconstitution before use
• No iv infusions to manage (or to fail)
• Reversible with protamine
• Familiar and available (A&E, ambulances etc)

11. A Consistent Message From Clinical Trials
A single position that fits all
the clinical trials

12. The Reality: Messages from the Evidence Base
• Heparin (60 - 70 u/kg) is the drug of choice
• Very similar efficacy to bivalirudin
• Comparable ischaemic outcomes
• Less acute stent thrombosis
• Very similar safety to bivalirudin
• Identical bleeding risks - when …
• Minimal (5-15%) selective GPI use
• No use of high dose heparin (100 - 150 u/kg)

13. Bivalirudin - A More Effective Anti-thrombotic ?
• Bivalirudin v Heparin - a 25 year journey
• Multiple trials
• Bivalirudin has NEVER bettered heparin
• In the prevention of thrombotic adverse events

14. A Slow and Faltering Start
• 1990 Development by Biogen (as Hirulog)
• Initial angioplasty trial
• HAS (aka BAT) N Engl J Med 1995;333:764-9
• Disappointing results
• 1994 - Decision for no further investment
• Product licensed to The Medicines Company
• Re-examination of data

15. A Slow and Faltering Start
• 1998 - new application for FDA approval
• PCI in unstable angina
• Application rejected (5:3 vote)
• Re-analysis of trial
• New outcome measures - ‘new results’
“Bivalirudin was equivalent but not superior to
heparin in preventing angioplasty complications”

16. A Slow and Faltering Start
• Dr Clive Meanwell (CEO The Medicines Company)
• 2000 FDA approval granted
• 2010 Extension of patent
"It now turns out that the NEJM paper was plain wrong."
(Heartwire news 21 Dec 2000)

17. Bivalirudin and Anti-Ischaemic Efficacy
• Cavender, Sabatine Lancet 2014; 384: 599-606
• 16 Trials 33 958 patients
• 2422 patients with MACE 1406 with major bleed
• Is Bivalirudin a more effective anti-thrombotic ?
• Look at MACE rates

18. Increased MACE with Bivaliudin
MACE
Death
MI
I-D Revasc
Stent Thrombosis
Acute
Sub Acute
0.4 0.8 1 1.25 2.5 5
Favours HeparinFavours Bivalirudin
RR = 1.09 (1.01-1.17) p = 0.02

19. Increased MACE with Bivalirudin
• MACE risk ratio 1.09 (1.01-1.17) p = 0.02
• Consistent in all presentations
• STEMI NSTEACS Elective

20. Increased MACE with Bivalirudin
• MACE risk ratio 1.09 (1.01-1.17) p = 0.02
• Consistent in all presentations
• STEMI NSTEACS Elective
• Advantage evident for all patterns of GPI use
• Planned GPI in both arms RR 1.08
• Planned GPI heparin alone RR 1.06
• Provisional GPI in both arms - current practice

21. Bivalirudin - A More Effective Anti-thrombotic ?
• Bivalirudin v Heparin - a 25 year journey
• Multiple trials
• Bivalirudin has NEVER bettered heparin
• In the prevention of thrombotic adverse events
• Bivalirudin does not have extra anti-platelet effect
• No evidence based mandate for recent trial design
• No logic for systematic differential use of GPI

22. • Routine (unselected) (widespread) use of GPI agents
• Does not improve ischaemic outcomes
• Results in increased bleeding
Routine v Selective GPI Use

23. • Tested in HORIZONS and BRIGHT trials
• Universal (unselective, routine) use of GPI
• Now rejected as mainstream treatment option
• Selective (intelligent) use is possible
• Consider background bleeding risk
• Patient Presentation Procedure
• Consider response to initial PCI therapy
Routine v Selective GPI Use

24. Does Bivalirudin Cause less Bleeding than Heparin?
• Bivalirudin will reduce bleeding … IF ….
• Heparin patients have higher rates of GPI use
• Optimum GPI strategy - unanswered questions
• Indications for selective use - not characterised
• Optimum rate for GPI use - not known
• Probably in the range 5 - 15%
• Observed rates in bivalirudin arms of trials
• Limited observational data from HEAT-PPCI

25. HEAT-PPCI: Primary MACE Outcome by Operator
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
RHS JLM AK MA RAP SM MF NDP CA WLM JDM PV BK DRR
Primary Outcome MACE Event Rates (95%CI)

26. HEAT-PPCI: GPI use and MACE
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
RHS JLM AK MA RAP SM MF NDP CA WLM JDM PV BK DRR
MACE% GP USE %

27. HEAT-PPCI Data: GPI Use and Bleeding
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00% 35.00%
BleedRate
GP 2b/3a Rate of Use
Scatter Plot Any Bleed v GP 2b/3a Use

28. Does Bivalirudin Cause less Bleeding than Heparin?
• Bivalirudin will reduce bleeding … IF ….
• Heparin patients have higher rates of GPI use
• Heparin is used at high dose

29. Bleeding Risk is Affected by Heparin Dose

30. Eurointervention 2015 Meta-analysis

31. MATRIX Trial

32. MATRIX Trial

33. Bivalirudin - The Reality
• Bivalirudin is not cost effective
• Cost is high
• No outcome advantage
• Outcomes may be less favourable

34. Bivalirudin - The Reality
• The drive to improve Bivalirudin outcomes
• Give heparin as well !!!
• Use a prolonged infusion
• Promising but failed when tested formally
• Cost implications (purchase + nursing time)
• Why ? Spend more to gain equivalence
‘Adding in the dangerous drug makes ours better’

35. Escalating Costs
• Final bivalirudin drug cost is a function of:
• Patient body weight
• Duration of PCI
• Duration and dose of any continued infusion
• Potential ‘upstream’ use
• Cost relative to unfractionated heparin (UK)
350 x 700x 1050x 1400x

36. Conclusions
• Heparin (50 - 70 u/Kg) is the drug of choice
• Bivalirudin bubble has burst
• Potential for annual global savings
• US $ 700 million
• The ‘bivalirudin story’ is interesting
• As ever - lessons to be learned for EBM ?
• ESC Revascularisation Guidelines 2014

37. ESC Guidelines 2014 STEMI Revascularisation
In summary, recent trials comparing bivalirudin with
UFH without systematic use of GPIIb/IIIa
antagonists uphold concerns over an excess risk
for acute stent thrombosis with bivalirudin, while
differences in major bleeding are small.
UFH I C Bivalirudin IIa B
EHJ doi:10.1093/eurheartj/ehu278

38. • Single centre RCT
• Trial recruitment: Feb 2012 - Nov 2013 22 months
• Bivalirudin v Unfractionated Heparin
• STEMI patients
• Randomised at presentation
• Acute phase management with Primary PCI

39. Inclusion Criterion
• All STEMI patients activating PPCI pathway
Exclusion Criteria
•Active bleeding at presentation
•Factors precluding administration of oral A-P therapy
•Known intolerance / contraindication to trial medication
•Previous enrolment in this trial

40. • Dual oral anti-platelet therapy pre-procedure
• Heparin: 70 units/kg body weight pre-procedure
• Bivalirudin: Bolus 0.75 mg/kg
Infusion 1.75 mg/kg/hr - procedure duration

41. • Dual oral anti-platelet therapy pre-procedure
• Heparin: 70 units/kg body weight pre-procedure
• Bivalirudin: Bolus 0.75 mg/kg
Infusion 1.75 mg/kg/hr - procedure duration
• GPI - Abciximab
• Selective (‘bailout’) use in both groups
• ESC guideline indications

42. At 28 days
Primary Efficacy Outcome Measure
• Major Adverse Cardiac Events (MACE) -
• All-cause mortality
• Cerebrovascular accident (CVA)
• Re-infarction
• Unplanned target lesion revascularisation (TLR)

43. At 28 days
Primary Efficacy Outcome Measure
• Major Adverse Cardiac Events (MACE)
Primary Safety Outcome Measure
•Major bleeding -
• Type 3-5 bleeding as per BARC definitions

44. 1917 patients scheduled for emergency angiography
29 (1.5%) already randomised in the trial
59 (3.0%) met one or more other exclusion criteria
1829 eligible for recruitment

45. 1917 patients scheduled for emergency angiography
29 (1.5%) already randomised in the trial
59 (3.0%) met one or more other exclusion criteria
1829 eligible for recruitment
1829 Randomised
Representative ‘Real-World’ Population

46. Assigned to Heparin 914 915 Assigned to Bivalirudin
Received allocated Rx 900
Received no study drug 14
Treatment cross-over 0
LMWH pre-procedure 3
907 Received allocated Rx
7 Received no study drug
1 Treatment cross-over
4 LMWH pre-procedure

47. Assigned to Heparin 914
Included in analysis 907
915 Assigned to Bivalirudin
905 Included in analysis
Consent not available
in surviving patients
Consent not available
in surviving patients
7 10
Received allocated Rx 900
Received no study drug 14
Treatment cross-over 0
LMWH pre-procedure 3
907 Received allocated Rx
7 Received no study drug
1 Treatment cross-over
4 LMWH pre-procedure

48. Characteristic Bivalirudin Heparin
Median age (years) 62.9 63.6
Female sex (%) 28.5 26.9
Caucasian race (%) 95.8 95.9
Diabetes mellitus (%) 12.6 15.1
Previous MI (%) 13.5 10.3
eGFR (ml/min/1.73m2) 80.0 80.0
Haemoglobin (g/dl) 13.6 13.7

49. Characteristic Bivalirudin (%) Heparin (%)
P2Y12 use - Any 99.6 99.5
- Clopidogrel 11.8 10.0
- Prasugrel 27.3 27.6
- Ticagrelor 61.2 62.7
GPI use 13.5 15.5
Radial arterial access 80.3 82.0
PCI performed 83.0 81.6

50. Characteristic Bivalirudin (%) Heparin (%)
Thrombectomy 59.1 57.6
Single vessel Tx 93.2 90.3
Any stent implant 92.8 92.2
DES implantation 79.8 79.9
TIMI III flow - post PCI 93.3 92.7

52. Bivalirudin Heparin
n % % n
MACE 79 8.7 % v 5.7 % 52
Absolute risk increase = 3.0% (95% CI 0.6, 5.4)
Relative risk = 1.52 (95% CI 1.1 – 2.1) P=0.01

53. Event curve shows first event experienced

54. Bivalirudin Heparin
n % % n
Death 46 5.1 % v 4.3 % 39
CVA 15 1.6% v 1.2% 11
Reinfarction 24 2.7% v 0.9% 8
TLR 24 2.7% v 0.7% 6
Any MACE 79 8.7 % v 5.7 % 52

55. Bivalirudin Heparin
n % % n
Death 46 5.1 % v 4.3 % 39
CVA 15 1.6% v 1.2% 11
Reinfarction 24 2.7% v 0.9% 8
TLR 24 2.7% v 0.7% 6
Any MACE 79 8.7 % v 5.7 % 52

56. Bivalirudin Heparin
n % % n
Death 46 5.1 % v 4.3 % 39
CVA 11 1.2% v 0.6% 6
Reinfarction 21 2.3% v 0.8% 7
TLR 1 0.1% v 0% 0
Any MACE 79 8.7 % v 5.7 % 52
Censored by the most significant event - in order displayed

57. Bivalirudin Heparin
n % % n
Death 46 5.1 % v 4.3 % 39
CVA 11 1.2% v 0.6% 6
Reinfarction 21 2.3% v 0.8% 7
TLR 1 0.1% v 0% 0
Any MACE 79 8.7 % v 5.7 % 52
Censored by the most significant event - in order displayed

58. Bivalirudin Heparin
n % % n
All Events 24 3.4 % v 0.9 % 6
Relative risk = 3.91 (95% CI 1.6 - 9.5) P=0.001
ARC definite or probable stent thrombosis events

59. Bivalirudin Heparin
n % % n
Definite 23 3.3 % v 0.7 % 5
Probable 1 0.1 % v 0.1 % 1
Acute 20 2.9 % v 0.9 % 6
Subacute 4 0.6% v 0% 0
ARC definite or probable stent thrombosis events

60. Bivalirudin Heparin
n % % n
Major Bleed 32 3.5 % v 3.1 % 28
Relative risk = 1.15 (95% CI 0.7 - 1.9) P=0.59
Major Bleed BARC grade 3-5

61. Bivalirudin Heparin
n % % n
Minor Bleed 83 9.2 % v 10.8 % 98
Major or Minor 113 12.5 % v 13.5 % 122
Minor Bleed P=0.25 Major or Minor P=0.54
Major Bleed BARC grade 3-5 Minor Bleed BARC grade 2

62. Subgroup Relative Risk (95% CI)
P Value for
interaction
All patients 1.52 (1.09, 2.13)
Arterial access site 0.87
Radial 1.58 (1.01, 2.48)
Femoral 1.45 (0.70, 2.98)
Diabetes 0.35
Yes 2.22 (1.04, 4.76)
No 1.54 (1.04, 2.28)
Age 0.11
≥75 1.09 (0.68, 1.77)
<75 1.97 (1.23, 3.16)
Favours Bivalirudin Favours Heparin
1

63. Subgroup Relative Risk (95% CI)
P Value for
interaction
P2Y12 agent used 0.78
Clopidogrel 1.34 (0.54, 3.31)
Prasugrel 1.91 (0.87, 4.21)
Ticagrelor 1.41 (0.93, 2.14)
Left Ventricular Function Impaired 0.67
Yes 1.28 (0.84, 1.95)
No 1.63 (0.64, 4.16)
PCI attempted 0.88
Yes 1.55 (1.06, 2.28)
No 1.45 (0.71, 2.96)
Favours Bivalirudin Favours Heparin
2

64. • Single centre
• Potential impact minimised by:
• Meticulous trial conduct
• Unselected representative population
• Study treatments are iv drugs (no ‘skill’ component)
• Multiple operators
• Outcomes as expected by national norms

65. • Single centre
• Open label
• Potential impact minimised by:
• Complete follow-up - No ‘lost’ cases
• Outcome measures were overt clinical events
• Most MI events involved angiographic imaging
• Independent blinded adjudication
• Open label used in HORIZONS and EUROMAX

66. • A unique study with 100% recruitment of eligible patients

67. • A unique study with 100% recruitment of eligible patients
Use of heparin rather than bivalirudin
• Reduced rate of major adverse events (NNT = 33)
• Fewer stent thromboses and reinfarction events

68. • A unique study with 100% recruitment of eligible patients
Use of heparin rather than bivalirudin
• Reduced rate of major adverse events (NNT = 33)
• Fewer stent thromboses and reinfarction events
• Consistent effect across pre-specified subgroups

69. • A unique study with 100% recruitment of eligible patients
Use of heparin rather than bivalirudin
• Reduced rate of major adverse events (NNT = 33)
• Fewer stent thromboses and reinfarction events
• Consistent effect across pre-specified subgroups
• No increase in bleeding complications

70. • A unique study with 100% recruitment of eligible patients
Use of heparin rather than bivalirudin
• Reduced rate of major adverse events (NNT = 33)
• Fewer stent thromboses and reinfarction events
• Consistent effect across pre-specified subgroups
• No increase in bleeding complications
• Potential for substantial saving in drug costs