The FDA ( Food and Drug Administration ) has informed the public about a possible increased risk of heart failure with Mirapex ( Pramipexole ), a drug used to treat Parkinson’s disease and restless legs syndrome. Results of recent studies suggest a potential risk of heart failure that needs further review of available data.
Pramipexole belongs to a class of medicines called dopamine agonists; it works by acting in place of dopamine, produced by specific areas of the brain that control movement. Parkinson's disease causes progressive loss of dopamine production in the brain.
FDA evaluated a pooled analysis of randomized clinical trials and found that heart failure was more frequent with Pramipexole than with placebo; however, these results were not statistically significant.
FDA also evaluated two epidemiologic studies that suggested an increased risk of new onset of heart failure with Pramipexole use. However, study limitations make it difficult to determine whether excess heart failure was related to Pramipexole use or other influencing factors.
Because of the study limitations, FDA is not able to determine whether Pramipexole increases the risk of heart failure. FDA is continuing to work with the manufacturer to clarify further the risk of heart failure with Mirapex.
Health care professionals should continue to follow the recommendations in the drug label when prescribing Mirapex. Patients should continue to take their Mirapex as directed and should contact their health care professional if they have any questions or concerns.
Data summary
A pooled analysis of randomized, placebo-controlled, parallel phase 2 and 3 clinical trials of Pramipexole, first submitted by the manufacturer to FDA in 2008 and later updated in 2010, found that the incidence of newly diagnosed heart failure was more frequent in patients taking Pramipexole ( n=12/4157 ) than in patients receiving placebo ( n=4/2820 ); however, the difference in incidence was not statistically significant.
To evaluate a possible association of Mirapex with heart failure, the manufacturer sponsored an epidemiologic study using the United Kingdom General Practice Research Database ( GPRD ). This was a case-control study in a cohort of users of anti-Parkinsonian drugs, aged 40 to 89 years. Seven hundred and eighty-three heart failure cases were matched to 7,454 controls.
The results showed that current use of any dopamine agonist, versus no use of a dopamine agonist, was associated with a statistically significant increase in risk for heart failure ( risk ratio [RR] = 1.58; 95% confidence interval [CI]: 1.26-1.96 ). Among the individual dopamine agonists, a statistically significant association was found for Pramipexole ( RR = 1.86; 95% CI: 1.21-2.85 ) and Cabergoline ( RR = 2.07; 95% CI: 1.39-3.07 ), compared to no use of these specific drugs.
The results of a second epidemiologic study to investigate the risk of heart failure associated with dopamine agonist use was recently published. This second study was a case-control study nested in a cohort of Parkinson’s disease patients who were new users of a dopamine agonist or Levodopa. Researchers used data from four population-based European databases. A total of 518 incident heart failure cases were matched to 38,641 controls. Findings of this study did not suggest that current use of ergot dopamine agonists as a class, or current use of non-ergot dopamine agonists as a class, were associated with an increased risk of heart failure when compared to use of Levodopa. However, among individual non-ergot dopamine agonists, only current use of Pramipexole was associated with an increased risk of heart failure when compared to Levodopa ( odds ratio [OR] = 1.61; 95% CI: 1.09-2.38 ). The increased risk for heart failure was present within the first three months of therapy ( OR = 3.06; 95% CI: 1.74-5.39 ) and in patients aged 80 years and older ( OR = 3.30; 95% CI: 1.62-7.13 ); the increased risk for heart failure was not significant in those who used Pramipexole longer than three months.
The epidemiologic studies had a number of limitations. In the GPRD study, the primary analysis did not restrict the study population by Parkinson’s disease diagnosis, and all users of anti-Parkinsonian drugs were included ( i.e., users of these drugs for Parkinson’s disease, restless legs syndrome, treatment of hyperprolactinemia, and for unidentified reasons ), which likely resulted in a more heterogeneous study population.
The results from the published Mokhles et al study, showing an increased risk for heart failure only in the first three months of therapy, are difficult to explain, since heart failure is generally considered to develop chronically.
XagenaMedicine2012