Midwest Heart Surgery Institute
Perfusion Department
Protocols and Guidelines for the Practice Perfusion

SECTION 5:  Argatroban (Novastan) Protocol

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Argatroban (Novastan) Protocol

Ver 1.3.903

Argatroban is a synthetic direct thrombin inhibitor that may be chosen as an alternate anticoagulant for patients that are heparin-intolerant, including those with congenital and acquired ATIII deficiencies, those with heparin-induced thrombocytopenia (HIT) and those with high levels of polymorphonuclear granulocyte elastase. Because argatroban has a fast acting anticoagulant effect without any cofactors such as ATIII, this drug is a favorable anticoagulant for heparin-intolerant patients with antithrombin III deficiencies requiring extracorporeal circulation. In adverse reactions to heparin, heparin acts as an antigen after complexing with platelet factor 4, which leads to life-threatening heparin-induced thrombocytopenia. As argatroban prevents heparin-induced platelet aggregation, it is effective for use as a therapeutic anticoagulant. [Matsuo, 1997 #10] Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It is metabolized by the liver with terminal elimination half-life of argatroban approximately 60 minutes. (package insert)

Test Used to Identify HIT II

• Platelet C serotinin release assay: 94% sensitivity with specificity of 100%, test is difficult, time-consuming, and requires radioactive isotopes.
• Heparin-induced platelet aggregation assay (HIPAA): 90% sensitivity with specificity of 100%, measures platelet aggregation optically. Utilization of a hapariniod (Orgaran (danaparoid)) to detect cross reactivity.
• Heparin-PF4 enzyme linked immunosorbent assay (PF 4 ELISA): immulonological test that depends on the direct detection of heparin-induced antibodies.
• Lumiaggregometry: platelet aggregation with simultaneous measurement of ATP release.
• Flow cytometric assays

How to Monitor Argatroban

• Activated clotting time values and the effect of argatroban during cardiopulmonary bypass have indicated a dose dependent response correlation. [Sakai, 1999 #11],¹
• When administered as a bolus dose, argatroban produced dose-related increases using an activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. ¹
• Any suitable ACT machine can be utilized to monitor the anticoagulant state.
• The target ACT range for PCI procedures is >300 sec and <450 sec. Target ACT range for CPB is >400 sec.
• Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. ¹

Dosing Regimen (Per manufacturer recommendation)

• Start infusion at 25 ug/kg/min and a of 350 ug/kg administered over 3-5 minutes – no argatroban is added to the pump (SLMC typically keeps 4 vials on hand).
• ACT should be checked 5-10 minutes after the bolus dose is completed.
• Therapeutic ACT values are usually attained with 10-15 minutes after initiating the bolus.
• Dosage adjustment may be required if ACT <400 seconds or >450 seconds
• If ACT < 300
• An additional dose of 150 ug/kg should be given; increase infusion dose to 30 ug/kg/min.
• If ACT > 450
• Decrease infusion dose to 15 ug/kg/min.
• While on CPB, the drug infusion will take place through the heart-lung machine and be diligently monitored by the perfusionist.

Dosing Regimen[Furukawa, 2001 #1]

• Initial bolus of 0.1 mg/kg – no argatroban is added to the pump (SLMC typically keeps 4 vials on hand, 1 vial lasts roughly 6 hrs at a rate of 10 microgrm/kg/hr).
• Infusion dose of 5 to 10 microgm/kg/hr. Bolus and infusion Dosing should begin 10 minutes before cannulation and initiation of CPB.
• While on CPB, the drug infusion will take place through the heart-lung machine and be diligently monitored by the perfusionist.

Cardioplegia Delivery

An intermittent blood-based cardioplegia system is contraindicated due to the rapid dissipation of the anticoagulant effect.¹ If blood-based cardioplegia is utilized, it must be continuous or be continuously recirculated in between delivery doses. It is recommended to use crystalloid cardioplegia – cold induction and cold maintenance with Dr. Seifert’s cardioplegia, with a maintenance dose every 20 minutes.

Circuit Monitoring

• Heparin coated circuits are contraindicated. This includes the use of the CDI heparin bonded in-line blood gas monitor components.
• Suggestion - The pre and post oxygenator pressures should be measured to give the perfusionist a better picture of the integrity of the oxygenator.
• Test verification of appropriate anticoagulation will be monitored every 20 minutes.

Things to Remember

• Argatroban, due to its small molecular size, can be removed with the hemoconcentrator; therefore, hemoconcentration should be avoided if possible.
• There is no reversal agent for argatroban.
• Half-life of argatroban is roughly 15 minutes (unaffected by dose)². Latest manufacturer information states a half-life between 39-51 mins.
• Once you have terminated bypass re-circulate circuit and send circuit volume to the cell saver as soon as possible (when A line is out). It is advisable to flush your entire circuit through with Plasmalyte to maintain a viable circuit.
• Heparin cannot be used with the cell saver – CPD or citrate could be used as the substitute for heparin.
• No dosage adjustment is necessary in patients with renal dysfunction; however, the dosage of argatroban should be decreased in patients with hepatic impairment. (package insert)
• Deep hypothermia circulatory arrest (DHCA) is currently contraindicated.

References

1. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000;20(3):318-29.

2. Kawada T, Kitagawa H, Hoson M, Okada Y, Shiomura J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin North Am 2000;14(2):445-57, x.