Outcomes following major bleeding in atrial fibrillation

This editorial refers to ‘Long-term clinical outcomes after major bleeding in patients with atrial fibrillation: the Fushimi AF registry’, by H. Ogawa et al. on pages 163–171. Atrial fibrillation (AF) increases the risk of thromboembolic strokes which are typically a more severe and debilitating phenotype.1 Oral anticoagulation (OAC) with the vitamin K antagonist warfarin reduces the risk of stroke at the expense of an increased risk of major extracranial haemorrhage and intracranial haemorrhage.2 International guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) in preference to warfarin (excluding patients with mechanical heart valves or moderate–severe mitral stenosis),3 as they provide a relative reduction of 19% for all stroke or systemic embolism, 51% for haemorrhagic stroke, and 52% for intracranial haemorrhage (ICH).4 However, they are associated with a 25% relative increase in the risk of gastrointestinal bleeding4 and, whilst major bleeding events in the context of anticoagulation for AF are associated with increased mortality,5,6 little is known about long-term outcomes after major bleeding in patients with AF. In the accompanying article, Ogawa et al.7 describe, for patients who have received OAC for stroke prophylaxis, clinical outcomes after a major bleeding event over a median period of follow-up of 3.5 years. They report findings for 4304 patients with AF enrolled since 2011 across 81 primary and secondary care institutions in Kyoto, Japan. In line with other studies, a high proportion was not prescribed OAC and many were prescribed an antiplatelet agent.8 As expected, major bleeding was more frequent among those prescribed OAC (2.2 per 100 person-years vs. 1.8 per 100 person-years). Notably, the group with major bleeds were older, more comorbid and had higher baseline thromboembolic (CHADS2 and CHADS2VA2SC score) and bleeding (HAS-BLED) risk scores. The cohort who suffered a major bleeding event subsequently had at least a two-fold higher risk of death and were nearly three times more likely to have stroke or systemic-embolism. Follow-up using electronic case record form collection found that at 5 years the cumulative all-cause mortality following a major bleed approached 60% compared with ∼20% in the non-major bleed group. Ogawa et al.7 also collected annual prescription information after a major bleeding event. They observed that 84% of patients restarted OAC (higher than previous studies), with 12.8% of patients having been converted from warfarin to NOAC. Notably, patients who re-started OAC were found to have a lower incidence of the composite outcome of mortality, stroke, systemic embolism, or recurrence of major bleeding over 5 years compared to the patients who did not. So, how should we approach the use of OAC after a major bleeding event? For patients with AF at high risk of stroke, the benefit of OAC is well established.2,4 Yet, it is understandable that clinicians may be wary of prescribing OAC for fear of recurrent bleeding, especially if this could prove fatal. The question becomes one of safety—does restarting OAC after a bleed increase the risk of recurrence, and if so, does this increased risk of bleeding outweigh the benefits of thromboembolic prophylaxis? Patients with preceding major bleeding events are under-represented in randomized controlled trials and have left a gap in the evidence base. The vast majority of information has, therefore, been derived from retrospective observational studies which predominantly comprise patients anticoagulated with warfarin. A meta-analysis of 10 studies, consisting of 5400 patients, found that re-initiation of warfarin after a gastrointestinal bleed was associated with a reduction in thromboembolic events and mortality, but that there was also an increase in recurrent bleeds.9 One retrospective observational study of 2991 patients compared the recommencement of NOACs vs. warfarin for AF after a gastrointestinal bleed. Both warfarin and NOACs were associated with decreased risk of thromboembolism. However, whilst warfarin and rivaroxaban resumption were associated with an increased risk of recurrent gastrointestinal bleeding on time-varying analysis, there was no association with resumption of dabigatran and apixaban and recurrent bleeding.10 For ICH, deciding on whether to re-initiate OAC is complicated by the high fatality rate associated with ICH and the shared risk factors between ischaemic stroke and ICH. Retrospective observational data from Germany and Denmark has suggested that re-introduction of OAC (overwhelmingly warfarin) for AF was associated with reduced rates of thromboembolic events and mortality without increased rates of re-bleeding.11,12 Conversely, the largest registry study of re-initiation of warfarin in AF, conducted in Taiwan, found an increased risk of ICH and suggested that the net benefit, calculated by numbers needed to treat vs. numbers needed to harm, only occurred among patients with CHADS2VA2SC score <6.6 Nonetheless, a meta-analysis of 12 cohort studies, involving 3431 patients, has supported a long-term survival benefit from OAC resumption without an increase in ICH recurrence.13 One observational study has compared the use of NOACs vs. warfarin after ICH in AF and showed that use of NOACs were associated with lower (though non-significant) risk of ischaemic stroke and recurrent ICH.14 Whilst this study by Ogawa et al. provides new insights into longer term outcomes after a major bleeding event for OAC, one must be mindful of its limitations. Most importantly, as an observational study, it provides only insights into associations and not causation. Information is not provided for factors such as the severity of major bleeding and ICH subtypes, which may have different associations with outcomes, or influenced clinical decisions to restart OAC. The time in therapeutic range for patients prescribed warfarin is not reported, which could also have bearing upon the safety and efficacy rates. So where does this leave us? From the current observational evidence, it appears that OAC re-initiation after a major bleeding event does not carry a prohibitively high bleeding risk. Even so higher levels of evidence are needed and will only arise from randomized controlled trials, such as the on-going APACHE-AF (Apixaban vs. Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation) trial.15 Given the complexities of competing thrombotic and bleeding risks, decisions about recommencing OAC for stroke prophylaxis in AF should be made following multi-disciplinary consultation.3 Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Quality of Care and Clinical Outcomes or of the European Society of Cardiology.