Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.

BACKGROUND: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile. OBJECTIVES: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose-response relationships. PATIENTS/METHODS: A total of 1238 patients were randomized to one of six double-blind apixaban doses [5, 10 or 20 mg day(-1) administered as a single (q.d.) or a twice-daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open-label warfarin (titrated to an International Normalized Ratio of 1.8-3.0). Treatment lasted 10-14 days, commencing 12-24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all-cause mortality during treatment. The primary safety outcome was major bleeding. RESULTS: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. CONCLUSIONS: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. RESULTS: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.

Bilateral vs. ipsilateral venography as the primary efficacy outcome measure in thromboprophylaxis clinical trials: a systematic review.

Contrast venography, in combination with symptomatic venous thromboembolism (VTE), is the standard efficacy outcome measure in clinical trials of thromboprophylaxis in major orthopedic surgery. It is uncertain whether performing bilateral venography offers any real advantage over venography of the operated leg alone. This study was undertaken to determine the risk of isolated contralateral deep vein thrombosis (DVT) following major orthopedic surgery and to evaluate whether bilateral venography, rather than venography on the operated leg alone, offers any gain in DVT detection and, thereby, improves efficiency in clinical study design. A systematic review of prospective studies that reported DVT incidence as the primary efficacy outcome based on mandatory bilateral venography in patients undergoing elective hip or knee arthroplasty or hip fracture repair was conducted. Based on the use of bilateral venography as a primary efficacy outcome measure, the incidence of any DVT is 16.7% following total hip replacement, 18.8% after hip fracture repair, and 33.8% after total knee replacement. While DVT risk in the operated leg varies depending on the type of surgery, the risk of isolated DVT in the non-operated leg is approximately 4% to 5% in all three procedures. By increasing the detection of any DVT, the use of bilateral venography reduces required sample size by 16% to 25% compared to ipsilateral venography. In clinical trials evaluating the efficacy of thromboprophylaxis in major orthopedic surgery, bilateral venography reduces the risk of undiagnosed DVT in the non-operated leg and improves the efficiency of study design by substantially reducing the sample size requirement.

The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study.

BACKGROUND: Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease. METHODS: In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8-11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding. RESULTS: The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin. CONCLUSIONS: In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.

Comparison of real-time B-mode ultrasonography and bilateral ascending phlebography for detection of postoperative deep vein thrombosis following elective hip surgery. The Venous Thrombosis Group.

A prospective study compared real-time B-mode ultrasound examination with bilateral ascending phlebography in the diagnosis of postoperative deep vein thrombosis in 60 patients undergoing elective total hip replacement. The overall sensitivity and specificity of the ultrasound method were 54 and 91%, respectively, and the positive and negative predictive values were 83 and 69%, respectively. The rather low overall sensitivity of the ultrasound method in this study was due to difficulty in detecting thrombi smaller than 1 cm wherever they were located in the deep veins, and in diagnosing thrombi in the calf, regardless of their size. We conclude that real-time B-mode ultrasonography is a technique that can easily be used routinely for detection of postoperative DVT in hip surgery, but its sensitivity for proximal thrombosis (63%) is too low for it to be used alone.

Thromboprophylaxis with low molecular weight heparin after major orthopaedic surgery is cost effective.

The objective of this analysis was to evaluate the socioeconomic consequences of routine administration of low molecular weight heparin (LMWH) as thromboprophylaxis in patients undergoing total hip arthroplasty, on the basis of data from a number of clinical studies. Despite the higher direct costs associated with LMWH, this regimen was more cost effective per thromboembolic complication prevented than no prophylaxis, dextran 70, or low dose unfractionated heparin. A sensitivity analysis was performed to address the outcome when the main factors in the economic analysis were changed; this had no significant effect on the conclusions of the study.

Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis.

BACKGROUND: Heparin has anti-inflammatory and immunomodulatory activity which may be of therapeutic benefit in the treatment of ulcerative colitis. AIM: To test whether low molecular weight heparin, given subcutaneously, would provide a significant therapeutic response compared with placebo in the treatment of mild to moderate ulcerative colitis. STUDY DESIGN: A prospective, double-blind, randomized, placebo-controlled, multi-centre trial comparing tinzaparin 175 anti-Xa IU/kg/day (innohep, LEO Pharma) subcutaneously for 14 days followed by tinzaparin 4500 anti-Xa IU/day subcutaneously for 28 days with placebo, administered subcutaneously once daily for up to 42 days. The primary outcome measure was the mean change in colitis activity from baseline to the end of study treatment assessed by the sum of scores of stool frequency, rectal bleeding, sigmoidoscopic appearance and histology. Secondary outcome measures included changes in individual activity indices and laboratory parameters. Patients were assessed at weekly intervals for 6 weeks and within 1 week of completing treatment. RESULTS: One hundred patients with active ulcerative colitis (up to six bloody stools per day, no fever, no tachycardia or systemic disturbances) were randomized. Forty-eight received tinzaparin and 52 received placebo. The difference in the mean percentage change in colitis activity from baseline to end of treatment (tinzaparin-placebo) was not statistically significant (P = 0.84). There was no difference between tinzaparin and placebo in any secondary outcome measure. One major bleed (rectal), occurred in a patient receiving placebo. CONCLUSION: This is the largest trial to date of heparin in ulcerative colitis. The results show no benefit of low molecular weight heparin over placebo in mild to moderately active ulcerative colitis.

A comparative review of the adverse effect profiles of heparins and heparinoids.

On the basis of the results of the 11 studies reviewed, thromboprophylaxis with unfractionated heparin, low molecular weight (LMW) heparin or a heparinoid (danaparoid sodium; Org 10172) in patients undergoing total hip replacement did not show any important clinical differences with respect to the tolerability profiles of the different compounds. However, as a result of the great variability in the presentation and evaluation of blood losses and bleeding complications in these studies, it is mandatory to perform a direct comparison of the different compounds in question in a double-blind, prospective clinical study.

Role of tissue factor pathway inhibitor in post surgical deep venous thrombosis (DVT) prophylaxis in patients treated with low molecular weight heparin.

Low molecular weight heparins (LMWHs) are now considered to be the drugs of choice for prophylaxis against deep venous thrombosis (DVT) in post operative patients undergoing both general and orthopaedic surgical procedures. Despite extensive research, the exact mechanism of the antithrombotic activity of LMWHs remains unclear. These agents have been shown to activate the fibrinolytic system and to directly inhibit both the activity and the generation of factor Xa and thrombin. New evidence suggests that LMWHs also stimulate the release of endogenous tissue factor pathway inhibitor (TFPI) from the vascular endothelium. This study was designed to investigate the role of TFPI in mediating the antithrombotic activity of LMWHs. We measured the plasma levels of TFPI in a group of post orthopaedic surgery patients treated with daily subcutaneous injections of LMWH and a group of patients treated with placebo. In the placebo group (n = 25), the plasma TFPI levels were slightly elevated immediately after surgery but returned to their baseline value by the fifth post operative day. In contrast, in the group of patients treated with LMWH (n = 34), the plasma levels of TFPI increased significantly and remained elevated for up to 7 days following surgery. However, the TFPI levels in both groups showed wide patient to patient variability. These results indicate that LMWHs stimulate the release of TFPI into the bloodstream of post surgical patients. This suggests the importance of TFPI in mediating the antithrombotic activity of LMWHs.

Poor correlation between soluble fibrin concentrations measured by two commercially available immunoassays.

Soluble fibrin (SF) has attracted considerable interest as a marker for haemostatic activation. Two new enzyme immunoassays for SF, Enzymun-Test FM (Boehringer Mannheim, Germany) and Fibrinostika Soluble Fibrin (Organon Teknika, Belgium) have recently become commercially available. We measured plasma levels of SF in clinically obtained blood samples in order to compare the two new assays. Blood was drawn from 10 healthy volunteers and from 149 patients on the first day after surgery for fractures of the upper part of the femur. Collection and processing was done according to the manufacturers' recommendations. In the patients, levels found by the two assays were significantly different. The Enzymun-Test assay reported a median (range) of 11.87 (2.66 - > 62.20) mg/l, whereas the Fibrinostika assay found a median (range) of 3.34 (1.08 - >10) mg/l. The correlation coefficient was 0.38 (Spearman). A poor correlation was thus found between values obtained by the two assays in the patient category chosen. Further validation of the assays is necessary.

Components of coagulation and fibrinolysis during thrombosis prophylaxis with a low molecular weight heparin (Enoxaparin) versus Dextran 70 in hip arthroplasty.

In a prospective randomized study heptest, thrombin-antithrombin complexes (TAT), D-dimer, and t-PA:ag were analysed pre- and postoperatively in 206 consecutive patients undergoing hip arthroplasty during thromboprophylaxis with either a LMW heparin (Enoxaparin) or Dextran 70. Deep vein thrombosis (DVT) developed in 6 of 102 (6%) Enoxaparin and in 21 of 104 (20%) Dextran patients diagnosed by bilateral phelobography. In the Enoxaparin group heptest showed a significant increase from the pre- to the postoperative level opposed to a significant decrease in the Dextran group. Postoperative levels of TAT, D-dimer, and t-PA:ag were significantly increased in both groups, however, TAT was significantly higher in patients in the Dextran group than in the Enoxaparin patients. D-dimer was significantly higher in Dextran patients with DVT postoperatively compared with patients without DVT. No differences concerning TAT or t-PA:ag were observed between patients with and without DVT in any of the groups.

Association between plasma levels of tissue plasminogen activator and postoperative deep vein thrombosis--influence of prophylaxis with a low molecular weight heparin. The Venous Thrombosis Group.

In a prospective, randomized controlled study, tissue plasminogen activator (t-PA) and tissue plasminogen activator antigen (t-PA:ag) were measured pre- and postoperatively in 40 consecutive patients undergoing total hip replacement. Patients received either a subcutaneous injection of low molecular weight heparin or placebo once daily. Deep vein thrombosis was diagnosed by bilateral phlebography. Patients who developed postoperative thromboembolic complications had significantly lower preoperative t-PA activity levels than patients who did not develop such complications. No difference was observed between the two groups with respect to t-PA:ag. Thromboprophylaxis with low molecular weight heparin did not cause any significant changes in t-PA activity and t-PA:ag. This study in high risk patients indicates that impaired fibrinolysis may be associated with development of thromboembolic complications after operation.

Markers of coagulation and fibrinolysis after fractures of the lower extremities.

The study was performed to detect activation of coagulation and fibrinolysis in terms of prothrombin fragment 1 and 2 (F1 + 2), thrombin-antithrombin III complex (TAT), fibrin degradation products (FbDP), fibrinogen degradation products (FgDP), and soluble fibrin monomers (FM) in plasma from 39 patients with fractures of the lower extremities. We found substantially elevated levels of the molecular markers at admission and on the day after admission (Day 1) compared with control levels. Admission levels of F1 + 2, TAT, FbDP and FgDP were significantly higher compared with levels on day 1, whereas levels of FM were not significantly different between the two days. Generally there were good correlations between all markers of coagulation and fibrinolysis at admission whereas correlations were weaker or absent on day 1. In conclusion we found substantial haemostatic activation as a immediate response to trauma. Increased levels of F1 + 2, TAT, FM, FbDP and FgDP appear to be a normal physiological reaction after fractures of the lower extremities.

Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty--the Danish Prolonged Prophylaxis (DaPP) Study.

The aim of this study was to compare the efficacy and safety of prolonged (35 days) thromboprophylaxis with a standard length (7 days) regimen of a low molecular weight heparin in patients undergoing total hip arthroplasty. The study was multicentre, randomised, double-blind, and prospective with two groups. Following seven days on a standard length regimen of dalteparin (5000 antifactor Xa units subcutaneously once daily starting 12 h before surgery), patients were randomized to continue the prophylaxis with either subcutaneous injections of dalteparin or placebo injections for a further 28 days. Efficacy was evaluated at the end of the study (day 35) in all patients with bilateral ascending phlebography to detect deep vein thrombosis. Bleeding complications and other adverse events were registered throughout the study period. Three hundred consecutive patients agreed to participate before the operation: 281 were finally randomised and 215 completed the study; two patients died before randomisation; 17 developed deep vein thrombosis; none developed pulmonary embolism; and five of 113 patients (4.4%, 95% CI 1-10%) developed deep vein thrombosis in the dalteparin group, compared with 12 of 102 (11.8%; 95% CI 6-20%) in the placebo group (p=0.039). Deep vein thrombosis in the proximal veins was diagnosed in one patient (0.9%; 95% CI 0-5%) in the dalteparin group, and in five (5.0%; 95% CI 2-11%) in the placebo group (p=0.076). Major bleeding was observed in one patient in the placebo group; minor bleeding complications and adverse events were equally distributed between the groups. We concluded that prolonged (35 days) thrombo prophylaxis with dalteparin is more effective than a standard length (7 days) regimen without increased risk of bleeding complications or other adverse events.

Clinical limitations of risk assessment models.

Appropriate thromboprophylaxis in hospital patients is effective in preventing clinically important venous thromboembolic events, including deep vein thrombosis (DVT) and fatal pulmonary embolism. Due to the risk of bleeding associated with pharmacological prophylaxis and the cost of administering prophylactic drugs, the clinical benefit and cost-effectiveness of thromboprophylaxis may be optimized by providing prophylaxis only to patients at risk of thrombosis, and tailoring the intensity of prophylaxis to the level of risk. Accurate assessment of patients' thromboembolic risk is therefore highly necessary. Thromboembolic risk is influenced by numerous factors. Several risk factor indices based on clinical risk factors and laboratory variables have been proposed since the 1970s, but these have not been widely adopted due to their complexity and lack of prospective validation. The method of deriving risk data on which these indices are based is questioned, and older prognostic indices excluded recently identified risk factors, particularly molecular factors such as the clotting factor V Leiden mutation, further undermining their clinical value. A number of much simpler risk assessment models (RAMs) have now been developed which stratify patients into low-, moderate- and high-risk categories. However, no RAM currently available provides comprehensive guidance for all patient groups. Use of poorly designed RAMs may fail to identify some patients at risk, leading to omission of prophylaxis and preventable thrombotic events. Certain patient groups develop DVT despite prophylaxis. Current RAMs are not validated to identify these patients. Well-designed and well-validated RAMs, incorporated into standard practice guidelines in hospitals, should contribute to improved clinical outcomes and economic benefits of prophylaxis.

Reduction of plasma levels of prothrombin fragments 1 and 2 during thromboprophylaxis with a low-molecular-weight heparin.

In a randomized double-blind placebo-controlled study, plasma levels of prothrombin fragment 1 and 2 and total fibrin/fibrinogen degradation products were measured preoperatively and on days 1, 3, 5 and 7 postoperatively in 131 patients undergoing total hip replacement. Patients received a subcutaneous injection of either a low molecular weight heparin (Logiparin) or placebo once daily. Postoperative deep vein thrombosis was diagnosed by bilateral phlebography 7 to 10 days after operation. In the placebo group postoperative levels of prothrombin fragments 1 and 2 and total fibrin/fibrinogen degradation products were significantly higher in patients with postoperative thromboembolic complications, whereas in the low-molecular-weight heparin group no statistical differences were observed. Compared with placebo the administration of a low-molecular-weight heparin was associated with a significant reduction in the levels of prothrombin fragments 1 and 2 and total degradation products. Our observations suggest that the postoperative thrombin generation is moderated by thromboprophylaxis with Logiparin.

Levels of thrombin--antithrombin-III complex and factor VIII activity in relation to post-operative deep vein thrombosis and influence of prophylaxis with a low-molecular-weight heparin.

In a randomized doubled-blind placebo-controlled study, plasma levels of thrombin-antithrombin-III (TAT) and factor VIII activity (VIII:C) were measured pre-operatively and on days 1, 3, 5 and 7 post-operatively in 70 consecutive patients undergoing total hip replacement. Patients received either a subcutaneous injection of low-molecular-weight heparin (LMWH) or placebo once daily. Post-operative deep vein thrombosis (DVT) was diagnosed by bilateral phlebography. The levels of TAT and VIII:C both increased significantly after operation and were not significantly influenced by LMWH. Thirty-three patients in whom post-operative DVT developed had a significantly lower level of VIII:C on day 7, compared with patients without DVT.

Perioperative thrombosis prophylaxis with low molecular weight heparins in elective hip surgery. Clinical and economic considerations.

A review and meta analysis of randomized prophylaxis studies in total hip arthroplasty (THA) surgery with the low molecular weight heparin (LMWH) compounds presently marketed in Europe. Thromboprophylaxis with recommended dosages of LMWH was significantly more effective than both placebo (no prophylaxis), dextran 70 and low-dose unfractionated heparin (UH) (5,000 IU thrice daily) in terms of protection against objectively diagnosed deep vein thrombosis (DVT), which is the main source of postoperative pulmonary embolism. The efficacy of LMWH was similar to that of adjusted-dose UH but only 2 studies have been conducted with this regimen so far. When combined with 0.5 mg dihydroergotamine (DHE), UH was as effective as LMWH, but DHE bears a definite risk of circulatory disturbances in the lower limbs. In all studies LMWH prophylaxis was safe under the clinical conditions. A cost-effectiveness analysis based on the reported efficacy and safety of LMWH in the European studies showed that, compared with no prophylaxis, dextran 70, and low-dose UH, LMWH prophylaxis used routinely in patients undergoing THA is more profitable for the health care system due to fewer expenses used on treatment of postoperative thromboembolic complications. LMWH therefore leads to better utilization of the economic resources.