The American journal of medicine
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Direct oral anticoagulants (DOACs) have been marketed in the United States since 2010. While numerous large-scale prospective phase 3 outcomes studies have documented the effectiveness of DOACs for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the primary safety concern with all of these drugs-as it is with the more established oral anticoagulant warfarin-is the risk of major bleeding. Postmarketing surveillance studies (PMSS) provide the opportunity to evaluate the safety of these recently approved drugs across a spectrum of patients that may be broader than those included in randomized controlled trials. This review will summarize the safety findings of numerous recently performed, large-scale PMSS evaluations, and consider the currently available evidence regarding the risks for bleeding in patients treated with DOACs, in order to give providers and patients additional evidence regarding the safety of DOACs.
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Stevens-Johnson syndrome and toxic epidermal necrolysis are severe mucocutaneous adverse drug reactions characterized by extensive epidermal detachment. The mortality rates have been reported to vary between 1% and 5% for Stevens-Johnson syndrome and 25% and 35% for patients with toxic epidermal necrolysis. Studies have shown that early recognition and prompt withdrawal of the causative agent leads to increased patient survival. ⋯ The onset and high mortality rate of Stevens-Johnson syndrome/toxic epidermal necrolysis may be related to unawareness of the early signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis, the common drug triggers that cause it, and what investigations (human leukocyte antigen typing in Asians) can be done to prevent it.
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As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. ⋯ As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, co-administer with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.
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More than 25% of all ischemic strokes per year are cryptogenic, that is, their cause is not determined after an appropriate evaluation. In 1988, it was reported that the incidence of a patent foramen ovale was 30 to 40% in young patients with a cryptogenic stroke compared with 25% in the general population. This led to the suspicion that cryptogenic strokes were due to paradoxical embolism, that is, a venous thrombus crossing a patent foramen ovale to enter the left atrium and then the arterial circulation. ⋯ Patients with cryptogenic strokes should be evaluated for the presence of venous thromboembolism. If venous thromboembolism is present, treatment should be the same as for pulmonary embolism: anticoagulation. If venous thromboembolism is not present, antiplatelet therapy is indicated.
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Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. ⋯ Supported by these interim results, idarucizumab has been approved in the United States and the European Union for use when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in patients with life-threatening or uncontrolled bleeding. Clinical use of idarucizumab should follow the same processes as patient enrollment in this study, which is projected to be completed in 2016. The outcomes achieved with this specific reversal agent are likely to be of continued interest to treating physicians.