Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Mortality increased when selegiline was added to levodopa in Parkinson disease

ACP J Club. 1996 May-June;124:57. doi:10.7326/ACPJC-1996-124-3-057


Source Citation

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 Dec 16;311:1602-7. [PubMed ID: 8555803]


Abstract

Objective

To compare the effectiveness of levodopa with levodopa plus selegiline in patients with early, mild Parkinson disease.

Design

Randomized controlled trial with mean 5.6-year follow-up.

Setting

93 National Health Service hospitals in the United Kingdom.

Patients

520 patients who had Parkinson disease with incapacity judged by their physicians to warrant dopaminergic treatment. Exclusion criteria were incapacitating cognitive impairment or previous failure to respond to dopaminergic drugs. Follow-up was 98%.

Intervention

249 patients were allocated to 62.5 mg of levodopa and benserazide, 3 times/d after meals. This dose was increased to 125 mg, 3 times/d, and maintained for 3 months. Further increases were left to the discretion of individual investigators. 271 patients were allocated to 5 mg of selegiline, 1 time/d for 1 week, then to an increase of 5 mg, 2 times/d for 3 weeks. Levodopa and benserazide were then added in the selegiline group as they were for the group allocated to levodopa and benserazide alone.

Main Outcome Measures

Mortality; disability scores (Hoehn and Yahr scale, North Western University disability scale, and Webster rating scale); and adverse reactions (dyskinesia, dystonia, and oscillations).

Main Results

Analysis was by intention to treat. Daily treatment with levodopa plus selegiline led to more deaths at 5.6 years than did levodopa alone (28% vs 18%, P = 0.005) (Table). The differences in disability scores between the 2 groups did not reach statistical significance. The groups did not differ for the number of patients who had adverse reactions, but moderate or severe interdose dyskinesias were more common in the patients who received levodopa plus selegiline (40% vs 25%, P = 0.04).

Conclusion

In patients with early, mild Parkinson disease, treatment with levodopa plus selegiline resulted in higher mortality than did treatment with levodopa alone.

Sources of funding: Parkinson's Disease Society of the United Kingdom; Roche Products; Britannia Pharmaceuticals; Sandoz Products.

For article reprint: Dr. A.J. Lees, Parkinson's Disease Research Group of the United Kingdom, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, England, UK. FAX 44-181-954-8560.


Table. Selegiline plus levodopa vs levodopa alone in Parkinson disease*

Outcome at mean of 5.6 y Selegiline plus levodopa Levodopa alone RRI (95% CI) NNH (CI)
Mortality 28% 18% 59% (15 to 121) 10 (6 to 32)

*Abbreviations defined in Glossary; RRI, NNH, and CI calculated from data in article.


Updated Commentary

This report by Lees and colleagues (1) kindled a persisting controversy over the safety of combination therapy with selegiline and levodopa. The result was unexpected but was taken seriously and resulted in a large drop in selegiline use, particularly in the United Kingdon. Update analysis found that the increase in mortality did not quite reach significance (hazard ratio 1.30, 95% CI 0.99 to 1.72), perhaps because the study was stopped when, by chance, mortality was high (2, 3). A retrospective observational study in 12,621 persons who had taken antiparkinsonian drugs also found a nonsignificant increase in mortality in those who had taken selegiline (absolute risk index 11%, 95% CI 0% to 23%).

No evidence of increased mortality was found in 1 large randomized controlled trial (RCT) and a nonsystematic review (6) (it omitted at least 1 relevant study). A lingering uncertainty remains over the safety of selegiline, which has not been entirely dispelled by a recent, more encouraging, small, matched cohort study. This study found a mortality advantage for selegiline alone or selegiline plus levodopa combination therapy againast levodopa monotherapy (relative risk 0.33, 95% CI 0.13 to 0.83) (7). The authors conceded that few patients were on selegiline alone, long-term survivors were more likely to be taking combination therapy, and patients on levodopa monotherapy may have had more severe disease.

4 large RCTs with between 9 months and 5 years of follow-up have found that selegiline delays or reduces the need for levodopa (8, 9, 10, 11), but this could be due to symptom reduction rather than a neuroprotective effect. 1 large RCT showed no clincially important difference after 4 years of selegiline (1).

There remains the possibility that selegiline is both useful and safe. A systematic review of these issues is under way and a further large trial is planned in the United Kingdom.

A. P. Moore, MB, ChB, MD
The Walton Centre for Neurology and NeurosurgeryLiverpool, England, UK


References

1. Lees AJ, for 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. 1999;311:1602-7.

2. Ben-Shlomo Y, Churchyard A, Head 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.

3. Counsell C. Effect of adding selegiline to levodopa in early, mild Parkinson's disease. BMJ 1998;317:1586.

4. Thorogood M, Armstrong B, Nichols T, Hollowell J. Mortality in people taking selegiline: observational study. BMJ. 1998;317:252-4.

5. The Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Ann Neurol. 1996;39:37-45.

6. Olanow C, Mylla V, Sotaniemi K, et al. Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Neurology. 1998;51:825-30.

7. Donnan P, Steinke D, Stubbings C, Davey P, MacDonald T. Selegiline and mortality in subjects with Parkinson's disease. Neurology. 2000;55:1758-89.

8. The Parkinson's 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.

9. Olanow CW, Hauser RA, Gauger L, et al. The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann Neurol. 1995;38:771-7.

10. Przuntek H, Conrad B, Dichgans J, et al. SELEDO: a five-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. Eur J Neruol. 1999;6:141-50.

11. Larson J, Boas J, Erdal J, et al. Does selegiline modify the progression of early Parkinson's disease? Results from a five year study. Eur J Neruol. 1999;6:539-47.