Download Long-term Use of Anti-inflammatory Drugs and Risk of Atrial Fibrillation

ORIGINAL INVESTIGATION
Long-term Use of Anti-inflammatory Drugs
and Risk of Atrial Fibrillation
Raffaele De Caterina, MD, PhD; Ana Ruigómez, MD, PhD; Luı́s Alberto Garcı́a Rodrı́guez, MD, MSc
Background: Previous reports have described an association between the use of corticosteroids (steroidal antiinflammatory drugs [SAIDs]) and the risk of atrial fibrillation (AF). We sought to determine the existence of a
similar association for non-SAIDs (NSAIDs).
Methods: We identified patients aged 40 to 89 years with
a first-ever diagnosis of AF in 1996 in a United Kingdom primary care database and classified them as having paroxysmal or chronic AF. After validation with their
primary care physicians, 1035 patients were confirmed
as having incident chronic AF and 525 as having paroxysmal AF. Two separate nested case-control analyses estimated the risk of first-time chronic and paroxysmal AF
among users of SAIDs and NSAIDs.
Results: We confirmed the previously reported association between current use of SAIDs and chronic AF (rate
A
Author Affiliations: Institute
of Cardiology and Center
of Excellence on Aging,
“G. d’Annunzio” University,
Chieti, Italy (Dr De Caterina),
and Centro Español
de Investigación
Farmacoepidemiológica,
Madrid, Spain (Drs Ruigómez
and Rodrı́guez).
ratio [RR], 2.49; 95% confidence interval [CI], 1.563.97). However, we also found that the current use of
NSAIDs was associated with an increased risk of chronic
AF (RR, 1.44; 95% CI, 1.08-1.91). Such risk was further
increased among long-term users with a treatment duration of longer than 1 year (RR, 1.80; 95% CI, 1.202.72). The increased risk of chronic AF was not explained by the occurrence of heart failure. The use of
NSAIDs was not associated with paroxysmal AF.
Conclusions: The use of NSAIDs, as for SAIDs, is associated with an increased risk of chronic AF. Because the
use of anti-inflammatory drugs in general is a marker for
underlying inflammatory disorders, inflammation may
be the common cause for the use of anti-inflammatory
drugs and chronic AF.
Arch Intern Med. 2010;170(16):1450-1455
TRIAL FIBRILLATION (AF) IS
a common condition. It affects 0.4% of the general
population1 but more than
6% of individuals older
than 80 years.2-4 The prevalence of AF is
increasing,5 even after adjustment for age.6,7
Atrial fibrillation reduces life expectancy.8,9 The most frequent pathoanatomical changes in AF are atrial fibrosis and loss
of atrial muscle mass. Histological examination of atrial tissue of patients with AF
has shown patchy fibrosis juxtaposed with
normal atrial fibers, which may account
for inhomogeneities of conduction.10-12 It
is difficult to distinguish between changes
due to AF and those due to associated heart
disease, but fibrosis may precede the onset of AF.13 Atrial fibrosis may be caused
by inflammation,14 as seen in cardiac sarcoidosis15 and autoimmune disorders.16
The coexistence of inflammatory diseases and AF, especially in the elderly, may
be causal. The use of anti-inflammatory
drugs may characterize a phenotype with
an underlying inflammatory substrate. Because of this, we hypothesized the existence of an association between the con-
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1450
sumption of anti-inflammatory drugs, of
which nonsteroidal anti-inflammatory drugs
(NSAIDs) represent the most common
therapeutic class, and AF. Herein, we report on such an association and speculate
on the possible underlying mechanisms.
METHODS
DATA SOURCE
The United Kingdom (UK) General Practice Research Database (GPRD) contains computerized information entered by primary care physicians in the UK. The vast majority of the UK
population is registered with a primary care
physician. At the time of the study, approximately 1500 physicians were participating in
the GPRD, covering a population of approximately 3 million individuals who are broadly
representative of the UK population. The primary care physicians hold the complete medical record of registered individuals, including
demographic data, all medical diagnoses, consultant and hospital referrals, and a record of
all prescriptions issued. Prescriptions are generated directly from the primary care physician’s computer and entered into the patient’s
computerized file.
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.
All information is recorded by physicians during consultations in a standardized fashion, and individual practices regularly anonymize and send these data to the Medicines and Healthcare Products Regulatory Agency (UK Department of Health),
which organizes them for use in research projects. Several validation studies have shown the accuracy and completeness of
data on diagnoses, medical information, and prescriptions recorded in the GPRD.17,18 Previous studies have also confirmed
the validity and utility of the GPRD for research on AF.19-22
CASE ASCERTAINMENT
In previous studies, we identified patients aged 40 to 89 years
with a first-ever recorded diagnosis of AF (International Classification of Diseases, Eighth Revision, 4163-4164) in 1996.20-22
Patients had to be registered with the general practitioner for
at least 2 years, and individuals with a history of cancer or heart
rhythm disorders were not included. For the purposes of the
studies, patients whose arrhythmia persisted for more than 1
week were classified as having chronic AF. Those whose arrhythmia reverted to sinus rhythm within 1 week, either spontaneously or after treatment, were labeled as having paroxysmal AF. The AF diagnosis was validated through a questionnaire
sent to primary care physicians, as detailed previously.21,22 In
summary, primary care physicians were asked to confirm
whether this AF episode was the first-ever diagnosis of AF for
their patients and to provide information on diagnostic tests,
procedures, and the etiology of the disorder, including details
of drug therapies. Patient confidentiality was always preserved. We obtained valid responses in 93% of the 2040 patients who were originally identified with AF and for whom validation of diagnosis was requested, and in the end, 1035 patients
were confirmed as having incident chronic AF and 525 as having paroxysmal AF.
NESTED CASE-CONTROL ANALYSES
Two separate case-control analyses were performed to estimate the risk of first-time chronic AF and paroxysmal AF among
users of NSAIDs. We included all patients with confirmed
chronic AF and paroxysmal AF, and the date of their initial diagnosis was the index date. We assigned a random date to all
members of the study cohort where AF cases were ascertained, and randomly sampled 2 groups of 5000 controls from
the pool of eligible members: one for the set of chronic AF cases
and the other for the set of paroxysmal AF cases. The random
date was used as the index date.
EXPOSURE DEFINITION
Exposure to NSAIDs and SAIDs was categorized as current when
the supply of the most recent prescription lasted until the index date or ended in the month before it; as recent when it ended
between 1 and 6 months before the index date; as past when it
ended more than 6 months before the index date; and as nonuse when there was no recorded use ever before the index date.
The effect of daily dose and treatment duration was examined
among current users.
Regarding oral SAIDs, prednisolone doses up to 5 mg/d were
classified as low, doses up to 10 mg/d as medium, and doses higher
than 10 mg/d as high. The corresponding cutoff values were
20 and 40 mg/d for hydrocortisone, 0.8 and 1.5 mg/d for dexamethasone, and 25 and 50 mg/d for cortisone. Regarding
NSAIDs, specific cutoff values for doses, in milligrams, were
as follows: acemetacin, 120; azapropazone, 600; diclofenac, 100;
diflunisal, 1500; etodolac, 400; fenbufen, 900; fenoprofen, 1200;
flurbiprofen, 150; ibuprofen, 1200; indomethacin, 75; keto-
Table 1. Rate Ratio (RR) of Chronic Atrial
Fibrillation (AF) According to Use, Treatment Duration, and
Daily Dose of Steroidal Anti-inflammatory Drugs (SAIDs) a
SAID Exposure
Timing
Nonuse
Current use
Recent use
Past use
Timing, d
ⱕ30
⬎30
31-365
⬎365
Daily dose
Low
Medium
High
Controls
(n = 5000)
Chronic AF
Cases
(n = 1035)
RR (95% CI)
4594
69
109
228
882
52
42
59
1 [Reference]
2.49 (1.56-3.97)
1.51 (0.89-2.57)
0.84 (0.60-1.18)
18
51
25
26
18
34
19
15
4.73 (2.01-11.16)
1.90 (1.09-3.31)
1.58 (0.76-3.25)
2.46 (1.06-5.69)
30
14
25
21
6
25
1.95 (0.95-4.02)
1.93 (0.61-6.10)
3.41 (1.68-6.90)
Abbreviation: CI, confidence interval.
ratio adjusted for age, sex, smoking, body mass index, alcohol use,
health care visits, ischemic heart disease, heart failure, valvular disease,
hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and
non-SAIDs.
a Rate
profen, 150; ketorolac, 30; mefenamic acid, 1000; meloxican,
7.5; nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200; tenoxicam, 10; and tiaprofenic acid, 600. Doses less
than or equal to the cutoff value were grouped under lowmedium doses, and doses greater than the cutoff value were
considered high doses. Duration of use was computed among
current users summing the days included in the time interval
of “consecutive” prescriptions and categorized into 3 groups:
use for less than 1 month, use between 1 month and 1 year,
and use for more than 1 year.
STATISTICS
We used unconditional logistic regression to compute multivariate estimates of odds ratios and 95% confidence intervals
(CIs) of AF associated with SAID or NSAID use as well as the
dose and duration response. All estimates were adjusted by age,
sex, and other risk factors, including smoking status; body mass
index; alcohol consumption; prior health care visits; presence
of diabetes, hypertension, heart failure, ischemic heart disease, or valvular heart disease; and use of digoxin, anticoagulants, and aspirin. Under our design of incidence density sampling, the odds ratio is an unbiased estimator of the incidence
rate ratio (RR).
RESULTS
RISK OF CHRONIC AF ACCORDING
TO USE, TREATMENT DURATION, AND DAILY
DOSE OF SAIDs
We found that use of SAIDs is associated with an increased risk of chronic AF (RR, 2.49; 95% CI, 1.56-3.97
for current use, and RR, 1.51; 95% CI, 0.89-2.57 for recent use), confirming previous findings (Table 1). When
we grouped low and medium doses in 1 category, the estimate of RR was 1.95 (95% CI, 1.05-3.60), and the cor-
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1451
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.
Table 2. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF)
According to Use, Treatment Duration, and Daily Dose of
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) a
NSAID Exposure
Timing
Nonuse
Current use
Recent use
Past use
Duration, d
ⱕ30
⬎30
31-365
⬎365
Daily dose b
Low-medium
High
Individual NSAID
Diclofenac
Ibuprofen
Indomethacin
Naproxen
Piroxicam
Other NSAIDs
Controls
(n=5000)
Chronic
AF Cases
(n=1035)
RR (95% CI)
2239
359
350
2072
423
119
79
414
1 [Reference]
1.44 (1.08-1.91)
1.24 (0.89-1.473)
1.11 (0.92-1.33)
125
234
127
107
22
97
42
55
1.04 (0.59-1.83)
1.57 (1.15-2.15)
1.35 (0.88-2.09)
1.80 (1.20-2.72)
210
149
76
43
1.45 (1.03-2.05)
1.41 (0.92-2.15)
107
128
20
40
14
50
33
44
5
13
4
20
1.33 (0.82-2.15)
1.31 (0.84-2.04)
1.18 (0.34-4.15)
1.22 (0.56-2.65)
1.79 (0.53-6.04)
2.25 (1.21-4.18)
Table 3. Rate Ratio (RR) of Paroxysmal Atrial Fibrillation
(AF) According to Use, Treatment Duration, and Daily Dose
of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) a
NSAID Exposure
Timing
Nonuse
Current use
Recent use
Past use
Duration, d
ⱕ30
⬎30
31-365
⬎365
Daily dose b
Low-medium
High
Individual NSAID
Diclofenac
Ibuprofen
Indomethacin
Naproxen
Other NSAIDs
Controls
(n=5000)
Paroxysmal
AF Cases
(n=525)
RR (95% CI)
2269
370
350
1911
225
62
43
195
1 [Reference]
1.18 (0.85-1.66)
0.99 (0.67-1.45)
0.94 (0.76-1.18)
116
254
136
118
11
51
16
35
0.85 (0.43-1.68)
1.30 (0.90-1.88)
0.85 (0.48-1.51)
1.74 (1.11-2.71)
194
176
43
19
1.39 (0.93-2.06)
0.90 (0.53-1.54)
116
112
31
46
65
19
17
2
8
16
1.05 (0.60-1.83)
1.17 (0.67-2.07)
0.41 (0.09-1.81)
1.57 (0.69-3.58)
1.63 (0.87-3.06)
Abbreviation: CI, confidence interval.
Abbreviation: CI, confidence interval.
a Rate ratio adjusted for age, sex, smoking, body mass index, alcohol use,
health care visits, ischemic heart disease, heart failure, valvular disease,
hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and
NSAIDs.
b Specific cutoff values for dose, in milligrams, were as follows:
aceclofenac, 200; acemetacin, 120; azapropazone, 600; diclofenac, 100;
etodolac, 400, fenbufen, 900; fenoprofen, 1200; flurbiprofen, 150; ibuprofen,
1200; indomethacin, 75; ketoprofen, 150; mefenamic acid, 1000; meloxican,
7.5; nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200;
tenoxicam, 10; and tiaprofenic, 600. Doses less than or equal to the cutoff
value were grouped under low-medium doses and doses greater than the
cutoff value were grouped under high doses.
responding estimate of RR among users of a high daily
dose was 3.41 (95% CI, 1.68-6.90). The main indication
for SAID treatment was respiratory disease (asthma and
chronic obstructive pulmonary disease), and the corresponding estimate of RR was 3.67 (95% CI, 1.96-6.88).
The estimate of RR for SAIDS among patients with paroxysmal AF was 1.37 (95% CI, 0.80-2.33).
RISK OF CHRONIC AF ACCORDING
TO USE, TREATMENT DURATION,
AND DAILY DOSE OF NSAIDs
We found that the current use of NSAIDs was associated with an RR of 1.44 (95% CI, 1.08-1.91) for chronic
AF. The increased risk tended to disappear with time
elapsing since last NSAID use (Table 2). The RR associated with the use of NSAIDs for more than 30 days was
1.57 (95% CI, 1.15-2.15), and the RR was highest for the
use of NSAIDs for more than 1 year (RR, 1.80; 95% CI,
1.20-2.72) (Table 2). We found no dose-response effect
in the association when we divided daily use into lowmedium and high (Table 2).
We also sought to ascertain whether individual NSAIDs
were different from each other in their relationship with
chronic AF. The increased RR occurred for all NSAIDs,
a Rate ratio adjusted for age, sex, smoking, body mass index, alcohol use,
health care visits, ischemic heart disease, heart failure, valvular disease,
hypertension, and use of digoxin, anticoagulants, aspirin, and NSAIDs.
b Specific cutoff values for dose, in milligrams, were as follows: aceclofenac,
200; acemetacin, 120; azapropazone, 600; diclofenac, 100; etodolac, 400;
fenbufen, 900; fenoprofen, 1200; flurbiprofen, 150; ibuprofen, 1200;
indomethacin, 75; ketoprofen, 150; mefenamic acid, 1000; meloxican, 7.5;
nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200; tenoxicam, 10;
and tiaprofenic, 600. Doses less than or equal to the cutoff value were grouped
under low-medium doses and doses greater than the cutoff value were grouped
under high doses.
although the 95% CI for individual NSAIDs always encompassed unity, as a result—most likely—of reduced
statistical power (Table 2). We found no association between the use of paracetamol and the risk of paroxysmal AF (RR, 0.98; 95% CI, 0.69-1.39) or chronic AF (RR,
1.00; 95% CI, 0.78-1.30).
RISK OF PAROXISMAL AF
ACCORDING TO USE, TREATMENT
DURATION, AND DAILY DOSE OF NSAIDs
Similar increased risk between use of NSAIDs and the risk
of chronic AF was not found for paroxysmal AF, with
the sole exception of users with more than 1 year of treatment, among whom the estimate of RR was 1.74 (95%
CI, 1.11-2.71) (Table 3).
INTERACTION BETWEEN USE OF NSAIDs AND
ANTECEDENTS OF HEART FAILURE IN THE
RELATIONSHIP WITH CHRONIC AF
Because it is conceivable that the long-term use of NSAIDs
becomes associated with AF owing to the known association of NSAIDs with increased risk of myocardial infarction, thereby causing more heart failure (HF), which
in turn causes a higher rate of AF among NSAIDs users,
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1452
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.
we hypothesized that the association is present only in
individuals with HF and absent in individuals without
HF. Among patients with HF, however, there was no major increased risk of chronic AF in current NSAID users
(RR, 0.93; 95% CI, 0.38-2.27). Conversely, among patients without HF, there was an increased risk of AF in
NSAID users (RR, 1.49; 95% CI, 1.10-2.02) (Table 4).
This finding indirectly speaks against a major role for HF
in mediating the association between the use of NSAIDs
and increased risk of chronic AF.
COMMENT
We found that the current use of NSAIDs is associated
with a statistically significant 44% increase in the risk of
chronic AF, while no similar association was found regarding paroxysmal AF. We also confirmed previous findings regarding the association of the use of SAIDs with
an increased risk of chronic AF.
Several drugs have been associated with an increased
risk of AF,23 but knowledge about the role of drugs in
the development of AF is scarce. In a comprehensive review article that was published in 2004,23 corticosteroids were included among the several drug categories
for which such an association had been reported. Indeed, several case reports and small-series observational studies,24-32 as well as 1 case-control study,33 had
reported on such an association. Such findings were confirmed in an extensive series based on the Rotterdam
Study,34 a population-based cohort study involving 7983
older adults.35 Several hypotheses were raised at that time
to explain the association: (1) high-dose corticosteroids
mediate (local) potassium efflux via a direct effect on the
cell membrane, which may induce arrhythmias25; (2) the
mineral corticosteroid effect of high doses of glucocorticosteroids can cause retention of sodium and fluid, which
in turn may cause hypertension, left atrial enlargement,
and congestive heart failure—all known risk factors for
AF36; and (3) corticosteroids may favor the development of late potentials and occasionally cause profound
peripheral vasodilatation and anaphylactic reactions.37,38 However, there is as yet no conclusive evidence for any of these mechanisms, and it was concluded then that high-dose corticosteroid therapy may
act as a trigger rather than as a single cause for AF, in
line with the earlier-described trigger-substrate relationship in drug-induced AF.23 The present report confirms
those earlier observations. Current and recent use of SAIDs
(mostly because of chronic obstructive pulmonary disease and rheumatic diseases) was associated with a higher
risk of AF with a clear dose-response relationship.
Importantly, however, our report now extends those
earlier observations to the therapeutic group of NSAIDs,
which are mostly devoid of the above-reported postulated proarrhythmogenic properties of SAIDs but share
with SAIDs the indication as treatment for chronic inflammatory conditions. We found, in particular, that the
current use of NSAIDs was associated with a significant
44% increased risk of chronic AF, with the risk tending
to disappear after the NSAID treatment was discontinued. The increased risk was present irrespective of treat-
Table 4. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF)
Associated With Use of Nonsteroidal Anti-inflammatory
Drugs (NSAIDs) Stratified According to Antecedents
of Heart Failure (HF) a
NSAID Exposure
Individuals with
antecedents of HF
Timing
Nonuse
Current use
Recent use
Past use
Individuals without
antecedents of HF
Timing
Nonuse
Current use
Recent use
Past use
Controls
Chronic
AF Cases
113
224
47
10
10
246
4887
93
25
13
93
811
1 [Reference]
0.93 (0.38-2.27)
0.68 (0.24-1.92)
0.93 (0.53-1.65)
2192
349
320
2026
330
94
66
321
1 [Reference]
1.49 (1.10-2.02)
1.31 (0.92-1.87)
1.14 (0.94-1.39)
RR (95% CI)
Abbreviation: CI, confidence interval.
a Rate ratio adjusted for age, sex, smoking, body mass index, alcohol use,
health care visits, ischemic heart disease, heart failure, valvular disease,
hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and NSAIDs.
ment duration, although our data are compatible with a
greater risk associated with long-term use. We found no
apparent dose-relationship when we divided daily use into
low-medium and high. In essence, the use of NSAIDs,
irrespective of the dosing, appeared to coincide with a
higher risk of AF. At the same time, we found no overall
association between use of NSAIDs and the risk of paroxysmal AF, although long-term NSAIDs users also presented an increased risk of paroxysmal AF.
The use of cyclooxygenase-2 inhibitors, both selective (coxibs) and traditional NSAIDs, has been found to
be associated with an increased risk of acute myocardial
infarction,39-43 largely currently interpreted as attributable to an increased risk of thrombosis after the impairment of prostacyclin production, which is mainly cyclooxygenase-2 dependent.44 This increased risk of
thrombosis might translate into an increased risk of late
HF, in turn explaining the higher risk of AF compared
with patients with no previous myocardial infarction.
However, such a hypothesis does not seem to be compatible with our data. When we stratified the analysis according to antecedents of HF, we found that the increased risk of chronic AF associated with the use of
NSAIDs was actually present in patients without HF but
absent in those with prior HF.
However, the association of increased risk of AF with
the use of NSAIDs does not imply a cause-and-effect relationship. Indeed, a likely explanation for our findings
is the existence of an underlying inflammatory condition, increasing the risk of AF on the one hand and
prompting the use of NSAIDs on the other. Underlying
inflammatory conditions could favor the onset or maintenance of AF. Atrial fibrosis is the most frequent pathoanatomical change found in AF. Patchy fibrosis in close
proximity with normal atrial fibers may account for conduction inhomogeneities,10-12 and it has been argued that
fibrosis precedes the onset of AF.13 Atrial fibrosis is cur-
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1453
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.
rently the main structural target for the proposed use of
drugs inhibiting the renin-angiotensin system in AF45,46
and may be caused by inflammation,14 as seen in cardiac
sarcoidosis15 and autoimmune disorders.16 Inflammation, possibly also through the production of thromboxane A2 and prostaglandin F2␣, has recently been shown
to cause inflammatory tachycardia.47 It is possible, and
we would like to propose, that conditions presenting systemic inflammation, such as autoimmune and rheumatic disorders, represent an independent risk factor for
atrial fibrosis and subsequently for an increased risk of
onset or persistence of AF. Consequently, the use of antiinflammatory drugs may be a proxy for an underlying
inflammatory substrate favoring AF. We believe that this
hypothesis deserves further investigation.
We acknowledge a few limitations of our study. The
diagnosis of chronic AF is not in keeping with the currently used distinction between AF that is amenable to
cardioversion (“persistent” AF) and AF for which cardioversion is deemed unsuitable (“permanent” AF)48 but
was the only one available at the time of the entry of data
in our primary care database, in which the duration of
AF was the only distinctive criterion between paroxysmal and chronic AF. Most likely, our definition of chronic
AF includes all cases of currently defined permanent AF
cases and a certain proportion of persistent AF cases. Confirmatory analyses of more recent databases should clarify
this better. The possibility of unknown confounders underlying the relationship cannot be totally discarded. Also,
we have no clear explanation for the stronger association of NSAID use with chronic AF than with paroxysmal AF. One possibility is that the underlying atrial fibrosis, caused by inflammation—for the presence of which
the use of anti-inflammatory agents is a marker—is a condition that predisposes more to perpetuating than to actually causing AF. Another possibility, however, is the
smaller sample size of paroxysmal AF cases (n=525) compared with chronic AF cases (n = 1035). Indeed, the estimates of risk associated with paroxysmal AF and chronic
AF were overlapping; actually—when analyzing the longterm use of NSAIDs defined as continuous use for more
than 1 year—the estimates were quite similar (RR, 1.74;
95% CI, 1.11-2.71 vs RR, 1.80; 95% CI, 1.20-2.72). All
such issues need to be addressed in future analyses. Furthermore, future studies on the association of SAIDs or
NSAIDs with AF should ideally include a description of
left ventricular function, atrial size and/or function, and
inflammatory markers, which would help to make the
association more biologically plausible.
Accepted for Publication: February 17, 2010.
Correspondence: Raffaele De Caterina, MD, PhD, Institute of Cardiology, c/o Ospedale SS Annunziata, Via dei
Vestini, 66013 Chieti, Italy ([email protected]).
Author Contributions: Study concept and design: De Caterina and Garcı́a Rodrı́guez. Acquisition of data: Ruigómez and Garcı́a Rodrı́guez. Analysis and interpretation of
data: De Caterina, Ruigómez, and Garcı́a Rodrı́guez. Drafting of the manuscript: De Caterina and Garcı́a Rodrı́guez.
Critical revision of the manuscript for important intellectual content: Ruigómez. Statistical analysis: Ruigómez and
Garcı́a Rodrı́guez. Obtained funding: Garcı́a Rodrı́guez.
Administrative, technical, and material support: Garcı́a
Rodrı́guez. Study supervision: De Caterina and Garcı́a
Rodrı́guez.
Financial Disclosure: None reported.
Funding/Support: The original data collection for the ascertainment of cases of AF was performed with an unrestricted research grant to Centro Español de Investigación Farmacoepidemiológica from AstraZeneca.
Additonal Contributions: We thank the participating primary care physicians for their collaboration in the validation of patients with AF.
REFERENCES
1. Ostrander LD Jr, Brandt RL, Kjelsberg MO, Epstein FH. Electrocardiographic findings among the adult population of a total natural community, Tecumseh, Michigan.
Circulation. 1965;31:888-898.
2. Flegel KM, Shipley MJ, Rose G. Risk of stroke in non-rheumatic atrial fibrillation.
Lancet. 1987;1(8532):526-529.
3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor
for stroke: the Framingham Study. Stroke. 1991;22(8):983-988.
4. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).
Am J Cardiol. 1994;74(3):236-241.
5. Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. Rising rates of hospital admissions for atrial fibrillation. Epidemiology. 2003;14(6):666-672.
6. Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D, D’Agostino RB. Secular
trends in the prevalence of atrial fibrillation: The Framingham Study. Am Heart
J. 1996;131(4):790-795.
7. Tsang TS, Petty GW, Barnes ME, et al. The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota:
changes over three decades. J Am Coll Cardiol. 2003;42(1):93-100.
8. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern
Med. 1994;154(13):1449-1457.
9. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the longterm risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/
Paisley study. Am J Med. 2002;113(5):359-364.
10. Guiraudon C, Ernst N, Yee R, Lein G. The pathology of drug resistant lone atrial
fibrillation in eleven surgically treated patients. In: Kingma J, Van Hernel N, Lie
K, eds. Atrial Fibrillation: A Treatable Disease? Dordrecht, the Netherlands: Kluwer Academic Publishers; 1992:41-57.
11. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res. 2002;54(2):230-246.
12. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation.
1997;96(4):1180-1184.
13. Bharti S, Lev M. Histology of the normal diseased atrium. In: Fall R, Podrid P,
eds. Atrial Fibrillation: Mechanism and Management. New York, NY: Raven Press;
1992:15-39.
14. Pokharel S, van Geel PP, Sharma UC, et al. Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme
is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased
phosphorylation of Smad2/3. Circulation. 2004;110(19):3129-3135.
15. Sharma OP, Maheshwari A, Thaker K. Myocardial sarcoidosis. Chest. 1993;103
(1):253-258.
16. Maixent JM, Paganelli F, Scaglione J, Lévy S. Antibodies against myosin in sera
of patients with idiopathic paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol.
1998;9(6):612-617.
17. Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ. 1991;
302(6779):766-768.
18. Jick SS, Kaye JA, Vasilakis-Scaramozza C, et al. Validity of the general practice
research database. Pharmacotherapy. 2003;23(5):686-689.
19. Rietbrock S, Heeley E, Plumb J, van Staa T. Chronic atrial fibrillation: incidence,
prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age ⬎75, Diabetes mellitus, and prior Stroke or transient ischemic attack
(CHADS2) risk stratification scheme. Am Heart J. 2008;156(1):57-64.
20. Ruigómez A, Johansson S, Wallander MA, Garcı́a Rodrı́guez LA. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC
Cardiovasc Disord. 2002;2:5.
21. Ruigómez A, Johansson S, Wallander MA, Garcı́a Rodrı́guez LA. Predictors and
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1454
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc Disord. 2005;5:20.
Ruigómez A, Johansson S, Wallander MA, Rodrı́guez LA. Incidence of chronic
atrial fibrillation in general practice and its treatment pattern. J Clin Epidemiol.
2002;55(4):358-363.
van der Hooft CS, Heeringa J, van Herpen G, Kors JA, Kingma JH, Stricker BH.
Drug-induced atrial fibrillation. J Am Coll Cardiol. 2004;44(11):2117-2124.
Ueda N, Yoshikawa T, Chihara M, Kawaguchi S, Niinomi Y, Yasaki T. Atrial fibrillation following methylprednisolone pulse therapy. Pediatr Nephrol. 1988;
2(1):29-31.
Fujimoto S, Kondoh H, Yamamoto Y, Hisanaga S, Tanaka K. Holter electrocardiogram monitoring in nephrotic patients during methylprednisolone pulse therapy.
Am J Nephrol. 1990;10(3):231-236.
Chikanza C, Fernandes L. Arrhythmia after pulse methylprednisolone therapy.
Br J Rheumatol. 1991;30(5):392-393.
McLuckie AE, Savage RW. Atrial fibrillation following pulse methylprednisolone
therapy in an adult. Chest. 1993;104(2):622-623.
Moretti R, Torre P, Antonello RM, Zorzon M, Cazzato G. Recurrent atrial fibrillation associated with pulse administration of high doses of methylprednysolone: a possible prophylactic treatment. Eur J Neurol. 2000;7(1):130.
Aslam AK, Vasavada BC, Sacchi TJ, Khan IA. Atrial fibrillation associated with
systemic lupus erythematosus and use of methylprednisolone. Am J Ther. 2001;
8(4):303-305.
Bocanegra TS, Castañeda MO, Espinoza LR, Vasey FB, Germain BF. Sudden death
after methylprednisolone pulse therapy. Ann Intern Med. 1981;95(1):122.
Moses RE, McCormick A, Nickey W. Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med. 1981;95(6):781-782.
Thompson JF, Chalmers DH, Wood RF, Kirkham SR, Morris PJ. Sudden death
following high-dose intravenous methylprednisolone. Transplantation. 1983;
36(5):594-596.
Huerta C, Lanes SF, Garcı́a Rodrı́guez LA. Respiratory medications and the risk
of cardiac arrhythmias. Epidemiology. 2005;16(3):360-366.
van der Hooft CS, Heeringa J, Brusselle GG, et al. Corticosteroids and the risk of
atrial fibrillation. Arch Intern Med. 2006;166(9):1016-1020.
Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol.
1991;7(4):403-422.
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in
adults: national implications for rhythm management and stroke prevention: the
AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;
285(18):2370-2375.
37. Freedman MD, Schocket AL, Chapel N, Gerber JG. Anaphylaxis after intravenous methylprednisolone administration. JAMA. 1981;245(6):607-608.
38. Ozen S, Tokgozoglu L, Saatci U. Are late potentials operative in arrhythmias following methylprednisolone pulse therapy. Int J Cardiol. 1992;36(2):234-235.
39. Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation. 2006;113(16):1950-1957.
40. Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113(12):
1578-1587.
41. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective
nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation.
2006;113(25):2906-2913.
42. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective
cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults.
Circulation. 2004;109(17):2068-2073.
43. Garcı́a Rodrı́guez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal antiinflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):
1628-1636.
44. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov. 2003;2(11):879-890.
45. Burstein B, Nattel S. Atrial structural remodeling as an antiarrhythmic target. J Cardiovasc Pharmacol. 2008;52(1):4-10.
46. Gillis AM. Angiotensin-receptor blockers for prevention of atrial fibrillation—a
matter of timing or target? N Engl J Med. 2009;360(16):1669-1671.
47. Takayama K, Yuhki K, Ono K, et al. Thromboxane A2 and prostaglandin F2alpha
mediate inflammatory tachycardia. Nat Med. 2005;11(5):562-566.
48. Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/
American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm
Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and
the European Society of Cardiology Committee for Practice Guidelines (Writing
Committee to Revise the 2001 Guidelines for the Management of Patients With
Atrial Fibrillation): developed in collaboration with the European Heart Rhythm
Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257e354.
Call for Papers
Less Is More
The Archives of Internal Medicine is excited to launch Less
Is More—a new feature identifying articles that provide
evidence about situations in which less health care results in better health. For more details, please see the editorial in the April 12, 2010, issue, page 584.
(REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010
1455
WWW.ARCHINTERNMED.COM
Downloaded from www.archinternmed.com at SPITALREGION ST GALLEN RORSCHACH, on November 18, 2010
©2010 American Medical Association. All rights reserved.