Risks of Cardiac Valve Regurgitation and Heart Failure Associated with Ergot- and Non-Ergot-Derived Dopamine Agonist Use in Patients with Parkinson's Disease: A Systematic Review of Observational Studies

Background Dopamine agonists (DAs) are commonly used in the therapy of Parkinson's disease (PD). However, several observational studies have suggested a putative association between DAs and specific cardiac adverse events. Objectives The aim of this study was to systematically review and summarize the available epidemiologic evidence on the association between use of ergot- and non-ergot-derived DAs and the risk of valvular heart disease, specifically cardiac valve regurgitation (CVR) and heart failure (HF) in patients with PD. Methods The databases MEDLINE/PubMed and EMBASE were searched for all relevant articles published before February 2015. Studies were eligible if they met the following inclusion criteria: exposure to any approved non-ergot- or ergot-derived DA, presentation of original data, inclusion of an unexposed reference group, and valvular heart disease or heart failure as the primary outcome of interest. Results Thirteen publications for CVR were identified (two nested case-control, one cohort and ten cross-sectional studies). Compared with non-ergot DAs or other anti-parkinsonian drugs, exposure to ergot-derived DAs pergolide and cabergoline was associated with an increased risk of CVR among PD patients. Incidence rate ratios (IRR) in the nested case-control and cohort studies ranged from 2.00 to 7.10 and 4.58 to 4.90, respectively. Longer treatment duration and higher dose of those DAs was also associated with a higher risk of CVR. Risk of HF was estimated in three nested case-control studies and one cohort study. Use of cabergoline (IRR range 1.30-2.39) and the non-ergot-derived DA pramipexole (IRR range 1.40-1.81) was associated with a higher HF risk among patients with PD. Pergolide may also be associated with a higher risk of HF. Conclusion Despite the heterogeneous methodological approaches of the included studies, there is strong evidence that treatment with pergolide and cabergoline is associated with a higher risk of CVR, and moderate evidence that treatment with pramipexole and cabergoline is associated with a higher risk of HF in patients with Parkinson's disease.