Barriers to the optimal use of anticoagulants after orthopaedic surgery.

Venous thromboembolism (VTE) and the consequent morbidity and mortality associated with this condition continue to be a problem following orthopaedic surgery. The vast majority of patients undergoing orthopaedic surgery receive some form of thromboprophylaxis. However, the use of inappropriate thromboprophylaxis is an important factor which may explain why the clinical burden of VTE is still considerable. Barriers to the use of appropriate thromboprophylaxis include the belief by some surgeons that pharmacological thromboprophylaxis increases the risk of bleeding and the asymptomatic nature of deep vein thrombosis. In addition, in patients at risk of VTE, thromboprophylaxis should be given beyond the standard duration recommended in international or national guidelines, and many surgeons have concerns about adherence and adverse events in the outpatient setting. Furthermore, currently available anticoagulants have drawbacks, including the need for monitoring, or a subcutaneous route of administration. The introduction and implementation of multi-faceted and integrated approaches to thromboprophylaxis could improve adherence with current guidelines, extend appropriate thromboprophylaxis according to risk factors, and improve patient outcomes in this setting. In addition, the development of new anticoagulants with more convenient administration regimens and no need for monitoring may help to achieve these objectives.

Differences in urinary prothrombin fragment 1 + 2 levels after total hip replacement in relation to venous thromboembolism and bleeding events.

BACKGROUND: Prothrombin fragment 1 + 2 is excreted in urine (uF1 + 2) as a result of thrombin generation and, therefore, may be a useful marker of coagulation status. OBJECTIVES: To assess uF1 + 2 levels after total hip replacement (THR) in patients with venous thromboembolism (VTE) and bleeding events. PATIENTS/METHODS: This study was conducted in parallel with a prospective, dose-finding study evaluating the efficacy and safety of different doses of rivaroxaban (Xarelto, Bayer HealthCare AG, Wuppertal, Germany) for thromboprophylaxis, relative to enoxaparin. Deep vein thrombosis was diagnosed by mandatory venography performed 5-9 days after THR, or earlier if symptomatic. Symptomatic pulmonary embolism was diagnosed by objective testing. Bleeding complications were registered and stratified into major bleeding, clinically relevant, non-major bleeding, and minor bleeding, using predefined criteria. RESULTS: Eighty-four patients had a VTE and 57 patients had a bleeding event (n = 722). Significantly higher median uF1 + 2 levels were observed in the VTE group on day 3 after THR (P = 0.03), compared with control. Median uF1 + 2 levels were lower in the bleeding group on day 3 after THR (P = 0.005) and on the day of venography (P = 0.36), compared with control. Comparisons between the VTE and bleeding groups showed significantly lower median uF1 + 2 levels in the bleeding group on day 3 after THR and on the day of venography (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS: Measurement of uF1 + 2 could provide a simple clinical test to evaluate non-invasively the intensity of coagulation activation after THR. However, further studies are required to confirm these encouraging preliminary results.

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.

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

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.

The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery.

BACKGROUND: The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. OBJECTIVES: To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. PATIENTS/METHODS: A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. RESULTS: In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are pound 27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. RESULTS are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. CONCLUSIONS: Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.

Accuracy of magnetic resonance imaging in the diagnosis of deep vein thrombosis in asymptomatic patients with injuries of the lower extremity. A pilot study.

This is a prospective comparative study of magnetic resonance imaging (MRI) of the deep veins versus contrast venography in consecutive patients treated for various injuries to their lower extremities, showing no clinical symptoms of deep vein thrombosis. The majority of examinations referred to in this study were performed according to the following methodology: First, the patient was subjected to MRI. Subsequently, within a 24-h interval, he/she was subjected to contrast venography. The acquired results were compared in a blinded manner. The diagnostic indices for MRI were calculated on the assumption that the results of contrast venography were sure to give an accurate indication of either presence or absence of thrombosis. Thirty-six patients were included in the study, of which 27 (15 males) completed it. The overall incidence of distal deep venous thrombosis (DVT) was 22% (6/27). One patient showed extension of a crural thrombus into the popliteal vein. MRI did not detect any of the thrombi. This lack of result was ascribed to failure to fully demonstrate all segments of the crural veins. However, MRI did show three proximal thrombi in the superficial femoral vein, which were not shown by the venograms. Thus, both the sensitivity and specificity of MRI were 0%, so MRI proved to be of no value in the diagnosis of asymptomatic deep venous thrombosis in this study.

Ultrasound for diagnosis of scaphoid fractures.

We investigated the diagnostic value of two different ultrasound scanning methods for the early diagnosis of acute scaphoid fractures. Fifty-seven patients with ten scaphoid fractures were assessed within a week of injury. The accuracy of the ultrasound assessment was 84% and its specificity was 91%. However, its sensitivity was only 50%. We conclude that ultrasound examination is unreliable for the diagnosis of acute scaphoid fractures.

Dose relation in the prevention of proximal vein thrombosis with a low molecular weight heparin (tinzaparin) in elective hip arthroplasty.

This is a review of a double-blind, prospective study comparing the thromboprophylactic efficacy and safety of two different prophylactic regimens of a low molecular weight heparin (tinzaparin) in 250 consecutive patients (aged < or 18) undergoing primary elective hip arthroplasty. Regimen 1: 75 U anti-Xa/kg BW (actual range 63 to 91) once daily started 12 hours before operation; and regimen 2: 50 U anti-Xa/kg BW (actual range 41 to 71) once daily started 2 hours before operation. Both regimens were administered in a weight-adjusted fashion and were continued for 7 days after operation or until full mobilization. Efficacy was evaluated by occurrence of postoperative deep vein thrombosis (DVT) diagnosed by bilateral ascending phlebography on day 7 +/- 2 after operation, and the venograms were evaluated in an assessor blind fashion by a panel of three expert radiologists. Safety was evaluated by the amount of blood lost and transfusion requirements during and after the operation; all bleeding complications, reoperations, adverse events and deaths were observed during the study. A 3-month follow-up on survival and occurrence of thromboembolism was performed on all randomized patients. The result was a significantly better protective effect against proximal DVT by regimen 1 compared with regimen 2. This was achieved with improved safety in terms of a significantly decreased need for blood transfusions during operation and fewer wound complications in the postoperative period in favor of regimen 1. Therefore, tinzaparin administered in a dosage of 75 U anti-Xa/kg BW 12 hours before surgery is significantly more protective against proximal DVT and safer than the standard regimen of 50 U anti-Xa/kg BW started 2 hours before surgery in patients undergoing primary elective hip arthroplasty.

Deep-vein thrombosis prophylaxis in orthopedic surgery: hip surgery.

Hip replacement surgery carries a high risk of thromboembolic complications, and pharmacological prophylaxis is routinely adopted in clinical practice. Meta-analyses have indicated that low molecular weight heparins (LMWHs) are clinically superior to conventional prophylaxis with unfractionated heparin. These analyses have regarded LMWHs as one chemical entity, despite differences in their physicochemical, biological, and pharmacodynamic properties. Comparing data from trials of different LMWHs is difficult despite standardization in trial design, patient selection criteria, and efficacy assessments, as the influences of concurrent disease and variation in venogram interpretation are difficult to interpret. Furthermore, variations in bleeding assessment limit conclusions on the safety profile of different LMWHs. Two clinical trials have compared enoxaparin with tinzaparin and reviparin respectively. Efficacy equivalence was demonstrated despite differences in the anti-Xa activities of the doses given. These trials support the position of the United States Food and Drug Administration and the World Health Organization that LMWHs are distinct, noninterchangeable compounds and cannot be therapeutically substituted based upon anti-factor Xa levels. The extent of clinical experience with each LMWH is an important factor influencing clinical use.

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.

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.

Managing the risk of thrombosis in the perioperative period in patients undergoing orthopedic and trauma surgery with low-molecular-weight heparin: enoxaparin.

Patients undergoing arthroplastic surgery of the lower limbs and those with multiple injuries have a high risk of thromboembolism. Enoxaparin is a highly effective antithrombotic drug that is well tolerated and without the need for monitoring. Numerous controlled trials in these patient groups have demonstrated enoxaparin to be at least as effective as heparin in reducing the occurrence of deep vein thrombosis while showing a tendency towards lower risk of bleeding complications; therefore, enoxaparin is recommended as thromboprophylaxis in patients undergoing major hip or knee surgery or suffering from multiple trauma.

Managing the risk of thrombosis in the perioperative period in patients undergoing orthopedic and trauma surgery with low-molecular-weight heparin: enoxaparin.

ABSTRACTPatients undergoing arthroplastic surgery of the lower limbs and those with multiple injuries have a high risk of thromboembolism. Enoxaparin is a highly effective antithrombotic drug that is well tolerated and without the need for monitoring. Numerous controlled trials in these patient groups have demonstrated enoxaparin to be at least as effective as heparin in reducing the occurrence of deep vein thrombosis while showing a tendency towards lower risk of bleeding complications; therefore, enoxaparin is recommended as thromboprophylaxis in patients undergoing major hip or knee surgery or suffering from multiple trauma.

Low molecular weight heparin for the prevention of deep vein thrombosis following orthopedic surgery.

Prophylaxis of postoperative thromboembolism is widely used because it has been shown to save lives and money. However, some surgeons are still reluctant to use general prophylaxis in high-risk orthopedic surgery. In total hip and total knee replacement the best method of prophylaxis is currently low molecular weight heparin started preoperatively and continued for 7 to 14 days or until the patient is fully ambulatory. A shorter prophylaxis period failed to be effective in an English study. At present there is an ongoing debate on the length of the period of risk, and whether there is a need for prophylaxis after discharge. Oral anticoagulation has been used for extended prophylaxis, but studies show that anticoagulant levels need to be monitored by repeated measurements by international normalized ratio. An alternative method would be to continue low molecular weight heparin injections for 4 to 5 weeks after surgery. No studies so far have evaluated the efficacy and safety of prolonged prophylaxis with low molecular weight heparin after discharge.

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.

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.

Survival in patients undergoing total hip arthroplasty in relation to thromboprophylaxis with low molecular weight heparin: a long-term follow-up study.

The aim of the study was to determine the long-term survival in patients undergoing total hip arthroplasty in relation to type of perioperatively administered thromboprophylaxis. Patients from seven randomized controlled trials of the effect of thromboprophylaxis on development of early thromboembolic complications after total hip arthroplasty were included in a follow-up analysis with death as the end-point. There was no difference in survival between groups receiving active thromboprophylaxis, but there was a general trend towards a better survival in the 3 placebo groups compared with low molecular weight heparin (LMWH), (RR: 1.53; C.I.: 1.04-2.25). There was a significant excess of cardiovascular deaths in the LMWH groups (RR: 2.48; CI: 1.45-4.24). Long-term prospective studies should be performed to assess the long-term effect of various thromboprophylactic regimens on morbidity and mortality after total hip arthoplasty.

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.

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.