Perfusion Policies 101: Agatroban

Editor’s Note:

Well it was one of those mornings where you are driving into work to do a routine cell saver case when all of a sudden your phone blows up and you are getting calls from the hospital operating room desk as well as several colleagues trying to figure out what is going on in terms of a heparin antibody issue – not fully blown out HIT-but a pathology of some sort that made the use of heparin as an anticoagulant a nonviable modality for the upcoming operation.

Recognizing that now we had fewer options than before, we as a group pretty much had to figure out what alternative anticoagulation methods were available to us, and equally more important if the components/drugs to achieve that approach were even available at the hospital I was going to.

Typically when you see a heparin allergy and patient is going to go on cardiopulmonary bypass it becomes a really big deal. In this case it was a vascular operation that required blood salvage in order to accomplish the task at hand.

My first thought was AngioMax- a drug I have used put patients with heparin allergies on bypass before, but never a fun exercise because you have to eliminate all sources of stasis in order to prevent clotting and/or  total destruction of your venous reservoir.

Here the solution seemed a little clearer, Argatroban was to be the drug of choice – and in this case- this particular drug was not something I had used before or had experience with. Teamwork really pays off when a lot of people go out of their way to either give you hints or links or options when it comes to deploying a technique you are unfamiliar with. I’d already made up my mind that I would use a ACD for the anticoagulant to be used in the cell saver – although erroneously the pharmacy thought there was heparin in ACD which to the best of my knowledge and after a thorough review of all the constituents listed on this particular IV solution, it was clear to me that in this case they were misinformed.

My strategy was to follow the pharmacological protocols for this drug as is listed on their website – and to do correlations with ACT draws and comparing them to PTT’s.

Through out the procedure and the case- they correlated well – and in hindsight- based on the anecdotal evidence before me-  I now consider the measurement of ACT’s as a reliable mechanism to establish the fact that a therapeutic level of anticoagulation can be achieved when using Argatroban.

Listed below is my strategy and some numbers that will perhaps help you if you find yourself having to use Argatroban for similar situations.  All feedback is welcomed so that we as a community can continue to help improve our practice when employing pharmacological approaches to unique situations that we encounter at the last minute.

9:15. 

Baseline- ACT 177

ptt 39

Game Plan:

Bolus Agatroban @ 150 mcg/Kg and maintenance drip at 2 mcg/kg/min

10:10

Argatroban Bolus- 10 min- ACT – 394

ptt > 120

10:45 

ACT- 461
Maintenance dose dropped down to 1mcg/kg/min

11:15

ACT- 434

11:20. 

Closing – agatroban drip maintained at 1mcg/kg/min

CBC drawn for plt #

Preop plts 60


Notes:

Onset- 5-10 min post Bolus

Metabolized by Liver

40-60 min half-life

Surgeon chose to maintain Argatroban drip post op to ensure graft viability-

Click on Image above to view Source Article

Argatroban

Pharmacologic classification: direct thrombin inhibitor
Therapeutic classification: anticoagulant
Pregnancy risk category B 

Available forms
Available by prescription only
Injection: 100 mg/ml

Indications and dosages 

Prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Adults: 2 mcg/kg/minute, administered as a continuous I.V. infusion; adjust dosage until the steady state PTT is 1.5 to 3 times the initial baseline value, not to exceed 100 seconds; maximum dose is 10 mcg/kg/minute.

≡ Dosage adjustment. For patients with moderate hepatic impairment, the initial dose should be reduced to 0.5 mcg/kg/min, administered as a continuous infusion. The PTT should be monitored closely and the dosage should be adjusted as clinically indicated.

Anticoagulation in patients with or at risk for HIT during percutaneous coronary interventions (PCI). Adults: 350 mcg/kg I.V. bolus over 3 to 5 minutes. Start a continuous I.V. infusion at a rate of 25 mcg/kg/minute. Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed.

≡ Dosage adjustment. To adjust the dosage, see below.

Activated clotting time Additional I.V. bolus Continuous I.V. infusion
< 300 seconds 150 mcg/kg 30 mcg/kg/ minute*
> 300 and < 450 seconds No additional bolus needed 25 mcg/kg/ minute
> 450 seconds No additional bolus needed 15 mcg/kg/ minute*
*Check activated clotting time again after 5 to 10 minutes.

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, administer an additional bolus of 150 mcg/kg and increase infusion rate to 40 mcg/ kg/minute. Check ACT again after 5 to 10 minutes.

Pharmacodynamics

Antithrombin action: Reversibly binds to the thrombin active site and inhibits thrombin-catalyzed or induced reactions, including fibrin formation, activation of coagulation factors V, VIII, and XIII, protein C, and platelet aggregation. Argatroban is capable of inhibiting the action of both free and clot-related thrombin.

Pharmacokinetics

Absorption: Administered I.V.

Distribution: Argatroban is distributed mainly in the extracellular fluid. Argatroban is 54% bound to human proteins, of which 34% is bound to α1-acid glycoprotein and 20% to albumin.

Metabolism: Metabolized mainly in the liver by hydroxylation. The formation of four metabolites is catalyzed in the liver by the cytochrome P-450 enzymes CYP3A/45. The primary metabolite (M1) is 20% weaker than that of the parent drug. The other metabolites are detected in low concentrations in the urine. The terminal elimination half-life ranges from 39 to 51 minutes.

Excretion: Primary excretion of argatroban is in the feces, presumably through the biliary tract.

Route Onset Peak Duration
I.V. Rapid 1-3 hr Until infusion stops

Contraindications and precautions 

Argatroban is contraindicated in patients hypersensitive to drug or its components and in patients with overt major bleeding.
Use cautiously in patients with hepatic disease; disease states that create an increased risk of hemorrhage, such as severe hypertension; very recent lumbar puncture, spinal anesthesia, or major surgery, especially involving the brain, spinal cord, or eye; and hematologic conditions linked to increased bleeding tendencies, such as congenital or acquired bleeding disorders and GI lesions and ulcerations.

Interactions 

Drug-drug. Oral anticoagulants: May prolong PT and INR and increase risk of bleeding. Monitor patient closely.
Thrombolytics: Increase risk of intracranial bleeding. Avoid use together.

Adverse reactions

CNS: fever, pain.
CV: atrial fibrillation, cardiac arrest, cerebrovascular disorder, hypotension, ventricular tachycardia.
GI: abdominal pain, diarrhea, GI bleeding, hemoptysis, nausea, vomiting.
GU: abnormal renal function, groin bleeding, hematuria, urinary tract infection.
Hematologic: anemia.
Respiratory: coughing, dyspnea, pneumonia.
Other: allergic reactions, brachial bleeding, infection, sepsis.

Effects on lab test results 

• May decrease hemoglobin and hematocrit.

Overdose and treatment

Excessive anticoagulation, with or without bleeding, may occur in argatroban overdose.
No specific antidote to argatroban is available if life-threatening bleeding occurs. Discontinue argatroban therapy immediately and monitor PTT and other coagulation tests. Provide symptomatic and supportive therapy.

=

Special considerations 

• Argatroban is intended for I.V. administration.

• All parenteral anticoagulants should be discontinued before administering argatroban.

• Obtain baseline coagulation tests, platelet counts, hemoglobin level, and hematocrit before therapy. Note any abnormalities.

• Ask patient about stomach ulcers or liver disease or if he has had recent surgery, radiation treatments, falls, or other injury.

• Administration of argatroban with antiplatelet drugs, thrombolytics, and other anticoagulants may increase the risk of bleeding.

• Hemorrhage can occur at any site in the body in patients receiving argatroban. Any unexplained drop in hematocrit or blood pressure or any other unexplained symptoms should lead to consideration of a hemorrhagic event.

• To convert to oral anticoagulant therapy, give warfarin with argatroban at doses of up to 2 mcg/ kg/ minute until the INR is above 4 on combined therapy. After argatroban is discontinued, repeat the INR in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the argatroban infusion. Repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

• Dilute in normal saline solution, D5W, or lactated Ringer’s injection to a final concentration of 1 mg/ml.

• Each 2.5-ml vial should be diluted 100-fold by mixing it with 250 ml of diluent.

• Mix the constituted solution by repeated inversion of the diluent bag for 1 minute.

• Prepared solutions are stable for up to 24 hours at 25° C (77° F).

• Argatroban is monitored by the PTT. Check PTT 2 hours after giving argatroban; dosage adjustments may be required to get a targeted PTT (1.5 to 3 times the baseline not to exceed 100 seconds). Steady-state is achieved within 1 to 3 hours after starting argatroban.

• Additional ACT should be drawn about every 20 to 30 minutes during a prolonged PCI procedure.

ALERT Don’t confuse argatroban with Aggrastat (tirofiban) or Orgaran (danaparoid).

Breast-feeding patients 
• It’s not known whether argatroban appears in breast milk. A decision should be made to discontinue either breast-feeding or drug, taking into account the importance of the drug to the mother.

Pediatric patients 
• The safety and efficacy in patients younger than age 18 haven’t been established.

Geriatric patients 
• Effectiveness of drug isn’t affected by age.

Patient education 

• Advise patient that drug can cause bleeding, and urge patient to report any unusual bruising or bleeding (nosebleeds, bleeding gums) or tarry stools to the prescriber immediately.

• Advise patient to avoid activities that carry a risk of injury, and instruct patient to use soft toothbrush and electric razor while taking argatroban.

• Instruct patient to call if wheezing, trouble breathing, or rash occurs.

• Tell patient to report if she is pregnant or breast-feeding or recently had a baby.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use

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