Current Clinical Applications of Bivalirudin: An Overview

Clinical Pharmacology of Bivalirudin

Bivalirudin is a direct thrombin inhibitor with specific and reversible actions.^1–6 It is a synthetic, 20-amino acid peptide with a molecular weight of 2180 daltons. Bivalirudin directly inhibits both circulating and bound thrombin by binding to its catalytic site and anion-binding exosite. The binding to thrombin is reversible, as the latter cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of the active site. Bivalirudin does not activate platelets and is not inhibited by platelet products. It produces a linear dose and concentration-dependent anticoagulation with subsequent prolongation of partial thromboplastin time (PTT) and prothrombin time (PT). At the most commonly utilized dose of 0.75 mg/kg IV bolus and 1.75 mg/kg/hour infusion during percutaneous coronary interventions (PCI), bivalirudin yields a mean activated clotting time (ACT) of 358 sec, 5 minutes after the initial bolus. If bivalirudin needs to be administered beyond the post procedural 4-hour infusion window, it can be continued at a rate of 0.2 mg/kg/hour. However, the administration of bivalirudin beyond the procedure time is optional and in fact, infrequently used. Bivalirudin is also partly cleared by renal mechanisms, and therefore, dose administration needs to be adjusted in patients with severe renal impairment (creatinine clearance 10–29 mL/min) (maintenance rate reduced to 1 mg/kg/hour), or in patients on hemodialysis (maintenance rate of 0.25 mg/kg/hour). The bolus dose is not altered with renal function. Once administered, there is no antidote to reverse bivalirudin anticoagulation effect. However, bivalirudin can be partly dialyzed (25% of the drug is cleared by hemodialysis).

Clinical Applications of Bivalirudin Bivalirudin in Percutaneous Coronary Interventions

Bivalirudin is currently approved as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty, or with the provisional use of glycoprotein (GP) IIb/IIIa inhibitors in elective non-emergent PCI. A review of the clinical trials of bivalirudin in PCI is presented below.

Bivalirudin Angioplasty Study Trial (BAT)

In the BAT trial,⁷ patients (n = 4312) with unstable angina and undergoing percutaneous transluminal angioplasty were randomized to bivalirudin versus high dose heparin. In this multi-center, double-blind trial, patients treated with bivalirudin (n = 2161) had a 22% reduction in the 7-day composite endpoint of death, myocardial infarction (MI) and repeat revascularization as compared to the heparin-treated patients (n = 2151) (6.2% versus 7.9%, p = 0.0386). The composite endpoint difference was sustained at 90 days (p = 0.012) and 180 days (p = 0.153). Major bleeding was significantly reduced by 62% with bivalirudin compared to heparin (9.3% versus 3.5%, p Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-1 trial In the REPLACE-1 trial,8 1056 patients at 77 sites in the U.S. undergoing contemporary coronary interventions were randomized in a large-scale pilot study to unfractionated heparin (70 U/kg initial bolus) versus bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). In contrast to the BAT trial, stents and GP IIb/IIIa inhibitors were used in 85% and 72% of patients, respectively. Furthermore, 56% of patients were pretreated with clopidogrel. The composite incidence of death, MI or urgent revascularization (before hospital discharge or within 48 hours) in the heparin group (n = 524) was 6.9% compared to 5.6% in the bivalirudin group (n = 532) (p = 0.4). Bivalirudin showed less major bleeding compared to heparin (2.1% versus 2.7%, respectively, p = 0.52). This trial confirmed the safety of the combined approach of bivalirudin with GP IIb/IIIa inhibition and demonstrated that bivalirudin can be effective in contemporary PCI. This study was not designed to address bivalirudin as a replacement to the combined therapy of heparin and GPIIb/IIIa inhibition during angioplasty.

Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-11 Trial

In the REPLACE-2 trial,⁹ 6,010 patients undergoing elective or urgent PCI at 233 sites in the United States, Canada, Europe and Israel were randomized in a double-blind, active-controlled trial of bivalirudin monotherapy (0.75 mg/kg bolus plus 1.75 mg/kg/hour for the duration of the PCI) with provisional GP IIb/IIIa inhibition (n = 2999) versus unfractionated heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (eptifibatide or abciximab) (n = 3011). The primary 30-day composite endpoint of death, MI, urgent repeat revascularization and in-hospital major bleeding was 9.2% in the bivalirudin arm versus 10% in the heparin-GP IIb/IIIa arm (p = 0.32). The secondary 30-day composite endpoint of death, MI and urgent revascularization in the bivalirudin group met the prespecified statistical criteria for non-inferiority to the heparin-GP IIb/IIIa group. Provisional GP IIb/IIIa inhibitors were administered to 7.2% of bivalirudin patients. Also, bivalirudin led to significantly less in-hospital major bleeding when compared to the heparin-GP IIb/IIIa inhibitor combination (2.4% versus 4.1%, p 11 clopidogrel pretreatment (85.8% in the bivalirudin arm versus 84.6% in the heparin arm), and irrespective of the pretreatment duration, did not affect the relative efficacy of bivalirudin when compared to heparin-GP IIb/IIIa inhibition. However, among the bivalirudin group, patients pretreated with 300 mg clopidogrel loading and 75 mg/day maintenance dose had a lower primary endpoint than patients who did not receive pretreatment (8.7% versus 12.9%, p = 0.007). A similar non-significant trend was seen with the heparin-GP IIb/IIIa arm (9.7% versus 11.7%, p = 0.2). This illustrates the importance of pretreatment of patients with clopidogrel prior to percutaneous intervention. The overall data from REPLACE-2 also continued to be consistent with 2 subgroup analyses that focused primarily on patients with renal impairment¹² and in diabetics.¹³ In the renal impairment subgroup, patients experienced higher ischemic and bleeding events and excess 12-month mortality. Bivalirudin provided, however, equivalent suppression of ischemic events comparable to heparin and GP IIb/IIIa inhibition, and fewer bleeding events irrespective of the degree of renal dysfunction. The REPLACE-2 trial enrolled 1624 diabetics and 4,368 non-diabetic patients.13 Compared with the non-diabetic, diabetic patients had a higher mortality at 1 year (3.06% versus 1.85%, p 14 showing that bivalirudin is associated with fewer bleeding complications with no evident increase in ischemic complications in patients undergoing PCI. Furthermore, a meta-analysis by Yusuf et al.¹⁵ has also shown that bivalirudin has a significant advantage over unfractionated heparin in reducing major bleeding during percutaneous interventional procedures. Recently, drug-eluting stents (DES) have been introduced as a powerful tool to reduce restenosis, the Achilles’ tendon of angioplasty. The REPLACE-2 trial was done prior to the introduction of DES. At this time, there is no published randomized data with the use of bivalirudin versus heparin and GP IIb/IIIa inhibitors in patients receiving DES. However, recently published “real world” experience suggests that the use of bivalirudin in patients with sirolimus-eluting stents (n = 1182) results in low rates of major adverse cardiac events (0.3% mortality, 4.4% MI, 1.7% target vessel revascularization [TLR]), stent thrombosis (0.6%) and major bleeding (0.8%).¹⁶ In this prospective registry, clopidogrel was administered before PCI in 79% of patients and only 5.3% received adjunctive GP IIb/IIIa inhibitors. Given the favorable data with the use of bivalirudin during PCI, the American Heart Association (AHA), the American College of Cardiology (ACC) and the Society for Cardiovascular Angiography and Interventions (SCA&I) jointly released their updated guidelines on the use of bivalirudin in PCI, granting it a Class IIa recommendation (weight of evidence in favor of usefulness) as an alternative to unfractionated heparin and GP IIb/IIIa inhibitors in non-high-risk patients undergoing elective PCI. The currently ongoing Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial¹⁷ is prospectively randomizing 13,800 patients with moderate to high-risk unstable angina and non-ST segment elevation MI to three different anticoagulation strategies, including bivalirudin with provisional GP IIb/IIIa inhibition, and enoxaparin or unfractionated heparin with planned GP IIb/IIIa inhibition. All patients undergo angiography and PCI, if needed, within 72 hours of randomization. The primary endpoint will be the composite endpoint of death, MI, urgent repeat revascularization and major bleeding at 30 days, with clinical follow-up at 1 year.

Bivalirudin in Patients with Heparin-Induced Thrombocytopenia (HIT)

The advantage of bivalirudin over heparin is also apparent in patients with a history of heparin-induced thrombocytopenia (HIT). In the multi-center, prospective, open-label The Anticoagulant Therapy with Bivalirudin to Assist in the performance of PCI in patients with HIT (ATBAT) study,18 the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing coronary intervention was evaluated. The primary endpoint of the study was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. In this study, 52 patients were enrolled. No patient had significant thrombocytopenia following the treatment with bivalirudin. Clinical success (absence of death, emergency bypass surgery or Q-wave MI) was achieved in 96%. In patients with a history of HIT, bivalirudin appeared safe and effective. Although not approved by the FDA for HIT, the AHA/ACC’s updated guidelines granted bivalirudin a Class I recommendation (general agreement that it is useful and effective) in patients with HIT and undergoing elective PCI.

Bivalirudin in Percutaneous Peripheral Interventions (PPI)

The use of bivalirudin in PPI is presently off-label. Currently, no randomized studies exist with bivalirudin versus unfractionated heparin in the periphery. Bivalirudin, however, was shown to offer very predictable anticoagulation in percutaneous interventions, including PPI,¹⁹ in contrast to unfractionated heparin.²⁰ Thrombin activation is expected to be significant in PPI because of the extent of atherosclerotic burden and large vessel size dilated with balloon angioplasty.²¹ Heparin (low dose with GP IIb/IIIa inhibitors or high dose heparin alone) continues to result in thrombin activation during PPI.²¹ Direct thrombin inhibition with bivalirudin, therefore, might offer some advantages over heparin in PPI by providing a more effective thrombin inhibition. Finally, the short half-life of bivalirudin might also allow early sheath removal, less bleeding complications, and a more reliable anticoagulation than heparin, with no need for frequent ACT measurements during long procedures.²² Experience with bivalirudin in the periphery has been recently published or presented at scientific meetings.^19,22–27 The data appear favorable, showing low major bleeding rate and adverse events compared to historic data with unfractionated heparin.²⁰ None of these studies, however, are randomized and double-blind. The Angiomax Peripheral Procedure Registry of Vascular Events Trial (APPROVE)¹⁹ is the largest, published, multi-center prospective registry in the periphery. In APPROVE, 503 patients underwent renal, iliac and infrainguinal interventions with bivalirudin as a primary anticoagulant. The REPLACE-2 dose was utilized and consisted of 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg/hour infusion during the length of the procedure. In this registry, ischemic events (death, amputation, unplanned urgent revascularization at the treated site, MI) were low (1.4%) and similar between vessel types. Protocol-defined major hemorrhage and TIMI major hemorrhage rates were 2.2% and 0.4%, respectively. The strongest predictor²⁸ of major bleeding alone at discharge (p = 0.0041) and at 30 days (p = 0.0016) was the number of exchanges to larger sheath size. Also, female gender (p = 0.08) and low weight (stratified by gender with 92 kg for males and 77 kg for females) (p = 0.096) showed a trend toward predicting major bleeding at 30 days. Recently, Allie et al.29 presented data on the use of bivalirudin and GP IIb/IIIa inhibitors in PPI in patients with chronic limb ischemia as compared to a historic control with heparin alone. In this non-randomized study, there was a trend toward lower 6-month secondary re-intervention and limb salvage rates (10.7% versus 18.8%; p = 0.0501 and 93.9% versus 88.5%; p = 0.053) in the bivalirudin-GP IIb/IIIa inhibitor group, compared to the unfractionated heparin group, respectively. Angiographically relevant distal embolization occurred less in the bivalirudin-GPIIb/IIIa inhibitor group (1.3% versus 5.4%). Limitations. Randomized trials are needed in the setup of contemporary PPI. The role of GP IIb/IIIa inhibitors in PPI is still poorly defined, but their role, along with bivalirudin, in chronic limb ischemia is promising.

Conclusion

In conclusion, bivalirudin is a very promising pharmacologic agent in PCI and could be used as a substitute to heparin and GP IIb/IIIa inhibitors in non-emergent interventions and in patients with HIT. Also, bivalirudin is safe and effective in PPI, but randomized trials are lacking. The use of bivalirudin in high-risk interventions such as emergent acute coronary syndromes or chronic limb ischemia appears promising, but more data is needed to demonstrate its safety and cost-effectiveness.