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

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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 bleeding. Consequently, we performed a phase convenience. 2 dose-finding study to assess the efficacy and safety of 4 Melagatran is a small molecule that provides different postoperative, fixed-dose, oral ximelagatran regi- potent, competitive, and direct inhibition of free and clot- mens compared with postoperative enoxaparin sodium as bound thrombin, but it must be administered parenter- prophylaxis against venous thromboembolism after total ally. Ximelagatran (formerly known as H 376/95; Exanta) knee replacement. is an oral prodrug that is converted to melagatran, the 9 active metabolite. In a recent international clinical trial of RESULTS preoperative administration of subcutaneous melagatran followed by oral ximelagatran as prophylaxis against PATIENT POPULATION venous thromboembolism after total hip or knee replacement, the highest melagatran-ximelagatran dose was sig- A total of 600 patients were randomized into the study; nificantly more effective than and as safe as low-molecular- the first patient was randomized in October 1998, and weight heparin (dalteparin sodium) prophylaxis started the last patient completed the study in January 2000. Pa-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 when a constant intraluminal filling defect was seen on at least We increased our total sample size to 600 patients to allow 2 images; thrombi were further subcategorized as affecting forinadequatevenograms.Theincidenceratesofvenousthrom- the proximal leg veins (popliteal or more proximal deep vein) boembolism were estimated using the observed proportions or isolated to the calf veins and as thrombi longer than 10 cm. (and corresponding 95% confidence intervals [CIs]) within Patients with clinically suspected acute pulmonary embolism treatment groups, and the presence or absence of a linear dose underwent a ventilation/perfusion lung scan; a high-speed, response was estimated using the Cochran-Armitage test for high-resolution (eg, spiral or electron beam) computed to- trend.13 The secondary objective was to compare the efficacy mographic scan of the chest with appropriate contrast injec- and safety of using ximelagatran vs enoxaparin. In addition tion; or a pulmonary angiogram. For patients undergoing a to the intention-to-treat analysis, we performed a secondary lung scan, pulmonary embolism was diagnosed when the scan efficacy analysis that included patients with an adequate veno- was interpreted as high probability based on a segmental or gram who met our a priori definition for protocol compliance. larger perfusion defect(s) with normal ventilation.12 For pa- Thesafetyanalysisincludedallpatientswhotookatleast1dose tients undergoing computed tomography or pulmonary an- of study medication. We estimated differences in proportions giography, pulmonary embolism was diagnosed based on a (and 95% CIs) between treatments and tested for treatment constant intraluminal filling defect within 1 or more pulmo- difference using the Fisher exact test. A central data coordi- nary arteries or abrupt cutoff of a vessel 2.5 mm or larger in nating center (AstraZeneca) performed all statistical analy- diameter. Bleeding was categorized as major if it was clinically ses. Data interpretation and manuscript preparation were overt and involved a critical site (eg, intracranial, retroperi- performed by the writing committee. However, AstraZeneca toneal, intraocular, spinal, or pericardial bleeding), caused a retained the right to review and comment on the manuscript bleeding index of 2.0 or greater (defined as the change in pre- before publication. bleed and postbleed hemoglobin levels plus the number of red blood cell units transfused), or prompted medical or sur- INTERIM ANALYSIS gical intervention at the operative site. Overt bleeding that did not meet these criteria was categorized as minor. Bleeding epi- An independent safety committee monitored the conduct of sodes were also categorized as clinically significant based on the study. The safety committee received all fatal or life- the judgment of the local investigator. In addition to the veno- threatening event reports within one business day and all other grams, all clinically suspected episodes of deep vein throm- reports within 5 calendar days. In addition, the safety com- bosis, pulmonary embolism, and major bleeding were adju- mittee reviewed regular reports of bleeding and venous throm- dicated by the central adjudication committee. boembolism event rates by treatment group and made rec- ommendations regarding continuing or stopping the study. STATISTICAL METHODS At the recommendation of the safety and executive commit- tees, the protocol was amended on September 28, 1999, to Baseline demographic and surgical characteristics were discontinue enrollment in the 8-mg ximelagatran arm. This compared descriptively. The primary study objective was recommendation was based on newly available data indicat- to assess the dose range of ximelagatran. The primary efficacy ing that 1 mg of melagatran started before surgery and given measure was the cumulative incidence of verified venous twice daily by subcutaneous injection followed by 8 mg of thromboembolism. The primary analysis was intention to treat oral ximelagatran twice daily was significantly inferior to low- and included all patients with an adequate venogram or molecular-weight heparin (dalteparin sodium) prophylaxis symptomatic, objectively documented venous thrombo- in a parallel study performed in Europe.9 To maintain blind- embolism. We estimated that the incidence of venous throm- ing, investigators completed the existing blocks of drug sup- boembolism would differ by 18% between the low- and high- plies. Thereafter, new drug supplies for ximelagatran with only dose ximelagatran groups. Assuming a linear dose response, 3 dose levels (12, 18, and 24 mg) were provided. The origi- we estimated that 80 evaluable patients per dose group would nal sample size was retained across the remaining 4 treat- provide 80% power (␣=.05) to detect a dose response, giv- ment groups so that the numbers of patients in the remain- ingatotalsamplesizeof400patientswithadequatevenograms. ing groups increased by approximately 10%.

tients in the 5 treatment arms were similar with regard protocol violations. After excluding these 28 patients, to baseline patient and surgical characteristics (Table 1). 415 patients remained and were included in the per- Fifty-five patients prematurely discontinued study treat- protocol analysis. Finally, 594 patients received at least ment; the 5 treatment arms did not differ significantly 1 dose of study medication and were included in the with regard to the reasons for premature discontinua- safety analysis. tion of study treatment (Table 2). Combining patients who did not undergo venography with patients who had CUMULATIVE INCIDENCE OF VENOUS an inadequate venogram, 157 patients had a nonevalu- THROMBOEMBOLISM able study efficacy measure and were excluded. The intention-to-treat analysis included the remaining 440 pa- As shown in Figure 2, the distribution of total study tients plus 3 additional patients who had symptomatic, medication doses was similar across the 5 treatment arms. objectively documented pulmonary embolism (Figure 1). Among the 4 ximelagatran groups, the 24-mg dose had No emergency unblinding occurred during the study. the lowest overall incidence of venous thromboembo- Twenty-eight patients had 1 or more protocol viola- lism (Table 3). Although the highest dose of ximela- tions (Table 2); the 5 treatment arms did not differ sig- gatran (24 mg) provided a 42% relative risk reduction nificantly with regard to the percentage of patients with in the overall venous thromboembolism rate compared

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Baseline Characteristics of 600 Patients Undergoing Total Knee Replacement by Treatment Assignment

Ximelagatran Group Enoxaparin Sodium Group, 8mg 12 mg 18 mg 24 mg 30 mg Characteristic (n = 85) (n = 134) (n = 126) (n = 130) (n = 125) Age, mean (SD), y 65 (10) 67 (11) 68 (10) 67 (11) 68 (10) Women, % 60 58 64 65 62 Body mass index, mean (SD), kg/m2 32.6 (5.7) 30.9 (6.0) 30.9 (6.0) 31.4 (5.7) 31.8 (7.0) Duration of surgery, mean (SD), min 100 (37) 96 (39) 91 (34) 86 (31) 97 (35) Surgical blood loss, mean (SD), mL 130 (132) 124 (177) 128 (179) 130 (168) 140 (167) Type of anesthesia, No. (%) General 43 (68) 68 (67) 50 (57) 70 (74) 69 (71) Spinal 14 (22) 21 (21) 29 (33) 22 (23) 25 (26) Epidural 4 (6) 5 (5) 2 (2) 1 (1) 3 (3) Spinal-epidural 1 (2) 5 (5) 2 (2) 1 (1) 0 Other 1 (2) 2 (2) 4 (5) 1 (1) 0 Antiembolism stocking, % 73 76 71 77 74 Dosing compliance, No. (%) 81 (95) 127 (95) 113 (90) 121 (93) 117 (94) Time to first ambulation, d 1.2 1.2 1.2 1.3 1.2

Table 2. Disposition of 600 Randomized Patients Undergoing Total Knee Replacement by Treatment Assignment

Ximelagatran Group Enoxaparin 8mg 12 mg 18 mg 24 mg Sodium Group, 30 mg Characteristic, No. % (n = 85) (n = 134) (n = 126) (n = 130) (n = 125) Discontinued study 6 (7) 10 (7) 15 (12) 12 (9) 12 (10) Adverse event 1 (1) 4 (3) 9 (7) 3 (2) 5 (4) Stopped by sponsor or investigator 3 (4) 4 (3) 3 (2) 4 (3) 4 (3) Withdrawn consent 0 2 (1) 1 (1) 1 (1) 2 (2) Lost to follow-up 1 (1) 0 1 (1) 2 (2) 1 (1) Ineligible 1 (1) 0 1 (1) 2 (2) 0 Completed study 79 (93) 124 (93) 111 (88) 118 (91) 113 (90) Venography not done or inadequate findings 22 (26) 33 (25) 39 (31) 35 (27) 28 (22) Intention-to-treat analysis 63 (74) 101 (75) 87 (69) 95 (73) 97 (78) Protocol violation* No surgery 0 0 0 2 (2) 0 Study medication noncompliance 3 (4) 7 (5) 11 (9) 6 (5) 8 (6) Concurrent antiplatelet or anticoagulant therapy 1 (1) 3 (2) 0 4 (3) 2 (2) Venography not performed within 6-12 d of surgery 1 (1) 0 1 (1) 0 2 (2) First dose not given within 24.5 h of surgery 1 (1) 4 (3) 3 (2) 2 (2) 2 (2) Per-protocol analysis 60 (71) 92 (69) 82 (65) 91 (70) 90 (72)

*Patients could have more than one protocol violation.

with the lowest dose of ximelagatran (8 mg), the abso- rin, the 24-mg dose of ximelagatran provided a 30% rela- lute difference was not significantly different (absolute tive risk reduction for overall venous thromboembo- reduction, 11.2%; 95% CI, −2.0% to 24.4%; P=.11), pos- lism. Again, however, the absolute difference between the sibly owing to the small sample size. Similarly, the high- 2 groups was not significantly different (absolute differ- est dose of ximelagatran provided a 52% relative risk re- ence, −6.9%; 95% CI, −18.0% to 4.2%; P=.3). The rate duction in the rate of proximal deep vein thrombosis or of proximal deep vein thrombosis or pulmonary embo- pulmonary embolism compared with the lowest dose of lism also was not statistically different between the 2 ximelagatran, but the absolute difference also was not sig- groups (absolute difference, 0.1%; 95% CI, −4.9% to 5.0%; nificantly different (absolute difference, 3.4%; 95% CI, PϾ.99). Among patients with venographically demon- −3.7% to 10.5%; P=.4). Thus, the tests for a linear dose strated deep vein thrombosis, fewer in the 24-mg ximela- response across the 4 ximelagatran groups for overall ve- gatran group (5.3%) and the enoxaparin group (6.2%) nous thromboembolism and proximal deep vein throm- had a thrombus longer than 10 cm compared with pa- bosis or pulmonary embolism were not statistically sig- tients in the other 3 ximelagatran groups (7.9%-14.3%). nificant (P=.3 and .7, respectively). In the per-protocol analysis, the cumulative incidence of The rates of overall venous thromboembolism and venous thromboembolism also was lowest in the 24-mg of proximal deep vein thrombosis or pulmonary embo- ximelagatran group, and the difference between the enoxa- lism among patients receiving enoxaparin were 22.7% and parin and 24-mg ximelagatran groups was not statisti- 3.1%, respectively (Table 3). Compared with enoxapa- cally different (P=.3) (Table 3).

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Three cases of nonfatal pulmonary embolism occurred during treatment—2 in the 18-mg ximelagatran Nonevaluable Efficacy Measure 22 33 39 35 28 = = = = = group and 1 in the 24-mg ximelagatran group. Two ad- n n n n n ditional patients developed pulmonary embolism dur- Ximelagatran ing follow-up—both were in the 24-mg ximelagatran 8 mg PO bid n = 63 n = 82 (n = 85) group. One case occurred 21⁄2 months after treatment ended, and the other occurred 7 days after treatment Ximelagatran 12 mg PO bid n = 101 n = 128 ended; the latter patient subsequently died. The rate of (n = 134) pulmonary embolism among the treatment groups was too low for meaningful comparison. Patients Ximelagatran Randomized R 18 mg PO bid n = 87 n = 118 (N = 600) (n = 126) CUMULATIVE INCIDENCE OF BLEEDING Ximelagatran 24 mg PO bid n = 95 n = 122 The total number of major bleeding events was low in (n = 130) the 4 ximelagatran groups. There was no significant trend Enoxaparin in major bleeding (P=.4), major or minor bleeding (P=.9), 30 mg SC bid n = 97 n = 120 or clinically significant bleeding events (P=.3) by ximela- (n = 125) gatran group (Table 4). The number of wound hema- 12-24 h 6-12 d 4 wk tomas also was low, and the incidence of wound hema- After Surgery After Surgery After Surgery tomas, the volume of postoperative blood loss or wound drainage, and the time to onset of major or minor bleed- Informed Total Knee Begin Study Evaluable Clinic Visit Consent Replacement Drug Venogram ing did not differ significantly among the 4 groups. Al- Surgery though the mean number of transfused red blood cell units was low (Ͻ1) for all ximelagatran groups, there was a Figure 1. Flow diagram detailing the study design, drug intervention, patient enrollment, patient withdrawal, study drug discontinuation, and duration of possible trend toward a higher mean number of trans- follow-up. PO indicates by mouth; bid, twice daily; and SC, subcutaneously. fused units with increasing ximelagatran dose (P=.09). Compared with the 8-mg ximelagatran group, the mean number of transfused units was marginally but signifi- 100 Ximelagatran, 8 mg (n = 85) cantly greater in the 24-mg group (P=.048). However, Ximelagatran, 12 mg (n = 134) the bleeding index did not differ significantly among the 80 Ximelagatran, 18 mg (n = 126) 4 groups. Ximelagatran, 24 mg (n = 130) The rates of major bleeding, major plus minor bleed- Enoxaparin, 30 mg (n = 125) ing, and clinically significant bleeding events in the enoxa- 60 parin group were 0.8%, 9.6%, and 1.6%, respectively; these

rates did not differ significantly compared with the 24-mg Patients, % 40 ximelagatran group (Table 4). Moreover, the rate of wound hematomas, mean volume of postoperative blood 20 loss and wound drainage, mean number of transfused red blood cell units, and bleeding index also were similar for 0 the 2 groups. The bleeding indices, however, were lower 0 1-9 10-18 19-24 in the 18-mg (3.0) and 24-mg (3.0) ximelagatran groups Study Drug Doses, Total No. compared with the enoxaparin group (3.4), and these dif- Figure 2. Distribution of total study medication doses by treatment ferences approached statistical significance (P=.07 and assignment. .051, respectively). Compared with the 8-mg ximelagatran group, the mean number of transfused units also was marginally but significantly greater in the enoxaparin the highest ximelagatran group. In the only placebo- group (P=.047). controlled prophylaxis trial after total knee replacement, the incidence of major bleeding was 2% in the pla- 2 COMMENT cebo group, which compares favorably with our observed 0% to 2.4% range of major bleeding rates among the 4 This study is the first, to our knowledge, to show that a ximelagatran groups. direct thrombin inhibitor given solely as a fixed oral dose The 24-mg dose of ximelagatran twice daily ap- and started after surgery is safe and effective as prophy- peared to be the most effective of the 4 doses tested, al- laxis against venous thromboembolism after total knee though the test for trend in ximelagatran dose efficacy replacement surgery. For ethical reasons, this study did did not reach statistical significance. Compared with the not include a placebo group. Based on previous studies, 8-mg ximelagatran dose, the 24-mg dose provided a 42% in the absence of prophylaxis the expected incidence of relative risk reduction in overall venous thromboembo- venous thromboembolism after total knee replacement lism and a 52% reduction in the relative risk of proxi- ranges from 40% to 84%.1 Using the most conservative mal deep vein thrombosis or pulmonary embolism. More- expected incidence (40%), ximelagatran provided a 33% over, the 11.2% absolute difference in overall venous to 61% relative risk reduction in overall venous throm- thromboembolism in favor of the 24-mg dose ap- boembolism cumulative incidence from the lowest to proached statistical significance (P=.11) and likely is clini-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 3. Cumulative Incidence of Venous Thromboembolism by Treatment Group

Ximelagatran Group Enoxaparin Characteristic 8mg 12mg 18mg 24mg Sodium Group, 30 mg Intention-to-treat analysis n = 63 n = 101 n = 87 n = 95 n = 97 Overall venous thromboembolism, % 27 20 29 16 23 Proximal deep vein thrombosis or pulmonary embolism, % 7 2 6 3 3 Pulmonary embolism, No. 0 0 2 1 0 Deep vein thrombosis Ͼ10 cm long, % 14895 6 Per-protocol analysis n = 60 n = 92 n = 82 n = 91 n = 90 Overall venous thromboembolism, % 28 20 29 15 21

Table 4. Cumulative Incidence of Bleeding by Treatment Group

Ximelagatran Group Enoxaparin 8mg 12 mg 18 mg 24 mg Sodium Group, 30 mg Characteristic (n = 84) (n = 134) (n = 124) (n = 127) (n = 125) Major bleeding, % 0020 1 Total bleeding, % 10 16 17 9 10 Significant bleeding events, % 0222 2 n = 78 n = 125 n = 110 n = 119 n = 116 Postoperative blood loss, mean (SD), mL 165 (256) 189 (310) 184 (260) 146 (274) 200 (310) Wound hematoma, % 4462 2 n = 80 n = 129 n = 114 n = 122 n = 120 Wound drainage, mean (SD), mL 258 (341) 253 (331) 250 (362) 255 (359) 283 (360) Transfused red blood cells, Mean, units 0.4 0.6 0.6 0.7 0.7 Any transfusion, % 22 35 38 35 37 n = 71 n = 118 n = 104 n = 117 n = 109 Bleeding index score, mean (SD) 3.2 (1.3) 3.2 (1.8) 3.0 (1.3) 3.0 (1.5) 3.4 (1.7)

cally important. The 24-mg dose of ximelagatran also ap- lism in patients undergoing total hip replacement (abso- peared to be safe. There were no major bleeding events lute difference, 7.1%; P=.001) and a 40% reduction in the in the 24-mg dose group. The major or minor bleeding, relative risk of proximal deep vein thrombosis (absolute significant bleeding event, and wound hematoma rates; difference, 3.0%; P=.01).16 Finally, our data indicate that the total volume of postoperative blood loss and wound the safety of the 24-mg dose of ximelagatran and enoxa- drainage; and the bleeding indices did not differ signifi- parin (both started after surgery) appears to be compa- cantly between the 8- and 24-mg dose groups. How- rable, with similar rates of bleeding complications and blood ever, the 24-mg group had a slightly but significantly loss, and similar transfusion requirements. higher transfusion requirement than the 8-mg group. It is unlikely that the results of this study are due to Administering 24 mg of ximelagatran twice daily also bias. The treatment groups had similar demographic and appears to be as effective, or possibly even more effective, surgical characteristics. The efficacy outcomes were than the current standard of prophylaxis in North determined by objective testing and were interpreted cen- America—low-molecular-weight heparin started after trally by experts who were blinded to treatment assign- surgery. Compared with enoxaparin, the 24-mg dose of ment. Unlike in total hip replacement, deep vein throm- ximelagatran provided a 30% relative risk reduction in over- bosis seldom occurs in the nonoperative leg after total all venous thromboembolism incidence in our study. Our knee replacement.1 Therefore, we performed unilateral findings are consistent with the results of the METHRO II venography of only the operative leg to avoid the addi- study,9 in which 3 mg of melagatran given by subcutane- tional contrast dye volume from bilateral venography. The ous injection before surgery followed by 24 mg of oral safety outcomes (eg, major and minor bleeding) were also ximelagatran twice daily after surgery provided a 35% rela- based on objective measures of hemoglobin change and tive risk reduction in overall venous thromboembolism transfusion requirement. Moreover, the 4 ximelagatran compared with administration of dalteparin sodium. In ad- groups were blinded, and all major bleeding events were dition, our findings are also consistent with those of other adjudicated centrally. The distribution of total study medi- trials7,14-16 investigating direct thrombin inhibitors as ve- cation doses was similar among treatment groups, and nous thromboembolism prophylaxis after total joint re- the results of the per-protocol analysis were entirely con- placement. For example, compared with enoxaparin, re- sistent with those of the intention-to-treat analysis. combinant desulfato-hirudin (desirudin) provided a 28% In summary, oral administration of ximelagatran relative risk reduction in overall venous thromboembo- after surgery and continued for at least 6 to 12 days

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 The AstraZeneca Arthroplasty Study Group

Jack Ansell, MD, Boston Medical Center, Boston, Mass; Stephen Bartol, MD, Group North Windsor, Windsor, Ontario; Wil- liam J. Bose, MD, Alabama Orthopedics, Mobile; Timothy J. Bray, MD, Reno Orthopedic Clinic, Reno, Nev; Frank A. Burke, MD, Bluegrass Orthopaedics, Lexington, Ky; Humayun Mahmood Cheema, MD, Saint Barnabas Medical Center, Livingston, NJ; Clifford W. Colwell, Jr, MD, Scripps Clinic, La Jolla, Calif; Larry D. Cordell, MD, Overland Park, Kan; Francisco Cordova, MD, Southwest Clinical Research, Inc, Phoenix, Ariz; Mark A. Crowther, MD, FRCPC, St Joseph’s Hospital, Hamilton, Ontario; Victor deKorompay, MD, FRSC, Manitoba Clinic, Winnipeg; David Drucker, MD, Staten Island University Hospital, Staten Island, NY; Karen Duane, MD, James A. Haley Veterans Hospital, Tampa, Fla; Gerald Dugan, MD, Kansas City, Mo; Donald G. Eckhoff, MD, Denver, Colo; Roger H. Emerson, Jr, MD, Texas Center for Joint Replacement, Plano, Tex; Bradley A. Fink, DO, Lower Bucks Orthopedic Group, Penndel, Pa; James Sidney Finley III, MD, Green Clinic, Ruston, La; Charles W. Francis, MD, University of Rochester Medical Center, Rochester, NY; Richard J. Friedman, MD, Department of Orthopedic Surgery– Medical University of South Carolina, Charleston, SC; Gurdev S. Gill, MD, Lubbock, Tex; Ian L. Gordon, MD, PhD, VA Long Beach Healthcare System, Long Beach, Calif; John A. Heit, MD, Mayo Clinic, Rochester, Minn; Steven F. Hoff, MD, Hill Top Research Inc, Portland, Ore; Michael G. Hogan, MD, Cumming, Ga; Joseph J. Jankiewicz, MD, San Diego, Calif; Mau- rice Jove, MD, Decatur, Ga; Joshua Kimelman, DO, Iowa Orthopedic Center, Des Moines; William Lanzer, MD, Seattle, Wash; Paul Lotke, MD, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia; Terence J. Matthews, MD, PA, Orthopaedic Associates Building, Ft Lauderdale, Fla; Leon Mead, MD, Anchor Research Center, Naples, Fla; Ram Mudiyam, MD, Fountain Valley, Calif; S. Curtiss Mull, MD, Lewis-Gale Clinic, Salem, Va; William J. Navigato, MD, Riverside, Calif; Paul Nicholls, MD, Lexington, Ky; Jill Ohar, MD, Saint Louis University Health Sciences Center, St Louis, Mo; David Puskas, MD, Thunder Bay, Ontario; Hubert Riegler, MD, Lattimore Orthopedics, Rochester, NY; Ronald Romanelli, MD, Orthopedic Center of Illinois, Springfield; Aaron G. Rosenberg, MD, Midwest Orthopedics, Chicago, Ill; Robert Schmidt, MD, PA, Fort Worth, Tex; Howard Schuele, MD, Clearwater, Fla; Mahipal M. Shah, MD, Pomona, Calif; Sami Srour, MD, Bakersfield, Calif; Daniel M. Stormont, MD, Monroe, Wis; James A. St. Ville, MD, Phoenix; Paul D. Stein, MD, Henry Ford Health System, Detroit, Mich; Randall Suarez, MD, Hill Top–MedQuest Research Inc, Greer, SC; Linda Vickars, MD, Vancouver, British Columbia; Philip Wells, MD, Ottawa Hospital, Civic Parkdale Clinic, Ottawa, Ontario; Gregory Wise, MD, Kettering, Ohio; Arnold A. Yashar, MD, Louisville, Ky; Rick Zarnett, MD, MSc, FRCSC, North York, Ontario; and Joseph Zucker, MD, Nalle Clinic, Charlotte, NC.

appears to be safe and effective as prophylaxis against ve- 4. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboem- nous thromboembolism after total knee replacement sur- bolism after knee arthroplasty: a randomized, double-blind trial comparing enoxa- gery. This was accomplished without laboratory moni- parin with warfarin. Ann Intern Med. 1996;124:619-626. 5. Heit JA, Berkowitz SD, Bona R, et al. Efficacy and safety of low molecular weight toring of the intensity of ximelagatran anticoagulation heparin (ardeparin sodium) compared to warfarin for prevention of venous throm- or adjustment of the ximelagatran dose. Of the 4 post- boembolism following total knee replacement: a double-blind, dose-ranging study. operative oral ximelagatran dose regimens tested, we be- Thromb Haemost. 1997;77:32-38. lieve that the most effective is 24 mg twice daily; this regi- 6. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is men appears to provide at least comparable efficacy and protected from inhibition by heparin-antithrombin III but is susceptible to inactiva- tion by antithrombin III–independent inhibitors. J Clin Invest. 1990;86:385-391. safety to postoperative low-molecular-weight heparin pro- 7. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with phylaxis. This hypothesis requires further testing in a use of recombinant hirudin. J Bone Joint Surg Am. 1997;79:326-333. phase 3 clinical trial. 8. Horlocker T, Heit JA. Low molecular weight heparin: biochemistry, pharmacol- ogy, perioperative prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg. 1997;85:874-885. Accepted for publication June 11, 2001. 9. Eriksson BI, Lindbratt S, Ka¨lebo P, et al. METHRO II: dose-response study of the This study was supported by a grant from Astra- novel oral, direct thrombin inhibitor, H376/95, and its subcutaneous formula- Zeneca LP. tion melagatran, compared with dalteparin as thromboembolic prophylaxis af- We are indebted to the members of the surgical, nurs- ter total hip or total knee replacement. Haemostasis. 2000;30(suppl 1):20-21. 10. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch ing, pharmacy, and support staff of all the study sites. The Surg. 1972;104:134-144. members of the Safety Committee were Bruce Davidson, MD, 11. Ka¨lebo P, Ekman S, Lindbratt S, et al. Percentage of inadequate phlebograms and Jack Hirsh, MD, and Robin Roberts. observer agreement in thromboprophylactic multicenter trials using standardized Corresponding author: John A. Heit, MD, Hematol- methodology and central assessment. Thromb Haemost. 1996;76:893-896. 12. Hull RD, Hirsh J, Carter CJ. Pulmonary angiography, ventilation lung scanning ogy Research, Plummer 549, Mayo Clinic, 200 First St SW, and venography for clinically suspected pulmonary embolism with abnormal lung Rochester, MN 55905. scan. Ann Intern Med. 1983;98:891-899. 13. Margolin BH. Test for trend in proportions. In: Kotz S, Johnson NL, eds. Ency- REFERENCES clopedia of Statistical Sciences. Vol 9. New York, NY: John Wiley & Sons Inc; 1988:334-336. 14. Ginsberg JS, Nurmohamed MT, Gent M, et al. Use of hirulog in the prevention of 1. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. venous thrombosis after major hip or knee surgery. Circulation. 1994;90:2385- Chest. 2001;119(suppl):132S-175S. 2389. 2. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis 15. Eriksson BI, Ekman S, Ka¨lebo P, Cachrisson B, Bach D, Close P. Prevention of after major knee surgery: a randomized, double-blind trial comparing a low mo- deep-vein thrombosis after total hip replacement: direct thrombin inhibition with lecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost. 1992; recombinant hirudin, CGP 39393. Lancet. 1996;347:635-639. 67:417-423. 16. Eriksson BI, Wille-Jørgensen P, Ka¨lebo P, et al. A comparison of recombinant 3. RD Heparin Arthroplasty Group. RD heparin compared with warfarin for preven- hirudin with low-molecular-weight heparin to prevent thromboembolic com- tion of venous thromboembolic disease following total hip or knee arthroplasty. plications after total hip replacement. N Engl J Med. 1997;337:1329- J Bone Joint Surg Am. 1994;76:1174-1185. 1335.

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