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Comparison of the Oral Direct Thrombin Inhibitor

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Comparison of the Oral Direct Thrombin Inhibitor ORIGINAL INVESTIGATION Comparison of the Oral Direct Thrombin Inhibitor Ximelagatran With Enoxaparin as Prophylaxis Against Venous Thromboembolism After Total Knee Replacement A Phase 2 Dose-Finding Study John A. Heit, MD; Clifford W. Colwell, MD; Charles W. Francis, MD; Jeffrey S. Ginsberg, MD; Scott D. Berkowitz, MD; James Whipple, MS; Gary Peters, MD; for the AstraZeneca Arthroplasty Study Group Background: Up to one third of patients who undergo Results: A total of 594 patients received at least 1 dose total knee replacement develop deep vein thrombosis af- of the study drug; 443 patients were evaluable for effi- ter surgery despite receiving low-molecular-weight hep- cacy. Rates of overall venous thromboembolism (and proxi- arin prophylaxis. Ximelagatran is a novel direct inhibi- mal deep vein thrombosis or pulmonary embolism) for the tor of free and clot-bound thrombin. 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), Methods: We performed a randomized, parallel, dose- respectively. Rates of overall venous thromboembolism finding study of 600 adults undergoing elective to- (22.7%) and proximal deep vein thrombosis or pulmo- tal knee replacement at 68 North American hospitals nary embolism (3.1%) for enoxaparin did not differ sig- to determine the optimum dose of ximelagatran to use nificantly compared with 24-mg ximelagatran (overall dif- as prophylaxis against venous thromboembolism ference, –6.9%; 95% confidence interval, −18.0% to 4.2%; after total knee replacement. Patients received either P=.3). There was no major bleeding with administration ximelagatran twice daily by mouth in blinded fixed of 24 mg of ximelagatran twice daily. doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 Conclusion: Fixed-dose, unmonitored ximelagatran, 24 to 24 hours after surgery and continuing for 6 to mg twice daily, given after surgery appears to be safe and 12 days. We measured the 6- to 12-day cumulative effective oral prophylaxis against venous thromboem- incidence of symptomatic or venographic deep vein bolism after total knee replacement. thrombosis, symptomatic pulmonary embolism, and bleeding. Arch Intern Med. 2001;161:2215-2221 ENOUS thromboembolism thrombin.6 Moreover, low-molecular- is a common complica- weight heparin currently must be given by From the Division of tion after total knee re- subcutaneous injection, which is incon- Cardiovascular Diseases, Mayo placement surgery. In the venient for some patients. Although oral Clinic and Mayo Foundation, absence of prophylaxis, ap- warfarin sodium prophylaxis is conve- Rochester, Minn (Dr Heit); the proximately 60% of patients have veno- nient, frequent laboratory monitoring and Department of Orthopedic V graphic evidence of deep vein thrombo- dose adjustment are required, and warfa- Surgery, Scripps Clinic, La 1 Jolla, Calif (Dr Colwell); sis at hospital discharge. Although rin is not as effective as low-molecular- 3-5 the Department of Medicine, prophylaxis with low-molecular-weight weight heparin. Clearly, more effective University of Rochester Medical heparin is effective and safe, approxi- and convenient prophylaxis is needed. Re- Center, Rochester, NY mately 30% of patients still develop deep cently, prophylaxis with a direct throm- (Dr Francis); the Division of vein thrombosis.2-5 Most of these thrombi bin inhibitor (recombinant desulfato- Hematology, McMaster are small, asymptomatic, and confined to hirudin or desirudin), which potently University, Hamilton, Ontario the deep veins of the calf. However, the inhibits clot-bound thrombin, was shown (Dr Ginsberg); and prevalence of proximal (eg, popliteal or to be significantly more effective than and AstraZeneca LP, Wayne, Pa more proximal) deep vein thrombosis, as safe as low-molecular-weight heparin (Drs Berkowitz and Peters and 7 Mr Whipple). A complete list of which is most frequently associated with after total hip replacement. However, the the members of the AstraZeneca symptomatic venous thromboembolism first dose was given immediately after spi- Arthroplasty Study Group and fatal pulmonary embolism, is still ap- nal anesthesia and before surgery, which appears in a box proximately 6%,5 possibly because hepa- might increase the risk for operative bleed- on page 2221. rins are poor inhibitors of clot-bound ing and formation of spinal hematomas.8 (REPRINTED) ARCH INTERN MED/ VOL 161, OCT 8, 2001 WWW.ARCHINTERNMED.COM 2215 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 PATIENTS AND METHODS STUDY DESIGN Using a multicenter, randomized, parallel study design, pa- STUDY POPULATION tients were randomly allocated to 1 of 5 treatment groups: ximelagatran at a fixed dose of 8, 12, 18, or 24 mg given twice Patients were eligible for enrollment if they provided writ- daily by mouth or enoxaparin sodium (Lovenox, Rhone- ten informed consent, were 18 years or older and not of Poulenc Rorer Pharmaceuticals Inc, Collegeville, Pa), 30 mg, childbearing potential if female (eg, postmenopausal or given twice daily by subcutaneous injection. For all 5 treat- surgically sterile), weighed 40 to 125 kg, and were sched- ment groups, the intensity of anticoagulation was not moni- uled for elective primary unilateral total knee replacement tored and the drug dose was not adjusted. Randomization was surgery. Patients were excluded for the following reasons: performed using a computer-generated randomization list previous objectively confirmed deep vein thrombosis or provided by AstraZeneca LP, Wayne, Pa; the randomization pulmonary embolism; anticipated use of an epidural was stratified in blocks of 5 patients. Ximelagatran adminis- or spinal catheter for more than 12 hours after surgery or tration was blinded and enoxaparin administration was open within 2 hours of administration of the first dose of study label. Study drug was first administered after adequate he- medication; traumatic epidural or spinal puncture; mostasis and within 12 to 24 hours after surgery and was con- planned external pneumatic compression prophylaxis tinued for 6 to 12 days. Patients who were discharged from (except passive antiembolism stockings); immobilization the hospital within 6 days after surgery received their re- because of trauma or other illness within 12 weeks maining study drug as outpatients. Drug compliance was as- of surgery; or long-term anticoagulant or antiplatelet sessed by counting the number of tablets or syringes (1) used therapy. Use of aspirin and nonsteroidal anti-inflam- during the inpatient period, (2) dispensed at hospital dis- matory drugs was discontinued 24 hours before surgery; charge, and (3) returned unused by the patient at the end of use of all other anticoagulants was stopped 7 days before the study. All patients were followed up clinically for at least surgery. Patients were also excluded if they had an allergy 4 weeks after surgery. The study was conducted at 68 North to contrast media or iodine, a clinical bleeding disorder, American community, university, or university-affiliated renal impairment (serum creatinine level Ͼ1.8 mg/dL hospitals. The protocol was approved by the institutional re- [Ͼ160 µmol/L]) or a renal transplant, previous intracra- view board of each investigational center. nial or retinal bleeding, previous or current drug or alco- hol abuse, an ischemic stroke within the previous 3 EVALUATION OF EFFICACY AND SAFETY months, gastrointestinal tract bleeding or ulcer verified by endoscopy within the previous year, major surgery within Patients were examined daily for symptoms and signs of ve- the previous 3 months, a malignant neoplasm being nous thromboembolism and bleeding while in the hospital. actively treated, uncontrolled hypertension (systolic After a minimum of 6 and a maximum of 12 days of treat- blood pressure Ͼ180 mm Hg or diastolic blood pressure ment, and within 12 hours after the last treatment dose, Ͼ100 mm Hg), liver disease or impairment (aspartate patients underwent unilateral ascending venography of the aminotransferase or alanine aminotransferase levels operative leg.10,11 Each venogram was interpreted by an in- Ͼ2-fold higher than normal), anemia (hemoglobin level dependent central adjudication committee consisting of ex- Ͻ10.0 g/dL), or thrombocytopenia (platelet count perts who were blinded to treatment allocation and who cat- Ͻ100ϫ103/µL). Patients who had previously participated egorized the venographic findings as diagnostic for deep vein in this study were excluded, as were patients who had thrombosis, normal, or inadequate. A venogram that lacked received another investigational agent within the previous adequate views of the distal external iliac, common and su- 30 days. Similarly, mentally or legally incapacitated perficial femoral, popliteal, and at least paired peroneal and patients and those with a condition that might interfere posterior tibial veins was categorized as inadequate; visual- with study participation or for whom study participation ization of the profunda femoris or anterior tibial veins was might cause significant risk were excluded. not a requirement. Deep vein thrombosis was diagnosed In addition, desirudin has not been studied as prophy- before surgery. In North America, however, prophylaxis laxis for total knee replacement; it also must be given usually is started after surgery because of concerns about as a subcutaneous injection, which potentially limits its operative
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