When is it safe to initiate anticoagulation (anticoagulant therapy) in a patient with ischemic stroke who has undergone hemorrhagic transformation?

From the Guidelines

It is reasonable to delay initiation of oral anticoagulation for 14 days after stroke onset in patients with ischemic stroke who have undergone hemorrhagic transformation, especially in those with larger cerebral infarcts or early signs of hemorrhage on neuroimaging. This recommendation is based on the most recent and highest quality study available, which suggests that anticoagulation reduces the risk of recurrent ischemic stroke but increases the risk of cerebral hemorrhage during the acute poststroke phase 1. The size of the hemorrhage, its stability on repeat imaging, blood pressure control, and the patient's underlying thrombotic risk all influence the timing of anticoagulation initiation.

When restarting anticoagulation, direct oral anticoagulants (DOACs) like apixaban or rivaroxaban are often preferred over warfarin due to their lower intracranial bleeding risk. Small hemorrhagic conversions may allow earlier anticoagulation resumption (around 14 days), while larger bleeds may require waiting 4 weeks or longer. Before restarting, it is essential to obtain follow-up brain imaging to confirm hemorrhage stabilization, ensure blood pressure is well-controlled (typically <140/90 mmHg), and consider starting with a reduced dose of anticoagulant initially. This cautious approach is necessary because hemorrhagic conversion represents disruption of the blood-brain barrier, and premature anticoagulation could exacerbate bleeding and worsen neurological outcomes.

Key factors to consider when deciding on the timing of anticoagulation initiation include:

• Size of the cerebral infarct: larger infarcts are associated with a higher risk of hemorrhagic transformation and worse bleeding with early initiation of anticoagulation
• Presence of early signs of hemorrhage on neuroimaging: patients with early signs of hemorrhage are at highest risk of further intracerebral bleeding and should delay initiation of oral anticoagulation
• Blood pressure control: ensuring blood pressure is well-controlled (typically <140/90 mmHg) is crucial before restarting anticoagulation
• Underlying thrombotic risk: patients with high-risk conditions requiring anticoagulation, such as atrial fibrillation, should balance the risk of recurrent hemorrhage against the risk of thromboembolism. According to the 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack, patients with stroke or TIA in the setting of AF are at increased risk of recurrent ischemic stroke and at risk for ICH 1.

In terms of specific anticoagulation regimens, the 2021 guideline suggests that anticoagulation reduces the risk of recurrent ischemic stroke but increases the risk of cerebral hemorrhage during the acute poststroke phase 1. The 2018 Chest guideline and expert panel report on antithrombotic therapy for atrial fibrillation also notes that early anticoagulation is associated with nonsignificantly reduced recurrent ischemic stroke but with increased intracranial bleeding, and no reduction in death or disability 1. However, the most recent and highest quality study available, the 2021 guideline, takes precedence in guiding clinical decision-making.

From the Research

Timing of Anticoagulation Initiation

The timing of anticoagulation initiation in patients with ischemic stroke who have undergone hemorrhagic transformation is a complex issue. Several studies have investigated this topic, providing insights into the optimal timing of anticoagulant therapy.

• A case report published in 2020 2 suggests that anticoagulation can be safely initiated as early as 6 days after the onset of hemorrhagic transformation in patients with mechanical heart valves and antithrombin deficiency.
• However, a study published in 2022 3 recommends delaying anticoagulation for at least 2 weeks, ideally 4 weeks, after a large ischemic stroke or hemorrhagic transformation, even in patients with high risk of thromboembolism.
• A pooled analysis of prospective studies and randomized trials published in 2023 4 found that initiating direct oral anticoagulants (DOACs) within 48 hours of acute ischemic stroke was not associated with an increased risk of hemorrhagic transformation.
• Another study published in 2022 5 investigated the timing of DOACs in patients with hemorrhagic transformation after endovascular treatment and found that early initiation of DOACs can prevent recurrent ischemic stroke and is unlikely to cause new intracranial hemorrhage or worsened hemorrhagic transformation.

Subtypes of Hemorrhagic Transformation

The timing of anticoagulation initiation may vary depending on the subtype of hemorrhagic transformation. For example:

• A study published in 2022 5 found that in patients with hemorrhagic infarction, early initiation of DOACs can prevent recurrent ischemic stroke and is unlikely to cause new intracranial hemorrhage or worsened hemorrhagic transformation.
• In patients with parenchymal hematoma, initiation of DOACs within 14 days appears to be safe and does not exacerbate the hematoma 5.
• A study published in 2018 6 found that patients with hemorrhagic transformation initiated anticoagulant therapy after a mean of 23.3 days from index stroke, compared to 11.6 days in patients without hemorrhagic transformation.

Clinical Outcomes

The clinical outcomes of patients with ischemic stroke who have undergone hemorrhagic transformation and initiated anticoagulant therapy vary. For example:

• A study published in 2018 6 found that hemorrhagic transformation was associated with increased mortality or disability at 90 days.
• A pooled analysis of prospective studies and randomized trials published in 2023 4 found that recurrent ischemic events were associated with poor functional outcomes.