Indirekte Metaanalyse randomisierter plazebokontrollierter klinischer Studien zu Rasagilin und Selegilin in der symptomatischen Behandlung der Parkinson-Krankheit

Zusammenfassung

Einführung:

Selegilin und Rasagilin sind in der Therapie der Parkinson-Krankheit bewährt. Da keine direkten randomisierten kontrollierten Studien durchgeführt wurden, erfolgte eine indirekte Metaanalyse.

Ziel:

Ziel war, die klinische Differenzierung zwischen Rasagilin und Selegilin basierend auf Wirksamkeit und Sicherheit bei idiopathischen Parkinsonsyndrom zu untersuchen.

Methoden:

Grundlage der Literaturrecherche waren Literatur-Datenbanken, Studienregister und Referenzen relevanter Publikationen. Studien wurden gemäß den Jadad- und Delphi-Kriterien ausgewählt. Die Analyse erfolgte anhand eines Modells mit fixen Effekten basierend auf standardisierten Mittelwertdifferenzen für Wirksamkeitskriterien und Risikodifferenzen der Sicherheitsoutcomes. Als Outcomes wurden UPDRS-Gesamtscore (primäres Outcome) und UPDRS-Motor-Score, Mental-Score und Aktivitäten des täglichen Lebens, die Schwab- und England-Skala, die Off Zeit sowie Sicherheit als sekundäre Outcomes verwendet.

Ergebnisse:

Rasagilin zeigte einen statistisch signifikanten Vorteil im primären Endpunkt des UPDRS-Gesamtscores (Monotherapie: p=0,048, Sensitivitätsanalyse: p=0,023; gepoolte Analysen: p=0,043, Sensitivitätsanalyse: p=0,014) und im sekundären UPDRS-Motor-Score (Monotherapie: p=0,049, Sensitivitätsanalyse: p=0,031; gepoolte Analysen: nicht signifikant; Sensitivitätsanalyse: p=0,046). Für die übrigen sekundären Outcome-Parameter wurde ein numerischer Vorteil für Rasagilin festgestellt. Abbruchraten aufgrund unerwünschter Ereignisse zeigten eine Tendenz zugunsten von Rasagilin. Das Risiko unerwünschter Ereignisse, wie Schwindelgefühl, Halluzinationen, Diarrhoe und Synkope, war unter Rasagilin geringer (je p<0,15).

Fazit:

Die indirekte Metaanalyse zeigte einen statistisch signifikanten und klinisch relevanten Vorteil für Rasagilin gegenüber Selegilin im primären Endpunkt. Die Überlegenheit von Rasagilin wurde auch mit numerischen Vorteilen bei Verträglichkeit und Sicherheit belegt.

Abstract

Introduction:

Selegiline and rasagiline are established in the treatment of Parkinson′s disease. As no direct randomised controlled trials on these drugs are available, an indirect meta-analysis was conducted.

Objective:

Goal of the meta-analysis was to examine the clinical differentiation between rasagiline and selegiline based on efficacy and safety in idiopathic Parkinson′s disease.

Methods:

Literature databases, study registries and references of relevant publications were the basis of our literature search. Studies were selected according to Jadad and Delphi criteria. The analysis used a fixed effects model based on standardised mean differences for efficacy criteria and risk differences of safety outcomes. As outcomes UPDRS (primary) and UPDRS motor functions, mental and ADL, the Schwab and England scale, the off-time as well as safety as secondary outcomes were used.

Results:

Rasagiline showed a statistically significant advantage in the primary endpoint UPDRS total scores (monotherapy: p=0.048, sensitivity analysis: p=0.023; pooled analyses: p=0.043, sensitivity analysis p=0.014) and the secondary endpoint UPDRS motor functions (monotherapy: p=0.049, sensitivity analysis p=0.031; pooled analyses: not significant, sensitivity analysis: p=0.046). For the other secondary outcome parameters, a numerical advantage for rasagiline was found. Discontinuation rates due to adverse effects showed a tendency in favour of rasagiline. Risk for adverse events such as dizziness, hallucinations, diarrhoea and syncope were lower with rasagiline than selegiline (each p<0.15).

Conclusion:

This meta-analysis showed a statistically significant and clinically relevant advantage for rasagiline over selegiline in the primary endpoint. The superiority of rasagiline was further substantiated with advantages in tolerability and safety.

Schlüsselwörter

Metaanalyse - Rasagilin - Selegilin - klinische Studie - Parkinson

Keywords

meta-analysis - rasagiline - selegiline - clinical trials - Parkinson′s disease

• Literatur

• 1 Leitlinien der Deutschen Gesellschaft für Neurologie. 4. überarbeitete Auflage. Stuttgart, New York: Thieme; 2008
• 2 DeLong MR, Juncos JL. Chapter 366. Parkinson’s disease and other extrapyramidal movement disorders. In: Fauc AS, Braunwald E, Kasper DL. et al., Hrsg Harrison’s Online. . McGraw-Hill; accessed Oct 24^th 2010
• 3 Brunton L, Parker K, Blumentahl D et al., Hrsg Goodman and Gilman’s Manual of Pharmacology and Therapeutics. New York:: McGraw-Hill; 2007. 343.
• 4 Leegwater-Kim J, Bortan E. The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging 2010; 5: 149-156
• 5 Olanow CW, Rascol O, Hauser R et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361: 1268-1278
• 6 Bar-Am OB, Amit T, Youdim MB. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci Lett 2004; 355: 169-172
• 7 Glenny AM, Altman DG, Song F et al. Indirect comparisons of competing interventions. Health Technol Assess 2005; 9: 1-134 iii–iv
• 8 Schöttker B, Lühmann D, Boulkhemair D et al. Indirekte Vergleiche von Therapieverfahren. Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland Bd 88. Köln 2009; Deutsches Institut für Medizinische Dokumentation und Information (DIMDI)
• 9 Song F, Altman DG, Glenny AM et al. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003; 326 (7387) 472
• 10 Higgins JPT, Green S. eds Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. updated September 2009). Section 6: Searching for studies. The Cochrane Collaboration: 2009. www.cochrane-handbook.org
• 11 Higgins JPT, Green S. eds Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. updated September 2009). Section 16.6.2: Indirect comparisons. The Cochrane Collaboration: 2009. www.cochrane-handbook.org
• 12 Higgins JPT, Green S. eds Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. updated September 2009). Section 9: Analysing data and undertaking meta-analyses. The Cochrane Collaboration: www.cochrane-handbook.org
• 13 Macleod AD, Counsell CE, Ives N et al. Monoamine oxidase B inhibitors for early Parkinson’s disease. Cochrane Database Syst Rev 2005; 20 CD004898
• 14 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12
• 15 Verhagen AP, de Vet HC, de Bie RA et al. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 1998; 51: 1235-1241
• 16 Fahn S, Elton R. Members of the UPDRS Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M. Hrsg Recent Developments in Parkinson’s Disease. Vol 2 Florham Park, NJ: Macmillan Health Care Information; 1987. 3–163 293-304
• 17 Siderowf A, McDermott M, Kieburtz K et al. Test-retest reliability of the unified Parkinson’s disease rating scale in patients with early Parkinson’s disease: results from a multicenter clinical trial. Mov Disord 2002; 17: 758-763
• 18 Yahr MD, Duvoisin RC, Schear MJ et al. Treatment of parkinsonism with levodopa. Arch Neurol 1969; 21: 343-354
• 19 Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s disease. In: Gillingham FJ, Donaldson IML. Hrsg Third Symposium of Parkinson’s Disease.. Edinburgh: E & S Livingston; 1969
• 20 Rabey JM, Sagi I, Huberman M et al. Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson’s disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000; 23: 324-330
• 21 Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59: 1937-1943
• 22 Rascol O, Brooks DJ, Melamed E et al. LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365: 947-954
• 23 Stern MB, Marek KL, Friedman J et al. Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson’s disease patients. Mov Disord 2004; 19: 916-923
• 24 Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62: 241-248
• 25 Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989; 245: 519-522
• 26 Shults CW. Effect of selegiline (deprenyl) on the progression of disability in early Parkinson’s disease. Parkinson Study Group. Acta Neurol Scand Suppl 1993; 146: 36-42
• 27 Myllylä VV, Sotaniemi KA, Hakulinen P et al. Selegiline as the primary treatment of Parkinson’s disease – a long-term double-blind study. Acta Neurol Scand 1997; 95: 211-218
• 28 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. 01) S36-S40
• 29 Nappi G, Martignoni E, Horowski R et al. Lisuride plus selegiline in the treatment of early Parkinson’s disease. Acta Neurol Scand 1991; 83: 407-410
• 30 Olanow CW, Hauser RA, Gauger L et al. The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 1995; 38: 771-777
• 31 Larsen JP, Boas J, Erdal JE. Does selegiline modify the progression of early Parkinson’s disease? Results from a five-year study. The Norwegian-Danish Study Group. Eur J Neurol 1999; 6: 539-547
• 32 Pålhagen S, Heinonen EH, Hägglund J et al. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology 1998; 51: 520-525
• 33 Zhao Wu-wie He, Xiao-jun, Zhang Zhi-feng et al. Influence of selegiline on dopaminergic neurons in patients with early Parkinson disease. Chinese J Clin Rehab 2005; 9: 190-192
• 34 Golbe LI. Long-term efficacy and safety of deprenyl (selegiline) in advanced Parkinson’s disease. Neurology 1989; 39: 1109-1111
• 35 Lees AJ. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Parkinson’s Disease Research Group of the United Kingdom. BMJ 1995; 311: 1602-1607
• 36 Dalrymple-Alford JC, Jamieson CF, Donaldson IM. Effects of selegiline (deprenyl) on cognition in early Parkinson′s disease. Clin Neuropharmacol 1995; 18: 348-359
• 37 Kirollos C, Charlett A, Bowes SG 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
• 38 Przuntek H, Conrad B, Dichgans J 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: 141-150
• 39 Takahashi M, Yuasa R, Imai T et al. Selegiline (L-deprenyl) and L-dopa treatment of Parkinson’s disease: a double-blind trial. Intern Med 1994; 33: 517-524
• 40 Ives NJ, Stowe RL, Marro J et al. Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 2004; 329 (7466) 593. Epub 2004 Aug 13.
• 41 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Memantin bei Alzheimer Demenz: Ergebnisse der unpublizierten Studien IE2101 und MEM-MD-22 sowie unpublizierter Responderanalysen. IQWiG-Berichte Nr. 74 2010; http://www.iqwig.de/download/Arbeitspapier_zu_Memantin_bei_Alzheimer_Demenz.pdf
• 42 Borenstein M, Hedges L, Rothstein H. Meta-analysis. Fixed effects vs. Random effects 2007; www.meta-analysis.com
• 43 Senn S. Statistical Issues in Drug Development. Chichester: John Wiley & Sons;; 1997
• 44 Senn S. The many modes of meta. Drug Information Journal 2000; 34: 535-549
• 45 Senn S. Trying to be precise about vagueness. Stat Med 2007; 26: 1417-1430
• 46 Schrag A, Sampaio C, Counsell N et al. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord 2006; 21: 1200-1207
• 47 Knudsen-Gerber DS. Selegiline and rasagiline: twins or distant cousins?. Guidel Cosnult Pharm 2011; 26 48-51
• 48 Callaghan RC, Cunningham JK, Sajeev G et al. Incidence of Parkinson’s disease among hospital patients with methamphetamine-use disorders. Mov Disord 2010; 25: 2333-2339