Aspirin as a Promising Agent for Decreasing Incidence of Cerebral Aneurysm

Rupture
David M. Hasan, Kelly B. Mahaney, Robert D. Brown, Jr, Irene Meissner, David G.
Piepgras, John Huston, Ana W. Capuano, James C. Torner and for the International
Study of Unruptured Intracranial Aneurysms Investigators

Stroke 2011, 42:3156-3162: originally published online October 6, 2011

doi: 10.1161/STROKEAHA.111.619411
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 Aspirin as a Promising Agent for Decreasing Incidence of
Cerebral Aneurysm Rupture
David M. Hasan, MD; Kelly B. Mahaney, MD; Robert D. Brown, Jr, MD, MPH; Irene Meissner, MD;
David G. Piepgras, MD; John Huston, MD; Ana W. Capuano, MPS, MS; James C. Torner, PhD; for
the International Study of Unruptured Intracranial Aneurysms Investigators

Background and PurposeChronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall
pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm
rupture.
MethodsSubjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from
the prospective untreated cohort (n1691) in a nested case control study. Cases were subjects who subsequently had
a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched
to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at
baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and
multivariable analyses were performed using conditional logistic regression.
ResultsA trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who
used aspirin 3 weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18 0.87); reference group, no use of
aspirin), patients in the once a month group had an OR of 0.80 (95% CI, 0.312.05), and patients in the once
a month to 2/week group had an OR of 0.87 (95% CI, 0.272.81; P0.025). In multivariable risk factor analyses,
patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95%
CI, 0.11 0.67; P0.03) compared with those who never take aspirin.
ConclusionsFrequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future
investigation in animal models and clinical studies is needed. (Stroke. 2011;42:3156-3162.)
Key Words: aspirin hemorrhage inflammation rupture unruptured aneurysm

T he etiology of the development of a saccular intracranial

artery aneurysm (IA) remains poorly defined. Recent
studies on IAs have contributed to the concept that chronic
inflammation plays a role in IA wall degeneration and
potentially increases subsequent risk of rupture. Approxi-
mately 30 000 cases of subarachnoid hemorrhage (SAH) are
diagnosed in the United States every year. According to a
meta-analysis of studies published between 1955 and 1996,
2.3% of the population have been estimated to have IAs.1 In
population-based studies in Western countries, SAH caused
by IA rupture comprises 0.8% to 7.0% of all strokes.2
Approximately 12% of patients die before receiving med-
ical attention3; 1-month case-fatality rates for hospitalized
patients range from 15% to 30%4,5 and more than one third
of those who survive have major neurological deficits.4
Furthermore, persistent cognitive deficits are present in
many survivors.
Current procedural options to prevent the rupture or rerupture
of an IA are clipping and endovascular therapy. Although these
treatments are effective in preventing hemorrhage from an
unruptured intracranial aneurysm (UIA), they are invasive and
not without significant associated risks.6 There is currently no
medical treatment that has been shown effective in preventing
rupture of an UIA. The efficiency of the option of systemic
pharmaceutical treatment targeting the inflammatory process
implicated in IA formation and rupture is very appealing.
To address the hypothesis of a potentially protective effect
of aspirin on risk of UIA rupture, we reviewed data collected
for the prospective cohort aspect of the International Study
of Unruptured Intracranial Aneurysms (ISUIA).7 We as-
sessed whether aspirin use and frequency of use were
associated with occurrence of UIA rupture and whether
history of smoking or hypertension had any interaction
with such an effect.

Received March 2, 2011; final revision received April 5, 2011; accepted April 8, 2011.
From the Department of Neurosurgery (D.M.H., K.B.M.), Carver College of Medicine, University of Iowa, Iowa City, IA; the Departments of
Neurology (R.D.B., I.M.), Neurosurgery (D.G.P.), and Radiology (J.H.), Mayo Clinic, Rochester, MN; and the Department of Epidemiology (A.W.C.,
J.C.T.), College of Public Health, University of Iowa, Iowa City, IA.
The findings of this study were presented at the International Stroke Conference in February 2011.
Correspondence to James C. Torner, PhD, Department of Epidemiology, College of Public Health, University of Iowa, C21P-1 GH, 200 Hawkins
Drive, Iowa City, IA 52245. E-mail james-torner@uiowa.edu
2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.619411

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3156 by guest on November 17, 2011
 Hasan et al Aspirin to Decrease Cerebral Aneurysm Rupture 3157

Methods and Materials Table 1. Matched CaseControl Group Composition (N271)

ISUIA is an epidemiological cohort study that involved the long- Control
term follow-up of 2 prospective cohorts: (1) untreated; and (2)
Total Cases Subjects
treated. Prospective case ascertainment was from 1991 to 1998
(Phases I and II). Prospective follow-up of the prospective cohort Characteristic No. Percent No. Percent No. Percent
(Phase III) was conducted from 2004 to 2007. One thousand six
hundred ninety-one patients were managed conservatively, 1917 Aneurysm
patients underwent surgery, and 451 patients underwent endovascu- maximum
lar intervention. The 1691 initially untreated patients are analyzed in diameter
this article. Five hundred forty-five patients who were initially 7 mm 71 26.2 13 22.4 58 27.2
enrolled in the conservative management group ultimately under-
went a surgical or endovascular procedure to secure an aneurysm 710 mm 51 18.8 10 17.3 41 19.2
during the overall follow-up period. Patients included 2 groups of 1124 mm 114 42.1 25 43.1 89 41.8
patients with UIA. Group 1 patients have no history of SAH and 25 mm 35 12.9 10 17.2 25 11.7
have a UIA; Group 2 patients have had an SAH with at least 1 other
UIA in which the etiology of the SAH was definitively treated. Aneurysm site
Patients were enrolled in 61 medical centers in the United States, Anterior 124 45.8 25 43.1 99 46.5
Canada, and Europe. Details of aneurysm and patient characteristics Posterior 147 454.2 33 56.9 114 53.5
in the treated and untreated cohorts are detailed in the ISUIA
publication in Lancet in 2003.7
To be eligible for the study, patients must satisfy the following cardiac arrhythmias, congestive heart failure, myocardial infarction,
clinical and radiological inclusion and exclusion criteria: patients family history of intracranial aneurysm hemorrhage, smoking, alco-
must have at least 1 UIA, which may or may not be symptomatic. hol consumption, use of anticoagulants, history of aneurysms,
Patients who have had a ruptured aneurysm at another location that interaction smoking and hypertension, and use of aspirin (ordinally
was isolated, trapped, clipped, or treated through endovascular scored or in categorical groups). The final model was determined by
obliteration must be able to care for themselves after the aneurysmal stepwise and backward elimination of the initial saturated model.
treatment (Rankin Grade 1 or 2) according to a follow-up evaluation
For verification of the association in the entire untreated cohort,
at 30 days post-treatment. Patients may or may not undergo surgical
the same cases and all of the unruptured patients were included in a
clipping or endovascular intervention for the UIA at the investiga-
Cox regression multivariate model. A total of 1678 participants of
tors discretion. Patients with fusiform, traumatic, or mycotic aneu-
the prospective untreated cohort who had information regarding age,
rysms are not eligible for the study. Also, patients with saccular
region, smoking status, and aneurysm location and size and were
aneurysms 2 mm maximum diameter are excluded.
used to verify results yielded from the nested case control analyses.
Hemorrhagic events were classified by diagnostic certainty and
location of aneurysmal rupture. Classification of certainty of hem- The model included the variables selected for the final model. UIA
orrhage events was based on uniform criteria. The adjudicated size and location were entered in a proportional hazards model that
hemorrhage events were defined as a primary hemorrhage if either: included the entire prospective untreated cohort.
(1) a definite or highly probable SAH of aneurysmal or unknown
etiology; or (2) a definite or highly probable intracranial hemorrhage Results
was determined to be of aneurysmal etiology. Suspected hemorrhage A total of 271 nested case control patients with untreated
included all hemorrhages of aneurysmal or uncertain etiology re- intracranial aneurysm were studied. The case control popu-
gardless of certainty.
Subjects were selected from the prospective untreated cohort
lation comprises 74% women; 52% are from Europe, 17%
(n1691) for a nested case control study. Cases were subjects who from Canada, and 30% from the United States. The mean age
subsequently had a primary aneurysmal hemorrhage over a 5-year was 57 years. Within the nested case control population,
period after UIA diagnosis. Four control subjects were matched to there were no significant differences in demographic and
each case where possible by site (anterior or posterior) and size behavioral characteristics (Table 1), reasons for performing
(2 mm) of the UIA (58 cases, 213 control subjects). Frequency of
aspirin use was based on the question How often is the patient cerebral angiography at the time of UIA diagnosis (Table 2),
taking aspirin and was comprised originally of 9 categories: or clinical characteristics (Table 3) by history of aspirin use.
never, less than once a month, once a month, less than once The initial analysis is presented in Table 4. A trend of
a week and more than once a month, 1 to 2 times a week, 3 to protective effect for risk of UIA rupture was observed
4 times a week, 5 to 6 times a week, daily, and unknown.
Because of limited numbers of subjects at certain aspirin use levels, according to frequency of aspirin use. Patients who used
frequency was grouped as never, once a month, once a aspirin 3 times weekly to daily had OR for hemorrhage 0.40
month to 2 times a week, and 3 times weekly to daily for the (95% CI, 0.18 0.87, reference group: no aspirin use),
categorical analyses. Aspirin frequency groups were then analyzed whereas patients in the once a month group had OR for
for risk of aneurysmal hemorrhage. Use of aspirin was also scored
hemorrhage 0.80 (95% CI, 0.312.05) and patients in the
assuming a linear equally spaced system to avoid overfitting. The
system consisted of a scoring from 1 to the number of category levels once a month to 2 times a week group had OR for
being analyzed with increments of 1. For example, for the multivar- hemorrhage 0.87 (95% CI, 0.272.81; probability value for
iate analyses, the ordinal score represented the following levels of linear association 0.025).
aspirin use: 1never, 2less than once a month, 3once a month, Table 5 shows the risk factor analyses with conditional
4less than once a week and more than once a month, 51 to 2
times a week, 63 to 4 times a week, 75 to 6 times a week, and logistic regression. Model 1 included aspirin as an equally
8daily. spaced interval score that represents the increasing use of
Bivariable and multivariable analyses were performed on the aspirin. There was a significant decreasing OR for hemor-
nested case control population using conditional logistic regression. rhage with the increasing use of aspirin (adjusted OR, 0.82;
The initial saturated model included age (continuous and grouped),
sex, UIA enrollment group, participating center location (by region),
95% CI, 0.71 0.94; P0.0051). Model 2 included aspirin use
multiple aneurysm, largest aneurysm size (maximal diameter), hy- grouped into the categories: never, once a month,
pertension, cardiac valvular disease, atrial fibrillationflutter, other once a month to 2 times a week, and 3 times a week to
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3158 Stroke November 2011

Table 2. Nested CaseControl Population Demographic and Behavioral Characteristics by History of Aspirin Use
No History of Aspirin Use History of Aspirin Use

Control Subjects Cases Control Subjects Cases

Characteristic No. Percent No. Percent P* No. Percent No. Percent P*

Age group, y 0.721 0.656
50 36 33 9 23.1 31 29.8 3 15.8
5069 55 50.5 21 53.8 53 51 9 47.4
70 18 16.5 9 23.1 20 19.2 7 36.8
Sex 0.359 0.320
Male 24 22.0 13 33.3 28 26.9 4 21.1
Female 85 78.0 26 66.7 76 73.1 15 78.9
Enrollment group 0.708 0.236
No SAH 79 72.5 31 79.5 90 86.5 15 78.9
SAH 30 27.5 8 20.5 14 13.5 4 21.1
Region 0.104 0.256
US 20 18.3 11 28.2 43 41.3 8 42.1
Canada 27 24.8 3 7.7 16 15.4 1 5.3
Europe 62 56.9 25 64.1 45 43.3 10 52.6
Smoking 0.561 0.075
Missing 0 0.0 0 0.0 1 1 0 0.0
No 26 23.9 12 30.8 23 22.1 9 47.4
Former 52 47.7 17 43.6 41 39.4 8 42.1
Current 31 28.4 10 25.6 39 37.5 2 10.5
SAH indicates subarachnoid hemorrhage.
*Using conditional Wald 2. No and unknown combined for analyses.

daily. Participants who take aspirin 3 a week to daily
presented significantly lower odds of hemorrhage (adjusted
OR, 0.27; 95% CI, 0.11 0.67; P0.03). Current smoking
status presented a weak negative association with hemorrhage
in the presence of aspirin use history (Tables 2 and 6). The
interaction of aspirin use and smoking was explored in the
multivariable analyses but did not remain as a significant
association.
A validation analysis was done using the entire prospective
untreated cohort. By definition the hemorrhage cases re-
mained the same. Using a proportional hazards regression,
there was also a significant decreasing hazard of aneurysm
rupture with increasing use of aspirin (adjusted hazard ratio,
0.89; 95% CI, 0.79 0.99; P0.03). A second model included
aspirin use grouped into the categories: never, once a
month, once a month to 2 times a week, and 3 times

Table 3. Reasons for Performing Cerebral Angiography Among Nested CaseControl Population by History of Aspirin Use
No History of Aspirin Use History of Aspirin Use

Control Subjects Cases Control Subjects Cases

Characteristic No. Percent No. Percent P* No. Percent No. Percent P*

Subarachnoid hemorrhage 0.548 0.650
No 83 76.1 34 87.2 91 87.5 16 84.2
Yes 26 23.9 5 12.8 13 12.5 3 15.8
Cerebral Infarction 0.809 0.598
No 108 99.1 38 97.4 88 84.6 12 63.2
Yes 1 0.9 1 2.6 16 15.4 7 36.8
Headaches 0.994 0.145
No 75 68.8 28 71.8 80 76.9 11 57.9
Yes 34 31.2 11 28.2 24 23.1 8 42.1
Transient ischemic attack 0.343 0.981
No 107 98.2 37 94.9 87 83.7 14 73.7
Yes 2 1.8 2 5.1 17 16.3 5 26.3
*Using conditional Wald 2.

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 Hasan et al Aspirin to Decrease Cerebral Aneurysm Rupture 3159

Table 4. Nested CaseControl Population Clinical History Information by History of Aspirin Use
No History of Aspirin Use History of Aspirin Use

Control Subjects Cases Control Subjects Cases

Characteristic No. Percent No. Percent P* No. Percent No. Percent P*

History of hypertension 0.946 0.993
No 67 61.5 21 53.8 49 47.1 8 42.1
Yes 42 38.5 17 43.6 54 51.9 11 57.9
Unknown 0 0.0 1 2.6 1 1.0 0 0.0
Cardiac valvular disease 0.994
(excluding MVP)
No 105 96.3 39 100 97 93.3 19 100
Yes 2 1.8 0 0.0 2 1.9 0 0.0
Unknown 2 1.8 0 0.0 5 4.8 0 0.0
Atrial fibrillationflutter 0.288 0.995
No 103 94.5 37 94.9 95 91.3 18 94.7
Yes 3 2.8 2 5.1 3 2.9 1 5.3
Unknown 3 2.8 0 0.0 6 5.8 0 0.0
Myocardial infarction 0.302 0.995
No 101 92.7 38 97.4 91 87.5 15 78.9
Yes 6 5.5 1 2.6 9 8.7 4 21.1
Unknown 2 1.8 0 0.0 4 3.8 0 0.0
Any relative with positive 0.837 0.896
history of aneurysms
No 81 74.3 34 87.2 78 75.0 17 89.5
Yes 16 14.7 4 10.3 17 16.3 1 5.3
Unknown 12 11 1 2.6 9 8.7 1 5.3
MVP indicates mitral valve prolapse.
*Using conditional Wald 2. No and unknown combined for analyses.
Exact conditional test: conditional distribution is degenerated.

a week to daily. Participants who take aspirin 3 a week to
daily had a significantly lower hazard of hemorrhage (ad-
justed hazard ratio, 0.45; 95% CI, 0.22 0.92; P0.03).
Discussion
The results of this study suggest that aspirin could conceiv-
ably play a role in reducing the risk of cerebral aneurysm
progression to rupture. ISUIA has previously demonstrated
the effect of size and aneurysm location as the key predictors
for aneurysmal hemorrhage with larger aneurysms and those
in the posterior communicating artery location and the ver-
tebrobasilar circulation at increased risk.7 The design of this
study was to control for these risk factors to examine
behavioral factors such as smoking and aspirin use. The
epidemiological evidence demonstrates an association of a
protective effect of aspirin use against hemorrhage, compar-
ing individuals reporting aspirin use with those reporting that
they never used aspirin (adjusted OR, 0.82; 95% CI, 0.71
0.94; P0.0051). However, there also appears to be a
dose-dependent relationship trend associating frequency of
aspirin use with risk of hemorrhage (patients who used
aspirin 3/week to daily have crude conditional OR for

Table 5. Nested CaseControl: Hemorrhages and Control Subjects (Matched by Site and Size)Frequency
of Aspirin Use
Control Subjects Cases
P for Linear Association
No. Percent No. Percent OR Conditional Odds*
Use of aspirin (grouped) 0.025
Never 109 73.6 39 26.4 1
Less than or equal to once a mo 23 79.3 6 20.7 0.80
More than once a mo to 2 times a wk 14 77.8 4 22.2 0.86
Three times a wk to daily 67 88.2 9 11.8 0.40
P0.14 for these grouping. P value of never versus ever0.0529. Tested using conditional logistic regression.
*Considering an equally spaced scoring of 4 levels using the conditional logistic model.

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3160 Stroke November 2011

Table 6. Risk Factor Analyses With Conditional Logistic Regression

Model I Model II

Unadjusted OR Adjusted OR Adjusted OR

Characteristic No. (95% CI) No. (95% CI) No. (95% CI)
Age (continuous) 271 1.02 (11.04) 270 1.03 (1.011.06) 270 1.03 (1.011.06)
Age group, y ... ...
50 80 Reference ... ...
5069 139 1.43 (0.693) ... ... ... ...
70 54 2.1 (0.894.96) ... ... ... ...
Region Reference Reference
US 82 Reference 82 82
Canada 47 0.33 (0.111.02) 47 0.24 (0.070.81) 47 0.24 (0.070.82)
Europe 142 1.1 (0.62) 141 0.90 (0.461.76) 141 0.93 (0.471.80)
Smoking
Missing 1
No 70 Reference 70 Reference 70 Reference
Former 118 0.58 (0.291.15) 118 0.75 (0.361.57) 118 0.78 (0.371.64)
Current 82 0.44 (0.20.97) 82 0.44 (0.191.00) 82 0.44 (0.191.00)
Any relative with positive history of aneurysms ... ...
No/unknown 233 Reference ... ...
Yes 38 0.55 (0.211.46) ... ... ... ...
Use of aspirin (grouped)
Never 148 Reference ... ... 148 Reference
Less than or equal to once a mo 29 0.8 (0.312.04) ... ... 29 0.64 (0.241.74)
More than once a mo to 2 times a wk 18 0.86 (0.272.81) ... ... 18 0.78 (0.222.82)
Three times a wk to daily 76 0.4 (0.180.87) ... ... 75 0.27 (0.110.67)
Score of aspirin use 271 0.86 (0.770.97) 270 0.82 (0.710.94) ... ...
OR indicates odds ratio; CI, confidence interval.

hemorrhage of 0.40 [95% CI, 0.18 0.87] and adjusted
conditional OR for hemorrhage of 0.19 [95% CI, 0.07
0.54] compared with never). This serves to strengthen
the association of aspirin use and decreased risk of
hemorrhage of an UIA.
Several studies of human aneurysm tissue have implicated
a role of inflammatory mediators in the development and
rupture of IAs. Chyatte found histological evidence of mac-
rophages, T-cells, immunoglobulin, and complement in an-
eurysm wall tissue specimens collected at the time of micro-
surgical repair.8 Frosen demonstrated similar findings of
macrophage and T-cell infiltration in surgical specimens from
unruptured and ruptured aneurysms9 and also found histolog-
ical evidence of increased expression of several inflammatory
receptors (vascular endothelial growth factor, transforming
growth factor-, and basic fibroblast growth factor) associ-
ated with aneurysm wall remodeling and rupture.10 Macro-
phages secrete matrix metalloproteinases, which degrade the
extracellular matrix and increased expression of matrix
metalloproteinase-2 and matrix metalloproteinase-9 have
been demonstrated in IAs.11 Dysregulation of the complement
pathway has also been implicated in IA pathophysiology,
because Tulamo demonstrated increased susceptibility to
complement activation, inflammation, and tissue damage in
the IA wall in a study of 26 unruptured and 26 ruptured IA
surgical specimens.12
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The role of inflammation in cerebral aneurysm formation
has also been supported with evidence from animal models of
cerebral aneurysms. Tears in the internal elastic lamina and
associated vascular wall remodeling have been thought to
precede IA formation, because the IA wall lacks the internal
elastic lamina, which normally provides structural strength
for cerebral artery walls.13 This process is thought to initiate
formation of cerebral aneurysms. Subsequent hemodynamic
stress on the endothelium leads to molecular signaling of
proinflammatory and proliferative pathways.14 Aoki et al
recently showed several lines of evidence that PGE2EP2
receptor signaling links hemodynamic stress to cerebral
aneurysm formation in rodents through activation of nuclear
factor B.15 Activation of transcription factor nuclear
factor B16 and resultant increased expression of monocyte
chemotactic protein-117 is highly chemotactic to inflam-
matory cells including macrophages, T-cells, natural killer
cells, and basophils. Hypertension-induced rodent models
of IAs have shown evidence of macrophages as the first
population of inflammatory cells infiltrating into the cere-
bral aneurysm wall after endothelial disruption.18 Further
supporting this histological evidence from human tissue
studies, rodent IA models have demonstrated a role of
aneurysm progression associated with macrophage-
secreted extracellular matrix-degrading proteolytic en-
zymes (matrix metalloproteinase-2 and -9).19
 Hasan et al
Aspirin has been shown to have inhibitory effects on
several inflammatory mediators postulated to play a role in
cerebral aneurysm pathology. Aspirin has been shown to
inhibit matrix metalloproteinase-2 and -9 expression20,21 as
well as to inhibit tumor necrosis factor- release in smooth
muscle cell cultures.22,23 Aspirin has also been found to
inhibit tumor necrosis factor- stimulated monocyte chemot-
actic protein-1 and interleukin-8 expression in human umbil-
ical vein endothelial cells.24 There is also evidence that
aspirin inhibits inflammatory cell adhesion in endothelial
cells by reducing nuclear factor B activity.25,26 Given this
evidence of inhibitory effects of aspirin at several steps in the
inflammatory cascade implicated in cerebral aneurysm patho-
physiology, aspirin may have potential as a therapeutic agent
to prevent cerebral aneurysm growth and rupture.
There are several limitations to this study. ISUIA is an
observational epidemiological study designed to evaluate risk
factors for UIA rupture. A protective effect of aspirin against
UIA rupture was observed. It was not noted to be a risk factor
for hemorrhage, which would have been plausible. The
mechanism by which aspirin attenuates the risk of aneurysm
rupture is not delineated without collection of biomarkers.
Longitudinal assessment of prior and subsequent aspirin
would be useful in the future to determine if there is a
time-dependent effect in protection.
Aspirin has not only anti-inflammatory properties, but also
significant antiplatelet effects and this is often the indication
for aspirin use, for example, ischemic cerebrovascular dis-
ease. Thus, a downstream-mediated antiplatelet effect of
aspirin cannot be excluded as the underlying mechanism.
Although efforts are made to control for other risk factors
known to predict aneurysm rupture (aneurysm site, size,
Group 1 versus Group 2, age, smoking history, etc), adjust-
ment can only be made for those measured confounders and
potential unmeasured confounders that are not available in
the data set and may actually affect rupture risk. There is also
a possibility that the lack of statistical difference in many
baseline comorbidities observed between cases and control
subjects may due to lack of statistical power. Furthermore,
information regarding statin use, which could further substan-
tiate the hypothesized mechanism of inhibition of inflamma-
tion, is not available for this population because it was not
collected as part of the prospective cohort study.
The study design and analysis were chosen to control for
key risk factors and to adjust for covariates associated with
use. There are limitations applicable to the statistical analysis.
Analysis was done in 2 ways using a categorical, ordinal
analysis and by an interval scoring system for aspirin use.
Scoring systems are limited in nature because there are many
possible approaches that can be adopted. We consider a linear
equally spaced system following how the data were captured
in the questionnaire to avoid overfitting. However, the results
were consistent. In addition, we performed a longitudinal
analysis with the full untreated cohort. This adds aneurysms
at decreased risk of rupture, for example, small, anterior
circulation aneurysms. The results were equally as strong.
Conclusions
Recent studies on IAs have strengthened the concept that
chronic inflammation plays a significant role in aneurysm
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Aspirin to Decrease Cerebral Aneurysm Rupture 3161
formation and potentially predisposes to IA wall degeneration
and rupture. The findings from the ISUIA cohort provide
epidemiological evidence of an association of frequent aspi-
rin use with reduced incidence of aneurysmal SAH. Further
investigation is needed to confirm this effect: (1) including
use of animal models of cerebral aneurysms to study the
mechanism of effect of aspirin on the inflammatory process
implicated in aneurysm formation and rupture; (2) further
observational data from other cohorts or aspirin clinical trials
for other end points; and (3) a clinical trial assessing the effect
of aspirin on cerebral aneurysms that are chosen to be
followed without interventional treatment.
Sources of Funding
The International Study of Unruptured Intracranial Aneurysms, on
which this study was based, was supported by a grant (R01-NS-
28492 and 1RC1-NS068092-01) from the National Institute of
Neurological Disorders and Stroke.
Disclosures
None.
References
1. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture
of intracranial aneurysms: a systematic review. Stroke. 1998;29:251256.
2. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology:
a review of population-based studies of incidence, prevalence, and case-
fatality in the late 20th century. Lancet Neurol. 2003;2:4353.
3. Schievink WI, Wijdicks EF, Parisi JE, Piepgras DG, Whisnant JP. Sudden
death from aneurysmal subarachnoid hemorrhage. Neurology. 1995;45:
871 874.
4. Longstreth WT Jr, Nelson LM, Koepsell TD, van Belle G. Clinical course
of spontaneous subarachnoid hemorrhage: a population-based study in
King County, Washington. Neurology. 1993;43:712718.
5. Biotti D, Jacquin A, Boutarbouch M, Bousquet O, Durier J, Ben Salem D,
Ricolfi F, Beaurain J, Osseby GV, Moreau T, Giroud M, Bejot Y. Trends
in case-fatality rates in hospitalized nontraumatic subarachnoid hemor-
rhage: results of a population-based study in Dijon, France, from 1985 to
2006. Neurosurgery. 2010;66:1039 1043; discussion 1043.
6. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J,
Holman R. International Subarachnoid Aneurysm Trial (ISAT) of neu-
rosurgical clipping versus endovascular coiling in 2143 patients with
ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360:
12671274.
7. Wiebers DO, Whisnant JP, Huston J III, Meissner I, Brown RD Jr,
Piepgras DG, Forbes GS, Thielen K, Nichols D, OFallon WM, Peacock
J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC. Unruptured
intracranial aneurysms: natural history, clinical outcome, and risks of
surgical and endovascular treatment. Lancet. 2003;362:103110.
8. Chyatte D, Bruno G, Desai S, Todor DR. Inflammation and intracranial
aneurysms. Neurosurgery. 1999;45:11371146; discussion 1146 1147.
9. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi
J, Jaaskelainen J. Remodeling of saccular cerebral artery aneurysm wall
is associated with rupture: histological analysis of 24 unruptured and 42
ruptured cases. Stroke. 2004;35:22872293.
10. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J,
Jaaskelainen J. Growth factor receptor expression and remodeling of
saccular cerebral artery aneurysm walls: implications for biological
therapy preventing rupture. Neurosurgery. 2006;58:534 541; discussion
534 541.
11. Caird J, Napoli C, Taggart C, Farrell M, Bouchier-Hayes D. Matrix
metalloproteinases 2 and 9 in human atherosclerotic and non-
atherosclerotic cerebral aneurysms. Eur J Neurol. 2006;13:1098 1105.
12. Tulamo R, Frosen J, Paetau A, Seitsonen S, Hernesniemi J, Niemela M,
Jarvela I, Meri S. Lack of complement inhibitors in the outer intracranial
artery aneurysm wall associates with complement terminal pathway acti-
vation. Am J Pathol. 2010;177:3224 3232.
13. Meng H, Metaxa E, Gao L, Liaw N, Natarajan SK, Swartz DD, Siddiqui
AH, Kolega J, Mocco J. Progressive aneurysm development following
hemodynamic insult. J Neurosurg. 2011;114:10951103.
3162 Stroke November 2011
14. Chien S. Effects of disturbed flow on endothelial cells. Ann Biomed Eng.
2008;36:554 562.
15. Aoki T, Nishimura M, Matsuoka T, Yamamoto Y, Furuyashiki T,
Kataoka H, Kitaoka S, Ishibashi R, Ishibazawa A, Miyamoto S, Morishita
R, Ando J, Hashimoto N, Nozaki K, Narumiya S. PGE-2-EP2 receptor
signaling in endothelium is activated by hemodynamic stress and induces
cerebral aneurysm through an amplifying loop VI NF-kB. Br J
Pharmacol. 2011;163:12371249.
16. Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K,
Moriwaki T, Ishibashi R, Nozaki K, Morishita R, Hashimoto N.
NF-kappaB is a key mediator of cerebral aneurysm formation.
Circulation. 2007;116:2830 2840.
17. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N.
Impact of monocyte chemoattractant protein-1 deficiency on cerebral
aneurysm formation. Stroke. 2009;40:942951.
18. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M,
Satoh K. Endothelial injury and inflammatory response induced by he-
modynamic changes preceding intracranial aneurysm formation: experi-
mental study in rats. J Neurosurg. 2007;107:405 411.
19. Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-
derived matrix metalloproteinase-2 and -9 promote the progression of
cerebral aneurysms in rats. Stroke. 2007;38:162169.
20. Yiqin Y, Meilin X, Jie X, Keping Z. Aspirin inhibits MMP-2 and MMP-9
expression and activity through PPARalpha/gamma and TIMP-1-
Downloaded from http://stroke.ahajournals.org/ by guest on November 17, 2011
mediated mechanisms in cultured mouse celiac macrophages.
Inflammation. 2009;32:233241.
21. Hua Y, Xue J, Sun F, Zhu L, Xie M. Aspirin inhibits MMP-2 and mmp-9
expressions and activities through upregulation of PPARalpha/gamma
and TIMP gene expressions in OX-LDL-stimulated macrophages derived
from human monocytes. Pharmacology. 2009;83:18 25.
22. Shackelford RE, Alford PB, Xue Y, Thai SF, Adams DO, Pizzo S.
Aspirin inhibits tumor necrosis factor alpha gene expression in murine
tissue macrophages. Mol Pharmacol. 1997;52:421 429.
23. Sanchez de Miguel L, de Frutos T, Gonzalez-Fernandez F, del Pozo V,
Lahoz C, Jimenez A, Rico L, Garcia R, Aceituno E, Millas I, Gomez J,
Farre J, Casado S, Lopez-Farre A. Aspirin inhibits inducible nitric oxide
synthase expression and tumour necrosis factor-alpha release by cultured
smooth muscle cells. Eur J Clin Invest. 1999;29:9399.
24. Yang YY, Hu CJ, Chang SM, Tai TY, Leu SJ. Aspirin inhibits monocyte
chemoattractant protein-1 and interleukin-8 expression in TNF-alpha
stimulated human umbilical vein endothelial cells. Atherosclerosis. 2004;
174:207213.
25. Weber C, Erl W, Pietsch A, Weber PC. Aspirin inhibits nuclear
factor-kappa B mobilization and monocyte adhesion in stimulated human
endothelial cells. Circulation. 1995;91:1914 1917.
26. Yotsui T, Yasuda O, Kawamoto H, Higuchi M, Chihara Y, Umemoto E,
Tanaka T, Miyasaka M, Rakugi H, Ogihara T. Aspirin prevents adhesion
of T lymphoblasts to vascular smooth muscle cells. FEBS Lett. 2007;581:
427 432.