Efficacy and Safety of Enoxaparin to Prevent Deep Venous Thrombosis after Hip Replacement Surgery

  1. Theodore E. Spiro, MD;
  2. Gerhard J. Johnson, MD;
  3. Michael J. Christie, MD;
  4. Roger M. Lyons, MD;
  5. Donald E. MacFarlane, MD, PhD;
  6. Ralph B. Blasier, MD;
  7. M. David Tremaine, MD; and
  8. for the Enoxaparin Clinical Trial Group*
     
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    Abstract

    Objective: To determine the most effective and safe dose of enoxaparin to prevent deep venous thrombosis in high-risk surgical patients.

    Design: A double-blind, randomized, multicenter clinical trial.

    Setting: Private, university, and government hospitals in the United States.

    Patients: 572 patients having elective hip replacement surgery, 568 of whom received study medication and had efficacy data available for evaluation.

    Interventions: Patients were randomly assigned to one of three subcutaneous enoxaparin regimens: 10 mg once daily (161 patients); 40 mg once daily (199 patients); and 30 mg every 12 hours (208 patients). Treatment was initiated within 24 hours after surgery and continued for as long as 7 days. Treatment with 10 mg enoxaparin once daily was discontinued prematurely after an interim analysis showed an increased deep venous thrombosis incidence in this treatment group.

    Measurements: Efficacy was determined by bilateral lower extremity venography, noninvasive vascular imaging methods, or clinical evidence on day 7 of treatment or earlier if clinically indicated.

    Results: Deep venous thrombosis occurred in 25% (40 of 161) of the patients who received 10 mg of enoxaparin once daily; in 14% (27 of 199) of those receiving 40 mg of enoxaparin once daily; and in 11% (22 of 208) in those receiving 30 mg of enoxaparin every 12 hours. The incidence of deep venous thrombosis was significantly higher in patients who received 10 mg of enoxaparin once daily compared with those who received 40 mg of enoxaparin once daily (P = 0.02) or those who received 30 mg of enoxaparin every 12 hours (P < 0.001). The difference between the patients who received 40 mg once daily and those who received 30 mg every 12 hours was not significant. Only two cases of pulmonary embolism were diagnosed, one in patients receiving 40 mg of enoxaparin and one in those receiving 10 mg once daily. The incidence of hemorrhagic complications differed significantly between patients who received 10 mg of enoxaparin once daily (5%, 8 of 161 patients) and those who received 30 mg of enoxaparin every 12 hours (13%, 26 of 208; P < 0.05).

    Conclusions: After surgery, enoxaparin, 40 mg once daily or 30 mg every 12 hours, is more effective than a regimen of 10 mg once daily to prevent deep venous thrombosis in patients having elective hip replacement surgery. The regimens of 40 mg once daily and 30 mg every 12 hours provided prophylaxis similar to the most effective drug treatments previously reported. The incidence of hemorrhagic episodes with the regimens of 40 mg once daily and 30 mg twice daily was higher than that observed with 10 mg once daily; however, major hemorrhage occurred in only 4% to 5% of patients receiving the higher-dose regimens. The risk-to-benefit ratio supports the use of enoxaparin as a therapeutic agent to prevent deep venous thrombosis in these patients.

    *For a list of investigators, see the Appendix

    Enoxaparin is a low-molecular-weight heparin with an average molecular weight of 4500 daltons that is obtained by controlled depolymerization of standard unfractionated porcine intestinal mucosal heparin (average molecular weight, 15 000 daltons) [1]. Enoxaparin and unfractionated heparin inhibit clotting indirectly by accelerating the formation of irreversible complexes between antithrombin III and several activated clotting factors, including factors IIa and Xa [2, 3]. Enoxaparin has several biological properties that differ from those observed in unfractionated heparin. In animal models, prevention of venous thrombosis by equipotent dosage regimens of enoxaparin or unfractionated heparin had equivalent antithrombotic activity. However, reduced hemorrhage was observed with enoxaparin [4, 5]. In in vitro studies, enoxaparin at concentrations with equivalent anti-factor Xa activity had four times less anti-factor IIa activity compared with unfractionated heparin [2, 3, 6]. Furthermore, in contrast to unfractionated heparin, enoxaparin had reduced interactions with platelets and plasma proteins in ex vivo experiments [7, 8]. Enoxaparin also has pharmacologic properties that are advantageous compared with unfractionated heparin. Administered intravenously, the half-life of enoxaparin was four times greater than that of unfractionated heparin (4.4 hours compared with 0.35 hours) [9, 10]. Its bioavailability after subcutaneous injection was more than 90% compared with 29% for unfractionated heparin [10]. These characteristics give enoxaparin potential clinical advantages, including a more predictable dose response and a reduced frequency of administration.

    Deep venous thrombosis and pulmonary embolism occur frequently in patients having total hip replacement surgery. Deep venous thrombosis has been observed in 40% to 70%, asymptomatic pulmonary embolism in as many as 25%, symptomatic pulmonary embolism in 4% to 19%, and fatal pulmonary embolism in as many as 6.7% of these patients [11-16]. Previous clinical trials showed that it was effective and safe for preventing deep venous thrombosis in patients having total hip replacement when administered after [17, 18] or before surgery [19]. A substantial risk reduction (71%) without an increase in hemorrhage was observed in the incidence of proximal and distal deep venous thrombosis in patients who had total hip replacement and were given 30 mg of enoxaparin subcutaneously after surgery every 12 hours for as long as 14 days, compared with patients who received placebo [17]. Although this study showed the efficacy of enoxaparin administered after surgery, it did not determine an optimum dose or satisfactorily define the drug's safety profile because only one enoxaparin dosing regimen was tested and too few patients were studied.

    Our dose-ranging study was done to compare the efficacy and safety of three postoperative enoxaparin dose regimens to prevent deep venous thrombosis in patients having total hip replacement surgery. It was designed to identify a clinically effective dose of enoxaparin with a minimal risk for hemorrhagic complications. We compared subcutaneous postoperative administration of 10 mg of enoxaparin once daily, 40 mg of enoxaparin once daily, and 30 mg of enoxaparin every 12 hours.

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    Methods

    Study Design

    This multicenter study was conducted as a randomized, double-blind, parallel-group clinical trial, with 32 institutions participating. The protocol and informed consent forms were approved by each center's institutional review board.

    Patients

    All patients gave written informed consent before entering the study. Men and women who were 31 years or older and were scheduled for hip replacement surgery, including primary and revision procedures, were eligible. Revision procedures included revision of the acetabular component, the femoral component, or both components.

    Noninvasive vascular examinations, including strain gauge or impedance plethysmography, Doppler sonography, and duplex or b-mode ultrasonography, were done within 14 days before surgery to provide baseline information and to exclude patients with identifiable deep venous thrombosis.

    Patients excluded from the study were women with child-bearing potential and patients who had ipsilateral hip surgery within 3 months. Other exclusion criteria included a history of deep venous thrombosis, pulmonary embolism, or both; heparin-associated thrombocytopenia; hemorrhagic disorders; allergy to heparin, protamine sulfate, or radiocontrast agents; eye, spinal cord, or nervous system surgery within 3 months; active ulcerative disease of the alimentary tract; uncontrolled hypertension; or use of nonsteroidal anti-inflammatory agents during the 4 days before surgery. Enrollment began in December 1988 and continued through September 1990.

    Dosing Schedule

    The efficacy and safety of three enoxaparin (Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, Pennsylvania) dose schedules were compared: 10 mg once daily, 40 mg once daily, and 30 mg every 12 hours. All doses of study medication were administered by subcutaneous injection. The first dose of study medication was administered within 24 hours after surgery, and the drug was continued for as long as 7 days.

    Evaluations and Scheduling

    The primary assessment for deep venous thrombosis was bilateral contrast venography performed on day 7 of treatment, earlier if clinically indicated, or on discharge from the hospital. Institutional physicians who were unaware of patient treatment assignment interpreted venograms and noninvasive vascular examinations. Additional assessments included daily clinical evaluations and noninvasive vascular examinations on treatment days 4 and 7 or as clinically indicated. Clinical evidence of venous thromboembolic disease was defined as documented treatment of clinically evident or symptomatic deep venous thrombosis or pulmonary embolism.

    Clinical Analysis

    The primary determinant of efficacy was the incidence of deep venous thrombosis as determined by venography, noninvasive vascular examinations, and clinical evidence. Clinical evidence included reported deep venous thrombosis or pulmonary embolism as an adverse event or the occurrence of symptoms and signs of venous thromboembolic diseases and associated therapy. The primary study conclusions for efficacy and safety outcomes were based on an analysis of all treated patients that included all patients who received at least one dose of study medication [20]. In addition, efficacy was analyzed for evaluable patients, those who received at least 75% of study medication, had adequate bilateral venography, and completed the study with no protocol violation.

    The primary determinants of safety were the incidence of major and minor hemorrhagic episodes, a decrease in hemoglobin of 20 g/L (2 g/dL) or more compared with the postoperative predose value, hemoglobin values less than 80 g/L (8 g/dL), clinically significant abnormal laboratory results, the number of transfusions required, and the occurrence of serious adverse events. Serious adverse events included death, life-threatening events, and events that resulted in prolonged hospitalization. A major hemorrhagic episode was overt hemorrhage associated with one or more of the following: death or a life-threatening clinical event; acute myocardial infarction or stroke; retroperitoneal or intracranial hemorrhage; postoperative transfusion of more than two units of packed red blood cells (excluding autologous blood); or a decrease of 20 g/dL or more in hemoglobin that was directly attributable to the overt hemorrhagic episode. A minor hemorrhagic episode was an overt hemorrhagic episode that did not meet criteria for classification as major.

    Interim Analysis

    Our study was changed from a three-arm to a two-arm trial on 11 May 1990 as a result of a blinded interim analysis conducted in March 1990. The analysis was done on 305 patients and resulted in the discontinuation of a treatment group identified only as “A” because of the high rate of treatment failure observed in that group. The study blinding was not broken when treatment group A was discontinued. Treatment group A was revealed to be the group receiving 10 mg of enoxaparin when the blinding was formally broken. Because of the smaller number of patients recruited into the group receiving 10 mg, the precision of the estimated incidence of deep venous thrombosis in that group was not as high as that for the other two treatment groups.

    Statistical Analysis

    The study population required was determined before initiation and assumed deep venous thrombosis rates of 25% in the group receiving 10 mg of enoxaparin once daily and 12.5% in groups receiving 40 mg once daily and 30 mg every 12 hours. Approximately 195 patients were required per treatment group to achieve 80% power when using a two-tailed test at a significance level of 0.05. Patients were assigned to treatment groups in a 1:1:1 ratio in blocks of six, using a computer-generated randomization schedule. A two-way logistic regression model, including factors for treatment group and center, was used to compare the treatment. Significance testing was done at the 0.025 level based on a Bonferroni correction for the two primary comparisons, 10 mg of enoxaparin once daily compared with 40 mg enoxaparin once daily and 30 mg every 12 hours, respectively [21]. The P values for these comparisons were multiplied by a factor of two to reflect the Bonferroni adjustment. Significance testing between the group receiving 30 mg of enoxaparin every 12 hours and that receiving 40 mg once daily was done at the 0.05 level of significance without Bonferroni adjustment. The incidence of treatment failure was summarized by treatment group in patient subpopulations defined by 1) demographic characteristics [age, sex, and race]; 2) type of surgery [primary or revision arthroplasty]; 3) type of anesthesia; or 4) use of acrylic bone cement and graduated compression stockings.

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    Results

    Patient Characteristics

    Five hundred seventy-two patients were randomized, and 568 patients received study medication (Table 1). The intent-to-treat analysis (that is, all treated patients) included 568 patients with clinical data. The patient demographic and surgical characteristics were similar in the three treatment groups (Table 2). All patients who received at least one dose of study medication were included in the efficacy and safety analyses. One hundred seventy-six treated patients did not meet all study requirements; the most common reason was inadequate bilateral venography. The incidence of protocol violations was essentially the same in all three treatment groups. Four hundred and eight patients (72%) were included in the evaluable-patient efficacy analysis. One hundred fifty-four patients did not have interpretable venograms and 6 did not receive sufficient therapy.

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    Table 1. Patient Disposition or Accountability with Study Medication
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    Table 2. Demographic and Surgical Characteristics for All Treated Patients

    Incidence of Deep Vein Thrombosis for All Treated Patients

    Eighty-nine of 568 patients (16%) had evidence of deep venous thrombosis (Tables 3 and 4). Evidence included definitive venography, supportive noninvasive vascular examinations, or other clinical evidence of treatment failure (1 patient in the group receiving 30 mg every 12 hours). The incidence of deep venous thrombosis was 25% among patients treated with 10 mg of enoxaparin once daily (40 of 161), 14% among patients treated with 40 mg once daily (27 of 199), and 11% among patients treated with 30 mg every 12 hours (22 of 208). A significantly higher incidence of deep venous thrombosis occurred in the patients receiving 10 mg of enoxaparin once daily compared with either those receiving 40 mg once daily (P = 0.02; odds ratio, 2.16; 95% CI, 1.21 to 4.1) or those receiving 30 mg every 12 hours (P < 0.001; odds ratio, 2.93; CI, 1.48 to 5.81). The incidence of deep venous thrombosis in the patients receiving 30 mg of enoxaparin every 12 hours was not significantly lower than that observed in those receiving 40 mg of enoxaparin once daily (P > 0.2; odds ratio, 1.36; CI, 0.73 to 2.53). Among all treated patients with available efficacy data, the distribution of deep venous thrombosis by proximal and distal sites was similar within each group. The incidence of proximal deep venous thrombosis for all treated patients was higher in the patients receiving 10 mg of enoxaparin once daily—11% compared with 5% for patients receiving 40 mg of enoxaparin once daily and 4% for those receiving 30 mg of enoxaparin twice daily.

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    Table 3. Incidence of Treatment Failure (Deep Venous Thrombosis)*
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    Table 4. Between-Group Comparison of the Incidence of Treatment Failures (Deep Venous Thrombosis)

    Incidence of Deep Venous Thrombosis in Evaluable Patients

    Seventy-three of 408 patients (18%) had venographically confirmed deep venous thrombosis (Tables 3 and 4). The incidence of deep venous thrombosis among patients treated with enoxaparin was 31% (36 of 161) in the patients receiving 10 mg once daily, 14% (21 of 149) in those receiving 40 mg once daily, and 11% (16 of 143) in those receiving 30 mg every 12 hours. The incidence of deep venous thrombosis was significantly higher among patients treated with 10 mg of enoxaparin once daily than among those treated with 40 mg once daily (P = 0.005; odds ratio, 2.74; CI, 1.29 to 5.82) or 30 mg every 12 hours (P < 0.001; odds ratio, 3.57; CI, 1.60 to 7.98). The difference between the incidence of deep venous thrombosis in those receiving 40 mg of enoxaparin once daily and in those receiving 30 mg every 12 hours was not significant (P > 0.2; odds ratio, 1.30; CI, 0.63 to 2.70). The incidence of proximal deep venous thrombosis for evaluable patients in the patients receiving 10 mg of enoxaparin once daily was higher than that observed in either those receiving 40 mg of enoxaparin once daily or those receiving 30 mg of enoxaparin every 12 hours (14% compared with 6% and 6%, respectively).

    The overall incidence of deep venous thrombosis was analyzed for demographic, surgical, and clinical characteristics, including sex, age, race, type of surgery or anesthesia, use of surgical cement, and use of graduated compression stockings. For each of these characteristics, the incidence of deep venous thrombosis in the group receiving 10 mg of enoxaparin once daily was higher than that observed in the groups receiving 40 mg once daily or 30 mg every 12 hours. No demographic variables (age or sex) were observed to affect the overall comparison of efficacy for evaluable patients treated with enoxaparin. Similarly, the type of surgery did not affect the incidence of deep venous thrombosis: 18% (59 of 335) in patients having primary procedures and 19% (14 of 73) in patients having revision procedures. The incidence of deep venous thrombosis in patients receiving epidural or spinal anesthesia was 20% (25 of 128) compared with 17% (48 of 280) in patients receiving general anesthesia. The incidence of deep venous thrombosis in patients with cemented prostheses was 22% (40 of 186) compared with 15% (33 of 221) in patients with noncemented prosthesis, a nonsignificant difference. However, graduated compression stockings conferred benefit, a 12% (28 of 234) incidence of deep venous thrombosis with graduated compression stockings and a 26% (45 of 174) incidence without stockings. Only this latter clinical characteristic achieved statistical significance (P < 0.001).

    Site of Deep Venous Thrombosis

    In all treatment groups, most patients who did not benefit from treatment had deep venous thrombosis located in the operative limb. Of the 73 evaluable patients with deep venous thrombosis, thrombi were identified in the operated limb in 48 patients, in the nonoperated limb in 9 patients, and in both limbs in 16 patients. The distribution was similar in all three treatment groups.

    Hemorrhagic Complications

    Among all treated patients, 55 of 568 patients (10%) had major or minor hemorrhagic episodes during the study (Table 5). The overall incidence of hemorrhagic episodes in the enoxaparin group receiving 10 mg once daily (5%; 8 of 161 patients) was significantly lower than the incidence observed in the enoxaparin group receiving 30 mg every 12 hours (13%; 26 of 208; P < 0.05). The incidence of hemorrhagic episodes was similar in the group receiving 40 mg of enoxaparin once daily (11%; 21 of 199) and the group receiving 30 mg every 12 hours (13%; 26 of 208).

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    Table 5. Comparison of Major and Minor Hemorrhagic Episodes

    The overall incidence of major hemorrhage (4%; 21 of 568 patients) was low in all three treatment groups. The incidence of major hemorrhage was 2% (3 of 161) in the group receiving 10 mg of enoxaparin once daily, 4% (7 of 199) in the group receiving 40 mg once daily, and 5% (11 of 208) in the group receiving 30 mg every 12 hours.

    Most major hemorrhagic episodes occurred at the operative site in all three treatment groups. The overall incidence of major hemorrhage at the operative site was 2% (13 of 568 patients). The incidence of major episodes of hemorrhage at the operative site was lower in the group receiving 10 mg of enoxaparin once daily (< 1%) than in either the group receiving 40 mg once daily (2%) or the group receiving 30 mg every 12 hours (4%). Seven of these patients had primary total hip replacement and 6 had revision total hip replacement. None of these patients had a primary diagnosis of rheumatoid arthritis. Eight episodes (1%) of major hemorrhage at nonoperative sites were observed. The onset of a major episode of hemorrhage occurred either on the day of surgery or by postoperative day 3 for most patients (18 of 21), by postoperative day 7 for another patient, and by follow-up for the two others. The median day of onset of major hemorrhagic episodes was postoperative day 4 for all three treatment groups.

    Twenty-seven percent of all treated patients (151 of 568) received at least one blood transfusion exclusive of intraoperative or recovery room transfusion through the end of study. The mean number of nonautologous units received overall by patients who had transfusions after surgery was 2.5 units (range, 1 to 13 units). The percentage of patients who received more than two units of nonautologous blood after surgery was 9% overall and was lower in the group receiving 10 mg of enoxaparin once daily (4%; 7 of 161) than in the groups receiving 40 mg once daily (13%; 25 of 199) and 30 mg every 12 hours (8%; 17 of 208). For patients who received transfusions, there was no difference between treatment groups for the mean number of units of nonautologous blood transfused after surgery.

    Abnormal Laboratory Results

    Abnormal laboratory values of possible clinical significance were observed in all three treatment groups for platelet count, hemoglobin concentration, and alanine aminotransferase level (Table 6).

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    Table 6. Clinically Significant Values for Selected Laboratory Variables

    The overall incidence of mild thrombocytopenia (> 100 × 109/L [100 000/microns3] and less than the lower limit of normal) was 12% (68 of 568) with incidences of 11% (17 of 161), 12% (23 of 199), and 13% (28 of 208) in the enoxaparin groups receiving 10 mg once daily, 40 mg once daily, and 30 mg every 12 hours, respectively. Only 4 of 568 enoxaparin-treated patients (< 1%) had moderate thrombocytopenia (between 20 and 100 × 109/L [20 000 to 100 000/microns3]) and in no case was the platelet count less than 50 × 109/L (50 000/microns3). Heparin-associated thrombocytopenia with thrombosis was reported in one patient, in association with subcutaneous unfractionated heparin therapy given for acute distal deep venous thrombosis that was diagnosed after the patient had completed treatment with 40 mg of enoxaparin once daily without a decreased platelet count. This patient tested positive for heparin-dependent antiplatelet antibody by serotonin-release assay.

    Thrombocytosis was observed in 92% (522 of 568) of patients, and 1% (5 of 568) had severe thrombocytosis (≥ 1000 × 109/L [1 000 000/microns3]). The incidence of thrombocytosis was similar in the three treatment groups.

    Twenty-eight percent (157 of 568) of patients experienced a decrease of 2 g/dL or greater in hemoglobin after surgery. In addition, 13% (72 of 568) of all patients had postoperative hemoglobin values during the study less than 80 g/L (8 g/dL). The proportion of patients with postoperative hemoglobin decreases of 20 g/L (2 g/dL) or more in the group receiving 30 mg of enoxaparin every 12 hours was greater than the proportion of patients with similar hemoglobin decreases in the group receiving 10 mg of enoxaparin once daily (P = 0.02). The proportion of patients with hemoglobin decreases of 20 g/L (2 g/dL) or more was similar in the group receiving 40 mg of enoxaparin once daily and the group receiving 10 mg once daily.

    Clinically significant increases in alanine aminotransferase, defined as increases greater than three times more than the upper limit of the normal reference range, were observed in 5% (29 of 568) of patients. The incidence of a clinically significant increase was 2% (4 of 161) in patients receiving 10 mg of enoxaparin once daily, 7% (13 of 199) in those receiving 40 mg once daily, and 6% (12 of 208) in those receiving 30 mg every 12 hours.

    Clinical Outcomes

    Two patient deaths, one postoperative myocardial infarction and one myocardial infarction that was attributed to a probable gastrointestinal hemorrhage in a patient with substantial coronary insufficiency and gastrointestinal angiodysplasia, were reported in the group receiving 40 mg of enoxaparin once daily; no patient deaths were reported in those receiving 10 mg once daily or 30 mg every 12 hours. In addition to the two patients who died, 39 were classified as having serious adverse events. These occurred in 8% (13 of 161, one related to study drug) of patients receiving 10 mg of enoxaparin once daily, in 8% (16 of 199, two related to study drug) of those receiving 40 mg once daily, and in 5% (10 of 208, one related to study drug) of patients receiving 30 mg every 12 hours. Pulmonary embolism developed subsequent to the establishment of a diagnosis of deep venous thrombosis at the end of study in two patients, one each receiving 10 mg of enoxaparin once daily and 40 mg once daily. Six patients (two in each treatment group) were rehospitalized to treat acute venous thromboembolism. Two of these patients had pulmonary embolism and the remaining four had deep venous thrombosis. No occurrences of pulmonary embolism were reported in patients receiving 30 mg of enoxaparin every 12 hours either during hospitalization or at follow-up. No sudden deaths were reported after discharge.

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    Discussion

    Enoxaparin is a low-molecular-weight heparin that has been evaluated in several previous total hip replacement surgery clinical trials [17-26]. In four of five randomized trials, enoxaparin-treated patients had a significantly lower incidence of deep venous thrombosis than did control participants receiving placebo, unfractionated heparin, or dextran without a significant increase in the risk for hemorrhage [17-19, 24, 25]. Enoxaparin has been compared directly with a standard three-times-daily heparin regimen in two controlled clinical trials [18, 19]. Enoxaparin was substantially more effective than heparin in preventing deep venous thrombosis, with no increase in the risk for hemorrhage. Deep venous thrombosis developed in 5% of enoxaparin-treated patients given 30 mg twice daily after surgery compared with 12% in patients receiving unfractionated heparin [18]. Deep venous thrombosis developed in 12% of patients given enoxaparin before surgery as a 40-mg once-daily regimen, compared with 25% in patients receiving unfractionated heparin [19]. In addition, enoxaparin has been reported to provide effective prophylaxis for deep venous thrombosis in patients having total knee arthroplasty; moderate- and high-risk abdominal, urologic, and pelvic surgery; and surgery for cancer [1, 27]. Despite the considerable experience gained through previous trials, important questions regarding the optimal dose and schedule of administration and the safety and efficacy of enoxaparin remained unanswered. Therefore, a randomized, multicenter clinical trial was initiated to evaluate three dose regimens of enoxaparin to prevent deep venous thrombosis in patients having total hip replacement surgery.

    The current study was done primarily to define further the dose-response relation for enoxaparin administered after surgery. Previous randomized clinical trials of enoxaparin evaluated subcutaneous doses of 30 mg every 12 hours initiated after surgery [17, 24], 40 mg once daily initiated before surgery [19, 25, 26], or 20 mg every 12 hours initiated before surgery [26]. A nonrandomized, dose-ranging study [28] compared four dose schedules: 60 mg once daily, 30 mg every 12 hours, 40 mg once daily, and 20 mg every 12 hours. All treatments were begun 12 hours before surgery. The incidence of deep venous thrombosis was similar (6% to 8%) in patients treated with each of the four regimens in the nonrandomized trial, but hemorrhage occurred more frequently in patients treated with 60 mg once daily or 30 mg every 12 hours. Deep venous thrombosis was observed in 1.7% to 19.4% of patients treated with enoxaparin in the randomized trials compared with 21.6% to 42% in control patients who received placebo, unfractionated heparin, or dextran [17, 19, 24-26]. Deep venous thrombosis was observed in 1.7% of patients treated with 20 mg of enoxaparin every 12 hours [26]; in 6.5%, 10.5%, and 12.5% of patients treated with 40 mg once daily [17, 25, 26]; and in 12% and 19.4% of patients treated with 30 mg every 12 hours [17, 24]. The incidence of proximal deep venous thrombosis (1.7% to 7.5%) was similar in patients treated with these dosing regimens. The efficacy of a single daily dose of enoxaparin was reported in one study to be similar to that of twice-daily administration [26]. However, this conclusion was not entirely justified because the incidence of deep venous thrombosis in the group treated with 20 mg every 12 hours was 1.7% (1 of 57) compared with 10.5% (6 of 57) in the group treated with 40 mg once daily. This difference was not statistically significant, but it suggested a trend favoring the twice-daily schedule.

    Several results of the current clinical trial are worthy of comment. First, the incidence of deep venous thrombosis was substantially greater in the patients treated with 10 mg of enoxaparin once daily than in patients treated with either 40 mg once daily or 30 mg every 12 hours. Although reduced efficacy was considered probable, the magnitude of the difference for those who had adequate bilateral venography (31% compared with 14% compared with 11%) suggested that the 10-mg once-daily dose was more effective than placebo [17]. This dose was associated with significantly less hemorrhage than the dose of 30 mg every 12 hours; however, it was clearly an inadequate dose for optimal deep venous thrombosis prophylaxis. The ineffectiveness of the 10-mg once-daily dose caused the premature closure of this arm of the study. In contrast, the higher of the two effective enoxaparin doses (30 mg every 12 hours) was not shown clearly to be superior to the lower effective dose (40 mg once daily), despite the fact that the incidence of deep venous thrombosis documented by venography was lower in patients treated with 30 mg of enoxaparin every 12 hours than in patients treated with 40 mg of enoxaparin once daily. It is premature to conclude that these two doses of enoxaparin are equally efficacious because an analysis of another study (conducted simultaneously) of enoxaparin compared with unfractionated heparin indicated that the dose of 30 mg every 12 hours was considerably superior to the 40-mg once-daily dose in regard to deep venous thrombosis prophylaxis [18]. The recommended dosage chosen for the hip replacement surgery prevention of deep venous thrombosis indication in the United States—30 mg administered subcutaneously every 12 hours, with the first dose of medication given within 24 hours after surgery—was based on the results of this study [18], the present study, and the results of a previously reported placebo-controlled trial [17].

    The distribution of thrombi between the proximal and distal veins of the lower extremity was similar for all three enoxaparin treatment groups. Approximately one half of the thrombi were proximal and therefore of greater clinical significance. The incidence of proximal thrombi observed is consistent with that in previous reports [17-19, 24-26, 29, 30] and reflects the selective proximal venous injury that occurs during elective hip replacement surgery [29]. The absolute incidence of proximal thrombi was lowest in the group receiving 30 mg of enoxaparin every 12 hours. Thrombi occurred predominantly (88%; 64 of 73) in the operative extremity.

    The incidence of hemorrhagic episodes in the group receiving 10 mg of enoxaparin once daily was substantially lower than that observed in the group receiving 30 mg every 12 hours group. The incidence of decreases in hemoglobin of 20 g/L (2 g/dL) or more and the occurrence of hemoglobin values less than 80 g/L (8 g/dL) were slightly lower in the group receiving 10 mg of enoxaparin once daily compared with that observed in either of the other two enoxaparin treatment groups. Although these differences in hemoglobin decreases and major hemorrhagic episodes were not significant, their trend is consistent with a dose-dependent hemorrhagic risk. An increased rate for hemorrhage in patients treated with clinically efficacious doses of low-molecular-weight heparins is not unexpected and was observed in the meta-analysis of trials of low-molecular-weight heparin compared with placebo in patients having general surgery. However, in those having orthopedic surgery, no difference in the incidence of hemorrhagic episodes was observed [22]. The results observed in the present study differed from those observed in a placebo-controlled trial in which enoxaparin and placebo recipients had a similar incidence of hemorrhage (4%) [17]. The small patient population involved in the latter study precluded any firm conclusions from being drawn from those findings. In one of two heparin-controlled trials, the group receiving 5000 units of heparin every 8 hours and the group receiving 30 mg of enoxaparin every 12 hours had a similar incidence of hemorrhagic complications (12%). In the second trial, the patients receiving 7500 units of heparin every 12 hours had a 9% incidence of hemorrhagic complications, which was significantly greater than the incidence of 5% in the group receiving 30 mg of enoxaparin every 12 hours (P = 0.04) [24]. In the former trial, the incidence of deep venous thrombosis was substantially decreased in the enoxaparin group (5%) compared with the heparin group (12%) [18]. The latter trial showed that although similar efficacy to enoxaparin was achieved by changing the heparin regimen to 7500 units twice daily, a substantial increase in hemorrhagic complications occurred [24].

    Moderate thrombocytopenia occurred in only 4 of 568 patients (fewer than 1%), which appears to be lower than the incidence of moderate thrombocytopenia in patients treated with unfractionated heparin [31, 32]. However, it is not known whether low-molecular-weight heparins are less likely than unfractionated heparin to cause thrombocytopenia [33]. In two enoxaparin-treated patients, the thrombocytopenia resolved while they received study medication. Enoxaparin therapy was discontinued in only two patients because of the thrombocytopenia. Heparin-associated thrombocytopenia with thrombosis [34] developed in one patient in association with the subcutaneous administration of unfractionated heparin after enoxaparin was discontinued.

    Increases in aminotransferase levels have been reported in as many as 60% of patients treated with unfractionated heparin of bovine or porcine origin [35, 36]. Such increases are reversible and are not associated with clinical symptoms. In the present study, threefold or greater increases in alanine aminotransferase levels occurred in 5% of patients overall and least frequently in the patients receiving 10 mg of enoxaparin once daily. The relation of individual occurrences of increased aminotransferase activity to study medication is uncertain because of recent extensive surgery; transfusion of salvage, autologous, and homologous blood products; and the concomitant administration of multiple medications.

    Thrombocytosis occurred in more than 522 (92%) of patients enrolled in this study. No differences in the incidence of mild, moderate, and severe thrombocytosis were observed among treatment groups. Platelet counts greater than 1000 × 109/L developed in five patients at follow-up. Thrombocytosis has been observed in other patients after surgery and occurs commonly after orthopedic procedures [37-39]. In such patients, peak platelet counts are reported to occur from 9 to 22 days (mean, 14 days) after surgery and to persist for 17 to 35 days (mean, 26 days) [38]. This type of reactive thrombocytosis is not considered to be associated with increased risk for venous thromboembolic complications [40].

    The overall incidence of clinically symptomatic post-discharge venous thromboembolic complications requiring rehospitalization was 1%. Because radiocontrast media-induced phlebitis is reported to occur in as many as 50% of patients assessed by Iodine-125-fibrinogen leg scans, some of these cases could represent this complication of venography [41-44]. However, post-discharge venous thromboembolic episodes related to the surgical procedure itself also occur with a reported incidence of as many as 25% when assessed by Iodine-125-fibrinogen leg scans and as many as 10% when assessed by ultrasonography [45, 46]. Such events also may account for some of the events observed.

    The results of this study indicate that enoxaparin is an effective agent to prevent deep venous thrombosis in patients having elective hip replacement surgery. Administered after surgery of 30 mg of enoxaparin every 12 hours or 40 mg once daily substantially reduces the incidence of deep venous thrombosis compared with an ineffective dose (10 mg given once daily). The incidence of hemorrhagic episodes with both the regimens of 40 mg once daily and 30 mg every 12 hours was higher than that observed with the 10-mg once-daily regimen; however, major hemorrhage occurred in only 4% to 5% of patients receiving the higher-dose regimens. The risk-to-benefit ratio supports the use of enoxaparin as a therapeutic agent to prevent deep venous thrombosis in these patients.

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    Appendix

    The following investigators and their associates participated in this study. Carlton G. Savory, MD, Hughston Sports Medicine Clinic, Columbus, Georgia; W. Kim Furman, MD, Sarasota Memorial Hospital, Sarasota, Florida; Justus J. Fiechtner, MD, Dakota Clinic, Fargo, North Dakota; Glyndon B. Shaver, MD, Asheville Veterans Affairs Medical Center, Asheville, North Carolina; Jack Ansell, MD, University of Massachusetts Medical School, Worcester, Massachusetts; William L. Overdyke, MD, Highland Clinic, Shreveport, Louisiana; Thomas Siesholtz, MD, Grand View Hospital, Sellersville, Pennsylvania; Robert Rodvien, MD, Pacific Presbyterian Hospital, San Francisco, California; Michael Christie, MD, Vanderbilt University Hospital, Nashville, Tennessee; Franklin G. Ebaugh, Jr., MD, Veterans Affairs Medical Center, Palo Alto, California; Richard E. White, Jr., MD, Presbyterian Hospital, Albuquerque, New Mexico; James R. Roberson, MD, Emory University School of Medicine, Atlanta, Georgia; Merrill Ritter, MD, Kendrick Memorial Hospital, Mooresville, Indiana; Michael E. Rader, MD, Nyack Hospital, Nyack, New York; David Fisher, MD, Methodist Hospital of Indiana, Inc., Indianapolis, Indiana; Curtiss M. Mull, MD, Lewis-Gale Clinic, Inc., Salem, Virginia; Robert Weinstein, MD, St. Elizabeth's Hospital, Boston, Massachusetts; Louis R. Jordan, MD, Sentera Leigh Memorial Hospital, Norfolk, Virginia; David Bessman, MD, University of Texas Medical Branch, Galveston, Texas; Ethan A. Natelson, MD, St. Joseph Hospital, Houston, Texas; Thomas Winters, MD, Orlando Regional Medical Center, Orlando, Florida; Leonard Stutman, MD, St. Vincent's Hospital and Medical Center, New York, New York; Sam T. Barnes, MD, Cookeville General Hospital, Cookeville, Tennessee; Victor H. Frankel, MD, Hospital for Joint Diseases Orthopedic Institute, New York, New York; Frederick M. Perkins, MD, University of Vermont, Clinical Research Center, Burlington, Vermont; William J. Maloney, MD, Stanford University Hospital, Stanford, California; and Robert Bona, MD, St. Francis Hospital and Medical Center, Hartford, Connecticut.

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    References

    1. 1.↵
      Buckley M, Sorkin EM. Enoxaparin: a review of its pharmacology and clinical application in the prevention and treatment of thromboembolic disorders. Drugs. 1992; 44:465-9.
    2. 2.↵
      Aiach M, Michaud A, Balian JL, Lefevre M, Woler M, Fourtillan J. A new low molecular weight heparin derivative: In vitro and in vivo studies. Thromb Res. 1983; 31:611-21.
    3. 3.↵
      Lindahl U, Backstrom G, Hook M, Thunberg L, Fransson L-A, Linker A. Structure of the antithrombin binding site of heparin. Proc Natl Acad Sci U S A. 1979; 76:3198-3202.
    4. 4.↵
      Cade JF, Buchanan MR, Boneu B, Ockelford P, Carter CJ, Cerskus AR, et al. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions. The influence of the method of preparation. Thromb Res. 1984; 35:613-25.
    5. 5.↵
      Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the haemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood. 1982; 59:1239-45.
    6. 6.↵
      Walenga JM, Fareed J, Hoppensteadt D. In vitro coagulant and amidolytic methods for evaluating the activity of heparin and a low molecular eight heparin derivative (PK-10169). Semin Thromb Haemostas. 1985; 11:17-25.
    7. 7.↵
      Brace LD, Fareed J, Tomeo J, Issleib S. Biochemical and pharmacological studies on the interaction of PK-10169 and its subfractions with human platelets. Haemostasis. 1986; 16:93-105.
    8. 8.↵
      Padilla A, Grey E, Pepper DS, Barrowcliffe TW. Inhibition of thrombin generation by heparin and low molecular weight heparin (LMW) heparins in the absence and presence of platelet factor 4 (PF4). Br J Hematol. 1992; 82:406-13.
    9. 9.↵
      Vinazzer H, Woler M. A new low molecular weight heparin fragment (PK-10169): in vitro and in vivo studies. Haemostasis. 1986; 16:106-15.
    10. 10.↵
      Dawes J, Bara L, Billaud E, Samama M. Relationship between biological activity and concentration of a low-molecular-weight-heparin (PK-10169) and unfractionated heparin after intravenous and subcutaneous administration. Haemostasis. 1986; 16:116-22.
    11. 11.↵
      Haake DA, Berkman SA. Venous thromboembolic disease after hip surgery. Risk factors, prophylaxis, and diagnosis. Clin Orthop. 1989; 242:212-31.
    12. 12.↵
      Harris WH, Salzman EW, Athanasoulis CA, Waltman AC, Desanctis RW. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med. 1977; 297:1246-9.
    13. 13.↵
      Harris WH, McKusick K, Athansoulis CA, Waltman AC, Strauss HW. Detection of pulmonary emboli after total hip replacement using serial (15C)O2 pulmonary scans. J Bone Joint Surg. 1984; 66-A:1388-93.
    14. 14.↵
      Johnson R, Green JR, Charnley J. Pulmonary embolism and its prophylaxis following the Charnley total hip replacement. Clin Orthop. 1977; 127:123-32.
    15. 15.↵
      Coventry MB, Nolan DR, Beckenbaugh RD. “Delayed” prophylactic anticoagulation: a study of results and complications in 2,012 total hip arthroplasties. J Bone Joint Surg. 1973; 55-A:1487-92.
    16. 16.↵
      Harris WH, Salzman EW, Athanasoulis C, Waltman AC, Desanctis RW. Comparison of warfarin, low-molecular-weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement. J Bone Joint Surg. 1974; 56-A:1552-62.
    17. 17.↵
      Turpie AG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, et al. A randomized, controlled trial of a low molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med. 1986; 315:925-9.
    18. 18.↵
      Spiro TE, Colwell CW, Trowbridge AA for the Enoxaparin Clinical Trial Group. A clinical trial comparing the efficacy and safety of enoxaparin, a low molecular weight heparin and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement surgery (Abstract). Blood. 1992; 80(Suppl 1):167.
    19. 19.↵
      Planes A, Vochelle N, Mazas F, Mansat C, Zucman J, Landais A, et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemostas. 1988; 60:407-10.
    20. 20.↵
      Gillings D, Koch G. The application of the principle of intention to treat to the analysis of clinical trials. Drug Infect J. 1991; 25:411-24.
    21. 21.↵
      Lentner M, Bishop T. Experimental Design and Analysis, First Edition. Breacksbury, VA: Valley Book Company; 1986:124.
    22. 22.↵
      Leizorowicz A, Haugh MC, Chapuis FR, Samama M, Boisel JP. Low molecular weight heparin in the prevention of perioperative thrombosis. BMJ. 1992; 305:913-20.
    23. 23.↵
      Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP, et al. Low molecular weight heparin versus standard heparin in general and orthopedic surgery: a meta-analysis. Lancet. 1992; 340:152-6.
    24. 24.↵
      Levine MN, Hirsh J, Gent M, Turpie AG, Leclerc J, Powers PJ, et al. Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med. 1991; 114:545-51.
    25. 25.↵
      The Danish Enoxaparin Group. Low-molecular-weight heparin (enoxaparin) vs. dextran 70: the prevention of postoperative deep vein thrombosis after total hip replacement. Arch Intern Med. 1991; 151:1621-4.
    26. 26.↵
      Planes A, Vochelle N, Bouthier J, Fagola M, Bellaud M. Use of enoxaparin, a low molecular weight heparin in elective hip surgery. Semin Thromb Haemostas. 1991; 17(Suppl 3):296-302.
    27. 27.↵
      Carter CA, Skoutakis VA, Spiro TE, West ME, Tooms RE, Joe RH, et al. Enoxaparin: the low molecular weight heparin for prevention of postoperative thromboembolic complications. Ann Pharmacother. 1993; 27:1223-30.
    28. 28.↵
      Planes A, Vochelle N, Ferru J, Przyrowski D, Clerc J, Fagola M, et al. Enoxaparine low molecular weight heparin: its use in the prevention of deep venous thrombosis following total hip replacement. Haemostasis. 1986; 16:152-8.
    29. 29.↵
      Stamatakis JD, Kakkar VV, Sagar S. Femoral vein thrombosis and total hip replacement. BMJ. 1977; 2:223-5.
    30. 30.↵
      Cruikshank MK, Levine MN, Hirsh J, Turpie AG, Powers P, Jay R, et al. An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemostas. 1989; 62:830-4.
    31. 31.↵
      Bell WR, Tomasulo PA, Alving BM, Duffy TP. Thrombocytopenia occurring during the administration of heparin. Ann Intern Med. 1976; 85:155-60.
    32. 32.↵
      Cola C, Ansell J. Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J. 1990; 119:368-74.
    33. 33.↵
      Lecompte T, Luo SK, Stieltjes N, Lecrubier C, Samama MM. Thrombocytopenia associated with low-molecular-weight heparin. Lancet. 1991; 338:1217.
    34. 34.↵
      Aburahma AF, Boland JP, Witsberger T. Diagnostic and therapeutic strategies of white clot syndromes. Am J Surg. 1991; 162:175-9.
    35. 35.↵
      Dukes GE, Sanders SW, Russo J, Swenson E, Burnakis TG, Saffle JR, et al. Transaminase elevation in patients receiving bovine or porcine heparin. Ann Intern Med. 1984; 100:646-50.
    36. 36.↵
      Sonnenblick M, Oren A, Jacobsohn W. Hyper-transaminasemia with heparin therapy. BMJ. 1975; 3:77.
    37. 37.↵
      Pepper H, Lindsay S. Responses of platelets, eosinophils and total leucocytes during and following surgical procedures. Surg Gynecol Obstet. 1960; 110:319-26.
    38. 38.↵
      Bunting RW, Doppelt SH, Lavine LS. Extreme thrombocytosis after orthopedic surgery. J. Bone Joint Surg. 1991; 73-B:687-8.
    39. 39.↵
      Breslow A, Kaufman RM, Lawsky AR. The effect of surgery on the concentration of circulating megakaryocytes and platelets. Blood. 1968; 32:393-401.
    40. 40.↵
      Buss DH, Stuart JJ, Lipscomb GE. The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: an analysis of 129 cases. Am J Hematol. 1985; 20:365-72.
    41. 41.↵
      Albrechtsson U, Olsson CG. Thrombotic side effects of lower-limb phlebography. Lancet. 1976; 1:723-4.
    42. 42.↵
      Bettman MA, Robbins A, Braun SD, Wetzner S, Dunnick NR, Finkelstein J. Contrast venography of the leg: diagnostic efficacy, tolerance and complication rates with ionic and nonionic contrast media. Radiology. 1987; 165:113-6.
    43. 43.↵
      Kristiansen P, Bergentz SE, Bergquist D, Nylander G. Thrombosis after elective phlebography as demonstrated by the 125I fibrinogen test. Acta Radiol (Diagn) (Stockh). 1981; 22:577-80.
    44. 44.↵
      Laerum F, Holm HA. Postphlebographic thrombosis. Radiology. 1981; 140:651-4.
    45. 45.↵
      Scurr JH, Coleridge-Smith PD, Hasty JH. Deep venous thrombosis: a continuing problem. BMJ. 1988; 297:28.
    46. 46.↵
      Trowbridge AA, Boese CK, Woodruff B, Brindley HH, Lowry WE, Spiro TE. Incidence of post-hospitalization proximal deep venous thrombosis following total hip replacement: a pilot study. Clin Orthop. 1994; 299:203-8.
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