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Dopamine Agonists and the Risk for Valvular Heart Disease

Two studies raise concerns about two antiparkinsonian drugs that are potent 5-HT_2B–receptor agonists.

Fenfluramine and dexfenfluramine are serotonin-receptor (5-hydroxytryptamine [5-HT]) agonists that have been associated with valvular heart disease lesions similar to those induced by serotonin-secreting carcinoid tumors. Pergolide and cabergoline, ergot-derived dopamine agonists used to treat Parkinson disease, are potent 5-HT_2B–receptor agonists hypothesized to cause valvular heart disease. Two European studies test that hypothesis. (Note: cabergoline is not approved to treat Parkinson disease in some countries, including the U.S., but is used for other conditions.)

Using the U.K.'s General Practice Research Database, researchers identified 11,417 patients (age 40–80) who had been prescribed at least two antiparkinsonian drugs from January 1988 through August 2005. Within that cohort, each case with newly diagnosed cardiac-valve regurgitation was matched with up to 25 controls according to age, sex, and date of study entry. The researchers identified all dopamine agonists that were prescribed to cases and controls for at least 12 months before the entry date. During a mean follow-up of 4.2 years, annual incidence rates of newly diagnosed cardiac-valve regurgitation were significantly higher with pergolide (30 per 10,000 patients exposed) and cabergoline (33 per 10,000 patients exposed) than with no exposure to a dopamine agonist (5.5 per 10,000 unexposed patients); this difference was not evident for other dopamine agonists.

In Italy, researchers conducted an echocardiographic study of the prevalence of valvular abnormalities among 155 patients taking antiparkinsonian drugs and 90 age- and sex-matched controls. The rate of any grade 3 or 4 regurgitation was much higher in pergolide users (23%) and cabergoline users (29%) than in users of non-ergot–derived dopamine agonists (0%) or those not using any dopamine agonist (6%). Relative risks (RRs) for moderate or severe valve regurgitation associated with pergolide use reached statistical significance for mitral regurgitation (RR, 6.3; P=0.008) and aortic regurgitation (RR, 4.2; P=0.01). With cabergoline use, only the RR for aortic regurgitation was significant (RR, 7.3; P<0.001).

Comment: The data from these two studies support the hypothesis that 5-HT_2B–receptor agonists are associated with increased risk for valvular heart disease. The evidence is consistent with, although does not prove, a causal relation. Nevertheless, as noted in an accompanying perspective piece, the risks are serious enough that the message to practitioners should be to avoid, if possible, prescribing medications that are potent 5-HT_2B–receptor agonists. For any clinician treating a patient with Parkinson disease, use of these medications should prompt concern about the potential for valvular heart disease.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology January 3, 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 during treatment with 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)