Several studies performed in the 1970s demonstrated that levodopa therapy improved mortality in PD. These studies compared the survival of levodopa-treated patients to the mortality rate demonstrated in the pre-levodopa Hoehn and Yahr study (122), which demonstrated that mortality was three times greater than the normal population. Nearly all studies indicated that levodopa improved survival with rates of 1.4 to 2.4 (119,120,123,124). Some investigators suggested that survival approached normal, whereas others indicated that the effect was only seen in the early years of therapy and then disappeared, suggesting that improvement was based on symptomatic responses. However, many of the studies have been criticized due to methodological flaws, problems with patient selection, and possible biases.
One study (125) utilized a population-based study design (retrospective) to avoid many of these flaws and examined the change in survival related to levodopa therapy. The study included patients treated from 1964 to 1978 to include patients treated early and late, as well as untreated cases. Results indicated that survival for all treated patients was significantly poorer than that of the general population, but was better in treated than in untreated PD. The improved survival over time was not linear. Throughout the 17 years of follow-up, there was reduced risk of death with levodopa therapy.
Rajput (114) compared 10-year survival of 215 patients from the pre-levodopa era and 719 from the post-levodopa era. The survival was significantly greater for the post-levodopa group and particularly for those who initiated therapy at Hoehn and Yahr stage <2.5. This study suggests that the timing of levodopa therapy is important in relation to survival. Several other studies have supported this conclusion. Diamond et al. (123) examined 359 patients treated between 1968 and 1977. They divided patients into three groups: one to three years of PD, four to six years of PD, and seven to nine years of PD. They used observed-to-expected death rate ratios from a similar group in the general population as measures of survival. When the duration of therapy was held constant at 15 years, the ratio was higher for patients with longer duration of disease. When the duration of disease was held constant at 17 years, the patients with longer duration of therapy had a better mortality ratio than the other two groups, suggesting early initiation of levodopa was beneficial to life expectancy.
Scigliano et al. (124) studied 145 patients seen from 1970 to 1983. Of those, 98 were treated for two or more years, whereas 47 were treated for less than two years. Mortality was found to be 2.5 times greater among the patients treated later, but a multivariate analysis taking into account age and disease severity made the difference nonsignificant. Nonetheless, the mortality among late starters was two times greater. There were biases that led to an underestimation of mortality in the delayed treatment group, including 47 patients who were lost to follow-up. The authors concluded that survival from early levodopa initiation is the same or better than late initiation.
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