J Neurosurg 101:921925, 2004

Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage

L. GERARD TOUSSAINT III, M.D., JONATHAN A. FRIEDMAN, M.D., EELCO F. M. WIJDICKS, M.D., DAVID G. PIEPGRAS, M.D., MARK A. PICHELMANN, M.D., JON I. MCIVER, M.D., ROBYN L. MCCLELLAND, PH.D., DOUGLAS A. NICHOLS, M.D., FREDRIC B. MEYER, M.D., AND JOHN L. D. ATKINSON, M.D.
Departments of Neurologic Surgery, Neurology, Neuroradiology, and Biostatistics, Mayo Graduate School of Medicine, Rochester, Minnesota; and Section of Neurosurgery, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
Object. Previous studies have indicated an increased incidence of death in patients with subarachnoid hemorrhage (SAH) who are currently receiving anticoagulation therapy. The significance of previous aspirin use in patients with SAH is unknown. The authors analyzed the effects of prior aspirin use on clinical course and outcomes following aneurysmal SAH. Methods. The medical records of 305 patients with angiogram-confirmed aneurysmal SAH who consecutively presented to our institution between 1990 and 1997 within 7 days of ictus were analyzed. Twenty-nine (9.5%) of these patients had a history of regular aspirin use before onset of the SAH. The Glasgow Outcome Scale (GOS) was used to measure patient outcome at the longest available follow up. Aspirin users were older on average than nonusers (59 years of age compared with 53 years; p = 0.018). The mean admission Hunt and Hess grades of patients with and without aspirin use were similar (2 compared with 2.3; p = 0.51). Two trends, which did not reach statistical significance, were observed. 1) The rebleeding rate in aspirin users was 14.3%, compared with a 4.7% rebleeding rate in nonusers (p = 0.06). 2) Permanent disability from vasospasm was less common among aspirin users (23% compared with 50%; p = 0.069). Outcomes did not differ between aspirin users and nonusers (mean GOS Score 3.83 compared with GOS Score 3.86, respectively; p = 0.82). Conclusions. Despite trends indicating increased rebleeding rates and a lower incidence of permanent disability due to delayed ischemic neurological deficits, there was no significant effect of previous aspirin use on overall outcome following aneurysmal SAH. Based on these preliminary data, the presence of an intracranial aneurysm is not a strict contraindication to aspirin use.

KEY WORDS subarachnoid hemorrhage cerebral aneurysm aspirin rebleeding vasospasm

SPIRIN is among the most widely used medications in the world, but its effect on outcome in patients following SAH is unclear. The population prevalence of regular (at least weekly) aspirin use ranges from 15 to 30%.13,21,23 In a medically trained cohort, the regular use of aspirin ranges from 40 to 72%.8 There are numerous reports in which the relationship between aspirin use and intracranial hemorrhage has been examined, with conflicting results.1,5,13,23 Even less clear is the role of transient platelet inhibition due to nonsteroidal antiinflammatory drug use as a risk factor for SAH3the preponderance of data do not indicate a statistically significant risk.2,10,12 There are too few investigations focusing on the effect of prehemorrhage aspirin use on outcome in patients after SAH. Because of its effect on platelet function, aspirin thera-

py before hemorrhage and, specifically, before SAH carries the theoretical risks of exacerbating the illness and complicating treatment. In neurosurgical patients, antiplatelet medication use is the most prevalent modifiable risk factor associated with a postoperative hematoma requiring evacuation.20 In contrast, aspirin use may offer beneficial effects after SAH. The efficacy of aspirin therapy in attenuating cerebral vasospasm following SAH has been demonstrated.14,15,17,25,27 To clarify these conflicting effects, we studied the impact of prehemorrhage aspirin use on outcome following aneurysmal SAH. Clinical Material and Methods We analyzed the hospital records of all patients with aneurysmal SAH who were admitted to a single institution between 1990 and 1997. For inclusion in the study, the patients had to meet the following criteria: 1) evidence of SAH detected by CT scanning or cerebrospinal fluid exam921

Abbreviations used in this paper: CT = computerized tomography; GOS = Glasgow Outcome Scale; SAH = subarachnoid hemorrhage.

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TABLE 1 Summary of patient characteristics at presentation*
Characteristic Aspirin Users (29 patients) Nonusers (276 patients) p Value

TABLE 3 Comparison of outcomes in patients after SAH based on aspirin use

No. of Patients (%) Aspirin Users (29 patients) Nonusers (276 patients)

age (yrs, mean SD) sex (no. of patients [%]) female male history of hypertension (no. of patients [%]) Hunt & Hess grade (mean SD) size of ruptured aneurysm in mm (mean SD) pst circulation aneurysm (no. of patients [%])

59.00

10.56 53.00

14.27

0.018 0.918
Outcome

18 (62.1) 11 (37.9) 14 (48.3) 2.00 9.00 0.87 6.63

174 (63) 102 (37) 119 (43.1) 2.30 10.00 1.24 6.61

p Value

0.594 0.510 0.191 0.055

4 (13.8)

85 (30.8)

* Pst = posterior; SD = standard deviation. Wilcoxon test. Chi-square test. Mean Hunt and Hess grades are expressed as Arabic numerals to allow for fractions.

ination; 2) presence of an aneurysm angiographically confirmed to be the source of the hemorrhage; and 3) presentation to the hospital within 7 days postictus. Patients were excluded for the presence of arteriovenous malformation, other vascular anomaly, or trauma confounding the identification of the source of the hemorrhage. Intraparenchymal hemorrhage, when present, was not a criterion for exclusion if the majority of the hemorrhage was subarachnoid. Demographic and pertinent clinical data were extracted from patient records. Aspirin use was identified by the patients medical history and physical examination obtained at admission, by a health questionnaire completed by the patient or a family member at admission, or by the most recent clinical notes made before onset of the SAH, which indicated regular aspirin use without evidence of a change in this regimen. Any duration of aspirin use before the ictus was included and aspirin use to relieve a headache associated with a likely sentinel hemorrhage was included if it was clearly separate from the ictal event leading to hospital admission. Rebleeding was defined as a clinical deterioration with evidence of recurrent hemorrhage on the CT scan. Symptomatic vasospasm was defined as a focal or global neurological deficit
TABLE 2 Treatment of patients with aneurysmal SAH
No. of Patients (%) Treatment Aspirin Users (29 patients) Nonusers (276 patients) p Value

pulmonary complication cardiac arrest preop rebleeding clinical vasospasm no. of patients w/ data available vasospasm absent vasospasm present permanent deficit due to vasospasm no. of patients w/ vasospasm in whom data were available: deficit absent deficit present survived outcome (mean GOS score SD) poor outcome (GOS score 3) good outcome (GOS score 4) * Chi-square test. Fisher exact test. Wilcoxon test.

8 (27.6) 0 (0.0) 4 (13.8) 28 15 (53.6) 13 (46.4) 13

58 (21.0) 11 (4.0) 13 (4.7) 268 169 (63.1) 99 (36.9)

0.414* 0.608 0.060 0.325*

0.069* 92 10 (76.9) 46 (50.0) 3 (23.1) 46 (50.0) 23 (79.3) 233 (84.4) 3.8 1.63 3.9 1.48 10 (34.0) 91 (33.0) 19 (65.5) 185 (67.0)

0.435 0.820 0.869*

referable to one or more vascular territories, in which transcranial Doppler measurements or cerebral angiography indicated arterial narrowing believed to have caused the neurological findings. Deficits from symptomatic vasospasm could not be explained by other causes of neurological deterioration (rebleeding, acute or worsening hydrocephalus, electrolyte disturbances, hypoxia, or seizures). The determination of a permanent deficit from vasospasm and global GOS9 scores were assigned to data collected at the longest available follow-up point (mean 16.4 months, range 3 days 10 years).
Statistical Analysis

external ventricular drainage shunt placement aneurysm treatment group none clip placement coil embolization both * Chi-square test. Fisher exact test.

10 (34.5) 3 (10.3) 2 (6.9) 26 (89.7) 1 (3.4) 0 (0.0)

76 (27.5) 36 (13.0) 27 (9.8) 216 (78.3) 28 (10.1) 5 (1.8)

0.429* 1.000 0.699

Comparisons between aspirin use and categorical variables were made using chi-square tests or Fisher exact tests when sample sizes were limited. Comparisons of mean values for continuous variables between aspirin users and nonusers were made using a two-sample t-test or the Wilcoxon rank-sum test. Adjusted logistic regression models for the odds of preoperative rebleeding and the odds of permanent deficit due to vasospasm were constructed to incorporate potential confounders into the analysis. Models included aspirin use, patient age, Hunt and Hess7 grade at admission, and a location of the aneurysm in the posterior circulation. Similar models were also used for the odds of clinical vasospasm, odds of permanent deficit due to vasospasm, and odds of poor outcome (GOS Score 3) at the longest available follow up.

Results A review of 1319 medical records was made. Three hundred eight medical records met the study inclusion criteria.
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TABLE 4 Multiple logistic regression models for rebleeding, clinical vasospasm, permanent deficit, and GOS score*
Odds of Rebleeding (303 patients) Variable OR 95% CI p Value Odds of Clinical Vasospasm (296 patients) OR 95% CI p Value OR Odds of Permanent Deficit (105 patients) 95% CI p Value Odds of GOS Score 3 (305 patients) OR 95% CI p Value

aspirin use yes vs no patient age (5-yr increases) Hunt & Hess (1-unit increases) pst circ aneurysm yes vs no

3.15 1.10 1.13 0.85

0.9110.88 0.911.32 0.751.72 0.262.74

0.070 0.330 0.560 0.780

1.50 1.00 1.23 0.83

0.673.34 0.921.09 1.001.50 0.491.40

0.320 0.980 0.048 0.480

0.35 0.96 1.37 1.13

0.091.41 0.821.13 0.912.05 0.472.74

0.14 0.63 0.13 0.79

1.31 1.18 2.21 1.78

0.543.18 1.071.31 1.742.80 0.993.20

0.540 0.001 0.001 0.054

* CI = confidence interval; circ = circulation; OR = odds ratio.

The records of three patients were excluded from the study because research authorization was denied, leaving 305 patient records for analysis. Of the 305 patients, 29 (9.5%) had a history of aspirin use before they experienced an SAH. Eighteen of these 29 patients used aspirin daily or every other day, whereas the remaining 11 patients used aspirin as needed for analgesia. The daily dose of aspirin ranged from 81 to 1950 mg. Aspirin users were older on average than nonusers (59 years of age compared with 53 years; p = 0.018). The mean admission Hunt and Hess grades of patients who used or did not use aspirin were similar (2 compared with 2.3; p = 0.51). Aspirin users were not statistically different from nonusers with regard to sex, history of hypertension, need for ventricular drainage or a shunt, or rate of surgical repair compared with endovascular treatment (Table 1). Aspirin users were slightly less likely to harbor posterior circulation aneurysms, but this difference was not significant (13.8% compared with 30.8%; p = 0.06). There was no statistical difference in treatment parameters between the two groups (Table 2). The outcome data illustrated two trends, neither of which reached statistical significance (Table 3). First, there was an increased rate of rebleeding in aspirin users (14.3% compared with a 4.7% rebleeding rate in nonusers; p = 0.06). Second, the overall incidence of symptomatic vasospasm did not differ between aspirin users and nonusers (46% compared with 37%; p = 0.44); however, there was a tendency for nonusers to die or suffer a permanent disability from vasospasm at a higher rate than aspirin users (50% compared with 23%; p = 0.069). In the entire series, preoperative rebleeding was associated with an increased risk of a poor outcome (GOS Score 3) at the last follow-up point (62.5% of patients with repeated bleeding had GOS Score 3 compared with 31.3% of those with no repeated bleeding; p = 0.01). Overall outcomes did not differ between aspirin users and nonusers (mean GOS Scores 3.83 and 3.86, respectively; p = 0.82). An examination of the GOS score as a categorical variable (Grade 3 compared with 4) also showed that aspirin use was not associated with a worse outcome (34.5% of aspirin users and 33% of nonusers with a poor outcome; p = 0.87). Controlling for patient age, Hunt and Hess grade, and location of the aneurysm in the posterior circulation did not alter the findings substantially (Table 4).
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Discussion Aspirin is a potent inhibitor of platelet activation. Its effects are mediated largely through irreversible acetylation of specific serine residues on prostaglandin H synthase1 and 2, which are also known as cyclooxygenase1 and 2, respectively. These enzymes catalyze the first two steps in the metabolic pathway from arachidonic acid to prostaglandin synthesis. The best-characterized metabolic products of this pathway include prostacyclin and thromboxane A2, which mediate contradictory effects on platelet activation and vascular smooth-muscle tone. Anucleate platelets cannot regenerate the cyclooxygenase enzyme, thereby allowing aspirin to induce an unrecovered depletion of thromboxane. The synthesis of prostacyclin in vascular endothelial cells remains because these cells can actively regenerate the cyclooxygenase enzyme to overcome aspirin inhibition. The net effect of aspirin is an inhibition in platelet activation and, thereby, a reduction in platelet-mediated thrombus formation. In the setting of SAH, previous aspirin use carries the theoretical risks of exacerbating the initial hemorrhage, increasing the rate of rebleeding, and complicating surgical procedures intended to secure the source of bleeding. Some evidence indicates that inhibitors of clot formation can complicate SAH. Systemic anticoagulation with warfarin therapy has been associated with poor outcome after SAH,22 whereas nonsteroidal antiinflammatory drug therapy after SAH has been implicated as a risk factor for intra- and postoperative hemorrhage.16 These risks, however, have not been translated to aspirin use, based on the results of a pilot trial of aspirin therapy following aneurysm clipping after SAH.6 In contrast, there are theoretical benefits to aspirin therapy in patients with SAH. The efficacy of aspirin in decreasing vascular smooth-muscle tone has been the impetus for undertaking animal and human investigations of aspirin in the treatment of post-SAH cerebral vasospasm. Animal models of SAH have shown a direct correlation among platelet activation, prostaglandin synthesis, and cerebral vasospasm.4,19,25 These models have also demonstrated the efficacy of aspirin therapy in attenuating cerebral vasospasm following SAH.15,24,27 Data are available in humans that again correlate thromboxane synthesis and platelet activation with a delayed ischemic neurological deficit from vasospasm.14,17 At least one author has reported reduced com923

L. G. Toussaint III, et al.

plications from vasospasm in patients taking aspirin before they suffered an SAH.11 Analysis of our data indicates that the overall clinical outcome following aneurysmal SAH in patients taking aspirin before hemorrhage is not different from those who were not taking aspirin. It must be emphasized, however, that trends not reaching statistical significance were identified, indicating that patients taking aspirin before SAH were more likely to suffer from rebleeding episodes, but less likely to suffer permanent deficit from vasospasm. Therefore, there is no net effect of aspirin use on outcomethe result of balancing an increasing risk of repeated hemorrhage and a decreasing risk of vasospasm-induced permanent deficits. The trend toward an increased risk of rebleeding in aspirin users is presumably based on impaired or unstable thrombus formation at the site of rupture on the aneurysm dome. An additional contributing mechanism may also be related to an immediate reduction in local vasospasm due to the direct vasodilatory effects of aspirin, which preserve a high arterial pressure to the rupture site. Rebleeding usually worsens clinical outcomes18 and did so in our entire series. It is possible that aspirin use predisposes patients with SAH to rebleeding episodes that are different from those experienced by nonusersmore frequent but smaller and/or less damaging. We are not ready, however, to base clinical recommendations on this conjecture. The most likely explanation for the lack of a difference in clinical outcome between the two groups is that the increased morbidity associated with increased repeated hemorrhage is counterbalanced by reduced vasospasm-related deficits in aspirin users. A systematic bias of the study toward better outcomes in aspirin users cannot be entirely excluded, because identification of aspirin use could have been less reliable in patients with clinically poor grades. Inclusion of familyprovided and previously documented medical information should have minimized this effect. Additionally, data on patients suffering sudden or early death from SAH who failed to be referred to our institution are not available for inclusion in this study. The observed trend of reduced death or permanent deficit from symptomatic vasospasm in aspirin users is consistent with the findings of previous studies. Substantive scientific evidence supports the theory that the effects of aspirin on the arachidonic acid metabolic pathway and platelet activation could protect patients from vasospasm.4,15,17,26 Such observations have been the impetus for performing a clinical trial of aspirin following SAH.6 Our data do not apply to therapeutic aspirin administration after SAH, and some reports indicate that a beneficial effect only occurs in those patients who take aspirin before SAH.8 Additional data on the safety and therapeutic benefit of aspirin use after SAH should clarify this issue. Assessing the advisability of aspirin use in patients with known unruptured aneurysms requires more data. Prospective trials have not confirmed an aspirin-induced increase in aneurysmal SAH.1,3 This study does not directly address the risk of rupture in patients with unruptured aneurysms who are on an aspirin regimen or the risk of ictal death from SAH. Although we acknowledge the trends shown in our data, based on the equivalent outcomes in patients in both groups we can offer no compelling recommendation against aspirin use in patients harboring unruptured intracranial aneurysms.
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Conclusions The findings of this study indicate trends toward an increased risk of rebleeding and a decreased risk of a permanent neurological deficit from vasospasm in patients who used aspirin before they suffered an SAH. The overall clinical outcomes in aspirin users, however, balance these risks and were no different from those of patients who had not used aspirin. The therapeutic benefit of aspirin use for vasospasm following SAH, particularly once an aneurysm has been secured by clipping or coil embolization, awaits further delineation.

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Manuscript received April 2, 2004. Accepted in final form July 30, 2004. Address reprint requests to: L. Gerard Toussaint III, M.D., Department of Neurologic Surgery, Mayo Graduate School of Medicine, 200 First Street SW, Rochester, Minnesota 55905. email: Toussaint. Gerard@mayo.edu.

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