Papers

Investigation by Parkinson's Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson's disease: further results of randomised trial and confidential inquiry

Y Ben-Shlomo, senior lecturer in clinical epidemiology, ^a A Churchyard, Kate Stillman research fellow, ^b J Head, lecturer in statistics, ^d B Hurwitz, senior lecturer in primary care, ^e P Overstall, consultant geriatrician, ^f J Ockelford, research administrator, ^g A J Lees, consultant neurologist. ^c

^a Department of Social Medicine, University of Bristol, Bristol BS8 2PR, ^b University College London Hospitals, London WC1, ^c National Hospital for Neurology and Neurosurgery, London WC1N 3BG, ^d Department of Epidemiology and Public Health, University College London Medical School, London WC1E 6BT, ^e Department of Primary Health Care and General Practice, Imperial College School of Medicine, London W2 1PG, ^f Hereford General Hospital, Hereford HR1 2PA, ^g Parkinson's Disease Research Group of the United Kingdom, National Hospital for Neurology and Neurosurgery

Correspondence to: Dr Lees

	Abstract

Objective: To determine whether the excess mortality observed in patients who received both levodopa and selegiline in a randomised trial could be explained by revised diagnosis of Parkinson's disease, autonomic or cardiovascular effects, more rapid disease progression, or drug interactions.
Design: Open randomised trial and blind comparison and reclassification of the cause of death of patients who were recruited from 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 treatment and a subgroup of 120 patients who died during the trial.
Interventions: Levodopa and a dopa decarboxylase inhibitor (arm 1), levodopa and a dopa decarboxylase inhibitor in combination with selegiline (arm 2), or bromocriptine alone (arm 3).
Main outcome measures: All cause 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 opinion 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 1995, when arm 2 was terminated, the hazard ratio for arm 2 compared with 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 1.33 (1.02 to 1.74) and after adjustment for other baseline factors it was 1.30 (0.99 to 1.72). The excess mortality seemed to be greatest in the third and fourth year of follow up. Cause specific death rates showed 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 diagnosis, disability rating scores, autonomic or cardiovascular events, other clinical features, or drug interactions. Patients who died in arm 2 were more likely to have had possible dementia and a history of falls before death compared with those who died in arm 1.
Conclusions: The results consistently show excess mortality in patients treated with combined levodopa and selegiline. Revised diagnosis, autonomic or cardiovascular events, or drug interactions could not explain this finding, but falls and possible dementia were more common in arm 2. The results do not support combined treatment in patients with newly diagnosed Parkinson's disease. In more advanced disease, combined treatment should perhaps be avoided in patients with postural hypotension, frequent falls, confusion, or dementia.

	Introduction

The Parkinson's Disease Research Group of the United Kingdom reported increased mortality in patients with early, mild Parkinson's disease who were randomly allocated combined levodopa and selegiline treatment (arm 2) compared with levodopa alone (arm 1).¹ Relative mortality was increased by about 60%, equivalent to one excess death for every 54 patients treated for 1 year. No clinically important differences in disability ratings were noted after either 1² or 4 years.¹ These results were unexpected as selegiline was thought to protect against nigral cell death,³ to slow disease progression,⁴ and to reduce death rates.⁵

This trial has generated much controversy about the role of selegiline in the management of Parkinson's disease. The number of selegiline prescriptions has almost halved in the United Kingdom since the findings of the trial were published (fig 1). Objections about the validity of the findings include inconsistency with other studies, the inappropriate use of an intention to treat analysis, lack of adjustment of results for early termination of arm 2, overall death rates being too high, the unreliability of death certification, and the possibility of differential misdiagnosis.^6-9

View larger version (15K): [in this window] [in a new window]   Fig 1.    Quarterly tracking data for selegiline prescriptions dispensed in United Kingdom before and after publication of results of Parkinson's Disease Research Group of the United Kingdom.1 Source: Scriptcount (Taylor Nelson AGB)volume of prescriptions dispensed based on representative sample of 300 pharmacies projected to give total for United Kingdom

Despite many of these criticisms being addressed, the reason for the excess mortality remains unclear. One suggested mechanism was that selegiline might increase the risk of a disturbance of cardiac rhythm or compromise the cardiovascular system through orthostatic hypotension.¹ Other possibilities are that combination treatment may have accelerated nigral cell death or that selegiline may have had an adverse drug interaction with a drug not included in the trial.

We report updated and new death rates in subjects in arms 1 and 2 and in those who were randomised from arm 3 (bromocriptine) to arms 1 or 2. Results are also presented from the cause of death inquiry study, which reviewed the clinical course, cause of death, and circumstances around the time of death for all participants who died before December 1993. 

	Subjects and methods

The trial methods have been reported. Briefly, 782 patients with early, mild Parkinson's disease were randomly allocated to one of three treatment arms: levodopa and a dopa decarboxylase inhibitor alone (arm 1); levodopa, a dopa decarboxylase inhibitor, and selegiline (arm 2); and bromocriptine alone (arm 3). If a patient could not tolerate the drugs or showed little functional improvement they could be rerandomised to one of the other two arms. The principal outcomes were mortality and disability ratings. After an interim analysis of deaths up to December 1993 it was decided to terminate arm 2; patients were informed of this in October 1995. 

The clinical record of every death before December 1993 was obtained from the relevant consultant, general practitioner, or nursing home. The records were systematically examined by JO, who recorded all drug treatment before death and deleted any references to antiparkinsonian drugs to conceal the trial arm. Data on severity of the disease within 3 months of death, comorbidity within 1 month of death, mobility within 1 month of death, and mode of death were recorded by AC on a standardised form.

A clinical summary of the clinical course, atypical clinical features, and comorbid medical conditions and a detailed résumé of events around the terminal illness was produced. Details of special investigations such as radiography and pathological and postmortem examination were included when available, but there was no access to the cause of death from the death certificate. A panel comprising a neurologist (AJL), geriatrician (PO), general practitioner (BH), and clinical epidemiologist (YB-S) reviewed each summary and assigned a cause of death according to ICD-9 (international classification of diseases, 9th revision).¹² The panel was blind to the death certificate and trial arm. Parkinson's disease was coded as the underlying cause of death if it contributed to the death because of severe debility.

The panel rated diagnostic certainty for the cause of death from 1 (confident) to 5 (guessing)¹³ and determined whether the diagnosis of Parkinson's disease might have been incorrect and whether the patient might have had dementia.

The reliability of the panel was ascertained by presenting again 20 cases selected at random and stratified on confidence rating at least 3 months later. This was to maximise the likelihood that the cases had been forgotten. Cause specific mortality rates were recalculated using the panel's classification to ascertain whether this altered the results based on death certificates in the previous report.¹ When the panel was unable to reach a diagnosis the cause was taken from the death certificate.

Statistical analysis
The death rates in arms 1 and 2 were compared using the log rank test and Kaplan-Meier survival curves. The relative mortality hazard ratio and 95% confidence intervals were calculated using Cox's proportional hazards model, which enabled adjustment for possible prognostic factors. The adequacy of the proportional hazards model was tested using a log-time interaction with treatment group to check whether the hazard ratio changed with follow up.¹⁴

	Results

Mortality
Our previous paper reported the results of the interim analysis of December 1994.¹ This analysis included deaths only before the end of 1993 because of the delay in notification of deaths from the NHS central register. This report provides data on mortality up to the end of September 1995, when arm 2 was terminated, providing an additional 21 months of follow up (average 6.8 years) and new results on 104 patients randomised from the bromocriptine arm to either arm 1 (53 patients) or 2 (51 patients).

View larger version (15K): [in this window] [in a new window]   Fig 2.    Cumulative percentage of deaths by treatment arm (Kaplan-Meier estimate). All patients randomly allocated to arms 1 and 2, including those randomised from arm 3. Numbers of patients surviving from years 1 to 9 were 294, 290, 282, 270, 254, 200, 146, 98, and 73 (arm 1); 317, 310, 291, 274, 258, 210, 140, 98, and 66 (arm 2)

Cause of death
Up to December 1993, 120 patients died (44/249 (17.7%) in arm 1 and 76/271 (28.0%) in arm 2). Twenty four cases had information from a postmortem examination. As information was not available for 21 cases because notes had been destroyed or lost, we relied only on information from the trial assessments, which may not have had information about the terminal event. The kappa coefficient¹⁵ for the 20 cases classified by the panel on the two occasions was 0.76 for the underlying cause of death, 0.73 for the confidence rating, and 1.0 for the diagnosis of Parkinson's disease (kappa >0.75, excellent; 0.40 to 0.75, fair to good; >0.40, poor). The panel reached a diagnosis in 90 cases. It decided that information was insufficient for the remaining 30 cases to be certain of the cause of death. The pattern of cause specific mortality based on the panel's classification was similar to that previously reported (table 3). Only Parkinson's disease showed an excess of deaths (hazard ratio 2.50 (1.32 to 4.73), whereas for other causes combined the hazard ratio was 1.21 (0.76 to 1.93).

Disability subscales
Previous analyses showed that progression of disability was similar in the two treatment groups. As this contrasts with the excess mortality from Parkinson's disease seen in arm 2, we examined this further by analysing the disability rating before death (table 5). There were no significant differences in any of the subscales between the two arms. Fifty two per cent of the disability ratings (91/176) were made within the year preceding death, 20% (35/176) within 1-2 years before death, and 28% (50/176) more than 2 years before death. This distribution was similar for arms 1 and 2.

Drugs
Ascertainment of the type of drugs taken around the time of death is important if the excess mortality observed with selegiline and levodopa is due to some acute toxic mechanism. We obtained drug information on 91 of the 120 patients who died, which was similar for arm 1 (31/44 (71%)) and arm 2 (60/76 (79%)) Almost all of the patients were taking levodopa 3 months before death (arm 1, 30/31 (97%); arm 2, 59/60 (98%)). In contrast, 23% (7/31) of the patients in arm 1 were no longer in the arm of treatment to which they had been randomised compared with 87% (52/60) taking selegiline in arm 2. 

	Discussion

The updated results show a relatively increased mortality for the combined levodopa and selegiline treatment compared with treatment with levodopa alone of around 35%, equivalent to one excess death per 75 patients treated for 1 year. The mortality ratios were remarkably consistent regardless of whether all deaths, deaths of patients who were rerandomised, or deaths in the first 5 years were considered. These estimates are lower than previously reported¹ and are more realistic, as the previous result was based on an interim analysis. Although our confidence intervals are comparatively narrow, they are all around unity so that some results are significant while others are not. Had arm 2 of the trial continued, it is possible that the mortality would have diminished further, and both previous and current results could simply reflect chance. However, the similarity of the size of the effect in patients rerandomised from arm 3 provides an independent replication of the findings seen for the main group allocated to arms 1 and 2. Whereas subjects withdrawn from arm 3 may be unrepresentative, the randomisation process ensures that the internal comparison is valid and can be viewed as a separate trial. In addition, the complete mortality results based on the first 5 years of follow up were not affected by the decision to terminate arm 2 of the trial and so are less likely to represent a random high value.

We emphasise that this trial fails to support the hope that combined treatment might be associated with reduced mortality or improvement in disability rating scales. Unfortunately, no data were collected on quality of life or mood, so we cannot comment on whether combined treatment may have benefited these measures.

Possible explanations
One problem with the observed excess mortality is the lack of a clear reason for this observation. Other conditions which mimic Parkinson's disease are difficult to diagnose as atypical features often develop only after several years¹⁶ and they have a worse prognosis than Parkinson's disease. We did not, however, find a higher rate of revised diagnosis in arm 2 compared with arm 1 (11% v 15%). Another criticism was that an intention to treat analysis was inappropriate because of the comparatively large number of patients who withdrew.⁹ Ideally, we would like to have had accurate drug data on all of the patients, including those who withdrew at the time arm 2 was terminated. For the subgroup of patients who died for whom data were available, most patients in arm 2 were still receiving combined treatment while only a fifth of patients in arm 1 had selegiline added to their drug regimen before they died.

Clinical implications
Despite uncertainties there are some clear clinical implications from these results. There is no evidence that combined treatment with levodopa and selegiline confers advantages over levodopa treatment alone in terms of mortality or morbidity in patients with early, mild Parkinson's disease. There seems little logic in giving patients with newly diagnosed disease combined treatment, although treatment might be started with selegiline alone and then withdrawn if levodopa treatment was indicated. Clinicians should determine whether the addition of selegiline for severely disabled patientd provides additional symptomatic benefit. In these patients quality of life is generally more important than quantity of life, and each case should be reviewed on its merits. However, if patients have clinically significant orthostatic hypotension, cardiac arrhythmias, confusional states, hallucinations, or deteriorating cognitive function, gradual and slow withdrawal of selegiline over 4 to 6 weeks should be seriously considered.

	Acknowledgments

Members of the Parkinson's Disease Research Group of the United Kingdom who recruited subjects and followed up patients for the trial: R Abbott, N Banerji, M Barrie, G Boddie, P Bradbury, C Clarke, R Clifford-Jones, R Corston, E Critchley, P Critchley, R Cull, J Dick, I Draper, C Ellis, G Elrington, L Findley, T Fowler, J Frankel, A Gale, C Gardner-Thorpe, W Gibb, J D Gibson, J M Gibson, R Godwin-Austen, R Greenwood, R Hardie, D Harley, C Hawkes, S Hawkins, M Hildick-Smith, R Hughes, L Illis, J Jestico, K Kafetz, R Kapoor, C Kennard, R Knight, R Kocen, A Lees, N Leigh, L Loizou, R Lenton, D MacMahon, C D Marsden, W Michael, J Mitchell, P Monro, P Murdoch, W Mutch, P Overstall, D Park, J D Parkes, B Pentland, G D Perkin, R Ponsford, N Quinn, M Rawson, J Rees, M Rice-Oxley, D Riddoch, F Schon, A Schapira, D Shepherd, G Stern, B Summers, C Turnbull, A Turner, S Vakil, C Ward, A Whiteley, A Williams.

Contributors: YB-S participated in designing, analysing, and interpreting results from the cause of death inquiry study, as well as in interpreting the results of the Parkinson's Disease Research Group of the United Kingdom trial and in writing the paper. JH participated in the design, analysis, and interpretation of the trial of the Parkinson's Disease Research Group of the United Kingdom, as well as helping to write the paper. JO participated in the design of the cause of death inquiry study, procured all the material, and blinded all the notes for the drugs for Parkinson's disease. AJL was involved in the design and conduct of the trial of the Parkinson's Disease Research Group of the United Kingdom as well as helping to write the paper; he will also act as guarantor for the paper. AC designed the standardised form, reviewed all the case notes, and produced the vignettes for the cause of death inquiry study. BH, PO, YB-S, and AJL reviewed all the vignettes and assigned the causes of death for the cause of death inquiry study. All the contributors read and critically commented on the paper.

Funding: Continued support from the Parkinson's Disease Society of the United Kingdom, which also provided additional funding for the cause of death study, and Roche Products. Unconditional sponsorship from Britannia Pharmaceuticals and Sandoz Products.

Conflict of interest: None.

	References

Top References

1. Lees AJ, on behalf of the Parkinson's Disease Research Group of the United Kingdom. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. BMJ 1995;311:1602-7. [Abstract/Free Full Text]
2. Parkinson's Disease Research Group of the United Kingdom. Comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson's disease: three years interim report. BMJ 1993; 307: 469-472.
3. Tatton WG, Greenwood CE. Rescue of dying neurones: a new action for deprenyl in MPTP parkinsonism. J Neurol Sci 1991; 30: 666-672.
4. Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989; 321: 1364-1371[Abstract].
5. Birkmayer W, Knoll J, Riederer P, Youdim MBH, Hars V, Marton J. Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson's disease: a long-term study. J Neural Transm 1985; 64: 113-127.
6. Olanow CW, Fahn S, Langston JW, Godbold J. Selegiline and mortality in Parkinson's disease. Ann Neurol 1996; 40: 841-845[Medline].
7. Silva M, Watts P, Jenner P. Effect of adding selegiline to levodopa in early, mild Parkinson's disease: Parkinson's disease is rarely a primary cause of death. BMJ 1996; 312: 703[Free Full Text].
8. Jellinger KA. Effect of adding selegiline to levodopa in early, mild Parkinson's disease: causes of death need confirmation. BMJ 1996; 312: 704[Free Full Text].
9. Gerlach M, Riederer P, Vogt H. Effect of adding selegiline to levodopa in early, mild Parkinson's disease: `on treatment' rather than intention to treat analysis should have been used. BMJ 1996; 312: 704.
10. Lees AJ, Head J, Ben-Shlomo Y. Effect of adding selegiline to levodopa in early, mild Parkinson's disease. BMJ 1996; 312: 704-705.
11. Lees AJ, Head J, Ben-Shlomo Y. Selegiline and mortality in Parkinson's disease: another view. Ann Neurol 1997; 41: 282-283[Medline].
12. World Health Organisation. Manual of the international classification of diseases, injuries, and causes of death, 9th revision. Geneva: World Health Organisation , 1978.
13. Alderson MR, Meade TW. Accuracy of diagnosis on death certificates compared with that in hospital records. Br J Prev Soc Med 1967; 21: 22-29[Medline].
14. Collett D. Modelling survival data in medical research. London: Chapman and Hall , 1994.
15. Fleiss JL. The measurement of interrater agreement. In: Fleiss JL, ed. Statistical methods for rates and proportions, , 1st ed. , New York: Wiley, 1981:212-236.
16. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonisma prospective study. Can J Neurol Sci 1991; 18: 275-278[Medline].
17. Wenning GK, Ben-Shlomo Y, Magalhes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1994; 117: 835-845[Abstract/Free Full Text].
18. Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger K, et al. Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiat 1996; 60: 615-620[Abstract/Free Full Text].
19. Turkka J, Suominen K, Tolonen U, Sotaniemi K, Myllyla VV. Selegiline diminishes cardiovascular autonomic responses in Parkinson's disease. Neurology 1997; 48: 662-667[Abstract/Free Full Text].
20. Churchyard A, Matthias CJ, Boonhongchuen P, Lees AJ. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson's disease. J Neurol Neurosurg Psychiatry 1997; 63: 228-234[Abstract/Free Full Text].
21. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997; 336: 1216-1222[Abstract/Free Full Text].
22. Brown RG, Marsden CD. How common is dementia in Parkinson's disease? Lancet 1984; 1: 1262-1265.
23. Ben-Shlomo Y, Whitehead AS, Davey Smith G. Parkinson's, Alzheimer's, and motor neurone disease: clinical and pathological overlap may suggest common genetic and environmental factors. BMJ 1996; 312: 724[Free Full Text].
24. Campbell AJ, Buchner DM. Unstable disability and the fluctuations of frailty. Age Ageing 1997; 26: 315[Free Full Text].

(Accepted 2 February 1998)