Ola E. Dahl

Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). CONCLUSIONS Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial

BACKGROUND After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial

BACKGROUND The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. METHODS 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. FINDINGS The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). INTERPRETATION Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial

Background: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double‐blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once‐daily, starting with a half‐dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once‐daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the dabigatran etexilate 220‐mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150‐mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non‐inferior to enoxaparin on the basis of the prespecified non‐inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow‐up. Conclusions: Dabigatran etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.

Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis in Patients after Elective Hip Arthroplasty: A Systematic Review

The use of accurate, objective venographic testing to detect deep venous thrombosis in patients who undergo hip arthroplasty has led to randomized trials of various prophylactic regimens against venous thromboembolism (123). The need for in-hospital prophylaxis has been firmly established (24, 25) and accepted in clinical practice. Evidence-based medicine guidelines (26) based on venographic end points recommend low-molecular-weight heparin (LMWH) prophylaxis or warfarin prophylaxis for 7 to 10 days in patients who undergo elective hip surgery (25). These guidelines are considered a grade 1A recommendation, which indicates a strong recommendation for a therapy that has a clear benefit; the recommendation is based on randomized clinical trials that do not have important limitations and that can apply to most patients in most circumstances without reservation (26). Recent surveys indicate that more than 90% of patients who have undergone elective hip surgery have received thromboprophylaxis (27, 28). The results of randomized trials in Europe indicate the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty (2934). In contrast, on the basis of relatively low rates of symptomatic venous thromboembolism observed in descriptive studies in North America with long-term follow-up, investigators have inferred that extended prophylaxis is not required (3539). For these reasons, the reports of the Fifth (24) and Sixth (25) American College of Chest Physicians Consensus Conferences stated that extended out-of-hospital prophylaxis by using LMWH may offer additional protection. This is a 2A recommendation because of uncertainty regarding the riskbenefit ratio (24) and cost-effectiveness (25). A grade 2A recommendation indicates unclear benefit based on randomized clinical trials without important limitations and is an intermediate-strength recommendation (26). A possible interpretation of the North American data (3539) is that extended prophylaxis is unnecessary for patients in the United States and Canada because of differences in clinical practice, a shorter length of hospital stay, and earlier patient ambulation compared with Europe. A recent epidemiologic study (27) used a linked hospital discharge database provided by the State of California to report the outcomes in 19 586 patients undergoing total-hip arthroplasty and 24 059 patients undergoing knee arthroplasty. Of the patients having elective hip surgery who had symptomatic venous thromboembolism, the median time of the event was postoperative day 17, whereas the median time in patients having knee surgery was postoperative day 7; most patients (>90%) received in-hospital prophylaxis. These findings strongly suggest a need for extended out-of-hospital prophylaxis in patients undergoing total-hip replacement but not for patients undergoing total-knee replacement. Given the uncertainty about the need for extended prophylaxis, we performed a systematic review to provide clinicians with a practical pathway for translating clinical research into practice. Methods To ensure high methodologic quality, we adhered to the 15 criteria for systematic review outlined by McAlister and colleagues (40, 41). The first 10 criteria assess methodologic rigor, and the last 5 criteria assess the scientific basis of treatment recommendations (40). We also adhered to the QUOROM (Quality of Reporting of Meta-analyses) guidelines (42) for the reporting of meta-analyses of randomized trials. We systematically identified published and unpublished articles for inclusion in this analysis, described variations in study design and execution, evaluated study quality (43), and quantified the relative benefits of extended prophylaxis with LMWH (44). We excluded studies that did not use venography to assess the presence or absence of deep venous thrombosis because previous studies have shown that noninvasive tests, including duplex ultrasonography, are relatively insensitive for detecting thrombosis in patients who have undergone hip replacement (25). Study Identification We attempted to identify all published and unpublished randomized trials that compared extended prophylaxis with LMWH versus out-of-hospital placebo in patients undergoing hip arthroplasty. A strategy was developed for locating all studies in the PubMed and MEDLINE databases that were published between January 1976 and May 2001; the search was not restricted to English-language journals. We augmented our MEDLINE search by manually reviewing the reference lists of original articles and review articles. We also reviewed abstracts in conference proceedings and through the Cochrane Library Database and contacted investigators and pharmaceutical companies. Study Eligibility Two investigators independently evaluated studies for inclusion in the systematic review, and any disagreements were resolved by discussion between these two investigators. Investigators were not blinded to journal titles, author names, or institutional affiliations. Studies were included if they 1) enrolled patients undergoing elective hip arthroplasty, 2) randomly assigned participants to treatment groups, 3) investigated the extended posthospital discharge efficacy of once-daily subcutaneous LMWH compared with out-of-hospital placebo for prevention of deep venous thrombosis, 4) objectively documented the presence or absence of all episodes of deep venous thrombosis and proximal venous thrombosis by using bilateral ascending contrast venography, and 5) used objective methods for assessing bleeding complications (2932, 45, 46). Abstracts that reported full methods and results were eligible for inclusion. Deep venous thrombosis was defined as constant intraluminal filling defects in the deep veins; proximal venous thrombosis was defined as constant intraluminal filling defects in the popliteal deep veins or in the more proximal deep veins. Data Extraction One study investigator collected data on the following study-level factors: 1) the type of LMWH prophylaxis used, 2) whether a high-risk dose, approved by a regulatory affairs authority, was used, 3) the frequency of administration of LMWH, 4) the length of in-hospital stay, 5) the time interval after surgery when venography was performed [in days], and 6) venographic findings. For the last factor, we noted new out-of-hospital findings on venography or combined in-hospital and out-of-hospital findings on venography; where both findings were reported, we analyzed new out-of-hospital findings, which were more conservative and more recent. Two investigators independently extracted data on the major outcomes, which were the frequency of 1) all episodes of deep venous thrombosis, 2) proximal venous thrombosis, 3) symptomatic deep venous thrombosis and pulmonary embolism, and 4) major-bleeding complications. They also recorded data on other variables, including death, minor bleeding, wound hematomas, and thrombocytopenia. After the two investigators made their respective independent selection of studies for inclusion in the analysis, we compared their selections and calculated the percentage of agreement between them and the coefficient (47). Investigator disagreements were resolved by discussion. Assessment of Study Quality We assessed the quality and strength of each study by examining four key issues: 1) true randomization by using a random-numbers table or a computer program; 2) the masking of the allocation sequences from the investigators, staff, and patients involved in the study; 3) double-blinding [45]; and 4) the proportion of patients with successful (adequate) venography. One investigator extracted these data from the primary studies. When details were not reported, we requested additional information from the authors. Data Synthesis and Statistical Analysis For each of the major outcomes, we calculated summary treatment effects as the relative risk and the number needed to treat for benefit (NNTB) to prevent one thromboembolic event. The relative risk was used as the primary measure of treatment effect. We considered a P value less than 0.05 to be statistically significant for all statistical tests. Analyses were performed by using the metan procedure (48) of Stata software, release 6.0 (Stata Corp., College Station, Texas). To assess the validity of combining results from individual studies, we used the MantelHaenszel test for statistical heterogeneity (49). The outcome values were combined in both fixed-effects and random-effects models to estimate treatment effects on outcomes for all the studies. The relative risk ratios were consistent among studies for the treatment effect of preventing venographically documented deep venous thrombosis (all episodes and cases of proximal deep venous thrombosis); however, the 95% CIs for the relative risk ratios within studies were relatively wide. Therefore, we combined the data to provide more precise estimates of relative risk and NNTB. Results for NNTB were based on random-effects analysis of risk. Sensitivity Analysis We performed a sensitivity analysis for each of the three major outcomes. To uncover possible publication bias, we created inverted funnel plots for the major outcomes by plotting odds ratios against the sample size for each study (50). Moreover, to identify any studies that exerted a disproportionate influence on the summary treatment effect, we performed repeated calculations in which the data from each individual study were deleted, one at a time. Trials that met all inclusion criteria except for onethe use of bilateral ascending venography to assess end points at the end of the out-of-hospital study intervalwere included in a secondary meta-analysis of symptomatic venous thromboembolism and major bleeding end points. Results Study Identification and Selection Our search strategies identified 206 potentially relevant studies. After an initial scanning of titles and abstracts, we excluded 184 studies: 160 studies did

Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement

Dabigatran etexilate is an oral low‐molecular‐weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150‐mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open‐label, 3‐way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open‐label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC0‐∞. A decrease in the mean dabigatran AUC0‐∞ (904 to 705 ng•h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC0–24 of dabigatran was 88% of the steady‐state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.

A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After Total Hip Replacement

Background— Rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—could be an alternative to heparins and warfarin for the prevention and treatment of thromboembolic disorders. Methods and Results— This randomized, double-blind, double-dummy, active-comparator–controlled, multinational, dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of venous thromboembolism in patients undergoing elective total hip replacement. Patients (n=873) were randomized to once-daily oral rivaroxaban doses of 5, 10, 20, 30, or 40 mg (initiated 6 to 8 hours after surgery) or a once-daily subcutaneous enoxaparin dose of 40 mg (given the evening before and ≥6 hours after surgery). Study drugs were continued for an additional 5 to 9 days; mandatory bilateral venography was performed the following day. The primary end point (composite of any deep vein thrombosis, objectively confirmed pulmonary embolism, and all-cause mortality) was observed in 14.9%, 10.6%, 8.5%, 13.5%, 6.4%, and 25.2% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=618, per-protocol population). No significant dose–response relationship was found for efficacy (P=0.0852). Major postoperative bleeding was observed in 2.3%, 0.7%, 4.3%, 4.9%, 5.1%, and 1.9% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=845, safety population), representing a significant dose–response relationship (P=0.0391). Conclusions— Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When both efficacy and safety are considered, these results suggest that 10 mg rivaroxaban once daily should be investigated in phase III studies.

Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial

BACKGROUND Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. METHODS Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. FINDINGS 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. INTERPRETATION This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.

Summary.  Background: Joint replacement surgery is an appropriate model for dose‐ranging studies investigating new anticoagulants. Objectives: To assess the efficacy and safety of a novel, oral, direct factor Xa (FXa) inhibitor – BAY 59‐7939 – relative to enoxaparin in patients undergoing elective total hip replacement. Methods: In this double‐blind, double‐dummy, dose‐ranging study, patients were randomized to oral BAY 59‐7939 (2.5, 5, 10, 20, or 30 mg b.i.d.), starting 6–8 h after surgery, or s.c. enoxaparin 40 mg once daily, starting on the evening before surgery. Treatment was continued until mandatory bilateral venography was performed 5–9 days after surgery. Results: Of 706 patients treated, 548 were eligible for the primary efficacy analysis. The primary efficacy endpoint was the incidence of any deep vein thrombosis, non‐fatal pulmonary embolism, and all‐cause mortality; rates were 15%, 14%, 12%, 18%, and 7% for BAY 59‐7939 2.5, 5, 10, 20, and 30 mg b.i.d., respectively, compared with 17% for enoxaparin. The primary efficacy analysis did not demonstrate any significant trend in dose–response relationship for BAY 59‐7939. The primary safety endpoint was major, postoperative bleeding; there was a significant increase in the frequency of events with increasing doses of BAY 59‐7939 (P = 0.045), but no significant differences between individual BAY 59‐7939 doses and enoxaparin. Conclusions: When efficacy and safety were considered together, the oral, direct FXa inhibitor BAY 59‐7939, at 2.5–10 mg b.i.d., compared favorably with enoxaparin for the prevention of venous thromboembolism in patients undergoing elective total hip replacement.

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II)

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.