The Physicians’ Health Study was a randomised trial of aspirin (325 mg every other day) and β carotene (50 mg on alternate days) for the primary prevention of cardiovascular disease and cancer among 22
071 US male physicians. Detailed descriptions of the study design and findings have been published.21 22
At study entry in 1982, participants were between 40 and 84 years; had no history of cardiovascular disease, cancer, or other serious illness; and had no indication for or contraindication to aspirin or non-aspirin NSAIDs. All participants were tolerant to a three month run-in phase of aspirin treatment. Baseline information was self reported and collected by a mailed questionnaire that asked about risk factors for disease as well as lifestyle variables. Ninety two per cent of the participants identified their ethnicity as white. Participants were sent follow-up questionnaires asking about study outcomes and other medical information, twice in the first year and then yearly. The aspirin arm was discontinued after an average of five years of follow-up because of a 44% risk reduction in myocardial infarction in the aspirin group.21
Post-trial follow-up is ongoing.23
We used follow-up information to 4 March 2008 in our analysis.
Ascertainment of Parkinson’s disease
We identified all participants who reported a new diagnosis of Parkinson’s disease on their annual survey between 1982 and 2008. To evaluate the accuracy of the self reporting of Parkinson’s disease, we performed a validation study using the available medical records of 73 participants who indicated a new diagnosis of Parkinson’s disease.24
In the Physicians’ Health Study, medical records were obtained for each reported study outcome (cardiac event, transient ischaemic attack, stroke, cancer, pulmonary embolism or death). A physician (JAD) evaluated the medical records of participants who reported Parkinson’s disease before developing an outcome event. The records were then reviewed independently by two physicians with training in neurology (TK and GL).
The clinical diagnosis of Parkinson’s disease was considered valid if record review revealed one or more of
- Established diagnosis of Parkinson’s disease in the medical record or Parkinson’s disease as cause of death on the death certificate
- Current use of medication for Parkinson’s disease such as dihydroxyphenylalanine (DOPA) or a DOPA agonist
- Neurological examination with physical findings consistent with parkinsonism (at least two of rest tremor, rigidity, bradykinesia, and postural instability) with no evidence of a secondary cause of parkinsonism such as stroke, history of encephalitis, brain tumour, or neuroleptic treatment in the year before disease onset. Patients who developed dementia or severe dysautonomia within the first year of diagnosis were not considered valid cases of Parkinson’s disease
- Patient with a diagnosis of Parkinson’s disease who was followed by a neurologist or a movement disorders specialist.
Of the 73 patients with available medical records, the self reported diagnosis of Parkinson’s disease was found to be valid in 90% (66 patients). In 7% it was not possible to exclude a secondary cause of parkinsonism, and in only 3% was the diagnosis of Parkinson’s disease incorrect.
Ascertainment of controls
A participant was considered a control if he was free of self reported Parkinson’s disease at the time of the diagnosis of the case (index date) and remained free of the disease for five years from the index date (to avoid the possibility of subclinical disease). However, we considered participants a control if they died within five years of the index date from a cause other than Parkinson’s disease to avoid bias. We used information from the questionnaire closest to the index date to define comorbidities and covariates for cases and controls. If this questionnaire was missing, information was imputed from prior questionnaires.
To better understand the influence of comorbidity in our analysis, we created two case-controls sets. In the first set, eligible controls were of the same age as the case. In the second set, participants were matched by age and by scores for confounding variables (comprising a modified Charlson comorbidity score, a score for indicators of NSAID use, and a score for side effects of NSAID use). Controls were selected from the study population in this manner: (a) we matched each case to all potential controls by age at baseline, (b) the date of the case diagnosis of Parkinson’s disease was assigned to each potential control as the index date, (c) the comorbidity score and two NSAID scores were calculated for each control at the time of the index date, and (d) up to five matched controls were randomly chosen from all potential controls with the same confounder scores as the case.
Definition of confounder scores
The comorbidity score was calculated using a modified version of the Charlson comorbidity index, a scoring system for common comorbid conditions that is weighted according to mortality risk.25
As participants in the Physicians’ Health Study were apparently healthy at baseline, the score reflected total comorbidities accumulated between study entry and the index date. Myocardial infarction, stroke, and cancer were study end points and were confirmed by medical record review. Other conditions were self reported by the study participants. The Charlson index categorises renal and liver disease as mild or as moderate to severe. Because we could not determine disease severity, we categorised all liver disease as mild and all renal disease as moderate to severe, as has been done in other modifications of the Charlson index.26
Solid tumours that were localised at presentation received a score of 2, while those that were metastatic received a score of 6.
A score for indications of NSAID use was calculated by assigning one point for each of the following conditions: 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 conditions: gastrointestinal bleeding, ulcer, and gastrointestinal 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 containing 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 participants 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.
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-aspirin NSAIDs (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 information 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 Parkinson’s disease (<74 years, ≥74 years) and smoking status (ever, never). We included interaction terms in the model to test for significant effect modification.