Mojgan Sani DPharm MBA
Deputy Chief Pharmacist, Surrey and Sussex NHS Trust, UK
Bivalirudin is a cost-effective strategy for anticoagulation in the setting of invasive cardiology, particularly in urgent or early percutaneous coronary intervention.
Acute coronary syndromes (ACS) are frequent and life-threatening episodes of acute myocardial ischaemia. The majority are caused by a sudden rupture of a coronary artery plaque, generating a downstream activation of platelets, coagulation cascade and thrombus formation.
After this initial event, activated platelets adhere to the endothelium and start to aggregate, creating an expanded response. Both platelet aggregation and coagulation activation create a severe impairment of the coronary blood flow, resulting in the clinical manifestations of both acute myocardial infarction (AMI) and non-ST segment elevation acute coronary syndrome (NSTEACS).
Coronary catheterisation and stent implantation are the state-of-the-art treatment for patients with ACS of moderate-to-high risk. The aim of this procedure is to restore coronary blood flow to the myocardial ischaemic heart. Ischaemic and haemorrhagic complications are life-threatening.
This review will focus on the use of bivalirudin in ACS patients.
Mechanism of action
Bivalirudin is a direct inhibitor of both fibrin-bound and soluble thrombin. It is used in ACS without ST-segment elevation (NSTE-ACS), or ST-segment elevation myocardial infarction (STEMI) planned for urgent or early percutaneous coronary intervention (PCI).
Thrombin plays a critical role in the thrombotic process, acting to cleave fibrinogen to fibrin monomers and to activate factor XIII to factor XIIIa, allowing fibrin to develop a cross-linked framework that stabilises the thrombus. Bivalirudin binds to the thrombin, preventing the cascade.
Both fibrin-bound and soluble thrombin are inhibited by bivalirudin, whereas heparin inhibits soluble thrombin only. Furthermore, unlike heparin, bivalirudin does not require cofactors and is not neutralised by platelet products. It has a unique pharmacological profile and, unlike other direct thrombin inhibitors, it undergoes predominant non-organ elimination (proteolysis), and has the shortest half-life (approximately 25 minutes).
One of the main clinical trials using bivalirudin in ACS patients is the ACUITY trial.(1–3) It was a prospective, randomised open-label trial of bivalirudin with or without glycoprootien IIb/IIIa inhibitor (arms B and C, respectively) versus unfractionated heparin (UFH) or enoxaparin with glycoprotein IIb/IIIa inhibitor (arm A) in approximately 14,000 patients categorised as moderate-to-high risk ACS.
Patients in arms B and C received 0.1mg/kg bolus of bivalirudin followed by 0.25mg/kg/hour continuous infusion throughout angiography. Different options were followed, depending on whether patients were to be managed medically or to proceed to PCI or coronary artery bypass grafting. For patients undergoing PCI, an additional intravenous bolus of 0.5mg/kg bivalirudin was administered and the rate of infusion increased to 1.75mg/kg/hour.
In arm A, UFH was administered in accordance to the standard guidelines for the management of ACS patients. Patients in arms A and B were also randomised to a glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor either upfront or at the time of randomisation (prior to intervention) or at the time of PCI.
Arm A: UFH or enoxoparin plus GPIIb/IIIa inhibitor
Arm B: bivalirudin plus GPIIb/IIIa inhibitor
Arm C: bivalirudin monotherapy.
Patients were included if 18 years of age or older, with unstable angina symptoms lasting more than ten minutes within the previous 24 hours and with at least one of the following:
Evidence of coronary artery disease (CAD)
New ST-segment depression or transient elevation
Elevated troponin I or T or CK(MB).
Patients were excluded if they presented with myocardial infarction (with acute ST-segment elevation or shock), thrombocytopenia, bleeding history or renal insufficiency (creatinine clearance <30ml/minute).
Following intervention, patients were allocated to either medical management (33%), PCI (56%) or CABG (11%).
The ACUITY trial at one year indicated that both bivalirudin plus a glycoprotein inhibitor and bivalirudin alone were as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with regards to long-term incidence of composite ischaemia and all-cause mortality. The trial provides robust data for bivalirudin efficacy in ACS population patients undergoing early or urgent intervention.
Bivalirudin and GPIIb/IIIa inhibitor was non-inferior to heparin and glycoprotein IIb/IIIa inhibtor with respect to ischaemic events, major bleeding and net clinical outcome at 30 days. Bivalirudin alone was non-inferior to heparin and GPIIb/IIIa inhibitor in terms of ischaemic events but was shown to be superior in terms of major bleeding outcomes and net clinical outcome at 30 days. At one year, there was no difference in bivalirudin and heparin group with respect to ischaemic and all-cause mortality.
The HORIZENS-AMI trial randomised over 3600 patients with STEMI undergoing primary PCI to therapy with UFH plus GPIIb/IIIa inhibition or bivalirudin monotherapy.(4) The two 30-day primary endpoints were non-CABG major bleeding and major adverse cardiac events, such as death, re-infarction, revascularisation or stroke and major bleeding. The trial showed that, in high-risk patients with STEMI, and those undergoing PCI, treatment with bivalirudin compared with heparin and GPIIb/IIIA inhibitor resulted in a significant reduction in 30-day major bleeding, thrombocytopenia and transfusions, with similar rates of ischaemic events. At one-year bivalirudin monotherapy, a significant absolute reduction of 1.4% in all-cause mortality and 1.7% absolute reduction in cardiac mortality was observed.
This was based on prevention of haemorrhagic complications after primary PCI in STEMI, because major bleeding is a powerful independent determinant of mortality. It was concluded that optimal drug selection and technique to minimise bleeding are essential to enhance outcomes for patients undergoing interventional therapies.
Guidelines published by the National Institute for Health and Clinical Excellence in 2012(5) agreed that the results of the HORIZONS-AMI trial showed statistically significant advantages for treatment with bivalirudin over treatment with heparin plus GPIIb/IIIa inhibitor both in terms of primary endpoint of major bleeding and the secondary outcome of all-cause mortality and cardiac mortality.
Dosage and administration
The initial dose of intravenous bivalirudin in patients with ACS (unstable angina and NSTEMI) undergoing urgent or early revascularisation is 0.1mg/kg bolus followed by 0.25mg/kg/hour for up to 72 hours.
Patients undergoing PCI may require an additional bolus of 0.5mg/kg with the infusion rate increased to 1.75mg/kg/hour for the duration of PCI. The dose is then decreased to 0.25mg/kg/hour post-PCI for 4–12 hours, as clinically necessary.
If a patient requires CABG, the bivalirudin infusion is continued until surgery. A bolus of 0.5mg/kg is given just before surgery (off pump) followed by 1.75mg/kg/hour during the procedure. For those patients undergoing CABG (on pump), bivalirudin infusion of 0.25mg/kg/hour is continued until one hour before surgery and is then discontinued and unfractionated heparin initiated.
Bivalirudin in contraindicated in patients with:
- Active bleeding or increased risk of bleeding due to haemostasis discorders and /or irreversible coagulation disorders
- Allergy to hirudins
- Severe uncontrolled hypertension
- Severe renal failure (glomerular filtration rate (GFR) <30ml/min).
- Coadministration with platelet inhibitors or anticoagulants
Bivalirudin is co-administered with aspirin and clopidogrel for ACS patients undergoing PCI. Combined use can be expected to increase risk of bleeding and therefore parameters of haemostatsis should be monitored regularly. In patients taking warfarin, the International normalised ratio should be monitored closely.
Bivalirudin kinetics is linear, with 100% bioavailability if given intravenously. It is distributed rapidly between plasma and extracellular fluid. The drug is metabolised with 20% of the dose excreted unchanged via urine. Elimination is thought to follow a two-compartment model; elimination follows a first-order process, with a terminal half-life of 25 minutes in patients with normal renal function.
No dose adjustment is required in mild renal impairment but the dose is decreased if patients’ GFR is <30ml/min.
No data are available in a patient with hepatic impairment but no dose adjustment is expected because bivalirudin is not metabolised via cytochrome P450 enzymes.
The majority of data on the side-effect profile of bivalirudin is based on the ACUITY trial. In the ACUITY trial, at least one adverse event occurred in around 23% of patients treated with bivalirudin, with or without a GPIIb/IIIa inhibitor. Minor bleeding was a common side-effect in the three treatment arms. Major and minor bleeding were significantly lower in patients who received bivalirudin alone compared with those on UFH or enoxaparin plus a GPIIb/IIIa inhibitor (p<0.001).
Cost effectiveness of bivalirudin versus heparin and GPIIb/IIIa inhibitors in patients undergoing primary PCI for acute STEMI was assessed in a UK health service perspective.(6) Major outcome measures were cost, quality-adjusted life-years and incremental cost effectiveness. The assessment concluded that bivalirudin use in this group of patients was cost effective, offering a high probability of dominance.
The ACUITY trial has concluded that substitution of UFH or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate-to-high risk ACS treated with GPIIB/IIIa inhibitors undergoing PCI. Anticoagulation with bivalirudin alone decreases the risk of haemorrhagic complications.
The use of bivalirudin instead of heparin and GPIIb/IIIa inhibitors in STEMI patients undergoing primary PCI has been shown to be cost effective together with treatment with aspirin and clopidogrel.
- Bivalirudin is a potent thrombin inhibitor with rapid and reversible action whose use has shown decreased mortality in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention or moderate-to-high-risk non-ST segment elevation acute coronary syndrome (NSTEACS) as a result reduced bleeding rates.
- The ACUITY and HORIZONS-AMI studies demonstrated net clinical benefit for patients receiving bivalirudin compared with those receiving heparin + glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors (less bleeding complications).
- Both studies emphasised the importance of an appropriate antiplatelet treatment (aspirin + clopidogrel/prasugrel with loading doses) for ACS patients receiving bivalirudin.
- Bivalirudin treatment should be considered in those with moderate-to-high risk bleeding complications: age >65 years; diabetes mellitus; renal function impairment; women; hypertension; previous cardiovascular accident; intra-aortic counterpulsation balloon.
- The use of bivalirudin instead of heparin and GPIIb/IIIa inhibitors in STEMI patients undergoing primary PCI has been shown to be cost effective together with treatment with aspirin and clopidogrel.
- Stone GW et al. Acute Catheterisation and Urgent Intervention Triage StrategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148(5):764–75.
- Stone GW et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355(21):2203–16.
- Stone GW et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catherterisation and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007;369:907–19.
- Stone GW et al. HORIZONS AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–30.
- National Institute for Health and Clinical Excellence. Bivalirudin for the treatment of ST-segment-elevation myocardial infarction. NICE technology appraisal guidance 230. http://publications.nice.org.uk/bivalirudin-for-the-treatment-of-st-segment-elevation-myocardial-infarction-ta230 (accessed 20 August 2012).
- Schwenkglenks M et al. Cost-effectiveness of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor in treatment of acute ST-segment elevation myocardial infarction. Heart 2012;98:544–51.