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(Stroke. 2003;34:379.)
© 2003 American Heart Association, Inc.

Original Contributions

Risk of Stroke Associated With Nonsteroidal Anti-Inflammatory Drugs

A Nested Case-Control Study

Søren Bak, MD; Morten Andersen, MD; Ioannis Tsiropoulos, MD; Luis Alberto García Rodríguez, MD; Jesper Hallas, MD; Kaare Christensen, MD David Gaist, MD

From the Departments of Epidemiology (S.B., K.C., D.G.) and Clinical Pharmacology (M.A., J.H.), Institute of Public Health, University of Southern Denmark, Odense, Denmark; Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain (L.A.G.R.); and Department of Neurology, Odense University Hospital, Odense, Denmark (S.B., I.T., D.G.).

Correspondence to David Gaist, Epidemiology, Institute of Public Health, University of Southern Denmark, Sdr Blvd 23A, 5000 Odense C, Denmark. E-mail dgaist{at}health.sdu.dk

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References References

 
Background and Purpose— Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with bleeding complications and may affect the risk of hemorrhagic stroke through inhibition of platelet cyclooxygenase-1. We performed a population-based case-control study to estimate the risk of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke in users of NSAIDs.

Methods— We used a population-based patient registry to identify all patients with a first-ever stroke discharge diagnosis in the period of 1994 to 1999. All diagnoses were validated according to predefined criteria. We selected 40 000 random controls from the background population. Information on drug use for cases and controls was retrieved from a prescription registry. Odds ratios were adjusted for age, sex, calendar year, and use of other medication. To evaluate the effect of various potential confounders not recorded in the register, we performed separate analyses on data from 2 large population-based surveys with more detailed information on risk factors.

Results— The cases were classified as intracerebral hemorrhage (n=659), subarachnoid hemorrhage (n=208), and ischemic stroke (n=2717). The adjusted odds ratio of stroke in current NSAID users compared with never users was 1.2 (95% CI, 0.9 to 1.6) for intracerebral hemorrhage, 1.2 (95% CI, 0.7 to 2.1) for subarachnoid hemorrhage and 1.2 (95% confidence interval, 1.0 to 1.4) for ischemic stroke. The survey data indicated that additional confounder control would not have led to an increase in relative risk estimates.

Conclusions— Current exposure to NSAIDs is not a risk factor for intracerebral hemorrhage or subarachnoid hemorrhage. Furthermore, NSAIDs probably offer no protection against first-ever ischemic stroke.

Key Words: anti-inflammatory agents, nonsteroidal • stroke • stroke, hemorrhagic

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References References

 
Nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain relief, especially in relation to rheumatic conditions. Although generally well tolerated, NSAIDs have been associated with serious adverse effects, including upper gastrointestinal bleeding and perforation.¹ Cyclooxygenase-1 mediates the biosynthesis of thromboxane, which causes platelet aggregation, vasoconstriction, and proliferation of vascular smooth muscle cells. Inhibition of thromboxane A₂ synthesis probably underlies the well-established antithrombotic properties, as well as the risk of bleeding complications associated with aspirin treatment.^2,3 Like aspirin, NSAIDs are inhibitors of cyclooxygenase-1 in platelets, and it is thus conceivable that exposure to NSAIDs might also increase the risk of hemorrhagic stroke and decrease the risk of ischemic stroke. To the best of our knowledge, the only published epidemiological study on NSAID exposure and hemorrhagic stroke showed no association between current use of NSAIDs and the risk of intracerebral hemorrhage.⁴ However, information on drug exposure was self-reported, and the risk of subarachnoid hemorrhage was not assessed.

See Editorial Comment, page 385

In contrast to aspirin, the association between NSAID exposure and the risk of ischemic stroke has not been previously studied. Small clinical studies have suggested that some NSAIDs may be effective in secondary prevention of myocardial infarction and thromboembolic complications in patients with heart disease.^5,6 Two epidemiological studies on the effect of NSAIDs in primary prevention, however, showed no association between NSAID use and the risk of first-ever myocardial infarction.^7,8

We used population-based registries to estimate the risk of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke in users of NSAIDs.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References References

 
We performed a nested case-control study using information from 3 population-based registries: the Patient Registry, Residence History Registry, and Odense University Pharmacoepidemiological Database in Funen County, Denmark (population, 465 000 inhabitants, 9% of the Danish population). Linkage across the registries was performed by use of the civil registration number, which is a unique and permanent identifier of each Danish resident. Furthermore, we analyzed data from 2 large population-based surveys^9,10 to study the association between the use of NSAIDs and various potential confounders not directly assessable in the case-control study. The method used to identify cases and controls has been described in detail elsewhere.¹¹ In brief, we identified all patients 20 years of age with a discharge diagnosis of intracerebral hemorrhage, ischemic stroke, subarachnoid hemorrhage, or unspecified stroke in the period of January 1, 1994, to December 31, 1999, who were free of such diagnoses in the period of January 1, 1973, to December 31, 1993. Only patients who were residents of Funen County at the time of discharge were included (n=5964).

The date of first admission for stroke was defined as the index date. Discharge records for all first stroke admissions were reviewed. Information on use of medication was suppressed, and 3 specialists in neurology then evaluated the discharge records according to predefined criteria (Table 1). Control subjects were identified through the Funen Residence History Registry, which contains continuously updated information on the civil registration number and residence history of all inhabitants of Funen County. For the period of 1994 to 1999, we identified all Funen County residents who were 20 years of age with no hospitalization for stroke between 1973 and 1993. These residents were allocated a random index date in the period of January 1, 1994, to December 31, 1999, and 40 000 controls with no stroke discharge diagnosis before their index date were chosen at random.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Cases and Controls

Exposure Definition
We retrieved information on reimbursed medicine in Funen County from the Odense University Pharmacoepidemiological Database.¹² For each prescription, the registry includes information on the civil registration number, date the prescription was presented, and package identification number, which enable identification of the brand, quantity, and form of the drug. The total drug content of the package is recorded as the number of defined daily doses (DDDs).¹³ The DDD is established by an expert panel as the typical maintenance dose required when the drug is used for its main indication in an adult. All drugs are classified according to the anatomic therapeutical chemical system.¹³ The indication for treatment and the dosing instruction are not recorded in the registry.

We retrieved all available information from the prescription registry on the use of NSAIDs and other drugs in cases and controls before the index date. Each recorded prescription was assumed to last a number of days equivalent to the number of issued DDDs. Prescriptions were regarded as consecutive when the supply of an NSAID ended <7 days before presentation of a new prescription for an NSAID. We defined a person as a current user of NSAIDs if the supply of the prescription lasted until the index date or ended within 30 days before the index date. Persons were defined as recent users if the supply of the prescription ended between 31 and 90 days before the index date; past users were those for whom the supply ended before 91 days before the index date. Persons with no prescriptions for NSAIDs before the index date were defined as never users.

We classified NSAIDs according to plasma half-life (<12 and 12 hours). An estimate of the daily NSAID dose in a series of consecutive prescriptions was calculated as the total number of issued DDDs divided by duration of use.

Potential Confounders
Information on diseases influencing the risk of stroke was not available from the registries. Instead, we retrieved information on the use of drugs, which can be regarded as proxy measures for these diseases. We used prescriptions for diuretics, ß-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, and antianginal drugs as proxy measures for hypertension, cardial arrhythmia, and ischemic heart disease. Antidiabetics and lipid-lowering drugs were used as proxy measures for diabetes and hyperlipidemia, respectively. An ever user of the drug in question was defined as a person with at least 1 prescription of the drug before the index date. A person with no recorded prescriptions for the drug was labeled a never user.

Furthermore, we used information on low-dose aspirin (tablets containing 75 to 150 mg acetyl salicylic acid) and anticoagulants, which might affect the risk of stroke through their influence on hemostasis. Current use and never use of each of these drugs were defined as for NSAIDs. Persons whose supply of the prescription ended >30 days before the index date were labeled past users.

Patients with subarachnoid hemorrhage commonly report an episode of severe headache within days or weeks before the stroke.¹⁴ This warning headache might be treated with NSAIDs and thus cause a false-positive association between NSAID exposure and the risk of subarachnoid hemorrhage (protopathic bias).¹⁵ We addressed this problem by reviewing the records of all patients with subarachnoid hemorrhage and current treatment with NSAIDs for 30 days. Patients with a probable episode of warning headache and subsequent administration of NSAIDs were identified. The extent of potential protopathic bias was also assessed in patients with intracerebral hemorrhage or ischemic stroke. We identified all patients currently treated with NSAIDs for 30 days who were admitted to the departments of neurology or neurosurgery because of intracerebral hemorrhage or ischemic stroke. Among these patients, we reviewed the records of all cases with intracerebral hemorrhage and a random sample of cases with ischemic stroke.

Data From Twin Surveys
The data from the case-control study did not allow control of smoking, alcohol intake, and body mass index. Furthermore, using drug exposure as a proxy measure for concomitant diseases only allowed partial adjustment for these diseases. To estimate the magnitude and direction of the association between these potential confounders and use of NSAIDs, we used data from 2 large population-based surveys conducted in 1998 to 1999, the Middle Aged Twins Survey⁹ and the Longitudinal Study of Ageing Danish Twins.¹⁰ The method used has been described in detail previously.¹¹ We identified 4411 participants without a stroke diagnosis according to the Danish National Patient Register.¹⁶ The participants completed a comprehensive structured interview that included questions on current medication, hypertension, diabetes, myocardial infarction, smoking habits, and alcohol intake. Information on current medication included use of prescribed medicine and over-the-counter drugs within a fortnight before the interview. We compared the current use of prescribed NSAIDs in the control population with the current use of prescribed and over-the-counter NSAIDs in the survey study to estimate the extent of over-the-counter use of NSAIDs. To achieve comparable time windows for current use of NSAIDs between the 2 cohorts, we identified all control subjects whose supply of the prescription for NSAIDs ended within 14 days before the index date. Current use of NSAIDs was compared between controls and survey participants after stratification for sex and age.

Statistical Analysis
We used unconditional logistic regression to calculate crude and adjusted odds ratios (ORs) and 95% CIs of the risk of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke. Separate analyses were performed for definite and probable ischemic stroke. To minimize the consequences of protopathic bias, we also calculated the risk of subarachnoid hemorrhage in current NSAID users after exclusion of cases with warning headache treated with NSAIDs.

The risk of intracerebral hemorrhage and ischemic stroke was calculated for each of the 5 most commonly used individual NSAIDs. To study the effect of NSAID plasma half-life, we calculated the risk of intracerebral hemorrhage and ischemic stroke in current users of NSAIDs with a half-life of <12 and 12 hours compared with the risk of never users. The effect of dose was estimated by comparison of the risk of stroke in never users of NSAIDs, current users of a lower daily dose (<1 DDD), and current users of a higher daily dose (1 DDD).

In the twin surveys, unconditional logistic regression was used to study the association between potential stroke risk factors and current use of NSAIDs.

The study was approved by the local ethics committee and the Danish registry board.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References References

 
We identified 4765 patients with a valid diagnosis of first-ever stroke in the period of January 1, 1994, to December 31, 1999. In all, 659 (13.8%) had intracerebral hemorrhage, 208 (4.4%) had subarachnoid hemorrhage, and 2717 (57%) had ischemic stroke (Table 1). Ever use of NSAIDs was registered in 2345 cases and 16 696 controls. No cases or controls were registered as users of selective inhibitors of cyclooxygenase-2.

Among patients with intracerebral hemorrhage, 56 (8.5%) were current users of NSAIDs compared with 1795 (4.5%) of the controls (Table 2). The adjusted relative risk of intracerebral hemorrhage in current NSAID users was 1.2 (95% CI, 0.9 to 1.6) compared with never users.

View this table: [in this window] [in a new window]   TABLE 2. Risk of Intracerebral Hemorrhage Associated With the Use of NSAIDs

Among patients with subarachnoid hemorrhage, 23 (11.1%) were current users of NSAIDs compared with 1795 (4.5%) of the controls. The adjusted relative risk of subarachnoid hemorrhage in current NSAID users was 2.1 (95% CI, 1.3 to 3.2) compared with never users. However, 9 patients had an episode of warning headache treated with NSAIDs within 2 weeks before the stroke. After exclusion of these cases, the adjusted relative risk of subarachnoid hemorrhage in current NSAID users was 1.2 (95% CI, 0.7 to 2.1) compared with never users.

Two hundred forty-eight (9.1%) of 2717 cases with ischemic stroke were current users of NSAIDs compared with 1795 (4.5%) of the controls (Table 3). The adjusted relative risk of ischemic stroke in current NSAID users was 1.2 (95% CI, 1.0 to 1.4) compared with never users. The relative risk of definite ischemic stroke, probable ischemic stroke, and clinical stroke in current NSAID users was 1.2 (95% CI, 1.0 to 1.4), 1.2 (95% CI, 0.9 to 1.5), and 1.1 (95% CI, 0.9 to 1.5), respectively, compared with never users. Intracerebral hemorrhage and ischemic stroke were not associated with the studied individual NSAIDs, plasma half-life, or estimated daily dose (Table 4).

View this table: [in this window] [in a new window]   TABLE 3. Risk of Ischemic Stroke Associated With the Use of NSAIDs

View this table: [in this window] [in a new window]   TABLE 4. Influence of Individual NSAIDs, Plasma Half-Life, and Dose and Treatment Duration on the Risk of Intracerebral Hemorrhage and Ischemic Stroke in Current Single Users Compared With Never Users

In all, 23 patients with intracerebral hemorrhage and 94 patients with ischemic stroke were currently treated with NSAIDs for <30 days. Of these, we reviewed the records of 15 patients (65%) with intracerebral hemorrhage and 25 patients (27%) with ischemic stroke and found that 1 patient (7%) with intracerebral hemorrhage and 3 patients (12%) with ischemic stroke were prescribed NSAIDs for symptoms associated with stroke.

In the survey studies of twins, we identified 243 current users and 4168 nonusers of NSAIDs with a mean age of 66.8 years (SD, 12.6 years). Current users of NSAIDs were predominantly women (adjusted OR, 1.7; 95% CI, 1.2 to 2.5), current smokers (adjusted OR, 1.7; 95% CI, 1.2 to 2.6), and persons with hypertension (adjusted OR, 2.0; 95% CI, 1.4 to 2.9). The prevalence of current NSAID use in females according to age (45 to 74 or 75 years) was 5.3% and 8.9% in the control population and 5.5% and 8.9% in the survey population. The corresponding figures in men were 3.9% and 5.3% in the control population and 3.5% and 5.3% in the survey population.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References References

 
The results of our study indicate that use of NSAIDs is not associated with an increased risk of intracerebral hemorrhage or subarachnoid hemorrhage. Furthermore, the risk of ischemic stroke was not reduced in patients with current exposure to NSAIDs. The present study has several strengths. We used a longstanding population-based registry to identify potential cases within a well-defined geographic area. Neurologists blinded to drug exposure information assessed discharge records for all potential cases according to predefined criteria. Finally, drug exposure was assessed through a prescription database and was therefore not susceptible to recall bias.

In the only previous study on NSAID exposure and risk of intracerebral hemorrhage, 42 of 331 cases and 47 of 331 controls were currently exposed to NSAIDs. The adjusted OR for intracerebral hemorrhage in NSAID users was 0.85 (95% CI, 0.45 to 1.61).⁴ This is consistent with the findings in our study.

We found an increased OR of subarachnoid hemorrhage in current NSAID users compared with never users. The increased risk was probably due entirely to protopathic bias because identification and removal of cases with headaches treated with NSAIDs shortly before admission abolished the association.

The association between use of NSAIDs and the risk of ischemic stroke has not been addressed previously. Our results, however, are consistent with the finding of no association between NSAID exposure and reduced risk of first-ever myocardial infarction.^7,8 In fact, from our findings, a small increased risk of ischemic stroke in current users of NSAIDs cannot be entirely excluded.

The well-established antithrombotic effect of low-dose aspirin is primarily related to an irreversible and almost complete inhibition of platelet cyclooxygenase-1.² In contrast, conventional NSAIDs inhibit cyclooxygenase-1 in an incomplete and reversible fashion, which is possibly not sufficient for an effective inhibition of thromboxane biosynthesis in vivo.⁷ Furthermore, through its action on endothelial cyclooxygenase-2, NSAIDs also inhibit the biosynthesis of prostacyclin, which is a platelet inhibitor, a vasodilator, and an inhibitor of vascular smooth muscle cell proliferation.² However, whether the apparently absent antithrombotic effect of NSAIDs is due to the incomplete inhibition of cyclooxygenase-1 or to the concomitant inhibition of cyclooxygenase-2 is unknown.

Several potential limitations of our study warrant consideration. First, information on potential confounders was not directly available in the nested case-control study. Using prescription data on current and previous use of other medication enabled us to adjust for other stroke risk factors, including hypertension, diabetes, atrial fibrillation, and ischemic heart disease. Smoking and alcohol intake, however, could not be adjusted for in the case-control study. Results from the population-based surveys indicated that NSAID users were predominantly women, current smokers, and individuals with hypertension or increased body mass index.

Provided that smoking is generally more common in NSAID users, our OR of intracerebral hemorrhage and subarachnoid hemorrhage in NSAID users compared with nonusers may be overestimated. Similarly, our risk estimate for ischemic stroke in current NSAID users compared with nonusers may represent an overestimate, and a small beneficial antithrombotic effect of NSAIDs could thus have been overlooked. However, if NSAID exposure was associated with a protective effect against ischemic stroke, we would expect past NSAID users to be at increased risk of ischemic stroke compared with current users of the drug because it is unlikely that past and current NSAID users differ significantly with respect to smoking habits. In the present study, we found no such difference between current and past users of NSAIDs.

In our study, information on over-the-counter NSAID use was not available. However, the prevalence of current NSAID use within age and sex strata was of the same magnitude in the control population and in the survey population, indicating that the use of over-the-counter NSAIDs was not substantial and virtually nonexistent in persons 75 of age.

Review of medical records indicated that protopathic bias was also present in cases with intracerebral hemorrhage or ischemic stroke but to a far lesser extent than for subarachnoid hemorrhage. The effect of protopathic bias would be an overestimation of the relative risk of stroke and probably explains the increased risk of stroke in the subgroup of current short-term NSAID users. However, considering the small proportion of cases with intracerebral hemorrhage or ischemic stroke treated with NSAIDs as a result of initial stroke symptoms, it is unlikely that these numbers would significantly change our main results.

In conclusion, our results indicate that current exposure to NSAIDs is neither a risk factor for intracerebral hemorrhage nor a risk factor for subarachnoid hemorrhage. Furthermore, NSAIDs probably offer no protection against first-ever ischemic stroke.

	Acknowledgments

 
This study was supported by the National Institute of Aging (grant NIA-PO1-AG08761). We would like to thank Merete Lindhøj for excellent secretarial assistance.

Received May 8, 2002; revision received September 3, 2002; accepted September 9, 2002.

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Editorial Comment

Adnan I. Qureshi, MD, Guest Editor
Nonsteroidal Anti-Inflammatory Drugs and the Risk of Intracerebral Hemorrhage
Nonsteroidal anti-inflammatory drugs (NSAIDs) are valuable therapeutic agents that are widely used. Annually 70 million NSAID-related prescriptions are dispensed in the United States, 10 million in Canada, and 25 million prescriptions in the United Kingdom.^1–4 Approximately 90% of all NSAIDs are used by persons aged >65 years.⁵ NSAIDs affect the activity of cyclo-oxygenase (COX)-1 and COX-2 enzymes that catalyze the formation of prothrombotic (thromboxane A₂) and antithrombotic (prostacyclin I₂) eicosanoids, respectively.⁶ Aspirin is a potent inhibitor of platelet COX-1 and induces irreversible inhibition of platelet aggregation. At low doses, aspirin selectively inhibits only thromboxane A₂ without effecting prostacyclin biosynthesis. Other NSAIDs inhibit both COX-1–derived thromboxane A₂ and COX-2–derived prostacyclin I₂ with limited selectivity.⁶ Therefore, platelet inhibitory effect is more prominent with aspirin. Aspirin use has been associated with a reduced risk of thrombotic events and possibly an increased risk for intracerebral hemorrhage (ICH).⁷ The effect of other NSAIDs on the risk of ICH is unclear. However, the issue poses a dilemma for use of NSAIDs in elderly population study that is already at risk for ICH.⁸

The study by Bak et al⁹ uses a population-based patient registry to identify all patients with a hospital discharge diagnosis of first stroke in Funen County, Denmark, between 1994 to 1999. The patient registry contains information on all discharges from nonpsychiatric hospitals in Funen County since 1973.¹⁰ A diagnosis of ICH was made if the patient had clinical signs of stroke according to the World Health Organization (WHO) definition¹¹ and the neuroimaging description (computed tomographic [CT] scan or MRI) or autopsy findings were compatible with ICH.¹⁰ The investigators compared the use of NSAIDs in 659 patients with ICH and 40 000 random controls selected from Funen County using a nested case-control design. The information regarding use of NSAIDs and other medication was determined from the prescription registry. The analysis adjusted for potential confounding medical conditions including hypertension, diabetes mellitus, and hyperlipidemia, which were identified by using medication prescribed as proxy measures. The risk of ICH or subarachnoid hemorrhage was not increased with the use of NSAIDs. The finding is similar to a previous study by Thrift et al¹² that examined the association between use of aspirin or other NSAIDs and ICH using a case-control study. The use of NSAIDs was compared between 331 patients with stroke and 331 age- and sex-matched controls. ICH was diagnosed by CT scan or postmortem examination. The patients or proxy were interviewed regarding use of aspirin and NSAIDs within the previous 14 days followed by confirmation using physician’s prescription, if possible. Low-dose aspirin or other NSAID use within the preceding 2 weeks was not associated with ICH after adjusting for hypertension, serum cholesterol, diabetes, previous cardiovascular disease, body mass index, exercise, alcohol intake, and smoking. Aspirin in doses >1225 mg/wk was associated with an increased risk for ICH. The investigators were unable to find an increased risk with use of aspirin in any particular group of patients stratified by blood pressure, serum cholesterol, or alcohol intake. Saloheimo et al⁷ evaluated the risk factors for ICH among 98 consecutive patients with ICH. The diagnosis of ICH was confirmed by a CT scan. A case-control design was used by selecting 206 community-based controls matched for age and sex. The information regarding cerebrovascular risk factors and use of NSAIDs was acquired by interview of the patients or relatives and controls. History of epistaxis and use of NSAIDs were associated with an increased risk for ICH. The risk was predominantly observed for aspirin, as exclusion of other NSAIDs from the analysis did not affect the relationship. High doses of aspirin, defined by use >1225 mg/wk, were being used in 31 of 38 users of aspirin. There was a positive interaction between the history of epistaxis and use of aspirin on the risk of ICH suggesting that the combination was potentially more deleterious.

The validity of the studies evaluating the association between use of NSAIDs and ICH is dependent on the accurate identification of cases (including methods used to diagnose ICH) and assessment of exposure to NSAIDs (prescriptions, self report, or proxy). Despite the limitations of case-control studies, the present evidence does not support an increased risk for ICH associated with use of NSAIDs other than aspirin. Aspirin use may increase the risk of ICH, particularly when used in high doses. Unless contrary evidence becomes available, NSAIDs with the exception of aspirin can be considered in patients without concerns for an increased risk of ICH.

Department of Neurology and Neurosciences

University of Medicine and Dentistry of New Jersey

Newark, New Jersey

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