Aspirin for Prevention of Subarachnoid Hemorrhage

Abstract

To the Editor: Subarachnoid hemorrhage (SAH) resulting from aneurysm rupture remains a morbid and highly lethal event despite advances in management and interventional techniques.1 There is currently a lack of safe, effective noninvasive therapies to prevent intracranial aneurysm rupture. Recently, a growing body of evidence supporting an important role for inflammation in the pathogenesis of intracranial aneurysm rupture has opened new horizons to neurosurgeons.2-5 In a recent article entitled “Antithrombotic Drugs and Risk of Hemorrhagic Stroke in the General Population,” García-Rodríguez and colleagues6 examined the relationship between hemorrhagic stroke and the use of antiplatelets and warfarin. The authors analyzed data from 1797 patients with intracerebral hemorrhage and 1340 patients with SAH from the Health Improvement Network database. With the use of density-based sampling, 10 000 control subjects free from hemorrhagic stroke were selected; the risk of hemorrhagic stroke was then assessed in users and nonusers of antiplatelets after rigorous adjustment for several demographic/lifestyle factors and comorbidities. Among the findings of this well-designed, well-conducted study, the authors found that long-term low-dose aspirin therapy has a protective effective against SAH and does not increase the risk of intracerebral hemorrhage.6 Furthermore, the trend toward decreased risk of SAH was particularly pronounced in those on long-term aspirin therapy (>3 years). These findings confirm our prior work on the protective role of aspirin against intracranial aneurysm formation and rupture.7-9 We have been impatiently waiting for such a study, and it is of utmost importance that our findings have been replicated by a different group from a different continent. In a nested case-control study from the International Study of Unruptured Intracranial Aneurysms, we had previously reported that aspirin use was associated with a lower risk of SAH, with a dose-dependent relationship trend associating frequency of aspirin use with risk of hemorrhage. Patients who had been taking aspirin at least 3 times weekly had a significantly lower risk of SAH (adjusted hazard ratio, 0.45; 95% confidence interval, 0.22-0.92; P = .03). The results of these 2 studies leave little room for doubt; the protective effect of aspirin against SAH is real. Moreover, aspirin use does not incur an increased risk of intracerebral hemorrhage, as previously speculated. Whether aspirin intake worsens the outcome of patients sustaining aneurysm rupture (as a result of increased bleeding) needs to be determined. The mechanism through which aspirin may decrease the risk of aneurysm rupture appears to be related to its anti-inflammatory effects. Inflammation is a key factor in the process of intracranial aneurysm formation and rupture.10 Several constituents of the inflammatory response are implicated, most typically macrophages and vascular smooth muscle cells. Numerous inflammatory molecules such as nuclear factor-κB, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 have also been found to play a major central role in the cascade of events leading to aneurysm rupture.10 Macrophage-derived matrix metalloproteinases digest the extracellular matrix, weaken the arterial wall, and ultimately result in aneurysm rupture. Aspirin has been shown to have inhibitory effects on several inflammatory mediators implicated in intracranial aneurysm pathology. Aspirin inhibits matrix metalloproteinase-2 and -9 and tumor necrosis factor-α release in smooth muscle cells.7 Aspirin reduces leukocyte adhesion to endothelial cells through inhibition of nuclear factor-κB and decreases the expression of monocyte chemotactic protein-1 and interleukin-8 in endothelial cells.7 Additionally, we have provided evidence that the walls of ruptured human intracranial aneurysms have higher immunohistochemical staining for cyclooxygenase-2 and microsomal prostaglandin E2 synthase 1, both of which are inhibited by aspirin.9 Furthermore, in a small trial in which we randomized patients harboring unruptured intracranial aneurysms into an aspirin-treated (81 mg daily for 3 months) group and an untreated (control) group, we found, using immunostaining and macrophage-targeted imaging (ferumoxytol-enhanced magnetic resonance imaging), that aspirin attenuates the inflammatory process in aneurysm walls.8 Specifically, expression of cyclooxygenase-2, microsomal prostaglandin E2 synthase 1, and macrophages was lower in the aspirin group, and there was a notable decrease in signal intensity on ferumoxytol-enhanced magnetic resonance imaging after 3 months of aspirin treatment.8 Collectively, these data strongly suggested that aspirin may potentially be used as a therapeutic agent to prevent intracranial aneurysm growth and rupture. Some investigators have attributed the protective effect of aspirin against aneurysm rupture to its antiplatelet effects. Indeed, inhibition of platelet activation may reduce endothelial injury, mural thrombus formation, and the subsequent aneurysm wall inflammation. Although this may be a plausible mechanism, the study by García-Rodríguez and colleagues6 showing no protective effect for clopidogrel (a more potent antiplatelet agent) against SAH clearly argues against this hypothesis. Larger studies, however, are needed to further assess this question because the number of patients taking clopidogrel in this study was relatively limited. Although several advances have been made in endovascular and microsurgical techniques, these procedures still carry a nonnegligible risk of morbidity and mortality. Pharmacological therapy such as aspirin is therefore the most promising strategy for developing safe and efficient treatments for patients harboring intracranial aneurysms. Additionally, aspirin is an inexpensive, widely available, safe drug that has several other health benefits, including the prevention of myocardial infarction, ischemic stroke, and colorectal cancer. Clinicians and patients are also very familiar with aspirin, its dosing regimen, and its side effects, which facilitates its use for the prevention of SAH. The dose of aspirin required to prevent aneurysm rupture is uncertain, but our previous findings support the presence of a dose-response relationship. For this reason and because the anti-inflammatory effect of aspirin is sought for aneurysm treatment, higher doses of aspirin for long periods may be needed. In conclusion, we can no longer overlook the findings of large, well-designed cohorts showing a protective effective of aspirin against aneurysm rupture. The stage is set for a randomized controlled trial to assess the safety and efficacy of aspirin in preventing SAH. Disclosures Dr Jabbour has served as a consultant for ev3, Codman Neurovascular, and Mizuho. The remaining authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.