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Rebound Inflammation and the Risk of Ischemic Stroke After Discontinuation of Aspirin Therapy

Rebound Inflammation and the Risk of Ischemic Stroke After Discontinuation of Aspirin Therapy In their retrospective, cross-sectional, case-control study of patients with multiple risk factors for cerebrovascular disease, Maulaz et al1 found increased risk of brain ischemic stroke in the 4 weeks after aspirin discontinuation (odds ratio, 3.34; 95% confidence interval, 1.07-10.39). These findings are consistent with previous studies, which showed that aspirin withdrawal may pose risk to coronary patients.2 Moreover, similar risks are reported after the cessation of nonsteroidal anti-inflammatory drug (NSAID) therapy.3 Taken together, these data suggest that there may be some common mechanism responsible for these withdrawal-related cardiovascular and cerebrovascular events. In the “Comment” section of the article, Maulaz et al1 focused on possible prothrombotic rebound effects after stopping aspirin, which have been reported in experimental studies. However, they omit the possibility that there may be some “rebound” inflammation after stopping aspirin for the duration of several weeks. The suggestion that the cardioprotective properties of low-dose aspirin may reflect its anti-inflammatory rather than antiplatelet effects first came from the demonstration that the beneficial effect of aspirin positively correlated with baseline levels of high-sensitivity C-reactive protein.4,5 This assumption is supported by compelling evidence that inflammation, as assessed by high-sensitivity C-reactive protein, is a strong independent predictor of the risk of future cardiovascular events, including ischemic stroke and transient ischemic attack.6-8 Further support for this hypothesis comes from pharmacological studies that have provided evidence that low doses of aspirin used for preventing atherothrombotic complications are sufficient to inhibit inflammation by triggering the formation of endogenous lipoxin analogues.9,10 Although the aspirin-acetylated cyclooxygenase-2 cannot produce prostaglandins from arachidonic acid, unlike other NSAIDs it retains the ability to generate monohydroxy fatty acids, which are converted by leukocyte 5-lipoxygenase to carbon-15 epimeric lipoxins, also termed aspirin-triggered lipoxins (ATLs).9 Similarly, aspirin impacts the biosynthesis of other lipoxin analogues named resolvins, which are derived from omega-3 fatty acids through the cyclooxygenase-2/lipoxygenase interaction pathway.11 The findings that ATLs and resolvins can be effectors of anti-inflammatory reactions and that low-dose aspirin (81 mg daily) is the most effective dose for ATL generation implicate that these novel lipid mediators might contribute to aspirin's beneficial action in preventing atherothrombosis.9 Moreover, observations that ATLs are sensitive to inhibition by “coxibs”9 and certain conventional NSAIDs9,12 may have implications for elucidating the high rate of aspirin resistance and the differences in cardiovascular effects between individual NSAIDs and their use in combination with aspirin. Hence, it may be concluded that the study by Maulaz et al adds a new dimension to this important issue. Back to top Article Information Correspondence: Dr Pijak, Department of Internal Medicine, University Hospital, Limbova 5, Bratislava 833 05, Slovak Republic (r.pijak@zutom.sk). Financial Disclosure: Dr Pijak has received consulting fees from local branches of Pfizer, Pharmacia, and Fournier Pharma, Bratislava, Slovak Republic. References 1. Maulaz ABBezerra DCMichel PBogousslavsky J Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2005;621217- 1220PubMedGoogle ScholarCrossref 2. Ferrari EBenhamou MCerboni PMarcel B Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45456- 459PubMedGoogle ScholarCrossref 3. Fischer LMSchlienger RGMatter CMJick HMeier CR Discontinuation of nonsteroidal anti-inflammatory drugs is associated with an increased risk of acute myocardial infarction. Arch Intern Med 2004;1642472- 2476PubMedGoogle ScholarCrossref 4. Ridker PMCushman MStampfer MJTracy RPHennekens CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men [erratum in: N Engl J Med. 1997;337:356]. N Engl J Med 1997;336973- 979PubMedGoogle ScholarCrossref 5. Ikonomidis IAndreotti FEconomou E et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999;100793- 798PubMedGoogle ScholarCrossref 6. Lindsberg PJGrau AJ Inflammation and infections as risk factors for ischemic stroke. Stroke 2003;342518- 2532PubMedGoogle ScholarCrossref 7. van Dijk EJPrins NDVermeer SE et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112900- 905PubMedGoogle ScholarCrossref 8. Rost NSWolf PAKase CS et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001;322575- 2579PubMedGoogle ScholarCrossref 9. Fiorucci SDistrutti EMencarelli A et al. Cooperation between aspirin-triggered lipoxin and nitric oxide (NO) mediates antiadhesive properties of 2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) (NO-aspirin) on neutrophil-endothelial cell adherence. J Pharmacol Exp Ther 2004;3091174- 1182PubMedGoogle ScholarCrossref 10. Chiang NBermudez EARidker PMHurwitz SSerhan CN Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci U S A 2004;10115178- 15183PubMedGoogle ScholarCrossref 11. Serhan CNHong SGronert K et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002;1961025- 1037PubMedGoogle ScholarCrossref 12. Mancini JAVickers PJO’Neill GPBoily CFalgueyret JPRiendeau D Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. Mol Pharmacol 1997;5152- 60PubMedGoogle Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Rebound Inflammation and the Risk of Ischemic Stroke After Discontinuation of Aspirin Therapy

Archives of Neurology , Volume 63 (2) – Feb 1, 2006

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Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.63.2.300-b
Publisher site
See Article on Publisher Site

Abstract

In their retrospective, cross-sectional, case-control study of patients with multiple risk factors for cerebrovascular disease, Maulaz et al1 found increased risk of brain ischemic stroke in the 4 weeks after aspirin discontinuation (odds ratio, 3.34; 95% confidence interval, 1.07-10.39). These findings are consistent with previous studies, which showed that aspirin withdrawal may pose risk to coronary patients.2 Moreover, similar risks are reported after the cessation of nonsteroidal anti-inflammatory drug (NSAID) therapy.3 Taken together, these data suggest that there may be some common mechanism responsible for these withdrawal-related cardiovascular and cerebrovascular events. In the “Comment” section of the article, Maulaz et al1 focused on possible prothrombotic rebound effects after stopping aspirin, which have been reported in experimental studies. However, they omit the possibility that there may be some “rebound” inflammation after stopping aspirin for the duration of several weeks. The suggestion that the cardioprotective properties of low-dose aspirin may reflect its anti-inflammatory rather than antiplatelet effects first came from the demonstration that the beneficial effect of aspirin positively correlated with baseline levels of high-sensitivity C-reactive protein.4,5 This assumption is supported by compelling evidence that inflammation, as assessed by high-sensitivity C-reactive protein, is a strong independent predictor of the risk of future cardiovascular events, including ischemic stroke and transient ischemic attack.6-8 Further support for this hypothesis comes from pharmacological studies that have provided evidence that low doses of aspirin used for preventing atherothrombotic complications are sufficient to inhibit inflammation by triggering the formation of endogenous lipoxin analogues.9,10 Although the aspirin-acetylated cyclooxygenase-2 cannot produce prostaglandins from arachidonic acid, unlike other NSAIDs it retains the ability to generate monohydroxy fatty acids, which are converted by leukocyte 5-lipoxygenase to carbon-15 epimeric lipoxins, also termed aspirin-triggered lipoxins (ATLs).9 Similarly, aspirin impacts the biosynthesis of other lipoxin analogues named resolvins, which are derived from omega-3 fatty acids through the cyclooxygenase-2/lipoxygenase interaction pathway.11 The findings that ATLs and resolvins can be effectors of anti-inflammatory reactions and that low-dose aspirin (81 mg daily) is the most effective dose for ATL generation implicate that these novel lipid mediators might contribute to aspirin's beneficial action in preventing atherothrombosis.9 Moreover, observations that ATLs are sensitive to inhibition by “coxibs”9 and certain conventional NSAIDs9,12 may have implications for elucidating the high rate of aspirin resistance and the differences in cardiovascular effects between individual NSAIDs and their use in combination with aspirin. Hence, it may be concluded that the study by Maulaz et al adds a new dimension to this important issue. Back to top Article Information Correspondence: Dr Pijak, Department of Internal Medicine, University Hospital, Limbova 5, Bratislava 833 05, Slovak Republic (r.pijak@zutom.sk). Financial Disclosure: Dr Pijak has received consulting fees from local branches of Pfizer, Pharmacia, and Fournier Pharma, Bratislava, Slovak Republic. References 1. Maulaz ABBezerra DCMichel PBogousslavsky J Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2005;621217- 1220PubMedGoogle ScholarCrossref 2. Ferrari EBenhamou MCerboni PMarcel B Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45456- 459PubMedGoogle ScholarCrossref 3. Fischer LMSchlienger RGMatter CMJick HMeier CR Discontinuation of nonsteroidal anti-inflammatory drugs is associated with an increased risk of acute myocardial infarction. Arch Intern Med 2004;1642472- 2476PubMedGoogle ScholarCrossref 4. Ridker PMCushman MStampfer MJTracy RPHennekens CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men [erratum in: N Engl J Med. 1997;337:356]. N Engl J Med 1997;336973- 979PubMedGoogle ScholarCrossref 5. Ikonomidis IAndreotti FEconomou E et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999;100793- 798PubMedGoogle ScholarCrossref 6. Lindsberg PJGrau AJ Inflammation and infections as risk factors for ischemic stroke. Stroke 2003;342518- 2532PubMedGoogle ScholarCrossref 7. van Dijk EJPrins NDVermeer SE et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112900- 905PubMedGoogle ScholarCrossref 8. Rost NSWolf PAKase CS et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001;322575- 2579PubMedGoogle ScholarCrossref 9. Fiorucci SDistrutti EMencarelli A et al. Cooperation between aspirin-triggered lipoxin and nitric oxide (NO) mediates antiadhesive properties of 2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) (NO-aspirin) on neutrophil-endothelial cell adherence. J Pharmacol Exp Ther 2004;3091174- 1182PubMedGoogle ScholarCrossref 10. Chiang NBermudez EARidker PMHurwitz SSerhan CN Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci U S A 2004;10115178- 15183PubMedGoogle ScholarCrossref 11. Serhan CNHong SGronert K et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002;1961025- 1037PubMedGoogle ScholarCrossref 12. Mancini JAVickers PJO’Neill GPBoily CFalgueyret JPRiendeau D Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. Mol Pharmacol 1997;5152- 60PubMedGoogle Scholar

Journal

Archives of NeurologyAmerican Medical Association

Published: Feb 1, 2006

Keywords: aspirin,inflammation,ischemic stroke

References

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