Cardiac Valve Regurgitation with Pergolide Compared with Nonergot Agonists in Parkinson Disease

ORIGINAL CONTRIBUTION Cardiac Valve Regurgitation With Pergolide Compared With Nonergot Agonists in Parkinson Disease

Richard B. Dewey, Jr, MD; Sharon C. Reimold, MD; Padraig E. O’Suilleabhain, MD

Background: Although most studies have suggested an Main Outcome Measure: Valve scores (1 indicates increased risk of valvulopathy (primarily regurgitation) trace; 2, mild; 3, moderate; and 4, severe) for the per- with pergolide mesylate use, one study suggested that this golide group were compared with those for the noner- problem may also occur with use of the non–ergot- got agonist control group. derived dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride. Results: The mean±SD valve regurgitation scores in the matched pergolide group compared with the nonergot Objective: To determine if cardiac valve regurgitation group were as follows: aortic, 0.83±1.23 vs 0.19±0.53 occurs more commonly in patients with Parkinson dis- (P=.01); mitral, 1.42±1.0 vs 0.39±0.65 (PϽ.001); and ease (PD) treated with pergolide than in those treated with tricuspid, 1.43±1.0 vs 0.19±0.53 (PϽ.001). Lifetime ex- nonergot agonists at a comparable dose. posure to a dopamine agonist was not statistically dif- ferent between the pergolide and nonergot agonist groups Design: A case-control study of echocardiographic find- (P=.18). ings of valve function in patients receiving dopamine agonists for PD. Conclusions: These data strengthen the conclusion that pergolide contributes to cardiac valve regurgita- Setting: University-based referral center. tion when used in the long term as a treatment for PD. There appears to be low risk of cardiac valve regurgita- Patients: Thirty-six patients with idiopathic PD taking tion when using non–ergot-derived dopamine ago- pergolide were compared with a matched control group nists. of patients taking nonergot agonists with regard to the frequency and severity of cardiac valve regurgitation. Arch Neurol. 2007;64:377-380

OLLOWING THE ORIGINAL common in pergolide-treated patients with description of pergolide- Parkinson disease (PD) than in the aged- associated valvular heart matched general population.4 Since our disease by Pritchett et al1 in study lacked a control group of patients 2002, several studies of this with PD who were not treated with per- phenomenon have been reported as sum- golide, it remained possible that the ob- F 2 marized in a recent review article. Al- served difference in valvular heart disease though most studies have suggested an in- was due to some factor inherent to PD creased risk of valvulopathy (primarily rather than to pergolide exposure. The present study was designed to address CME course available at this limitation by prospectively collecting a conceptually ideal control group for com- www.archneurol.com parison with the previously described pergolide-treated cohort. Our hypothesis was regurgitation) with pergolide mesylate use, that if pergolide itself was the cause of per- Author Affiliations: one study suggested that this problem may golide-associated valvular heart disease, Department of Neurology also occur with use of the non–ergot-de- (Drs Dewey and O’Suilleabhain) then the frequency of valvular regurgita- and Division of Cardiology rived dopamine agonists pramipexole di- tion in pergolide-treated patients would ex- (Dr Reimold), University of hydrochloride and ropinirole hydrochlo- ceed that in patients with PD of a similar 3 Texas Southwestern Medical ride. In our previous study, we showed that age who were treated with non–ergot- Center at Dallas. valvular regurgitation was 2 to 3 times more derived dopamine agonists.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table. Clinical Characteristics, Agonist Dose, and Valve Scores of the Pergolide-Treated Cohort and the Matched Nonergot Agonist–Treated Controls

Pergolide Group Nonergot Agonist Controls

Valve Score Valve Score

Age, y Dose, mg/d Aortic Mitral TricuspidAge, y Agonist* Dose, mg/d Aortic Mitral Tricuspid 77 3.0 2 2 2 79 Pramipexole 5.0 1 0 0 74 1.0 0 0 2.5 76 Pramipexole 0.125 0 0 0 68 3.0 3 2 2 69 Pramipexole 2.25 0 0 0 46 6.0 0 1 0 46 Ropinirole 24.0 0 0 1 65 6.0 1 2 1 66 Pramipexole 4.5 0 0 0 76 0.375 2 0 2 76 Ropinirole 9.0 0 1 0 56 4.0 0 2 2 55 Ropinirole 12.0 0 0 0 68 1.5 0 2 1 69 Pramipexole 3.0 0 0 0 63 3.0 0 1 0 64 Pramipexole 3.0 0 0 0 85 2.0 1 0 1 76 Ropinirole 9.0 0 0 0 64 1.5 0 1 0 63 Ropinirole 15.0 2 0 0 67 3.0 2 0 1 71 Pramipexole 1.5 0 0 0 72 4.0 0 2.5 2.5 73 Pramipexole 3.0 0 1 1 83 2.0 2 2 2 84 Ropinirole 12.0 1 0 0 71 4.5 0 0 2.5 72 Ropinirole 15.0 0 2 2 76 3.0 2 2 2 76 Ropinirole 9.0 0 1 0 72 3.0 0 1.5 1.5 73 Pramipexole 4.5 0 0 0 56 0.75 2 2.5 1.5 56 Pramipexole 6.0 0 0 0 53 2.0 0 1 1 54 Ropinirole 12.0 0 0 0 62 3.0 3 2 2 63 Pramipexole 4.0 0 0 0 69 4.5 1 3 3 71 Pramipexole 0.5 0 0 0 61 4.5 4 3 1 62 Ropinirole 20.0 0 1 0 43 4.0 0 0 1 48 Ropinirole 10.0 0 0 0 65 3.0 0 3 3 64 Pramipexole 3.0 0 2 0 78 6.0 0 2 3 76 Ropinirole 18.0 2 0 0 63 0.375 0 1 0 64 Ropinirole 12.0 0 0 0 50 3.0 4 3 3 52 Pramipexole 1.5 0 1 0 76 3.0 0 1 0 76 Ropinirole 24.0 0 1 0 68 3.0 0 2 2 68 Ropinirole 20.0 0 0 0 66 3.0 0 1 1 68 Pramipexole 4.5 0 1 0 70† 0.4 0 0 0 82† Pramipexole 1.5 0 1 0 58 4.5 0 2 0 61 Pramipexole 4.0 0 0 1 73 1.5 0 0 0 74 Pramipexole 2.25 0 0 0 80 3.0 0 2 3 83 Pramipexole 4.5 1 2 2 57 2.5 0 0 1 56 Pramipexole 9.0 0 0 0 54 5.0 1 1.5 1 55 Pramipexole 3.0 0 0 0

*Pramipexole was given as pramipexole dihydrochloride, ropinirole as ropinirole hydrochloride. †These patients had restless legs syndrome, not Parkinson disease.

METHODS selected as controls if they had a significant history of exposure to pergolide. All 36 control echocardiograms were read by the same cardiologist (S.C.R.), who was blinded to patient We searched our clinical documentation system for patients identity and agonist treatment. Cardiac valve regurgitation with PD who had been treated by 1 of us and who were taking was rated semiquantitively after the method described in the a nonergot dopamine agonist (pramipexole or ropinirole); Framingham Heart Study6 and expressed numerically accord- these 336 patients were listed by age, sex, and dose of dopa- ing to the following method: 1 indicates trace; 2, mild; 3, mine agonist. For each of our original pergolide-treated patients, 2 to 3 patients identified by this search who were of moderate; and 4, severe. Valvular regurgitation in the original similar age and agonist dose and of the same sex were listed as pergolide cohort was rated using the same scale, and half of potential controls. It was important to control for age because these 46 patients had echocardiography performed and the valvular regurgitation increases with age,5 and agonist dose results read at another institution. For some such patients, was controlled because we found a dose-response relationship echocardiographic reports indicated an intermediate degree of between lifetime pergolide exposure and risk of regurgitation valve regurgitation (such as mild to moderate), in which case in our original study.4 Our research nursing staff then an intermediate score (such as 2.5) was assigned. attempted to contact potential control patients by telephone Valve scores of the matched control patients were com- and, after several months of this effort, 36 patients (matching pared with those of the pergolide cohort using the Wilcoxon 36 patients from the original pergolide cohort of 46 patients) signed rank test. Since 10 of the original pergolide cohort mem- were identified who agreed to undergo a transthoracic echo- bers could not be matched to controls, we compared valve scores cardiogram with attention to valve function. Patients were not of this group with those of the 36 pergolide-treated patients

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15 000 1.75

1.50 12 500

1.25 10 000

1.00 7500

Valve Score Valve 0.75

Lifetime Dose in Pergolide Equivalents 5000 0.50

2500 0.25

0 0 Aortic Mitral Tricuspid Pulmonic Lifetime Lifetime (P = .01) (P <.001) (P <.001) (P = .11) Pergolide Dose Nonergot Dose

Figure 1. Valve scores of the pergolide-mesylate–treated patients with Figure 2. Lifetime dose of agonist used in the pergolide-mesylate–treated matched controls (n=36) compared with the nonergot agonist–treated patients (for whom matched controls existed) compared with the nonergot control group (n=36). Error bars represent SEM. agonist–treated control patients (paired t test; P=.18). Nonergot agonist dose is expressed in pergolide equivalents (1 mg of pergolide mesylate=1 mg of pramipexole dihydrochloride=4 mg of ropinirole hydrochloride). who were successfully matched to controls using the Mann- Whitney U test to determine if these groups were substantially similar. To determine if nonergot agonist–treated control pa- monic regurgitation. The mean±SD lifetime agonist dose tients were exposed to a similar dose of agonist as the per- comparing the pergolide cohort with the nonergot co- golide cohort, we first converted the nonergot agonist dose to hort expressed in pergolide equivalents was similar pergolide equivalents using the following formula, as sug- (5307±3880 vs 4356±3342; P =.18), as shown in 7 gested by Grosset et al : 1 mg of pramipexole dihydrochlo- Figure 2. Although 20 of the nonergot agonist–treated ride=1 mg of pergolide mesylate=4 mg of ropinirole hydro- patients had nonzero scores for 1 or more valves (56%), chloride. Lifetime agonist dose in the nonergot agonist cohort was compared with the lifetime agonist dose in the pergolide in no case were these abnormalities symptomatic. No pa- cohort using the paired t test. All control patients who partici- tients taking nonergot agonists had worse than mild re- pated in this study provided written informed consent before gurgitation in any valve, whereas regurgitation of this se- undergoing echocardiography, and the study was approved by verity was seen in at least 1 valve in 11 pergolide-treated the University of Texas Southwestern institutional review board. patients.

RESULTS COMMENT

The 36 control patients (25 men and 11 women) taking This study strengthens the conclusion we drew from nonergot agonists are compared with the pergolide co- our earlier work that pergolide most likely injures car- hort in the Table. All but 1 pair of patients had PD, and diac valves in patients with PD who take this drug in the age matching was reasonably successful. Valve scores the long term. Our present data suggest that pergolide are shown in Figure 1 for the aortic, mitral, and tricus- itself is the most likely offending agent (rather than pid valves. No significant difference was found between some other unknown factor associated with PD) and the mean±SD valve scores in the matched (n=36) and un- that nonergot agonists are much less likely to cause matched (n=10) pergolide groups: aortic, 0.83±1.2 vs regurgitant valvulopathy. This conclusion is concordant 0.80±0.92 (P=.80); mitral, 1.42±1.0 vs 0.90±0.88 (P=.17); with the recent publication of Peralta et al.8 This induc- and tricuspid, 1.43±1.0 vs 1.3±0.82 (P=.74). By con- tion of valve regurgitation is plausibly related to the trast, the mean±SD valve scores of the matched per- stimulation of serotonin receptors by pergolide,9 a fea- golide group differed significantly from those of the non- ture it shares with fenfluramine hydrochloride,10 a drug ergot agonist control group: aortic, 0.83±1.23 vs 0.19±0.53 associated with valvulopathy.11 Although we have shown (P=.01); mitral, 1.42±1.0 vs 0.39±0.65 (PϽ.001); and tri- that pergolide is associated with more valve regurgita- cuspid, 1.43±1.0 vs 0.19±0.53 (PϽ.001). tion than the nonergot dopamine agonists, most of our No statistically significant difference was found be- affected pergolide-treated patients had mild regurgita- tween the pergolide and nonergot agonist groups for pul- tion, which was asymptomatic. Whether continued treat-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ment with pergolide would have produced clinically im- Statistical analysis: O’Suilleabhain. Obtained funding: portant valvulopathy in these individuals is unknown. Dewey. Administrative, technical, and material support: The strength of our study is the matching of noner- Dewey and Reimold. Study supervision: Dewey. got agonist–treated patients with those in the pergolide Financial Disclosure: None reported. cohort by age, sex, diagnosis, and lifetime dose of ago- Funding/Support: This study was supported in part by nist. This matching reduces the likelihood that some un- the Jean Walter Center for Research in Movement Dis- known factor is the underlying cause of valvular regur- orders at the University of Texas Southwestern Medical gitation seen in pergolide-treated patients. Our study has Center. 1 important limitation in that echocardiography of half Acknowledgment: We thank Daniel G. Baseman, BS, for of the pergolide cohort was performed and the results his assistance with identification of potential control pa- read at other institutions, and despite significant efforts tients and Carmen Sandlin for her coordination of the to obtain these outside studies for our own internal re- study, consenting of patients, and randomization of echo- view, we were unsuccessful in obtaining a sufficient num- cardiograms. ber of them to address this limitation. Nevertheless, since the valve scoring method we used is that typically used REFERENCES by most echocardiographers in the routine use of this test clinically, we doubt that this limitation significantly af- 1. Pritchett AM, Morrison JF, Edwards WD, Schaff HV, Connolly HM, Espinosa RE. fected the results. Valvular heart disease in patients taking pergolide. 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