Dopamine agonists and ischemic complications in Parkinson's disease: a nested case-control study.

Abstract

It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied.
Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD.
We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified.
The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists.
This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.

Full text

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PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Dopamine agonists and ischemic complications
in Parkinson’s disease: a nested case–control study
Maurits E. L. Arbouw & Kris L. L. Movig &
Henk-Jan Guchelaar & Cees Neef & Toine C. G. Egberts
Received: 17 February 2011 /Accepted: 7 June 2011 /Published online: 22 July 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
Background It has been suggested that ergoline dopamine
agonists can cause ischemic complications. The effect of
dopamine agonists in general on the prevalence of ischemic
events in patients with Parkinson’s disease (PD) has not
been studied.
Objective Our aim was to investigate the association
between the use of dopamine agonists and hospitalization
due to ischemic events in patients with PD.
Methods We performed a nested case–control study using
the PHARMO Institute for Drug Outcome Research
database. All patients issued at least one prescription for
levodopa after the age of 55 years between 1994 and 2006
were initially identified. Cases were patients who were
hospitalized for the first time after November 1997 for an
ischemic event and were matched to as many as four
controls. Exposure to dopamine agonists during the year
preceding the index date was identified.
Results The study population consisted of 542 cases and
2,155 controls. The mean effect of dopamine agonist use 1
year prior to the index date on ischemic events requiring
hospitalization is shown with 95% probability in the
0.95–1.49 range. Stratified results according to the type of
dopamine agonist showed no risk differences between
ergoline and nonergoline agonists.
Conclusions This study does not support an association
between dopamine agonist use and an increased risk of
ischemic events requiring hospitalization.
Keywords Parkinson’s disease.Dopaminergic drugs.
Ischemic complications
Abbreviations
PD
ICD-9-CM
Parkinson’s disease
International Classification of Diseases 9th
edition
Defined daily dose
Odds ratios
Confidence intervals
DDD
OR
CI
Introduction
Dopamine agonists (DAs) are mainly used as (initial)
monotherapy and adjunctive pharmacotherapy to levodopa
in patients with Parkinson’s disease (PD). Ergoline DAs
M. E. L. Arbouw:T. C. G. Egberts (*)
Department of Clinical Pharmacy,
Division Laboratory and Pharmacy,
University Medical Center Utrecht,
PO Box 85500, 3508 GA Utrecht, The Netherlands
e-mail: a.c.g.egberts@umcutrecht.nl
M. E. L. Arbouw:T. C. G. Egberts
Division of Pharmacoepidemiology and Pharmacotherapy,
Utrecht Institute for Pharmaceutical Sciences, Faculty of Science,
Utrecht University,
Utrecht, The Netherlands
M. E. L. Arbouw:K. L. L. Movig
Department of Clinical Pharmacy, Medisch Spectrum Twente,
Enschede, The Netherlands
H.-J. Guchelaar
Department of Clinical Pharmacy and Toxicology,
Leiden University Medical Center,
Leiden, The Netherlands
C. Neef
Department of Clinical Pharmacy and Toxicology,
University Hospital Maastricht,
Maastricht, The Netherlands
Eur J Clin Pharmacol (2012) 68:83–88
DOI 10.1007/s00228-011-1084-6

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(bromocriptine, lisuride, cabergoline, pergolide), derivates
from ergot alkaloids, were the first DAs available for
treating PD. The nonergoline DAs (ropinirole, pramipexole)
have become available during the past 10 years. It has been
suggested that DAs, and more specifically, ergoline DAs,
can cause ischemic complications. In 1993, there was
suspicion that use of bromocriptine tosuppresspostpartum
lactation could cause adverse cardiovascular and cerebro-
vascular effects, mainly acute myocardial infarction and
stroke [1, 2], but this was not confirmed in a retrospective
cohort study [3]. Furthermore, it is known that intermittent,
chronic, and excessive use of ergotamine, an ergot alkaloid
used to treat migraine, can lead to serious ischemic adverse
events such as peripheral ischemia, arterial stenosis,
myocardial infarction, and cerebral ischemia [4–6]. A more
recent study also demonstrated that overuse of ergotamine,
is associated with increased risk of ischemic complications,
especially in those using drugs for cardiovascular disease [7].
Furthermore, it has been suggested that DAs could cause
peripheral edema [8, 9] and orthostatic hypotension [10].
Orthostatic hypotension is a risk factor for coronary heart
disease events [11] and ischemic stroke [12]. However, the
effect of DAs in general and ergoline DAs specifically on the
prevalence of ischemic events in patients with PD has not
been studied.
The objective of our study was to evaluate in PD patients
the association between the use of DAs and the occurrence of
ischemic complications requiring hospitalization, including
coronary, peripheral, and cerebral vascular ischemic events.
Methods
Setting and study design
We performed a nested case–control study using the
PHARMO Institute for Drug Outcome Research record
linkage system. This includes pharmacy dispensing records
from community pharmacies linked to hospital discharge
records of all 950,000 community-dwelling residents of
25 population-defined areas in The Netherlands from
1985 onward [13]. Because virtually all patients in The
Netherlands are registered with a single community
pharmacy, independent of prescriber, pharmacy records
are virtually complete with regard to prescription drugs.
Participants of the PHARMO population enter the data-
base with the first prescription filled in a PHARMO
community pharmacy and are followed till the last
prescription. The computerized drug-dispensing histories
contain information concerning dispensed drug, dispensing
date, prescriber, amount dispensed, prescribed dose regimen,
and estimated duration of use. The duration of use of each
dispensed drug is estimated by dividing the number of
dispensed units by the prescribed number of units to be used
per day. Patient information per prescribed drug includes
gender and date of birth. The database does not provide
information concerning the indications for use of the
drugs—in this case the diagnosis of PD.
Hospital discharge records are obtained from the Dutch
Medical Register (LMR) from PRISMANT, an institute that
since the 1960s collects all hospital discharge records in
The Netherlands in a standardized format. These records
include detailed information concerning discharge diagnoses,
diagnostic, surgical and treatment procedures, type and
frequency of consultations with medical specialists, and dates
of hospital admission and discharge. All diagnoses are coded
according to the International Classification of Diseases, 9th
edition (ICD-9-CM).
Study base
All patients with at least one prescription for a levodopa-
containing drug after the age of 55 between 1 January 1994
and31December2006wereinitiallyidentified.VandeVijver
and colleagues have shown that 94% of patients >55 years
who are using levodopa in The Netherlands were diagnosed
with PD [14]. In addition, to be included in the study base,
all patients were required to be registered as active in the
PHARMO database after 1 November 1997.
Case and control definition
Cases were defined as all patients from the study base who
were hospitalized for the first time after 1 November 1997
for a coronary, peripheral, or cerebral vascular event. This
date was chosen to show a contrast between ergoline and
nonergoline DAs, because the nonergoline agonists were
introduced in The Netherlands shortly after that date. These
diagnoses are: ischemic heart disease (ICD-9-CM codes
410, 411, and 413), cerebral ischemia (ICD-9-CM codes
433–436, 437.0, 437.1, and 437.6), and peripheral ischemia
[Raynaud’s syndrome (ICD-9-CM code 443.0), unspecified
peripheral vascular disease (ICD-9-CM code 443.9),
vascular insufficiency of intestine (ICD-9-CM code 557.0
and 557.9), and gangrene (ICD-9-CM code 785.4)]. The
index date was the date of hospital admission. Further
criteria for both cases and controls were at least 12 months
of observation in PHARMO before the index date, and the
theoretical end date of the last dispensed drug in the
PHARMO database had to be no more than 180 days before
the index date. For each case patient, up to four control
patients who were at risk for an ischemic event on the
corresponding index date were randomly sampled. Controls
werematchedtocasepatientsaccordingtogender,durationof
prescription history available (within 365 days), and age
(within 5 years). Each control was included only once.
84Eur J Clin Pharmacol (2012) 68:83–88

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Exposure definition
For all cases and controls, we identified exposure to all
DAs during the 1 year preceding the index date. DAs
included the ergoline agonists bromocriptine, cabergoline,
pergolide, lisuride, quinagolide; and the nonergoline
agonists ropinirole and pramipexole. Patients were classi-
fied as a DA user when they had at least one prescription
within 1 year before the index date and as no user if they
had no prescription for any DA within 1 year before the
index date. Subsequently, according to the type of DA used,
users were stratified as using an ergoline or a nonergoline
DA. Those who received more than one type of DA in the
year before their index date were grouped according to the
agonist group prescribed for the longest period during
12 months. If two or more agonists were taken for the same
number of months, patients were classified according to the
most recent use. Current use was defined as use that was
still in effect at the index date, recent use as use within
6 months before the index date, and past use as use
within 12 months before the index date. Total DA
consumption per patient was estimated by the sum of
defined daily doses (DDDs) dispensed 1 year before the
index date. One DDD was defined as 40 mg bromocrip-
tine, 3 mg cabergoline, 3 mg pergolide, 3.6 mg lisuride
(based on 0.6 mg for indication lactation inhibition),
0.075 mg quinagolide, 6 mg ropinirole, or 2.5 mg
pramipexole (http://www.whocc.no/atc_ddd_index).
Potential confounding factors
To adjust for factors that may confound the association
between ergoline DA use and the occurrence of ischemic
complications, the following covariates were studied as
potential confounders: prior hospitalization before November
1997 due to ischemic event, other prior hospitalization 1 year
priortotheindexdate,comedicationusepriortotheindexdate
(fenfluramine, dexfluramine, ergotamine, dihydroergotamine
or methysergide), other comedication use 1 year prior to the
index date [levodopa, antidepressants, antidiabetics, gastroin-
testinal drugs (proton pump inhibitors, H2-antagonists),
nonsteroidal anti-inflammatory drugs (NSAIDs), hormones
(orally administered anticonceptives and hormonal replace-
ment therapy), and drugs to treat cardiovascular disease
(angiotensin-converting enzyme inhibitors, beta-blockers,
calcium antagonists, diuretics, nitrates, digoxin, vitamin-K
antagonists, antiplatelet therapy, lipid-lowering therapy)].
Data analysis
For cases and controls, the prevalence of each characteristic
at or during the period 1 year prior to the index date was
determined. Differences between cases and controls were
examined using Fisher’s exact test for categorical variables
and independent samples Student’s t test for continuous
variables. Conditional logistic regression was used to
estimate the strength of the association between the use of
DAs and ischemic complications requiring hospitalization,
expressed as crude and adjusted odds ratios (OR) with 95%
confidence intervals (CI). The overall logistic regression
model included all potentially confounding factors that
changed the natural logarithm of the risk estimate between
DA use and the occurrence of ischemic complications
by >10%. In a subanalysis, patients were stratified to
current use, recent use, and past use. Furthermore, patients
were categorized to the intensity of DA use: 0, >0 to <150,
150 to <300, 300 to <450, and Q450 DDD. Microsoft
Access was used for database management and internal
quality procedures. All statistical analyses were performed
with SPSS (version 16.0.2).
Results
A flow chart of inclusion is presented in Fig. 1. The study
base consisted of 8,094 patients. We identified 542 case
patients who were hospitalized due to ischemic events and
2,155 matched control patients.
Characteristics of the study population at the index date
are described in Table 1. Cases were hospitalized more
frequently than controls and more frequently used drugs
used in cardiovascular, gastrointestinal, and diabetic
treatment. There was no difference in amount of levodopa
users between cases and controls. Most ischemic events
were of a cardiovascular nature (47.4%). Cerebrovascular
events occurred in 45.0% of cases and peripheral ischemic
events in 7.6%. Four of the 542 case patients (0.7%) were
hospitalized for the diagnosis of valvular heart disease ever
before the index date.
The final regression model included drugs to treat
cardiovascular disease, prior hospitalization 1 year before
the index date, and prior hospitalization due to ischemic
event before November 1997. Table 2 shows that the mean
effect of DA use 1 year prior to the index date on ischemic
events requiring hospitalization was with 95% probability
in the 0.95–1.49 range. Stratified results according to DA
type used show that there were no risk differences between
ergoline and nonergoline DA users. Risk estimates for
ischemic events after stratification to current, recent, or past
use remained in the same order (Table 3). There was no
relationship between the intensity of DA use expressed as
number of DDD and the risk of ischemic events requiring
hospitalization.
We performed an exploratory analysis in which we
stratified users of an ergoline DA (1 year before the index
date) to type of DA used >1 year before the index date.
Eur J Clin Pharmacol (2012) 68:83–8885

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Accordingly, we stratified users of a nonergoline DA
(1 year before the index date) to type of DA used >1 year
before the index date. A main finding was that compared to
never use, nonergoline DA use with ergoline use >1 year
before the index date was associated with a higher risk of
ischemic events (adjusted OR 1.72; 95% CI 1.33–2.07).
Discussion
This study does not support an association between DA use
and an increased risk of ischemic events requiring hospi-
talization. Type of DA used (ergoline or nonergoline) and
intensity of use does not influence the risk estimate.
Pharmacologically, we expected an increased risk of
Table 1 Baseline characteristics of cases (ischemic event) and
controls (no ischemic event)
CharacteristicsCases
(n=542),
no. (%)
Controls
(n=2,155),
no. (%)
P value*
Gender
Female
Male
Age, years, mean (SD)
Prior hospitalization due to
ischemic event before
November 1997
Other prior hospitalization
(1 year prior to index date)
Comedication
Fenfluramine
Dexfluramine
Ergotamine
Methysergide
Comedication (1 year prior to index date)
Antidepressants
Benzodiazepines
Antidiabetics
Orally administered
contraceptives
HRT
Gastrointestinal
NSAIDs
Cardiovascular
Levodopa
NS
227 (41.9) 907 (42.1)
315 (58.1) 1,248 (57.9)
75.4 (8.0)
44 (8.1)
75.2 (7.9)
0 (0)
NS
<0.001
206 (38.0) 555 (25.8)<0.001
1 (0.2)
2 (0.4)
4 (0.7)
0 (0)
3 (0.1)
4 (0.2)
11 (0.5)
0 (0)
NS
NS
NS
NS
50 (9.2)
135 (24.9) 480 (22.3)
55 (10.1)
0 (0)
208 (9.7) NS
NS
0.001
NS
134 (6.2)
5 (0.2)
7 (1.3)
103 (19.0) 264 (12.3)
119 (22.0) 400 (18.6)
269 (49.6) 767 (35.6)
391 (72.1) 1,563 (72.5) NS
43 (2.0)NS
<0.001
NS
<0.001
NS not significant, SD standard deviation, HRT hormone replacement
therapy, NSAIDs nonsteroidal anti-inflammatory drugs
*Fisher’s exact test for comparison of proportions and independent t
samples for comparisons of means between cases and controls
Study base: 8094 patients
1126 patients hospitalised with
ischemic event after november 1997
542 case patients
2155 matched control patients
Excluded 584 patients:
- 510 patients: no minimum
drug history of one year
- 74 patients: theoretical end
date of the last dispensed drug
was more than 180 days
before the index date
Fig. 1 Case and control patient inclusion
Table 2 Association between use of a dopamine agonist (DA) in
general and stratified by type 1 year prior to the index date and
hospitalization due to ischemic event
Cases
(n=542),
no. (%)
Controls
(n=2,155),
no. (%)
Crude OR
(95% CI)
Adjusted OR
(95% CI)
No dopamine
agonist use
Dopamine
agonist use
Ergot use
366
(67.5)
176
(32.5)
103
(19.0)
73
(13.5)
1,516
(70.3)
639
(29.7)
381
(17.7)
258
(12.0)
1.0 (Ref)1.0 (Ref)
1.16
(0.94–1.43)
1.13
(0.88–1.46)
1.20
(0.89–1.62)
1.19
(0.95–1.49)
1.22
(0.93–1.60)
1.15
(0.83–1.57)
Nonergot use
Adjusted for use of drugs to treat cardiovascular disease and prior
hospitalization 1 year before the index date and for prior hospitaliza-
tion due to ischemic event before November 1997
OR odds ratio, CI confidence interval, Ref reference
86 Eur J Clin Pharmacol (2012) 68:83–88

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ischemic events with DA use in general, and probably an
even higher risk with ergoline DA use specifically. First,
it is known that all DAs may cause orthostatic hypoten-
sion as a direct effect and from interactions with
baroreflex and sympathoneural pathophysiological mech-
anisms that are part of the disease process [10].
Orthostatic hypotension is a risk factor, but probably not
a major risk factor, for coronary heart disease events [11]
and ischemic stroke [12]. Coronary heart disease events
are explained by rapid displacement of blood volume to
the lower body—up to 30% of thoracic blood volume—
that causes postural blood pressure change [11]. Ischemic
stroke is explained by decreased cerebral perfusion due to
the drop in pressure, and indirectly by the contribution of
postural hypotension to cerebral hypoperfusion through
myocardial ischemia and concomitant hemodynamic in-
stability [12]. Second, peripheral edema has been reported
as a rare complication of ergoline DAs [15]. Recent
studies demonstrate that peripheral edema occurs in up to
16% of users of the nonergoline DA pramipexole [8, 9],
with most cases occurring after 2 years of treatment [8]
and with a higher risk in patients with coronary artery
disease [9]. Thus, peripheral edema is now suggested as a
more general effect of DA therapy, which might increase the
risk of adverse cardiovascular events. Finally, it is suggested
that short-term use of the ergoline DA bromocriptine to
suppress postpartum lactation could cause adverse cardiovas-
cular and cerebrovascular effects, mainly acute myocardial
infarction and stroke, due to vasospastic events [1, 2]. A
possible mechanism would be coronary artery spasm with
possible thrombus formation at the spasm site [1]. However,
in a retrospective cohort study, this suspicion could not be
confirmed [3]. Overuse of ergotamine, another ergot alkaloid
used to treat migraine, has been associated with an increased
risk of ischemic events requiring hospitalization [7]. In PD
treatment, DAs are used long term. This could implicate a
higher risk of adverse cardiovascular and cerebrovascular
effects by ergoline DAs. Apparently, however, DAs do not
exert these effects in a manner that leads to an increased risk
of ischemic events. Also, there was no association between
cumulative dose used in the year before the index date and
ischemic events.
Some patients in this study may have discontinued
therapy >1 year before the index date; however, we
investigated exposure to DAs for only 1 year preceding
the index date. A history in the PHARMO database
of >1 year prior to the index date was not an inclusion
criterion. In a exploratory analysis, we demonstrated that
users of a nonergoline DA 1 year before the index date with
ergoline use >1 year before the index date had a higher risk
of ischemic events compared to never users (adjusted OR
1.72; 95% CI 1.33–2.07). Thus, it seems that past use of
ergoline DAs increases the risk of ischemic events.
However, we have no clear explanation for this exploratory
result. Recently, several studies have been published
supporting a causal relationship between the occurrence of
irreversible valvular heart disease and treatment with the
ergoline DAs pergolide and cabergoline [16, 17]. It is
suggested that this valvulopathy is mediated by stimulation of
5-HT2Breceptors, causing inappropriate mitogenic stimula-
tion of normally quiescent valve cells [18]. However,
hospitalization for the indication valvular heart disease is
coded by ICD-9-CM codes (i.e., 424 and 425) other than
those used in our study. In addition, only 0.7% of our case
patients were hospitalized for the diagnosis of valvular heart
disease before the index date. Thus, we do not believe that
the increased risk of ischemic events by past ergoline DA
use could be explained by a higher risk of valvular heart
disease.
Several limitations of this study should be mentioned.
First, hospital ICD-9 codes may not always be accurate.
Table 3 Association between use of all dopamine agonists (DAs),
ergoline DAs, and nonergoline DAs 1 year prior to the index date and
hospitalization due to ischemic event stratified to current, recent, and
past use
Cases
(n=542),
no. (%)
Controls
(n=2,155),
no. (%)
Crude OR
(95% CI)
Adjusted OR
(95% CI)
No dopamine
agonist use
All dopamine agonists
Current use
366 (67.5) 1,516(70.3) 1.0 (Ref)1.0 (Ref)
60 (11.1)218 (10.1) 1.16
(0.84–1.60)
1.13
(0.88–1.46)
1.36
(0.72–2.58)
1.11
(0.79–1.56)
1.21
(0.93–1.59)
1.40
(0.73–2.69)
Recent use 103 (19.0) 381 (17.7)
Past use13 (2.4) 40 (1.9)
Ergot use
Current use 5 (0.9)23 (1.1) 0.91
(0.34–2.42)
1.10
(0.84–1.43)
2.12
(0.89–5.04)
0.79
(0.26–2.34)
1.20
(0.91–1.60)
2.15
(0.87–5.33)
Recent use90 (16.6) 342 (15.9)
Past use 8 (1.5)16 (0.7)
Nonergot use
Current use55 (10.1) 195 (9.0) 1.20
(0.86–1.68)
1.41
(0.73–2.69)
0.88
(0.33–2.33)
1.15
(0.81–1.63)
1.27
(0.64–2.52)
0.92
(0.34–2.47)
Recent use13 (2.4)39 (1.8)
Past use 5 (0.9)24 (1.1)
Adjusted for use of drugs to treat cardiovascular disease and prior
hospitalization 1 year before the index date and for prior hospitaliza-
tion due to ischemic event before November 1997
OR odds ratio, CI confidence interval, recent use >0–180 days before
index date, past use >180–360 days before index date
Eur J Clin Pharmacol (2012) 68:83–8887

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Dutch validity studies for the ICD-9 codes that we used
have not been published. False negatives, meaning that
among the controls one could find some cases, would
have weakened our results. False positives, i.e., not all
cases were truly cases, would also lead to weaker results.
Second, the intensity of DA use may be a marker of PD
severity. PD seems to be not only a movement disorder
due to dopamine loss in the nigrostriatal system of the
brain, but it also involves postganglionic sympathetic
noradrenergic lesions. Orthostatic hypotension frequently
occurs in patients with PD, irrespective of dopaminergic
medication [10]. However, excess risk of adverse coronary
artery events or ischemic stroke has not been reported
among patients with PD [19, 20]. Thus, disease severity
itself seems not to be a confounding factor. Furthermore,
although adjusted for potential confounders, residual
confounding may exist because a few factors known to
be associated with increased risk of coronary and
cerebrovascular complications—such as smoking, family
history, obesity, and lack of fitness—were unknown. Last,
there is small chance that PD patients treated with DAs
may not have been identified. Patients with at least one
prescription for a levodopa-containing drug after the age
of 55 were included in the study base. Although all PD
patients will eventually start levodopa, some patients may
have begun treatment outside the inclusion period.
Strengths of this study are that our sample size was
substantial, and we routinely collected longitudinal data
on drug exposure and hospitalizations. Patients were
included irrespective of socioeconomic status: the study
was population-based and provided real-life data on DA
intake. Overall, contrary to case reports, this population-
based study does not provide evidence to support an
association between ischemic events and DA use—or
more specifically—ergoline DA use.
Conflicts of interest
Pharmacotherapy employing authors Arbouw and Egberts has
received unrestricted funding for pharmacoepidemiological research
from GlaxoSmithKline, Novo Nordisk, the privately/publicly funded
Top Institute Pharma (www.tipharma.nl, as well as cofunding from
universities, government, and industry), the Dutch Medicines Evaluation
Board, and the Dutch Ministry of Health.
The division of Pharmacoepidemiology &
Open Access
Creative Commons Attribution Noncommercial License which
permits any noncommercial use, distribution, and reproduction in
any medium, provided the original author(s) and source are
credited.
This article is distributed under the terms of the
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