Levodopa as Initial Parkinson Treatment Shows Best Long-Term Prognostic Outcome for Quality of Life

Carl Clarke, MD

After 15 years of follow-up, findings from the PD MED EARLY trial showed that patient-rated quality of life (QoL) was slightly better in patients who started levodopa (LD) than LD-sparing therapies, in spite of the small increase in dyskinesia. Monoamine oxidase (MAOB) inhibitors appeared as effective as dopamine agonists (DA), with slightly better QoL than catechol-O-methyl transferase (COMT) inhibitors.^1,2

These data were part of 2 presentations from the 2023 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held August 27-31 in Copenhagen, Denmark. Led by Carl Clarke, MD, professor of clinical neurology at the University of Birmingham, the first analysis included 1593 newly diagnosed UK-based patients with PD who were randomly assigned 1:1:1 to LD-sparing therapy, either DA or MAOB inhibitor, or LD alone, with the primary outcome of the mobility dimension on the patient-rated Parkinson’s Disease Questionnaire (PDQ-39) QoL scale.

The trial was designed to evaluate which of these drug classes provides the greatest, long-term control and best QoL for patients with early PD. Over 15 years of follow-up, patients randomized to LD alone averaged 2.4-points (CI, 0.6-4.3; P = .01) better than patients on LD-sparing agents. In addition, this group showed significantly better PDQ-39 activities of daily living and summary index, and EuroQol (EQ)-5D scores. At the conclusion of the 15-year follow-up, dyskinesia was reported in 70% of patients on LD vs 63% of those on LD-sparing therapies (P = .005).

Subgroup analyses showed no between-group differences on outcomes based on age (<70 years vs ≥70 years) and level of disability at baseline (Hoehn and Yahr rating, 1-1.5 vs 2-5). Investigators observed findings that suggested a slightly reduced rate of dementia (HR, 0.84; 95% CI, 0.73-0.98), but there was no evidence of any difference in mortality or institutionalization rates.

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The second analysis from the trial focuses specifically on a cohort of patients (n = 485) who were randomized to either DA or dopamine degradation inhibitor (DDI) therapy such as an MAOB inhibitor or COMT inhibitor. Over 10-year follow-up, there were no significant between-group differences between DA and DDI therapy in any patient-rated QoL measure or in institutionalization, dementia, or mortality. Of note, PDQ-39 mobility scores were 4.8-points (CI, 1.3-8.3; P = .007) better with MAOB inhibitors than COMT inhibitors.²

Additional details from the analysis showed borderline significant differences on the PDQ-39 activities of daily living, emotional well-being and social support dimensions together with the summary index favoring MAOB inhibitors. Similar trends were observed for EQ-5D. There were no between-group differences on rates of institutionalization, dementia, or mortality. Exploratory analyses showed similar magnitude differences favoring DA over COMT inhibitors; however, these did not reach statistical significance.

In the original PD MED trial, published in Lancet Neurology in 2014, findings showed small but persistent benefits for patient-rated mobility scores in LD-treated patients over LD-sparing therapy. Between 2000 and 2009, PDQ-39 mobility scores were 1.4-points (95% CI, 0.0-2.9; P = .05) better in patients on MAOB inhibitors compared with those allocated to DA. In total, 28% of patients on DA and 23% of those on MAOB inhibitors discontinued allocated treatment because of adverse events compared with just 2% of those on LD (P <.0001).³

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REFERENCES
1. Clarke C, Rick C, Patel S, et al. 15-year effects of initiating treatment for Parkinson’s disease with dopamine agonists or monoamine oxidase B inhibitors compared with levodopa: final results of PD MED early disease randomization. Presented at: 2023 MDS Congress; August 27-31; Copenhagen, Denmark. Abstract 41
2. Clarke C, Rick C, Patel S, et al. Long-term effectiveness of adjuvant treatment with catechol-o-methyltransferase or monoamine oxidase B inhibitors compared with dopamine agonists in Parkinson’s disease uncontrolled by levodopa: final results of the PD MED LATER randomized clinical trial. Presented at: 2023 MDS Congress; August 27-31; Copenhagen, Denmark. Abstract 42.
3. MD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomized trial. Lancet Neurol. 2014;384(9949):1196-1205. doi:10.1016/S0140-6736(14)60683-8