|Ximelagatran versus warfarin for prophylaxis of venous thromboembolism in major orthopedic surgery: systematic review of randomized controlled trials
|Yoshida W B, El Dib R P, de Alvarenga Yoshida R, de Abreu Maffei F H
This review evaluated ximelagatran as prophylactic treatment in older patients undergoing knee surgery. The authors concluded that a higher dose of ximelagatran is more effective than warfarin in reducing the incidence of venous thromboembolism, but it increases the frequency of alanine aminotranferase elevation in the follow-up period. This was a well-conducted review and the conclusions are likely to be reliable. Ximelagatran has since been withdrawn from the market.
To evaluate the effectiveness of ximelagatran for prophylaxis of venous thromboembolism (VTE) in patients undergoing major orthopaedic knee surgery.
The Cochrane Peripheral Vascular Diseases Group’s records (to May 2005), the Cochrane CENTRAL Register (Issue 2, 2005), MEDLINE (1966 to May 2005), EMBASE (1980 to May 2005) and LILACS (1982 to May 2005) were searched; the search terms were reported. AstraZeneca was contacted and the Internet searched to identify unpublished studies. References of relevant review articles and advertisement folders were also checked for further studies.
Study designs of evaluations included in the review
Studies of randomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the review
Studies comparing ximelagatran with warfarin were eligible for inclusion. The included studies were of ximelagatran administered in 24- or 36-mg doses twice daily (b.i.d.), started the morning after surgery. Ximelagatran was administered without prior subcutaneous melagatran. Warfarin was used as control in all of the studies, and was started the evening of surgery at a target International Normalised Ratio of 2.5. All studies were of oral drug administration.
Participants included in the review
Studies of patients undergoing major knee surgery were eligible for inclusion. The included studies were of patients undergoing knee arthroplasty or knee replacement. The mean age of the participants ranged from 66.9 to 68 years. The studies were conducted in hospitals and centres in the USA, Canada, Mexico, Brazil and Israel.
Outcomes assessed in the review
Studies of VTE, deep vein thrombosis (DVT) at any site, pulmonary embolism (PE) or unexplained death were eligible for inclusion. Secondary outcomes eligible for inclusion were; frequency of major VTE, frequency of any bleeding, frequency of severe bleeding, volume of blood loss, volume of blood transfused, frequency of patients receiving transfusion, bleeding index, frequency of alanine aminotransferase (ALT) elevation, and death. The outcomes reported in the review were the frequencies of total VTE, major VTE, PE fatal PE, severe bleeding and any bleeding, deaths and frequency of ALT elevation.
How were decisions on the relevance of primary studies made?
Two reviewers independently assessed trials for inclusion, with two other reviewers arbitrating in the case of disagreement. Where agreement could not be reached, and where the study authors could not resolve the issue, the study was excluded.
Assessment of study quality
Study quality was assessed using an established Cochrane approach. Method of randomisation, allocation concealment, single or double-blinding, the use of intention-to-treat analysis and sample size calculations were also noted for each included study. Two reviewers independently carried out the validity assessment, with two other reviewers arbitrating in the case of disagreement. Where consensus could not be reached, and where the study authors could not resolve the issue, the study was excluded.
Two reviewers independently extracted the data, with two other reviewers consulted in the case of disagreement. Authors were contacted for further information, where necessary. Data on drug dosage and numbers of patients with total VTE, major VTE, PE, severe bleeding and any bleeding were extracted. The numbers of deaths during treatment and follow-up periods, the number of fatal PE, and the number of patients with ALT elevation more than three times the upper normal limit at the end of treatment and during follow-up, were also extracted. The data were used to calculate relative risks (RRs) with 95% confidence intervals (CIs).
Methods of synthesis
How were the studies combined?
The studies were combined by pooling the RRs in a meta-analysis (unspecified method).
How were differences between studies investigated?
Heterogeneity was measured using the I-squared test. Subgroup analysis was carried out separately for the two doses of ximelagatran.
Results of the review
Three RCTs (n=5,284) were included. The analysis appears to have been based on a subgroup of 4,914 older participants.
All of the studies were double-blind RCTs, and two used a computer for randomisation. All studies also used intention-to-treat analysis, had independent and blinded assessment of the outcomes, and independent adjudication of safety and mortality. No details of allocation concealment were given in any of the studies. There was no evidence of statistical heterogeneity.
Ximelagatran was associated with a significantly reduced risk of total VTE at the dose of 36 mg b.i.d. (RR 0.72, 95% CI: 0.64, 0.81, p<0.00001) (2 trials, n=3,186), but not at the dose of 24 mg b.i.d. (2 trials, n=1,759). Ximelagatran did not significantly reduce the risk of major VTE or PE compared with warfarin at either the lower or higher dose.
Ximelagatran at a dose of 24 mg b.i.d. was associated with a significantly smaller incidence of ALT elevation at three times the upper limit at the end of treatment (RR 0.33, 95% CI: 0.12, 0.91, p=0.03) (1 trial, n=1,394). There was no difference between ximelagatran administered at 36 mg b.i.d. and warfarin at the end of treatment. However, during the 4- to 6-week follow-up period, ximelagatran at 36 mg b.i.d. was associated with significantly greater frequency of ALT elevation (RR 6.97, 95% CI: 1.26, 38.50, p=0.03) (2 trials, n=3,564).
No significant differences were found between ximelagatran at either dose and warfarin in incidence of severe bleeding, any bleeding, or deaths. Independent adjudication by the trials Central Committee established that, apart from PE (one fatality in each of the ximelagatran and warfarin groups), most deaths were not attributable to the treatment.
The authors stated that AstraZeneca has subsequently withdrawn ximelagatran from the market because of an adverse event (severe liver injury) found in another clinical trial.
Ximelagatran is more effective at the higher dose of 36 mg b.i.d, but at the expense of greater frequency of ALT elevation in the follow-up period.
The inclusion criteria for this review were clearly defined. However, the analysis appears to have been restricted to older participants, which was not specified in the inclusion criteria, and this limits the ability to generalise the findings to younger populations. Several relevant sources were searched and appropriate strategies were used to minimise publication bias. Appropriate steps were taken to minimise error and bias in the study selection, validity assessment and data extraction processes. The studies appear to have been of a good quality, although the review could have benefited from further information about the quality and characteristics of individual studies. There was no evidence of statistical heterogeneity between the studies, therefore the decision to combine the results in a meta-analysis was appropriate. The review was based on a small number of studies, however, the sample sizes were large and the studies were conducted across multiple sites. The authors’ conclusions reflect the evidence presented and are likely to be reliable. It should be noted that AstraZeneca has subsequently withdrawn ximelagatran from the market following the occurrence of adverse events.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated the need for further studies in order to reach definite conclusions about mortality rates. For longer term use there is a need to develop an algorithm for preventing ALT elevation. It should be noted that ximelagatran has now been withdrawn from the market because of the occurrence of adverse events.
Yoshida W B, El Dib R P, de Alvarenga Yoshida R, de Abreu Maffei F H. Ximelagatran versus warfarin for prophylaxis of venous thromboembolism in major orthopedic surgery: systematic review of randomized controlled trials. Sao Paulo Medical Journal 2006; 124(6): 355-361
Subject indexing assigned by NLM
Aged; Anticoagulants /administration & dosage /adverse effects; Azetidines /administration & dosage /adverse effects; Benzylamines /administration & dosage /adverse effects; Brazil /epidemiology; Epidemiologic Methods; Hemorrhage /epidemiology /etiology; Humans; Knee /surgery; Orthopedic Procedures; Pulmonary Embolism /epidemiology /etiology; Thromboembolism /prevention & control; Venous Thrombosis /epidemiology /prevention & control; Warfarin /administration & dosage /adverse effects
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.