Abstract
Background and Purpose
Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm (IA) wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of IA rupture.
Methods
Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case-control study. Cases were subjects who subsequently suffered a proven aneurysmal SAH during a 5-year follow-up period. Four controls were matched to each case by site and size of aneurysm (58 cases, 213 controls). 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.
Results
A trend of a protective effect for risk of UIA rupture was observed. Patients who used aspirin 3x weekly - daily had an odds ratio (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=0.31-2.05) and patients in the “> once a month – 2x/week” group had an OR of 0.87 (95% CI=0.27-2.81) (p= 0.025). In multivariable risk factor analyses, patients who used aspirin three times weekly to daily had a significantly lower odds of hemorrhage (Adjusted OR=0.27, 95% CI 0.11-0.67, p=0.03) compared to those who never take aspirin.
Conclusions
Frequent aspirin use may confer a protective effect for risk of IA rupture. Future investigation in animal models and clinical studies is needed.
Keywords: Unruptured Aneurysm, Aspirin, Inflammation, Rupture, Hemorrhage
Introduction
The 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. About 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 IAs1. In population based studies in western countries, SAH caused by IA rupture comprises 0.8-7.0% of all strokes.2. Approximately 12% of patients die before receiving medical attention3; one month case-fatality rates for hospitalized patients range from 15-30%4, 5 and more than one third of those who survive have major neurologic deficits4. Furthermore, persistent cognitive deficits are present in many survivors.
Current procedural options to prevent the rupture or re-rupture of an IA are clipping and endovascular therapy. While these treatments are effective in preventing hemorrhage from an unruptured intracranial aneurysm (UIA), they are invasive and not without significant associated risks6. There is currently no medical treatment which 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 assessed whether aspirin use and frequency of use was associated with occurrence of UIA rupture and whether history of smoking or hypertension had any interaction with such an effect.
Methods and Materials
ISUIA is an epidemiological cohort study that involved the long-term follow-up of two prospective cohorts: 1) untreated and 2) treated. Prospective case ascertainment was from 1991-1998 (Phases I and II). Prospective follow-up of the prospective cohort (Phase III) was conducted from 2004-2007. One thousand six hundred ninety-one patients were managed conservatively, 1917 patients underwent surgery and 451 patients underwent endovascular intervention. The 1,691 initially, untreated patients are analyzed in this paper. Five hundred forty five patients who were initially enrolled in the conservative management group ultimately underwent a surgical or endovascular procedure to secure an aneurysm during the overall follow-up period. Patients included two groups of UIA patients. Group 1 patients have no history of subarachnoid hemorrhage (SAH) and have a UIA; Group 2 patients have had an SAH with at least one other UIA where the etiology of the SAH was definitively treated. Patients were enrolled in 61 medical centers in the United States, Canada, and Europe. Details of aneurysm and patient characteristics 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 clinical and radiologic inclusion and exclusion criteria: patients must have at least one UIA, which may or may not be symptomatic. Patients who have had a ruptured aneurysm at another location that was isolated, trapped, clipped, or treated through endovascular obliteration must be able to care for themselves after the aneurysmal treatment (Rankin grade 1 or 2) according to a follow-up evaluation at 30 days post-treatment. Patients may or may not undergo surgical clipping or endovascular intervention for the UIA at the investigator’s discretion. Patients with fusiform, traumatic, or mycotic aneurysms are not eligible for the study. Also, patients with saccular aneurysms less than 2 mm maximum diameter are excluded.
Hemorrhagic events were classified by diagnostic certainty and location of aneurysmal rupture. Classification of certainty of hemorrhage events was based upon uniform criteria. The adjudicated hemorrhage events were defined as a primary hemorrhage if either: 1) a definite or highly probable SAH of aneurysmal or unknown etiology or 2) a definite or highly probable intracranial hemorrhage determined to be of aneurysmal etiology. Suspected hemorrhage included all hemorrhages of aneurysmal or uncertain etiology regardless of certainty.
Subjects were selected from the prospective untreated cohort (n=1691) for a nested case-control study. Cases were subjects who subsequently suffered a primary aneurysmal hemorrhage over a 5 year period after UIA diagnosis. Four controls were matched to each case where possible by site (anterior or posterior) and size (+/− 2 millimeters) of the UIA (58 cases, 213 controls). Frequency of aspirin use was based on the question “How often is the patient taking aspirin” and was comprised originally of 9 categories: “never”, “less than once a month”, “once a month”, “less than once a week and more than once a month”, “1-2 times a week, “3-4 times a week”, “5-6 times a week”, “daily”, and “unknown”. Because of limited numbers of subjects at certain aspirin use levels, frequency was grouped as “never,” “< once a month,” “> once a month – 2 times a week,” and “three times weekly to daily” for the categorical analyses. Aspirin frequency groups were then analyzed for risk of aneurysmal hemorrhage. Use of aspirin was also scored assuming a linear equally spaced system to avoid over fitting. The system consisted of a scoring from 1 to the number of category levels being analyzed with increments of one. For example for the multivariate analyses, the ordinal score represented the following levels of aspirin use:1=Never, 2=less than once a month, 3=once a month, 4=less than once a week and more than once a month, 5= 1-2 times a week, 6=3-4 times a week, 7=5-6 times a week, 8=daily.
Bivariable and multivariable analyses were performed on the nested case-control population using conditional logistic regression. The initial saturated model included age (continuous and grouped), sex, UIA enrollment group, participating center location (by region), multiple aneurysm, largest aneurysm size (maximal diameter), hypertension, cardiac valvular disease, atrial fibrillation-flutter, other cardiac arrhythmias, congestive heart failure, myocardial infarction, family history of intracranial aneurysm hemorrhage, smoking, alcohol consumption, use of anticoagulants, history of aneurysms, interaction smoking and hypertension, and use of aspirin (ordinally scored or in categorical groups). The final model was determined by stepwise and backward elimination of the initial saturated model.
For verification of the association in the entire untreated cohort, the same cases and all of the unruptured patients were included in a Cox regression multivariate model. A total of 1678 participants of the prospective untreated cohort who had information regarding age, region, smoking status, aneurysm location and size and were used to verify results yielded from the nested case-control analyses. The model included the variables selected for the final model. UIA size and location were entered in a proportional hazards model that included the entire prospective untreated cohort.
Results
A total of 271 nested case-control patients with untreated intracranial aneurysm were studied. The case-control population comprises 74% women; 52% are from Europe, 17% from Canada and 30% from the United States. The mean age was 57 years. Within the nested case-control population there were no significant differences in demographic and behavioral characteristics (table 1), reasons for performing cerebral angiography at the time of UIA diagnosis (table 2), or clinical characteristics (table 3) by history of aspirin use.
Tables: 1.
Matched Case-Control Group Composition (N=271)
| Total | Cases | Controls | ||||
|---|---|---|---|---|---|---|
| Characteristic | N | (%) | N | (%) | N | (%) |
| Aneurysm Maximum Diameter | ||||||
| <7 mm | 71 | 26.2 | 13 | 22.4 | 58 | 27.2 |
| 7-10 mm | 51 | 18.8 | 10 | 17.3 | 41 | 19.2 |
| 11-24mm | 114 | 42.1 | 25 | 43.1 | 89 | 41.8 |
| >= 25mm | 35 | 12.9 | 10 | 17.2 | 25 | 11.7 |
| Aneurysm Site | ||||||
| Anterior | 124 | 45.8 | 25 | 43.1 | 99 | 46.5 |
| Posterior | 147 | 454.2 | 33 | 56.9 | 114 | 53.5 |
Table 2.
Nested case-control population demographical and behavioral characteristics by history of aspirin use
| No history of aspirin use |
History of aspirin use |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | Controls | Cases | |||||||
| Characteristic | N | (%) | N | (%) | p-value* | N | (%) | N | (%) | p-value* |
| Age group | 0.721 | 0.656 | ||||||||
| <50 | 36 | 33 | 9 | 23.1 | 31 | 29.8 | 3 | 15.8 | ||
| 50-69 | 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 | ||||||||
| USA | 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 | 1 | 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 | ||
Using conditional Wald Chi-square. No and unknown combined for analyses.
Table 3.
Reasons for performing cerebral angiography among nested case-control population by history of aspirin use
| No history of aspirin use |
History of aspirin use |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | Controls | Cases | |||||||
| Characteristic | N | (%) | N | (%) | p- value* |
N | (%) | N | (%) | p- value* |
| 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 | ||
| 0.809 | 0.598 | |||||||||
| Cerebral Infarction | ||||||||||
| 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 | 0.343 | 0.981 | ||||||||
| Attack | ||||||||||
| 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 Chi-square.
The initial analysis is presented in table 4. A trend of protective effect for risk of UIA rupture was observed according to frequency of aspirin use. Patients who used aspirin three times weekly to daily had odds ratio (OR) for hemorrhage 0.40 (95% CI 0.18-0.87, reference group: no aspirin use), while patients in the “< once a month” group had OR for hemorrhage 0.80 (95% CI 0.31-2.05) and patients in the “> once a month – 2 times a week” group had OR for hemorrhage 0.87 (95% CI 0.27-2.81) (p-value for linear association 0.025).
Table 4.
Nested case-control population clinical history information by history of aspirin use
| No history of aspirin use |
History of aspirin use |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | p- value* |
Controls | Cases | p- value* |
|||||
| Characteristic | N | (%) | N | (%) | N | (%) | N | (%) | ||
| 0.946 | 0.993 | |||||||||
| History of hypertension | ||||||||||
| 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 (excluding MVP) |
0.994 | ** | ||||||||
| 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 fibrillation-flutter | 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 | ||
| 0.837 | 0.896 | |||||||||
| Any relative with positive 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 | ||
Using conditional Wald Chi-square. No and unknown combined for analyses.
Exact conditional test - conditional distribution is degenerated.
Table 5 shows the risk factor analyses with conditional logistic regression. Model 1 included aspirin as an equally spaced interval score that represents the increasing use of aspirin. There was a significant decreasing odds ratio for hemorrhage with the increasing use of aspirin (adjusted OR=0.82, 95% CI 0.71-0.94, p-value= 0.0051). Model 2 included aspirin use grouped into the categories: “never,” “< once a month,” “> once a month – 2 times a week,” and “3 times a week to daily.” Participants that take aspirin 3 times a week to daily presented significantly lower odds of hemorrhage (adjusted OR=0.27, 95% CI 0.11-0.67, p-value=0.03). 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.
Table 5.
Nested case-control: hemorrhages and controls (matched by site and size) – frequency of aspirin use
| Controls |
Cases |
P-value for linear association conditional odds* |
||||
|---|---|---|---|---|---|---|
| N | (%) | N | (%) | Odds Ratio | ||
| Use of aspirin (grouped) | ||||||
| Never | 109 | 73.6 | 39 | 26.4 | 1 | 0.025 |
| <= Once a month | 23 | 79.3 | 6 | 20.7 | 0.80 | |
| > Once a month - 2 times a week | 14 | 77.8 | 4 | 22.2 | 0.86 | |
| 3 times a week - daily | 67 | 88.2 | 9 | 11.8 | 0.40 | |
P-value =0.14 for these grouping. P-value of never versus ever=0.0529.
Tested using conditional logistic regression.
Considering an equally spaced scoring of 4 levels, using the conditional logistic model.
Table 6.
Risk factor analyses with conditional logistic regression
| Model I |
Model II |
|||||
|---|---|---|---|---|---|---|
| Characteristic | N | Unadjusted Odds Ratio (95% CI) |
n | Adjusted Odds Ratio (95% CI) |
n | Adjusted Odds Ratio (95% CI) |
| Age (continuous) | 271 | 1.02 (1-1.04) | 270 | 1.03 (1.01-1.06) | 270 | 1.03 (1.01-1.06) |
| Age group | ||||||
| <50 | 80 | Reference | --- | --- | --- | --- |
| 50-69 | 139 | 1.43 (0.69-3) | --- | --- | --- | --- |
| 70+ | 54 | 2.1 (0.89-4.96) | --- | --- | --- | --- |
| Region | ||||||
| USA | 82 | Reference | 82 | Reference | 82 | Reference |
| Canada | 47 | 0.33 (0.11-1.02) | 47 | 0.24 (0.07-0.81) | 47 | 0.24 (0.07-0.82) |
| Europe | 142 | 1.1 (0.6-2) | 141 | 0.90 (0.46-1.76) | 141 | 0.93 (0.47-1.80) |
| Smoking | ||||||
| Missing | 1 | |||||
| No | 70 | Reference | 70 | Reference | 70 | Reference |
| Former | 118 | 0.58 (0.29-1.15) | 118 | 0.75 (0.36-1.57) | 118 | 0.78 (0.37-1.64) |
| Current | 82 | 0.44 (0.2-0.97) | 82 | 0.44 (0.19-1.00) | 82 | 0.44 (0.19-1.00) |
| Any relative with positive history of aneurysms |
||||||
| No/Unknown | 233 | Reference | --- | --- | --- | --- |
| Yes | 38 | 0.55 (0.21-1.46) | --- | --- | --- | --- |
| Use of aspirin (grouped) | ||||||
| Never | 148 | Reference | --- | --- | 148 | Reference |
| <= Once a month | 29 | 0.8 (0.31-2.04) | --- | --- | 29 | 0.64 (0.24-1.74) |
| > Once a month - 2 | 18 | 0.86 (0.27-2.81) | --- | --- | 18 | 0.78 (0.22-2.82) |
| 3 times a week – daily | 76 | 0.4 (0.18-0.87) | --- | --- | 75 | 0.27 (0.11-0.67) |
| Score of aspirin use | 271 | 0.86 (0.77-0.97) | 270 | 0.82 (0.71-0.94) | --- | --- |
A validation analysis was done using the entire prospective untreated cohort. By definition the hemorrhage cases remained 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, p-value= 0.03). A second model included aspirin use grouped into the categories: “never,” “< once a month,” “> once a month – 2 times a week,” and “3 times a week to daily.” Participants that take aspirin 3 times a week to daily had a significantly lower hazard of hemorrhage (adjusted hazard ratio=0.45, 95% CI 0.22-0.92, p-value=0.03).
Discussion
The results of this study suggest that aspirin could conceivably 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 vertebrobasilar circulation at increased risk7. The design of this study was to control for these risk factors to examine behavioral factors such as smoking and aspirin use. The epidemiologic evidence demonstrates an association of a protective effect of aspirin use against hemorrhage, comparing individuals reporting aspirin use with those reporting that they never used aspirin (adjusted OR=0.82, 95% CI 0.71-0.94, p-value= 0.0051). However, there also appears to be a dose-dependent relationship trend associating frequency of aspirin use with risk of hemorrhage (patients who used aspirin “3x/week to daily” have crude conditional odds ratio (OR) for hemorrhage of 0.40 (95% CI 0.18-0.87), and adjusted conditional odds ratio (OR) for hemorrhage of 0.19 (95% CI 0.07-0.54), compared to “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 histologic evidence of macrophages, T cells, immunoglobulin and complement in aneurysm wall tissue specimens collected at the time of microsurgical repair8. Frösen demonstrated similar findings of macrophage and T-cell infiltration in surgical specimens from unruptured and ruptured aneurysms9, and also found histologic evidence of increased expression of several inflammatory receptors (vascular endothelial growth factor, VEGF, transforming growth factor – beta, TGFβ, and basic fibroblast growth factor, (bFGF) associated with aneurysm wall remodeling and rupture10. Macrophages secrete matrix metalloproteinases (MMPs) which degrade the extracellular matrix and increased expression of MMP-2 and MMP-9 have been demonstrated in IAs11. Dysregulation of the complement pathway has also been implicated in IA pathophysiology, as 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 specimens12. 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, as the IA wall lacks the internal elastic lamina, which normally provides structural strength for cerebral artery walls13. This process is thought to initiate formation of cerebral aneurysms. Subsequent hemodynamic stress on the endothelium leads to molecular signaling of proinflammatory and proliferative pathways14. Aoki et al. recently showed several lines of evidence that PGE2 –EP2 receptor signaling links hemodynamic stress to cerebral aneurysm formation in rodents through activation of NF-kB15. Activation of transcription factor nuclear factor kappa B (NFkB)16, and resultant increased expression of monocyte chemotactic protein-1 (MCP-1)17 is highly chemotactic to inflammatory 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 cerebral aneurysm wall following endothelial disruption18. Further supporting the above histologic evidence from human tissue studies, rodent IA models have demonstrated a role of aneurysm progression associated with macrophage-secreted extracellular matrix-degrading proteolytic enzymes (MMP-2 and -9)19.
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 MMP-2 and -9 expression20, 21 as well as to inhibit tumor necrosis factor-alpha (TNF-α) release in smooth muscle cell cultures22, 23. Aspirin has also been found to inhibit TNF-α stimulated MCP-1 and interleukin-8 expression in human umbilical vein endothelial cells24. There is also evidence that aspirin inhibits inflammatory cell adhesion in endothelial cells by reducing NF-kB activity25, 26. Given this evidence of inhibitory effects of aspirin at several steps in the inflammatory cascade implicated in cerebral aneurysm pathophysiology, 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 epidemiologic 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 anti-platelet effects and this is often the indication for aspirin use, e.g. ischemic cerebrovascular disease. Thus, a down-stream mediated anti-platelet 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 vs. group 2, age, smoking history, etc.), adjustment can only be made for those measured confounders and potential unmeasured confounders which are not available in the data set may actually affect rupture risk. There is also a possibility that the lack of statistical difference in many baseline comorbidities observed between cases and controls may due to lack of statistical power. Further, information regarding statin use, which could further substantiate the hypothesized mechanism of inhibition of inflammation, is not available for this population as 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 two ways using a categorical, ordinal analysis and by an interval scoring system for aspirin use. Scoring systems are limited in nature as there are many possible approaches that can be adopted. We consider a linear equally spaced system following how the data was captured in the questionnaire to avoid over fitting. 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, e.g. small, anterior circulation aneurysms. The results were equally as strong.
Conclusion
Recent studies on IAs have strengthened the concept that chronic inflammation plays a significant role in aneurysm formation and potentially predispose to IA wall degeneration and rupture. The findings from the ISUIA cohort provide epidemiologic evidence of an association of frequent aspirin 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 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 endpoints and 3) a clinical trial assessing the effect of aspirin on cerebral aneurysms that are chosen to be followed without interventional treatment.
Acknowledgments
Sources of Funding: The International Study of Unruptured Intracranial Aneurysms, on which this study was based, was supported by a grant (R01-NS-28492) from the National Institute of Neurological Disorders and Stroke.
The International Study of Unruptured Intracranial Aneurysms, on which this study was based, was supported by a grant (R01-NS-28492) from the National Institute of Neurological Disorders and Stroke
Footnotes
Conflict of Interest/Disclosure: none.
The findings of this study were presented at the International Stroke Conference in February 2011.
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