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| 2. |
- Christersson, Christina, et al.
(författare)
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Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischemic events : Observations from the ESTEEM trial
- 2007
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 28:6, s. 692-698
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding. METHODS AND RESULTS: In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding. CONCLUSION: A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.
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| 3. |
- Christersson, Christina, et al.
(författare)
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Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction
- 2005
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 3:10, s. 2245-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.
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| 4. |
- Christersson, Christina, 1966-
(författare)
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Regulation of Tissue Factor and Coagulation Activity : Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs). In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes. Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.
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| 5. |
- Connolly, Stuart J., et al.
(författare)
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Dabigatran versus warfarin in patients with atrial fibrillation
- 2009
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 361:12, s. 1139-1151
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)
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| 6. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Pathophysiologic mechanisms of persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome
- 2008
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 156:3, s. 588-594
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently, a high prevalence of small persistent cardiac troponin I (cTnI) elevations has been reported in patients who had been stabilized after a recent episode of acute coronary syndrome (ACS). We now have studied the associations of persistently elevated cTnI levels to cardiac performance, inflammation, coagulation, coronary status, and treatment strategy in these patients. METHODS AND RESULTS: Cardiac troponin I was determined at 6 weeks, 3 months, and 6 months after randomization in 898 stabilized ACS patients from the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC) II trial and using the high-sensitive Access AccuTnI assay (Beckman Coulter, Fullerton, CA). All patients were followed up for at least 5 years. Persistent cTnI elevation >0.01 microg/L at the 3 measurement instances was detected in 233 patients (26%). N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6 months (OR 2.5, 95% CI 2.0-3.1), male sex (OR 2.2, 95% CI 1.4-3.7), and randomization to an early invasive strategy (OR 1.8, 95% CI 1.2-2.7) independently predicted persistently elevated cTnI levels. Persistently cTnI-positive patients in the invasive cohort had significantly lower NT-proBNP levels compared to noninvasively treated patients, indicating that the mechanisms causing cTnI elevation in this group may be prognostically less harmful. No independent associations were found for markers of inflammation or coagulation. CONCLUSION: Persistent cTnI elevation occurs frequently late after an ACS. The NT-proBNP level at 6 months was the strongest predictor for elevated cTnI levels that thus appear to be predominantly related to impaired left ventricular function.
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| 7. |
- Ezekowitz, Michael D., et al.
(författare)
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Rationale and design of RE-LY : randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran
- 2009
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 157:5, s. 805-810
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin K antagonists (VKAs) are effective for stroke prevention in patients with atrial fibrillation (AF) but are difficult to use. Dabigatran etexilate is a prodrug that is rapidly converted to the active direct thrombin inhibitor dabigatran. It is administered in a fixed dose without laboratory monitoring and is being compared with warfarin (international normalized ratio 2-3) in the RE-LY trial. Two doses of dabigatran (110 and 150 mg BID) are being evaluated. RE-LY is a phase 3, prospective, randomized, open-label multinational (44 countries) trial of patients with nonvalvular AF and at least 1 risk factor for stroke. Recruitment concluded with a total of 18,113 patients. Patients who were VKA-naive and experienced are included in balanced proportions. The primary outcome is stroke (including hemorrhagic) or systemic embolism. Safety outcomes are bleeding, liver function abnormalities, and other adverse events. Adjudication of end points is blinded to drug assignment. The trial is expected to accrue a minimum of 450 events with a minimum 1-year of follow-up. RE-LY is the largest AF stroke prevention trial yet undertaken. It is unique because it includes equal numbers of VKA-experienced and naive patients and evaluates 2 different dosages of dabigatran, which may allow tailoring of dosing to individual patient needs. The worldwide site distribution and broad range of stroke risk further increase the general applicability of the trial. Results are expected in 2009.
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| 8. |
- James, Stefan K, et al.
(författare)
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An acute inflammatory reaction induced by myocardial damage is superimposed on a chronic inflammation in unstable coronary artery disease
- 2005
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 149:4, s. 619-626
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Inflammation plays an important role in unstable coronary artery disease (CAD). We assessed the kinetics of inflammatory markers from symptom onset in patients with unstable CAD and their relation to myocardial damage.METHODS:Serial measurements of inflammatory mediators were performed in consecutive patients with unstable CAD enrolled at selected sites in the FRISC II (n = 558) and the GUSTO IV (n = 404) trials. The time from symptom onset was calculated for every serum sample (total 4400 samples).RESULTS:Median levels of interleukin 6 and C-reactive protein reached their peaks at 36 to 42 hours and at 48 to 54 hours, respectively, from symptom onset and returned to early postsymptom levels within 6 weeks. The early increase occurred almost exclusively in patients with baseline troponin T elevation (>0.01 microg/L). In contrast, median levels of fibrinogen increased continuously up to 120 hours after symptom onset, independently of myocardial damage. At 6 months, fibrinogen levels were still higher than in the early phase after symptom onset. The median levels of interleukin 6, C-reactive protein, and fibrinogen were still higher at 6 months than in healthy controls matched for age and sex to a population with unstable CAD.CONCLUSIONS:An early acute inflammatory reaction induced by myocardial damage seems to be superimposed on a chronic inflammatory condition, both of which might influence long-term outcome in unstable CAD.
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| 9. |
- Oldgren, Jonas, 1964-, et al.
(författare)
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Effects of fondaparinux in patients with ST-segment elevation acute myocardial infarction not receiving reperfusion treatment
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:3, s. 315-23
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: At least one quarter of ST-segment elevation myocardial infarction (STEMI) patients do not receive reperfusion therapy, and these patients are at high risk for new ischaemic events. We evaluated fondaparinux treatment vs. usual care, i.e. placebo or unfractionated (UF) heparin, in a pre-specified subgroup of 2867 (out of 12 092) patients not receiving reperfusion treatment in the OASIS-6 trial. METHODS: In all, 1458 patients were randomized to fondaparinux 2.5 mg once daily subcutaneously up to 8 days and 1409 patients to usual care (control). Randomization was stratified by indication for UF heparin (stratum II, n = 1226) or not (stratum I, n = 1641) based on the investigator's judgment. RESULTS: The proportion of patients who suffered death or myocardial re-infarction at 30 days (primary outcome) was 12.2% in the fondaparinux vs. 15.1% in the control group, hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.65-0.98. There was no increase in severe bleedings, HR 0.82; CI 0.44-1.55, or strokes, HR 0.62; CI 0.29-1.33. Consequently, the composite of death, myocardial re-infarction, or severe bleeding were significantly reduced at 30 days, HR 0.81; CI 0.67-0.99. Reductions in death or myocardial re-infarction at 30 days were consistent in stratum I with fondaparinux vs. placebo, HR 0.88; 95% CI 0.65-1.19, and in stratum II with fondaparinux vs. UF heparin infusion for 24-48 h (n = 806), HR 0.74; CI 95% 0.57-0.97, P = 0.41 for heterogeneity. CONCLUSION: In STEMI patients not receiving reperfusion treatment, fondaparinux reduces the composite of death or myocardial re-infarction without an increase in severe bleedings or strokes as compared to placebo or UF heparin.
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| 10. |
- Oldgren, Jonas, et al.
(författare)
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Influence of prolonged dalteparin treatment on coagulation, fibrinolysis and inflammation in unstable coronary artery disease
- 2005
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 258:5, s. 420-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Unstable coronary artery disease (CAD) is a multi-factorial disease involving thrombotic and inflammatory processes. Short-term low molecular weight (LMW) heparin treatment reduces coagulation activity and clinical events. We investigated the influence of prolonged treatment on coagulation, fibrinolysis and inflammation. METHODS AND RESULTS. Serial blood samples were obtained from 555 of 2,267 unstable CAD patients in the FRISC II study. Patients were treated with the LMW heparin dalteparin 120 IU kg(-1) s.c. twice daily for 5-7 days and randomized to placebo (n=285) or gender and weight-adjusted doses of dalteparin (5,000 or 7,500 IU) twice daily (n=270) for 3 months. Dalteparin persistently depressed coagulation activity with, when compared with placebo, lower median levels of factor VIIa (63 IU mL(-1) vs. 84 IU mL(-1)), prothrombin fragment 1 + 2 (0.86 nmol L(-1) vs. 1.09 nmol L(-1)) and D-dimer (21 microg L(-1) vs. 43 microug L(-1)) after 3 months, all P<0.01. Reactivation of coagulation activity was observed after cessation of both short-term and prolonged dalteparin treatment. Higher levels of tPA/PAI-1 complex (11.7 microg L(-1) vs. 6.5 microg L(-1), P<0.001) and von Willebrand factor (162% vs. 136%, P<0.001) were found during prolonged dalteparin treatment. Interleukin-6, C-reactive protein and fibrinogen levels were unaffected by dalteparin treatment. CONCLUSIONS. Three months dalteparin treatment resulted in a sustained and pronounced reduction of coagulation activity, which corresponds to the observed reduction in death and myocardial infarction during the initial 6 weeks in the FRISC II study. The persistently elevated levels of tPA/PAI-1 complex and von Willebrand factor might reflect effects on platelets and endothelial cells and thus contribute to the gradually decreased efficacy by prolonged dalteparin treatment in unstable CAD.
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