C Warren Olanow has lectured at conferences spon- sored by Orion, which distributes selegiline in. Europe. James H Godbold has no conflict ofinterest.
whole, P values at interim analyses would have to be considerably less than 0-01 to achieve significance with any of the common group sequential designs.3 Similarly, confidence intervals reported should be greater than 95%. Thus it is not clear that reports of significance are valid. Finally, levodopa was given to all patients at a daily dose of 375 mg rather than adjusted according to clinical need. Microdialysis studies show that selegiline significantly increases brain dopamine concentrations in rodents after administration of levodopa.4 In our study, patients treated with selegiline required significantly less levodopa than patients taking levodopa alone. During the British study the median dose of levodopa was increased to 625 mg in the levodopa group but did not have to be changed in the patients taking levodopa plus selegiline despite their having comparable clinical benefits and increased dopaminergic side effects. Thus patients taking selegiline may have received much more levodopa than necessary, a factor that was related to increased mortality in the Prado study.5 We take the British report seriously and will continue to monitor mortality in our patients. Because of the reassuring findings of our study and the increasing evidence of possible neuroprotective benefits related to selegiline, however, we do not recommend that patients should stop taking selegiline on the basis of the results of the British study alone. C WARREN OLANOW* Professor, department of neurology JAMES H GODBOLD*
Research associate professor, department of community medicine Mount Sinai Medical Center,
Box 1137, New York, NY 10029, USA
Later in the disease selegiline is used to diminish fluctuations in symptoms, particularly those due to end of dose fading. We note the trend towards lower disability scores in the study patients given selegiline. This supports the anecdotal impression of reduced disability and improved quality of life in patients given the drug, which may be more subtle than the rating scales used could show. Anecdotally, many older patients have reduced the dose or stopped taking selegiline because of side effects (commonly psychological). Some find lower doses effective and better tolerated: a recent audit of our patients showed that a quarter took less than the 10 mg stated in the datasheet. One octogenarian has found by personal experimentation that a daily dose of 1-25 mg (half a 5 mg tablet on alternate days) is sufficient to maintain control. If he omits the drug his control deteriorates after several days, to be re-established within days of his resuming the drug. We are unable to find sufficient pharmacokinetic, pharmacodynamic, or safety data on long term treatment in aging patients, but one of us has suggested that further attention should be focused on these aspects since we may be using too high a dose for too long.4 Possible explanations of the findings of the Parkinson's Disease Research Group include the loss of monoamine oxidase B selectivity, the effects of selegiline's amphetamine metabolites, and interactions with other drugs.' Until further analysis of these mortality data is available it would be wrong to deny patients the benefit of this drug, though perhaps it should be used more carefully than hitherto. Its continued use, especially in older patients, merits further study (including an assessment of its effect on quality of life), as does the investigation of lower doses.
WILLIAM KOLLER* Professor
D G MACMAHON*
Consultant physician
R BLAND* Consultant physician
Department of Neurology, University of Kansas, Kansas City, KS 66160, USA
Cornwall Healthcare Trust, Bamcoose Hospital,
*C Warren Olanow and William Koller have worked as consultants to, and have performed research sponsored by, Somerset Pharmaceuticals, which distributes selegiline in the United States. In addition, C Warren Olanow has lectured at conferences spon-
*D G MacMahon is chairman of the Parkinson's disease special interest group of the British Geriatrics Society and has been paid for advice by Roche Products, DuPont Pharma, SmithKline Beecham, Britannia Pharmaceuticals, and Scherer DDS. Both authors have received support and educational grants to attend meetings from several pharmaceutical companies and have participated in research trials with some of the above companies. Both authors participated in the Parkinson's Disease Research Group's trial.
Redruth, Cornwall TR15 3ER
sored by Orion, which distributes selegiline in Europe. James H Godbold has no conflict of interest. 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 2
3 4
5
selegiline in patients with early, mild Parkinson's disease. BMJ 1995;311:1602-7. (16 December.) Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, et al. A longitudinal double blind controlled study of the affect of deprenyl and levodopa on the progression of the signs and symptoms of Parkinson's disease. Ann Neurol 1995;38:771-7. Fleming TR, Harrington DP, O'Brien PC. Designs for group sequential trials. Control Clin Trials 1984;5:348-61. Brannan T, Prikhojan A, Martinez-Tica J, Yahr MD. In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-dopa and dopamine metabolism. JNeural Transm (in press). Przuntek H, WeIzel D, Blumner E, Danielcyk W, Letzel H, Kaiser HJ, et al. Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: Prado study discontinued. Eur_ Clin Pharmacol 1992;43:357-63.
Selegiline is effective and safe in early stages ED1TOR,-The safety of selegiline is being questioned in view of the unexpected findings of the Parkinson's Disease Research Group,' which contrast with previous reports of the drug's safety and efficacy.2" Treatment with selegiline alone in the early stage of Parkinson's disease was not an option in this trial, and the findings cannot be extrapolated to this indication. The effect of early selegiline on symptoms is well proved, though it was originally misinterpreted as neuroprotection. The drug's safety in the early period is confirmed by the fact that the survival curves overlap in the first two years in the research group's trial.
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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. (16 December.) 2 Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl Med .71989;321:
1364-71.
deaths in arm 2 were directly attributed to Parkinson's disease itself, this information being obtained from death certificates. We were surprised to find that Parkinson's disease featured as a primary cause of death, as most patients with the disease die of its complications. Accurate determination of the cause of death can be revealing in attempts to determine a causal relation between treatment and outcome. The authors speculate that excess adverse events in the selegiline group (arm 2) may have resulted from deleterious effects on the cardiovascular and cerebrovascular systems. The data in their table 3, however, do not support this, with total deaths attributable to vascular disease overall being 20 in arm 1 (levodopa alone) and 21 in arm 2, with a relative death rate per 1000 patient years of 14-6 to 14-0 respectively. It is well recognised that in a minority of patients initially treated for Parkinson's disease the diagnosis is subsequently revised.2 We also recognise that data should be analysed on an intention to treat basis. With such a high proportion of patients being withdrawn from the study (52% in arm 1 and 45% in arm 2), interpretation of results with regard to causality becomes more hazardous. As groups were analysed on an intention to treat basis, roughly half of the patients could have been taking a non-trial drug and yet still figure in the analysis. We believe that the assertions in Donald B Calne's editorial are premature.' A considerable body of evidence shows oxidative stress and damage, in conjunction with mitochondrial dysfunction, in substantia nigra from patients with Parkinson's disease. Any case made against the use of selegiline in Parkinson's disease does not reflect the role that these biochemical abnonnalities may have in the pathogenesis of dopaminergic cell death. We agree with the research group that data from further studies should be available for scrutiny before a radical change in prescribing practice is recommended. MARK T SILVA
MRC research fellow PAUL M WATTS MRC research fellow PETERJENNER Director
Neurodegenerative Diseases Research Centre, Pharmacology Group, King's College London, London SW3 6LX 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.
BM_J1995;311:1602-7. (16 December.)
2 Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatty 1992;55: 181-4. 3 Calne DB. Selegiline in Parkinson's disease. BMJ 1995;311: 1583-4. (16 December.)
3 Parkinson Study Group. Effect of tocopherol and deprenyl on the
progression of disability in early Parkinson's disease. N Engl
MedJ 1993;328:176-83. 4 MacMahon DG. The use of selegiline in elderly patients: current
indications and future potential. Reviews in Contemporary Pharmacotherapy 1992;3:77-85. 5 Johnson FN, Sandler M. The pharrnacology of selegiline. Reviews in Contemporary Pharmacotherapy 1992;3:51-65.
Parkinson's disease is rarely a primary cause ofdeath ED1TOR,-AS many patients with Parkinson's disease in Britain currently receive selegiline, any conclusions drawn from the Parkinson's Disease Research Group's study will have important implications.' The decision to close arm 2 of the trial (levodopa plus selegiline) may precipitate a change in prescribing practice. While the research group does not draw any firm conclusions about the causal relation between treatment with selegiline and excess mortality, many readers will nevertheless infer such a connection. Several points are relevant. Most of the excess
Selegiline may be toxic in presence of increased dopamine concentrations ED1TOR,-In the trial carried out by the Parkinson's Disease Research Group of the United Kingdom levodopa plus selegiline seemed to offer no clinical benefit over levodopa alone, although less levodopa was required for the combined treatment.' Mortality was significantly higher with the combined treatment. These findings contradict several earlier reports that selegiline, either alone or in combination, confers a beneficial effect in Parkinson's disease. During the course of Parkinson's disease a progressive degeneration of nigrostriatal dopaminergic neurones occurs, with the remaining neurones becoming further stressed because of increased dopamine turnover (that is, the ratio of homovannilic acid to dopamine is increased). This increases oxidative stress. Reactive oxygen species can be generated from dopamine by both
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deamination and auto-oxidation. It has been suggested that selegiline reduces oxidative stress and thus might be beneficial in parkinsonism. Catechols, including dopamine and levodopa, are known to be cytotoxic. We have investigated whether selegiline protects neurones against toxicity induced by dopamine or levodopa in SH-SY5Y catecholaminergic neuroblastoma cells. We found that in fact selegiline exacerbated the toxicity induced by dopamine, even though selegiline itself at a concentration as high as 100 ,mol/l was without effect (C T Lai and P H Yu, 6th international amine oxidase workshop, Saskatoon, Canada, 1994). This exacerbation of toxicity was dose dependent with respect to both dopamine and selegiline. As little as 0-1 ,umol selegiline/l caused a small but significant increase in toxicity induced by dopamine. Although levodopa is as toxic as dopamine towards SH-SY5Y cells, selegiline did not exacerbate its toxicity. Structural analogues of selegiline such as 4-methylselegiline, one of its metabolites ((-)-N-methylamphetamine), and a monoamine oxidase A inhibitor (clorgyline) also exacerbated toxic effects induced by dopamine. These observations suggest that selegiline may be toxic in vivo towards certain cells when dopamine concentrations are increased, and this might be relevant to the increased mortality seen in patients with Parkinson's disease treated with selegiline and levodopa combined. Although the neuroprotective effect of selegiline has been questioned, the drug seems to offer symptomatic relief to patients with Parkinson's and Alzheimer's diseases, and it exhibits neurorescue effects in several animal models.2 Some new, specific, irreversible monoamine oxidase B inhibitors, the aliphatic propargylamines,3 which rescue neurones in several in vivo systems, do not exacerbate toxicity induced by dopamine in the above SH-SY5Y system. These compounds could be a useful alternative chemotherapy, offering both symptomatic benefit and neuroprotective and rescue properties without toxicity. PHYU*
Professor CT LAI Postdoctoral fellow A A BOULTON*
Professor Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon,
Saskatchewan,
and (c) deaths from all causes. The difference in mortality between arms 1 and 2 was compared with the log rank test, and the difference in survival between the arms was significant. For a confirmatory assessment of the difference in mortality between these arms, however, the reported P values need to be adjusted according to the value of ox. Further adjustments to the value of a need to be made because the reported P values were the result of (at least) a second interim analysis and of three comparisons (arm 1 with arm 2, arm 1 with arm 3, and arm 2 with arm 3). Secondly, although adjustments for age, sex, and other baseline prognostic factors were performed with the Cox proportional hazards model, the group did not test further relevant prognostic clinical factors, such as the duration of pre-treatment, concomitant diseases (for example, cardiova-scular diseases, diabetes mellitus, bronchopulmonary diseases), and concomitant treatment unrelated to Parkinson's disease. Such factors, however, may affect mortality. Finally, 51-8% of the patients were withdrawn from arm 1 but only 45-4 % from arm 2. It is unclear, however, what treatment most of these patients were taking at the time of death. To determine whether the excess mortality in arm 2 was really an effect of treatment the mortality has to be analysed by an "on treatment" approach rather than by the intention to treat analysis used. Although this was in fact done and the ratio of the mortality in arm 2 to that in arm 1 was similar to that obtained with the intention to treat analysis, the research group does not state whether the difference was significant. As can be approximated from the 95% confidence interval, the difference in mortality was not significant. M GERLACH
P RIEDERER
Privatdozent
Professor
Clinical Neurochemistry, Hospital of Psychiatry,
University of Wurzburg, D-97080 Wurzburg,
Germany H VOGT
Professor Institute for Applied Mathematics and Statistics,
University of Wurzburg, D-97070 Wurzburg,
Germany 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. (16 December.)
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. (16 December.) 2 Yu PH, Davis BA, Zuo DM, Zhang X, Fang J, Lai CT, et al. Neurochemical, neuroprotective and neurorescue effects of 2-hexyl N-methylpropargylamine (2-HxMP), a new MAO-B
inhibitor without amphetamine-like properties. Prog Brain Res 1995;106:1 13-21. 3 Yu PH, Davis BA, Boulton AA. Aliphatic propargylamines: potent selective irreversible monoamine oxidase B inhibitors. J
Med Chem 1992;35:3705-13.
"On treatment" rather than intention to treat analysis should have been used EDrroR,-On the basis of intention to treat analysis the Parkinson's Disease Research Group of the United Kingdom concludes that mortality was significantly higher with combination treatment of levodopa and selegiline (arm 2) than with levodopa alone (arm 1).1 This conclusion, however, is not justified, for several reasons. Firstly, the main measures of the outcome of treatment were (a) serial assessments of disability, (b) the frequency and severity of adverse events,
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K AJELLINGER
Director Ludwig Boltzmann Institute of Clinical Neurobiology, Lainz-Hospital, A-1 130 Vienna, Austria 1 Lees AJ on behalf of the Parkinson's Disease Research 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. (16 December.) 2 Przuntek H, Welzel D, Blumner E, Danielczyk W, Letzel H, Kaiser H-J, et al. Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: Prado study discontinued. EurJ Clin Pharmacol 1992;43:357-63. 3 Moussa MMA, Shafie MZ, Khogali MM, El-Sayed AM, Sugathan TN, Cherian G, et al. Reliability of death certificate diagnosis. J Clin Epidemiol 1990;43:1285-95. 4 Jeilinger KA. Neurodegenerative disorders with extrapyramidal features-a neuropathological review. J Neural Transm
1995;46[suppll:33-56. 5 Wermuth L, Stenager EN, Stenager E, Boldsen J. Mortality in patients with Parkinson's disease. Acta Neurol Scand 1995;92: 55-8. 6 Mlki-lkola A, Heinonen E, Helajdrvi H. Safety report on selegiline and mortality. Helsinki: Orion-Farmos, 1995:1-27.
Authors' reply
Canada S7N 5E4
*P H Yu and A A Boulton are two of the authors of patents on the aliphatic propargylamines held by the University of Saskatchewan.
to be revised in 6 10% of patients in the study, four studies have shown that only 76-84% of patients with clinically diagnosed Parkinson's disease had this disorder at necropsy.4 Thirdly, most patients with Parkinson's disease die of secondary or coincidental disorders.25 This is confirmed by a personal necropsy series of 600 patients with the disease (505 with confirmed Parkinson's disease of Lewy body type)4: under 2% died of akinetic or hyperthermic states in late stages of illness. Fourthly, the mortality data in the research group's study are at variance with those in 10 previous long term trials of selegiline in Parkinson's disease: among 2047 patients (959 given selegiline, 1088 controls) there were 58 deaths, two occurring months after selegiline was stopped.6 The mortality was 2-7% in the selegiline group (2-5% exluding the two late deaths) and 2-9% in the control group (P=0 7). Causes of death were heart and embolic diseases, neoplasms, etc; Parkinson's disease was never mentioned. Hence the causes of death in the research group's study need further confirmation. From an ethical viewpoint I do not understand why the trial continued after the analysis in December 1994 (one year before publication) showed significant differences in mortality between arms 1 and 2-a result that brought other studies to a premature end.2
Causes ofdeath need confirmation EDrroR,-After 5-4 years of follow up the Parkinson's Disease Research Group reports a significantly higher mortality in patients with early, mild Parkinson's disease given levodopa plus selegiline (arm 2) than in those given levodopa alone (arm 1). Although the causes of the 60% increased mortality "remain to be elucidated," the group concludes that the data "cast doubts on the chronic use of selegiline."' This conclusion seems conjectural. Firstly, the suggested deleterious effects of selegiline on the cardiovascular system are disproved by the fact that deaths due to heart or cardiovascular disease were not increased in arm 2. However, baseline data did not include data on cardiovascular and other concomitant diseases, which are present in about half of patients with Parkinson's disease2 and are a major factor in outcome. Secondly, significant differences in the cause of death were due to Parkinson's disease being 3-5 times more commonly cited as a cause in arm 2. Causes of death, however, were based only on entries in death certificates, the reliability of which remains debatable,3 and "postmortem confirmation . . . was available only in a small number of cases." While the clinical diagnosis had
EDITOR,-We emphasised that a causal relation between long term selegiline (10 mg/day) and the increased mortality in arm 2 of our trial (levodopa plus selegiline) had not been established. The meta-analysis done by Orion combined trials of selegiline alone with those of combination treatment and is therefore not directly comparable. Even so, the calculated mortality odds ratio for studies with more than 3-5 years of follow up is 0-94 (95% confidence interval 0 55 to 1-61) and is compatible with our results. Our trial does not exclude the possibility that selegiline may have mild neuroprotective effects but questions its clinical relevance. We also failed to find important advantages for combination treatment with respect to dyskinesias and motor fluctuations. Longer follow up of a cohort by the United States Parkinson Study Group has come to similar findings.' After careful deliberation we decided that all patients receiving selegiline in the trial should be notified of the results before publication and, as a precaution, advised to withdraw selegiline. The results of the withdrawal of selegiline and its effect on disability and subsequent requirements of levodopa, with mortality to December 1994, will be available in six months' time. C Warren Olanow and colleagues comment that the number of deaths in our study is extremely
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