Prospective, long-term study of the effect of cabergoline on valvular status in patients with prolactinoma and idiopathic hyperprolactinemia

Abstract

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range :121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology.

Echocardiography and monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia: A joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology

“…In a follow‐up of 192/747 patients from the original cross‐sectional study by Drake et al, with median duration of cabergoline therapy 34 (24‐42) months, no association was found between cumulative doses of cabergoline and clinically significant valvular abnormality . The third study followed 100 subjects for a median interval 62.5 (34.8‐77) months between echocardiography following a median total duration of cabergoline therapy for 124.5 months (median dose 277.8 mg) and found no significant alterations in valve structure or function . One of these studies had a median follow‐up of 10 years, although the potential expected duration of treatment with cabergoline can sometimes be longer.…”

Cabergoline for hyperprolactinemia: getting to the heart of it

“…The mean cumulative dose in the study by Vroonen L et al was 277.8 mg, interquartile range (IQR) 121.4-427.8 [18], similar to another recent prospective study in which cumulative dose was 232 mg, with IQR 91-551 mg [17], less than one tenth of the mean cumulative dose associated clinically significant valulopathy in men with Parkinson's [1]. The absence of a significant association with cumulative dose of cabergoline among the few hyperprolactinemic patients who developed valvular dysfunction [17,18], may be due to the fact that the sample size was too small to show this and/or that the cumulative dose was lower than the threshold dose required to see this association. Of note in the prospective study by Drake et al among 192 patients, even though a significant association of cumulative dose and valvular insufficiency was not found, four of the five patients who had interval progression to grade 3 (moderate) had received a cumulative dose of cabergoline higher than the mean, and in three of these cumulative dose was >1000 mg.…”

“…The cumulative dose reached after many years in patients treated with cabergoline for prolactin disorders does not nearly approach the critical threshold reported in the studies of Parkinson's patients, in which cumulative doses averaged >2 g (mean was 2820 mg with standard deviation (SD) of 2515 mg) in the group with trace or mild valvular regurgitation and >4 g (mean was 4015 mg with SD of 3208 mg) in those with clinically significant disease (moderate or severe regurgitation) [1]. The mean cumulative dose in the study by Vroonen L et al was 277.8 mg, interquartile range (IQR) 121.4-427.8 [18], similar to another recent prospective study in which cumulative dose was 232 mg, with IQR 91-551 mg [17], less than one tenth of the mean cumulative dose associated clinically significant valulopathy in men with Parkinson's [1]. The absence of a significant association with cumulative dose of cabergoline among the few hyperprolactinemic patients who developed valvular dysfunction [17,18], may be due to the fact that the sample size was too small to show this and/or that the cumulative dose was lower than the threshold dose required to see this association.…”

“…None reported clinically significant valvular heart disease [8][9][10][11][12][13][14][15] with the single exception in a cohort with a high rate of background hypertension [7] and for which the prospective follow up of this cohort receiving ongoing cabergoline therapy, failed to show progressive * Lisa B. Nachtigall lnachtigall@mgh.harvard.edu disease [16]. While the preliminary cross-sectional data were essentially negative, including mean cumulative doses in these studies that ranged from 146-443 mg [7][8][9][10][11][12][13][14][15], long term randomized prospective studies have recently become available [16][17][18] and the one by Vroonen et al in this issue is the longest in duration with a median interval between echocardiograms of 62.5 months and a median total duration of therapy with cabergoline of 124.5 months, and this study was unique, among the prospective studies, by virtue of the inclusion a control group of non cardiac patients at baseline [18]. The prospective randomized controlled study by Vroonen et al from CHU Liège in Belgium, reported in this issue of Endocrine, is reassuring in the lack of clinically relevant valvular heart disease seen in pituitary patients treated with typical doses of dopamine agonists [18] and confirms similar findings among patients with prolactin disorders prospectively evaluated [16,17] as well as a prior prospective study among patients treated for acromegaly [19].…”

“…While the preliminary cross-sectional data were essentially negative, including mean cumulative doses in these studies that ranged from 146-443 mg [7][8][9][10][11][12][13][14][15], long term randomized prospective studies have recently become available [16][17][18] and the one by Vroonen et al in this issue is the longest in duration with a median interval between echocardiograms of 62.5 months and a median total duration of therapy with cabergoline of 124.5 months, and this study was unique, among the prospective studies, by virtue of the inclusion a control group of non cardiac patients at baseline [18]. The prospective randomized controlled study by Vroonen et al from CHU Liège in Belgium, reported in this issue of Endocrine, is reassuring in the lack of clinically relevant valvular heart disease seen in pituitary patients treated with typical doses of dopamine agonists [18] and confirms similar findings among patients with prolactin disorders prospectively evaluated [16,17] as well as a prior prospective study among patients treated for acromegaly [19]. Given the bulk of data, including the many cross sectional studies and the newly reported perspective studies in patients with prolactin disorders treated with cabergoline, it is not unreasonable to consider baseline echocardiography in patients in whom chronic treatment with cabergoline is planned but to reserve mandating ongoing follow up echocardiography to those with the following: (1) baseline echocardiogram demonstrating significant abnormalities, (2) increased risk of valvular disease, (3) signs or symptoms of valvular disease, (4) high cumulative doses of cabergoline (those who receive higher doses and/or very long duration of therapy).…”