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. 1998 Dec 5;317(7172):1586.

Effect of adding selegiline to levodopa in early, mild Parkinson’s disease

Formal systematic review of data on patients in all relevant trials is required

Carl Counsell 1
PMCID: PMC1114394  PMID: 9836669

Editor—The increased death rate with selegiline in the Parkinson’s Disease Research Group’s trial highlights the problem of interpreting the results of a small trial in isolation. Ben-Shlomo et al emphasised the internal consistency of this finding,1 which is not surprising because much of the original data were reanalysed. The hazard ratio was lower than in the original report (1.32 v 1.57), which suggests that the trial might have stopped on a random high.

There is no formal systematic review of all unconfounded randomised trials comparing long term selegiline with control treatment in patients with early Parkinson’s disease. One attempt by the manufacturers of selegiline did not say which trials were included.2 I found three such trials in the Cochrane controlled trials register, with follow up ranging from 2.5 to 8.2 years—that is, after the increase in deaths with selegiline started in the Parkinson’s Disease Research Group’s trial.3–5 Two trials did not start levodopa treatment for the first few months, unlike the Parkinson’s Disease Research Group’s trial, but most patients had been taking levodopa for several years at the end of follow up.3,4 In one trial all patients were switched to selegiline treatment after 1.5 years, which would dilute any treatment effect.3

I performed a meta-analysis of the number of deaths at the last available follow up (figure). This is simplistic because of unequal follow up periods in the selegiline and control arms in some trials, but the results did not change after accounting for this. The results are based on under 2000 patients and show a non-significant 16% increase in the relative risk of death with selegiline (lower than that seen in the Parkinson’s Disease Research Group’s trial). None of the other trials showed a trend against selegiline, but the confidence intervals were wide and compatible with an excess of deaths. There was no evidence of heterogeneity among the trials.

The Parkinson’s Disease Research Group’s trial found more falls and possible dementia in those who died in the selegiline arm, but this is difficult to interpret without similar data for survivors. Dementia is a poor prognostic factor and is probably associated with a greater risk of falling. Rather than selegiline causing dementia, it might be that, by chance and despite randomisation, more patients in the selegiline arm had a propensity to develop dementia.

This crude meta-analysis suggests that selegiline is unlikely to reduce mortality, but whether it increases mortality remains unclear. A formal systematic review of all relevant trials using data on individual patients data to assess survival, disability, and the risk of dementia is needed. This will require close collaboration between all the trialists. Unfortunately, a recent meta-analysis6 considered only survival and did not include the two largest trials.1,3

Figure.

Figure

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Effect of long term selegiline and control treatment in early, mild Parkinson’s disease on death at end of follow up. PDRG-UK=Parkinson’s Disease Research Group of the United Kingdom

References

  • 1.Ben-Schlomo Y, Churchyard A, Head J, Hurwitz B, Overstall P, Ockelford J, et al. 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. BMJ. 1998;316:1191–1196. doi: 10.1136/bmj.316.7139.1191. (18 April.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Mäki-Ikola O, Kilkku O, Heinonen E. Effect of adding selegiline to levodopa in early, mild Parkinson’s disease. BMJ. 1996;312:702. [PMC free article] [PubMed] [Google Scholar]
  • 3.Parkinson’s Study Group. Mortality in DATATOP. A multi-center trial in early Parkinson’s disease. Ann Neurol. 1998;43:318–325. doi: 10.1002/ana.410430309. [DOI] [PubMed] [Google Scholar]
  • 4.Myllylä VV, Sotaruemi KA, Hakulinen P, Mäki-Ikola O, Heinonen EH. Selegiline as the primary treatment of Parkinson’s disease—a long-term double-blind study. Acta Neurol Scand. 1997;95:211–218. doi: 10.1111/j.1600-0404.1997.tb00101.x. [DOI] [PubMed] [Google Scholar]
  • 5.Larsen JP, Boas J Norwegian-Danish Study Group. The effects of early selegiline therapy on long-term levodopa treatment and Parkinsonian disability: an interim analysis of a Norwegian-Danish 5-year study. Movement Disorders. 1997;12:175–182. doi: 10.1002/mds.870120207. [DOI] [PubMed] [Google Scholar]
  • 6.Olanow C, Myllylä V, Sotaniemi K, Larsen J-P, Pålhagen S, Przuntek H, et al. Effect of selegiline on mortality in patients with Parkinson’s disease: a meta-analysis. Neurology. 1998;51:825–830. doi: 10.1212/wnl.51.3.825. [DOI] [PubMed] [Google Scholar]
BMJ. 1998 Dec 5;317(7172):1586.

Evidence is insufficient to show that combined treatment increases mortality

Helena Aaltonen 1, Olavi Kilkku 1, Esa Heinonen 1, Outi Mäki-Ikola 1

Editor—The conclusions of the Parkinson’s Disease Research Group of the United Kingdom in its interim analysis of 1995 that levodopa and selegiline treatment is associated with increased mortality were premature as no significant differences in mortality were found after an additional 21 months of follow up (6.8 years in total; hazard ratio 1.32 (95% confidence interval 0.98 to 1.79)).1-1 Moreover, when the results were analysed according to an on treatment approach no significant differences in the overall mortality were found between the groups in the interim or in the last analysis.1-1 Furthermore, no difference was found in mortality between the patients randomised to receive bromocriptine (one of the three original study arms) and those to receive selegiline and levodopa, although the authors did not mention this in the final report. No significant differences were found in the causes of death between the groups.

Table.

Proportions of deaths and overall mortality in 11 clinical studies of treatment of Parkinson’s disease with selegiline

Study Selegiline No selegiline
Olanow et al 199821-150 14/297 17/292
Caraceni et al 19973 25/155 25/156
Di Rocco et al 19964 30/109 40/67
Rinne et al1-151 3/30 10/30
Parkinson’s Study Group 19985 70/399 67/401
Birkmayer et al 19856 118/564 114/377
Ben-Shlomo et al 19981 103/271 73/249
Total 363/1825 (19.9%) 346/1572 (22%)
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1-150

Meta-analysis of 5 trials. 

1-151

Submitted for publication. 

Two main problems that may have caused biases in the study have been discussed in the literature. Firstly, patients were allowed to be rerandomised to another group after their original randomisation. Secondly, patients still receiving the original treatment, rerandomised patients, and those withdrawn from the study regardless of how long before and what kind of treatment they had received since withdrawal were included in the analysis. Furthermore, mortality curves became separate between the second and third year of follow up, after which they progressed in parallel. This phenomenon is difficult to explain with any relevant biological mechanism; thus the observed difference could be due to problems in study design.

We performed a meta-analysis on the binary data of all available clinical studies since data on individual patients were not available from all studies (table). Overall, 363 out of 1825 patients given selegiline died (19.9%) compared with 346 out of 1572 who were not given selegiline (22%). In fact, mortality was significantly lower in the group given selegiline (hazard ratio 0.82 (0.69 to 0.97); P=0.02).

Given the possibility of a biased study design and methodological limitations of the study by the Parkinson’s Disease Research Group and the fact that no other clinical study has reported similar findings, there is not enough evidence to claim that the combination of selegiline and levodopa increases mortality in patients with Parkinson’s disease.

References

  • 1-1.Ben-Schlomo Y, Churchyard A, Head J, Hurwitz B, Overstall P, Ockelford J, et al. 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. BMJ. 1998;316:1191–1196. doi: 10.1136/bmj.316.7139.1191. (18 April.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Olanow C, Myllylä V, Sotaniemi K, Larsen J-P, Pålhagen S, Przuntek H, et al. Effect of selegiline on mortality in patients with Parkinson’s disease: a meta-analysis. Neurology. 1998;51:825–830. doi: 10.1212/wnl.51.3.825. [DOI] [PubMed] [Google Scholar]
  • 1-3.Caraceni TA. Dopamine agonists and deprenyl in comparison to levodopa for initial treatment in patients with Parkinson’s disease [abstract] Mov Disord. 1997;12:81. [Google Scholar]
  • 1-4.Di Rocco A, Culliton D, Yahr M. Comparative mortality and longevity in parkinsonian patients with l-dopa and selegiline [abstract] Mov Disord. 1996;11:708. [Google Scholar]
  • 1-5.Parkinson’s Study Group. Mortality in DATATOP. A multi-center trial in early Parkinson’s disease. Ann Neurol. 1998;43:318–325. doi: 10.1002/ana.410430309. [DOI] [PubMed] [Google Scholar]
  • 1-6.Birkmayer W, Knoll J, Riederer P, Youdim M, Hars V, Marton J. Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson’s disease: a longterm study. J Neural Transm. 1985;64:113–127. doi: 10.1007/BF01245973. [DOI] [PubMed] [Google Scholar]

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