Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials

Thromboembolism Unit, Hamilton General Hospital, Hamilton, Ontario, L8L 2X2, Canada.
Circulation (Impact Factor: 14.43). 11/2009; 120(20):2006-11. DOI: 10.1161/CIRCULATIONAHA.109.872630
Source: PubMed


Bleeding is a strong predictor of death in patients hospitalized for arterial thrombosis who are treated with antithrombotic therapy, but the prognostic importance of bleeding in patients receiving antithrombotic prophylaxis for venous thromboembolism is uncertain.
Using Cox proportional hazards modeling, we examined the association between major bleeding and death at 30 days using pooled individual patient data from 8 large randomized controlled trials (n=13 085) comparing fondaparinux with control (low-molecular-weight heparin or placebo) for the prophylaxis of venous thromboembolism in hospitalized surgical or medical patients. Patients who developed major bleeding were older, were more likely to be male, had a lower body weight and lower creatinine clearance, and were more likely to be receiving fondaparinux. At 30 days, the risk of death was 7-fold higher among patients with a major bleeding event (8.6% versus 1.7%; adjusted hazard ratio, 6.96; 95% confidence interval, 4.60 to 10.51). There was a consistent pattern of reduced mortality in patients treated with fondaparinux irrespective of whether patients experienced major bleeding (6.8% versus 11.4%; hazard ratio, 0.58; 95% confidence interval, 0.27 to 1.23) or no major bleeding (1.5% versus 1.9%; hazard ratio, 0.77; 95% confidence interval, 0.59 to 1.02; P for heterogeneity=0.47).
Major bleeding in hospitalized surgical and medical patients participating in venous thromboembolism prevention trials is a strong predictor of mortality.

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    • "We excluded patients receiving intravenous thrombolytic from our study. A pooled analysis of eight large randomized controlled trials (n = 13,085) of fondaparinux versus placebo (LMWH or LDUH) in medical and surgical patients reported that age, fondaparinux, lower body weight and lower CrCl were predictors of major hemorrhage [23]. We reduced bias in our study by matching patients based on age, body weight and CrCl, in addition to a number of other covariates (gender, NIHSS, atrial fibrillation, diabetes, antiplatelet use, warfarin use, the duration of VTE anticoagulant and IPC use) in order to examine the relationship between VTE anticoagulant (fondaparinux versus UFH) and hemorrhagic events. "
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    ABSTRACT: Unfractionated heparin (UFH), low molecular weight heparin or fondaparinux are recommended for venous thromboembolism (VTE) prophylaxis in acutely ill medical patients. There are limited data on the safety of fondaparinux for VTE prophylaxis in ischemic stroke. We examined adverse event frequency in hospitalized patients with ischemic stroke who received VTE prophylaxis with fondaparinux versus UFH.Materials and Methods We performed a propensity score matched analysis on a retrospective cohort of 644 consecutive patients with acute ischemic stroke receiving fondaparinux (n = 322) or UFH (n = 322) for VTE prophylaxis. Patients who received intravenous tPA and continuous intravenous infusions of UFH were excluded. The primary outcome was major hemorrhage (intracranial or extracranial) and the secondary outcome was total hemorrhage (major and minor hemorrhage) during hospitalization. We also examined the rate of symptomatic VTE.ResultsMean age of the matched cohort was 71.3 ± 14.1 years, median NIHSS score was 4 (IQR 1–11), median duration of anticoagulant exposure was 5 (IQR 3–8) days, and 98.1% received antiplatelet medications. In the matched cohort, there were less observed major hemorrhages in the fondaparinux group 1.2% (4/322) compared to UFH 3.7% (12/322), but this difference was not significant (OR = 0.33, 95% CI 0.08–1.10, p = 0.08). There were also no significant differences in total hemorrhage (p = 0.15), intracranial hemorrhage (p = 0.48), major extracranial hemorrhage (p = 0.18) and symptomatic VTE (p = 1.00) between the groups.Conclusions Fondaparinux is not associated with increased hemorrhagic complications compared with UFH in patients with ischemic stroke. There were low rates of symptomatic VTE in both groups.
    Thrombosis Research 12/2014; 135(2). DOI:10.1016/j.thromres.2014.11.041 · 2.45 Impact Factor
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    • "Pharmacological VTE prophylaxis is recommended as the main mode of VTE prophylaxis for most hospitalized patients by the latest American College of Chest Physicians' guidelines and there is no doubt that it will remain the most important method to prevent VTE.[32] Elderly patients have, however, a much higher risk of bleeding after receiving pharmacological VTE prophylaxis than younger patients, partly due to frequent occurrences of renal impairment and drug interactions.[33] Evidence suggests that bleeding from antithrombotic agents is a strong predictor of mortality and will reduce the overall benefits of VTE prophylaxis in hospitalized patients.[28],[34] As such, we have to interpret the benefit to risk ratio of many pharmacological VTE prophylactic agents when applied to hospitalized elderly patients with caution. "
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    ABSTRACT: Venous thromboembolism (VTE) is the commonest cause of preventable death in hospitalized patients. Elderly patients have higher risk of VTE because of the high prevalence of predisposing co-morbidities and acute illnesses. Clinical diagnosis of VTE in the elderly patient is particularly difficult and, as such, adequate VTE prophylaxis is of pivotal importance in reducing the mortality and morbidities of VTE. Omission of VTE prophylaxis is, however, very common despite continuous education. A simple way to overcome this problem is to implement universal VTE prophylaxis for all hospitalized elderly patients instead of selective prophylaxis for some patients only according to individual's risk of VTE. Although pharmacological VTE prophylaxis is effective for most patients, a high prevalence of renal impairment and drug interactions in the hospitalized elderly patients suggests that a multimodality approach may be more appropriate. Mechanical VTE prophylaxis, including calf and thigh compression devices and/or an inferior vena cava filter, are often underutilized in hospitalized elderly patients who are at high-risk of bleeding and VTE. Because pneumatic compression devices and thigh length stockings are virtually risk free, mechanical VTE prophylaxis may allow early or immediate implementation of VTE prophylaxis for all hospitalized elderly patients, regardless of their bleeding and VTE risk. Although the cost-effectiveness of this Multimodality Universal STat ('MUST') VTE prophylaxis approach for hospitalized elderly patients remains uncertain, this strategy appears to offer some advantages over the traditional 'selective and single-modal' VTE prophylaxis approach, which often becomes 'hit or miss' or not implemented promptly in many hospitalized elderly patients. A large clustered randomized controlled trial is, however, needed to assess whether early, multimodality, universal VTE prophylaxis can improve important clinical outcomes of hospitalized elderly patients.
    Journal of Geriatric Cardiology 06/2011; 8(2):114-20. DOI:10.3724/SP.J.1263.2011.00114 · 1.40 Impact Factor
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    • "Linked-database Study [22] Sub-study of RCT [21] Community-based Study [14] Cardiovascular/ "
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    ABSTRACT: Combination warfarin-ASA therapy is currently used in approximately 800,000 patients in North America as long-term treatment for the primary and secondary prevention of atherothrombotic and thromboembolic diseases. Despite a potentially complementary action of anticoagulant and antiplatelet drugs, the use of combination warfarin-ASA therapy is not based on compelling evidence of a net therapeutic benefit, with the exception of patients with a mechanical heart valve. On the other hand, there is more compelling and consistent evidence that combination warfarin-ASA therapy confers a 1.5- to 2.0-fold increased risk for serious bleeding compared with use of warfarin alone. In everyday practice, clinicians should combine the best available evidence with clinical judgment, considering that in most clinical scenarios, clinical practice guideline may not provide clear recommendations for patients who should, and should not, receive combination warfarin-ASA therapy. The objectives of this review are to describe which patients are receiving combined warfarin-aspirin therapy, to summarize the evidence for the therapeutic benefit and harm of combined warfarin-ASA therapy, and to suggest practical guidelines as to which patients should, and should not, receive such treatment.
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