Mortality in people taking selegiline: observational study

Introduction

The Parkinson's Disease Research Group trial of drug treatments for Parkinson's disease began in 1985 following earlier indications of a beneficial effect of selegiline. The trial included 822 patients with early Parkinson's disease randomised into one of three treatment arms: levodopa and dopa decarboxylase inhibitor (arm 1), levodopa and dopa decarboxylase inhibitor combined with selegiline (arm 2), and bromocriptine (arm 3).1 A pre-planned interim analysis in December 1994 revealed a significant difference in mortality between arms 1 and 2, and the group decided to stop treating patients with selegiline and to publish these results. There was an average of 5.6 years follow up, and the mortality hazard ratio comparing arm 2 with arm 1 was 1.57 (95% confidence interval 1.07 to 2.31) after adjustment for age, sex, level of disability before treatment, duration of Parkinson's disease, and year of entry to the trial.2

After the publication of these results we were asked by the Medicines Control Agency to evaluate mortality among patients taking antiparkinsonian drugs whose medical records were included in the General Practice Research Database.

Methods

The General Practice Research Database is a longitudinal dynamic database of medical records collected from a panel of general practitioners throughout the United Kingdom. Anonymised patient records are collected regularly from around 500 participating practices providing information on drug treatment, diagnoses, and important clinical events. There are around 3.5 million patients currently registered on the database. The database has been widely used and validated in a range of studies.3

Patients registered with a participating practice who were aged between 35 and 90 years and who had received at least one prescription for an antiparkinsonian drug, whether or not a diagnosis of Parkinson's disease had been recorded, were eligible for inclusion. Patients prescribed an antipsychotic drug before or at the same time as their first antiparkinsonian drug and patients prescribed an antiparkinsonian drug before age 35 were excluded to avoid including drug-induced parkinsonism. Age, sex, aspects of medical history, a detailed history of the prescription of antiparkinsonian or antipsychotic drugs, and the fact and date of death were collected. We started follow up on the date a patient's practice began submitting data (earliest in 1987) or when a patient joined the practice, if later, and we ended it six months before the last data collection from the practice (usually in 1996) or when a patient left the practice, to allow time to confirm whether patients were alive should there be no record of a death before that date.

Patients' time under observation was divided into treatment groups, with the operational rule that a patient began taking the drug prescribed on the day of prescription and stopped on the day of the next prescription for the same drug type or 60 days after prescription, whichever came first. We report here the results for the three treatment groups of levodopa (with dopa decarboxylase inhibitor), selegiline, and selegiline in combination with levodopa. Time during which patients took other antiparkinsonian drugs was excluded from this analysis. The treatment history before a patient's practice began submitting data was not known.

Follow up was further divided by potential confounding or modifying factors that vary with time: age, calendar year, diagnosis group (record of a diagnosis of Parkinson's disease or not), previous use of any antidepressants, concurrent prescription for a tricyclic antidepressant, concurrent prescription for a selective serotonin reuptake inhibitor, history of cerebrovascular disease, and history of ischaemic heart disease.

Death rates by treatment were calculated by dividing the number of deaths by the total person-time of observation of patients taking a specific drug or combination of drugs. Poisson regression analysis was used to obtain rate ratios with adjustment for potentially confounding variables.

Results

A total of 12 621 patients with a mean age of 72.5 years (range 35 to 89) were included in the study with a mean follow up of 1.7 years. The prevalence of patients with a record of taking antiparkinsonian drugs in the database varied between 18.5 and 19.0 per 10 000. Sixty per cent of the patients (7588) were already taking antiparkinsonian drugs at the start of their follow up; 9196 (73%) had a diagnosis recorded, of whom 8937 (97%) had Parkinson's disease. The standardised mortality ratio for the whole cohort compared with the population of England and Wales was 2.02 (2163 deaths; 95% confidence interval 1.94 to 2.11), an overall death rate of 11 per 100 patient years. There were 1720 deaths in patients taking one of the three treatments included in this analysis during about 14 000 person years of observation.

In all, 8708 (69%) patients received only one drug or combination of drugs during the period of follow up. Table 1 shows the mortality ratios by treatment group adjusted for age and sex and 10 other potential confounding factors. There was a 11% (95% confidence interval 0% to 23%) increase in the risk of death associated with using selegiline either alone or in combination with levodopa compared with using levodopa alone. However, there was a significant interaction of treatment group with age (P=0.005) and with diagnosis (P=0.006—code simplified to parkinsonism v other or none).

Table 2 shows the mortality ratios by treatment group compared with the levodopa alone group stratified into age and diagnosis groups. These interactions reflected variations in the rate ratios for using selegiline alone. There is little evidence that rate ratios for selegiline with levodopa were affected. There was a higher death rate among younger patients (aged under 80 years) taking selegiline alone, which was significant in those aged 70-79 years. The association of mortality with use of selegiline on its own was positive (and significant) in patients with a recorded diagnosis of Parkinson's disease and negative in those without such a record.

Discussion

Our large cohort study includes more than 14 000 person-years of observation. The observed doubling of risk of mortality in these patients is similar to that observed in a smaller cohort study of elderly people (aged over 65 years) with parkinsonian symptoms in New England.4 The prevalence of users of parkinsonian drugs in our cohort (18-19 per 10 000) was slightly greater than the prevalence of 15 per 10 000 consulting for Parkinson's disease reported in the general practice morbidity study,5 which may indicate that a minority of our patients did not have Parkinson's disease. As described above, 27% of patients did not have any diagnosis recorded and 3% of the remainder had a diagnosis other than Parkinson's disease. When subjects were separated into those with and without a diagnosis of Parkinson'sdisease the effect of taking selegiline alone differed in the two groups but was the same for those taking selegiline with levodopa (table 2).