Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

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 The clinical development of ximelagatran was terminated and the drug withdrawn from the market.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.

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.

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.

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.

Prevention of venous thromboembolism after surgery: a review of enoxaparin.

This review discusses the problem of deep vein thrombosis (DVT) after operation and identifies three levels of risk of DVT: low (less than 10 per cent), moderate (10-40 per cent) and high (40-80 per cent). Special emphasis is placed on the most recent prophylactic treatment, low molecular weight heparins (LMWHs), particularly enoxaparin. Several LMWHs are now available, but they differ slightly and each must be evaluated on its own merits. In general, however, LMWHs are both effective and safe in those patients at moderate or high risk of DVT. Thromboprophylaxis is cost effective when analysed using health-economic methodology.