A score for indications of NSAID use was calculated by assigning one point for each of the following condi- tions: migraine, frequent headache (reported ≥3 times), osteoarthritis, inflammatory arthritis, cerebrovascular disease, and coronary artery disease. A score for NSAID side effects or contraindications was calculated by assigning a point for each of the following condi- tions: gastrointestinal bleeding, ulcer, and gastro- intestinal symptoms (nausea, vomiting, dyspepsia, dysphagia).
Assessment of NSAID use
Participants completed annual questionnaires asking about compliance with the study medication (aspirin and β carotene), outside use of aspirin, drugs contain- ing aspirin or non-aspirin NSAIDs, and their possible side effects. Non-study aspirin and NSAID use was reported as the number of days of use in the preceding 12 months, and was categorised as 0, 1–14, 15–60, or
>60 days. Regular use of aspirin and other NSAIDs was defined as >60 days’ use per year. We included both study and non-study aspirin use in the definition of the aspirin variable. Because few participants had no regular aspirin exposure, cumulative exposure to aspirin was categorised as 0–4, 5–9, 10–14, or ≥15 years of regular use. As regular NSAID use was a contraindication to study participation, few partici- pants were regular users of non-aspirin NSAIDs for the first five years of the trial. Cumulative non-aspirin NSAID use was categorised as 0, 1–2, 3–4, or ≥5 years.
Statistical analysis
Using conditional logistic regression, we calculated the odds ratio and 95% confidence interval of prior non-aspirin NSAID or aspirin use by participants with Parkinson’s disease and by their controls in each case-control set. We defined NSAID exposure in three ways: (a) ever versus never regular use for non-aspirinNSAID (0–4 years v >4 years for aspirin), (b) days of use in the year before matching, and (c) years of regular use. To investigate the possibility of increased NSAID use just before identification of Parkinson’s disease as the result of symptoms from the undiagnosed disease, we repeated the above analyses using information on NSAID use from five years before the index date. All analyses were adjusted for the following risk factors for Parkinson’s disease: smoking (never, past, current), alcohol use (daily, weekly, monthly), vigorous exercise (sufficient to cause sweating) (ever, never), and body mass index (<25, 25–<30, ≥30). These covariates were updated during the study, and we used the infor- mation closest to the matching date. We adjusted for aspirin use when estimating the effects of non-aspirin NSAIDs and vice versa. To evaluate potential effect modification, we stratified the analyses of cumulative NSAID use by mean age at identification of Parkin- son’s disease (<74 years, ≥74 years) and smoking status (ever, never). We included interaction terms in the model to test for significant effect modification.
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