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Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone

Population-Level Incidence and Risk Factors for Pulmonary
Toxicity Associated With Amiodarone
Cynthia Anne Jackevicius, BScPhm, PharmD, MSca,b,c,d, Albert Tom, PharmDa, Vidal Essebag, MD, PhDe, Mark J. Eisenberg, MD, MPHe, Elham Rahme, PhDe, Jack Ven Tu, MD, PhDb,c, Karin Humphries, MBA, DScf, Hassan Behlouli, PhDe, and Louise Pilote, MD, MPH, PhDe,* Estimates from clinical trials and small observational studies of the incidence of pulmonary
toxicity (PT) associated with amiodarone range from 1% to 10%. We report a unique study
of the population-based incidence and potential predictors of PT in a real-world atrial
fibrillation (AF) population. We conducted a retrospective cohort study of patients
years old discharged with AF using linked administrative databases from Quebec, Canada
from 1999 to 2007. "Users" and "nonusers" of amiodarone were identified by prescriptions
dispensed within 7 days after hospital discharge. PT was defined through International
Classification of Diseases, Ninth Revision
and Tenth Revision codes for pulmonary fibrosis,
alveolar/interstitial lung disease, and adult respiratory distress syndrome. Potential risk
factors for PT were identified using multivariable Cox regression. PT occurred in 250 of 6,460
amiodarone users (3.87%) and 676 of 50,993 nonusers (1.33%). Age-standardized PT incidences
were 28.30 and 16.02 per 1,000 person-years in men and women users, respectively, and 14.05
and 8.82 per 1,000 person-years in nonusers, respectively. It was associated with amiodarone
exposure at all doses (
<200 mg/day, hazard ratio 1.62, 1.35 to 1.96; >200 mg/day, 1.46, 1.22 to
1.75). Other predictors of PT included increasing age (1.01 per year, 1.00 to 1.02), male gender
(1.37, 1.19 to 1.57), chronic obstructive pulmonary disease (2.53, 2.21 to 2.89), and renal disease
(1.26, 1.06 to 1.50). In conclusion, the population-based incidence of amiodarone PT is in the
lower range of what has been previously reported. However, patients with AF who use
amiodarone have an approximately 50% higher risk of PT than nonusers. Clinicians may be
able to use the present results to identify patients at higher risk for PT and implement strategies
to increase monitoring or select alternative therapy.

2011 Elsevier Inc. All rights reserved.
(Am J Cardiol 2011;108:705–710)
Amiodarone is a highly effective Its pulmonary PT secondary to amiodarone has long 1/2 life causes long-lasting major adverse effects (pul- nonspecific diagnostics; however, impairment of diffusion monary toxicity [PT], thyroid dysfunction, hepatotoxicity, capacity for carbon monoxide, total lung capacity, and and skin Amiodarone PT, first reported in forced vital capacity are Increased age, pre- 1980, is 1 of the most serious adverse effects, thus limiting existing lung disease, dose, and duration of therapy are its The incidence of amiodarone PT is reported to be potential risk Although higher doses tend to 0% to 10% (0% to 8% in randomized controlled trials, 2% be more toxic, low doses of amiodarone can cause serious to 8% in prospective cohorts and case series, and ⬍2% in Meta-analyses have provided estimates of Mortality is estimated at 1% to amiodarone However, participants in clinical trials Onset of amiodarone PT is unpredictable and in- are usually healthier than the general population. Although sidious, often remaining a diagnosis of exclusion, after many case series have described the nature of the presen- consideration of heart failure, pulmonary embolism, and tation of amiodarone PT, the samples were small or thestudies were limited to a single center. Given these limita-tions, there is a need to estimate the population-level inci- dence of and risk factors for amiodarone PT. Furthermore, Western University of Health Sciences, Pomona, California; bInstitute as new drug and nondrug therapies for rhythm control in for Clinical Evaluative Sciences, Toronto, Ontario, Canada; cUniversity of atrial fibrillation (AF) become available, there is a need to Toronto, Toronto, Ontario, Canada; dUniversity Health Network, Toronto,Ontario, Canada; eMcGill University, Montreal, Quebec, Canada; fProvin- revisit the risks of existing therapies in a contemporary cial Health Services Authority, Vancouver, British Columbia, Canada.
patient cohort.
Manuscript received January 12, 2011; revised manuscript received andaccepted April 21, 2011.
This work was funded by an operating grant from the Canadian Insti- We conducted a retrospective observational cohort study tutes for Health Research, Ottawa, Ontario, Canada.
of patients with AF using linked administrative data. For *Corresponding author: Tel: 514-934-1934, ext 34667; fax: 514-843- patient identification, we used the hospital discharge ab- E-mail address: (L. Pilote).
stract database Maintenance et Exploitation des Données 0002-9149/11/$ – see front matter 2011 Elsevier Inc. All rights reserved.
The American Journal of Cardiology ( pour l'Étude de la Clientèle Hospitalière, which contains inpatient diagnostic and therapeutic procedures codes. Med- Baseline characteristics of patients with atrial fibrillation with and ications were identified by the drug identification number without amiodarone exposure in the provincial prescription claims database Régie de l'Assurance Maladie du Québec for information on medi- cation use and duration of therapy, which is available only (n ⫽ 6,460) (n ⫽ 50,933) for those ⱖ65 years old. Survival data were obtained fromthe Maintenance et Exploitation des Données pour l'Étude de la Clientèle Hospitalière and Régie de l'Assurance Mala- die du Québec databases.
Chronic obstructive pulmonary Subjects were included if they were ⱖ65 years old and discharged with a primary or secondary diagnosis of AF from January 1, 1999 through March 31, 2007 identified Diabetes mellitus according to International Classification of Diseases, Ninth Coronary artery disease Revision and Tenth Revision (ICD-9/10) codes 427.3, Stroke (including transient 427.31, and 427.32/I48. We conducted an internal valida- tion using AF diagnoses in the hospital discharge abstract database and the physician billing database. To ensure pa- Chronic kidney disease tients had nontransient AF and for patients without a pri- mary diagnosis of AF, 2 secondary diagnoses of AF were Median CHADS2 score required. For patients with ⬎1 AF diagnosis code, the first Concurrent use of nonamiodarone hospitalization discharge date was the cohort entry date.
Concurrent use of rate-control Patients were excluded if they had AF coded as a compli- cation; a history of valvular disease/surgery; AF within 30 Concurrent use of strong days of coronary artery bypass surgery, pericardial surgery, cytochrome P450 3A4 or structural cardiac repair; history of pulmonary fibrosis within 12 months; or were residents of long-term care fa- Concurrent use of corticosteroids Concurrent use of medications Exposure was determined based on amiodarone prescrip- associated with pulmonary tions filled within 7 days of index hospital discharge. A sensitivity analysis was conducted by extending this period CHADS2 ⫽ congestive heart failure, hypertension, age ⱖ75 years, to 30 days. Those without an amiodarone prescription were diabetes mellitus, stroke.
considered nonusers. Discontinuation of an amiodarone pre-scription was defined as the end date of the last filledprescription plus 60 days or end of follow-up, whichever came first. The 60-day period was used because of the long Pulmonary toxicity events by diagnosis category* 1/2 life of amiodarone and to avoid miscoding patients who Postinflammatory pulmonary fibrosis were late in refilling their prescription as unexposed. To Other pulmonary insufficiency calculate incidence, quantity, tablet strength, and days of Pulmonary insufficiency after trauma and surgery supply of each amiodarone prescription were used to create Other interstitial pulmonary disorders an average daily dose (milligrams per day). Patients were Other specified alveolar and parietoalveolar categorized into low-dose (ⱕ200 mg/day) or high-dose Idiopathic fibrosing alveolitis (⬎200 mg/day) groups.
Acute respiratory distress syndrome Patients were followed from AF diagnosis until occur- Other (each ⬍1% in frequency) rence of the study outcome of first principal or secondary PT diagnosis (pulmonary fibrosis ICD-9/10 515/J84, J84.1,J84.8, J84.9, J70.2, J70.3, J70.4, J70.8, J70.9; idiopathic *Some patients had ⬎1 diagnosis type coded; therefore, coding diagno- pulmonary fibrosis ICD-9 516.3; or other alveolar/intersti- sis events ⫽ 948, whereas actual patient events ⫽ 926.
tial disease ICD-9 516; adult respiratory distress syndromeICD-9/10 518.5, 518.82/J80) or March 31, 2007, whichever Potential risk factors for the development of PT that we came first. Idiopathic pulmonary fibrosis was included be- evaluated included patient demographics (age, gender), co- cause PT is more likely a result of amiodarone-associated morbidities within previous 12 months (chronic obstructive pulmonary fibrosis rather than idiopathic pulmonary fibro- pulmonary disease [COPD], heart failure, diabetes mellitus, sis. We considered a broad definition of PT because it may hypertension, coronary artery disease, stroke, chronic kid- be diagnosed as pulmonary fibrosis, interstitial pneumonitis, ney disease [CKD], hypothyroidism, liver disease), AF pulmonary alveolitis, or acute respiratory distress syn- medications (nonamiodarone antiarrhythmics, rate-con- Death was documented if it occurred before trol medications [␤ blockers, verapamil, diltiazem, the end of the follow-up period (in the absence of the PT digoxin]), amiodarone dose (ⱕ200 or ⬎200 mg/day, non- outcome). Follow-up for each subject was censored after the users 0 mg), and strong cytochrome 3A4 inhibitors first PT diagnosis, drug discontinuation, end of follow-up, (erythromycin, clarithromycin, ketoconazole, itracona- or death, whichever came first.
zole, nelfinavir, or ritonavir).

Arrhythmias and Conduction Disturbances/Pulmonary Toxicity Associated With Amiodarone rson-y
Amiodarone ADD ≤ 200 mg Amiodarone ADD > 200 mg Figure 1. Age-adjusted incidence rate (per 1,000 person-years) of pulmonary toxicity by gender and dose. ADD ⫽ average daily dose.
Time to Development of Pulmonary Toxicity
tion Fr 0.4
ropor 0.3
Figure 2. Time to development of pulmonary toxicity.
Descriptive statistics were used to compare baseline char- any amiodarone. The crude mortality rate for those who de- acteristics between groups. Crude and age-standardized inci- veloped PT was estimated. Multivariable Cox proportional dence rates of PT overall and stratified by gender, amiodarone hazards models were used to estimate hazard ratios with 95% dose, and significant risk factors for PT (number per 1,000 confidence intervals for outcome of PT between exposed and person-years) were estimated for users and nonusers. The ref- unexposed subjects and to identify potential predictors of PT.
erence group for age standardization was all patients in the AF Sensitivity analyses included dose– gender and dose–age inter- cohort for fiscal year 2002. Crude incidence of PT in users was action terms and exposure based on prescriptions filled within calculated by dividing the number of subjects with PT by the 30 days (instead of 7 days) of index hospital discharge. All p sum of observation times of all subjects who were exposed to values were 2-sided. Data were analyzed using SAS 9.1 (SAS The American Journal of Cardiology ( Amiodarone was associated with a significantly in- Adjusted estimate of factors associated with pulmonary toxicity creased risk of PT when adjusting for potential confounders at doses ⱕ200 mg/day (hazard ratio 1.62, 95% confidenceinterval 1.35 to 1.96) and ⬎200 mg/day (hazard ratio 1.46, Amiodarone ⱕ200 vs 0 mg/day 1.22 to 1.75). A significantly increased risk of PT was also Amiodarone ⬎200 vs 0 mg/day associated with male gender, increased age, COPD, and Gender (male gender is reference) CKD. Patients with COPD had the highest risk of develop- ing PT (2.53, 2.21 to 2.89). Although patients who were Chronic obstructive pulmonary taking strong cytochrome P450 3A4 inhibitors had a trend toward increased risk of PT, it was not significant (hazard ratio 1.53, 0.96 to 2.44), whereas subjects who were taking concurrent rate-control medications had a significantly Diabetes mellitus lower risk of PT (hazard ratio 0.85, 0.75 to 0.97; Coronary artery disease Sensitivity analyses including dose– gender and dose–age Stroke (including transient interaction terms found no evidence of interaction. Sensi- tivity analyses that defined use of amiodarone within 30 Chronic kidney disease days instead of 7 days of index AF diagnosis revealed consistent estimates for risk of amiodarone PT (hazard ratio Concurrent use of nonamiodarone 1.84, 1.58 to 2.14; 1.79, 1.56 to 2.07, respectively).
Concurrent use of rate-control Concurrent use of strong cytochrome We found a nearly threefold higher crude incidence of P450 3A4 inhibitors PT in amiodarone users compared to nonusers. Our inci- CI ⫽ confidence interval; HR ⫽ hazard ratio.
dence of almost 4% in users confirms results from previousstudies reporting an incidence from 0% to Afteradjustment for potential confounders, risk of PT remained Institute, Cary, North Carolina). This study was approved by ⬎50% higher in amiodarone users than nonusers. However, the ethics review board of McGill University, Montreal, Que- our crude incidence rates were approximately 2 times those bec, Canada and Western University of Health Sciences, found in previous meta-analyses and possi- Pomona, California.
bly because our cohort is population based, whereas patientsenrolled in randomized controlled trials were younger with fewer co-morbidities, and we defined PT in a broader sense In total 57,393 patients were included in the cohort: by ICD-9/10 codes to ensure we captured the various diag- 6,460 users and 50,933 nonusers. Significantly more men noses under which PT might be coded. Definitions of PT in were in the user than in the nonuser group. COPD, heart randomized controlled trials would likely be more stringent, failure, diabetes, coronary artery disease, hypothyroidism, which could account for the lower incidence of PT.
and CKD were significantly higher in the user group. Con- We did not find a dose–response relation with amioda- versely, age, stroke/transient ischemic attack, and liver dis- rone use and development of PT using adjusted analysis in ease were significantly higher in nonusers. As expected, users contrast to previous studies reporting increased risk at were less likely to be receiving rate-control and nonamioda- higher amiodarone Although previous studies rone antiarrhythmic medications than nonusers have reported that PT is related to amiodarone dose, it is Crude incidences of PT were 3.87% (250 of 6,460) for important to note that lower amiodarone doses have also users and 1.33% (676 of 50,993) for nonusers. The most been associated with serious Our findings con- common PT diagnosis was ICD-9 code 515.9 (postinflam- firm this by showing a crude incidence rate of PT with matory pulmonary fibrosis; A higher age-stan- ⱕ200 mg/day nearly 2 times that of nonusers. We would dardized incidence of PT was found in users than nonusers expect 11 more men users and 7 more women users to have and in men than women Men and women users PT for every 1,000 person-years treated with the lower- had incidences of 28.30 and 16.02 cases per 1,000 person- range dose of ⱕ200 mg/day compared to nonusers using our years, respectively, whereas men and women nonusers had age-standardized incidence rates.
estimates of 14.05 and 8.82 cases per 1,000 person-years, Risk of PT was greater in men, older patients, and those respectively. Age-standardized incidence of PT had a slight with COPD and CKD. We found a nearly 40% increased dose response, with an increase in incidence with doses risk of PT in men versus women. Although previous studies ⱖ200 mg/day Incidences in users with and did not show male gender to be a risk factor for amiodarone without COPD were 35.63 and 15.36 cases per 1,000 per- PT, men have rates of idiopathic pulmonary fibrosis 50% to son-years, respectively, whereas in nonusers with and with- 80% higher than Certain PT risk factors that out COPD incidences were 21.80 and 7.59 cases per 1,000 we cannot examine with administrative data such as smok- person-years, respectively. PT events continued to cumulate ing may be higher in men than in women, increasing their over the follow-up period The crude mortality risk. Patients were 1% more likely to have PT for each rate for those who developed PT was 75.7%.
incremental year of age. Results of previous studies have Arrhythmias and Conduction Disturbances/Pulmonary Toxicity Associated With Amiodarone not been entirely consistent with age as a risk factor for in a younger population. However, because AF mainly affects elderly patients, the age restriction of our data may Pre-existing COPD more than doubled the risk of PT, the be less concerning. Many baseline characteristics differed highest risk of all characteristics examined, which warrants between amiodarone users and nonusers. Although we ad- caution with amiodarone use in patients with COPD. Risk of justed for these differences and all known confounders in PT in amiodarone users with previous lung disease has been the Cox model, unknown confounders may be associated inconsistent in previous Several studies with PT. We defined PT by ICD coding that was more rather have found an increased risk of acute respiratory distress than less inclusive. Although this may have increased the syndrome and acute respiratory failure postoperatively in overall incidence of PT, differential misclassification bias of patients after cardiac and pulmonary surgery who were PT would not be expected. The nonusers' PT incidence rate amiodarone Patients with a history of COPD of 1.33% may partly represent the underlying rate of idio- who take amiodarone and present with nonspecific symptoms pathic pulmonary fibrosis in the general population and of respiratory distress may be assumed to have COPD exac- misclassification of nonusers who during follow-up subse- erbation but in fact may have undiagnosed amiodarone PT.
quently became amiodarone users.
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