How should argatroban be dosed for a cardiac procedure in HIT-positive patients?

Comment by InpharmD Researcher

A comprehensive search was unable to identify a consensus with respect to dosing of argatroban in HIT-positive patients undergoing ablation for atrial fibrillation. One case report of a patient with a history of HIT undergoing radiofrequency catheter ablation for atrial fibrillation describes the successful use of a 10 mg argatroban bolus followed by a continuous infusion of 0.7 mcg/kg/min and periodic 3-mg doses to maintain activated clotting time (ACT) of 300-400 seconds. Available literature describing argatroban dosing in the setting of cardiac procedures typically utilizes the standard dosing recommendations for patients with or at risk for HIT undergoing percutaneous coronary intervention (initial bolus of 350 mcg/kg with an infusion of 25 mcg/kg/min adjusted based on ACT). However, it is unknown if this dosing strategy is effective specifically in HIT-positive patients requiring ablation for atrial fibrillation.

Background

The American Society of Hematology 2018 guidelines recommend that in patients with acute heparin-induced thrombocytopenia (HIT) with critical illness, increased bleeding risk, or increased potential for urgent procedures, argatroban or bivalirudin may be preferred due to shorter duration of effect. In patients with moderate or severe hepatic dysfunction, it is advisable to avoid argatroban or use a reduced dose. Specifically in patients with acute HIT or subacute HIT A who require percutaneous coronary intervention (PCI), bivalirudin is suggested rather than a different non-heparin anticoagulation. If bivalirudin is not available or there is a lack of institutional experience, argatroban may be used as a suitable substitute. Dosing recommendations for argatroban in HIT patients requiring urgent procedures or PCI are not provided. [1]

A 2020 review suggested that in patients with contraindications to unfractionated heparin, anticoagulation therapy with an intravenous direct thrombin inhibitor (DTI) remains a feasible option during left-sided ablation procedures. Available data describing anticoagulation with bivalirudin and argatroban in this setting are primarily limited to sporadic case reports. According to a more recently published multicenter experience, a total of 53 patients with contraindications to heparin (72% HIT and 21% heparin allergy) undergoing either catheter ablation of atrial fibrillation (n= 34) or episodes of ventricular arrhythmia (n= 19) received bivalirudin (75%) or argatroban (25%) therapy. Overall, 72% underwent activated clotting time monitoring, and 32% received additional DTI boluses, with results reporting no major bleeding or embolic complications. Notably, dosing regimens of argatroban in this study appeared to be identical to the recommended regimen for patients with HIT undergoing PCI, specifically with a bolus of 350 mcg/kg, followed by infusion of 25 mcg/kg/min; additional argatroban bolus doses were administered when the ACT was <300 s. Nevertheless, argatroban use in the setting of catheter ablation of atrial fibrillation only represented a small patient population. As such, future large randomized trials are warranted to test the role of DTIs in left-sided ablation procedures. [2], [3]

Relevant Prescribing Information

Dosing in Patients Undergoing Percutaneous Coronary Intervention:
Initial Dosage: Initiate an infusion of Argatroban in Sodium Chloride Injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes. Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed if the ACT is greater than 300 seconds. [4]

Dosage Adjustment: If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later. If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later. Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure. In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. Check the ACT after each additional bolus or change in the rate of infusion. [4]

Monitoring Therapy: For use in PCI, therapy with Argatroban in Sodium Chloride Injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure. [4]

Continued Anticoagulation after PCI: If a patient requires anticoagulation after the procedure, Argatroban in Sodium Chloride Injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range. [4]

Dosing in Patients with Hepatic Impairment:
For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in argatroban clearance relative to those with normal hepatic function. Monitor the aPTT closely, and adjust the dosage as clinically indicated.
Achievement of steady state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.
For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved. Use of Argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal should be avoided. [4]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

How should argatroban be dosed for a cardiac procedure (ablation for atrial fibrillation) in HIT-positive patients?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-2 for your response.

Atrial Fibrillation in a Patient with Heparin-induced Thrombocytopenia Successfully Treated by Radiofrequency Catheter Ablation Using a Direct Thrombin Inhibitor
Design	Case report
Case presentation	A 74-year-old man was admitted to a hospital in Japan for radiofrequency catheter ablation (RFCA) to address his persistent atrial fibrillation (AF). His medical history included coronary artery disease (CAD), congestive heart failure (CHF), diabetes mellitus, hypertension, dyslipidemia, sleep apnea-hypopnea syndrome, and chronic kidney disease. He had experienced multiple CHF episodes, leading to several hospital admissions, including a prior clinical diagnosis of heparin-induced thrombocytopenia (HIT), which prevented the use of heparin. Anticoagulation therapy using apixaban and treatment with the anti-arrhythmic agent Bepridil had been initiated. Additionally, he had been prescribed a renin-angiotensin system inhibitor, beta-blocker, statin, diuretics, mineralocorticoid receptor antagonist, calcium channel blocker, and sodium-glucose cotransporter 2 inhibitor. A 12-lead electrocardiogram showed AF. Echocardiography revealed a reduced left ventricular ejection fraction (LVEF) of 36%, normal valvular function, and no signs of structural heart disease. The left atrial (LA) dimension measured 53.6 mm. His CHADS2/CHA2DS2-VASc score was 3/5. Anticoagulation therapy using apixaban was continued until the day before the RFCA procedure and was temporarily halted on the morning of RFCA. Following a 3 mg bolus injection of argatroban, a double transseptal puncture was performed with guidance from intracardiac echocardiography. An additional 7-mg dose of argatroban was administered, and a continuous infusion of 3 mg/h (0.7 mcg/kg/min) was initiated. Periodic 3-mg doses of argatroban were also given to maintain the activated coagulation time (ACT) within the range of 300 to 400 seconds. The ACT was measured at 381 seconds and subsequently monitored every 15 minutes during the procedure to ensure it remained within the 300-400 second range. Circumferential Pulmonary vein (PV) antrum isolation (PVAI) and isolation of the LA posterior wall, along with ablation of epicardial connections involving PVs, were carried out under electroanatomic guidance with a three-dimensional mapping system until bidirectional conduction block between the LA and PVs was achieved, all while isoproterenol was administered. Subsequently, programmed stimulation failed to induce any arrhythmias, including AF. RFCA effectively treated the AF without any complications. Apixaban anticoagulation therapy was promptly reinstated following the RFCA procedure. He reportedly continued this anticoagulation therapy and remained in good health without any symptoms for one year post-RFCA.
Study Author Conclusions	To our knowledge, this was the first report concerning AF in a patient with HIT successfully and safely treated by RFCA using the direct thrombin inhibitor Argatroban in Japan

References:

Sakai T, Takemoto M, Ueno J, et al. Atrial Fibrillation in a Patient with Heparin-induced Thrombocytopenia Successfully Treated by Radiofrequency Catheter Ablation Using a Direct Thrombin Inhibitor. Intern Med. 2022;61(18):2747-2751. doi:10.2169/internalmedicine.9288-21

Atrial Fibrillation in a Patient with Heparin-induced Thrombocytopenia Successfully Treated by Radiofrequency Catheter Ablation Using a Direct Thrombin Inhibitor
Design	Case report
Case presentation	An 81-year-old man was admitted to the hospital to undergo radiofrequency catheter ablation (RFCA) of paroxysmal atrial fibrillation (AF). Relevant past medical history included hypertension and cerebrovascular apoplexy at the age of 80 years. Despite anticoagulation therapy with apixaban and antiarrhythmic agents, including 100 mg per day of Bepridil and 40 mg per day of Aprindine, he still experienced several attacks of paroxysmal AF with intolerable palpitations. On admission, the patient exhibited normal cardiac sounds, laboratory analysis, sinus rhythm, and left ventricular and valvular function. On the morning of RFCA, given the unreachable activated coagulation time (ACT) goals with repetitive heparin administration, heparin resistance was suspected after ruling out heparin-induced thrombocytopenia (HIT). Thus, the decision was made to initiate a 10 mg dose of Argatroban Hydrate, followed by 4 mg/h (1.6 mg/kg/min) continuous infusion to maintain the ACT at 300-400 s. After an administration of Argatroban Hydrate^® for 10 min, the ACT was 391 s. Then, the RFCA of AF was resumed. Periodic intraoperative ACTs were maintained within the target. The procedure overall was uneventful, and the AF was successfully treated by RFCA without any complications. The patient was eventually diagnosed with AT-III deficiency and was continued on anticoagulation therapy because of his history of cerebrovascular apoplexy associated with AF.
Study Author Conclusions	It has been previously reported that heparin resistance can be caused by different conditions: AT-III deficiency or abnormalities, cardiopulmonary bypass, increased heparin clearance, an increase of other heparin binding proteins, peripartum period, and neoplasias. In this case, a direct thrombin inhibitor was administered during the procedure without having an established diagnosis. Indeed, an AT-III deficiency was considered as a potential cause of the heparin resistance and confirmed by the efficacy of a direct thrombin inhibitor administration. To the best of the authors' knowledge, this is the first report concerning AF in a patient with an AT-III deficiency successfully and safely treated by RFCA using the direct thrombin inhibitor, Argatroban Hydrate.

References:

Kang H, Takemoto M, Tayama KI, Kosuga KI. A case report of atrial fibrillation in a patient with heparin resistance associated with an antithrombin III deficiency successfully treated by radiofrequency catheter ablation using a direct thrombin inhibitor. Eur Heart J Case Rep. 2019;3(1):yty166. Published 2019 Jan 9. doi:10.1093/ehjcr/yty166