William Geerts

Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty

BACKGROUND This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. METHODS In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. RESULTS A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). CONCLUSIONS A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.)

A COMPARISON OF LOW-MOLECULAR-WEIGHT HEPARIN ADMINISTERED PRIMARILY AT HOME WITH UNFRACTIONATED HEPARIN ADMINISTERED IN THE HOSPITAL FOR PROXIMAL DEEP-VEIN THROMBOSIS

BACKGROUND Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches. METHODS Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day. RESULTS Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all. CONCLUSIONS Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

A prospective study of venous thromboembolism after major trauma.

BACKGROUND Although deep-vein thrombosis and pulmonary embolism are considered common complications after major trauma, their frequency and the associated risk factors have not been carefully quantified. METHODS We performed serial impedance plethysmography and lower-extremity contrast venography to detect deep-vein thrombosis in a cohort of 716 patients admitted to a regional trauma unit. Prophylaxis against thromboembolism was not used. RESULTS Deep-vein thrombosis in the lower extremities was found in 201 of the 349 patients (58 percent) with adequate venographic studies, and proximal-vein thrombosis was found in 63 (18 percent). Three patients died of massive pulmonary embolism before venography could be performed. Before venography, only three of the patients with deep-vein thrombosis had clinical features suggestive of the condition. Deep-vein thrombosis was found in 65 of the 129 patients with major injuries involving the face, chest, or abdomen (50 percent); in 49 of the 91 patients with major head injuries (53.8 percent); in 41 of the 66 with spinal injuries (62 percent); and in 126 of the 182 with lower-extremity orthopedic injuries (69 percent). Thrombi were detected in 61 of the 100 patients with pelvic fractures (61 percent), in 59 of the 74 with femoral fractures (80 percent), and in 66 of the 86 with tibial fractures (77 percent). A multivariate analysis identified five independent risk factors for deep-vein thrombosis: older age (odds ratio, 1.05 per year of age; 95 percent confidence interval, 1.03 to 1.06), blood transfusion (odds ratio, 1.74; 95 percent confidence interval, 1.03 to 2.93), surgery (odds ratio, 2.30; 95 percent confidence interval, 1.08 to 4.89), fracture of the femur or tibia (odds ratio, 4.82; 95 percent confidence interval, 2.79 to 8.33), and spinal cord injury (odds ratio, 8.59; 95 percent confidence interval, 2.92 to 25.28). CONCLUSIONS Venous thromboembolism is a common complication in patients with major trauma, and effective, safe prophylactic regimens are needed.

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

A Comparison of Low-Dose Heparin with Low-Molecular-Weight Heparin as Prophylaxis against Venous Thromboembolism after Major Trauma

BACKGROUND Patients who have had major trauma are at very high risk for venous thromboembolism if they do not receive thromboprophylaxis. We compared low-dose heparin and a low-molecular-weight heparin with regard to efficacy and safety in a randomized clinical trial in patients with trauma. METHODS Consecutive adult patients admitted to a trauma center who had Injury Severity Scores of at least 9 and no intracranial bleeding were randomly assigned to heparin (5000 units) or enoxaprin (30 mg), each given subcutaneously every 12 hours in a double-blind manner, beginning within 36 hours after the injury. The primary outcome was deep-vein thrombosis as assessed by contrast venography performed on or before day 14 after randomization. RESULTS Among 344 randomized patients, 136 who received low-dose heparin and 129 who received enoxaparin had venograms adequate for analysis. Sixty patients given heparin (44 percent) and 40 patients given enoxaparin (31 percent) had deep-vein thrombosis (P=0.014). The rates of proximal-vein thrombosis were 15 percent and 6 percent, respectively (P=0.012). The reductions in risk with enoxaparin as compared with heparin were 30 percent (95 percent confidence interval, 4 to 50 percent) for all deep-vein thrombosis and 58 percent (95 percent confidence interval, 12 to 87 percent) for proximal-vein thrombosis. Only six patients (1.7 percent) had major bleeding (one in the heparin group and five in the enoxaparin group, P=0.12). CONCLUSIONS Low-molecular-weight heparin was more effective than low-dose heparin in preventing venous thromboembolism after major trauma. Both interventions were safe.

Safety of Withholding Heparin in Pregnant Women with a History of Venous Thromboembolism

BACKGROUND Women with a history of venous thromboembolism may be at increased risk for venous thromboembolic events during pregnancy. In these women, the decision to give or withhold heparin in the antepartum period is controversial, because accurate estimates of the frequency of recurrent thromboembolic events if antepartum heparin is withheld are not available. METHODS We prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. Our primary objective was to determine the rate of antepartum recurrence of venous thromboembolism. Laboratory studies were performed to identify thrombophilia in 95 women. RESULTS Three of the 125 women (2.4 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 0.2 to 6.9 percent). There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 1.2 to 16.2 percent). CONCLUSIONS The risk of recurrent antepartum venous thromboembolism in women with a history of venous thromboembolism is low, and therefore routine antepartum prophylaxis with heparin is not warranted.

Dalteparin versus unfractionated heparin in critically ill patients.

BACKGROUND The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients. METHODS In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle. RESULTS There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046). CONCLUSIONS Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

Subcutaneous Heparin Versus Low-Molecular-Weight Heparin as Thromboprophylaxis in Patients Undergoing Colorectal Surgery: Results of the Canadian Colorectal DVT Prophylaxis Trial: A Randomized, Double-Blind Trial

ObjectiveTo compare the effectiveness and safety of low-dose unfractionated heparin and a low-molecular-weight heparin as prophylaxis against venous thromboembolism after colorectal surgery. MethodsIn a multicenter, double-blind trial, patients undergoing resection of part or all of the colon or rectum were randomized to receive, by subcutaneous injection, either calcium heparin 5,000 units every 8 hours or enoxaparin 40 mg once daily (plus two additional saline injections). Deep vein thrombosis was assessed by routine bilateral contrast venography performed between postoperative day 5 and 9, or earlier if clinically suspected. ResultsNine hundred thirty-six randomized patients completed the protocol and had an adequate outcome assessment. The venous thromboembolism rates were the same in both groups. There were no deaths from pulmonary embolism or bleeding complications. Although the proportion of all bleeding events in the enoxaparin group was significantly greater than in the low-dose heparin group, the rates of major bleeding and reoperation for bleeding were not significantly different. ConclusionsBoth heparin 5,000 units subcutaneously every 8 hours and enoxaparin 40 mg subcutaneously once daily provide highly effective and safe prophylaxis for patients undergoing colorectal surgery. However, given the current differences in cost, prophylaxis with low-dose heparin remains the preferred method at present.

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary.  Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.

Predictors of the post‐thrombotic syndrome during long‐term treatment of proximal deep vein thrombosis

Summary.  Background: The post‐thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). Objectives: To evaluate predictors of the post‐thrombotic syndrome, including intensity of long‐term anticoagulation, and to assess the impact of the post‐thrombotic syndrome on quality of life. Patients and methods: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty‐five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional‐intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long‐term warfarin therapy (target INR 2.5 vs. INR 1.7). Post‐thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease‐specific quality of life was compared in patients with and without the post‐thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post‐thrombotic syndrome and of its severity. Results: After an average follow‐up of 2.2 years, the prevalence of post‐thrombotic syndrome was 37% and of severe post‐thrombotic syndrome was 4%. Quality of life was worse in patients with the post‐thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post‐thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post‐thrombotic syndrome. Conclusions: The post‐thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long‐term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post‐thrombotic syndrome, this finding requires further evaluation in prospective studies.