Cabergoline, pergolide linked to cardiac-valve regurgitation

Concern over possible valvulopathy with the use of certain ergot-derived dopamine agonists is further supported by 2 studies published in The New England Journal of Medicine (NEJM) regarding the incidence of cardiac-valve regurgitation in patients taking these types of drugs, which are FDA-approved to treat Parkinson disease and hyperprolactinemia and sometimes used off-label to treat restless legs syndrome.

For their nested case-control analysis, René Schade, MD, et al used data gathered from the United Kingdom General Practice Research Database, an extensive collection of computerized medical records from select primary care practices. The cohort of 11,417 participants included all patients aged 40 to 80 years who had received ≥2 prescriptions for antiparkinsonian drugs between January 1988 and August 2005.

Of the 31 patients who had newly diagnosed cardiac-valve regurgitation, 6 were taking pergolide, 6 were taking cabergoline, and 19 had no current or recent exposure to a dopamine agonist. Each patient was matched with up to 25 control subjects (n=663).

The authors observed an even greater risk of cardiac-valve regurgitation with higher dosages of and increased exposure to pergolide and cabergoline. Adjusted incidence-rate ratios rose to 37.1 (95% CI, 5.1–270.6) for patients taking >3 mg pergolide daily and 50.3 (95% CI, 6.6–381.4) for patients taking >3 mg cabergoline daily; adjusted incidence-rate ratios among patients using the drugs for ≥6 months were 9.8 (95% CI, 2.9–33.1) for pergolide and 7.8 (95% CI, 2.2–27.4) for cabergoline.

The authors discussed evidence that demonstrated that preferential activation of the 5-hydroxytryptamine 2B (5-HT_2B) receptor expressed on heart valves can lead to prolonged mitogenic effects in cardiac fibromyoblasts; this can induce valvular fibroplasia. Both pergolide and cabergoline are potent agonists of the 5-HT_2B receptor.

A study by Renzo Zanettini, MD, et al in the same issue of NEJM echoed these findings. Using echocardiography, the authors observed that cardiac-valve regurgitation in any valve was 23% more likely in pergolide-treated patients (P=.001) and 29% more likely in cabergoline-treated patients( P<.001) than in control patients (6%); there was no increased risk among patients taking non-ergot-derived dopamine agonists.

The study included 155 patients taking dopamine agonists for Parkinson disease; case patients were matched with 90 controls. The convenience sample was subdivided into 3 groups based on drug exposure (pergolide [n=64], cabergoline [n=49], and non-ergot-derived dopamine agonists [n=42]); all patients had been taking the drug for ≥12 months and had no exposure to other dopamine agonists.

The RR for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (95% CI, 1.4–28.3; P=.008), 4.2 for aortic regurgitation (95% CI, 1.2–15.0; P=.01), and 5.6 for tricuspid regurgitation (95% CI, 0.7–49.7; P=.16); corresponding RRs in the cabergoline group were 4.6 (95% CI, 0.9–22.8; P=.09), 7.3 (95% CI, 2.2–24.8; P<.001), and 5.5 (95% CI, 0.6–51.6; P=.12), respectively. Greater cumulative dosages of both pergolide and cabergoline were observed to yield more severe regurgitation.

The authors also measured mitral-valve tenting to assess leaflet stiffening and apical displacement of mitral leaflet coaptation. Localized or diffuse leaflet thickening was observed in 17 of the pergolide-treated and 8 of the cabergoline-treated patients. No cases were observed in the non-ergot or control groups. Patients in all 3 treatment groups exhibited significantly higher mitral tenting areas than patients in the control group.

The authors said their findings support the hypothesis of ergot-related fibrosis involving valve leaflets and subvalvular apparatus but they stopped short of justifying a moratorium: "Although the observation that this [valvular fibrosis] process occurs with both pergolide and cabergoline suggests a class effect, studies of the activity of serotonin-receptor-subtype 5-HT_2B agonists suggest that some other agents in this class, such as lisuride and terguride, may not have similar consequences."

In an accompanying editorial, Bryan L. Roth, MD, PhD, said these and similar findings support the need for action: "Clearly, practitioners should avoid prescribing drugs that are potent 5-HT_2B receptor agonists." Dr Roth said he and his colleagues have urged pharmaceutical companies and regulatory agencies to use extreme caution before launching clinical trials involving 5-HT_2B receptor-related drugs, noting their concerns are, in part, to avoid another "fen-phen"-type situation, as ergot-derived dopamine receptor agonists were components of the now-banned diet drug combination.

SOURCES Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007;356:29–38.

Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med. 2007;356:39–46.

Roth BL. Drugs and valvular heart disease [editorial]. N Engl J Med. 2007;356:6–9.