Drug Criteria & Outcomes
Lepirudin (Refludan) for the treatment of HIT
By Tina Hussey, PharmD
Clinical Specialist, Drug Information
University of North Carolina Health Care System
Chapel Hill
Introduction:
Heparin-induced thrombocytopenia (HIT) can be a serious complication of heparin therapy and occurs in two ways.1-3 The milder form of HIT occurs in about 10% to 20% of patients and usually develops after one to four days of heparin therapy, resulting in a mild thrombocytopenia.2-3 Platelet counts usually remain above 100,000 per microliter.2 This form of HIT, type I, occurs due to a direct interaction between heparin and platelets.2-3 The more serious form of HIT, type II, is attributed to an immune-mediated reaction to heparin. This form of HIT usually occurs after five to 10 days of heparin therapy, with the platelet count dropping to between 30,000 and 55,000 per microliter. The type II reaction is much more severe and can be associated with life-threatening thromboembolic complications. The incidence of this more critical form has been shown in the literature to vary from 0% to 30% depending on study population, heparin regimen, and heparin type. Although HIT more commonly occurs in patients receiving larger doses, it has been shown to occur in patients receiving small doses, as well.2-3
Low-molecular-weight heparins (LMWH) are obtained by depolymerization of unfractionated porcine heparin, resulting in fragments weighing less than 10,000 daltons.2-3 LMWH have almost 100% cross-reactivity with unfractionated heparin and should not be recommended for patients with HIT unless cross-reactivity is absent by in vitro platelet aggregation assays. Danaparoid is a low-molecular-weight heparinoid that differs from unfractionated heparin and LMWH. Danaparoid is a mixture of heparin sulfate, dermatan sulfate, and chondroitin sulfate.1-3 Although each component is structurally different from unfractionated heparin, the cross-reactivity with heparin-dependent antibody approaches 10% to 20%.2-3 Ancrod is a defibrinogenating agent extracted from snake venom that is distinct from heparin and has not been shown to have cross-reactivity.2 Ancrod does not suppress thrombosis in all cases and is not readily available in the United States. Argatroban is a synthetic direct thrombin inhibitor that very recently received FDA approval for the prevention and treatment of HIT.
The anticoagulant agent hirudin is found naturally in medicinal leeches (Hirudo medicinalis).4 Medicinal leeches have been used in hemostasis since ancient times, necessitating at least 50,000 leeches annually to obtain adequate amounts of hirudin for this purpose.4 Lepirudin, a recombinant hirudin, is approved by the FDA for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications.5-6
Indications:
Lepirudin (Refludan), by Aventis Pharmaceuti-cals (formerly Hoechst Marion Roussel), is indicated for anticoagulation in patients with HIT and associated thromboembolic disease to prevent further thromboembolic complications.5
Pharmacology:
Lepirudin is a recombinant hirudin derived from yeast cells.5 Lepirudin is composed of 65 amino acids and is identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminal end and the absence of a sulfate group on the tyrosine at position 63. Lepirudin binds to free and clot-bound thrombin to block its thrombogenic activity. The activity of lepirudin is measured in antithrombin units (ATUs). One ATU is the amount of lepirudin required to neutralize one unit of World Health Organization preparation of thrombin. The activity of lepirudin is about 16,000 ATU/mg.
Pharmacokinetics:
Lepirudin primarily distributes into extracellular fluids with an initial terminal half-life of 10 minutes.5 In young healthy volunteers, the terminal half-life is approximately 1.3 hours. The clearance of lepirudin has been shown to differ depending on renal function, age, and gender. The clearance of lepirudin is proportional to glomerular filtration rate; the elimination half-life has been shown to be prolonged up to two days in some patients with renal dysfunction. In 16 patients with renal impairment (creatinine clearance < 80 mL/min), the mean clearance of lepirudin was 61 mL/min. The clearance of lepirudin is reduced by about 25% in women compared to men and 20% in younger individuals compared to the elderly. In 18 healthy young subjects aged 18 to 60 years, the mean clearance was 164 mL/min compared to 139 mL/min seen in 10 healthy elderly subjects aged 65 to 80 years. The metabolism of lepirudin has not been well-established; however, it is thought to be metabolized by the release of amino acids from catabolic hydrolysis of the parent compound. Approximately 48% of the drug is eliminated in the urine as unchanged drug or fragments of the parent drug.
Pharmacodynamics:
The pharmacodynamic effect of lepirudin on the proteolytic activity of thrombin has been assessed using the activated partial thromboplastin time (aPTT).5 An increase in aPTT was observed with increasing plasma concentrations of lepirudin. No saturable effect was seen at a dose of 0.5 mg/kg body weight given by intravenous bolus, which was the highest dose tested.
Clinical trials:
The effectiveness of lepirudin for HIT was evaluated in two multicenter, prospective, open-label, historically controlled clinical trials; these trials, HAT-1 and HAT-2, are the basis for the FDA-approved indication of lepirudin for HIT.5-7 The trials had similar study design, primary and secondary objectives, and used similar dosing regimens. Both studies used the same historical control group which was compiled from a recent retrospective registry of patients with HIT. The historical control group consisted of 120 patients with HIT who were treated with therapies that did not include lepirudin (e.g., danaparoid, phenprocoumon, LMWH, aspirin, thrombolytics) or were not treated with anticoagulation. In both trials, patients were divided into four categories with different dosing regimens based on body weight (BW) as follows:5-7
A1 — acute HIT patients with thrombosis (HAT-1, n=51; HAT-2, n=65)
- Dosing: IV bolus: 0.4 mg/kg BW; IV infusion: 0.15 mg/kg BW/h x 2-10 days
- Dosing: IV bolus: 0.2 mg/kg BW; IV infusion: 0.1 mg/kg BW/h x 2-10 days
B — HIT patients without thrombosis (HAT-1, n=18; HAT-2, n=43)
- Dosing: Continuous infusion: 0.1 mg/kg BW/h x 2-10 days
C — HIT patients undergoing cardiopulmonary bypass (HAT-1, n=8; HAT-2, n=4)
- Dosing: Priming of heart lung machine: 0.2 mg/kg BW; IV bolus: 0.25 mg/kg BW; Additional boluses: 5 mg (to maintain Ecarin Clotting Time [ECT] > 250 seconds or Activated Coagulation Time [ACT] > 350 seconds)
Changes in dose were made to maintain aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually the median of the laboratory normal range for aPTT or the patient’s baseline aPTT prior to anticoagulation) between 1.5 and three.5-6 For aPTTs below the desired range, the infusion rate was increased by 20% and the aPTT was repeated four hours later. For aPTTs above the desired range, the infusion was discontinued for two hours then restarted at 50% of the previous rate with no boluses given. In patients receiving oral anticoagulation, the dose of lepirudin was decreased while still maintaining aPTT at least 1.5 times baseline values while the INR was less than two. Lepirudin was discontinued when the INR was more than 2.
Patient demographics were similar between treatment groups and historical controls, except for age.5-6 Patients in the historical control group tended to be older than patients treated with lepirudin. The primary endpoints for HAT-1 and HAT-2 were platelet recovery and effective anticoagulation. Platelet recovery was defined as an increase in platelet count by at least 30% of nadir to values greater than 100,000. Effective anticoagulation was defined as aPTT ratio greater than 1.5 with a maximum total 40% increase in the initial infusion rate. Platelet counts were not monitored closely in the historical control group and most patients in this group did not receive therapy that affected aPTT; therefore, comparisons could not be made based on the primary endpoints. Between patient groups, however, comparisons could be made. Of patients in group A1, 90% in the HAT-1 study met the primary endpoint of platelet recovery; 95% of those in HAT-2 met the same endpoint. All patients in group A2 (in both studies) had platelet recovery. Those reaching the primary endpoint of successful anticoagulation included 84% of patients in group A1 and 60% in group A2 (for HAT-1), and 77% of patients in group A1 and 33% in group A2 (for HAT-2). The percentage of patients reaching the primary endpoints when evaluating groups combined is as follows:5-6
• HAT-1: Eighty-six percent (all groups combined) met platelet count endpoint, 77% met anticoagulation endpoint, 65% met combined endpoints.
• HAT-2: Ninety-two percent (all groups combined) met platelet count endpoint, 74% met anticoagulation endpoint, 69% met combined endpoints.
Patients receiving lepirudin were compared to historical controls with respect to combined endpoints of thromboembolic complications, limb amputations, and death.6 In HAT-1, 71 patients receiving lepirudin were compared to 120 historical controls, and in HAT-2, 59 patients receiving lepirudin were compared to 120 historical controls. A significant difference between the groups in the combined endpoint at days 7 and 35 was found in HAT-1. At day 7, the incidence of the combined endpoint was 9.9% in those receiving lepirudin compared to 23% in historical controls. At day 35, the incidence was 25.4% in the lepirudin group and 52.1% in historical controls. In HAT-2, the cumulative incidence at day 7 for the lepirudin group was 17.9% compared to 21.3% in historical controls. At day 28, the cumulative incidence was 33.2% and 40.3%, respectively.
Adverse reactions:
The most common adverse events occurring in the HAT-1 and HAT-2 studies were hemorrhagic, including:6
• bleeding from puncture sites and wounds, 14.1%;
• anemia or isolated drop in hemoglobin, 13.1%;
• other hematoma and unclassified bleeding, 11.1%;
• hematuria, 6.6%;
• gastrointestinal and rectal bleeding, 5.1%
• epistaxis, 3.0%;
• hemothorax, 3.0%;
• vaginal bleeding, 1.5%.
Nonhemorrhagic events included fever (6.1%), abnormal liver function (6.1%), pneumonia (4%), sepsis (4%), allergic skin reactions (3%), heart failure (3%), abnormal kidney function (2.5%), unspecified infections (2.5%), multiorgan failure (2%), pericardial effusion (1%), and ventricular fibrillation (1%). Additional information from clinical pharmacology studies and clinical studies other than HIT show that intracranial bleeding occurred in 0.6% (seven out of 1,134 patients) of patients with acute myocardial infarction who received both lepirudin and thrombolytic agents.5 In addition, airway reactions (e.g., cough, bronchospasm, stridor, dyspnea) occurred in 1% to 10% of patients receiving lepirudin in these studies.
Pregnancy and lactation:
Lepirudin is rated a pregnancy category B drug,5 meaning either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect that was not confirmed in controlled studies in women in their first trimester.8 Studies have found no evidence of harm to the fetus at intravenous doses up to 30 mg/kg/day in pregnant rats (1.2 times the recommended maximum total daily dose in humans) and rabbits (2.4 times the recommended maximum total daily dose in humans).5 Studies did show that pregnant rats given lepirudin during organogenesis and perinatal-postnatal periods exhibited an increased incidence of maternal mortality. In pregnant rats, lepirudin does cross the placental barrier at intravenous doses of 1 mg/kg. Because there are no controlled studies of lepirudin in pregnant women, and animal studies do not always predict what happens in humans, it is recommended that lepirudin be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus.
It is not known whether lepirudin is excreted in breast milk.5 Considering that many drugs are excreted in breast milk and that there is the potential for serious adverse events in the infant, a decision should be made to discontinue nursing or to discontinue the drug. The importance of the drug to the mother should be taken into account.
Contraindications:
Lepirudin is contraindicated in patients with known hypersensitivity to hirudin.5
Warnings:
Intracranial bleeding following the administration of lepirudin concomitantly with thrombolytic therapy has occurred and can be life-threatening.5 For patients at increased risk of bleeding, the potential risks of bleeding should be assessed compared to the anticipated benefits.5 In particular, this includes the following conditions: recent puncture of large vessels or organ biopsy; anomaly of vessels or organs; recent cerebrovascular accident, stroke, intracerebral surgery, or other neuroaxial procedures; severe uncontrolled hypertension; bacterial endocarditis; advanced renal impairment; hemorrhagic diathesis; recent major surgery; and recent major bleeding (e.g., intracranial, gastrointestinal, intraocular, or pulmonary bleeding).
Reductions in the bolus and maintenance dose of lepirudin in patients with renal failure must be made.5 Relative overdoses can occur in these patients even at standard doses.
Dosage and administration:
Adult patients with HIT or associated thromboembolic disease should be initially treated with lepirudin 0.4 mg/kg (maximum 44 mg) intravenously (slowly, over 15 to 20 seconds) as a bolus, followed by lepirudin 0.15 mg/kg (maximum 16.5 mg/h) as a continuous intravenous infusion.5 Patients weighing more than 110 kg should receive the maximum initial bolus of 44 mg and the maximum initial infusion dose of 16.5 mg/h.
The loading dose and infusion rate of lepirudin should be reduced in patients with renal impairment.5 Dosage adjustments should be based on creatinine clearance (ClCr), when determined by a reliable method and by serum creatinine (SCr) when ClCr is not available. In all patients with renal impairment, the bolus dose should be reduced to 0.2 mg/kg. Recommendations for reductions in infusion rate are as follows:5
• 0.075 mg/kg/h (50% of standard rate) for ClCr 45-60 mL/min or SCr of 1.6-2 mg/dL;
• 0.045 mg/kg/h (30% of standard rate) for ClCr 30-44 mL/min or SCr of 2.1-3 mg/dL;
• 0.0225 mg/kg/h (15% of standard rate) for ClCr 15-29 mL/min or SCr of 3.1-6 mg/dL;
• Avoid or stop infusion for ClCr < 15 mL/min or SCr of > 6 mg/dL. Additional intravenous boluses of 0.1 mg/kg can be considered every other day if the apt ratio falls below 1.5.
Monitoring parameters and dose adjustments:
The aPTT ratio should generally be used to adjust the infusion rate of lepirudin.5 The aPTT ratio is the patient’s aPTT at a given time over an aPTT reference value. The reference value is usually the median of the laboratory normal for aPTT. The target range for the aPTT ratio should be between 1.5 and 2.5. Higher aPTT ratios have been shown in clinical studies to increase the risks of bleeding episodes without increasing the clinical efficacy. A baseline aPTT ratio should be obtained prior to initiating therapy with lepirudin. Lepirudin should not be started if the baseline aPTT ratio is 2.5 or greater to avoid initial overdosing. After starting therapy, the initial aPTT ratio should be obtained four hours after the start of the infusion with follow-up aPTT ratios obtained at least once daily. More frequent monitoring is recommended in patients with renal or liver impairment.
An aPTT ratio outside of the target range should not be acted upon until it is confirmed unless there is clinical need to react immediately.5 If a confirmed aPTT is above the target range, the lepirudin infusion should be held for two hours and restarted at 50% of the original infusion rate with no additional bolus. The aPTT ratio should be obtained four hours after the start of the infusion. If the confirmed aPTT is below the therapeutic range, the infusion rate should be increased in increments of 20%. The aPTT ratio should be obtained four hours later. An infusion rate of more than 0.21 mg/kg/h should not be used unless the patient has been tested for coagulation abnormalities, which might prevent an appropriate response in aPTT.
Drug interactions:
Thrombolytics given concomitantly with lepirudin may increase the risk of bleeding and enhance the effect of lepirudin on aPTT prolongation.5 Concomitant administration with warfarin may also increase the risk of bleeding.
Dosage forms available:
Lepirudin is supplied in vials that each contain 50 mg of lepirudin as a white powder for injection or infusion.5
One vial of lepirudin is required to make the bolus injection.5 Two vials of lepirudin are required to make a 500 mL bag with a final concentration of 0.2 mg/mL for intravenous infusion. At an associated wholesalers price (AWP) of $126 per vial, the cost of lepirudin in one bag would therefore be approximately $252. The recommended standard infusion rate for a 70 kg patient is 53 mL/h; a 500 mL bag would last about nine hours. This patient would need approximately three bags per day. Therefore, for a 70 kg patient, the cost for a bolus dose and continuous infusion would be approximately $882.
The doses of danaparoid vary depending on the patient’s condition, weight, history of HIT, and other factors.9 Generally, the recommended dose of danaparoid for patients with HIT and established DVT (thrombosis less than five days old) is 2,500 antifactor Xa units given as an IV bolus, then 400 units/hour (4 hours), then 300 units/hour (4 hours), then 150-200 units/hour for five to seven days. AWP for a 0.6 mL ampule of danaparoid is $112.80. Therefore, a 70 kg patient would require approximately 7,700 antifactor Xa units on the first day of therapy which would cost approximately $1,157. Subsequent days of therapy would cost approximately $541 based on a continuous infusion of 150 units/hour.
Discussion:
Lepirudin is available with approval by the FDA for anticoagulation in patients with heparin-induced thrombocytopenia.5,6 Danaparoid and ancrod have been used as well, but are not FDA-approved for this indication.1-3 Ancrod is not currently available in the United States. Danaparoid appears to have a 10% to 20% cross-reactivity in vitro with heparin-dependent antibody. Lepirudin does not cross-react with heparin-induced antibodies, as demonstrated by rapid and sustained platelet recovery.5,6 In addition, the half-life of lepirudin is approximately 10 minutes, which allows for easy titration up or down in the case of an adverse event.5 The half-life of danaparoid is approximately 24 hours.10
References:
1. Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia. Postgrad Med 1998; 103(2):169-78.
2. Brieger DB, Mak KH, et al. Heparin-induced thrombocytopenia. J Am Coll Cardiol 1998; 31:1449-59.
3. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79:1-7.
4. Markwardt F. The development of hirudin as an antithrombotic drug. Thrombotic Research. 1994; 74(1):1-23.
5. Refludan package insert. Kansas City, MO: Hoechst Marion Roussel; 1998 March.
6. David E. Vitt, RPh. Personal communication (letter). Hoechst Marion Roussel; September 10, 1998.
7. Greinacher A, Volpel H, Hach-Wunderle, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 1999; 99:73-80.
8. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation. 5th ed. Baltimore, MD: Williams and Wilkins; 1998.
9. Wilde MI, Markham A. Danaparoid: a review of its pharmacology and clinical use in the management of heparin-induced thrombocytopenia. Drugs 1997; 54(6):903-24.
10. Organon package insert. West Orange, NJ. Organon Inc; 1997 January.
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