European Journal of Endocrinology (2008) 159 R11–R14 ISSN 0804-4643

RAPID COMMUNICATION Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease Ammar Wakil, Alan S Rigby1, Andrew L Clark2, Anna Kallvikbacka-Bennett2 and Stephen L Atkin3 Michael White Diabetes Centre, Hull Royal Infirmary, Brocklehurst Building, 220-236 Anlaby Road, Hull HU3 2RW, UK, 1Department of Academic Cardiology, University of Hull, Hull, UK, 2Castle Hill Hospital, Castle Road, Cottingham, UK and 3Department of Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull, UK (Correspondence should be addressed to A Wakil; Email: [email protected])

Abstract Objective: Recent trials suggest that using ergot-derived dopamine agonists such as cabergoline in the treatment of Parkinson’s disease is associated with an increased risk of valvular heart disease. However, the dose of cabergoline used to treat hyperprolactinaemia is considerably less than that used in Parkinson’s disease. Design and methods: A cross-sectionalcomparative assessment. Forty-four patients treated with cabergoline for hyperprolactinaemia underwent transthoracic echocardiography and were compared with 566 sequential subjects complaining of palpitations, taken from a contemporary echocardiography database. Results: The mean cumulative dose of cabergoline in the cases was 311 mg. There was no significant, severe or moderate, right- or left-sided valvular regurgitation in either group. Left heart: in the mitral and aortic valves, the rate of mild and trivial valvular regurgitation was not different between the two groups. Right heart: mild tricuspid and pulmonary regurgitation on colour Doppler alone was increased significantly in the cabergoline group, odds ratios of 3.1 and 7.8 respectively (95% confidence interval 1.0–9.6 and 0.8–78.4, PZ0.04 and P!0.0001 respectively). Conclusion: Cabergoline at doses sufficient to suppress hyperprolactinaemia for a period of 3–4 years is not associated with an increased risk of clinically significant valvular regurgitation.

European Journal of Endocrinology 159 R11–R14

Introduction treated for at least 6 months were identified and agreed to participate. None had the exclusion criteria of Cabergoline, a D2-specific ergot-derived dopamine co-secretion of growth hormone, known cardiac agonist, is indicated for the treatment of Parkinson’s disease, including rheumatic heart disease, myocardial disease and hyperprolactinaemia (1, 2). Recent reports infarction within 6 months, diabetes, connective tissue have highlighted a high risk of clinically significant disease, Parkinson’s disease, carcinoid syndrome and valvular heart disease in patients with Parkinson’s the use of homeopathic medication, anorectic or other disease treated with ergot-derived dopamine agonists ergot-derived therapy. No subject was taking antihy- including cabergoline at a dose of more than 3 mg daily, pertensive or lipid-lowering medication. All subjects whilst the dose used to treat hyperprolactinaemia is underwent transthoracic echocardiography between often between 0.5 and 1 mg twice weekly (1–3). May and September 2007. The comparison group was However, it is unknown whether patients with hyper- selected from a contemporary echocardiographic data- prolactinaemia treated with smaller doses of cabergoline base. They were consecutive control subjects presenting are also at risk of clinically significant valvular with a complaint of palpitations with no other known regurgitation. The mechanism underlying the valvular underlying cardiac diagnosis or other past medical defect has been suggested to be due to ergot-derived history. None of the control had the above exclusion dopamine agonist initiation of abnormal fibrogenesis criteria. Controls were included in this analysis only if through activation of serotonin receptors 5-HT , that 2B the heart was morphologically normal and had normal are abundant in the fibroblasts of heart valves (4). left ventricular systolic function. Ethical permission was given by Hull and East Riding Local Research Ethics Committee (LREC). Subjects and methods Routine echocardiographic assessment was per- formed on all patients including M-mode, 2D images Forty-four subjects prescribed cabergoline for isolated and colour flow Doppler recordings using a ‘Vivid 5’ (GE excess prolactin secretion of any cause that had been Healthcare, Chalfont St. Giles, UK) system operating at

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3.4 MHz. Measurements were taken in accordance with Table 1 Patients’ characteristics. American Echocardiography Society/European Associ- ation of Echocardiography guidelines (5, 6).All Control Cabergoline echocardiography was carried out by one non-blinded Total number 566 44 trained operator who was blind to the reason for the Female/male (%) 383/566 (67.6) 32/44 (72.7) scan other than for a query of valvular regurgitation Mean age, yearsGS.D. 36.3G8.7 41.8G13.2 and the patients were part of the normal procedure list Microprolactinoma (%) – 20 (45.4) as for the control population. Echocardiograms were Macroprolactinoma (%) – 10 (22.7) Hyperprolactinaemia (%) – 10 (22.7) reread by an expert in the field (ALC). The duration and Stalk syndrome (%) – 3 (6.9) total cumulative dose of cabergoline were calculated Others (%) – 1 (2.3) from a retrospective analysis of clinical records. Mean duration of cabergoline – 44.8 (33) dose in months (median) Weekly dose range of – 0.25–4 Statistical analysis cabergoline in mg Mean cumulative dose of – 311 (86) The cases and controls were analysed by calculating cabergoline in mg (median) odds ratios (ORs) with 95% confidence intervals (CIs). The OR is an approximation to the relative risk (7). The c2-test was used to compare group differences on two degrees of freedom. An arbitrary level of 5% statistical or moderate, valvular regurgitation in any of the four significance (two-tailed) was assumed. cardiac valves in either group. Furthermore, none of One of the statistical issues that needed to be the patients on cabergoline had abnormal heart addressed was that of multiple testing when there are morphology on echocardiography. multiple variables to be tested and the possible inflation of a Type I error. There is no consensus among Left heart echocardiography statisticians on what procedure to adopt to allow for multiple comparisons (8, 9). The Bonferroni correction In the left heart, i.e. mitral and aortic valves, the rate of (whereby the threshold for significance is simply mild and trivial regurgitation was not different between reduced by the number of comparisons made) is the two groups. In the cabergoline group, mild mitral known to be too conservative (10); therefore, we have regurgitation OR was 0.4 (95% CI 0.04–2.6, PZ0.5) followed the recommendations of Perneger (9) and not while mild aortic regurgitation OR was 1.7 (95% CI adjusted for this. 0.2–13.7, PZ0.2) as depicted in Table 2.

Right heart echocardiography Results In the right heart, the ORs of mild tricuspid regurgita- Table 1 depicts the patients’ characteristics. Forty-four tion detectable on colour Doppler alone was 3.1 in the patients had at least 6 months treatment with caber- cabergoline group (95% CI 1–9.6, PZ0.04) while goline. All patients had been initiated and maintained that for mild pulmonary regurgitation was 7.8 (95% on cabergoline alone. There were no significant, severe CI 0.8–78.4, P!0.0001), as depicted in Table 2.

Table 2 Colour Doppler echocardiography findings.

Valve findings Control number; NZ566 Cabergoline number; NZ44 Odds ratios (95% CI) P value

Tricuspid None 237 10 1 Trivial regurgitation 291 29 2.4 (1.1–5.0) Mild regurgitation 38 5 3.1 (1.0–9.6) 0.04 Pulmonary None 517 22 1 Trivial regurgitation 46 21 10.7 (5.5–21) Mild regurgitation 3 1 7.8 (0.8–78.4) !0.0001 Mitral None 255 20 1 Trivial regurgitation 273 23 1.1 (0.6–2.0) Mild regurgitation 38 1 0.4 (0.04–2.6) 0.5 Aortic None 550 41 1 Trivial regurgitation 8 2 3.4 (0.7–16.3) Mild regurgitation 8 1 1.7 (0.2–13.7) 0.2

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Discussion mean duration of treatment with dopamine agonists of 96 months was significantly associated with clinically We found that in patients taking low dose cabergoline insignificant (mild) aortic and tricuspid regurgitation, for prolactin excess, there was no increased valvular but not with clinically significant (moderate and severe) regurgitation, of any grade, in the left heart. In the right regurgitation (17). However, in the prolactinoma group, heart, there was an increased risk of (clinically there was no significant difference in the rate of valvular insignificant) mild grade tricuspid and pulmonary regurgitation between those treated with cabergoline, valves regurgitation in the cabergoline group. mean duration of 62 months, and those treated without The increase in right-sided regurgitation was cabergoline (17). The issue of changes in valvular probably due to the inherent under-reporting of trivial morphology with cabergoline has been described with and mild valvular regurgitation in the control group emphasis on tenting, thickening and more recently that was referred for palpitations, whilst those taking calcifications. The tenting area of the mitral valve was cabergoline were referred for a query of valvular reported to be significantly greater in the cabergoline regurgitation. A mild degree of pulmonary regurgita- group and, although this did not correlate with the dose tion is a normal variant since it is seen in the majority of of cabergoline, it correlated with the degree of valve adults using modern imaging platforms; in the same thickening in the cabergoline group (14). Others have way, that the tricuspid valve often exhibits mild degrees reported mixed results of the association between leaflet of valvular regurgitation (11). The prevalence of right thickening and cabergoline with one group reporting no heart valvular regurgitation, both at the pulmonary evidence of leaflet thickening in those with moderate and tricuspid areas, was 100% in 32 healthy subjects valvular regurgitation (16), while another reported a with structurally normal hearts using colour Doppler significant thickening in the tricuspid valves of patients echocardiography (12). The likelihood is that during a treated with cabergoline when compared with control standard echocardiographic examination, the operator (17). The latter group also reported a significantly may not report minor degrees of right-sided valvular higher rate of calcifications in the mitral and aortic regurgitation as these are ‘normal’. By contrast, valves of the cabergoline group compared with control, because the echocardiograms for the cabergoline though the calcifications did not reflect in a mild, group were performed specifically to detect any valvular moderate or severe valvular regurgitation in the regurgitation, any regurgitation at all was reported. corresponding valves. Even if we accept that rates of regurgitation in the In a study of 49 patients treated with cabergoline for tricuspid and pulmonary valves were significantly Parkinson’s disease, clinically significant mitral regur- different between the two groups, the number of gitation was seen in 5, aortic regurgitation in 12 patients patients was low (giving very wide confidence intervals and tricuspid regurgitation in 3 patients (18). The mean around the OR) and the regurgitation was clinically cumulative dose of cabergoline was 2820 mgover a mean insignificant in all subjects. We found no significant duration of 24 months compared with 311 mg over a difference between the cases and controls for mitral mean of 44 months in the present study. In Parkinsonian valve disease (Table 2). This is a function of power (13). patients, the correlation of cabergoline dose to the The prevalence of mild mitral disease in the controls was echocardiographic findings is unclear, with the adjusted 38/566 (6.7%) and in the cases was 1/44 (2.3%). We incidence rate ratios for cardiac valve regurgitation for had a power of !5% (5% significance, two-tailed) to cabergoline being reported to be particularly high at doses detect this difference (our calculations assumed a above 3 mg daily for 6 months or more (3),thoughothers control:case ratio of 13:1 and make an allowance for have not confirmed this (19). There is a correlation rounding errors). This means that a prospective study to between the tenting area of the affected valve and the show that this difference was statistically significant cumulative dose of dopamine agonists in patients with with adequate power (80%) would require five times the Parkinson’s disease (20). In our series, patients were sample size. screened routinelyand no patient had valvular thickening Previous reports in Parkinsonian patients have and the tenting area was not measured. suggested that the principal concern with cabergoline One of the limitations to this study is the selection bias use was left-sided valvular regurgitation, and we have that could have risen from including the sequential seen no such risk in our patients. Our findings support controls investigated for palpitations, as the observers three of the four published echocardiographic studies on were not blinded, and the indications for the echocardio- the association between cabergoline in endocrine grams were different between the two groups. This may disease and valvular lesions (14–16). We did not see have potentially caused an overestimation of positive any clinically significant moderate or severe valvular findings in the valves of the cabergoline group, as the regurgitation while others reported 1.9, 7 and 5.7% observer was directed to look for valvular lesions, and moderate valvular regurgitation in their cabergoline potentially an underestimate of valvular findings in the groups though each was not statistically significant in controls. However, applying the same exclusion criteria to comparison with their reference control groups (14– controls and patients would have addressed any con- 16). The fourth cross-sectional study observed that a founding effect of this bias in the result.

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