Does Bivalirudin Improve Outcomes in Contemporary Percutaneous Coronary Intervention?

  

    
Trial 
    
N 
    
PCI Population 
    
Primary Outcome 
      
Definition 
    
Primary Outcome Result 
    
Bleeding Outcome Definition 
    
Bleeding Outcome Result 
    
Myocardial Infarction 
    
All Stent Thrombosis 
    
All-Cause Death 
    
Notes 
  
  

    
Bivalirudin    vs UFH + GPI
    
 
  
  

    
REPLACE-2 (2003) [4]
    
6010
    
Non-primary PCI
    
Death, MI, urgent repeat revascularization at 30 days, in-hospital    bleeding
    
Bivalirudin: 9.2%
      
 
      
UFH:
      
10.0%
      
 
      
P = 0.32
    
Major bleeding
    
Bivalirudin:
      
2.4%
      
 
      
UFH:
      
4.1%
      
 
      
P <0.001
    
Bivalirudin: 7.0%
      
 
      
UFH:
      
6.2%
      
 
      
P = 0.23
    
NR
    
Bivalirudin:
      
0.2%
      
 
      
UFH:
      
0.4%
      
 
      
P = 0.26
    
86% received pre-PCI with P2Y12 inhibitor
  
  

    
ACUITY (PCI subgroup, 2007)) [6]
    
5180
    
Non-primary PCI
    
Death, MI, unplanned revascularization for ischemia, major bleeding at    30 days*
    
Bivalirudin:
      
12%
      
 
      
UFH:
      
13%
      
 
      
P = 0.057
    
Non-CABG major bleeding (co-primary outcome)
    
Bivalirudin:
      
4%
      
 
      
Heparin:
      
7%
      
 
      
P <0.0001
    
Bivalirudin:
      
6%
      
 
      
Heparin:
      
6%
      
 
      
P = 0.19
    
Bivalirudin:
      
1%
      
 
      
Heparin:
      
1%
      
 
      
P = 0.87
    
Bivalirudin:
      
1%
      
 
      
Heparin:
      
0.9%
      
 
      
P = 0.53
    
69% received pre-PCI with P2Y12 inhibitor
      
 
      
Excludes the bivalirudin + GPI arm
      
 
      
Heparin includes UFH or enoxaparin
  
  

    
HORIZONS-AMI(2008) [10]
    
3602
    
Primary PCI
    
Death, reinfarction, TVR for ischemia, stroke, major bleeding at 30    days
    
Bivalirudin:
      
9.2%
      
 
      
UFH:
      
12.1%
      
 
      
P = 0.005
    
Non-CABG major bleeding (co-primary endpoint)
    
Bivalirudin:
      
4.9%
      
 
      
UFH:
      
8.3%
      
 
      
P =<0.001
    
Bivalirudin:
      
1.8%
      
 
      
UFH:
      
1.8%
      
 
      
P = 0.90†
    
Bivalirudin:
      
2.5%
      
 
      
UFH:
      
1.9%
      
 
      
P = 0.30
    
Bivalirudin:
      
2.1%
      
 
      
UFH:
      
3.1%
      
 
      
P = 0.047
    
100% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
Acute stent thrombosis (within 24 hours) increased with bivalirudin    (1.3% vs 0.3%, P <0.001)
  
  

    
ISAR-REACT 4 (2011) [7]
    
1721
    
Non-primary PCI
    
Death, large recurrent MI, urgent TVR, major bleeding at 30 days
    
Bivalirudin:
      
11.0%
      
 
      
UFH:
      
10.9%
      
 
      
P = 0.94
    
Major bleeding
    
Bivalirudin:
      
2.6%
      
 
      
UFH:
      
4.6%
      
 
      
P = 0.02
    
Bivalirudin:
      
11.4%
      
 
      
UFH:
      
12.0%
      
 
      
P = NS
    
Bivalirudin:
      
0.7%
      
 
      
UFH:
      
0.6%
      
 
      
P = NS**
    
Bivalirudin:
      
1.6%
      
 
      
UFH:
      
1.4%
      
 
      
P = NS
    
100% received pre-PCI P2Y12 inhibitor per protocol
  
  

    
EUROMAX(2013) [12]
    
2218
    
Primary PCI
    
Death or non-CABG major bleeding at 30 days
    
Bivalirudin:
      
5.1%
      
 
      
Heparin:
      
8.5%
      
 
      
P = 0.001
    
Non-CABG major bleeding
    
Bivalirudin:
      
2.6%
      
 
      
Heparin:
      
6.0%
      
 
      
P =<0.001
    
Bivalirudin:
      
1.7%
      
 
      
Heparin:
      
0.9%
      
 
      
P = 0.08†
    
Bivalirudin:
      
1.6%
      
 
      
Heparin:
      
0.5%
      
 
      
P = 0.02**
    
Bivalirudin:
      
2.9%
      
 
      
Heparin:
      
3.1%
      
 
      
P = 0.86
    
91% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
47% radial arterial access
      
 
      
Heparin includes UFH or enoxaparin
      
 
      
Acute stent thrombosis (within 24 hours) increased with bivalirudin    (1.1% vs 0.2%, P = 0.007)
  
  

    
BRIGHT(2015) [16]
    
1465
    
Primary PCI
    
Death, reinfarction, ischemia-driven TVR, stroke, bleeding at 30 days
    
Bivalirudin:
      
8.8%
      
 
      
UFH:
      
17.0%
      
 
      
P = <0.001
    
All bleeding (BARC types 1-5)
      
 
      
 
      
 
      
 
      
 
      
BARC 3-5 bleeding
    
Bivalirudin:
      
4.1%
      
 
      
UFH:
      
12.3%
      
 
      
P = NR (significant)
      
 
      
Bivalirudin:
      
0.5%
      
 
      
UFH:
      
2.1%
      
 
      
P = NR (significant)
    
Bivalirudin:
      
1.0%
      
 
      
UFH:
      
0.8%
      
 
      
P = NS†
    
Bivalirudin:
      
0.6%
      
 
      
UFH:
      
0.7%
      
 
      
P = NS
    
Bivalirudin:
      
1.8%
      
 
      
UFH:
      
2.1%
      
 
      
P = NS
    
97% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
 
      
78% radial arterial access
      
 
      
UFH dose was 60 units/kg
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion with    post-PCI infusion
  
  

    
 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
  
  

    
Bivalirudin vs    UFH monotherapy
    
 
  
  

    
Hirulog Angioplasty Study (1995) [2]
    
4098
    
Non-primary PCI
    
In-hospital death, MI, abrupt vessel closure, or rapid clinical    deterioration of cardiac origin
    
Bivalirudin:
      
11.4%
      
 
      
UFH:
      
12.2%
      
 
      
P = NS
    
Major bleeding
    
Bivalirudin:
      
3.8%
      
 
      
UFH:
      
9.8%
      
 
      
P =<0.001
    
Bivalirudin:
      
3.2%
      
 
      
UFH:
      
3.9%
      
 
      
P = 0.20
    
NR
    
Bivalirudin:
      
0.4%
      
 
      
UFH:
      
0.2%
      
 
      
P = 0.27
    
No pre-PCI P2Y12 inhibitor
      
 
      
UFH dose was 175 units/kg bolus followed by 18-24 hour infusion of 15    units/kg/hr
      
 
      
Bivalirudin dose was 1.0 mg/kg bolus followed by2.5 mg/kg/h infusion    for 4 hours and 0.2 mg/kg/hr infusion for 14-20 hours
  
  

    
ISAR-REACT 3(2008) [8]
    
4570
    
Non-primary PCI
    
Death, MI, urgent TVR for ischemia at 30 days, in-hospital major    bleeding
    
Bivalirudin:
      
8.3%
      
 
      
UFH:
      
8.7%
      
 
      
P = 0.57
    
Major bleeding
    
Bivalirudin:
      
3.1%
      
 
      
UFH:
      
4.6%
      
 
      
P = 0.008
    
Bivalirudin:
      
5.6%
      
 
      
UFH:
      
4.8%
      
 
      
P = NR
    
Bivalirudin:
      
0.5%
      
 
      
UFH:
      
0.4%
      
 
      
P = 0.52**
    
Bivalirudin:
      
0.1%
      
 
      
UFH:
      
0.2%
      
 
      
P = NR
    
100% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
UFH dose was 140 units/kg
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion
  
  

    
HEAT-PPCI(2014) [13]
    
1829
    
Primary PCI
    
Death, stroke, reinfarction, TLR at 28 days
    
Bivalirudin:
      
8.7%
      
 
      
UFH:
      
5.7%
      
 
      
P = 0.01
    
Major bleeding (BARC type 3-5; primary safety outcome)
    
Bivalirudin:
      
3.5%
      
 
      
UFH:
      
3.1%
      
 
      
P = 0.59
    
Bivalirudin:
      
2.7%
      
 
      
UFH:
      
0.9%
      
 
      
P = 0.004
    
Bivalirudin:
      
3.4%
      
 
      
UFH:
      
0.9%
      
 
      
P = 0.001
    
Bivalirudin:
      
5.1%
      
 
      
UFH:
      
4.3%
      
 
      
P = 0.43
    
>99% received P2Y12 inhibitor per protocol
      
 
      
UFH dose was 70 units/kg
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion
      
 
      
81% radial arterial access
      
 
      
82% underwent PCI
      
 
      
Acute stent thrombosis (within 24 hours) increased with bivalirudin    (2.9% vs 0.9%, P = 0.007)
  
  

    
BRIGHT(2015) [16]
    
1464
    
Primary PCI
    
Death, reinfarction, ischemia-driven TVR, stroke, bleeding at 30 days
    
Bivalirudin:
      
8.8%
      
 
      
UFH:
      
13.2%
      
 
      
P = 0.008
    
All bleeding (BARC types 1-5)
      
 
      
 
      
 
      
 
      
 
      
BARC 3-5 bleeding
    
Bivalirudin:
      
4.1%
      
 
      
UFH:
      
7.5%
      
 
      
P = NR (significant)
      
 
      
Bivalirudin:
      
0.5%
      
 
      
UFH:
      
1.5%
      
 
      
P = NS
    
Bivalirudin:
      
1.0%
      
 
      
UFH:
      
1.2%
      
 
      
P = NS†
    
Bivalirudin:
      
0.6%
      
 
      
UFH:
      
0.9%
      
 
      
P =NS
    
Bivalirudin:
      
1.8%
      
 
      
UFH:
      
1.8%
      
 
      
P = NS
    
96% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
UFH dose was 100 units/kg
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion with    post-PCI infusion
      
 
      
79% radial arterial access
      
 
  
  

    
NAPLES III (2015) [15]
    
837
    
Non-primary PCI
    
In-hospital major bleeding
    
See bleeding outcome
    
In-hospital major bleeding (primary outcome)
    
Bivalirudin:
      
3.3%
      
 
      
UFH:
      
2.6%
      
 
      
P = 0.54
    
Bivalirudin:
      
22.0%
      
 
      
UFH:
      
21.5%
      
 
      
P = NS
    
Bivalirudin:
      
0.5%
      
 
      
UFH:
      
0.5%
      
 
      
P = 0.99
    
Bivalirudin:
      
2.4%
      
 
      
UFH:
      
1.4%
      
 
      
P = 0.31
    
100% received pre-PCI P2Y12 inhibitor per protocol
      
 
      
UFH dose was 70 units/kg
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion
      
 
      
No radial access
      
 
      
Outcomes except for bleeding are assessed at 30 days
  
  

    
MATRIX(2015) [17]
    
7213
    
Primary and non-primary PCI
    
Death, MI, or stroke at 30 days‡
    
Bivalirudin:
      
10.3%
      
 
      
UFH:
      
10.9%
      
 
      
P = 0.44
    
Any bleeding
      
 
      
 
      
 
      
 
      
 
      
 
      
BARC type 3 or 5
    
Bivalirudin:
      
11.0%
      
 
      
UFH:
      
13.6%
      
 
      
P = 0.001
      
 
      
Bivalirudin:
      
1.4%
      
 
      
UFH:
      
2.5%
      
 
      
P = <0.001
    
Bivalirudin:
      
8.6%
      
 
      
UFH:
      
8.5%
      
 
      
P = 0.93
    
Bivalirudin:
      
1.0%
      
 
      
UFH:
      
0.6%
      
 
      
P = 0.048**
    
Bivalirudin:
      
1.7%
      
 
      
UFH:
      
2.3%
      
 
      
P = 0.04
    
82% received a pre-PCI oral ant platelet agent other than aspirin
      
 
      
25.9% of UFH-treated patients received a GPI compared to 4.6% of    bivalirudin-treated patients
      
 
      
UFH dose was 70-100 units/kg without GPI or 50-70 units/kg with GPI
      
 
      
Bivalirudin dose was 0.75 mg/kg bolus and 1.75 mg/kg/h infusion with    or without post-PCI infusion
      
 
      
50% radial arterial access
      
 
  

Table 1:  Summary of major randomized controlled trials of heparin (UFH, enoxaparin, or both) and bivalirudin to support percutaneous coronary intervention. All endpoints are assessed at the same time as the primary endpoint unless otherwise noted. ACS = Acute Coronary Syndrome; BARC = Bleeding Academic Research Consortium; CABG = Coronary Artery Bypass Grafting; GPI = Glycoprotein Iib/Iiia Inhibitor; N = Sample Size; NR = Not Reported; NS = Not Significant; PCI = Percutaneous Coronary Intervention; TLR = Target-Lesion Revascularization; TVR = Target-Vessel Revascularization. *The other primary outcomes were major bleeding at 30 days (see table) and the composite of death, MI, and unplanned revascularization for ischemia at 30 days (no difference between groups). **Definite stent thrombosis. †Reinfarction. ‡The other primary efficacy endpoint was the composite of death, MI, stroke, or BARC type 3 or 5 bleeding at 30 days (no difference between groups).

Subsequently, the use of GP IIb/IIIa inhibitors with UFH became routine, and PCI progressed from balloon angioplasty to coronary stenting. Therefore, the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial randomized 6010 patients undergoing urgent or elective PCI to bivalirudin with provisional GP IIb/IIIa inhibitor use (actual use in 7.2%) or UFH with routine GP IIb/IIIa inhibitor use (actual use in 96.5%) [4]. There was no difference in the primary composite outcome of 30-day death, MI, urgent revascularization, and in-hospital major bleeding (9.2% vs 10.0% for bivalirudin vs UFH, P = 0.32), but in-hospital major bleeding was reduced in favor of bivalirudin (2.4% vs 4.1%, P <0.001). The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13,819 patients with unstable angina or non-ST segment elevation myocardial infarction (NSTEMI) to UFH or enoxaparin with routine GP IIb/IIIa inhibitor use, bivalirudin with GP IIb/IIIa inhibitor use, or bivalirudin monotherapy [5]. All patients had coronary angiography within 72 hours of randomization, and analysis of the subgroup of 7789 patients undergoing PCI showed no difference in the composite of ischemic outcomes and major bleeding at 30 days. However, major bleeding not related to Coronary Artery Bypass Grafting (CABG) was significantly reduced with bivalirudin monotherapy compared to heparin (UFH or enoxaparin) with routine GP IIb/IIIa inhibitor use (4% vs 7%, P<0.0001) [6]. Notably, lack of pre-treatment with a thienopyridine appeared to confer a slightly elevated risk for ischemic events with bivalirudin monotherapy. Finally, the double-blind Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4 (ISAR-REACT 4) trial randomized 1721 patients with an NSTEMI to UFH with routine GP IIb/IIIa inhibitor use or bivalirudin with provisional GP IIb/IIIa use. At 30 days, there was no difference in the primary composite endpoint of death, MI, urgent Target Vessel Revascularization (TVR), or major bleeding (10.9% vs 11.0% for UFH vs bivalirudin, respectively; P = 0.94). Again, bivalirudin was superior with regard to major bleeding (2.6% vs 4.6%, P = 0.02) [7].

In the mid 2000’s, pre-treatment with a clopidogrel became common practice and was thought to mitigate the benefit of concomitant GP IIb/IIIa inhibitor use during PCI. Therefore, the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 3) trial randomized 4570 patients with stable or unstable angina undergoing PCI who were pre-treated with 600 mg of clopidogrel to UFH monotherapy or bivalirudin monotherapy [8]. Notably, the UFH dose was nearly double the current guideline-recommended dose (140 units/kg vs 70- 100 units/kg) [9]. At 30 days, there was no difference the primary composite endpoint of 30-day ischemic outcomes or in-hospital major bleeding, but in-hospital major bleeding was significantly reduced in the bivalirudin arm (3.1% vs 4.6%, P = 0.008).

Trials in Primary PCI

A wave of trials of bivalirudin in the primary PCI population began several years after the trials in patients undergoing non-primary PCI. The first was the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial which randomized 3602 patients with STEMI undergoing primary PCI to UFH with routine GP IIb/IIIa inhibitor use or bivalirudin monotherapy [10]. Pre-treatment with clopidogrel or ticlopidine was required by protocol. The primary outcome consisted of the composite of major bleeding, death, reinfarction, TVR for ischemia, and stroke at 30 days and was reduced in the bivalirudin arm (9.2% vs 12.1%, P = 0.005). This was driven by non-CABG major bleeding (4.9% vs 8.3%, P <0.001), but bivalirudin also conferred an overall mortality benefit (2.1% vs 3.1%, P = 0.047). These benefits came at the cost of an increased risk of acute stent thrombosis (1.3% vs 0.3%, P <0.001 in favor of UFH) with no difference in stent thrombosis at 30 days. Furthermore, non-CABG bleeding (6.9% vs 10.5%, P = 0.0001), all-cause mortality (5.9% vs 7.7%, P = 0.03), and cardiac mortality (2.9% vs 5.1%, P = 0.001) favored bivalirudin at 3 years [11]. Similarly, the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) study randomized 2218 patients with STEMI to bivalirudin monotherapy or UFH with routine GP IIb/IIIa inhibitor use during transport, with nearly half of patients having radial access [12]. The primary outcome of death or non-CABG major bleeding at 30 days was reduced in the bivalirudin arm (5.1% vs 8.5%, P = 0.001), driven by non-CABG major bleeding (2.6% vs 6.0%, P <0.001), and came at the cost of increased acute stent thrombosis (1.1% vs 0.2%, P = 0.007). Notably, the mortality difference seen in HORIZONS-AMI was not replicated in EUROMAX.

Mirroring the shift in bivalirudin trials in non-primary PCI, primary PCI trials evolved with contemporary practice to compare bivalirudin monotherapy to heparin monotherapy. The first such study was the single-center How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEATPPCI) study that caused much controversy when it was published in 2014. Designed as a pragmatic trial utilizing delayed consent, the investigators randomized 1829 patients with STEMI (97% of patients not previously enrolled) to UFH monotherapy or bivalirudin monotherapy [13]. Bailout GP IIb/IIIa use was low in both arms (13- 15%), all but 9 patients received a P2Y12 inhibitor loading dose, and 82% of patients underwent PCI. Surprisingly, the primary efficacy outcome consisting of the composite of all-cause mortality, stroke, reinfarction, and unplanned target lesion revascularization at 28 days was reduced in the UFH arm (5.7% vs 8.7%, P = 0.01). Again, acute stent thrombosis was increased with bivalirudin compared to UFH (0.9% vs 2.9%, P = 0.007). Perhaps even more surprisingly, the primary safety outcome of major bleeding (Bleeding Academic Research Consortium [BARC] [14] type 3-5) at 28 days was equal in both arms (3.1% vs 3.5% for UFH and bivalirudin, respectively; P = 0.59).

Shortly thereafter, the single-center Novel Approaches for Preventing or Limiting Events (NAPLES) III trial randomized 837 patients at increased bleeding risk and without cardiac biomarker elevation who were undergoing PCI to UFH monotherapy or bivalirudin monotherapy [15]. GP IIb/IIIa use was minimal in both arms, and there was no difference in the primary outcome of in-hospital major bleeding (2.6% vs 3.3% for UFH vs bivalirudin, respectively; P = 0.54). In addition, there was no difference in MI, stent thrombosis, or death at 30 days or one year. Although this trial was considerably smaller than most others in the same arena, it is useful in that its findings are similar to those of HEAT-PPCI.

Next, the multicenter Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial (BRIGHT) randomized 2194 patients undergoing primary PCI for STEMI (over 87%) or emergent NSTEMI to bivalirudin monotherapy with a post-PCI infusion, UFH monotherapy, or UFH with the GP IIb/IIIa inhibitor tirofiban [16]. Nearly all patients were pre-treated with a P2Y12 inhibitor and just under 80% of patients had radial access. The primary composite outcome of all-cause death, reinfarction, ischemia-driven TVR, stroke, or bleeding at 30 days occurred in 8.8% of bivalirudin-treated patients, 13.2% of UFH monotherapy-treated patients (P = 0.008), and 17.0% of UFH and tirofiban-treated patients (P = <0.001). This difference was driven by BARC type 1-5 bleeding (4.1% vs 7.5% vs 12.3% for bivalirudin, UFH, and UFH with tirofiban, P <0.001), while there was a trend towards reduced BARC type 3-5 bleeding with bivalirudin monotherapy compared to UFH monotherapy. No difference was seen in death, reinfarction, stroke, or stent thrombosis, and findings persisted out to one year. Notably, while nearly all prior trials had used Angiomax (The Medicines Company, Parsippany, NJ), BRIGHT used a generic formulation (Salubris Pharmaceuticals Co, China).

Most recently, the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) trial randomized 7213 patients with an ACS (55.6% STEMI) and planned for PCI to UFH or bivalirudin monotherapy [17]. Additionally, patients receiving bivalirudin were further randomized to bivalirudin cessation at the conclusion of PCI or a post- PCI bivalirudin infusion. The primary outcomes were the composite of Major Adverse Cardiac Events (MACE) defined as death, MI, or stroke as well as the composite of MACE or major bleeding (net adverse clinical events, or NACE). There was no significant difference between UFH and bivalirudin in either primary outcome, nor did a post-PCI bivalirudin infusion impact rate of TVR or stent thrombosis. However, major bleeding (BARC type 3 or 5) was decreased with bivalirudin (1.4% vs 2.5%, P <0.001) as was any bleeding, and it was fatal bleeds that largely drove decreases in all-cause (1.7% vs 2.3%, P = 0.04) and cardiac (1.5% vs 2.2%, P = 0.03) mortality with bivalirudin. However, definite stent thrombosis was increased with bivalirudin (1.0% vs 0.6%, P = 0.048). Importantly, 25.9% of patients in the UFH arm and 4.6% of patients in the bivalirudin arm received a GP IIb/ IIIa inhibitor, and 82% of patients received clopidogrel, prasugrel, or ticagrelor prior to angiography.

The Controversy Continues

So what are we to make of these seemingly similar studies with divergent outcomes? Does bivalirudin truly have a lower risk of bleeding than UFH, or is the increased bleeding risk with UFH conferred by the much higher rate of concomitant GP IIb/IIIa inhibitor use? If a bleeding benefit is present, is it obliterated by the shift to a radial-first arterial access strategy? Do bivalirudin-treated patients have an increased risk of acute stent thrombosis? And finally, is the potential mortality benefit of bivalirudin over UFH real?

The advantage of bivalirudin monotherapy over UFH with a GP IIb/IIIa inhibitor for bleeding outcomes is effectively incontrovertible. However, in contemporary practice GP IIb/IIIa inhibitors have largely been relegated to use for complications of PCI including noreflow or a high thrombus burden. The currently relevant comparison is bivalirudin monotherapy to UFH monotherapy, and for that the evidence is less clear. The only large randomized clinical trial to address this question in the non-primary PCI population is the ISARREACT 3 trial which showed reduced bleeding in favor of bivalirudin [8]. However, the UFH dose was nearly twice that recommended by current PCI guidelines (140 units/kg bolus as compared to the recommended 70-100 units/kg bolus), a difference which biased the results in favor of bivalirudin. In contrast, NAPLES III was a much smaller trial in non-primary PCI but used guideline-consistent UFH and bivalirudin dosing and showed equivalent major bleeding (by the REPLACE bleeding definition) between UFH and bivalirudin [15]. In primary PCI, MATRIX showed a benefit for bleeding with bivalirudin, but GP IIb/IIIa use was more than 5 times greater in the UFH arm, again biasing results in favor of bivalirudin [17]. Additionally, the single-center HEAT-PPCI trial showed no difference in BARC type 3-5bleeding, and the multicenter BRIGHT trial, which used a generic bivalirudin different than all other trials, showed less BARC type 1-5 bleeding with bivalirudin and a trend towards less BARC type 3-5 bleeding [13,16]. Finally, two recent meta-analyses showed no difference in bleeding between bivalirudin and heparin monotherapy in patients undergoing PCI [18,19]. Therefore, whether bivalirudin truly improves bleeding outcomes over UFH monotherapy remains somewhat unclear. We are inclined to think that while there may be some reduction in bleeding risk with bivalirudin over UFH, the difference is probably small.

Interestingly, two recent observational studies have suggested a major reduction or elimination of any benefit in bleeding outcomes conferred by bivalirudin over UFH when radial arterial access is used in preference to femoral access [20,21]. However, the randomized trials noted above do not support this. MATRIX randomized patients to femoral or radial access (each arm had 50% of each), and access site did not modify the effect of anticoagulant on any of the major outcomes [17]. In addition, BRIGHT had high rates of radial access and showed a reduction in all bleeding including both access siterelated and non-access site-related bleeding [16]. Therefore, although access site-related bleeding rates are reduced with radial compared to femoral arterial access, it appears that this does not eliminate the possibility of a bleeding advantage favoring bivalirudin.

The available trials are largely consistent in the conclusion that bivalirudin does not confer a significant benefit with regard to ischemic outcomes compared to either UFH or UFH with a GP IIb/ IIIa inhibitor. However, HORIZONS-AMI, EUROMAX, and HEATPPCI all showed an increase in acute stent thrombosis while HEATPPCI and MATRIX showed an increase in definite stent thrombosis with bivalirudin compared to either UFH or UFH with a GP IIb/IIIa inhibitor [10,12,13,17]. Although this has generally not translated into a long-term difference in stent thrombosis and does not appear to impact mortality (indeed, mortality has occasionally been lower in the bivalirudin arm despite increased stent thrombosis!), stent thrombosis can still be a very morbid and devastating complication. Therefore, although relatively rare, the increase in stent thrombosis with bivalirudin is a major cause for concern.

Finally, both HORIZONS-AMI and MATRIX showed a mortality benefit to bivalirudin over UFH with and without GP IIb/IIIa inhibitor use [10,17] First, it is important to note that mortality was one of many secondary outcomes in both trials, and the P-values were marginally significant in both. Therefore, it remains possible that these mortality differences are simply the result of type I statistical error. Furthermore, both HORIZONS-AMI and MATRIX suggested that the mortality benefit of bivalirudin was likely driven by reductions in major or fatal bleeding. Therefore, if the finding of a mortality reduction is not the result of statistical error, it likely depends on the ability of bivalirudin to decrease bleeding. As we have argued above, this remains to be convincingly demonstrated for UFH monotherapy compared to bivalirudin monotherapy, which is the comparison most relevant to contemporary practice.

Conclusion

Within the contemporary PCI environment marked by provisional use of GP IIb/IIIa inhibitors and common pre-treatment with potent oral antiplatelet regimens, the purported bleeding benefit conferred by bivalirudin monotherapy compared to UFH monotherapy during PCI is small at best and non-existent at worst. Furthermore, the clear signal for increased acute stent thrombosis with bivalirudin should give operators pause. These facts combined with the considerable cost savings of UFH over bivalirudin suggest that given the available evidence, UFH should be the preferred anticoagulant to support PCI. Future clinical trials should look to address the gaps in evidence noted above, with particular attention paid to the non-primary PCI setting which has a different peri-procedural risk profile and a paucity of evidence for the contemporary anticoagulation environment.

References

1. 1. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990; 86: 385-391.
2. 2. Bittl JA, Strony J, Brinker JA, Ahmed WH, Meckel CR, Chaitman BR, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med. 1995; 333: 764-769.
3. 3. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J. 2001; 142: 952-959.
4. 4. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003; 289: 853-863.
5. 5. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006; 355: 2203-2216.
6. 6. Stone GW, White HD, Ohman EM, Bertrand ME, Lincoff AM, McLaurin BT, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet. 2007; 369: 907-919.
7. 7. Kastrati A, Neumann FJ, Schulz S, Massberg S, Byrne RA, Ferenc M, et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med. 2011; 365: 1980-1989.
8. 8. Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Büttner HJ, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med. 2008; 359: 688-696.
9. 9. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58: e44-122.
10. 10. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008; 358: 2218-2230.
11. 11. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet. 2011; 377: 2193-2204.
12. 12. Steg PG, van't Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013; 369: 2207-2217.
13. 13. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014; 384: 1849-1858.
14. 14. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011; 123: 2736-2747.
15. 15. Briguori C, Visconti G, Focaccio A, Donahue M, Golia B, Selvetella L, et al. Novel approaches for preventing or limiting events (Naples) III trial: randomized comparison of bivalirudin versus unfractionated heparin in patients at increased risk of bleeding undergoing transfemoral elective coronary stenting. JACC Cardiovasc Interv. 2015; 8: 414-423.
16. 16. Han Y, Guo J, Zheng Y, Zang H, Su X, Wang Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015; 313: 1336-1346.
17. 17. Valgimigli M, Frigoli E, Leonardi S, Rothenbühler M, Gagnor A, Calabrò P, et al. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med. 2015; 373: 997-1009.
18. 18. Navarese EP, Schulze V, Andreotti F, Kowalewski M, Kolodziejczak M, Kandzari DE, et al. Comprehensive meta-analysis of safety and efficacy of bivalirudin versus heparin with or without routine glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndrome. JACC Cardiovasc Interv. 2015; 8: 201-213.
19. 19. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014; 384: 599-606.
20. 20. Sciahbasi A, Rigattieri S, Cortese B, Belloni F, Russo C, Ferraironi A, et al. Bivalirudin or heparin in primary angioplasty performed through the transradial approach: results from a multicentre registry. Eur Heart J Acute Cardiovasc Care. 2014; 3: 268-274.
21. 21. Perdoncin E, Seth M, Dixon S, Cannon L, Khandelwal A, Riba A, et al. The comparative efficacy of bivalirudin is markedly attenuated by use of radial access: insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Eur Heart J. 2015.