Cardiac Valvular Disease Associated with the Dopamine Agonists Pergolide and Cabergoline

Abstract & Commentary

By Claire Henchcliffe, MD, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.

Synopsis: Two large independent studies raise further concern over increased risk of serious cardiac valve disease in patients treated for Parkinson's disease with ergoline dopamine agonists, pergolide and cabergoline.

Sources: Schade R, et al. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation. N Engl J Med. 2007;356:29-38.

Zanettini R. et al. Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease. N Engl J Med. 2007;356:39-46.

These 2 studies address concern over the likely association of cardiac valve disease with use of pergolide and cabergoline, dopamine agonists for symptomatic relief in Parkinson's disease and restless legs syndrome. Zanettini and colleagues used transthoracic echocardiography to determine the prevalence of cardiac valve regurgitation in 155 patients with Parkinson's disease, who had taken dopamine agonists for at least 12 months. Cases were compared with 90 age- and gender-matched controls. Those with known valvulopathy preceding agonist exposure, or prior use of ergot-derived drugs including anorectics were excluded. Mean patient age was 63.4 ± 9.2 years and 63% were male. Average daily drug doses were pergolide: 2.8 ± 1.2 mg; cabergoline: 3.6 ± 2.1 mg; pramipexole: 3.0 ± 1.1 mg; and ropinirole: 10 ± 3.3 mg. Clinically significant grade 3-4 regurgitation occurred more frequently in those taking pergolide (23%) and cabergoline (29%) than in those taking ropinirole or pramipexole (0%), or in control subjects (6%). Moreover, cumulative drug dose was higher in those with grade 3-4 regurgitation than those with grade 0-2 regurgitation.

Schade and colleagues examined a cohort of 11,417 subjects from the United Kingdom General Practice Research Database who were prescribed antiparkinsonian drugs between 1988-2005. Thirty-one cases were identified with new onset valve disease, and matched with 663 controls without valve disease but taking anti-parkinsonian medications. For cases, mean age was 73.0 ± 7.8, 65% were male, 29 had Parkinson's disease, 3 had restless legs syndrome, and one had hyperprolactinemia. Exposure to pergolide and cabergoline was associated with increased rates of cardiac valve regurgitation, with adjusted incidence rate ratios of 7.1 (95% C.I. 2.3-22.3) and 4.9 (95% C.I. 1.5-15.6) respectively, with higher association in those exposed > 6 months or taking >3 mg daily of either drug. There was no association with use of either ropinirole or pramipexole.

Commentary

Based upon a number of previous studies and case reports, pergolide carries a black-box warning regarding increased risk of cardiac valve disease, and recently a milder warning was issued for cabergoline. These 2 studies further support such concerns. Pergolide has been widely used for treatment of Parkinson's disease, and has also been studied in restless legs syndrome. Cabergoline is used in the United States to treat hyperprolactinemia, but is used in many countries as a long-acting dopamine agonist useful in Parkinson's disease treatment. Development of cardiac valve disease (fibrotic changes in valve leaflets), as well as pergolide-associated retroperitoneal and pleuropulmonary fibrosis, is thought to stem from activation of 5HT2B receptors. It may thus stimulate mitogenesis via multiple pathways including Src kinase activation, potentially resulting in valvular "overgrowth" and hence regurgitation.1 Pergolide and cabergoline are both potent agonists of 5HT2B receptors, whereas other commonly used dopamine agonists do not possess significant 5HT2B agonist activity. Accordingly, no association of cardiac valve disease with exposure to ropinirole and pramipexole was evident in these two studies. Given the alternatives now available in treatment of Parkinson's disease, it seems advisable to simply avoid the use of pergolide in Parkinson's disease. For patients who have been exposed, they should be counseled, undergo cardiac evaluation, and given the opportunity to switch medication.

Reference

1. Roth, BL. Drugs and Valvular Heart Disease. N Engl J Med. 2007;356:6-9.