Neurology -- Correspondence for Miyasaki et al., 58 (1) 11-17

Correspondence published:

Reply to Letter to the Editor: Janis M Miyaski, Wayne Martin, Oksana Suchowersky, William Weiner and Anthony E Lang (6 May 2002)

Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based: Rivka Inzelberg, Edna Schechtman and Puiu Nisipeanu (6 May 2002)

Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review: Repor: Roger L. Albin, MD, Kirk A. Frey, MD, PhD, John L. Goudreau, DO, PhD, Sharin Y. Sakurai, MD, PhD. (25 February 2002)

Reply to Letter to the Editor 6 May 2002

Janis M Miyaski
Toronto Western Hospital Toronto Canada,
Wayne Martin, Oksana Suchowersky, William Weiner and Anthony E Lang
Send Correspondence to journal:
Re: Reply to Letter to the Editor

miyasaki{at}uhnres.utoronto.ca Janis M Miyaski, et al.

We welcome the letter by Inzelberg et al. regarding our AAN practice parameter. [1] The validity of their analysis however, is tenuous since each study determined its endpoints in a different manner. As the authors point out, direct head-to- head trials are the most valid method to compare drugs. The role of the practice guideline is to examine existing literature to answer specific questions and thereby assist neurologists in their treatment or investigative decisions.
Reference:
1. Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson's disease: An evidence- based review. Neurology 2002;58:11-17.

Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based 6 May 2002

Rivka Inzelberg
Hillel Yaffe Medical Center Hadera Israel,
Edna Schechtman and Puiu Nisipeanu
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Re: Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based

irivka{at}tx.technion.ac.il Rivka Inzelberg, et al.

We have read with interest the practice parameter by Miyasaki et al. [1] concerning the use of dopamine agonists (DA) in the treatment of early Parkinson's disease (PD) patients. The authors stressed in this evidence- based review that Cabergoline (CBG), Pramipexole (PRX), and Ropinirole (ROP) were shown to be superior to levodopa (LD) in delaying the motor fluctuations and dyskinesias. However, they did not recommend any of the three DA as the first choice of treatment, arguably since there have been no adequate trials comparing these drugs to each other as monotherapy in early PD.
In order to address this issue we compared the three DA [2, 3, 4, 5] concerning the common primary and secondary outcomes of the studies, namely the onset of dyskinesia and mean change from baseline UPDRS. Analysis used odds ratios and 95 % confidence intervals (CI), Fisher's exact test, the absolute risk reduction (ARR) and 95% CI. Mean changes from baseline in UPDRS parts II [Activities of Daily Living (ADL)] and III (Motor) were compared by t-test for unequal variances.
The reduction of the risk for dyskinesia relative to LD was more prominent for PRX and ROP than CBG (CBG (p=0.0074), PRX and ROP (p<0.0001). Odds ratios (95% CI) relative to LD were 0.38 (0.19-0.78) CBG, 0.25 (0.13-0.47) PRX and 0.31 (0.18-0.53) ROP. The ARR (95% CI) was 8.0 % (2.2-13.7) CBG, 20.7 % (11.7-29.8) PRX and 25 % (13.6-36.7) ROP. The comparison of ARR for the three drugs among themselves showed a considerable borderline difference (p=0.05) only between CBG and ROP (17% greater reduction with ROP). Changes in UPDRS scores were reported for parts II (ADL) and III (Motor) only for PRX and ROP. The differences for ADL were not considerably different for ROP than for LD (p=0.08). The mean change in ADL was substantially worse for PRX than for LD (p<0.001). Similar analysis for part III of UPDRS showed that PRX and ROP were worse than LD (PRX p=0.001, ROP p=0.008). Thus the superiority of LD over both DA was similar.
Our analysis suggests that among all three, PRX and ROP were better than CBG concerning the risk of developing dyskinesia. In parallel, the side effect profiles of the three DA were similar to each other. Although indirect analysis of data carries difficulties and its results should be accordingly interpreted, it is still the only present way to compare data available on several drugs, which were not evaluated in head-to-head trials. [5]
References
1- Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson's disease: An evidence- based review. Neurology 2002;58:11-17.
2- Rinne UK, Bracco F, Chouza C et al. Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Drugs 1998;55 (Suppl 1) 23-30.
3- Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson's disease. JAMA 2000;284:1931-1938.
4- Rascol O, Brooks D, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484-1491.
5- Inzelberg R, Carasso RL, Schechtman E, Nisipeanu P. A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease. Clin Neuropharmacology 2000;23:262-266.

Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review: Repor 25 February 2002

Roger L. Albin, MD,
Professor of Neurology
University of Michigan,
Kirk A. Frey, MD, PhD, John L. Goudreau, DO, PhD, Sharin Y. Sakurai, MD, PhD.
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Re: Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review: Repor

ralbin{at}umich.edu Roger L. Albin, MD, et al.

We commend Miyasaki et al. and the Quality Standards Subcommittee for the development of the new Practice Parameter on initial treatment of PD [1]. There is one point on which we disagree with the parameter. Miyasaki et al. address the controversial topic of initial L-dopa versus initial dopamine agonist treatment and take an agnostic position about the choice of initial dopaminomimetic therapy. They stress possible trade-offs between the greater efficacy of L-dopa and the putative reduction in motor complications reported with initial agonist therapy. We disagree with the conclusion that initial agonist treatment "results in fewer motor complications (wearing off, dyskinesias, on-off motor fluctuations) than levodopa treatment." The three comparator studies of initial agonist therapy versus initial L-dopa demonstrate greater efficacy of L-dopa in treating the motor and ADL features of PD. Initial agonist treated subjects had poorer UPDRS motor scores than L-dopa treated subjects. This obscures direct comparison of dyskinesia frequency between the agonist and L-dopa treated study arms. Patients with more advanced PD often have very steep dose-response curves for both the dyskinetic and anti-parkinsonian effects of dopaminomimetic therapy, and have similar thresholds for the dyskinesias and anti-parkinsonian effects [2]. Initial agonist treated subjects may have a lower frequency of dyskinesias than initial L-dopa treated subjects because of lower treatment intensity rather than treatment mechanism. A different problem exists with the claim that initial agonist therapy results in less 'wearing off' than initial L-dopa treatment. Agonists have significantly longer half-lives than L-dopa. It is not surprising that subjects on agonists experienced less wearing off. Is this a benefit of initial agonist treatment or of just predictable pharmacokinetics and pharmacodynamics? Could the same results be obtained by using agonists as L-dopa adjuncts? Settling these plausible questions requires crossover design trials, which are not incorporated into the existing comparator trials. No studies demonstrated any advantage of initial agonist treatment with respect to on-off motor fluctuations.
The three comparator studies show that L-dopa is more efficacious and has fewer side-effects. Treatment with L-dopa is less expensive and easier to initiate than agonists. Agonists need to have a substantial advantage to be preferred to L-dopa for initial treatment. That advantage has yet to be demonstrated unequivocally.
(1) Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson's disease: An evidence-based review. Neurology 2002;58:11-17. (2) Nutt JG. Clinical pharmacology of levodopa-induced dyskinesia. Annals of Neurology 2000;47(suppl 1):S160-S164.