Clinical Trial Results. org Published in New England Journal of Medicine January 4 th, 2007 Rene Schade, M.D., Frank Andersohn, M.D., Samy Suissa, Ph.D. Wilhelm Haverkamp, M.D., Ph.D., and Edeltraut Garbe, M.D., Ph.D. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Background Pergolide and cabergoline are potent agonists of the 5- hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic properties.Pergolide and cabergoline are potent agonists of the 5- hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic properties. Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation.Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation. Pergolide and cabergoline are potent agonists of the 5- hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic properties.Pergolide and cabergoline are potent agonists of the 5- hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic properties. Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation.Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation. Schade, et al New Engl J Med. 2007; 356 (1)

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac- Valve Regurgitation: Study Design Case Patients (newly diagnosed with valvular disease: 6 pergolide, 6 cabergoline, 19 no dopamine agonist exposure within 1 yr) n=31 n=31 Control Patients (matched 25:1 Case Patient) n=663 n=663 12,794 patients years of age prescribed two antiparkinsonian drugs between , each patient newly diagnosed with cardiac valvular disease was matched with up to 25 control patients according to age, sex, and date of entry Nested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices. 12,794 patients years of age prescribed two antiparkinsonian drugs between , each patient newly diagnosed with cardiac valvular disease was matched with up to 25 control patients according to age, sex, and date of entry Nested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices. Schade, et al. New Engl J Med Jan; 356(1): 29 – 38. Exclusion Criteria: Hx of RHD, congenital HD, CHF, dilated cardiomyopathy, endocarditis or myocarditis, carcinoid syndrome, IV drug abuse, heart valve abnormalities (ie: MV prolapse and murmurs), receiving drugs associated with valvulopathy, <12 months of recorded data before date of exit, MI within 3 years of diagnosis of valvular regurgitation, prexisting valvular HD, or no confirmation of diagnosis  Primary Endpoint: New diagnosis of valve disease

Clinical Trial Results. org Characteristic No. of Pts. (%) Case Patients (n=31 ) Controls (n=663 ) Age (yrs  SD) 73.0   6.9 Male 20 (65) 448 (68) Current Smoker 7 (23) 105 (16) Diabetes 3 (10) 74 (11) Hypertension 7 (23) 203 (31) Coronary Disease 4 (13) 135 (20) Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Baseline Characteristics* Schade, et al New Engl J Med. 2007; 356 (1) *Plus-minus values are means ± SD. Case patients and controls were matched for age, sex, and year of entry into the study cohort. Percentages may exceed 100 because of overlap between categories

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Baseline Characteristics* Characteristics No. of pts. (%) Case Patients (n=31) Controls (n=663) Indication for use of a dopamine agonist Parkinson’s Disease Parkinson’s Disease 29 (94) 569 (86) Restless Leg Syndrome Restless Leg Syndrome 3 (10) 25 (4) Hyperprolactinemia Hyperprolactinemia 1 (3) 21 (3) Not Recorded Not Recorded 1 (3) 66 (10) Current Use of other antiparkinsonian drugs‡ Levodopa Levodopa 23 (74) 505 (76) Amantadine Amantadine 5 (16) 26 (4) Selegiline Selegiline 4 (13) 143 (22) Apomorphine Apomorphine 1 (3) 6 (1) Anticholingergic drugs Anticholingergic drugs 2 (7) 55 (8) Schade, et al New Engl J Med. 2007; 356 (1) *Case patients and controls were matched for age, sex, and year of entry into the study cohort. Percentages may exceed 100 because of overlap between categories ‡This category includes use during the 6 months before the index date.

Clinical Trial Results. org Characteristic no. of pts. (%) Pergolide (n=6 ) Cabergoline(n=6) No Dopamine Agonist (n=19 ) Valvular Regurgitation† Mitral Mitral Aortic Aortic Tricuspid Tricuspid 4 (67) 3 (50) 0 5 (83) 3 (50) 17 (89) 4 (21) 0 No. of Valves Involved (83) 1 (17) 0 3 (50) 2 (33) 17 (89) 4 (21) 0 Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Case Patient Valvular Regurgitation Characteristics Schade, et al. New Engl J Med Jan; 356(1): 29 – 38. Characteristics of 31 Case Patients with Cardiac-Valve Regurgitation, According to Use of A Dopamine Agonist †Percentages may exceed 100 because of overlap between the categories † Percentages may exceed 100 because of overlap between the categories

Clinical Trial Results. org Exposure no. of pts. (%) Case Patients (n=31) Controls(n=663) Adjusted Incidence-Rate Ratio (95% CI)* No current or recent use of a dopamine agonist‡ 19 (61) 530 (80) 1.0 Bromocriptine0 19 (3) Cabergoline 6 (19) 34 (5) 4.9 ( ) Pergolide 6 (19) 26 (4) 7.1 ( ) Lisuride0 1 (0) Pramipexole0 23 (3) Ropinirole0 Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint Schade, et al. New Engl J Med Jan; 356(1): 29 – 38. Current Use of Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine ‡This is the reference category, defined as no use of dopamine agonist during the 12 months before the index date.

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac- Valve Regurgitation: Primary Endpoint (cont.) The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists.The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists. For amantadine, the only concurrent medication found to have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3).For amantadine, the only concurrent medication found to have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3). The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists.The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists. For amantadine, the only concurrent medication found to have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3).For amantadine, the only concurrent medication found to have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3). Schade, et al. New Engl J Med Jan; 356(1): 29 – 38.

Clinical Trial Results. org Exposure no. of pts. (%) Case Patient n=31 Controln=663 Adjusted Incidence- Rate Ratio (95% CI)* P Value No current or recent use of a dopamine agonist† 19(61)530(80)1 Last Daily Dose Pergolide Pergolide <3mg <3mg >3mg >3mg 3(10) 3(10) 21(3)5(1)5.1( ( )0.07 Cabergoline Cabergoline <3mg <3mg >3mg >3mg2(7)4(13)31(5)3(0)2.6( )50.3( )0.01 Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont.) *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine. †This is the reference category, defined as no use of a dopamine agonist during the 12 months before the index date. Influence of the Daily Dose of Pergolide or Cabergoline Schade, et al New Engl J Med. 2007; 356 (1)

Clinical Trial Results. org Exposure no. of pts. (%) Case Patients (n=31 ) Controls(n=663) Adjusted Incidence-Rate Ratio (95% CI)* No current or recent use of a dopamine agonist† 19 (61) 530 (80) 1 Cumulative duration of use Pergolide Pergolide <6 mo <6 mo ≥6 mo ≥6 mo Cabergoline Cabergoline <6 mo <6 mo ≥6 mo ≥6 mo0 6 (19) 0 4 (1) 22 (3) 11 (2) 23 (4) 9.8 (2.9 – 33.1) 7.8 (2.2 – 27.4) Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.) Schade, et al. New Engl J Med Jan; 356(1): 29 – 38. Influence of the Cumulative Duration of Use on the Risk of Cardiac-Valve Regurgitation. *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine. †This is the reference category, defined as no use of a dopamine agonist during the 12 months before the index date.

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont) The adjusted incidence rate ratios were particularly elevated for daily doses greater than 3mg of pergolide (37.1; 95% CI, 1.5 to 15.6) and 3mg of cabergoline (50.3; 95% CI, 6.6 to 381.4), as well for a duration of use of 6 months or more.The adjusted incidence rate ratios were particularly elevated for daily doses greater than 3mg of pergolide (37.1; 95% CI, 1.5 to 15.6) and 3mg of cabergoline (50.3; 95% CI, 6.6 to 381.4), as well for a duration of use of 6 months or more. Schade, et al New Engl J Med. 2007; 356 (1)

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac Valve Regurgitation : Limitations Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results.Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results. Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline.Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline. Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results.Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results. Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline.Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline. Schade, et al New Engl J Med. 2007; 356 (1)

Clinical Trial Results. org Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Summary This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation.This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation. There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole).There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole). These findings are supported by a number of other case reports and echocardiography studies.These findings are supported by a number of other case reports and echocardiography studies. This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation.This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation. There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole).There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole). These findings are supported by a number of other case reports and echocardiography studies.These findings are supported by a number of other case reports and echocardiography studies. Schade, et al New Engl J Med. 2007; 356 (1)