Download Dopamine Agonists and the Risk of Cardiac

Dopamine Agonists and the Risk of
Cardiac Valve Regurgitation
Published in New England Journal of Medicine
January 4th, 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.
Clinical Trial Results . org
Dopamine Agonists and the Risk of Cardiac
Valve Regurgitation: Background
• Pergolide and cabergoline are potent agonists of the 5hydroxytryptamine 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.
Clinical Trial Results . org
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
Dopamine Agonists and the Risk of CardiacValve Regurgitation: Study Design
12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 19882005, 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.
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
Case Patients (newly diagnosed
with valvular disease: 6 pergolide,
6 cabergoline, 19 no dopamine
agonist exposure within 1 yr)
Control Patients (matched 25:1
Case Patient)
n=31
n=663

Primary Endpoint: New diagnosis of valve disease
Clinical Trial Results . org
Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.
Dopamine Agonists and the Risk of Cardiac
Valve Regurgitation: Baseline Characteristics*
Characteristic
Case Patients
Controls
No. of Pts. (%)
(n=31 )
(n=663 )
Age (yrsSD)
73.0 7.8
73.5 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)
*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
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
Dopamine Agonists and the Risk of Cardiac
Valve Regurgitation: Baseline Characteristics*
Case
Patients
(n=31)
Controls
(n=663)
Parkinson’s Disease
29 (94)
569 (86)
Restless Leg Syndrome
3 (10)
25 (4)
Hyperprolactinemia
1 (3)
21 (3)
Not Recorded
1 (3)
66 (10)
Levodopa
Amantadine
23 (74)
5 (16)
505 (76)
26 (4)
Selegiline
4 (13)
143 (22)
Apomorphine
1 (3)
6 (1)
Anticholingergic drugs
2 (7)
55 (8)
Characteristics
No. of pts. (%)
Indication for use of a dopamine agonist
Current Use of other antiparkinsonian drugs‡
*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
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
Dopamine Agonists and the Risk of Cardiac-Valve
Regurgitation: Case Patient Valvular Regurgitation Characteristics
Characteristics of 31 Case Patients with Cardiac-Valve Regurgitation,
According to Use of A Dopamine Agonist
Characteristic
no. of pts. (%)
Valvular Regurgitation†
Mitral
Aortic
Tricuspid
No. of Valves Involved
1
2
3
Pergolide
(n=6 )
Cabergoline
(n=6)
No
Dopamine
Agonist
(n=19 )
4 (67)
3 (50)
0
5 (83)
5 (83)
3 (50)
17 (89)
4 (21)
0
5 (83)
1 (17)
0
1 (17)
3 (50)
2 (33)
17 (89)
4 (21)
0
† Percentages may exceed 100 because of overlap between the categories
Clinical Trial Results . org
Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.
Dopamine Agonists and the Risk of Cardiac-Valve
Regurgitation: Primary Endpoint
Current Use of Dopamine Agonists and the Risk of Cardiac-Valve
Regurgitation
Case
Exposure
Controls Adjusted Incidence-Rate
Patients
Ratio
no. of pts. (%)
(n=663)
(n=31)
(95% CI)*
No current or recent use of
a dopamine agonist‡
19 (61)
530 (80)
0
19 (3)
Cabergoline
6 (19)
34 (5)
4.9 (1.5-15.6)
Pergolide
6 (19)
26 (4)
7.1 (2.3-22.3)
Lisuride
0
1 (0)
Pramipexole
0
23 (3)
Ropinirole
0
23 (3)
Bromocriptine
1.0
*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
Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.
Dopamine Agonists and the Risk of CardiacValve 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.
• 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).
Clinical Trial Results . org
Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.
Dopamine Agonists and the Risk of Cardiac
Valve Regurgitation: Primary Endpoint (cont.)
Influence of the Daily Dose of Pergolide or Cabergoline
Exposure
no. of pts. (%)
No current or recent
use of a dopamine
agonist†
Last Daily Dose
Pergolide
<3mg
>3mg
Cabergoline
<3mg
>3mg
Case
Patient
n=31
Control
n=663
19(61)
530(80)
Adjusted IncidenceRate Ratio
(95% CI)*
P Value
1
0.07
3(10)
3(10)
21(3)
5(1)
5.1(1.3-20.4
37.1(5.1-270.6)
0.01
2(7)
4(13)
31(5)
3(0)
2.6(0.5-12.8)
50.3(6.6-381.4)
*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
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
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
Regurgitation.
Exposure
no. of pts. (%)
No current or recent use of
a dopamine agonist†
Cumulative duration of use
Pergolide
<6 mo
≥6 mo
Cabergoline
<6 mo
≥6 mo
Case
Controls
Patients
(n=663)
(n=31 )
Adjusted
Incidence-Rate
Ratio
(95% CI)*
19 (61)
530 (80)
1
0
6 (19)
4 (1)
22 (3)
9.8 (2.9 – 33.1)
0
6 (19)
11 (2)
23 (4)
7.8 (2.2 – 27.4)
*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
Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.
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.
Clinical Trial Results . org
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
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.
• 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.
Clinical Trial Results . org
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.
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.
• 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.
Clinical Trial Results . org
Schade, et al New Engl J Med. 2007; 356 (1) 29-38.