Increased Risk of Stroke Associated With Nonsteroidal Anti-Inflammatory Drugs A Nationwide Case-Crossover Study

George Institute for International Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
Stroke (Impact Factor: 5.72). 09/2010; 41(9):1884-90. DOI: 10.1161/STROKEAHA.110.585828
Source: PubMed


Limited studies assessed cerebrovascular safety of individual nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the risk of ischemic and hemorrhagic stroke associated with short-term use of selective and nonselective NSAIDs in a Chinese population with a high incidence of stroke.
A retrospective case-crossover study was conducted by analyzing the Taiwan National Health Insurance Database. We identified all ischemic and hemorrhagic stroke patients in 2006, aged >or=20 years, based on International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes from inpatient claims and defined the index date as the date of hospitalization. For each patient, we defined case period as 1 to 30 days before the index date and control period as 91 to 120 days before the index date. A pharmacy prescription database was searched for NSAID use during the case and control periods. We calculated adjusted ORs and their 95% CIs with a conditional logistic regression model.
A total of 28 424 patients with ischemic stroke and 9456 patients with hemorrhagic stroke were included. For ischemic stroke, a modest increased risk was evident for all oral NSAIDs with adjusted ORs (95% CI) ranging from 1.20 (1.00 to 1.44) for celecoxib to 1.90 (1.39 to 2.60) for ketorolac. For hemorrhagic stroke, oral ketorolac was associated with a significantly higher risk with OR of 2.69 (1.56 to 4.66). Significantly increased risk was found for parenteral NSAIDs, in particular ketorolac, with an OR of 3.92 (3.25 to 4.72) for ischemic stroke and 5.98 (4.40 to 8.13) for hemorrhagic stroke.
Use of selective and nonselective NSAIDs was associated with an increased risk of both ischemic and hemorrhagic stroke, strikingly high for parenteral ketorolac.

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    • "At present, it is not fully understood why individuals with arthritis may report higher likelihood of stroke. Rincón et al. [19] have speculated that a state of chronic inflammation may contribute to an elevated risk of stroke, whereas others have proposed that the pathway may be more related to atrial fibrillation and heart failure [20], either directly [21] or through long-term use of glucocorticoids [22] and NSAID medication [23]. These studies notwithstanding our analyses revealed an association with most of the traditional risk factors for stroke (e.g., hypertension, heart disease, and diabetes). "
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    ABSTRACT: Arthritis is a chronic inflammatory condition commonly associated with mobility restriction and reduced activity. To date, the extent to which arthritis is an independent risk factor for stroke is unclear, and important, in light of an aging population. The purpose of this study was to (i) quantify the cross-sectional association between stroke and arthritis and (ii) to determine whether the relationship differed in physically active and inactivemiddle-aged and older adults. Data was derived from the 2010 Canadian Community Health Survey (N = 47 188; ≥30 y). Multivariable logistic regression was used to estimate the association between arthritis and stroke in models adjusted for age, physical activity (PA), and demographic factors. Overall, individuals with arthritis were 4 times more likely to report a history of stroke (OR = 3.8, 95% CI = 3.06-4.68), whereas those who were engaged in at least moderate PA (≥ 1.5 kcal/kg/day) were less than half as likely (0.45, 0.92-0.62). This effect was moderated by age, as younger (30-65 y: 3.27, 2.22-4.83) but not older adults (>65 y: 1.04, 0.8-1.35) with arthritis had elevated odds of stroke. Both physical inactivity and arthritis are associated with higher odds of stroke, effects of which are the strongest amongst 30-65 year olds.
    Stroke Research and Treatment 04/2014; 2014:651921. DOI:10.1155/2014/651921
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    • "Because of the use of within-subject comparison, the case-crossover design auto-adjusts for unmeasured time-invariant confounding factors among different patients.21,22 This design has proven very useful in recent pharmacoepidemiologic studies.23,24 "
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    ABSTRACT: Background Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. Methods We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 1997–2007 were analyzed. The case period was defined as the 30 days before admission; the periods 90 to 120 days and 180 to 210 days before admission were used as control periods. Prescribing status of ACE inhibitors and ARBs during the 3 periods was assessed for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) for pneumonia associated with use of ACE inhibitors and ARBs. Results We identified 10 990 cases of hospitalization for new pneumonia. After adjustment for time-variant confounding factors, pneumonia was not associated with use of ACEI or ARBS: the ORs were 0.99 (95% CI, 0.81–1.21) and 0.96 (0.72–1.28), respectively. No association was seen for cumulative defined daily doses (DDDs), as compared with nonusers, for 0 to 30, 31 to 60, or more than 60 DDDs. The results were found to be robust in sensitivity analysis. Conclusions Neither the use nor cumulative dose of ACE inhibitors or ARBs was associated with pneumonia among the Taiwanese general population.
    Journal of Epidemiology 08/2013; 23(5). DOI:10.2188/jea.JE20120112 · 3.02 Impact Factor
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    • "There were other safety concerns related to ketorolac [55], such as acute renal failure [56] and stroke [57]. Due to reports of anaphylactic shock leaded to patient death with use of ketoroloac, the Department of Health of Taiwan government has ruled that a new warning must be added to the package insert of all ketorolac-containing products from 2008 onwards. "
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    ABSTRACT: Previous studies have documented the increased cardiovascular risk associated with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs). Despite this, many old NSAIDs are still prescribed worldwide. Most of the studies to date have been focused on specific oral drugs or limited by the number of cases examined. We studied the risk of new acute myocardial infarction (AMI) hospitalization with current use of a variety of oral and parenteral NSAIDs in a nationwide population, and compared our results with existing evidence. We conducted a case-crossover study using the Taiwan's National Health Insurance claim database, identifying patients with new AMI hospitalized in 2006. The 1-30 days and 91-120 days prior to the admission were defined as case and matched control period for each patient, respectively. Uses of NSAIDs during the respective periods were compared using conditional logistic regression and adjusted for use of co-medications. 8354 new AMI hospitalization patients fulfilled the study criteria. 14 oral and 3 parenteral NSAIDs were selected based on drug utilization profile among 13.7 million NSAID users. The adjusted odds ratio, aOR (95% confidence interval), for risk of AMI and use of oral and parenteral non-selective NSAIDs were 1.42 (1.29, 1.56) and 3.35 (2.50, 4.47), respectively, and significantly greater for parenteral than oral drugs (p for interaction<0.01). Ketorolac was associated with the highest AMI risk among both of oral and parenteral NSAIDs studied, the aORs were 2.02 (1.00, 4.09) and 4.27 (2.90, 6.29) respectively. Use of oral flurbiprofen, ibuprofen, sulindac, diclofenac, and parenteral ketoprofen were also significantly associated with increased AMI risk. The results of the present study were consistent with the majority of evidence from previous studies. The collective evidence revealed the tendency of increased AMI risk with current use of some NSAIDs. A higher AMI risk associated with use of parenteral NSAIDs was observed in the present study. Ketorolac had the highest associated risk in both oral and parenteral NSAIDs studied. Though further investigation to confirm the association is warranted, prescribing physicians and the general public should be cautious about the potential risk of AMI when using NSAIDs.
    BMC Cardiovascular Disorders 02/2012; 12(1):4. DOI:10.1186/1471-2261-12-4 · 1.88 Impact Factor
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