Bivalirudin

Article Author:
Beric Berlioz
Article Editor:
Devang Sanghavi
Updated:
7/2/2020 1:48:43 PM
PubMed Link:
Bivalirudin

Indications

Bivalirudin is a direct thrombin inhibitor (DTI) with specific actions indicated for intravenous (IV) anticoagulation in patients with acute myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), and thrombosis in patients with a history of heparin-induced thrombocytopenia (HIT).[1][2] More recently, bivalirudin has been explored and utilized off label, in patients undergoing cardiopulmonary bypass and extracorporeal membrane oxygenation and for deep venous thrombosis prophylaxis (ECMO).[3][4][5]

FDA-labeled indications

  • Percutaneous coronary intervention - thrombosis, in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome; prophylaxis
  • Percutaneous coronary intervention - thrombosis; prophylaxis

Non- FDA-labeled indications

  • Acute myocardial infarction, an adjunct to thrombolytic therapy
  • Acute myocardial infarction - percutaneous coronary intervention - thrombosis; prophylaxis
  • Deep venous thrombosis; prophylaxis
  • Heparin-induced thrombocytopenia with thrombosis - heart surgery - thromboembolic disorder; prophylaxis
  • Peripheral arterial bypass - thromboembolic disorder; prophylaxis
  • Thromboembolic disorder
  • Thromboembolic disorder; prophylaxis - unstable angina

Mechanism of Action

Bivalirudin is an inhibitor of thrombin, an essential factor within the coagulation cascade crucial to thrombus formation. Thrombin serves to cleave fibrinogen into fibrin. Subsequently, fibrin monomers then covert factor XIII to factor XIIIa, allowing for stabilization of the thrombus. Additionally, fibrin activates factor V and VIII, further promoting thrombin and platelet activation.[6]   

Bivalirudin inhibits thrombin specifically by binding both to the catalytic site, and the anion-binding exosite on thrombin within thrombi and the circulation. This action is in contrast to glycosaminoglycans anticoagulants. Such medications, including unfractionated heparin and low molecular weight heparin. Heparins act to inhibit thrombin, indirectly, by serving as an enzyme that catalyzes anti-thrombin, a serine protease inhibitor that forms a covalent bond with thrombin.[7] This mechanism offers potential advantages, including a more predictable pharmacologic response. Additionally, bivalirudin does not bind to platelet factor 4 and thus does not share cross-reactivity with antibodies in patients who have a history of HIT.  

Administration

Bivalirudin is typically available as a 250 mg powder available for reconstitution with 5ml of sterile water or ready to injection as a 5 mg/ml solution.

For Percutaneous Coronary Intervention

  • Patients with no history of heparin-induced thrombocytopenia: A bolus dose, given intravenously of 0.75 mg/kg. Immediately following the bolus dose, an infusion of 1.75 mg/kg/h for the duration of the procedure. Five minutes following the bolus, an ACT should be drawn, and additional bolus doses of 0.3 mg/kg given as necessary to achieve a therapeutic ACT.
  • For patients with a history of heparin-induced thrombocytopenia: In this patient population, an intravenous bolus of 0.75 mg/kg. The following infusion rate is the same as above, 1.75 mg/kg/h for the entire procedure. 
  • At the discretion of the prescribing clinician, the infusion may continue for up to four hours after the intervention. Vigilance is necessary, watching closely for signs of bleeding as outlined below (see Toxicity). 

In patients undergoing revascularization therapy, who present with ST-segment elevated myocardial infarction, the recommendation is to continue the intraoperative infusion for four hours post-procedure to reduce the risk of in-stent thrombosis. Following this, the bivalirudin infusion may continue at a decreased rate of 0.2 mg/kg/h, for up to 20 hours, at the discretion of the prescribing physician. 

Adverse Effects

  • The most common adverse effects include hypotension, backache, and nausea.
  • Rare but severe side effects include hemorrhage, coronary artery stent thrombosis, ventricular fibrillation, renal failure
  • The risk of hemorrhage increases with bivalirudin plus streptokinase and aspirin
  • Fetal risk in pregnancy cannot be ruled out. 

Contraindications

  • Active of major bleeding
  • Hypersensitivity to bivalirudin or its components

Monitoring

  • Activated clotting time (ACT): 5 minutes after the initial bolus
  • Activated partial thromboplastin time (aPTT) (1.5 to 2.5 times the patient’s baseline value)
  • Signs or symptoms of bleeding
  • Major hemorrhagic events
  • Signs or symptoms including myocardial ischemia in patients after a primary PCI

Toxicity

The toxic effects related to bivalirudin administration primarily pertain to bleeding. There is no minimum toxic dose listed, and complications can occur at therapeutic doses.  In a study by Gleason et al., the no-observed-adverse-effect level, administered to rats intravenously over a 24 hour period, was 2000mg/kg/24hr.[8] Bivalirudin has used in the pediatric and infant population, but currently, there is not enough data to recommend dosing adjustments in pediatric patients.[9][10] 

Approximately 1.4 to 3.8 % of patients will develop significant hemorrhage. Reports exist of intracranial bleeding, retroperitoneal bleeding, and clinically overt bleeding in patients undergoing PCI for the treatment of unstable angina. This risk increases with the concomitant use of aspirin and streptokinase.[11] In the majority of patients, the primary site of bleeding was at the catheterization site.

In the event of bleeding, evaluation of the need for anticoagulation, and the decision to reduce or discontinue the infusion requires clinical judgment.

Supportive care, including a fluid bolus and transfusion of platelets or packed red blood cells in thrombocytopenic/anemic patients, is recommended. In patients with continued bleeding, fresh frozen plasma, prothrombin complex concentrations, and cryoprecipitate may merit consideration. Note that this comes with an inherent risk of developing thromboembolic events.

There is no reversal agent available for bivalirudin.

Appropriate monitoring includes a CBC, prothrombin time (PT), aPTT, international normalized ratio (INR). Note that there may be variable responses with these values. Renal function requires monitoring as well, as the Bivalirudin excretion is primarily via the kidneys.

Enhancing Healthcare Team Outcomes

Bivalirudin has proven an effective anticoagulant used by interventional cardiologists during PCI in patients with acute coronary syndrome. It is also an ideal anticoagulant in patients with a history of HIT and has predictable pharmacologic effects. As its use increases, its applications have broadened to include patients who require anticoagulation on cardiopulmonary bypass, ECMO, and deep venous prophylaxis. Given that patients receiving bivalirudin will be in the hospital setting, overdose is rare. Despite this, a multidisciplinary approach to monitoring such patients is necessary. Communication between proceduralists, physicians, pharmacists, and nurses is necessary to ensure optimal patient outcomes. Evaluation begins with the appropriate monitoring of patients, including careful assessment at the bedside. A high degree of clinical suspicion should be maintained for bleeding, as the clinical manifestations may be confounded by other comorbidities in the typical patient requiring bivalirudin. Patients should be monitored for hypotension, tachycardia, oozing at IV sites should be sought out, with suspicion for hemorrhage. Laboratory evaluation and imaging studies may be warranted. As a guideline for therapeutic response, the aPTT is the most commonly used metric. Dosing regimens should then be adjusted accordingly by a pharmacist. Dosing protocols have been developed for monitoring bivalirudin therapy, and are usually specific to the institution. 


References

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[2] Warkentin TE,Greinacher A,Koster A, Bivalirudin. Thrombosis and haemostasis. 2008 May     [PubMed PMID: 18449412]
[3] Janjua T,Nussbaum E,Lowary J,Babbini V, Bivalirudin as a bridge for anticoagulation in high risk neurosurgical patients with active DVT or high risk of thrombosis. Neurocritical care. 2013 Jun     [PubMed PMID: 23568093]
[4] Koster A,Dyke CM,Aldea G,Smedira NG,McCarthy HL 2nd,Aronson S,Hetzer R,Avery E,Spiess B,Lincoff AM, Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. The Annals of thoracic surgery. 2007 Feb     [PubMed PMID: 17257990]
[5] Berlioz B,Kaseer HS,Sanghavi DK,Guru PK, Bivalirudin resistance in a patient on veno-venous extracorporeal membrane oxygenation with a therapeutic response to argatroban. BMJ case reports. 2020 Jan 7     [PubMed PMID: 31915185]
[6] Weisel JW,Litvinov RI, Fibrin Formation, Structure and Properties. Sub-cellular biochemistry. 2017     [PubMed PMID: 28101869]
[7] Weitz JI,Middeldorp S,Geerts W,Heit JA, Thrombophilia and new anticoagulant drugs. Hematology. American Society of Hematology. Education Program. 2004     [PubMed PMID: 15561696]
[8] Gleason TG,Chengelis CP,Jackson CB,Lindstrom P, A 24-hour continuous infusion study of bivalirudin in the rat. International journal of toxicology. 2003 May-Jun     [PubMed PMID: 12851152]
[9] Buck ML, Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and Children. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2015 Nov-Dec     [PubMed PMID: 26766931]
[10] Nagle EL,Dager WE,Duby JJ,Roberts AJ,Kenny LE,Murthy MS,Pretzlaff RK, Bivalirudin in pediatric patients maintained on extracorporeal life support. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2013 May     [PubMed PMID: 23648880]
[11] White HD,Aylward PE,Frey MJ,Adgey AA,Nair R,Hillis WS,Shalev Y,Brown MA,French JK,Collins R,Maraganore J,Adelman B, Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Circulation. 1997 Oct 7     [PubMed PMID: 9337184]