Pergolide and valvular heart disease: the lower the better?

Recently, several publications have confirmed the association between pergolide use and valvular heart disease (VHD). 1–3 The serotonin 2B (5HT 2b ) receptor has been proposed as the key pathway through which pergolide and other drugs activate valvular fibroblasts to proliferate and to produce myxoid substance and collagen, leading to valvular thickening and insufficiency. 4 This can explain the occurrence of VHD with 5HT 2b agonists such as pergolide and cabergoline, while drugs without 5HT 2b activity have not been reported to cause valvulopathy (i.e. pramipexole, lisuride). These recent findings have led to the voluntary withdrawal of pergolide in the US (mars 2007) and to an increased awareness of, and recommendations for a more careful use of pergolide by neurologists in Europe. The studies that reported an association between pergolide and VHD were mainly conducted in older patients with Parkinson's disease who usually require higher dosages of pergolide compared with patients with restless leg syndrome or hyperprolactinemia. Even at low dose, pergolide remains also useful for many patients with Parkinson's disease. By consequence, this risk-benefit issue has become an important subject. The above-mentioned studies also pointed out that the risk of developing VHD depended on the cumulative dose of pergolide (daily dosage × days taken). High cumulative dosages of pergolide (>5 mg/day) were associated with an increased risk compared with lower dosages. 1 In addition, few studies reported a low or nil incidence of VHD in patients taking low dosages of pergolide. In Japan, Muraka et al.5 could not find an increased risk of VHD in 40 patients who took low-dose pergolide (0.05–1.5 mg/day for 2–115 months) compared with 44 non-ergot-derived dopamine controls. Also Kim et al.6 described no increase in valvulopathy in 36 pergolide patients (0.25–4.5 mg/day) compared with 20 age-matched controls. In a study by Ruzicka et al. , 7 no significant VHD disease was found in 90 patients under pergolide compared with 36 controls. The authors explained this by the lower dosage of pergolide (2.93 ± 0.75 mg/day for 51 ± 20 months) in their study population. A recent and larger study by Yamashiro et al.8 could not reveal an increased number of valvular regurgitation in 192 patients treated with pergolide 1.2 ± 0.7 mg for 53 ± 32 months compared with 79 controls. In fact, these studies confirm the dose-dependent relationship of pergolide for the development of VHD and also give more evidence that low-dose pergolide (<5 mg) treatment reduces the risk of VHD. Similar findings were obtained with a lower dose of cabergoline where no significantly increased risk of clinically relevant cardiac valve disorders were found in 102 subjects treated with long-term therapy at the doses used in endocrine practice (with a cumulative dose of 18–1718 mg). However, the tenting area was significantly higher in the cabergoline group and an association with subclinical changes in mitral valve geometry could not be completely excluded. 9 In this issue of the EJECHO , Worthington et al. present a case of a 49-year-old woman with restless leg syndrome who developed severe restrictive mitral and aortic regurgitation requiring double valve replacement. Clinical and pathological examination identified pergolide as the most likely cause. Remarkably, she only received 0.625 g/day for 5 years. To the best of our knowledge, this is the lowest dose of pergolide reported that has been associated with severe VHD. This case-report illustrates that a safe cut-off dose of pergolide probably does not exist, and even at very low dosages of pergolide one must be watchful. Interindividual differences in susceptibility for the toxic valvular effects of drugs may exist. The results of published studies of pergolide showed that over two-thirds of patients do not develop valvulopathy, despite several years' exposure, suggesting that susceptibility is a key factor. Subgroups of patients may be at a higher risk of VHD. 10 The recommendations by the ACC/AHA for patients who have used anorectic drugs, published in 1998, cannot be applied to current pergolide use. At this moment, no guidelines have been issued by the ESC or ACC/AHA regarding the cardiac management and attitude towards the use of ‘valvulopathic’ drugs. This is mainly due to the retrospective or cross-sectional nature of the studies available, as prospective clinical trials are difficult to be conducted because of evident ethical considerations. Small animal models of drug-induced VHD may overcome this problem, where questions such as dose-dependency, reversibility and also therapeutical strategies can be prospectively examined in a controlled environment. 11 In 2005 Corvol et al.12 published a revised version of the French agency for drug security (AFSSAPS), proposing a practical recommendation for pergolide use. In agreement with the latter, we also advise that patients requiring pergolide should be informed of the potential risk and carefully evaluated before and during their treatment and screened with serial echocardiography. In that way, drug-induced VHD can be diagnosed more easily and earlier even when the drug dose is low.