Elsevier

World Neurosurgery

Volume 74, Issues 2–3, August–September 2010, Pages 279-285
World Neurosurgery

Peer-Review Report
Emergency Reversal of Antiplatelet Agents in Patients Presenting with an Intracranial Hemorrhage: A Clinical Review

https://doi.org/10.1016/j.wneu.2010.05.030Get rights and content

Objective

Prehospital use of antiplatelet agents has been associated with an increased risk for intracranial hemorrhage (ICH) as well as a secondary increase in ICH volume after the initial hemorrhage. Strategies to reestablish platelet aggregation are used in clinical practice, but without any established guidelines or recommendations. This article serves to evaluate the literature regarding “reversal” of antiplatelet agents in neurosurgical populations.

Methods

PubMed and MEDLINE databases were searched for publications from 1966 to 2009 relating to intracranial hemorrhage and antiplatelet agents. The reference sections of recent articles, guidelines, and reviews were reviewed and pertinent articles identified. Studies were classified by two broad subsets: those describing intracranial hemorrhage relatable to a traumatic mechanism and those with a spontaneous intracranial hemorrhage. Two independent auditors recorded and analyzed study design and the reported outcome measures.

Results

For the spontaneous intracranial hemorrhage group, nine reports assessing antiplatelet effects on various outcome measures were identified. Eleven studies evaluating the use of prehospital antiplatelets before a traumatic intracranial hemorrhage were examined.

Conclusion

The data assessing the relationship between outcome and prehospital antiplatelet agents in the setting of ICH is conflicting in both the trauma and the stroke literature. Only one retrospective review specifically addressed outcomes after attempted reversal with platelet transfusion. Further study is needed to determine whether platelet transfusion ameliorates hematoma enlargement and/or improves outcome in the setting of acute ICH.

Introduction

Prophylactic treatment with anticoagulants and antiplatelet agents has clear benefits in select patients with cardiac and vascular diseases (23, 41). Over the previous decade, there has been a significant increase in the use of these agents for primary prevention of stroke and heart disease and for prophylaxis and after percutaneous cardiac interventions. Patients experiencing intracranial hemorrhage (ICH) while fully anticoagulated have been reported to present with larger hematoma volumes and suffer a worse prognosis compared to control groups with normal coagulation profiles (15, 19, 45). Further study has demonstrated that ICH progression in anticoagulated patients could be halted, and mortality significantly reduced, with a prompt reversal of anticoagulation (26). Some investigators have also reported that a prehospital antiplatelet regimen may be associated with hematoma expansion, an increased mortality rate, and a poor functional outcome (25, 44, 47, 52). As such, many institutions have established protocols to “reverse” the impairment of platelet aggregation caused by antiplatelet agents in patients presenting with ICH.

Several antiplatelet agents are commonly used in the outpatient setting. Aspirin is widely used for a variety of indications including risk reduction from transient ischemic attacks, prevention of primary myocardial infarction, and prevention of colorectal cancer (34). Aspirin irreversibly binds to the cyclooxygenase-1 (COX-1) enzyme and subsequently inhibits production of thromboxane A2, a potent eicosanoid involved in platelet aggregation (28). Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically used for relief from arthritis and headache pain. This class of medications acts upon on COX-1 in a reversible, dose-dependent inhibition; as the drug concentration decreases, COX-1 regains its enzymatic activity. Aspirin differs from NSAIDs functionally in that aspirin-induced COX-1 inhibition is irreversible, secondary to protein acetylation (53). Clopidogrel and ticlopidine both selectively and irreversibly inhibit the P2Y12 ADP receptor. These agents have been used effectively to treat a wide range of cardiovascular and cerebrovascular diseases, such as for prophylaxis after coronary or intracranial stent placement. Because of an active metabolite, clopidogrel in particular persists after cessation of the medication. Some studies have demonstrated a higher incidence of postoperative bleeding with clopidogrel as compared to aspirin, prompting some experts to recommend aggressive antiplatelet reversal for up to 4 days after the last known dose (56).

This review will focus on the treatment of ICH in patients taking prehospital NSAIDs, aspirin and clopidogrel (Plavix), and ticlopidine (Ticlid). Given the heterogeneity of the etiology of intracranial hemorrhages, spontaneous ICH and traumatic hemorrhages will be reviewed separately. The pertinent literature is evaluated and reviewed for evidence-based recommendations or guidelines to provide treatment guidance to clinicians for patients presenting with antiplatelet associated intracranial hemorrhages.

Section snippets

Literature Review

PubMed and MEDLINE databases were searched for publications from 1966 to the present using MeSH terms antiplatelet, aspirin, clopidogrel (Plavix), ticlopidine (Ticlid), intracranial hemorrhage, head injury, traumatic hemorrhage, subdural hematoma, and stroke. The search was limited to articles in the English language and those relating to human subjects older than age 18 years. Reference sections of recent articles, guidelines, and reviews were reviewed and pertinent articles identified.

Spontaneous ICH

Spontaneous intracerebral hemorrhage constitutes 10 % to 15% of all strokes and is a devastating stroke subtype. Clinical trials of surgical interventions have failed to demonstrate a consistent benefit (35). Many predictors of negative outcome have been consistently described in patients suffering from spontaneous ICH, including oral anticoagulant therapy (15, 45). Furthermore, warfarin use has been associated with larger volumes of ICH on baseline imaging, subsequent ICH growth, and increased

Traumatic ICH

Traumatic brain injury (TBI) is responsible for more than 1 million hospital visits, roughly 200,000 hospital admissions, and 50,000 deaths in the United States annually (51). Given the considerable increase in the use of antiplatelet agents for stroke prevention and cardiac prophylaxis, many patients taking antiplatelet agents will subsequently experience intracranial hemorrhage secondary to TBI. In an attempt to reduce the increased morbidity and mortality associated with TBI in patients on

Options for Reversal

The literature regarding “reversal” of prehospital aspirin therapy after acute intracranial hemorrhage is equivocal. At many institutions, it is standard practice to recommend platelet transfusion in the setting of intracranial hemorrhage in an effort to stem the salicylate effect upon platelet aggregation (22). Although there is no specific antidote, the aspirin effect is believed to be reversed by one platelet transfusion (1 single donor or 5 pooled concentrates) (4, 54). Furthermore, other

Effect of Pharmacokinetics

There is a known substantial variation in patient response to antiplatelet medications (21). This diversification of molecular effectiveness among patients may, in part, explain some of the conflicting outcome results seen in the retrospective reviews presented in Table 1, Table 2. Recently, Naidech et al. (37, 38, 39) reported several studies linking objective measures of platelet function with increased mortality, increased early clot growth, worse functional outcomes at 3 months, and

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    Conflict of interest statement: The authors declare that the commentary was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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