Early Treatment in Parkinson Disease May Have Small Benefit

Lieneke van den Heuvel, PhD student

New observational study data suggest that early initiation of treatment in patients with Parkinson disease may offer small improvements in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores but does not appear to worsen outcomes.

Using a cohort of 302 patients with de novo Parkinson disease from the Parkinson's Progression Markers Initiative (PPMI), lead author Lieneke van den Heuvel, PhD student, and coauthor Bastiaan R. Bloem, MD, PhD, medical director, Department of Neurology, Radboud University Medical Center, and colleagues observed that after 2 years there was a small improvement for those who started treatment earlier, though it was not significant. Additionally, there were similar nonsignificant improvements in subsequent years.

“We found no statistically significant differences in most secondary outcomes, including the presence of motor fluctuations, nonmotor symptoms, MDS‐UPDRS Part II scores, and the Schwab and England Activities of Daily Living Scale,” Bloem et al. wrote. There was an increased presence of dyskinesias in year 3, though the confidence intervals included 0 at both years 2 and 4.

For each year after year 2, there were slightly fewer patients available for analysis—year 3 (n = 311) and year 4 (n = 295)—but this varied due to the exclusion of those who had not initiated treatment when outcome measures were collected, in addition to dropouts. As well, not all assessments fulfilled OFF criteria and thus were excluded. In total, 155 MDS‐UPDRS III measurements were available at year 2, 178 at year 3, and 194 at year 4.

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Of those using medications, 45% used levodopa, 16% used dopamine agonists, 13% used other medications (mainly MAO‐B inhibitors), and 25% utilized combination therapy.

When analyzing the effects of 1-year-longer treatment with only levodopa (n = 82), there was an improvement in UPDRS Part III scores in the second year, but these effects were not significant in the subsequent 2 years after, with large range confidence intervals. Bloem et al. noted that “the effects on the other outcomes were also inconclusive with wide confidence intervals.”

Importantly, the group identified that the consideration of time-varying cofounding in cohort-study data interpretation is underlined by these findings. They explained that without that consideration, the negative outcomes were attributable to therapy rather than to the worse disease state upon treatment initiation. This effect might be clarified, they noted, by the fact that those with worse disease states warrant earlier treatment compared to those with mild disease. Specifically, when adjusting for this cofounding, Bloem et al. observed a slightly more beneficial effect of longer treatment on UPDRS Part III scores in the models that lacked this adjusting.

The group added that the findings of this assessment support prior randomized controlled trial findings of a lack of clinical disease progression with earlier initiation of dopaminergic treatment. As well, the absence of strong evidence of more adverse effects with earlier treatment (levodopa‐induced dyskinesias or motor fluctuations) can alleviate the concerns regarding those effects with early initiation of dopaminergic therapy.

Additionally, they acknowledged that in seeking to estimate the effects of early treatment with the methods utilized—clinical outcomes—it is not possible to determine mechanistic factors at hand without biomarker-based analysis. “For example, patients who start on medication earlier may—because of their improved motor performance—have been able to better engage a more active lifestyle; an active lifestyle is also associated with lower MDS‐UPDRS motor scores,” they wrote.

REFERENCE
van den Heuvel L, Evers LJW, Meinders MJ, et al. Estimating the Effect of Early Treatment Initiation in Parkinson's Disease Using Observational Data. Movement Disord. Published October 27, 2020. doi: 10.1002/mds.28339.