Basic Chemical and Pharmacological Properties

Bivalirudin is an anticoagulant and acts as direct thrombin antagonist. Chemically it constitutes a synthetic congener of the naturally occuring drug Hirudin (found in the salvia of the medicinal leech Hirudo medicinalis).

Bivalirudin is referred to as d-Phenylalanyl-l-prolyl-l-arginyl-l-prolylglycylglycylglycylglycyl-l-asparaginylglycyl-l-alpha-aspartyl-l-phenylalanyl-l-alpha-glutamyl-l-alpha-glutamyl-l-isoleucyl-l-prolyl-l-alpha-glutamyl-l-isoleucyl-l-prolyl-l-alpha-glutamyl-l-alpha-glutamyl-l-tyrosyl-l-leucine.

The pharmacological difference between both drugs is that Hirudin is an irreversible inhibotor of thrombin while Bivalirudin is a reversible one. This leads to a relatively small rate of severe bleedings under Bivalirudin compared to standard therapy (see below under section comparative results).

When delivered by i.v.-infusion with a rate of 2.5 mg/kg and hour the mean steady-state-concentration is 12.4 µg/ml. The drug is metabolized by enzymes of the protease type with one inactive main-metabolite. Approximately 20 % are found in the urine as unchanged Bivalirudin. The half-life of Bivalirudin is 25 +- 12 minutes.

The clinical onset of action is almost immediate after i.v.-bolus. Bivalirudin prolongs a number of coagulation parameters due to its mode of action. These are the activated clotting time (ACT), the activated partial thromboplastin time (aPPT), the thrombin time (TT), and the prothrombin time (PT). After termination of treatment the coagulation parameters return to normal within 1 to 2 hours indicating a short action of Bivalirudin resulting in a good controllability of therapy.

Existing Drug Forms

In Europe Bivalirudin is sold under the brand name Angiox®, in other countries under Angiomax® (year of obtained license = 2005 in most countries). The drug is intended for parenteral (i.v.) use only. One vial contains 250mg.

Indications

Bivalirudin is licensed to reduce the risk of acute ischemic complications, for example death due to myocardial infarction or need for urgent revascularization procedures, in patients with unstable angina pectoris undergoing percutaneos transluminal coronary angioplasty (PTCA).

Contraindications and Precautions

• The drug must not be given to patients with clinically relevant preexisting bleeding disorders of any origin.

• Allergy to Bivalirudin or other ingredients of the preparation.

• Women planning to become pregnant (Pregnancy Category B) or wishing to start breast-feeding (effects on the newborn not known) should ask their clinician.

• Patients with significantly reduced renal function should receive Bivalirudin in reduced doses.

Side Effects

The main risk is the occurence of severe bleedings in 2.4 % of patients in clinical studies. Geriatric patients experienced more bleeding episodes than younger patients.

So far neither allergic reactions (even in patients with antibodies to Bivalirudin) nor thrombocytopenia associated with the use of heparin (HIT) have been seen.

Possible Interactions Bivalirudin may in combination with other anticoagulants (Heparines, Thrombolytics, GP-Blockers, Coumarines, Aspirin) lead to increased bleeding tendencies. No data exists regarding the use of Dextran containing plasma-expanders.

Dose Regime

It is recommended to start therapy with an inital i.v.-bolus injection of 0.75 mg/kg followed by i.v.-infusion at a rate of 1.75mg/kg and hour for the duration of PTCA. Efficiacy of therapy should be measured during infusion by obtaining the above mentioned coagulation parameters. After withdrawal of Bivalirudin and normalization of all affected coagulation parameters, further 'minimal anticoagulation', for example with Aspirin, may be indicated.

Comparative Results

In a large comparative 30-days study encompassing 6,010 patients (called REPLACE2 study) Bivalirudin was compared to a standard therapy of either Abciximab or Eptifibatid plus initial Heparin bolus. Regarding the primary endpoint (death, myocardial infarction, urgent revascularization procedures, severe bleedings) no statistically significant difference between Bivalirudin and standard therapy was noticed (9.2 versus 10.0 %). Regarding ischemic complications (death, myocardial infarction, and urgent revascularization procedures) there was also no statistically significant difference (7.6 vs. 7.1 %). But the risk for severe bleedings was 2.4 % in the Bivalirudin group compared to 4.1 % in the standard therapy-group; a significant difference.

Conclusions

Bivalirudin has the potential to become an important anticoagulant during PTCA procedures because of the reduced likelihood of severe bleedings as compared to standard therapy, the ready reversibility of its action after the end of PTCA, and the lack of allergic reactions and thrombocytopenia compared to Heparin.

References

• AHFS Database online
• http://www.pharmazeutische-zeitung.de/index.php?id=121&type=0 (in German)