Two recent case-control studies published in the New England Journal of Medicine ^1,2 reported that pergolide and cabergoline, which are ergot-derived dopamine agonists, commonly used in Parkinson's disease may be associated with an increased risk of heart valvulopathy.

The study by Rene Schade et al ¹ demonstrated that the association between the use of pergolide or cabergoline and heart valvulopathy. They identified 31 cases of clinically or echocardiographically diagnosed, new-onset heart valve regurgitation among 11,417 patients in the UK General Practice Research Database who were prescribed anti-Parkinson's disease agents from 1988 to 2005. Of the 31 cases, six were exposed to pergolide, six to cabergoline and 19 had not been exposed to any dopamine agonist in the previous 12 months. The incidence rates of newly diagnosed cardiac-valve regurgitation were 30 per 10,000 per year for pergolide, 33 per 10,000 per year for cabergoline, and 5.5 per 10,000 per year for no exposure to any dopamine agonist. The rate of heart valve regurgitation was increased in those on pergolide (incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not in the group on other dopamine agonists. The study also concluded that the risk was particularly high among patients who had taken daily doses of pergolide or cabergoline > 3mg; the risk was increased only among those who had taken either drug for ≥ 6 months. The risk was not increased among patients treated with other dopamine agonists i.e. bromocriptine, lisuride, pramipexole and ropinirole.

In another article, Renzo Zanettini et al ² studied 155 patients taking dopamine agonists and 90 healthy control subjects. The frequency of clinically important valve regurgitation (moderate to severe, grade 3 to 4) was significantly higher in 23.4% of those on pergolide (n=15) and 28.6% of those on cabergoline (n=14) as compared to the group on non-ergot derived dopamine agonists (0%) and control subjects (5.6%). It was observed that patients with grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than those with lower grades.

It has been proposed that the valvular damage induced by the ergot-derived dopamine agonists may be mediated by the serotoninergic system. Drugs like pergolide and cabergoline have shown to be potent agonists of the serotonin (also known as 5-hydroxytryptamine) receptor subtype 5HT2B, which is expressed in heart valves to mediate mitogenesis. Proliferation of fibroblasts (which could lead to inducing valvular fibroplasias) may therefore occur within valve tissue when the 5HT2B receptors are stimulated. 1,2 Appetite suppressants such as fenfluramine and dexfenfluramine are also known to interact with the 5HT2B receptor; and both drugs were withdrawn worldwide in 1997 due to increased risk for serious damage to the heart valves.

Pergolide is used with levodopa and carbidopa for the treatment of Parkinson's disease. Valvular heart disease was first described in association with pergolide in 2002. However, the recent studies suggest that the condition might occur more frequently than what earlier post-market reports suggested. In light of the additional safety information and the availability of alternative treatments for Parkinson's disease that do not have comparable safety problems, pergolide was voluntarily withdrawn from the US market on 29 March 2007. It is still available and marketed in other countries including Australia, Canada, and the United Kingdom.

Pergolide (Celance® 0.05mg and 0.25mg) has been registered by HSA since 1992. However, the product has not been marketed in Singapore since July 2005 due to low demand. HSA has received four local reports of heart valvular abnormalities associated with pergolide. Patients were all Chinese men, age between 55 and 71 years. They had been taking pergolide for 1.7 to 5.2 years before they were found to have aortic, mitral and/or tricuspid regurgitation after screening.

Cabergoline (Dostinex® 0.5mg, Pfizer) has been registered in Singapore since 1997. It is indicated for the inhibition of physiologic lactation soon after parturition and suppression of established lactation. It is also licensed for the treatment of hyperprolactinaemic disorders. Cabergoline is not marketed for the treatment of Parkinson's disease in some countries including Singapore, US and Canada. The dose of cabergoline for the treatment of Parkinson's disease (2–6mg per day) is higher than the dose recommended for hyperprolactinaemic disorders (0.25–2mg per week). Although the risk of heart valvulopathy is reported in the two studies to be associated with the use of higher doses of cabergoline, prescribers should nevertheless be aware of the potential risk of valvulopathy especially the drug is used long-term.