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

Richard Steeds; Craig Stiles; Vishal Sharma; John Chambers; Guy Lloyd; William Drake

Disclosures

Clin Endocrinol. 2019;90(5):662-669. 

In This Article

Current Evidence

Following publication of the adverse effects of DA agonists at high dose in PD, several groups published single institution, cross-sectional case-control studies investigating the link between chronic DA therapy at low dose in hyperprolactinaemia and the presence of valvular abnormalities (Table 1).[10–23] These were all limited by small size. Moreover, the control groups in each study contained only healthy individuals or those referred for other cardiac symptoms, eg palpitations, who were then found to have normal echocardiography, rather than untreated patients with hyperprolactinaemia. One study in 50 patients found an increase in the prevalence of moderate (27/50; 54%) but not of mild tricuspid regurgitation (TR) among those treated with cabergoline at a median dose 280 mg for a median duration of 72 months compared to controls (9/50; 18%).[11] The distinction between mild and moderate TR was made in this paper by the extent to which retrograde flow filled the atrium, which is a method known to be subject to error, and technical and haemodynamic variation. Furthermore, the difference in degree of TR was found in the absence of any changes to the thickness or restriction of the valve leaflets. In another study of 78 patients (mean cumulative dose 363 mg; mean treatment duration 60 months), mild tricuspid regurgitation was found more often (32/78, 41%) among those taking DA agonists than in controls (20/78, 26%), although there was no graded association with cumulative dose and there was no difference in 'clinically significant' valve disease.[12] Again, the difference in degree of TR was found in the absence of any changes to the thickness or restriction of the valve leaflets. The same study also suggested an increase in aortic calcification, which is difficult to understand from a pathophysiological perspective and has not been replicated elsewhere. Thereafter, two more similar-sized case-controlled studies suggested other morphological changes.[13,17] In 102 patients (mean cumulative cabergoline dose 204 mg; mean treatment duration 79 months),[13] there was an increase in mitral valve tenting area but no difference in leaflet thickness and no change in any other valves. In 103 patients (mean cumulative cabergoline dose 174 mg; mean treatment duration 46 months),[17] there was a new category of 'sub-clinical fibrosis', defined by increased leaflet echogenicity and/or increased cusp thickness (>3 mm mitral; >2 mm other valves) but with no difference in the degree of regurgitation. These data also contrast with the results of 10 similar sized, single institution case-control studies that found no link between DA use and significant restrictive valve defects or regurgitation.[10,14–16,18–23] Finally, a large multi-centre cross-sectional study based in the United Kingdom of 747 patients taking DA agonists (median cabergoline dose 152 mg) showed no association between cumulative doses of cabergoline or bromocriptine and the age-corrected prevalence of valvular abnormalities.[24] In summary, case-control studies investigating DA-agonist valvulopathy in hyperprolactinaemia have provided poor quality data, using different diagnostic criteria, multiple testing in small groups and lack of standardised assessment of valve morphology. There are isolated case reports of restrictive valve disease after cabergoline but these have either been in cases treated with high dose[8,25] or in patients with co-morbidity,[26] and in one case developing bowel obstruction after diagnosis of dopamine agonist valvulopathy without exclusion of co-existing neuroendocrine tumour.[27]

In addition to the cross-sectional, case-control studies, there have been three studies with serial follow-up (Table 2). The first, small, single-centre study examined 45 patients receiving cabergoline for prolactinoma (mean cabergoline dose 401 mg) with baseline and then repeat echocardiography at 2 years, and found neither valve stenosis nor development of valvular regurgitation.[28] 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.[5] 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.[29] 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.

Meta-analyses have been performed however, that suggest a small effect may be present, although again there are limitations to these statistical studies.[30,31] Firstly, the meta-analyses have all been influenced by data from one early single centre case-control study, in which 27/50 (54%) patients compared to 9/50 (18%) controls were reported as having moderate-severe TR[11] Interestingly, the same group subsequently reported a follow-up study in which there were no reported differences in the risk of TR between controls and cabergoline-treated patients. Secondly, although these meta-analyses indicated a possible increased risk of mild-moderate tricuspid regurgitation, they were not associated with the typical features of valve thickening and restriction, and no clinically significant valve lesions were identified. If, as is widely accepted, it is the interaction of cabergoline with 5HT2B receptors that mediates the abnormal valvular function then, by analogy with carcinoid heart disease, this should be accompanied by characteristic changes in valve morphology (leaflet thickening, restricted movement and calcification). A major barrier to progress in the field is the fact that long-term, detailed studies of the size sufficient to exclude an effect would be costly to perform and require considerable expertise to ensure consistent, reliable and quantitative echocardiographic assessment. It is important to note that in all studies performed, bromocriptine has not been implicated with any valvular abnormalities.

Alternative imaging modalities, for example cardiovascular magnetic resonance imaging, do not provide adequate spatial or temporal resolution to compete with echocardiography for detailed assessment of valve structure and function. Moreover, a prospective, placebo-controlled design amongst young women with hyperprolactinaemia and oligo-amenorrhea would be unethical; and any effects of cabergoline would be impossible to separate from those caused by/associated with restoration of physiological oestrogen secretion. The expectation that existing clinical networks could produce accurate, large volume data by applying current MHRA guidelines on surveillance by echocardiography also appears unlikely, since adherence to current recommendations is poor. In a service evaluation performed by NHS Highland (North), only 2/45 patients started on a DA agonist had echocardiography prior to starting therapy.[33]

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