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Research Letter |

Association of Amiodarone Use With Acute Pancreatitis in Patients With Atrial Fibrillation A Nested Case-Control Study FREE

Alvaro Alonso, MD, PhD1; Richard F. MacLehose, PhD1; Pamela L. Lutsey, PhD1; Suma Konety, MD2; Lin Y. Chen, MD, MS2
[+] Author Affiliations
1Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis
2Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis
JAMA Intern Med. 2015;175(3):449-450. doi:10.1001/jamainternmed.2014.6927.
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Published online

Amiodarone hydrochloride is an antiarrhythmic drug frequently used in the treatment of atrial fibrillation (AF). Isolated reports13 have suggested that use of amiodarone may cause acute pancreatitis. To our knowledge, this potential adverse effect of amiodarone has not been explored in large studies. We assessed whether use of amiodarone or other antiarrhythmic drugs indicated for AF management is associated with developing acute pancreatitis in a large US population.

We conducted a nested case-control study using the Truven Health MarketScan Commercial and MarketScan Medicare Supplemental Databases for January 1, 2007, through December 31, 2012. These databases include health insurance claims that span all levels of care (inpatient and outpatient services, outpatient pharmacy services) and enrollment data from employers and health plans across the United States that provide private coverage for employees, their spouses, and their dependents and for individuals and their dependents with Medicare supplemental coverage. All patient information was Health Insurance Portability and Accountability Act compliant, deidentified, commercially available secondary data; therefore, the institutional review board at the University of Minnesota deemed this analysis exempt from review.

Case patients were patients with nonvalvular AF (NVAF) admitted to the hospital with a primary diagnosis of acute pancreatitis during the study period (International Classification of Diseases, Ninth Revision, Clinical Modification code 577.0). Five control patients with NVAF were matched with each case patient by sex, year of birth, and MarketScan enrollment date selected from individuals enrolled at the time of the pancreatitis hospitalization (index date). Information on use of amiodarone, other medications, and comorbidities before the index date for case and control patients was obtained. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95% CIs of acute pancreatitis by use of amiodarone and other antiarrhythmic drugs (each using separate regression models) and time since initiation and cumulative use of amiodarone, adjusting for confounders (Table 1).

Table Graphic Jump LocationTable 1.  Selected Characteristics of Case and Control Patients, MarketScan, 2007-2012a

We included 1686 case patients and 8430 matched control patients (3972 women [39.3%]; mean age, 71 years; Table 1). Ever users had increased odds of acute pancreatitis compared with never users (Table 2), particularly when amiodarone therapy was initiated within 12 months before the event date. The multivariable OR was 1.86 (95% CI, 1.41-2.45) vs 1.21 (95% CI, 0.89-1.64) if more than 12 months had elapsed since initiation (P = .04 for the difference between the 2 ORs) compared with never users. Cumulative use was not associated with increased odds of acute pancreatitis (P for trend among users = .49). Use of other antiarrhythmic drugs was not associated with acute pancreatitis (Table 2).

Table Graphic Jump LocationTable 2.  Acute Pancreatitis by Previous Use of Selected Antiarrhythmic Drugs in Patients With Nonvalvular Atrial Fibrillation, MarketScan, 2007-2012a

In this study of health care utilization data, use of amiodarone but not of other antiarrhythmic drugs was associated with a 50% increased odds of acute pancreatitis among patients with NVAF. The odds were almost doubled in the 12 months after amiodarone therapy initiation and did not depend on cumulative use of amiodarone. Considering an incidence of acute pancreatitis of 3 to 4 cases per 10 000 adults per year,4 the observed association would result in approximately 1 to 2 additional cases of acute pancreatitis per 10 000 amiodarone users per year. A few isolated case reports of acute pancreatitis possibly linked to amiodarone use have been described in the literature.13 The mechanisms responsible for this association are unknown, although direct cytotoxicity or immune-mediated pathways, as described for amiodarone-related pulmonary toxic effects, could be potential explanations.5

Strengths of our study include the prospective assessment of medication use, the large sample size, and the availability of information on comorbidities and use of other medications potentially associated with increased risk of acute pancreatitis. Limitations are related to the use of health care utilization data: limited information on the validity of claims for acute pancreatitis, absence of clinical variables that characterize severity of the episode (eg, blood markers of acute pancreatitis), and the select group of patients included in this database.

Our results indicate that acute pancreatitis could be an adverse effect of amiodarone use, an effect that may not be shared by other antiarrhythmic drugs. Even though the absolute risk of acute pancreatitis in the general population is low, health care professionals should be aware of this potential association in the treatment of patients with NVAF or acute pancreatitis. Further research should replicate our findings and determine potential mechanisms.

Corresponding Author: Alvaro Alonso, MD, PhD, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S Second St, Ste 300, Minneapolis, MN 55454 (alonso@umn.edu).

Published Online: January 19, 2015. doi:10.1001/jamainternmed.2014.6927.

Author Contributions: Dr Alonso had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Alonso, MacLehose.

Acquisition, analysis, or interpretation of data: Alonso, Lutsey, Konety, Chen.

Drafting of the manuscript: Alonso.

Critical revision of the manuscript for important intellectual content: MacLehose, Lutsey, Konety, Chen.

Statistical analysis: Alonso, MacLehose.

Obtained funding: Alonso.

Administrative, technical, or material support: Alonso.

Study supervision: Chen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant UL1TR000114 from the National Center for Advancing Translational Sciences of the National Institutes of Health and by grant 12.15 from the University of Minnesota Academic Health Center (Dr Alonso).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Bosch  X, Bernadich  O.  Acute pancreatitis during treatment with amiodarone. Lancet. 1997;350(9087):1300.
PubMed   |  Link to Article
Famularo  G, Minisola  G, Nicotra  GC, De Simone  C.  Acute pancreatitis caused by amiodarone. Eur J Emerg Med. 2004;11(5):305-306.
PubMed   |  Link to Article
Chen  YY, Chen  CY, Leung  KK.  Acute pancreatitis and amiodarone: a case report. World J Gastroenterol. 2007;13(6):975-977.
PubMed   |  Link to Article
Frey  CF, Zhou  H, Harvey  DJ, White  RH.  The incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994-2001. Pancreas. 2006;33(4):336-344.
PubMed   |  Link to Article
Papiris  SA, Triantafillidou  C, Kolilekas  L, Markoulaki  D, Manali  ED.  Amiodarone: review of pulmonary effects and toxicity. Drug Saf. 2010;33(7):539-558.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Selected Characteristics of Case and Control Patients, MarketScan, 2007-2012a
Table Graphic Jump LocationTable 2.  Acute Pancreatitis by Previous Use of Selected Antiarrhythmic Drugs in Patients With Nonvalvular Atrial Fibrillation, MarketScan, 2007-2012a

References

Bosch  X, Bernadich  O.  Acute pancreatitis during treatment with amiodarone. Lancet. 1997;350(9087):1300.
PubMed   |  Link to Article
Famularo  G, Minisola  G, Nicotra  GC, De Simone  C.  Acute pancreatitis caused by amiodarone. Eur J Emerg Med. 2004;11(5):305-306.
PubMed   |  Link to Article
Chen  YY, Chen  CY, Leung  KK.  Acute pancreatitis and amiodarone: a case report. World J Gastroenterol. 2007;13(6):975-977.
PubMed   |  Link to Article
Frey  CF, Zhou  H, Harvey  DJ, White  RH.  The incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994-2001. Pancreas. 2006;33(4):336-344.
PubMed   |  Link to Article
Papiris  SA, Triantafillidou  C, Kolilekas  L, Markoulaki  D, Manali  ED.  Amiodarone: review of pulmonary effects and toxicity. Drug Saf. 2010;33(7):539-558.
PubMed   |  Link to Article

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