Lancet Neurology 2013 published a metaanalysis of studies showing no benefit of anticoagulation in acute stroke. However, like Freddy Krueger, the debate will not die. Below is an excerpt from the editorial by Hart et al. that lays out some of the remaining points of contention.
A meta-analysis of 24 trials involving 23 748 patients with acute stroke found that early anticoagulation compared with no anticoagulation reduced recurrent ischaemic stroke and venous thromboembolism at the cost of increased intracranial and extracranial haemorrhage, with no overall reduction in death or disability.2 Consequently, guidelines for stroke management now recommend that anticoagulants should not be used for the management of acute stroke caused by common cerebrovascular disorders (including atrial fibrillation).3 Nonetheless, the question remains: are there acute stroke patients at high risk of thrombotic events and low risk of bleeding who might yet benefit from early anticoagulant therapy?
In this issue of The Lancet Neurology, William Whiteley and colleagues4 report the results of a pooled individual patient-level analysis of the five largest randomised trials that have tested heparins in patients with acute ischaemic stroke. The authors developed risk prediction models to identify acute stroke patients The analyses by Whiteley and colleagues provide no support for the use of anticoagulants in the management of patients with acute stroke, but the results must be interpreted with caution. First, despite careful efforts by the investigators to derive the best risk-prediction models, they were only modestly predictive of thromboembolic and bleeding events (C-statistics in the order of 0·6), thereby reducing the quality of the evidence and limiting the strength of the conclusions. Second, the conclusion must necessarily be restricted to the subgroups common to the trial databases; for example, the presence of large artery atherosclerosis was not considered.5 Third, uncertainty remains regarding the role of heparins in patients with uncommon conditions resulting in acute brain ischaemia. These include patients with acute cerebral venous thrombosis, small-to-moderate brain infarcts due to cerebral arterial dissection, aseptic embolism from prosthetic cardiac valves, mobile left ventricular thrombi, and aortic arch plaque with protruding overlying thrombi.
The balance between risks and benefits of heparins also remains unclear for patients with acute transient ischaemic attack or minor ischaemic strokes who were poorly represented in the randomised trials. These patients have a low risk of secondary haemorrhagic transformation because they do not have substantial areas of acute brain necrosis. A randomised trial that assessed the combination of clopidogrel plus aspirin in patients with acute transient ischaemic attack found a benefit of the intensive antiplatelet therapy,6 and other trials testing dual antiplatelet therapy in patients with acute ischaemic attack or minor ischaemic stroke are ongoing.7 Whether early anticoagulation provides benefit for these patients needs to be assessed.
Recently introduced novel oral anticoagulants that selectively target thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban) are attractive candidates for acute stroke treatment because they work rapidly (within 2–3 h) after oral administration. The most important advantage of the novel oral anticoagulants over warfarin is the sharply decreased risk of intracerebral haemorrhage seen during long-term treatment in patients with atrial fibrillation.8 If the novel oral agents are associated with a similarly low risk of secondary brain haemorrhage after acute stroke, the balance between risks and benefits of early anticoagulation might be altered in favour of treatment, making this a priority for future research.
Despite multiple randomised trials testing heparins in patients with acute ischaemic stroke, and also the rigorous efforts by Whiteley and colleagues to identify subsets of patients defined by thromboembolic and bleeding risk that might benefit from early anticoagulation, the value of this approach has not been established for any patient group.4 However, promising early data with the use of combined antiplatelet therapy and the emergence of novel oral anticoagulants with a rapid onset of action and low risk of intracranial haemorrhage means that anticoagulant therapies for patients with acute brain ischaemia remains a fruitful area for future clinical research.
