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Risk of Cardiac Valve Regurgitation with Dopamine Agonist use in Parkinson’s Disease and Hyperprolactinaemia

A Multi-Country, Nested Case-Control Study

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Abstract

Background: There is growing evidence that ergot dopamine agonists may induce cardiac valve regurgitation (CVR) in persons with Parkinson’s disease. It is unclear whether the CVR risk is increased with ergot-dopamine agonist use in persons with hyperprolactinaemia, in whom the dose is much lower.

Objective: The aim of the study was to explore the association between different dopamine agonists and CVR in patients with Parkinson’s disease or hyperprolactinaemia.

Design: Nested case-control studies conducted separately in cohorts of Parkinson’s disease and hyperprolactinaemia patients. Cases were patients who developed newly diagnosed CVR. Controls were CVR-free patients from the same cohorts and were matched to cases by age, sex, database and calendar year.

Setting and Patients: Study patients were identified from over 4.5 million persons in The Health Improvement Network (THIN; UK), Health Search (Italy), and Integrated Primary Care Information (IPCI; the Netherlands) general practice databases in the years 1996–2007. The Parkinson’s disease cohort included new users of dopamine agonists or levodopa, while the hyperprolactinaemia cohort included new users or non-users of dopamine agonists.

Main Outcome Measure: Risk of newly diagnosed CVR with dopamine agonist use compared with levodopa use in the Parkinson’s disease cohort, and dopamine agonist-naïve patients in the hyperprolactinaemia cohort.

Results: In the Parkinson’s disease cohort (7893 dopamine agonist users, 11 766 levodopa users), 85 incident CVR cases were identified. Increased CVR risk was observed for ergot dopamine agonists (adjusted OR [ORadj] 3.82; 95% CI 2.14, 6.81), but not for non-ergot dopamine agonists (ORadj 1.20; 95% CI 0.63, 2.29).

In the hyperprolactinaemia cohort (6740 dopamine agonist users and 14299 dopamine agonist-naïve patients), 37 CVR cases were identified during a mean follow-up of 4.5 years and 3.5 years for new users and non-users of dopamine agonists, respectively. However, no association with ever use of ergot dopamine agonists was observed (ORadj 0.47; 95% CI 0.20,1.19).

Conclusion: Ergot-derived dopamine agonists are associated with an increased risk of CVR in Parkinson’s disease but not in hyperprolactinaemia patients.

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Acknowledgements

C. de Luise and D. Ross are employees of Pfizer and own Pfizer stock. As an employee of Erasmus MC and project leader of the IPCI database, M.C.J.M. Sturkenboom has been involved in studies that were contracted by various pharmaceutical companies. Research grants have been received from Pfizer, Merck, Johnson & Johnson, Amgen, Roche, GlaxoSmithKline, Boehringer, Yamanouchi and Altana. M.C.J.M. Sturkenboom has been a consultant to Pfizer on issues not related to this paper. G. van Camp received preliminary funds for the study “Effect of chronic administration of candidate 5HT2b agonist/antagonist on the cardiac valves in an in vivo rat model: evaluation with echocardiography and pathology”, which was then subsequently cancelled by Pfizer. G. van Camp has also been a consultant for AstraZeneca and Pfizer, has received honoraria from AstraZeneca, Pfizer, GE, Philips, Boston Scientific and Biotronic, and has received research grants from AstraZeneca and Pfizer. A. Colao received grants from Pfizer for research projects in neuroendocrinology. Ron Herings is an employee of the PHARMO Institute. This research institute performs financially supported studies for several pharmaceutical companies, including Pfizer. R. Schade has been a consultant to Axxonis Pharma AG and has received grants from Schering AG. J. Dieleman has been involved in studies conducted with grants from Pfizer, Boehringer, Lilly and AstraZeneca. G. Trifirò, E. van Soest, K. Verhamme, G. Mazzaglia, E. Brusselle, W. Haverkamp, R. Zanettini and M. Mokhles have no conflicts of interest to declare.

G. Brusselle, A. Colao, W. Haverkamp, R. Schade, G. van Camp, and R. Zanettini were all members of the Scientific Advisory Board of the project resulting in this paper. G. Trifirò had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; G. Trifirò, M. Sturkenboom, K. Verhamme and C. de Luise played a major role in the study concept and design; analysis and interpretation of data, as well as drafting of the manuscript, was mainly performed by G. Trifirò, M. Sturkenboom, M. Mokhles, J. Dieleman, E. van Soest and G. Mazzaglia; all the authors carried out a critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.

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Authors and Affiliations

  1. Department of Medical Informatics, Erasmus University Medical Center, Dr Molewaterplein 50, PO Box 1738, 3000 DR, Rotterdam, the Netherlands

    Gianluca Trifirò, M. Mostafa Mokhles, Jeanne P. Dieleman, Eva M. van Soest, Katia Verhamme, Rene chade & Miriam C. Sturkenboom

  2. IRCCS Centro Neurolesi ‘Bonino-Pulejo’, Messina, Italy

    Gianluca Trifirò

  3. Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy

    Gianluca Trifirò

  4. Italian College of General Practitioners, Florence, Italy

    Giampiero Mazzaglia

  5. PHARMO Institute, Utrecht, the Netherlands

    Ron Herings

  6. Department of Epidemiology, Pfizer, Inc., New York, NY, USA

    Cynthia de Luise

  7. Established Products Business Unit, Pfizer, Inc., New York, NY, USA

    Douglas Ross

  8. Department of Respiratory Medicine, University of Ghent, Ghent, Belgium

    Guy Brusselle

  9. Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy

    Annamaria Colao

  10. Medizinische Klinik m. S. Kardiologie Campus Virchow-Klinikum Charitém, Universitätsmedizin Berlin, Berlin, Germany

    Wilhelm Haverkamp

  11. Department of Cardiology, UZ Brussel, Brussels, Belgium

    Guy van Camp

  12. Cardiac Rehabilitation Unit, Istituti Clinici di Perfezionamento, Milan, Italy

    Renzo Zanettini

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  1. Gianluca Trifirò
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  9. Douglas Ross
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  14. Guy van Camp
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Correspondence to Gianluca Trifirò.

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Trifirò, G., Mokhles, M.M., Dieleman, J.P. et al. Risk of Cardiac Valve Regurgitation with Dopamine Agonist use in Parkinson’s Disease and Hyperprolactinaemia. Drug Saf 35, 159–171 (2012). https://doi.org/10.2165/11594940-000000000-00000

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  • DOI: https://doi.org/10.2165/11594940-000000000-00000

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