Enhancing the Benefit of Bivalirudin in Percutaneous Coronary Intervention: Is High Risk of Bleeding the Key?

Abstract

Bivalirudin is a potent direct thrombin inhibitor that can reduce thrombus burden during acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) by blocking formation of fibrin and by suppressing platelet aggregation [1]. When compared with heparin, bivalirudin has several theoretical mechanistic advantages that include activity against clot-bound thrombin, inhibition of thrombin-induced platelet activation, short plasma half-life, linear pharmacokinetics less affected by plasma proteins and renal insufficiency, and an unaffected platelet activation during PCI [1]. These properties of bivalirudin provide a more predictable inhibition of coagulant activity than does heparin, with less degree of inter-patient variability in anticoagulation response. Moreover, its binding to thrombin is non-competitive and reversible, and hemostatic capacity is more readily restored; hence bleeding, as well as ischemic complications, may be reduced [2]. In the first randomized trial (HAS [Hirulog Angioplasty Study]) comparing bivalirudin with heparin in over 4000 patients undergoing PCI for unstable or post-infarction angina, bivalirudin was at least as effective as high-dose heparin in preventing ischemic complications, and it carried a lower risk of bleeding [3]. Nevertheless, development of bivalirudin was suspended because of the unfavorable cost comparison with heparin. Only recently did the development of a less expensive manufacturing process encourage interest from researchers to further support the efficacy and safety of this anticoagulant therapy. Re-analysis of the original HAS using contemporary endpoints and intention-to-treat analysis showed a 22 % reduction in major adverse cardiac events (including death, ACS, and revascularization) and a 62 % reduction in bleeding with bivalirudin at 7 days [4]. In the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) trial [5], bivalirudin with provisional glycoprotein IIb/IIIa blockade (which was administered in about 7 % of patients) was proven to be statistically non-inferior to heparin plus planned glycoprotein IIb/IIIa inhibitors during PCI with regard to suppressing ischemic events after PCI, but was superior in preventing hemorrhagic complications. More recently, bivalirudin provided similar protection from ischemic events as glycoprotein IIb/IIIa inhibitors, but with lower bleeding rates in the ACUITY (Acute Catheterisation and Urgent Intervention Triage strategy) trial [6]. Although the evidentiary landscape in support of antithrombotic treatment choices during PCI has been enriched by these trials, recent data from clinical trials and pooled analyses questioned the role of bivalirudin in the setting of planned and primary PCI [7–12]. In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, the use of bivalirudin was associated with a This comment refers to the article available at doi:110.1007/s40256015-0113-8.