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.;

Clinical Trial Results . orgClinical Trial Results . org

Valvular Heart Disease and the Use of Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s DiseaseDopamine Agonists for Parkinson’s Disease

Valvular Heart Disease and the Use of Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s DiseaseDopamine Agonists for Parkinson’s Disease

Renzo Zanettini, M.D.; Angelo Antonini, Renzo Zanettini, M.D.; Angelo Antonini, M.D.;M.D.;

Gemma Gatto, Gemma Gatto, M.D.;M.D.; Rosa Gentile, Rosa Gentile, M.D.;M.D.;

Silvana Tesei, Silvana Tesei, M.D.;M.D.; and Gianni Pezzoli, and Gianni Pezzoli, M.D.M.D.

Published in the New England Journal of MedicinePublished in the New England Journal of Medicine

January 4, 2007January 4, 2007

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease


Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Background


• Ergot-derived dopamine receptor agonists, Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of which are frequently used in the treatment of Parkinson’s disease, have been associated Parkinson’s disease, have been associated with an increased risk of valvular heart with an increased risk of valvular heart disease.disease.

• In particular, pergolide, cabergoline, and In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the receptor agonists, have been related to the occurrence of valvular heart disease.occurrence of valvular heart disease.

• Ergot-derived dopamine receptor agonists, Ergot-derived dopamine receptor agonists, which are frequently used in the treatment of which are frequently used in the treatment of Parkinson’s disease, have been associated Parkinson’s disease, have been associated with an increased risk of valvular heart with an increased risk of valvular heart disease.disease.

• In particular, pergolide, cabergoline, and In particular, pergolide, cabergoline, and bromocriptine, all ergot-derived dopamine bromocriptine, all ergot-derived dopamine receptor agonists, have been related to the receptor agonists, have been related to the occurrence of valvular heart disease.occurrence of valvular heart disease.

Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.Zanettini et al. N Engl J Med; 2007 Jan. 356(1): 39-46.




• Although non-ergot-derived dopamine agonists may Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned.fibrotic reactions has been questioned.

• The goal of the present study was to assess the The goal of the present study was to assess the prevalence of valvular disease in patients treated prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects dopamine agonists and in a group of control subjects without Parkinson’s disease.without Parkinson’s disease.

• Although non-ergot-derived dopamine agonists may Although non-ergot-derived dopamine agonists may represent a valid alternative for the treatment of represent a valid alternative for the treatment of Parkinson’s disease, their safety with regard to Parkinson’s disease, their safety with regard to fibrotic reactions has been questioned.fibrotic reactions has been questioned.

• The goal of the present study was to assess the The goal of the present study was to assess the prevalence of valvular disease in patients treated prevalence of valvular disease in patients treated with pergolide, cabergoline, or non-ergot-derived with pergolide, cabergoline, or non-ergot-derived dopamine agonists and in a group of control subjects dopamine agonists and in a group of control subjects without Parkinson’s disease.without Parkinson’s disease.



Pergolide Pergolide

GroupGroup

n=64n=64

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Study DesignValvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Study Design

Cabergoline Cabergoline

GroupGroup

n=49n=49

Control Control

SubjectsSubjects

n=90n=90

245 patients total: 155 patients attending the out-patient service of the Parkinson Institute of the 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 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 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 without Parkinson’s disease recruited from among relatives of patients, acquaintances of medical staff, or

referred to echocardiography laboratory for arterial hypertension or fitness evaluationreferred to echocardiography laboratory for arterial hypertension or fitness evaluationConvenience Sample.Convenience Sample.

245 patients total: 155 patients attending the out-patient service of the Parkinson Institute of the 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 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 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 without Parkinson’s disease recruited from among relatives of patients, acquaintances of medical staff, or

referred to echocardiography laboratory for arterial hypertension or fitness evaluationreferred to echocardiography laboratory for arterial hypertension or fitness evaluationConvenience Sample.Convenience Sample.

Primary Endpoint: Valve regurgitationPrimary Endpoint: Valve regurgitation Secondary Endpoint: Leaflet thickening, Mitral-valve tenting areaSecondary Endpoint: Leaflet thickening, Mitral-valve tenting area

Primary Endpoint: Valve regurgitationPrimary Endpoint: Valve regurgitation Secondary Endpoint: Leaflet thickening, Mitral-valve tenting areaSecondary Endpoint: Leaflet thickening, Mitral-valve tenting area

transthoracic echocardiographic examination transthoracic echocardiographic examination

Non-ergot-derived Non-ergot-derived

dopamine agonistsdopamine agonists

n=42n=42



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Baseline Characteristics

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Baseline Characteristics

Characteristic*Characteristic* Pergolide Pergolide GroupGroup (n=64)(n=64)

Cabergoline Cabergoline Group Group (n=49)(n=49)

Non-Ergot-Non-Ergot-Derived GroupDerived Group

(n=42)(n=42)

All All PatientsPatients(n=155)(n=155)

Control Control GroupGroup(n=90)(n=90)

Age Age (yr)(yr) 65.365.3++8.5 8.5 61.561.5++9.89.8 62.762.7++9.89.8 63.463.4++9.29.2 63.563.5++10.110.1

Male Male ## (%)(%) 41 (64)41 (64) 27 (55)27 (55) 29 (69)29 (69) 97 (63)97 (63) 52 (58)52 (58)

Body Mass Body Mass IndexIndex

24.724.7++3.43.4 2525++3.33.3 25.425.4++3.53.5 25.125.1++3.43.4 26.126.1++3.43.4

HTN HTN ## (%)(%) 18 (28)18 (28) 13 (27)13 (27) 10 (24)10 (24) 42 (27)42 (27) 26 (29)26 (29)

Systolic BP Systolic BP (mm Hg)(mm Hg)

138.8138.8++13.313.3 136136++12.612.6 133.1133.1++1111 136.2136.2++12.912.9 136.5136.5++1010

Diastolic BP Diastolic BP (mm Hg)(mm Hg)

78.978.9++8.18.1 79.479.4++6.26.2 77.577.5++8.28.2 78.778.7++7.97.9 77.277.2++7.87.8

DiabetesDiabetes # (%) # (%) 4 (6)4 (6) 4 (8)4 (8) 2 (5)2 (5) 10 (6)10 (6) 4 (4)4 (4)

Coronary Heart Coronary Heart Disease Disease # (%)# (%)

3 (5)3 (5) 2 (4)2 (4) 3 (7)3 (7) 8 (5)8 (5) 3 (3)3 (3)

Years since Years since Parkinson’s Parkinson’s DiagnosisDiagnosis

11.211.2++55 77++5.85.8 8.88.8++4.54.5 NANA NANA


*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.


Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral Regurgitation

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral Regurgitation

Grade of Mitral Grade of Mitral Regurgitation Regurgitation No. of Pts. (%)No. of Pts. (%)

Pergolide Pergolide Group Group (n=64)(n=64)

Cabergoline Cabergoline GroupGroup(n=49)(n=49)

Non-Ergot-Non-Ergot-Derived Group Derived Group

(n=42)(n=42)

Control Control Group Group (n=90)(n=90)

0 - 10 - 1 19 (30)19 (30) 11 (22)11 (22) 26 (62)26 (62) 48 (53)48 (53)

22 36 (56)36 (56) 33 (67)33 (67) 16 (38)16 (38) 40 (44)40 (44)

33 6 (9)6 (9) 4 (8)4 (8) 00 2 (2)2 (2)

44 3 (5)3 (5) 1 (2)1 (2) 00 00

p valuep value <0.001<0.001 <0.001<0.001 0.270.27 --



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Aortic Regurgitation

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Aortic Regurgitation

Grade of Aortic Grade of Aortic RegurgitationRegurgitation No. of Pts. (%)No. of Pts. (%)

Pergolide Pergolide GroupGroup (n=64)(n=64)

Cabergoline Cabergoline GroupGroup (n=49)(n=49)


(n=42)(n=42)

Control Control GroupGroup (n=90)(n=90)

0 – 10 – 1 34 (53)34 (53) 22 (45)22 (45) 31 (74)31 (74) 66 (73)66 (73)

22 21 (33)21 (33) 15 (31)15 (31) 11 (26)11 (26) 21 (23)21 (23)

33 8 (12)8 (12) 12 (24)12 (24) 00 3 (3)3 (3)

44 1 (2)1 (2) 00 00 00

p-valuep-value 0.020.02 <0.001<0.001 0.680.68 --

N Engl J Med; 356(1): 39-46N Engl J Med; 356(1): 39-46


Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Tricuspid Regurgitation

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Tricuspid Regurgitation

Grade of Grade of Tricuspid Tricuspid RegurgitationRegurgitation (%) (%)

Pergolide Pergolide GroupGroup (n=64)(n=64)

Cabergoline Cabergoline GroupGroup (n=49)(n=49)


(n=42)(n=42)

Control Control GroupGroup (n=90)(n=90)

0 – 10 – 1 17 (27)17 (27) 8 (16)8 (16) 23 (55)23 (55) 47 (52)47 (52)

22 56 (76)56 (76) 38 (78)38 (78) 19 (45)19 (45) 42 (47)42 (47)

33 4 (6)4 (6) 2 (4)2 (4) 00 1 (1)1 (1)

44 00 1 (2)1 (2) 00 00

p-valuep-value 0.0020.002 <0.001<0.001 0.700.70 --

N Engl J Med; 356(1): 39-46N Engl J Med; 356(1): 39-46


Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Valvular Regurgitation

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Valvular Regurgitation

• The frequency of The frequency of clinically significant clinically significant valve disease (grade 3 valve disease (grade 3 to 4 regurgitation) was to 4 regurgitation) was significantly higher in significantly higher in the pergolide group the pergolide group (23.4%, p=0.001) and (23.4%, p=0.001) and cabergoline group cabergoline group (28.6%, p<0.001) as (28.6%, p<0.001) as compared to the control compared to the control group (5.6%).group (5.6%).

• There was no There was no significant difference in significant difference in frequency of moderate frequency of moderate to severe valvular to severe valvular regurgitation between regurgitation between the non-ergot-derived the non-ergot-derived group (0%) and the group (0%) and the control group (5.6%).control group (5.6%).

Fre

qu

enc

y o

f V

alvu

lar

Re

gu

rgit

atio

n (

%)

Fre

qu

enc

y o

f V

alvu

lar

Re

gu

rgit

atio

n (

%)

Frequency (%) of moderate to severe (grade 3 to 4) valvular Frequency (%) of moderate to severe (grade 3 to 4) valvular regurgitation in any valveregurgitation in any valve

23.4%

28.6%

0.0%

5.6%

0%

5%

10%

15%

20%

25%

30%

PergolideGroup

CabergolineGroup

Non-Ergot-DerivedGroup

ControlGroup

23.4%

28.6%

0.0%

5.6%

0%

5%

10%

15%

20%

25%

30%

PergolideGroup

CabergolineGroup


ControlGroup

n=64n=64 n=49n=49n=42n=42

n=90n=90

p=0.001p=0.001

p<0.001p<0.001

p=0.17p=0.17



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Composite Regurgitation Score

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Composite Regurgitation Score

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

PergolideGroup

CabergolineGroup


ControlGroup

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

PergolideGroup

CabergolineGroup


ControlGroup

n=64n=64 n=49n=49 n=42n=42 n=90n=90Co

mp

osi

te R

egu

rgit

atio

n S

core

Co

mp

osi

te R

egu

rgit

atio

n S

core

4.84.8++2.012.01

p<0.001p<0.001

5.145.14++1.841.84

p<0.001p<0.001

3.43.4++1.291.29

p=0.44p=0.44

3.273.27++2.022.02

Mean composite regurgitation scores of all treatment groupsMean composite regurgitation scores of all treatment groups

• The mean composite The mean composite regurgitation scores regurgitation scores were significantly were significantly higher in both the higher in both the pergolide group pergolide group (p<0.001) and the (p<0.001) and the cabergoline group cabergoline group (p<0.001) as (p<0.001) as compared with the compared with the control group.control group.

• There was no There was no significant difference significant difference in mean composite in mean composite regurgitation scores regurgitation scores between the non-between the non-ergot-derived group ergot-derived group and the control and the control group.group.



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Leaflet Thickening

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Leaflet Thickening

• Patients treated with Patients treated with ergot-derived dopamine ergot-derived dopamine agonists demonstrated agonists demonstrated a significantly higher a significantly higher frequency of localized frequency of localized or diffuse leaflet or diffuse leaflet thickening.thickening.

• No leaflet thickening No leaflet thickening was observed in the was observed in the non-ergot-derived non-ergot-derived group or in the control group or in the control group.group.

Fre

qu

enc

y o

f L

eafl

et

Th

ick

enin

g (

%)

Fre

qu

enc

y o

f L

eafl

et

Th

ick

enin

g (

%)

Frequency (%) of leaflet thickening of any valveFrequency (%) of leaflet thickening of any valve

27%

16%

0% 0%0%

5%

10%

15%

20%

25%

30%

PergolideGroup

CabergolineGroup


ControlGroup

27%

16%

0% 0%0%

5%

10%

15%

20%

25%

30%

PergolideGroup

CabergolineGroup


ControlGroup

n=64n=64 n=49n=49n=42n=42

n=90n=90

p<0.001p<0.001

p<0.001p<0.001

p=NAp=NA



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral-Valve Tenting

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Mitral-Valve Tenting

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

PergolideGroup

CabergolineGroup


ControlGroup

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

PergolideGroup

CabergolineGroup


ControlGroup

n=64n=64 n=49n=49 n=42n=42 n=90n=90Mit

ral-

valv

e te

nti

ng

are

a (c

mM

itra

l-va

lve

ten

tin

g a

rea

(cm

22 ))

2.952.95++0.810.81

p=0.001p=0.001

3.13.1++0.800.80

p<0.001p<0.0012.82.8++0.620.62

p=0.002p=0.002

2.372.37++0.490.49

Mitral tenting area in each of the treatment groupsMitral tenting area in each of the treatment groups

• The mitral The mitral tenting area in tenting area in each of the three each of the three drug treatment drug treatment groups was groups was significantly significantly higher than that higher than that observed in the observed in the control groupcontrol group



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Limitations

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Limitations

• Limited non-randomized sample of patients used Limited non-randomized sample of patients used for analysis. for analysis.

• A larger, randomized comparison would be more A larger, randomized comparison would be more definitive.definitive.

• Limited non-randomized sample of patients used Limited non-randomized sample of patients used for analysis. for analysis.

• A larger, randomized comparison would be more A larger, randomized comparison would be more definitive.definitive.



Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease: Summary


• The frequency of clinically important valve The frequency of clinically important valve regurgitation was significantly increased in patients regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists.taking non-ergot-derived dopamine agonists.

• The observed relationship between the severity of The observed relationship between the severity of valvular functional impairment and the presence of valvular functional impairment and the presence of the typical morphologic alterations found in patients the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and fibrosing process involving the valve leaflets and subvalvular apparatus.subvalvular apparatus.

• The frequency of clinically important valve The frequency of clinically important valve regurgitation was significantly increased in patients regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists.taking non-ergot-derived dopamine agonists.

• The observed relationship between the severity of The observed relationship between the severity of valvular functional impairment and the presence of valvular functional impairment and the presence of the typical morphologic alterations found in patients the typical morphologic alterations found in patients in the ergot group supports the hypothesis of a in the ergot group supports the hypothesis of a fibrosing process involving the valve leaflets and fibrosing process involving the valve leaflets and subvalvular apparatus.subvalvular apparatus.





• The finding of a significantly increased mean mitral The finding of a significantly increased mean mitral tenting area in both patients treated with ergot-derived tenting area in both patients treated with ergot-derived and those treated non-ergot-derived dopamine and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease.with dopamine agonists for Parkinson’s disease.

• In conclusion, the study demonstrates a significant In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine-patients being treated with ergot-derived dopamine-receptor agonists for Parkinson’s disease.receptor agonists for Parkinson’s disease.

• The finding of a significantly increased mean mitral The finding of a significantly increased mean mitral tenting area in both patients treated with ergot-derived tenting area in both patients treated with ergot-derived and those treated non-ergot-derived dopamine and those treated non-ergot-derived dopamine agonists, suggests that follow-up echocardiographic agonists, suggests that follow-up echocardiographic monitoring is advisable in all patients being treated monitoring is advisable in all patients being treated with dopamine agonists for Parkinson’s disease.with dopamine agonists for Parkinson’s disease.

• In conclusion, the study demonstrates a significant In conclusion, the study demonstrates a significant increase in the risk of heart-valve regurgitation in increase in the risk of heart-valve regurgitation in patients being treated with ergot-derived dopamine-patients being treated with ergot-derived dopamine-receptor agonists for Parkinson’s disease.receptor agonists for Parkinson’s disease.


Documents

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.;