NSAIDS: Not Associated With Cerebral Hemorrhage but not Protective vs Ischemic Stroke

Abstracts & Commentary

Sources: Bak S, et al. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Stroke. 2003;34:379-386; Johnsen SP, et al. Nonaspirin nonsteroidal anti-inflammatory drugs and risk of hospitalization for intracerebral hemorrhage. Stroke. 2003;34:387-391.

Inhibition of thromboxane A2 synthesis by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) underlies the risk of bleeding complications associated with their use. Aspirin use is associated with a reduced risk of thrombotic events and possibly an increased risk for intracerebral hemorrhage (ICH).1 Therefore, exposure to NSAIDs also might increase the risk of ICH and decrease the risk of ischemic stroke.

Bak and colleagues used a population-based patient registry to identify all patients with a hospital discharge diagnosis of first stroke in 1 county in Denmark. They compared the use of NSAIDs in patients (659 with ICH, 208 with subarachnoid hemorrhage [SAH], 2717 with ischemic stroke) and in 40,000 controls randomly selected from the same county. Information regarding use of NSAIDs and other medications was determined from the prescription registry. The analysis was adjusted for potential confounding medical conditions including hypertension, diabetes mellitus, and hyperlipidemia.

Current exposure to NSAIDs did not increase the risk of ICH or SAH and offered no protection against first-ever ischemic stroke.

In another unrelated Danish study, Johnsen and associates used data from a county hospital patient register to identify 912 cases of first ICH and 9059 sex- and age-matched population-based controls. All prescriptions for NSAIDs before the date of admission for ICH were identified through a prescription registry. Analysis was adjusted for potential confounding factors including medical diagnoses and medications. Patients prescribed nonaspirin NSAIDs were not at an increased risk of being hospitalized for ICH. This finding was true for all subgroups, including the elderly and patients with a previous discharge diagnosis of hypertension.


The studies of Bak and Johnsen support the findings of previous studies. Thrift and associates1 examined the association between the use of aspirin and other NSAIDs and ICH. Low-dose aspirin or other NSAID use was not associated with ICH. Aspirin in doses greater than 1225 mg/wk (175 mg/d), however, was associated with an increased risk for ICH. Saloheimo and colleagues reported similar results.2

Therefore, based on present evidence, NSAIDs other than aspirin can be prescribed for patients without increasing their risk of ICH.

The failure of NSAIDs to protect against ischemic stroke is not surprising. In contrast to even low-dose aspirin, conventional NSAIDs inhibit cyclo-oxygenase (COX)-1 in an incomplete and reversible fashion, which may not be sufficient to effectively inhibit thromboxane A2 biosynthesis. Through their effect on COX-2, NSAIDs also inhibit the biosynthesis of prostacyclin I2, a platelet inhibitor and vasodilator. It is not known, however, whether the absent antithrombotic effect of NSAIDs is due to the incomplete inhibition of COX-1 or to the concomitant inhibition of COX-2.

Clinicians have been aware that an interaction between aspirin and NSAIDs exists3 and that when used in combination, NSAIDs may antagonize the protective effects of aspirin in patients with established cardio- or cerebrovascular disease. MacDonald and Wei4 found an increased mortality in patients with a hospital discharge diagnosis of cardiovascular disease who used aspirin plus ibuprofen compared with users of aspirin alone. They did not adjust for potentially confounding medical conditions, which renders their results inconclusive but still of cautionary value. Based on present information, clinicians should advise their patients taking aspirin for secondary protection to limit their use of NSAIDs or avoid them altogether. — John J. Caronna

Dr. Caronna is Vice-Chairman, Department of Neurology, Cornell University Medical College New York, NY


1. Thrift AG, et al. BMJ. 1999;318:759-764.

2. Saloheimo P, et al. Stroke. 2001;32:399-404.

3. Catella-Lawson F, et al. N Engl J Med. 2001;345: 1809-1817.

4. MacDonald TM, Wei L. Lancet. 2003;361:573-574.

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