Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients
http://www.100md.com
《英国医生杂志》
1 Birmingham Clinical Trials Unit, University of Birmingham, Birmingham B15 2RR, 2 Department of Neurology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, 3 Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZN, 4 Department of Neurology, City Hospital NHS Trust, Birmingham B18 7QH
Correspondence to: Natalie Ives n.j.ives@bham.ac.uk
Abstract
Clinical decline in Parkinson's disease results from degeneration of nigrostriatal dopaminergic neurones. This process may be mediated by oxidative free radicals, which in animal models of Parkinson's disease can be inhibited by monoamine oxidase type B inhibitors (MAOBIs), such as selegiline.1 Consequently, selegiline has been used either alone or in addition to levodopa in both early and later Parkinson's disease in the hope that it may slow disease progression. Clinical trials in the 1980s, such as the DATATOP study,2 suggested that selegiline might have a neuroprotective effect, but this remains controversial.3 Further uncertainty about MAOBIs arose in 1995, when a study by the Parkinson's Disease Research Group of the United Kingdom (UK-PDRG) closed its selegiline arm after finding 57% higher mortality in patients receiving combined selegiline and levodopa treatment compared with patients on levodopa alone.4 Other randomised trials have, however, failed to show any increase in mortality.5 6
To clarify the role of MAOBIs, we did a meta-analysis of data from all published trials comparing any MAOBI with either levodopa or placebo in early Parkinson's disease. Meta-analyses give a more accurate view of the randomised evidence, because they include more patients than does any single trial, so random errors are smaller. Also, by reviewing data from all relevant trials, a more balanced assessment is obtained.
Methods
Trials and patients
We identified 18 randomised trials of MAOBI treatment in early Parkinson's disease. (See fig A on bmj.com for QUORUM statement flow diagram.) We excluded one crossover study, as the trial did not provide data split by treatment period.14 We therefore included 17 trials involving 3525 patients in this meta-analysis (table 1 and table on bmj.com).4 15-36 Thirteen trials were of selegiline, three were of lazabemide, and one was of rasagiline. Duration of treatment varied from six weeks to 10 years; shorter trials assessed symptomatic control and tolerability, and longer trials assessed disease progression and mortality. One trial contributed data to more than one comparison (MAOBI v placebo and MAOBI+LD v LD).24 In the UK-PDRG study, patients who had inadequate symptom control or were unable to tolerate their original allocation to the dopamine agonist bromocriptine were re-randomised to selegiline plus levodopa or levodopa alone.4
Table 1 Characteristics of trials of monoamine oxidase type B inhibitors included in meta-analysis
Table 2 shows the methodological quality of the included trials. Ten trials described the method of randomisation used (blocking, random number generator, computer); only four trials clearly had an adequate concealment of allocation procedure (by virtue of a central randomisation service). All trials provided information on blinding (15/17 trials were double blind), and all trials reported follow up data, although some trials did not include all randomised patients in the final analyses despite claiming to have used an intention to treat analysis.
Table 2 Methodological quality of included studies
Mortality
Mortality data were available from nine trials of selegiline and one of lazabemide (fig 1). We considered the UK-PDRG study, which initially reported 76/271 (28%) deaths in the selegiline arm compared with 44/249 (18%) deaths in the levodopa arm (odds ratio 1.57, 95% confidence interval 1.09 to 2.30; P = 0.015) to be hypothesis generating.4 In the other trials, which we treated as confirmatory studies, no excess of deaths occurred with MAOBI compared with the control arm (15.5% v 18.2% deaths; odds ratio 1.02, 0.84 to 1.25; P = 0.8). Taking all available data, 287 (20%) deaths occurred in 1436 MAOBI patients compared with 257 (21%) in 1215 control patients (odds ratio 1.13, 0.94 to 1.34; P = 0.2). We found no significant heterogeneity between trials (P = 0.6), even including the UK-PDRG study.
Fig 1 Mortality in trials of monoamine oxidase type B inhibitors. (LD=levodopa; MAOBI=monoamine oxidase type B inhibitor; O-E=observed minus expected; RR=re-randomisation data from UK-PDRG. *Data from subsequent follow up of UK-PDRG trial—patients counted only once in total denominator)
Clinical disability rating scales
Data from rating scales were available from only six trials of selegiline.15 19 24 26 27 32 Unified Parkinson's disease rating scale scores at three months were 2.7 (95% confidence interval 1.4 to 4.1; P = 0.00009), 1.8 (0.8 to 2.7; P = 0.0004), and 0.9 (0.5 to 1.4; P = 0.00007) points better with selegiline than with control for total score, motor score, and activities of daily living score (see figs B-D on bmj.com). The large DATATOP study accounted for more than 65% of the patients analysed and more than 79% of patients in the MAOBI versus placebo comparison.32 However, combined results from the other two studies of MAOBI versus placebo were consistent with those from DATATOP and independently significant (P = 0.004).15 19
Need for levodopa
For the 12 trials comparing an MAOBI with placebo, data on the need for levodopa were available from eight studies with a median follow up of 13 months (range 3 months to 5 years).19-23 26 31 33 A highly significant reduction in the need for levodopa occurred in patients randomised to an MAOBI compared with those on placebo (odds ratio 0.57, 0.48 to 0.67; P < 0.00001; fig 2). For trials comparing selegiline and levodopa with levodopa alone, adequate data on dose of levodopa for meta-analysis were available from two trials.24 27 The dose of levodopa needed for adequate symptom control was 67 (14 to 119; P = 0.01) mg lower in the selegiline arm.
Fig 2 Need for levodopa treatment in trials comparing monoamine oxidase type B inhibitors and placebo. (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor. *Rasagiline. O-E and variance based on published time to event analyses)
Motor complications
Data on motor complications were available from five trials.25 27 28 30 35 A 25% reduction in motor fluctuations occurred in patients randomised to an MAOBI (odds ratio 0.75, 0.59 to 0.95; P = 0.02; fig 3). However, we found no difference in the incidence of dyskinesia between the MAOBI and non-MAOBI groups (odds ratio 0.97, 0.75 to 1.26; P = 0.8; fig 3). We found no evidence of heterogeneity between the trials or the three treatment comparisons for either outcome.
Fig 3 Incidence of motor complications in trials of monoamine oxidase type B inhibitors. (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor. *Motor fluctuations defined as on-off or end of dose fluctuations, wearing off, or random oscillations)
Side effects and withdrawals
More side effects were reported in patients randomised to an MAOBI, which was of borderline significance (odds ratio 1.36, 1.02 to 1.80; P = 0.04). Data on specific side effects were rarely reported, so any subanalysis of these data is of limited value. More MAOBI patients than non-MAOBI patients withdrew owing to adverse events (odds ratio 2.16, 1.44 to 3.23; P = 0.0002; fig 4), with some evidence of heterogeneity between trials (P = 0.03) but not between the three treatment comparisons (P = 0.09). This heterogeneity was explained by the atypical results in the UK-PDRG study, which reported significantly more dropouts due to adverse events in the open label selegiline plus levodopa arm than with levodopa alone (14% v 3%). In contrast, significantly more patients were withdrawn from this trial in the levodopa arm owing to protocol violations (1% v 15%); 28/37 patients were withdrawn following the introduction of selegiline to their treatment regimen after publication of the DATATOP trial results. An analysis of the data on dropouts due to adverse events for placebo controlled trials only (that is, excluding the UK-PDRG and Italy studies) showed no difference between MAOBI and non-MAOBI patients (odds ratio 1.52, 0.87 to 2.68; P = 0.1), with no evidence of heterogeneity between trials (P = 0.2) or between the two treatment comparisons (P = 0.9).
Fig 4 Withdrawal of patients due to adverse events in trials of monoamine oxidase type B inhibitors (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor)
We found no difference between the two groups (MAOBI v non-MAOBI) in the overall numbers of patients withdrawing from the trials (18% v 19%; odds ratio 1.06, 0.87 to 1.28; P = 0.6). However, patients withdrew from different trials for quite varied reasons—such as lack of efficacy, toxicity, patients given selegiline by their general practitioners after publication of the DATATOP study—and this is reflected in the significant heterogeneity between trials (P = 0.007), making it difficult to interpret overall withdrawal rates.
Discussion
Heikkila RE, Manzino L, Cabbat FC, Duvoisin RC. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984;311: 467-9.
Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 1989;46: 1052-60.
Lang AE, Lees AJ. MAO-B inhibitors for the treatment of Parkinson's disease. Mov Disord 2002;17(suppl 4): S38-44.
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.
Olanow CW, Myllyla VV, Sotaniemi KA, Larsen JP, Palhagen S, Przuntek H, et al. Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Neurology 1998;51: 825-30.
Counsell C. 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. BMJ 1998;317: 1586.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
Early Breast Cancer Trialists' Collaborative Group. Treatment of early breast cancer. Vol 1: Worldwide evidence 1985-1990. Oxford: Oxford University Press, 1990.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22: 719-48.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. analysis and examples. Br J Cancer 1977;35: 1-39.
Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339: 1-15,71-85.
Parmar M, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17: 2815-34.
Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res 1993;2: 121-45.
Teravainen H. Selegiline in Parkinson's disease. Acta Neurol Scand 1990;81: 333-6.
Mally J, Kovacs AB, Stone TW. Delayed development of symptomatic improvement by (-) deprenyl in Parkinson's disease. J Neurol Sci 1995;134: 143-5.
Parkinson Study Group. A controlled trial of lazabemide (Ro19-6327) in untreated Parkinson's disease. Ann Neurol 1993;33: 350-6.
Parkinson Study Group. A controlled trial of lazabemide (Ro 19-6327) in levodopa-treated Parkinson's disease. Arch Neurol 1994;51: 342-7.
Nappi G, Martignoni E, Horowski R, Pacchetti C, Rainer E, Bruggi P, et al. Lisuride plus selegiline in the treatment of early Parkinson's disease. Acta Neurol Scand 1991;83: 407-10.
Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo Parkinsonian patients: the French selegiline multicenter trial. Mov Disord 1993;8(suppl 1): S36-40.
Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002;59: 1937-43.
Palhagen S, Heinonen EH, Hagglund J, Kaugesaar T, Kontants H, Maki-Ikola O, et al. Selegiline delays the onset of disability in de novo Parkinsonian patients. Neurology 1998;51: 520-5.
Kirollos C, Charlett A, Bowes SG, Purkiss AG, O'Neill CJA, Weller C, et al. Time course of physical and psychological responses to selegiline monotherapy in newly diagnosed, idiopathic parkinsonism. Eur J Clin Pharmacol 1996;50: 7-18.
Parkinson Study Group. Effect of lazabemide on the progression of disability in early Parkinson's disease. Ann Neurol 1996;40: 99-107.
Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, et al. The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann Neurol 1995;38: 771-7.
Caraceni T, Musicco M. Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease: a randomized multicenter study. Parkinsonism Relat Disord 2001;7: 107-14.
Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989;245: 519-22.
Larsen JP, Boas J, Erdal JE for the Norwegian-Danish Study Group.. Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. Eur J Neurol 1999;6: 539-47.
Przuntek H, Conrad B, Dichgans J, Kraus PH, Krauseneck P, Pergande G, et al. SELEDO: a 5-year long-term trial on the effect of selegiline in early parkinsonian patients treated with levodopa. Eur J Neurol 1999;6: 141-50.
Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992;42: 339-43.
Myllyla VV, Heinonen EH, Vuorinen JA, Kilkku OI, Sotaniemi KA. Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease. Acta Neurol Scand 1995;91: 177-82.
Myllyla VV, Sotaniemi KA, Hakulinen P, Maki-Ikola O, Heinonen EH. Selegiline as the primary treatment of Parkinson's disease: a long-term double-blind study. Acta Neurol Scand 1997;95: 211-8.
Parkinson Study Group. Effects of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321: 1364-71.
Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993;328: 176-83.
Parkinson Study Group. Mortality in DATATOP: a multicenter trial in early Parkinson's disease. Ann Neurol 1998;43: 318-25.
Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y on behalf of the Parkinson's Disease Research Group of the United Kingdom. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001;57: 1687-94.
Ben-Shlomo 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: 1191-6.
Ives NJ, Stowe RL, Shah L, Hawker RJ, Clarke CE, Gray RG, et al. Meta-analysis of 5038 patients in 28 randomised trials comparing dopamine agonists with levodopa. Alzheimer's and Parkinson's diseases: new perspectives. 6th International Conference AD/PD, Seville, Spain, May 8-12 2003. Book of abstracts: 119.
Jenkinson C, Fitzpatrick R, Peto V. The Parkinson's disease questionnaire: user manual for the PDQ-39, PDQ-8 and PDQ summary index. Oxford: Health Services Research Unit, University of Oxford, 1998.(Natalie J Ives, statistic)
Correspondence to: Natalie Ives n.j.ives@bham.ac.uk
Abstract
Clinical decline in Parkinson's disease results from degeneration of nigrostriatal dopaminergic neurones. This process may be mediated by oxidative free radicals, which in animal models of Parkinson's disease can be inhibited by monoamine oxidase type B inhibitors (MAOBIs), such as selegiline.1 Consequently, selegiline has been used either alone or in addition to levodopa in both early and later Parkinson's disease in the hope that it may slow disease progression. Clinical trials in the 1980s, such as the DATATOP study,2 suggested that selegiline might have a neuroprotective effect, but this remains controversial.3 Further uncertainty about MAOBIs arose in 1995, when a study by the Parkinson's Disease Research Group of the United Kingdom (UK-PDRG) closed its selegiline arm after finding 57% higher mortality in patients receiving combined selegiline and levodopa treatment compared with patients on levodopa alone.4 Other randomised trials have, however, failed to show any increase in mortality.5 6
To clarify the role of MAOBIs, we did a meta-analysis of data from all published trials comparing any MAOBI with either levodopa or placebo in early Parkinson's disease. Meta-analyses give a more accurate view of the randomised evidence, because they include more patients than does any single trial, so random errors are smaller. Also, by reviewing data from all relevant trials, a more balanced assessment is obtained.
Methods
Trials and patients
We identified 18 randomised trials of MAOBI treatment in early Parkinson's disease. (See fig A on bmj.com for QUORUM statement flow diagram.) We excluded one crossover study, as the trial did not provide data split by treatment period.14 We therefore included 17 trials involving 3525 patients in this meta-analysis (table 1 and table on bmj.com).4 15-36 Thirteen trials were of selegiline, three were of lazabemide, and one was of rasagiline. Duration of treatment varied from six weeks to 10 years; shorter trials assessed symptomatic control and tolerability, and longer trials assessed disease progression and mortality. One trial contributed data to more than one comparison (MAOBI v placebo and MAOBI+LD v LD).24 In the UK-PDRG study, patients who had inadequate symptom control or were unable to tolerate their original allocation to the dopamine agonist bromocriptine were re-randomised to selegiline plus levodopa or levodopa alone.4
Table 1 Characteristics of trials of monoamine oxidase type B inhibitors included in meta-analysis
Table 2 shows the methodological quality of the included trials. Ten trials described the method of randomisation used (blocking, random number generator, computer); only four trials clearly had an adequate concealment of allocation procedure (by virtue of a central randomisation service). All trials provided information on blinding (15/17 trials were double blind), and all trials reported follow up data, although some trials did not include all randomised patients in the final analyses despite claiming to have used an intention to treat analysis.
Table 2 Methodological quality of included studies
Mortality
Mortality data were available from nine trials of selegiline and one of lazabemide (fig 1). We considered the UK-PDRG study, which initially reported 76/271 (28%) deaths in the selegiline arm compared with 44/249 (18%) deaths in the levodopa arm (odds ratio 1.57, 95% confidence interval 1.09 to 2.30; P = 0.015) to be hypothesis generating.4 In the other trials, which we treated as confirmatory studies, no excess of deaths occurred with MAOBI compared with the control arm (15.5% v 18.2% deaths; odds ratio 1.02, 0.84 to 1.25; P = 0.8). Taking all available data, 287 (20%) deaths occurred in 1436 MAOBI patients compared with 257 (21%) in 1215 control patients (odds ratio 1.13, 0.94 to 1.34; P = 0.2). We found no significant heterogeneity between trials (P = 0.6), even including the UK-PDRG study.
Fig 1 Mortality in trials of monoamine oxidase type B inhibitors. (LD=levodopa; MAOBI=monoamine oxidase type B inhibitor; O-E=observed minus expected; RR=re-randomisation data from UK-PDRG. *Data from subsequent follow up of UK-PDRG trial—patients counted only once in total denominator)
Clinical disability rating scales
Data from rating scales were available from only six trials of selegiline.15 19 24 26 27 32 Unified Parkinson's disease rating scale scores at three months were 2.7 (95% confidence interval 1.4 to 4.1; P = 0.00009), 1.8 (0.8 to 2.7; P = 0.0004), and 0.9 (0.5 to 1.4; P = 0.00007) points better with selegiline than with control for total score, motor score, and activities of daily living score (see figs B-D on bmj.com). The large DATATOP study accounted for more than 65% of the patients analysed and more than 79% of patients in the MAOBI versus placebo comparison.32 However, combined results from the other two studies of MAOBI versus placebo were consistent with those from DATATOP and independently significant (P = 0.004).15 19
Need for levodopa
For the 12 trials comparing an MAOBI with placebo, data on the need for levodopa were available from eight studies with a median follow up of 13 months (range 3 months to 5 years).19-23 26 31 33 A highly significant reduction in the need for levodopa occurred in patients randomised to an MAOBI compared with those on placebo (odds ratio 0.57, 0.48 to 0.67; P < 0.00001; fig 2). For trials comparing selegiline and levodopa with levodopa alone, adequate data on dose of levodopa for meta-analysis were available from two trials.24 27 The dose of levodopa needed for adequate symptom control was 67 (14 to 119; P = 0.01) mg lower in the selegiline arm.
Fig 2 Need for levodopa treatment in trials comparing monoamine oxidase type B inhibitors and placebo. (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor. *Rasagiline. O-E and variance based on published time to event analyses)
Motor complications
Data on motor complications were available from five trials.25 27 28 30 35 A 25% reduction in motor fluctuations occurred in patients randomised to an MAOBI (odds ratio 0.75, 0.59 to 0.95; P = 0.02; fig 3). However, we found no difference in the incidence of dyskinesia between the MAOBI and non-MAOBI groups (odds ratio 0.97, 0.75 to 1.26; P = 0.8; fig 3). We found no evidence of heterogeneity between the trials or the three treatment comparisons for either outcome.
Fig 3 Incidence of motor complications in trials of monoamine oxidase type B inhibitors. (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor. *Motor fluctuations defined as on-off or end of dose fluctuations, wearing off, or random oscillations)
Side effects and withdrawals
More side effects were reported in patients randomised to an MAOBI, which was of borderline significance (odds ratio 1.36, 1.02 to 1.80; P = 0.04). Data on specific side effects were rarely reported, so any subanalysis of these data is of limited value. More MAOBI patients than non-MAOBI patients withdrew owing to adverse events (odds ratio 2.16, 1.44 to 3.23; P = 0.0002; fig 4), with some evidence of heterogeneity between trials (P = 0.03) but not between the three treatment comparisons (P = 0.09). This heterogeneity was explained by the atypical results in the UK-PDRG study, which reported significantly more dropouts due to adverse events in the open label selegiline plus levodopa arm than with levodopa alone (14% v 3%). In contrast, significantly more patients were withdrawn from this trial in the levodopa arm owing to protocol violations (1% v 15%); 28/37 patients were withdrawn following the introduction of selegiline to their treatment regimen after publication of the DATATOP trial results. An analysis of the data on dropouts due to adverse events for placebo controlled trials only (that is, excluding the UK-PDRG and Italy studies) showed no difference between MAOBI and non-MAOBI patients (odds ratio 1.52, 0.87 to 2.68; P = 0.1), with no evidence of heterogeneity between trials (P = 0.2) or between the two treatment comparisons (P = 0.9).
Fig 4 Withdrawal of patients due to adverse events in trials of monoamine oxidase type B inhibitors (O-E=observed minus expected; LD=levodopa; MAOBI=monoamine oxidase type B inhibitor)
We found no difference between the two groups (MAOBI v non-MAOBI) in the overall numbers of patients withdrawing from the trials (18% v 19%; odds ratio 1.06, 0.87 to 1.28; P = 0.6). However, patients withdrew from different trials for quite varied reasons—such as lack of efficacy, toxicity, patients given selegiline by their general practitioners after publication of the DATATOP study—and this is reflected in the significant heterogeneity between trials (P = 0.007), making it difficult to interpret overall withdrawal rates.
Discussion
Heikkila RE, Manzino L, Cabbat FC, Duvoisin RC. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984;311: 467-9.
Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 1989;46: 1052-60.
Lang AE, Lees AJ. MAO-B inhibitors for the treatment of Parkinson's disease. Mov Disord 2002;17(suppl 4): S38-44.
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.
Olanow CW, Myllyla VV, Sotaniemi KA, Larsen JP, Palhagen S, Przuntek H, et al. Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Neurology 1998;51: 825-30.
Counsell C. 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. BMJ 1998;317: 1586.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
Early Breast Cancer Trialists' Collaborative Group. Treatment of early breast cancer. Vol 1: Worldwide evidence 1985-1990. Oxford: Oxford University Press, 1990.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22: 719-48.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. analysis and examples. Br J Cancer 1977;35: 1-39.
Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339: 1-15,71-85.
Parmar M, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17: 2815-34.
Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res 1993;2: 121-45.
Teravainen H. Selegiline in Parkinson's disease. Acta Neurol Scand 1990;81: 333-6.
Mally J, Kovacs AB, Stone TW. Delayed development of symptomatic improvement by (-) deprenyl in Parkinson's disease. J Neurol Sci 1995;134: 143-5.
Parkinson Study Group. A controlled trial of lazabemide (Ro19-6327) in untreated Parkinson's disease. Ann Neurol 1993;33: 350-6.
Parkinson Study Group. A controlled trial of lazabemide (Ro 19-6327) in levodopa-treated Parkinson's disease. Arch Neurol 1994;51: 342-7.
Nappi G, Martignoni E, Horowski R, Pacchetti C, Rainer E, Bruggi P, et al. Lisuride plus selegiline in the treatment of early Parkinson's disease. Acta Neurol Scand 1991;83: 407-10.
Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo Parkinsonian patients: the French selegiline multicenter trial. Mov Disord 1993;8(suppl 1): S36-40.
Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002;59: 1937-43.
Palhagen S, Heinonen EH, Hagglund J, Kaugesaar T, Kontants H, Maki-Ikola O, et al. Selegiline delays the onset of disability in de novo Parkinsonian patients. Neurology 1998;51: 520-5.
Kirollos C, Charlett A, Bowes SG, Purkiss AG, O'Neill CJA, Weller C, et al. Time course of physical and psychological responses to selegiline monotherapy in newly diagnosed, idiopathic parkinsonism. Eur J Clin Pharmacol 1996;50: 7-18.
Parkinson Study Group. Effect of lazabemide on the progression of disability in early Parkinson's disease. Ann Neurol 1996;40: 99-107.
Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, et al. The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann Neurol 1995;38: 771-7.
Caraceni T, Musicco M. Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease: a randomized multicenter study. Parkinsonism Relat Disord 2001;7: 107-14.
Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989;245: 519-22.
Larsen JP, Boas J, Erdal JE for the Norwegian-Danish Study Group.. Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. Eur J Neurol 1999;6: 539-47.
Przuntek H, Conrad B, Dichgans J, Kraus PH, Krauseneck P, Pergande G, et al. SELEDO: a 5-year long-term trial on the effect of selegiline in early parkinsonian patients treated with levodopa. Eur J Neurol 1999;6: 141-50.
Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992;42: 339-43.
Myllyla VV, Heinonen EH, Vuorinen JA, Kilkku OI, Sotaniemi KA. Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease. Acta Neurol Scand 1995;91: 177-82.
Myllyla VV, Sotaniemi KA, Hakulinen P, Maki-Ikola O, Heinonen EH. Selegiline as the primary treatment of Parkinson's disease: a long-term double-blind study. Acta Neurol Scand 1997;95: 211-8.
Parkinson Study Group. Effects of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321: 1364-71.
Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993;328: 176-83.
Parkinson Study Group. Mortality in DATATOP: a multicenter trial in early Parkinson's disease. Ann Neurol 1998;43: 318-25.
Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y on behalf of the Parkinson's Disease Research Group of the United Kingdom. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001;57: 1687-94.
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