title: A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.
abstract: OBJECTIVE
  Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases.
  
  
  METHODS
  In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD).
  
  
  RESULTS
  For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results.
  
  
  CONCLUSIONS
  By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.
authors.affiliation: Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CA, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Afonso
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448, Witten, Germany.|Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Heusnerstraße 40, 42283, Wuppertal, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schmiedl
authors.affiliation: Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy & Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Hebelstrasse 2 (Markgräflerhof), 4031, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Becker
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France.
authors.forename: S
authors.initials: S
authors.lastname: Tcherny-Lessenot
authors.affiliation: Global Epidemiology, Novartis Pharma AG, 4002, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Primatesta
authors.affiliation: Novartis Pharma AG, Apartado 708, 08080, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Plana
authors.affiliation: Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CA, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Souverein
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: NIVEL, Netherlands Institute for Health Services Research, Postbus 1568, 3500 BN, Utrecht, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Korevaar
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hasford
authors.affiliation: Epidemiology, Pfizer, 235 E 42nd St, New York, NY, 10017, USA.
authors.forename: R
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CA, Utrecht, The Netherlands.
authors.forename: M C H
authors.initials: MC
authors.lastname: de Groot
authors.affiliation: Global Epidemiology, Novartis Pharma AG, 4002, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Schlienger
authors.affiliation: Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CA, Utrecht, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Klungel
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Marchioninistr. 15, 81377, Munich, Germany. marietta.rottenkolber@med.uni-muenchen.de.
authors.forename: M
authors.initials: M
authors.lastname: Rottenkolber
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D016208:Databases, Factual; D005060:Europe; D006801:Humans; D009203:Myocardial Infarction / Q000139:chemically induced*; D011320:Primary Health Care; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012107:Research Design; D014481:United States
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists
keywords: Acute myocardial infarction; Long-acting beta-2-agonists; Methodological comparison; Secondary data analysis