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Ximelagatran/melagatran against conventional anticoagulation: a meta-analysis based on 22,639 patients
L Testa1, F Andreotti, G G L Biondi Zoccai
1Institute of Cardiology, Catholic University, Largo F. Vito 1-00168 Rome, Italy. ltes@tiscali.it
Background:
The oral direct thrombin inhibitor ximelagatran, and its active form, melagatran, have been tested in various clinical conditions as a promising alternative to conventional anticoagulant therapy (CAT), despite some concerns over potentially serious liver injury.
Objectives:
To assess its risk/benefit profile, a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing xi-/melagatran to CAT was performed.
Methods:
Leading medical databases were searched. The rates of major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, nonfatal pulmonary embolism), major bleeds (MB), and hepatotoxicity were compared. Out of 140 potentially relevant citations, 13 RCTs enrolling 22,639 patients were included. Indications for treatment were: 1) perioperative prophylaxis of deep vein thrombosis (DVT); 2) management of DVT; and 3) stroke prevention in atrial fibrillation.
Results:
Overall, the risk of MAE (OR 0.98 [0.83-1.17]) and MB (OR 1.01 [0.69-1.47]) did not differ significantly between xi-/melagatran and CAT. There was a clear trend towards an increased risk of hepatotoxicity (OR 1.74 [0.50-6.01]), with an incidence of 5.8% with xi-/melagatran versus 2.3% with CAT (p<0.001); more specifically, the rate of hepatotoxicity was markedly augmented in the management of DVT (OR 5.16 [3.38-7.89]), for treatment durations > or = 3 months (OR 6.73 [5.01-9.05]), and in the prevention of atrial fibrillation-related stroke (OR 8.31 [5.65-12.23]). Two fatal cases of liver injury occurred with xi-/melagatran.
Conclusions:
Although comparable to CAT in terms of MAE and MB, xi-/melagatran carries a prohibitive risk of hepatotoxicity that cannot be ignored. Newer long-term alternatives are urgently needed.
Insights
Ximelagatran showed similar risks for major adverse events and bleeds compared to conventional anticoagulant therapy. However, ximelagatran significantly increased the risk of hepatotoxicity, indicating a need for safer long-term alternatives.
Area of Science:
- Pharmacology and Therapeutics
- Clinical Trial Analysis
- Drug Safety and Hepatotoxicity
Background:
- Ximelagatran, an oral direct thrombin inhibitor, was investigated as an alternative to conventional anticoagulant therapy (CAT).
- Concerns regarding potential serious liver injury associated with ximelagatran use were noted.
Purpose of the Study:
- To systematically review and meta-analyze randomized controlled trials (RCTs) comparing ximelagatran/melagatran with CAT.
- To assess the risk/benefit profile of ximelagatran, focusing on major adverse events (MAE), major bleeds (MB), and hepatotoxicity.
Main Methods:
- A systematic search of leading medical databases was conducted.
- 13 RCTs involving 22,639 patients were included, comparing ximelagatran/melagatran to CAT.
- Outcomes analyzed included MAE, MB, and hepatotoxicity across various indications: DVT prophylaxis, DVT management, and atrial fibrillation stroke prevention.
Main Results:
- Ximelagatran/melagatran demonstrated no significant difference in MAE (OR 0.98) or MB (OR 1.01) compared to CAT.
- A significant trend towards increased hepatotoxicity was observed (OR 1.74), with incidence rates of 5.8% vs 2.3% (p<0.001).
- Hepatotoxicity risk was markedly higher in DVT management (OR 5.16), treatment durations ≥3 months (OR 6.73), and atrial fibrillation stroke prevention (OR 8.31), with two fatal liver injury cases.
Conclusions:
- Ximelagatran is comparable to CAT regarding MAE and MB but presents a prohibitive risk of hepatotoxicity.
- The elevated risk of liver injury necessitates caution and highlights the urgent need for safer long-term anticoagulant alternatives.
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