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- Agnelli, G, et al.
(författare)
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Safety assessment of new antithrombotic agents : Lessons from the EXTEND study on ximelagatran.
- 2009
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 123:3, s. 488-497
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Tidskriftsartikel (refereegranskat)abstract
- 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 The clinical development of ximelagatran was terminated and the drug withdrawn from the market.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.
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| 2. |
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| 3. |
- Dahl, O. E., et al.
(författare)
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Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use
- 2008
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Ingår i: International angiology. - 0392-9590. ; 27:1, s. 60-7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
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| 5. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement
- 2009
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Ingår i: Journal of Bone and Joint Surgery. - 0301-620X. ; 91:5, s. 636-44
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Tidskriftsartikel (refereegranskat)abstract
- A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening in preventing symptomatic venous thromboembolism and all-cause mortality, without increasing major bleeding.
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| 6. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study
- 2008
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7836. ; 6:3, s. 457-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inhibitors of factor (F) IXa show potent antithrombotic activity with a low risk of bleeding in preclinical models. We investigated the anticoagulant potential of oral TTP889, a small molecule that inhibits up to 90% of FIXa activity at therapeutic doses, using a clinical model of extended prophylaxis in hip fracture surgery (HFS). METHODS: In this multicenter, randomized, double-blind study, 261 patients received oral TTP889 (300 mg once daily) or placebo starting 6-10 days after HFS, and standard thromboprophylaxis for 5-9 days. Treatment was continued for 3 weeks and all patients then underwent mandatory bilateral venography. The primary efficacy outcome was venous thromboembolism (VTE; venographic or symptomatic deep vein thrombosis or pulmonary embolism) during treatment, and it was evaluated centrally by an independent adjudication panel. The main safety outcome was bleeding (major, clinically relevant non-major, and minor events). RESULTS: Two hundred and twelve patients with an evaluable venogram were included in the efficacy analysis. The primary efficacy outcome occurred in 32.1% (35/109) of patients who had been allocated TTP889, and 28.2% (29/103) of patients on placebo (P = 0.58). There were no major bleeding events, and only two clinically relevant non-major bleeding events with TTP889. CONCLUSION: Partial FIXa inhibition with TTP889 300 mg daily was not effective for extended prevention of VTE after standard prophylaxis for up to 9 days. Coupled with the low incidence of bleeding episodes, this suggests a lack of antithrombotic potential. Further investigation of TTP889 in different clinical settings is needed. (Clinical trial registration information URL: http://www.clinicaltrials.gov. Unique identifier: NCT00119457).
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