| 1. |
- Schulman, S., et al.
(författare)
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Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months
- 2006
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:4, s. 734-742
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Tidskriftsartikel (refereegranskat)abstract
- Background: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long-term morbidity and mortality is unclear. Aim: To investigate the long-term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. Methods: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow-up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post-thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. Results: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow-up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent gering risk factor - especially with venous insufficiency at baseline - signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28-1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83, 95% CI 1.44-2.23) or from myocardial infarction or stroke (SIR 1.28, 95% CI 1.00-1.56).The duration of anticoagulation did not have a statistically significant effect on any of the long-term outcomes. Conclusion: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed. © 2006 International Society on Thrombosis and Haemostasis.
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| 2. |
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| 4. |
- Eriksson, Henry, 1946, et al.
(författare)
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Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran
- 2005
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Ingår i: Thromb Haemost. - 0340-6245. ; 94:3, s. 522-7
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Tidskriftsartikel (refereegranskat)abstract
- The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.
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| 8. |
- Schulman, S., et al.
(författare)
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Ximelagatran for the secondary prevention of venous thromboembolism: a complementary follow-up analysis of the THRIVE III study
- 2005
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Ingår i: Thromb Haemost. - 0340-6245. ; 94:4, s. 820-4
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Tidskriftsartikel (refereegranskat)abstract
- In the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13 patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and one VTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36; P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36; P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36, 1.93; P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.
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| 9. |
- Secin, Fernando P, et al.
(författare)
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Multi-institutional Study of Symptomatic Deep Venous Thrombosis and Pulmonary Embolism in Prostate Cancer Patients Undergoing Laparoscopic or Robot-Assisted Laparoscopic Radical Prostatectomy
- 2008
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 53:1, s. 134-145
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The true incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing laparoscopic radical prostatectomy is unknown. Our aim was to determine the incidence of symptomatic DVT and PE and the risk factors for these complications. METHODS: Fourteen surgeons from 13 referral institutions from both Europe and the United States provided retrospective data for all 5951 patients treated with laparoscopic radical prostatectomy (LRP), with or without robotic assistance, since the start of their institution's experience. Symptomatic DVT and PE within 90 d of surgery were regarded as venous thromboembolism (VTE). DVT was diagnosed mostly by Doppler ultrasound or contrast venography and PE by lung ventilation/perfusion scan or chest computed tomography or both. Statistical analysis included evaluation of incidence of symptomatic DVT and PE and risk factors as determined by exact methods and logistic regression. RESULTS: Of 5951 patients in the study, 31 developed symptomatic VTE (0.5%; 95% confidence interval [CI], 0.4%, 0.7%). Among patients with an event, 22 (71%) had DVT only, 4 had PE without identified DVT, and 5 had both. Two patients died of PE. Prior DVT (odds ratio [OR]=13.5; 95%CI, 1.4, 61.3), current tobacco smoking (OR=2.8; 95%CI, 1.0, 7.3), larger prostate volume (OR=1.18; 95%CI, 1.09, 1.28), patient re-exploration (OR=20.6; 95%CI, 6.6, 54.0), longer operative time (OR=1.05; 95%CI, 1.02, 1.09), and longer hospital stay (OR=1.05; 95%CI, 1.01, 1.09) were associated with VTE in univariate analysis. Neoadjuvant therapy, body mass index, surgical experience, surgical approach, pathologic stage, perioperative transfusion, and heparin administration were not significant predictors. CONCLUSIONS: The incidence of symptomatic VTE after LRP is low. These data do not support the administration of prophylactic heparin to all patients undergoing LRP, especially those without risk factors for VTE.
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| 10. |
- Wahlander, K., et al.
(författare)
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Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long-term secondary prevention of venous thromboembolism
- 2006
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Ingår i: Br J Haematol. - : Wiley. - 0007-1048 .- 1365-2141. ; 133:1, s. 68-77
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Tidskriftsartikel (refereegranskat)abstract
- The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.
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| 17. |
- Buller, H, et al.
(författare)
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General discussion
- 2005
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Ingår i: Pathophysiology of haemostasis and thrombosis. - : S. Karger AG. - 1424-8832 .- 1424-8840. ; 3434 Suppl 1, s. 31-34
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Tidskriftsartikel (refereegranskat)
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| 18. |
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| 19. |
- Cullberg, M., et al.
(författare)
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Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis
- 2005
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Ingår i: Clin Pharmacol Ther. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 77:4, s. 279-90
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis. METHODS: A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models. RESULTS: The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat. CONCLUSIONS: The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.
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| 21. |
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| 22. |
- Harenberg, Job, et al.
(författare)
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Recommendations on biosimilar low-molecular-weight heparins
- 2009
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 7:7, s. 1222-1225
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Tidskriftsartikel (refereegranskat)abstract
- Based on the results of large clinical trials, several low-molecular-weight heparins (LMWHs) have been approved for prophylaxis and the treatment of venous and arterial thromboembolism. As a result of expiration or pending expiration of patent protection of the originator LMWHs, many generic or biosimilar LMWHs have been approved in some countries and more are likely to be approved elsewhere. Their greater availability may reduce the treatment costs. The Working Party on Requirements for Development of Biosimilar LMWHs of the Subcommittee on Control of Anticoagulation, Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis has reached a consensus on recommendations to ensure the quality of biosimilar LMWHs as compared with the originator LMWHs.
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| 31. |
- Schulman, S, et al.
(författare)
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Anticoagulants and their reversal
- 2007
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Ingår i: Transfusion medicine reviews. - : Elsevier BV. - 0887-7963. ; 21:1, s. 37-48
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Tidskriftsartikel (refereegranskat)
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| 38. |
- Schulman, S, et al.
(författare)
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Dabigatran etexilate: future directions in anticoagulant treatment
- 2009
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Ingår i: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723. ; 1515 Suppl 1, s. 32S-41S
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Tidskriftsartikel (refereegranskat)abstract
- Dabigatran etexilate is a novel, oral reversible direct thrombin inhibitor in the clinical development for the treatment and prevention of thromboembolic diseases. Clinical data indicate that dabigatran etexilate has immediate onset of effect, no need for monitoring, predictable and consistent pharmacokinetics and pharmacodynamics—all features that differentiate it from oral vitamin K antagonists (VKAs). Completed phase III studies demonstrated a comparable efficacy and safety profile to enoxaparin in the prevention of venous thromboembolism (VTE) after orthopedic surgery. Ongoing phase III trials are now evaluating the long-term use of dabigatran etexilate for the treatment and secondary prevention of VTE and for prevention of stroke in patients with atrial fibrillation, as a replacement for VKAs. With an immediate, reliable, and predictable anticoagulant effect without the need for coagulation monitoring and the lack of long-term safety concerns, dabigatran etexilate may be a prospective candidate that offers additional benefit over VKAs and parenteral anticoagulants in these settings.
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| 39. |
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| 41. |
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| 42. |
- Schulman, S
(författare)
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Getting intimate with the venous thrombus
- 2009
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Ingår i: Journal of thrombosis and haemostasis : JTH. - : Elsevier BV. - 1538-7836. ; 7:8, s. 1266-1267
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Tidskriftsartikel (refereegranskat)
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| 43. |
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| 44. |
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| 46. |
- Schulman, S
(författare)
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More on: vitamin K antagonists and cancer
- 2008
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Ingår i: JOURNAL OF THROMBOSIS AND HAEMOSTASIS. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 6:8, s. 1442-1443
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 47. |
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| 49. |
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| 50. |
- Schulman, S
(författare)
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Rivaroxaban in orthopedic surgery--a change of paradigm?
- 2009
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Ingår i: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723. ; 15:6, s. 613-620
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Tidskriftsartikel (refereegranskat)abstract
- Two selective, orally available anticoagulant agents, although with different targets in the coagulation cascade, have recently been approved in many countries on the indication of prophylaxis against venous thromboembolism (VTE) after major joint arthroplasty. This review discusses mainly the antifactor Xa drug, rivaroxaban, with a focus on the orthopedic trials. Pharmacokinetic characteristics and other clinical development programs with rivaroxaban are briefly reviewed. Although the aim of this article is not to review the direct thrombin inhibitor, dabigatran etexilate, some comparisons are made. For clinical results, these are obviously indirect and conclusions must be drawn with caution until head-to-head comparisons are performed. Whether the introduction of rivaroxaban is a change of paradigm will ultimately be decided in the eyes and mind of the beholder.
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