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    • Andexanet alpha is a modified recombinant FXa

    2018-10-30

    Andexanet alpha is a modified recombinant FXa lacking enzymatic activity which is currently in an earlier stage of development for neutralisation of direct and indirect FXa inhibitors. A phase 3 study to evaluate the effect of andexanet in bleeding patients receiving FXa-inhibitors started in 2015. In addition, a small molecule ciraparantag has entered phase I clinical trials. Ciraparantag binds non-covalently to anticoagulants, inhibiting the anticoagulant effects of low molecular weight heparins, fondaparinux, oral FXa inhibitors and dabigatran (Greinacher et al., 2015).
    Restarting Oral Anticoagulation After Ischaemic or Haemorrhagic Stroke and Major Gastrointestinal Bleeding The observed incidence of early (within 14days) recurrent ischaemic stroke is 8% (Berge, 2000). Early glut 1 of anticoagulation may thus be effective in preventing early recurrence. This potential benefit must, however be balanced with the potential risk for ICH. Observational data suggest that independent predictors for symptomatic haemorrhagic transformation of ischaemic stroke are large infarct, previous haemorrhagic stroke and low platelet count (Lee et al., 2010). For patients without high-risk features, the risk for symptomatic ICH whilst undergoing anticoagulation therapy is 1.5% within 14days (Lee et al., 2010). In the European Atrial Fibrillation Trial (EAFT), which enrolled patients with TIA or minor stroke, oral anticoagulation was found to be effective in a protocol that initiated warfarin within 14days of symptom onset in approximately half of the patients ([European atrial fibrillation trial (EAFT), 2015). In most trials of NOACs, the study drug could not be started within 7 to 14days of a stroke event (Connolly et al., 2009; Granger et al., 2011; Patel et al., 2011). However, the RE-LY trial delayed eligibility for 6months after a severe stroke (Diener et al., 2010). Recent guidelines from the American Heart Association/American Stroke Association advise that for most patients with a stroke or TIA in the setting of AF, it is reasonable to initiate OAC within 14days after the onset of neurological symptoms; however, in the presence of high risk for haemorrhagic conversion, it is reasonable to delay initiation of OAC beyond 14days (Kernan et al., 2014). ICH occurs in up to 1% of patients on OAC per year and it is the most feared and devastating complication of this treatment (Lansberg et al., 2012). AF patients who experience an ICH are at very high risk of ischemic stroke and mortality if uracil are not on antithrombotic therapy (Brønnum Nielsen et al., 2015). Factors contributing to recurrent ICH include increasing age, concomitant use of aspirin or nonsteroidal anti-inflammatory drugs, uncontrolled hypertension, spontaneous ICH, lobar bleed and cerebral amyloid angiopathy (Nielsen et al., 2015; Qureshi et al., 2001). Patients with lobar haemorrhage, microbleeds or cerebral amyloid angiopathy remain at higher risk for anticoagulant-related ICH recurrence than thromboembolic events and may be best managed without anticoagulants. Patients with deep hemispheric ICH and a baseline risk of ischemic stroke >6.5% per year, that corresponds to CHA2DS2-VASc ≥5, may have net benefit from restarting anticoagulation. To date, a reasonable recommendation regarding time from stroke to resumption of anticoagulation therapy would be 8–10weeks (Lansberg et al., 2012; Paciaroni and Agnelli, 2014). Reported rates of major bleeding among individuals with AF taking oral VKAs vary widely ranging from 1.3% to 7.2% per year. This variability of the values reflects the differences in the studies patient populations and the methodology employed (Lip et al., 2011). Most bleeding events are gastrointestinal bleedings (Hansen et al., 2010). The largest published cohort study was contacted in Denmark and included 4602 patients with AF discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Among patients surviving the first 90days after gastrointestinal bleeding, restarting single treatment with oral anticoagulation was associated with the lowest risk of all-cause mortality and thromboembolism. In one medium size retrospective cohort study analysis of patients who developed major gastrointestinal bleedings whilst taking warfarin and later had evidence of the bleeding resolution, restarting warfarin was independently associated with decreased mortality (adjusted hazard ratio 0.66, 95% CI 0.55–0.80, p<0.0001) (Qureshi et al., 2014). In a smaller observational cohort study resuming OAC after hospitalisation for gastrointestinal bleedings was associated with a significantly decreased adjusted risk of major thromboembolic events over 90days, without a significantly increased risk of recurrent gastrointestinal bleedings (Sengupta et al., 2015). These data support the recommendation that OAC should be continued after an episode of gastrointestinal bleedings whenever possible.