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Oldgren J.,Uppsala University | Budaj A.,Postgraduate Medical School | Granger C.B.,Duke Clinical Research Institute | Khder Y.,Boehringer Ingelheim | And 5 more authors.
European Heart Journal | Year: 2011

AimAfter an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran. Methods and resultsIn this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2 on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60) or non-ST-elevation (40) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n 369), 75 mg (n 368), 110 mg (n 406), 150 mg (n 347), or placebo (n 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95 confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45 at weeks 1 and 4, respectively (P< 0.001). Fourteen (3.8) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6) in 50 mg, 18 (4.9) in 75 mg, 12 (3.0) in 110 mg, and 12 (3.5) in the 150 mg dabigatran groups. ConclusionsDabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction. © 2011 The Author. Source


Flaker G.C.,University of Missouri | Eikelboom J.W.,Hamilton Health Sciences | Shestakovska O.,Hamilton Health Sciences | Connolly S.J.,Hamilton Health Sciences | And 6 more authors.
Stroke | Year: 2012

Background and Purpose: Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin K antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin. Methods: The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding. Results: The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin >50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category. Conclusions: Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information: www.clinicaltrials.gov. Unique identifier: NCT 00496769. © 2012 American Heart Association, Inc. Source


De Caterina R.,University G.O.C. | Connolly S.J.,Hamilton Health Sciences | Pogue J.,Hamilton Health Sciences | Chrolavicius S.,Hamilton Health Sciences | And 4 more authors.
European Heart Journal | Year: 2010

Aims:To assess the risk of death after the occurrence of different types of non-fatal events in patients with atrial fibrillation (AF). Antithrombotic therapies in AF have primarily focused on stroke prevention and bleeding. However, strokes and bleeds differ in severity, and the level of severity may differently impact mortality.Methods and results: We analysed the risk of subsequent mortality after the occurrence of non-fatal vascular and bleeding events in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-W trial. In the 3371 patients randomized to vitamin K antagonists and the 3335 patients randomized to clopidogrel plus aspirin in ACTIVE-W, the hazard ratio (HR) and 95 confidence intervals (95 CIs) for subsequent death associated with the occurrence of non-fatal stroke was 5.58 (95 CI 3.84-8.10, P < 0.0001). Both ischaemic (HR 5.29, 95 CI 3.53-7.93, P < 0.0001) and haemorrhagic strokes (HR 7.38, 95 CI 2.74-19.9, P < 0.0001) increased mortality, but transient ischaemic attacks did not. Disabling strokes (Rankin's score ≥3) increased mortality (HR 9.54; 95 CI 6.42-14.2, P< 0.0001), but non-disabling strokes did not. Severe bleeding increased mortality (HR 3.35, 95 CI 2.12-5.27, P < 0.0001), but major bleeding that was not severe according to the study definitions did not.Conclusion: Non-fatal strokes increased mortality in ACTIVE-W, but non-disabling strokes did not. Among major bleeding events, only those also classified as severe increased mortality. Future research should emphasize the prevention of disabling strokes and severe bleeds and place less emphasis on non-disabling stroke or major bleeds that are not severe. © European Society of Cardiology The Author 2010. All rights reserved. Source


Borg J.-J.,03 Level 3 | Aislaitner G.,National Organization for Medicines EOF | Pirozynski M.,Postgraduate Medical School | Mifsud S.,European Union
Drug Safety | Year: 2011

Amendments to the European pharmacovigilance legislative framework are expected to come into force in 2011, following the adoption of the proposed amendments to Directive 200183EC on the community code relating to medicinal products for human use (hereinafter referred to as the Directive) and to Regulation (EC) No. 7262004 laying down community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (EMA) hereinafter referred to as the Regulation. The Regulation shall apply 18 months after publication in the Official Journal of the European Union. The amendments to the Directive and the Regulation will induce changes in the EU in terms of evaluation of risk associated with medicinal products as well as the framework on how the EU takes harmonized regulatory action on drug safety. In this review, the text agreed between the European Parliament and Council is examined and compared with the pharmacovigilance legislative framework currently in force. We argue that the new legislation has improved numerous uncertainties in current legislative framework and provides for the following: (i) clear roles, responsibilities and obligations for the key responsible parties; (ii) rationalization of EU decision making on drug safety issues in order to deliver measures that are equally and fully implemented for all relevant products across the community with a view to preventing unnecessary patient exposure to risks; (iii) strengthening medicine safety transparency and communication so that the understanding and trust of patients and health professionals in the safety of medicines will improve, as well as the penetration of key warnings; (iv) strengthening companies pharmacovigilance systems, allowing companies to improve their systems constantly while reducing administrative burden; (v) ensuring the proactive and proportionate collection of high-quality data relevant to the safety of medicines through risk management and structured data collection in the form of Post-Authorization Safety Studies (PASS), together with rationalized single-case and periodic reporting of suspected adverse drug reactions (ADRs); (vi) involvement of stakeholders in pharmacovigilance through direct patient reporting of suspected ADRs and inclusion of patients and healthcare professionals in decision making; and (vii) simplification of the current community pharmacovigilance procedures with consequent efficiency gains for both the pharmaceutical industry and medicines regulators.For the first time, companies can be made legally liable to carry out PASS and Post-Authorization Efficacy Studies. The amendments to the Regulation and to the Directive will strengthen the European network on pharmacovigilance. A Pharmacovigilance Risk Assessment Committee (PRAC) based at the EMA will be set up, which will be responsible for all matters related to pharmacovigilance at an EU level. Three European databases will be strengthened (EudraVigilance, EudraPharm and the European Pharmacovigilance issues Tracking Tool) as well as the setting up of an EU safety portal to better inform the public on all safety issues being discussed at an EU level. Public hearings at the PRAC will improve transparency in the decision-making process, whilst details and results of all PASS agreed to by the PRAC will also be made publically available. © 2011 Adis Data Information BV. All rights reserved. Source


Swahn E.,Linkoping University | Alfredsson J.,Linkoping University | Afzal R.,McMaster University | Budaj A.,Postgraduate Medical School | And 5 more authors.
European Heart Journal | Year: 2012

Aims: The aim of this study was to compare benefits and risks of a routine invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes. Methods and results: We randomly assigned 184 women, either to a routine or to a selective invasive strategy as a substudy to the OASIS 5 trial, who were followed for 2 years. Meta-analysis of data from previous randomized trials was also done. There were no significant differences between the two treatment strategies in the primary outcome death/myocardial infarction (MI)/stroke [21.0 vs. 15.4%, HR = 1.46, 95% CI (0.73-2.94)], in the secondary outcome death/MI [18.8 vs. 14.3%, HR = 1.39, 95% CI (0.67-2.88)], or separately analysed outcomes MI [12.9 vs. 13.3%, HR = 0.95, 95% CI (0.42-2.19)] or stroke [2.3 vs. 4.4%, HR = 0.67, 95% CI (0.12-3.70)]. However, there were significantly more deaths after 1 year (8.8 vs. 1.1%, HR = 9.01, 95% CI (1.11-72.90) and a higher rate of major bleeding at 30 days [8.8 vs. 1.1%, HR = 11.45, 95% CI (1.43-91.96)] in the routine invasive strategy group. A meta-analysis including 2692 women in previous randomized trials, with a gender perspective, showed no significant difference in the composite outcome death/MI, OR = 1.18, 95% CI (0.92-1.53) but a higher mortality with a routine invasive strategy for women, OR = 1.51, 95% CI (1.00-2.29). Conclusion: The rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy compared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined with data from previous trials, there does not appear to be a benefit of an early invasive strategy in women with ACS, which differs from the results in men. These data emphasize the lack of clear evidence in favour of an invasive strategy in women and suggest caution in extrapolating the results from men to women. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. Source

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