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Dopamine Agonists and Heart Valve Changes

Two studies find increased risks associated with use of pergolide and cabergoline.

Two new studies report increased frequencies of heart valve changes in patients taking pergolide or cabergoline, dopamine agonists used in the treatment of Parkinson disease (PD). A companion piece explains the likely mechanism.

Schade and colleagues performed a case-control analysis of information from a database of 11,417 patients with significant exposure to antiparkinsonian drugs during a 17-year interval. They identified 81 cases of newly recognized valvular regurgitation, of which 31 lacked another etiology. The 663 controls (antiparkinsonian-drug users without valve abnormalities) were matched for age, sex, and duration of treatment. Treatment with pergolide for more than 6 months increased the relative risk for valvular heart disease by a factor of 7.1, cabergoline by 4.9; patients with doses above 3 mg/day had substantially greater risks. There were no cases attributed to bromocriptine or lisuride, two other ergot-derived dopamine agonists. There were no cases in patients on ropinirole or pramipexole, two newer dopamine agonists with a different molecular skeleton.

Zanettini and colleagues examined echocardiographs of 155 patients taking dopamine agonists and 90 controls without PD, matched for age, sex, and presence of hypertension. The researchers used an internationally accepted standard for abnormality on echocardiography. There were 64 patients taking pergolide for at least 1 year, 49 patients taking cabergoline for at least 1 year, and 42 patients taking ropinirole or pramipexole for at least one year. Compared with controls, patients exposed to pergolide had significantly increased risks for mitral and aortic regurgitation, and cabergoline users had a significantly increased risk for aortic regurgitation. Patients taking other dopamine agonists did not have valve regurgitation (though some had early tenting of the mitral leaflet). The authors noted a direct relation between risk and cumulative dose exposure.

Comment: Dopamine agonists are useful in the treatment of Parkinson disease, both as adjunctive therapy for patients with motor fluctuations, and as initial monotherapy. Dopamine agonists have common side effects, including nausea, sedation, and leg edema. Mounting evidence suggests that some of the ergot-derived dopamine agonists can cause heart valve changes (Lancet 2004; 363:1179, Neurology 2006; 67:1225, and Mov Disord 2006; 21:1109). These new studies demonstrate a significant risk for valve regurgitation in patients who take pergolide or cabergoline. Despite the different methods used, both studies show a similar relative risk and a cumulative dose effect. The newer, non-ergot dopamine agonists ropinirole and pramipexole do not appear to cause valve changes; nor do two ergot dopamine agonists (bromocriptine and lisuride), according to the findings by Schade and colleagues. These authors suggest that activation of the 5-HT_2B receptor, rather than the ergot molecular skeleton, is the pathogenic factor for this class of drugs. Fenfluramine, ergotamine, and methysergide can also cause heart valve changes, likely by a similar mechanism.

Pergolide and cabergoline were in widespread use in the U.S. and Europe for years before these problems were identified. Further studies are required to better define the elements of risk associated with antiparkinsonian medications, including older drugs like amantadine that are not known to interact with 5-HT_2B receptors. For now, pramipexole and ropinirole should be used for patients who need a dopamine agonist. For treatment of restless legs syndrome and hyperprolactinemia, the doses are lower but the same considerations apply.

— Lewis Sudarsky, MD

Dr. Sudarsky is Director of Movement Disorders, Department of Neurology, Brigham and Women's Hospital, and Associate Professor of Neurology, Harvard Medical School, Boston.

Published in Journal Watch Neurology January 30, 2007

Citation(s):

Schade R et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007 Jan 4; 356:29-38.

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Zanettini R et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007 Jan 4; 356:39-46.

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Roth BL. Drugs and valvular heart disease. N Engl J Med 2007 Jan 4; 356:6-9.

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• Medline abstract (Free)