1. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease Renzo Zanettini, M.D.; Angelo Antonini, M.D.; Gemma Gatto, M.D.; Rosa Gentile, M.D.; Silvana Tesei, M.D.; and Gianni Pezzoli, M.D. Published in the New England Journal of Medicine January 4, 2007 Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease

2. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Background Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of Parkinson’s disease, have been associated with an increased risk of valvular heart disease.Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of Parkinson’s disease, have been associated with an increased risk of valvular heart disease. In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the occurrence of valvular heart disease.In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the occurrence of valvular heart disease. Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of Parkinson’s disease, have been associated with an increased risk of valvular heart disease.Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of Parkinson’s disease, have been associated with an increased risk of valvular heart disease. In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the occurrence of valvular heart disease.In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the occurrence of valvular heart disease. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

3. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Background Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned.Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned. The goal of the present study was to assess the prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects without Parkinson’s disease.The goal of the present study was to assess the prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects without Parkinson’s disease. Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned.Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned. The goal of the present study was to assess the prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects without Parkinson’s disease.The goal of the present study was to assess the prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects without Parkinson’s disease. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

4. Clinical Trial Results. org PergolideGroupn=64 Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Study Design CabergolineGroupn=49 ControlSubjectsn=90 245 patients total: 155 patients attending the out-patient service of the Parkinson Institute of the Instituti Clinici di Perfezionamento, Milan between January and June 2005, and taking only one type of dopamine agonist for Parkinson’s disease for at least 12 months and 90 control subjects without Parkinson’s disease recruited from among relatives of patients, acquaintances of medical staff, or referred to echocardiography laboratory for arterial hypertension or fitness evaluation Convenience Sample. 245 patients total: 155 patients attending the out-patient service of the Parkinson Institute of the Instituti Clinici di Perfezionamento, Milan between January and June 2005, and taking only one type of dopamine agonist for Parkinson’s disease for at least 12 months and 90 control subjects without Parkinson’s disease recruited from among relatives of patients, acquaintances of medical staff, or referred to echocardiography laboratory for arterial hypertension or fitness evaluation Convenience Sample.  Primary Endpoint: Valve regurgitation  Secondary Endpoint: Leaflet thickening, Mitral-valve tenting area  Primary Endpoint: Valve regurgitation  Secondary Endpoint: Leaflet thickening, Mitral-valve tenting area transthoracic echocardiographic examination Non-ergot-derived dopamine agonists n=42 Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

5. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Baseline Characteristics Characteristic* Pergolide Group (n=64) Cabergoline Group (n=49) Non-Ergot- Derived Group (n=42) (n=42) All Patients (n=155) Control Group (n=90) Age (yr) 65.3+8.5 61.5+9.8 62.7+9.8 63.4+9.2 63.5+10.1 Male # (%) 41 (64) 27 (55) 29 (69) 97 (63) 52 (58) Body Mass Index 24.7+3.4 25+3.3 25.4+3.5 25.1+3.4 26.1+3.4 HTN # (%) 18 (28) 13 (27) 10 (24) 42 (27) 26 (29) Systolic BP (mm Hg) 138.8+13.3 136+12.6 133.1+11 136.2+12.9 136.5+10 Diastolic BP (mm Hg) 78.9+8.1 79.4+6.2 77.5+8.2 78.7+7.9 77.2+7.8 Diabetes # (%) 4 (6) 4 (8) 2 (5) 10 (6) 4 (4) Coronary Heart Disease # (%) 3 (5) 2 (4) 3 (7) 8 (5) 3 (3) Years since Parkinson’s Diagnosis 11.2+5 7+5.8 8.8+4.5 NANA Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46. *Plus-minus values are means ± SD. The body-mass index is the weight in kg divided by the square of the height in m. NA denotes not applicable.

6. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral Regurgitation Grade of Mitral Regurgitation No. of Pts. (%) Pergolide Group (n=64) Cabergoline Group (n=49) Non-Ergot- Derived Group (n=42) Control Group (n=90) 0 - 1 19 (30) 11 (22) 26 (62) 48 (53) 2 36 (56) 33 (67) 16 (38) 40 (44) 3 6 (9) 4 (8) 0 2 (2) 4 3 (5) 1 (2) 00 p value <0.001<0.0010.27- Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

7. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Aortic Regurgitation Grade of Aortic Regurgitation No. of Pts. (%) Pergolide Group (n=64) (n=64) Cabergoline Group (n=49) Non-Ergot- Derived Group (n=42) Control Group (n=90) 0 – 1 34 (53) 22 (45) 31 (74) 66 (73) 2 21 (33) 15 (31) 11 (26) 21 (23) 3 8 (12) 12 (24) 0 3 (3) 4 1 (2) 000 p-value0.02<0.0010.68- N Engl J Med; 356(1): 39-46

8. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Tricuspid Regurgitation Grade of Tricuspid Regurgitation (%) Pergolide Group (n=64) (n=64) Cabergoline Group (n=49) Non-Ergot- Derived Group (n=42) Control Group (n=90) (n=90) 0 – 1 17 (27) 8 (16) 23 (55) 47 (52) 2 56 (76) 38 (78) 19 (45) 42 (47) 3 4 (6) 2 (4) 0 1 (1) 40 1 (2) 00 p-value0.002<0.0010.70- N Engl J Med; 356(1): 39-46

9. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Valvular Regurgitation The frequency of clinically significant valve disease (grade 3 to 4 regurgitation) was significantly higher in the pergolide group (23.4%, p=0.001) and cabergoline group (28.6%, p<0.001) as compared to the control group (5.6%).The frequency of clinically significant valve disease (grade 3 to 4 regurgitation) was significantly higher in the pergolide group (23.4%, p=0.001) and cabergoline group (28.6%, p<0.001) as compared to the control group (5.6%). There was no significant difference in frequency of moderate to severe valvular regurgitation between the non-ergot-derived group (0%) and the control group (5.6%).There was no significant difference in frequency of moderate to severe valvular regurgitation between the non-ergot-derived group (0%) and the control group (5.6%). Frequency of Valvular Regurgitation (%) Frequency (%) of moderate to severe (grade 3 to 4) valvular regurgitation in any valve n=64 n=49 n=42 n=90 p=0.001 p<0.001 p=0.17 Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

10. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Composite Regurgitation Score n=64 n=49 n=42 n=90 Composite Regurgitation Score 4.8+2.01 p<0.001 5.14+1.84 p<0.001 3.4+1.29 p=0.44 3.27+2.02 Mean composite regurgitation scores of all treatment groups The mean composite regurgitation scores were significantly higher in both the pergolide group (p<0.001) and the cabergoline group (p<0.001) as compared with the control group.The mean composite regurgitation scores were significantly higher in both the pergolide group (p<0.001) and the cabergoline group (p<0.001) as compared with the control group. There was no significant difference in mean composite regurgitation scores between the non- ergot-derived group and the control group.There was no significant difference in mean composite regurgitation scores between the non- ergot-derived group and the control group. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

11. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Leaflet Thickening Patients treated with ergot-derived dopamine agonists demonstrated a significantly higher frequency of localized or diffuse leaflet thickening.Patients treated with ergot-derived dopamine agonists demonstrated a significantly higher frequency of localized or diffuse leaflet thickening. No leaflet thickening was observed in the non-ergot-derived group or in the control group.No leaflet thickening was observed in the non-ergot-derived group or in the control group. Frequency of Leaflet Thickening (%) Frequency (%) of leaflet thickening of any valve n=64 n=49 n=42 n=90 p<0.001 p<0.001 p=NA Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

12. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral-Valve Tenting n=64 n=49 n=42 n=90 Mitral-valve tenting area (cm 2 ) 2.95+0.81 p=0.001 3.1+0.80 p<0.001 2.8+0.62 p=0.002 2.37+0.49 Mitral tenting area in each of the treatment groups The mitral tenting area in each of the three drug treatment groups was significantly higher than that observed in the control groupThe mitral tenting area in each of the three drug treatment groups was significantly higher than that observed in the control group Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

13. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Limitations Limited non-randomized sample of patients used for analysis.Limited non-randomized sample of patients used for analysis. A larger, randomized comparison would be more definitive.A larger, randomized comparison would be more definitive. Limited non-randomized sample of patients used for analysis.Limited non-randomized sample of patients used for analysis. A larger, randomized comparison would be more definitive.A larger, randomized comparison would be more definitive. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

14. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Summary The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists.The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists. The observed relationship between the severity of valvular functional impairment and the presence of the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and subvalvular apparatus.The observed relationship between the severity of valvular functional impairment and the presence of the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and subvalvular apparatus. The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists.The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists. The observed relationship between the severity of valvular functional impairment and the presence of the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and subvalvular apparatus.The observed relationship between the severity of valvular functional impairment and the presence of the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and subvalvular apparatus. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.

15. Clinical Trial Results. org Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Summary The finding of a significantly increased mean mitral tenting area in both patients treated with ergot- derived and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease.The finding of a significantly increased mean mitral tenting area in both patients treated with ergot- derived and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease. In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine- receptor agonists for Parkinson’s disease.In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine- receptor agonists for Parkinson’s disease. The finding of a significantly increased mean mitral tenting area in both patients treated with ergot- derived and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease.The finding of a significantly increased mean mitral tenting area in both patients treated with ergot- derived and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease. In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine- receptor agonists for Parkinson’s disease.In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine- receptor agonists for Parkinson’s disease. Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.