The Association Between Dopamine Agonists and Cardiac Valvulopathy, Fibrosis and Other Cardiopulmonary Events

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01052948
• Collaborator: (none)
• Enrollment: 86,939
• Duration (Months): 35

Study Details

Study Description

Brief Summary

To assess the association between cabergoline and other dopamine agonists (DAs), and symptomatic, diagnosed serious cardiopulmonary disorders, including:

1. Cardiac valve regurgitation

2. Diffuse Pleural/pulmonary thickening and pericardial and retroperitoneal fibrosis

3. Heart failure

4. Total, cardiac and respiratory mortality

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease; Hyperprolactinemia	Other: Retrospective study-; Other: Retrospective study-; Other: Retrospective study-; Other: Retrospective study-

Study Design

• Study Type: Observational
• Actual Enrollment: 86939 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: The Association Between Dopamine Agonists and Cardiac Valvulopathy, Fibrosis and Other Cardiopulmonary Events
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Cohort 1 All persons who newly start one of the dopamine agonists (DA) after start of eligibility period	Other: Retrospective study-
Cohort 2 All persons who started levodopa after start of eligibility period and had not been treated with dopamine agonists anytime prior.	Other: Retrospective study-
Cohort 3 All persons with newly diagnosed hyperprolactinemia who had not been treated with dopamine agonists anytime prior.	Other: Retrospective study-
Cohort 4 healthy controls from general population matched on age, gender, index date and general practitioner (GP) practice to persons exposed to dopamine agonists	Other: Retrospective study-

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Fibrotic Valvular Heart Disease Per 10,000 Participant-Years of Follow-Up [Up to 12 years]

   Occurrence of: mitral stenosis with insufficiency, other unspecified mitral valve diseases, mitral or aortic valve stenosis, insufficiency, or disorders, multiple involvement of mitral and aortic valves, mitral and aortic valve diseases, unspecified, diseases of tricuspid valve, tricuspid valve disorders, specified as nonrheumatic, pulmonary valve disorders, endocarditis, valve unspecified, endomyocardial fibrosis, endocardial fibroelastosis, other primary or secondary cardiomyopathies, cardiomyopathy, functional and undiagnosed cardiac murmurs, other abnormal heart sounds.

2. Number of Participants With Fibrosis Per 10,000 Participant-Years of Follow-Up [Up to 12 years]

   Occurrence of: idiopathic retroperitoneal fibrosis, occlusion not otherwise specified (NOS) of ureter, diffuse (idiopathic) (interstitial) pulmonary fibrosis, Hamman-Rich syndrome, interstitial pneumonia (desquamative) (lymphoid), fibrosis of lung (atrophic; confluent; massive; perialveolar; peribronchial) chronic or unspecified, pulmonary or pleural fibrosis, abnormal communication between pericardial and pleural sacs, pleural fold anomaly, adhesive or constrictive pericarditis, pericardial fibrosis

3. Number of Participants With Heart Failure Per 10,000 Participant-Years of Follow-Up [Up to 12 years]

   Occurrence of: unspecified acute edema of lung, heart failure, acute pulmonary heart disease, or acute cor pulmonale

4. Number of Participants With All-Cause Mortality Per 10,000 Participant-Years of Follow-Up [Up to 12 years]

   All participants who died independent of the cause to include instantaneous death, death occurring in less than 24 hours from onset of symptoms, not otherwise explained, unattended death and other causes of ill defined morbidity and mortality. Cause of death was coded and classified as either cardiovascular or respiratory.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• At least one year registered with the general practitioner (GP), one year of valid data from the GP, or the date of software conversion (if GP software systems had changed) and meeting criteria for any one of the 4 cohorts as defined.

Exclusion Criteria:

• rheumatic heart disease

• congenital heart disease: includes structural defects, congenital arrhythmias, and cardiomyopathies

• dilated cardiomyopathy (congestive cardiomyopathy

• pericardial, pleural, pulmonary or retroperitoneal fibrosis

• endocarditis or myocarditis

• carcinoid syndrome

• intravenous drug abuse

• fibrotic valvular heart disease

• pleural/pulmonary/pericardial/retroperitoneal fibroses

• use of fenfluramine or amiodarone within 3 years prior to date of diagnosis of fibrotic valvular heart disease

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01052948
• Other Study ID Numbers: A7231031
• First Posted: Jan 21, 2010
• Last Update Posted: Mar 23, 2011
• Last Verified: Mar 1, 2011

• Keywords provided by , ,: dopamine agonists; cabergoline; Parkinson's disease; hyperprolactinemia; epidemiology; cardiac valvulopathy
• Additional relevant MeSH terms: Parkinson Disease; Hyperprolactinemia; Heart Valve Diseases

Study Results

Participant Flow

Recruitment Details	Noninterventional retrospective cohort study.

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
Period Title: Overall Study
STARTED	27812	14669	15147	29311
COMPLETED	27812	14669	15147	29311
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)	Total
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.	Total of all reporting groups
Overall Participants	27812	14669	15147	29311	86939
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.7 (20.1)	76.8 (0.1)	40.0 (0.1)	49.4 (0.1)	52.0 (21.4)
Sex: Female, Male (Count of Participants)
Female	22084 79.4%	7666 52.3%	13398 88.5%	21992 75%	65140 74.9%
Male	5728 20.6%	7003 47.7%	1749 11.5%	7319 25%	21799 25.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Fibrotic Valvular Heart Disease Per 10,000 Participant-Years of Follow-Up
Description	Occurrence of: mitral stenosis with insufficiency, other unspecified mitral valve diseases, mitral or aortic valve stenosis, insufficiency, or disorders, multiple involvement of mitral and aortic valves, mitral and aortic valve diseases, unspecified, diseases of tricuspid valve, tricuspid valve disorders, specified as nonrheumatic, pulmonary valve disorders, endocarditis, valve unspecified, endomyocardial fibrosis, endocardial fibroelastosis, other primary or secondary cardiomyopathies, cardiomyopathy, functional and undiagnosed cardiac murmurs, other abnormal heart sounds.
Time Frame	Up to 12 years

Outcome Measure Data

Analysis Population Description

Per protocol.

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
Measure Participants	27812	14669	15147	29311
Number [Participants/10,000 Participant-Years]	21 0.1%	21 0.1%	NA NaN	52 0.2%

2. Primary Outcome

Title	Number of Participants With Fibrosis Per 10,000 Participant-Years of Follow-Up
Description	Occurrence of: idiopathic retroperitoneal fibrosis, occlusion not otherwise specified (NOS) of ureter, diffuse (idiopathic) (interstitial) pulmonary fibrosis, Hamman-Rich syndrome, interstitial pneumonia (desquamative) (lymphoid), fibrosis of lung (atrophic; confluent; massive; perialveolar; peribronchial) chronic or unspecified, pulmonary or pleural fibrosis, abnormal communication between pericardial and pleural sacs, pleural fold anomaly, adhesive or constrictive pericarditis, pericardial fibrosis
Time Frame	Up to 12 years

Outcome Measure Data

Analysis Population Description

Per protocol.

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
Measure Participants	27812	14669	15147	29311
Number [Participants/10,000 Participant-Years]	2 0%	5 0%	NA NaN	8 0%

3. Primary Outcome

Title	Number of Participants With Heart Failure Per 10,000 Participant-Years of Follow-Up
Description	Occurrence of: unspecified acute edema of lung, heart failure, acute pulmonary heart disease, or acute cor pulmonale
Time Frame	Up to 12 years

Outcome Measure Data

Analysis Population Description

Per protocol.

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
Measure Participants	27812	14669	15147	29311
Number [Participants/10,000 Participant-Years]	69 0.2%	161 1.1%	NA NaN	201 0.7%

4. Primary Outcome

Title	Number of Participants With All-Cause Mortality Per 10,000 Participant-Years of Follow-Up
Description	All participants who died independent of the cause to include instantaneous death, death occurring in less than 24 hours from onset of symptoms, not otherwise explained, unattended death and other causes of ill defined morbidity and mortality. Cause of death was coded and classified as either cardiovascular or respiratory.
Time Frame	Up to 12 years

Outcome Measure Data

Analysis Population Description

Per protocol.

Arm/Group Title	Dopamine Agonist (Cohort 1)	Levodopa (Cohort 2)	Hyperprolactinemia (Cohort 3)	Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.	Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.	Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.	Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
Measure Participants	27812	14669	15147	29311
Number [Participants/10,000 Participant-Years]	170 0.6%	803 5.5%	NA NaN	719 2.5%

Adverse Events

Adverse Event Reporting Description	Information about adverse events was not collected during this observational, noninterventional, case control study.
Arm/Group Title	Dopamine Agonist (Cohort 1)		Levodopa (Cohort 2)		Hyperprolactinemia (Cohort 3)		Healthy Controls (Cohort 4)
Arm/Group Description	Participants with Parkinson's Disease (PD)/Parkinsonism, Restless Legs Syndrome (RLS) or hyperprolactinemia (previously treated) who newly started one of the ergot-derived Dopamine Agonists (DAs): Lisuride, Cabergoline, Metergoline, Bromocriptine, Pergolide, Dihydroergocryptine mesylate, Quinagolide, Ropinirole, Pramipexole, Piribedil, or Rotigotine.		Participants with PD/Parkinsonism or RLS who newly started treatment with Levodopa: Levodopa and decarboxylase inhibitor; Levodopa, decarboxylase inhibitor and catechol-O-methyl transferase [COMT] inhibitor; MeLevodopa; MeLevodopa and decarboxylase inhibitor; or EtiLevodopa and decarboxylase inhibitor and had not been treated with DAs anytime prior.		Participants with newly diagnosed hyperprolactinemia (excluding postpartum hyperprolactinemia), who had not been treated with DAs anytime prior.		Healthy control participants matched (1:1) with participants in the DA cohort (Cohort 1) for age (exact year), gender, database and date of start of DA.
All Cause Mortality
	Dopamine Agonist (Cohort 1)		Levodopa (Cohort 2)		Hyperprolactinemia (Cohort 3)		Healthy Controls (Cohort 4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dopamine Agonist (Cohort 1)		Levodopa (Cohort 2)		Hyperprolactinemia (Cohort 3)		Healthy Controls (Cohort 4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Dopamine Agonist (Cohort 1)		Levodopa (Cohort 2)		Hyperprolactinemia (Cohort 3)		Healthy Controls (Cohort 4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.