Drug Criteria & Outcomes: Formulary evaluation of direct thrombin inhibitors
Drug Criteria & Outcomes
Formulary evaluation of direct thrombin inhibitors
By Michelle Newman, PharmD*
Mechanism of action
Argatroban and lepirudin are direct thrombin inhibitors. Argatroban reversibly binds to the catalytic site of thrombin. It also is capable of inhibiting the action of both free and clot-association thrombin. Lepirudin binds irreversibly to both the catalytic and substrate-recognition sites of thrombin. Both argatroban and lepirudin lack any structural homology with heparin and do not cross-react with heparin. Danaparoid is a heparinoid that acts by antithrombin-mediated inhibition of Xa and IIa. It is associated with cross-reactivity with unfractionated heparin (UFH) for heparin-induced thrombocytopenia (HIT) antibodies.
Indications
Argatroban and lepirudin are indicated for treatment of thrombosis in patients with HIT. Argatroban also is approved for prophylaxis of thrombosis in this population. Danaparoid is indicated for prophylaxis of postoperative deep vein thrombosis (DVT) and in patients undergoing elective hip replacement surgery. It is not approved for patients with HIT, but has been used for this purpose.
Pharmacokinetics
The pharmacokinetics of argatroban, lipirudin, and danaparoid are summarized in Table 1.
Dosing
The recommended initial dose for argatroban is 2 mcg/kg/min, administered as a continuous infusion. aPTT should be monitored two hours after initiating therapy. Dosing adjustments may be required to attain the target aPTT: 1.5-3.0 times the initial baseline value (not to exceed 100 seconds). The dose of argatroban should not exceed 10 mcg/kg/min. Dosage adjustment is required in patients with hepatic impairment. For patients with moderate hepatic impairment, the initial dose should be 0.5 mcg/kg/min. The aPTT should be monitored closely, and the dosage should be adjusted as indicated. No dosage adjustment is necessary for renal impairment.
The recommended initial dose for lepirudin is a bolus of 0.4 mg/kg followed by 0.15 mg/kg/hr (up to 110 kg) infusion. The dose should be titrated to achieve an aPTT of 1.5-2.5 times the initial baseline. Monitoring of aPTT should be done four hours after start of lepirudin infusion and at least once daily thereafter. A dosage adjustment is recommended in patients with a serum creatinine greater than 1.5 mg/dL. No dosage adjustment is necessary for patients with hepatic impairment.
Danaparoid is administered subcutaneously or intravenously. Therapeutic doses of danaparoid reported in the literature vary, generally ranging from 2,000 units to 4,500 units per 24 hours, usually divided into two or three daily doses. Specific recommendations for dosage reduction have not been established for danaparoid, but caution is recommended by the manufacturer for patients with serum creatinine of 2 mg/dL or greater. At present, modest dosage reductions should be considered in those patients with a creatinine clearance of less than 20. Antifactor Xa levels should be monitored in patients with renal failure and in patients who weigh less than 60 kg or greater than 90 kg who are taking danaparoid. Because Antifactor Xa levels may take several days to obtain, they may not be practical for use in short-term therapy.
Contraindications
Argatroban is contraindicated in patients with overt major bleeds or in patients hypersensitive to the product or its components. Lepirudin is contraindicated in patients who are hypersensitive to hirudins. Danaparoid is contraindicated in severe hemorrhagic diathesis (e.g., hemophilia, idiopathic thrombocytopenic purpura); active major bleeding state, including hemorrhagic stroke in the acute phase; and hypersensitivity to danaparoid or pork products.
Warnings/precautions
Warnings and precautions are similar with the three drugs. The warnings for argatroban include hemorrhage that can occur at any site in the body and the discontinuation of all parenteral anticoagulants before administration of argatroban. Precautions include administering argatroban to patients with hepatic disease and concomitant use with warfarin, which may result in a prolonged international normalizing ratio (INR).
Lepirudin’s warnings include carefully assessing the risk of administration vs. its anticipated benefit in patients with an increased risk of bleeding, and use in patients with renal function impairment. Roughly 40% of patients develop antihirudin antibodies that may lead to an increase in anticoagulant effects. Hepatic injury (cirrhosis) also may lead to an increase in anticoagulant effects. Like argatroban, when used concomitantly with warfarin, lepirudin results in a prolonged INR.
While taking danaparoid, cross-reactivity with UFH can occur with antiplatelet antibodies in patients with HIT. Patients who are sulfite-sensitive may experience an allergic-type reaction, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes while taking danaparoid. It is recommended that complete blood counts, including a platelet count and a stool occult blood test be done periodically while on danaparoid, lepirudin, and argatroban to monitor for bleeding and platelet count recovery.
Adverse reactions
Excessive bleeding has been reported in up to 45% of patients treated with danaparoid for thromboembolism prophylaxis, with major hemorrhagic episodes (including GI bleeding and wound hematoma) occurring in up to 6% of patients.
The adverse events reported for argatroban and lepirudin cannot be directly compared, as these events were evaluated in separately controlled clinical trials. Argatroban’s hemorrhagic events were divided into major and minor events. (See Table 2.)
With the current information available, it is unknown if either drug causes fewer hemorrhagic events with the recommended doses. Nonhemorrhagic adverse events associated with argatroban, lepirudin, and danaparoid are listed in Table 3.
Drug interactions
Argatroban, lepirudin, and danaparoid may interact with other anticoagulants, antiplatelet drugs, and thrombolytics by increasing the risk of bleeding. Intracranial bleeding occurred in 1% of patients receiving argatroban and 0.6% of patients receiving lepirudin concomitantly with thrombolytics. Warfarin may prolong the INR with argatroban and lepirudin.
Conversion to oral therapy
The manufacturers of lepirudin and argatroban have provided guidelines for switching to oral therapy. To switch to oral therapy (such as warfarin) from lepirudin, gradually reduce the dose of lepirudin to achieve an aPTT ratio of 1.5 before initiating oral therapy. As soon as an INR of 2 is reached on combined therapy, lepirudin therapy should be discontinued. When initiating oral therapy on argatroban, the infusion of argatroban should be < 2 mcg/kg/min. Once the INR is > 4 on combined therapy, discontinue argatroban. Repeat an INR in 4-6 hours. If the INR is below the desired therapeutic range, resume the argatroban infusion and repeat the procedure daily until the desired range is achieved.
Clinical trials
The safety and efficacy of argatroban has been evaluated in two prospective, open-label, historically controlled studies. These studies were similar in design, objectives, and treatment options. Both studies included males and nonpregnant females 18-80 years of age with a clinical diagnosis of HIT with or without thrombosis. Patients with a documented unexplained aPTT > 200% control, coagulation disorder, or bleeding diathesis; lumbar puncture within the last seven days; or a history of previous aneurysm, hemorrhagic stroke, or recent thrombotic stroke within the past six months were excluded from these studies.
The initial dose of argatroban given in each study was 2 mcg/kg/min as a continuous infusion. Dosage adjustments were made to achieve an aPTT of 1.5-3.0 times the baseline. The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputations (all causes), or new thrombosis during the treatment or follow-up period of 37 days. The secondary endpoints were the evaluation of the event rates for the components of the composite endpoint and the time to event.
The first study enrolled 304 patients to receive argatroban and retrospectively evaluated 193 patients for historical controls. The result for the composite endpoint of argatroban is 34.2% vs. 43.0% for the control group. The author stated it was a significant improvement; however, no P values were given. The time to first event also was increased in the argatroban group. The second study showed similar results with fewer of the composite endpoints and an increased time to first event for argatroban. These studies currently have not been published, and evaluation of statistical significance is not available for study endpoints.
Lepirudin also was evaluated in two prospective, open-label, historically controlled trials that were similar in study design. These studies included patients who were 18 years old or older with a diagnosis of HIT based on clinical criteria and presence of HIT antibodies. The patient also must have had a definite need for parenteral antithrombotic therapy or prophylaxis. The studies excluded patients who required hemodialysis or hemofiltration; were anticipated to comply poorly; had known hypersensitivity to r-hirudin; or were pregnant. The efficacy was based on the comparison of combined and individual incidences of death, amputations, new thromboembolic complications, and incidences of bleeding with the lepirudin group and the control group. Patients in the lepirudin group were on average seven years younger and had more multiple thromboembolic complications at baseline. The results of the combined endpoints at day 35 were reduced significantly (P = 0.014) for the lepirudin group vs. the control group (9.9% vs. 23.0%). Bleeding rates were similar in both groups.
In the second study, fewer of the lepirudin-treated patients experienced an event at day 35, but it was not statistically significant. Bleeding events occurred statistically more often in the lepirudin group than the control group (P = 0.0001). These bleeding events were minor, not requiring transfusion and no intracranial bleeds were observed. Limitations for historical controlled studies include an increased risk of bias in the selection of the control patients, and missing data may have a large effect on the study results. These studies were also not blinded or randomized due to ethical reasons.
Danaparoid has not been extensively studied for the treatment of HIT, even though it is commonly used. A retrospective review of 42 patients with acute or past HIT included patients with a likely diagnosis of HIT based on several criteria. Criteria included a decrease in platelet count by 50% from baseline, interval of HIT onset > 5 days in cases of initial exposure or interval of < 4 days in cases of re-exposure, normalization of platelet count within 10 days after cessation of heparin therapy, and a thromboembolic complication during heparin therapy. Patients received 600-800 units every 12 hours either after nonvascular surgery or in medical situations, and 100-300 units/hr infusion post cardiac surgery for prevention of venous thromboembolic complications. For treatment of acute thromboembolism complications, a step-down infusion rate was advised: 400 units/hr for 4 hours, 300 units/hr for 4 hours, and then the maintenance infusion rate of 100-370 units/hr. Twenty-six patients were treated for acute HIT. In this group, no new thrombotic complications developed while on danaparoid; however, danaparoid failed to treat a thrombotic complication of HIT in two patients (7.6%), and three patients experienced bleeding complications, one minor and two major events. At the one-month follow-up after the withdrawal of danaparoid, no thrombosis had recurred.
In the prophylaxis group, 16 patients were treated for 20 events and no thrombotic complication occurred during the danaparoid treatment period. One minor hemorrhagic event occurred during the treatment period and one recurrence of DVT occurred during the one-month follow-up. Overall, the mean time of platelet count recovery was six days. The overall mortality was eight of 42 patients (19%), and the mortality caused by thromboembolic complications was two of 42 patients (5%). Cross-reactivity occurred in three of 46 patients (6.5%) without thrombotic complications. The study reliability is limited because of a small sample size and a retrospective design, and statistical significance was not well assessed.
Cost
At Huntsville Hospital in Huntsville, AL, danaparoid 1,500 units Q 12 hours is less expensive than the recommended doses of argatroban or lepirudin. An average daily argatroban regimen is approximately $50 less expensive than that of lepirudin, at the surveyed hospital.
Summary
Currently, danaparoid does not appear to be the drug of choice to treat HIT for several reasons. It has a 5-10% cross-reactivity with UFH antibodies. It has a much longer half-life than lepirudin and argatroban and is more difficult to monitor. It is contraindicated in patients with hypersensitivity to pork, and it should not be given to people with sulfite allergies. The dose needs to be adjusted in renal impairment, but the manufacturer has not established guidelines. Also, guidelines are not available for transitioning to oral therapy.
Argatroban and lepirudin are similar in many ways. Neither product cross-reacts with UFH and both have a short half-life. The monitoring parameters, adverse events, drug interactions, product stability/compatibility, and ease of dosing and administration are similar. Argatroban can be used in patients with renal impairment because dosage adjustment is not necessary. It also should be considered as alternative therapy for patients who develop antibodies to lepirudin, which increases anticoagulation effects. Lepirudin should be considered for patients with hepatic impairment.
See Table 4 for a quick reference guide and summary of all three therapies.
(Editor’s note: * written while a PharmD candidate at McWhorter School of Pharmacy, Samford University, Birmingham, AL. If you or your institution has a drug review [similar to those published in Drug Criteria & Outcomes] that Drug Utilization Review readers would find helpful in clinical practice, please contact Sue Coons at: [email protected].)
Resources
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