Argatroban and warfarin dosing in heparin-induced thrombocytopenia

Let’s start with a patient case.  A 45 year old woman is referred to the hospital after seeing her primary care physician for unusual bruising.  She was discharged four days ago after a two day hospitalization for an asthma exacerbation.  Her PMH includes HTN and asthma.  Her CBC reveals platelets of 73 (baseline 190) and the comprehensive metabolic panel and CBC are otherwise within normal limits.  The diagnosis of heparin-induced thrombocytopenia (HIT) is suspected since she received heparin for DVT prophylaxis during her recent hospitalization.

To see another post on how to determine the probability of HIT by using the 4 T's score, click here.

If the diagnosis of HIT is confirmed, discontinuation of all forms of heparin is paramount.  This includes unfractionated heparin and low molecular weight heparins (including flushes and heparin-coated catheters).

After diagnosis, the decision needs to be made whether to institute a non-heparin anticoagulant, a vitamin K antagonist, and/or simply discontinue all heparins.

HIT can be characterized into two categories, HITT and isolated HIT:

If thrombosis is present (HITT – heparin-induced thrombocytopenia with thrombosis), the use of a non-heparin anticoagulant is recommended over simply discontinuing heparins or immediately initiating/continuing warfarin.¹

If thrombosis is not present (isolated HIT), the use of a non-heparin anticoagulant is also recommended over simply discontinuing heparins or immediately initiating/continuing warfarin.¹  This is evidenced by prospective cohort studies using historical controls.  They found that argatroban has been shown to have significantly reduced new thrombosis (and a reduced composite endpoint which included all-cause mortality) compared with holding heparin alone. Additionally, bleeding rates were similar between groups.² Some retrospective case series have quantified the rates of new thrombosis when holding heparin was the only intervention in isolated HIT.  These studies measured that in patients with isolated HIT who are not treated with a non-heparin anticoagulant, the risk of thrombosis is 17-55%.^3-5

The CHEST 2012 guidelines recommend argatroban, lepirudin, or danaparoid over other non-heparin anticoagulants in both HITT and isolated HIT.¹  To make things simpler, neither lepirudin nor danaparoid are being produced in the United States any longer.  Argatroban is also recommended in patients with renal insufficiency because it is not cleared or adjusted renally.

Dosing and titrating argatroban

When initiated, argatroban should be dosed the same in those with HITT and isolated HIT.  Standard dosing is 2 mcg/kg/minute continuous IV infusion with no loading dose (unless the patient has hepatic impairment which uses lower doses).  Before the infusion is started, the patient’s baseline aPTT needs to be measured in order to determine the target range.  The goal aPTT for argatroban is 1.5 to 3 times the patient’s baseline value.  Since the half-life of argatroban is roughly 45 minutes, steady-state is reached two hours after initiation or any dosage change so the aPTT should be checked at that time and the infusion should be adjusted accordingly.  There’s no standard titration but an example of a dosing strategy could look like this:⁶

aPTT	Infusion adjustment	Next aPTT
Subtherapeutic	Increase by 0.5 mcg/kg/minute	2 hours later
Therapeutic	None	2 hours later, then daily if within range (so you need two in a row before decreasing monitoring to daily)
3-4 times baseline	Decrease by 0.5 mcg/kg/minute	2 hours later
4-5 times baseline	Hold for 1 hour, half the rate	2 hours later
>5 times baseline	Hold until aPTT therapeutic, then half the rate	Every hour until within range

Bridging to warfarin

Conversion to warfarin raises some difficulty since argatroban raises the PT (and therefore INR) in addition to the aPTT.  Therefore, in order to assess if a therapeutic INR (pertaining to warfarin) has been reached, the argatroban infusion needs to be temporarily held and labs drawn.  Holding of the argatroban to check the argatroban-free INR does not need to be done until the INR of the combination argatroban-warfarin is >4.  The argatroban should be held for 4 to 6 hours before the INR is checked.  If the argatroban-free INR is above 2 (goal is 2-3), the warfarin can continue to be dosed daily and the argatroban does not need to be restarted.  If the INR is <2, the argatroban should be restarted and warfarin should continue to be dosed daily until the INR is further elevated on the combination therapy.⁷ A duration of 5 days overlap is recommended and an argatroban-free INR that is within therapeutic range should be achieved before discontinuing the infusion.  Additionally, loading doses of warfarin are not recommended and a platelet >150 should be reached before warfarin initiation.¹

Back to the patient case:

Once it is determined that the probability of HIT is high, the following should occur:

1)      Discontinuation of all heparin and low molecular weight heparin products.

2)   Add heparin allergy to all medical records.

3)      The baseline aPTT should noted before initiating a non-heparin anticoagulant.  In this case, whether there is a known thrombus or not, the new anticoagulant should be started given the high risk of a thrombosis developing (17-55% as mentioned above). 

4)      Argatroban should be initiated at 2 mcg/kg/minute and an aPTT should be drawn in 2 hours.

5)      The argatroban should be adjusted following that result to the target of 1.5 to 3 times the patient’s baseline aPTT. 

6)      When the patient’s platelets recover to >150, warfarin should be initiated at no more than 5 mg per day and INR should be checked daily. 

7)      When the INR reaches >4, the argatroban should be turned off and an INR should be measured 4-6 hours later.  If within the therapeutic range of 2-3 at this point, the argatroban does not need to be restarted.

Take home points:

• Argatroban raises the INR alone and when administered with warfarin
• The goal aPTT for argatroban is 1.5 to 3 times the patient’s individual baseline value
• If the patient has hepatic impairment, be sure to adjust the dose of argatroban being used since there is significant variation (see prescribing information)
• At North Shore University Hospital, argatroban prescribing is restricted to hematology/oncology and a medication safety fact sheet will be provided
• Argatroban is very expensive and may cost around $1,000 per day depending on the dose being used

References:

1.  Linkins L, Dans AL, Moores LK, et al.  Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic therapy and prevention of thrombosis 9^th ed.  Chest  2012;141:e495S-e530S.

2.  Lewis BE, Wallis DE, Leya F.  Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.  Arch Intern Med  2003;163(15):1849-56.

3.  Wallis DE, Workman DL, Lewis BE, et al.  Failure of early heparin cessation as treatment of heparin-induced thrombocytopenia.  Am J Med  1999;106(6):629-635.

4.  Warkentin TE, Kelton JG.  A 14-year study of heparin-induced thrombocytopenia.  Am J Med  1996;101(5):502-7.

5.  Zwicker JI, Uhl L, Huang WY, et al.  Thrombosis and ELISA optical density values in hospitalized patient with heparin-induced thrombocytopenia.  J Thromb Haemost  2004;2(12):2133-7.

6.  Ansara AJ, Arif S, Warhurst RD.  Weight-based argatroban dosing nomogram for treatment of heparin-induced thrombocytopenia.  Ann Pharmacother  2009;43(1):9-18.

7.  Argatroban Prescribing Information.  GlaxoSmithKline March, 2014.

photo by miketnorton