Argatroban Order Set for Heparin-Induced Thrombocytopenia (HIT) Or Suspected HIT

[Patient Identifier]

Argatroban Order Set for Heparin-Induced Thrombocytopenia (HIT) or suspected HIT

Patient weight = ______kg Page 1 of 4  Discontinue ______(See physician information sheet for a list heparin sources to consider)  Add heparin to allergy list  Baseline PTT, PT/INR, CBC, and LFTs (if not done in previous 24 hours)  No IM or intrathecal (IT) injections while on argatroban

Optional Diagnostic Orders*  Heparin/platelet factor 4 antibody test (note: ~50% false positive rate)  If heparin/ platelet factor 4 antibody test positive, send serotonin-release assay test  Bilateral lower extremity ultrasound

Medications Argatroban 1 mg/mL 0.9% NaCl ( 50 mg / 50 mL Infusion Vial ) (one of the boxes MUST be checked)  0.5 micrograms/kg/min (hepatic impairment, total bilirubin > 1.5 mg/dL)  1 microgram/kg/min (heart failure, multi-organ system failure, anasarca, or post-cardiac surgery)  2 micrograms/kg/min Vitamin K to correct Protein C & S depletion (one of the boxes MUST be checked)  Administer Vitamin K 10 mg IV over 30 min (recommended if warfarin given in the past 5 days)  Do not administer Vitamin K Warfarin Discontinue any active or pending orders for warfarin now. When platelets > 150,000, initiate the Argatroban to Warfarin Transition Protocol. Pharmacy will dose warfarin and manage daily using the protocol.

Monitoring  PTT 4 hours after infusion started or any infusion rate change  PTT every morning if no infusion rate change in past 24 hours  CBC every morning. If platelets < 150,000 do not administer warfarin.

Nursing Orders  Assess patient for other sources of heparin, and notify physician (See table in Nursing Information page)  Document all infusion rates, PTTs and other requested data on the Argatroban Flowsheet  Adjust argatroban infusion rate based on PTT results as follows (Goal PTT = 45 - 75 seconds)  Do not administer warfarin unless platelets > 150,000 (unless specific physician order directs otherwise) This is a HIGH ALERT medication; See Nurse Information Sheet or the Flowsheet for dose calculations PTT result Argatroban rate change Next PTT PTT < 45 seconds  argatroban infusion rate by 20% 4 hours from rate change PTT 45-75 seconds No change In AM PTT 76-80 seconds  argatroban infusion by 10% 4 hours from rate change PTT 81-85 seconds  argatroban infusion by 20% 4 hours from rate change PTT > 85 seconds Stop infusion x 1 hour, then  by 50% 4 hours from when infusion restarted  If 2 consecutive PTT are > 100 or < 40, call hematologist MD Signature: ______Date: ______Time: ______Restricted to Hematology and Board-certified Critical Care Practitioners RN Signature: ______Date: ______Time: ______

Origination date: 3/09, update 6/10, 6/11; 9/11;2/14; 4/14; 5/14 *Treatment and Prevention of Heparin-Induced Thrombocytopenia. CHEST 2012;141(2)(suppl):e495S-530S.

*1224* [Patient Identifier]

Argatroban to Warfarin Transition Protocol Page 2 of 4

The Department of Pharmacy will dose and manage warfarin daily using this protocol

 Warfarin will not be started until platelets are > 150,000 x109/L, unless specifically documented by the MD  Warfarin and argatroban will overlap for at least 5 days (even if INR > 2 in the presence or absence of argatroban)  INRs will be ordered at least baseline on the day warfarin is initiated, and daily until transition complete.  Warfarin will be initiated at a dose of 2.5 - 5 mg daily, unless reason exists to expect other dose to be more suitable. Dosage considerations include: response to administered doses, vitamin K administration, goal INR, laboratory values trends and drug interactions.  When INR > 4 and at least day 4 of argatroban + warfarin, the infusion and INR measurement off argatroban will be managed as outlined in the Warfarin Effect on INR Assessment flowchart (see below).  The Argatroban Flowsheet will be maintained by the pharmacist and kept in the chart.

Warfarin Effect on INR Assessment Flowchart (use when INR > 4, and ≥ 4 days of argatroban + warfarin)

IF Argatroban infusion ≤2 mcg/kg/min OR IF Argatroban infusion >2 mcg/kg/min

HOLD argatroban infusion DECREASE argatroban infusion to 2 mcg/kg/min

Redraw INR 4 hours post-hold Redraw INR 4 hours post-rate change

If result is

Immediately after INR is redrawn, INCREASE

< 2 ≥ 2 argatroban infusion rate to previous rate

st Resume infusion Is this the 1 & repeat process occurrence of INR If result is in 24 hours ≥ 2 after a 4 hour argatroban hold?

INR > 4 INR ≤ 4

Yes No HOLD argatroban Make no additional infusion changes & repeat DC Argatroban process in 24 hours (A therapeutic INR (≥ 2) on warfarin without argatroban interference for 2 consecutive days Redraw INR 4 hours post-hold is necessary before argatroban is permanently discontinued)

*1224* Patient Identifier Label Argatroban Monitoring Flowsheet Goal PTT = 45 - 75 Page 3 of 4 Date/Time

Platelets Hemoglobin (g/dL)

PTT (sec) Argatroban Dose (mcg/kg/min) INR during Argatroban

INR without argatroban Warfarin Dose

Date/Time

Platelets Hemoglobin (g/dL)

PTT (sec) Argatroban Dose (mcg/kg/min) INR during Argatroban

INR without argatroban Warfarin Dose

Date/Time

Platelets Hemoglobin (g/dL)

PTT (sec) Argatroban Dose (mcg/kg/min) INR during Argatroban

INR without argatroban Warfarin Dose Warfarin should not be started until platelets are > 150,000 x109/L Warfarin and argatroban should overlap for at least 5 days (even if INR >2) A therapeutic INR (> 2) on warfarin without argatroban interference for 2 days is necessary before argatroban is permanently discontinued

*1237* [Patient Identifier] Argatroban Flowsheet

Argatroban Infusion Initiation (1 mg/mL concentration) Patient Weight: ______kg

Dose : ______mcg/kg/min = ______mL/hr

Started at ______(date)______(time); PTT due ______(date/time)

Signature:______

Goal PTT = 45 - 75 seconds Page 4 of 4 Current Infusion Rate Change On hold New Infusion Rate Date Time of PTT Change made at until % increase PTT due at Signature PTT mcg/kg/min mL/hr needed? (time) (time) or decrease mcg/kg/min mL/hr (date/time) Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No

PTT result Argatroban dose change New Rate Calculation Next PTT PTT < 45 seconds  argatroban infusion rate by 20% Rate x 0.2 = N, Rate + N = New Rate 4 hours from rate change PTT 45-75 seconds No change In AM PTT 76-80 seconds  argatroban infusion by 10% Rate x 0.1 = N, Rate – N = New Rate 4 hours from rate change PTT 81-85 seconds  argatroban infusion by 20% Rate x 0.2 = N, Rate – N = New Rate 4 hours from rate change PTT > 85 seconds Stop infusion x 1 hour, then  by 50% Rate x 0.5 = N, Rate – N = New Rate 4 hours from when infusion restarted If 2 consecutive PTT are > 100 or < 35, call hematologist or ordering physician Origin: 5/09 Revised: 6/10, 6/11

*1236*

Physician Information Sheet-Argatroban and Heparin Induced Thrombocytopenia

 If the patient has significant hepatic impairment, the Direct Thrombin Inhibitor bivalirudin relies on renal and enzymatic degradation, and may be used with a greater degree of dosing certainty.

 A clinical pharmacist will monitor all patients on Argatroban. As needed, they will make recommendations regarding: protocol adjustments to achieve desired PTTs. Warfarin will be initiated and managed by a pharmacist, according to the Argatroban to Warfarin Transition Protocol.

Heparin, heparin-like products and heparin-containing products to avoid (unless HIT is ruled-out) Some devices, such as intra-aortic balloon pumps utilize heparin in their circuitry. All ancillary therapies need to be assessed. Heparin-containing Products* Heparin-like products Heparin-containing products used at RSFH* Heparin flushes Dalteparin (Fragmin) Swan-Ganz catheter (Edwards Lifesciences; 831HF75) Heparin lock-solutions Enoxaparin (Lovenox) Gore Viabahn Grafts (WL Gore & Associates; VBH051002, VBH051502, VBH050502, VBH061002, VBH061502, VBH060502, VBH071002, VBH071502, VBH070502) Some Dialysis solutions Tinzaparin (Innohep) Guidewires (Cook Medical; G00692, G27036, G00512, G00716, G01382, G02246) Shunt Sensor for CDI System 500 (Terumo Corp CDI510H) *This table is not guaranteed to be all-inclusive. An individualized assessment of all devices and materials is recommended.

Estimating the pretest probability of Heparin Induced Thrombocytopenia: the Four T’s 2 points 1 point 0 point  30-50% platelet decrease  > 50% platelet decrease to OR  < 30% platelet decrease Thrombocytopenia nadir > 20 x 109/L  > 50 % platelet fall BUT surgery OR Score ______AND no surgery within within preceding 3 days  nadir < 10 x 109/L preceding 3 days OR  nadir 10-19 x 109/L Timing of platelet count  consistent with day 5–10 decrease,  day 5–10 after start of heparin but not clear (eg, missing platelet  platelet count decrease ≤ 4 decrease or thrombosis OR counts) days without heparin exposure (Day 0 = first day of most recent heparin  ≤ 1 day (with recent heparin OR in past 100 days exposure) exposure within past 5–30 days)  ≤ 1day (heparin exposure within past 31–100 days) Score ______OR  platelet decrease after day 10 Thrombosis (or other clinical  proven new thrombosis  recurrent venous thrombosis in (venous or arterial) patient receiving therapeutic  Thrombosis suspected sequelae) OR anticoagulants Score _____  skin necrosis at injection site OR OR  erythematous skin lesions at  post-IV heparin bolus heparin injection sites anaphylactoid reaction OR OR  suspected thrombosis (awaiting  adrenal hemorrhage confirmation) oTher cause for No explanation for platelet count Possible other cause is evident: Probable other cause is Thrombocytopenia decrease is evident  sepsis without proven microbial present: Score ______source  within 72 h of surgery  thrombocytopenia associated with  confirmed initiation of ventilator bacteremia/fungemia  other  chemotherapy or radiation within past 20 days  posttransfusion purpura (PTP)  platelet count < 20 AND given a drug implicated in causing ITP (see list below)  non-necrotizing skin lesion at LMWH injection site  other Total Score = ______6-8= high, 4-5 = intermediate, 0-3 = low Adapted from: Linkins LA, Dans AL, Moores LK, et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia. CHEST 2012;141(2)(suppl):e495S- 530S.

Drugs Implicated in drug-induced immune thrombocytopenia (D-ITP) Relatively common: glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban), quinine, quinidine, sulfa antibiotics, carbamazepine, vancomycin Less Common: actinomycin, amitriptyline, amoxicillin, piperacillin, nafcillin, cephalosporins (cefazolin, ceftazidime, ceftriaxone), celecoxib, ciprofloxacin, esomeprazole, fexofenadine, fentanyl, fucidic acid, furosemide, gold salts, levofloxacin, metronidazole, naproxen, oxaliplatin, phenytoin, propranolol, propoxyphene, ranitidine, rifampin, suramin, trimethoprim,

NOT PART OF THE MEDICAL RECORD

Nurse Information Sheet-Argatroban

INDICATION Anticoagulant for the prophylaxis or treatment of thrombosis in patients with Heparin-induced thrombocytopenia (HIT) or when an anticoagulant is needed in a patient with a heparin allergy.

CONTRAINDICATION Overt major bleeding

CAUTIONS Severe hypertension; recent lumbar puncture, spinal anesthesia, or major surgery (especially involving the brain, eye or spinal cord)

CLINCIAL PHARMACOLOGY Anticoagulant that works by directly inhibiting thrombin, the final step in fibrin, or clot, formation

PHARMACOKINETICS  Half-life of approximately 45 minutes in patients with normal hepatic function (renal dysfunction has no effect on argatroban)  Full anticoagulant effects are produced within 3-5 hours of the infusion  There is no specific antidote if excessive doses are administered or bleeding occurs  Reversal of anticoagulant effects takes about 2-4 hours after the infusion is discontinued.

MONITORING  The target PTT is 45-75 seconds. The PTT will be checked every 4 hours until therapeutic (adjust per protocol) and then daily. A CBC will also be obtained daily to assess for any decline in hemoglobin and monitor platelet recovery (in the case of HIT).  In the patient with HIT it is imperative to vigilantly assess for the development of any thrombosis (arterial or venous), even after argatroban has been initiated. For arterial thrombi assess: extremities for decreased pulses or coolness, symptoms of a TIA/stroke, chest pain, or abdominal pain. For venous clots assess: limb swelling, pain, redness or warmth.  Bleeding may also occur at any site in the body (eg, hematoma, puncture sites and wounds, gastrointestinal bleeding, hematuria, intracranial bleeds, epistaxis)  DO NOT administer any IM or intrathecal (IT) injections

DRUGS AND PRODUCTS TO AVOID Patients with HIT or possible HIT need to avoid ALL heparin products, as they can set off the clotting cascade in these patients and cause thrombosis. Below is a list of drugs and heparin-containing products to avoid.

EFFECT ON INR Argatroban increases the INR. It is common to have INRs of 4 or 8 in patients on higher argatroban doses. This INR does not indicate a higher risk of bleeding, as it would in the patient receiving warfarin. It is purely a lab test phenomenon. If an INR is checked and is elevated, do not make empiric changes to the argatroban infusion or hold any ordered warfarin doses. Check with the hematologist involved in the patient’s care, the pharmacist, or the attending physician if further information is required.

DOSE ADJUSTMENTS Adjust per the protocol based on the PTT. All dosage adjustments and PTTs should be recorded on the Argatroban Flowsheet, and kept in the MAR section of the chart.

NEW RATE CALCULATION GUIDELINES PTT result Argatroban rate change New Rate Calculation PTT < 45 seconds  argatroban infusion rate by 20% Rate x 0.20 = N, Rate + N = New Rate PTT 45-75 seconds No change PTT 76-80 seconds  argatroban infusion by 10% Rate x 0.1 = N, Rate – N = New Rate PTT 81-85 seconds  argatroban infusion by 20% Rate x 0.2 = N, Rate – N = New Rate PTT > 85 seconds Stop infusion x 1 hour, then  by 50% Rate x 0.5 = N, Rate – N = New Rate

NOT PART OF THE MEDICAL RECORD Patient Identifier Label