Published in New England Journal of Medicine January 4 th , 2007

Clinical Trial Results . orgClinical Trial Results . org

Published in New England Journal of Medicine Published in New England Journal of Medicine January 4January 4thth, 2007, 2007

Published in New England Journal of Medicine Published in New England Journal of Medicine January 4January 4thth, 2007, 2007

Rene Schade, M.D., Frank Andersohn, Rene Schade, M.D., Frank Andersohn, M.D., Samy Suissa, Ph.D. Wilhelm M.D., Samy Suissa, Ph.D. Wilhelm

Haverkamp, M.D., Ph.D., and Edeltraut Haverkamp, M.D., Ph.D., and Edeltraut Garbe, M.D., Ph.D.Garbe, M.D., Ph.D.

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation


Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Background

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Background

• Pergolide and cabergoline are potent agonists of the 5-Pergolide and cabergoline are potent agonists of the 5-hydroxytryptamine 2B receptor expressed on heart hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic bromocriptine and lisuride have antagonistic properties. properties.

• Previous case reports and echocardiographic studies Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation.increase the risk of cardiac-valve regurgitation.

• Pergolide and cabergoline are potent agonists of the 5-Pergolide and cabergoline are potent agonists of the 5-hydroxytryptamine 2B receptor expressed on heart hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic bromocriptine and lisuride have antagonistic properties. properties.

• Previous case reports and echocardiographic studies Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation.increase the risk of cardiac-valve regurgitation.

Schade, et al New Engl J Med. 2007; 356 (1) 29-38. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.


Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Study Design

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Study Design

Case Patients (newly diagnosed Case Patients (newly diagnosed with valvular disease: 6 pergolide, with valvular disease: 6 pergolide,

6 cabergoline, 19 no dopamine 6 cabergoline, 19 no dopamine agonist exposure within 1 yr)agonist exposure within 1 yr)

n=31n=31

Case Patients (newly diagnosed Case Patients (newly diagnosed with valvular disease: 6 pergolide, with valvular disease: 6 pergolide,

6 cabergoline, 19 no dopamine 6 cabergoline, 19 no dopamine agonist exposure within 1 yr)agonist exposure within 1 yr)

n=31n=31

Control Patients (matched 25:1 Case Control Patients (matched 25:1 Case Patient)Patient)

n=663n=663

Control Patients (matched 25:1 Case Control Patients (matched 25:1 Case Patient)Patient)

n=663n=663

12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 1988-12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 1988-2005, each patient newly diagnosed with cardiac valvular disease was matched with up 2005, each patient newly diagnosed with cardiac valvular disease was matched with up

to 25 control patientsto 25 control patients according to age, sexaccording to age, sex, , and date of entryand date of entryNested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices.Nested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices.

12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 1988-12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 1988-2005, each patient newly diagnosed with cardiac valvular disease was matched with up 2005, each patient newly diagnosed with cardiac valvular disease was matched with up

to 25 control patientsto 25 control patients according to age, sexaccording to age, sex, , and date of entryand date of entryNested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices.Nested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices.

Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

Exclusion Criteria:Exclusion Criteria: Hx of RHD, congenital HD, CHF, dilated cardiomyopathy, endocarditis or myocarditis, 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 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 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 diagnosisdiagnosis of valvular regurgitation, prexisting valvular HD, or no confirmation of diagnosis

Exclusion Criteria:Exclusion Criteria: Hx of RHD, congenital HD, CHF, dilated cardiomyopathy, endocarditis or myocarditis, 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 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 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 diagnosisdiagnosis of valvular regurgitation, prexisting valvular HD, or no confirmation of diagnosis

Primary Endpoint: New diagnosis of valve diseasePrimary Endpoint: New diagnosis of valve disease Primary Endpoint: New diagnosis of valve diseasePrimary Endpoint: New diagnosis of valve disease


CharacteristicCharacteristicNo. of Pts. (%)No. of Pts. (%)

Case PatientsCase Patients(n=31 )(n=31 )

ControlsControls(n=663 )(n=663 )

Age (yrsAge (yrsSD)SD) 73.0 73.0 7.87.8 73.5 73.5 6.96.9

Male Male 20 (65) 20 (65) 448 (68)448 (68)

Current SmokerCurrent Smoker 7 (23)7 (23) 105 (16)105 (16)

Diabetes Diabetes 3 (10)3 (10) 74 (11)74 (11)

HypertensionHypertension 7 (23)7 (23) 203 (31)203 (31)

Coronary DiseaseCoronary Disease 4 (13)4 (13) 135 (20)135 (20)

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Baseline Characteristics*



*Plus-minus values are means ± SD. Case patients and controls were matched for age, sex, and year of entry into the *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 categoriesstudy cohort. Percentages may exceed 100 because of overlap between categories




CharacteristicsCharacteristicsNo. of pts. (%)No. of pts. (%)

Case Case PatientsPatients(n=31)(n=31)

ControlsControls(n=663)(n=663)

Indication for use of a dopamine agonistIndication for use of a dopamine agonist

Parkinson’s Disease Parkinson’s Disease 29 (94)29 (94) 569 (86)569 (86)

Restless Leg Syndrome Restless Leg Syndrome 3 (10)3 (10) 25 (4)25 (4)

HyperprolactinemiaHyperprolactinemia 1 (3)1 (3) 21 (3)21 (3)

Not RecordedNot Recorded 1 (3)1 (3) 66 (10)66 (10)

Current Use of other antiparkinsonian drugsCurrent Use of other antiparkinsonian drugs‡‡

LevodopaLevodopa 23 (74) 23 (74) 505 (76)505 (76)

AmantadineAmantadine 5 (16)5 (16) 26 (4)26 (4)

SelegilineSelegiline 4 (13)4 (13) 143 (22)143 (22)

ApomorphineApomorphine 1 (3)1 (3) 6 (1)6 (1)

Anticholingergic drugsAnticholingergic drugs 2 (7)2 (7) 55 (8)55 (8)


**Case patients and controls were matched for age, sex, and year of entry into the study cohort. Percentages may exceed 100 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 categoriesbecause of overlap between categories‡‡This category includes use during the 6 months before the index date.This category includes use during the 6 months before the index date.


CharacteristicCharacteristicno. of pts. (%)no. of pts. (%)

PergolidePergolide(n=6 )(n=6 )

CabergolineCabergoline(n=6)(n=6)

No No Dopamine Dopamine

AgonistAgonist(n=19 )(n=19 )

Valvular RegurgitationValvular Regurgitation†† MitralMitral AorticAortic TricuspidTricuspid

4 (67)4 (67)3 (50)3 (50)

00

5 (83)5 (83)5 (83)5 (83)3 (50)3 (50)

17 (89)17 (89)4 (21)4 (21)

00

No. of Valves InvolvedNo. of Valves Involved 11 22 33

5 (83)5 (83)1 (17)1 (17)

00

1 (17)1 (17)3 (50)3 (50)2 (33)2 (33)

17 (89)17 (89)4 (21)4 (21)

00

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Case Patient Valvular Regurgitation Characteristics

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Case Patient Valvular Regurgitation Characteristics


Characteristics of 31 Case Patients with Cardiac-Valve Regurgitation, Characteristics of 31 Case Patients with Cardiac-Valve Regurgitation, According to Use of A Dopamine AgonistAccording to Use of A Dopamine Agonist

†† Percentages may exceed 100 because of overlap between the categoriesPercentages may exceed 100 because of overlap between the categories


ExposureExposureno. of pts. (%)no. of pts. (%)

Case Case PatientsPatients(n=31)(n=31)


Adjusted Incidence-Rate Adjusted Incidence-Rate RatioRatio

(95% CI)*(95% CI)*

No current or recent use of No current or recent use of a dopamine agonista dopamine agonist‡‡ 19 (61)19 (61) 530 (80) 530 (80) 1.01.0

BromocriptineBromocriptine 00 19 (3)19 (3)

CabergolineCabergoline 6 (19)6 (19) 34 (5)34 (5) 4.9 (1.5-15.6)4.9 (1.5-15.6)

PergolidePergolide 6 (19)6 (19) 26 (4)26 (4) 7.1 (2.3-22.3)7.1 (2.3-22.3)

LisurideLisuride 00 1 (0)1 (0)

PramipexolePramipexole 00 23 (3)23 (3)

RopiniroleRopinirole 00 23 (3)23 (3)

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint


Current Use of Dopamine Agonists and the Risk of Cardiac-Valve Current Use of Dopamine Agonists and the Risk of Cardiac-Valve RegurgitationRegurgitation

*The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine*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.This is the reference category, defined as no use of dopamine agonist during the 12 months before the index date.


Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.)Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.)

• The rate of cardiac-valve regurgitation was elevated The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists.currently exposed to other dopamine agonists.

• For amantadine, the only concurrent medication found to For amantadine, the only concurrent medication found to have a significant association with cardiac –valve have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3).(95% CI, 1.1 to 11.3).

• The rate of cardiac-valve regurgitation was elevated The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists.currently exposed to other dopamine agonists.

• For amantadine, the only concurrent medication found to For amantadine, the only concurrent medication found to have a significant association with cardiac –valve have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3).(95% CI, 1.1 to 11.3).




Case Case Patient Patient n=31n=31

ControlControln=663n=663

Adjusted Incidence-Adjusted Incidence-Rate Ratio Rate Ratio (95% CI)*(95% CI)*

P ValueP Value

No current or recent No current or recent use of a dopamine use of a dopamine agonistagonist†† 19(61)19(61) 530(80)530(80) 11

Last Daily DoseLast Daily Dose

PergolidePergolide <3mg<3mg >3mg>3mg

3(10) 3(10) 3(10)3(10)

21(3)21(3)5(1)5(1)

5.1(1.3-20.45.1(1.3-20.437.1(5.1-270.6)37.1(5.1-270.6)

0.070.07

CabergolineCabergoline <3mg<3mg >3mg >3mg

2(7)2(7)4(13)4(13)

31(5)31(5)3(0)3(0)

2.6(0.5-12.8)2.6(0.5-12.8)50.3(6.6-381.4)50.3(6.6-381.4)

0.010.01

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont.)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.*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.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 CabergolineInfluence of the Daily Dose of Pergolide or Cabergoline




Case Case PatientsPatients(n=31 )(n=31 )


Adjusted Adjusted Incidence-Rate Incidence-Rate

RatioRatio(95% CI)*(95% CI)*

No current or recent use of No current or recent use of a dopamine agonista dopamine agonist†† 19 (61)19 (61) 530 (80)530 (80) 11

Cumulative duration of useCumulative duration of use PergolidePergolide <6 mo<6 mo ≥≥6 mo6 mo CabergolineCabergoline <6 mo<6 mo ≥≥6 mo6 mo

006 (19)6 (19)

006 (19)6 (19)

4 (1)4 (1)22 (3)22 (3)

11 (2) 11 (2) 23 (4)23 (4)

9.8 (2.9 – 33.1)9.8 (2.9 – 33.1)

7.8 (2.2 – 27.4)7.8 (2.2 – 27.4)

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.)

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.)


Influence of the Cumulative Duration of Use on the Risk of Cardiac-Valve Influence of the Cumulative Duration of Use on the Risk of Cardiac-Valve Regurgitation.Regurgitation.

*The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine.*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.This is the reference category, defined as no use of a dopamine agonist during the 12 months before the index date.


Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont)

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont)

• The adjusted incidence rate ratios were The adjusted incidence rate ratios were particularly elevated for daily doses greater than particularly elevated for daily doses greater than 3mg of pergolide (37.1; 95% CI, 1.5 to 15.6) and 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), 3mg of cabergoline (50.3; 95% CI, 6.6 to 381.4), as well for a duration of use of 6 months or more.as well for a duration of use of 6 months or more.

• The adjusted incidence rate ratios were The adjusted incidence rate ratios were particularly elevated for daily doses greater than particularly elevated for daily doses greater than 3mg of pergolide (37.1; 95% CI, 1.5 to 15.6) and 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), 3mg of cabergoline (50.3; 95% CI, 6.6 to 381.4), as well for a duration of use of 6 months or more.as well for a duration of use of 6 months or more.



Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Limitations

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Limitations

• Detection bias could be a concern, since pergolide was Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results.prior to September 2003 showing no material change in results.

• Underdiagnosing the incidence of asymptomatic cases could Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline. true risks associated with pergolide and cabergoline.

• Detection bias could be a concern, since pergolide was Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results.prior to September 2003 showing no material change in results.

• Underdiagnosing the incidence of asymptomatic cases could Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline. true risks associated with pergolide and cabergoline.



Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Summary

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Summary

• This study showed that the use of pergolide or cabergoline, This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation. newly diagnosed cardiac-valve regurgitation.

• There was no evidence of increased risk among patients There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole). not derived from ergot (such as ropinirole or pramipexole).

• These findings are supported by a number of other case These findings are supported by a number of other case reports and echocardiography studies. reports and echocardiography studies.

• This study showed that the use of pergolide or cabergoline, This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation. newly diagnosed cardiac-valve regurgitation.

• There was no evidence of increased risk among patients There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole). not derived from ergot (such as ropinirole or pramipexole).

• These findings are supported by a number of other case These findings are supported by a number of other case reports and echocardiography studies. reports and echocardiography studies.


Documents

Published in New England Journal of Medicine January 4 th , 2007