INVESTIGATION BY PARKINSONS-DISEASE RESEARCH GROUP OF UNITED-KINGDOM INTO EXCESS MORTALITY SEEN WITH COMBINED LEVODOPA AND SELEGILINE TREATMENT IN PATIENTS WITH EARLY MILD PARKINSONS-DISEASE - FURTHER RESULTS OF RANDOMIZED TRIAL AND CONFIDENTIAL INQUIRY

Objective: To determine whether the excess mortality observed in patie nts who received both levodopa and selegiline in a randomised trial co uld be explained by revised diagnosis of Parkinson's disease, autonomi c or cardiovascular effects, more rapid disease progression, or drug i nteractions. Design: Open randomised trial and blind comparison and re classification of the cause of death of patients who were recruited fr om 93 hospitals between 1985 and 1990 and who had died before December 1993 in arms 1 and 2. Setting: United Kingdom. Subjects: 624 patients with early Parkinson's disease who were not receiving dopaminergic tr eatment and a subgroup of 120 patients who died during the trial. Inte rventions: Levodopa and a dopa decarboxylase inhibitor (arm 1), levodo pa and a dopa decarboxylase inhibitor in combination with selegiline ( arm 2), or bromocriptine alone (arm 3). Main outcome measures: All cau se mortality for 520 subjects in arms 1 and 2 and for 104 subjects who were randomised into these arms from arm 3. Cause specific mortality for people who died in the original arms 1 and 2 on the basis of the o pinion of a panel, revised diagnosis and disability ratings, evidence from clinical records of either autonomic or cardiovascular episodes, other clinical features before death, and drug interactions. Results: After extended follow up (mean 6.8 years) until the end of September 1 995, when arm 2 was terminated, the hazard ratio for arm 2 compared wi th arm 1 was 1.32 (95% confidence interval 0.98 to 1.79). For subjects who were randomised from arm 3 the hazard ratio for arm 2 was 1.54 (0 .83 to 2.87). When all subjects were included the hazard ratio was 1.3 3 (1.02 to 1.74) and after adjustment for other baseline factors it wa s 1.30 (0.99 to 1.72). The excess mortality seemed to be greatest in t he third and fourth year of follow up. Cause specific death rates show ed an excess of deaths from Parkinson's disease only (hazard ratio 2.5 (1.3 to 4.7)). No significant differences were found for revised diag nosis, disability rating scores, autonomic or cardiovascular events, o ther clinical features, or drug interactions. Patients who died in arm 2 were more likely to have had possible dementia and a history of fal ls before death compared with those who died in arm 1. Conclusion: The results consistently show excess mortality in patients treated with c ombined levodopa and selegiline. Revised diagnosis, autonomic or cardi ovascular events, or drug interactions could not explain this finding, but falls and possible dementia were more common in arm 2. The result s do not support combined treatment in patients with newly diagnosed P arkinson's disease. Ln more advanced disease, combined treatment shoul d perhaps be avoided in patients with postural hypotension, frequent f alls, confusion, or dementia.