A Afonso1, S Schmiedl2,3, C Becker4, S Tcherny-Lessenot5, P Primatesta6, E Plana7, P Souverein1, Y Wang5, J C Korevaar8, J Hasford9, R Reynolds10, M C H de Groot1, R Schlienger6, O Klungel1, M Rottenkolber11. 1. Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CA, Utrecht, The Netherlands. 2. Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448, Witten, Germany. 3. Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Heusnerstraße 40, 42283, Wuppertal, Germany. 4. Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy & Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Hebelstrasse 2 (Markgräflerhof), 4031, Basel, Switzerland. 5. Global Pharmacovigilance and Epidemiology, Sanofi, Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France. 6. Global Epidemiology, Novartis Pharma AG, 4002, Basel, Switzerland. 7. Novartis Pharma AG, Apartado 708, 08080, Barcelona, Spain. 8. NIVEL, Netherlands Institute for Health Services Research, Postbus 1568, 3500 BN, Utrecht, The Netherlands. 9. Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Marchioninistr. 15, 81377, Munich, Germany. 10. Epidemiology, Pfizer, 235 E 42nd St, New York, NY, 10017, USA. 11. Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Marchioninistr. 15, 81377, Munich, Germany. marietta.rottenkolber@med.uni-muenchen.de.
Abstract
PURPOSE: 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.
PURPOSE: 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 COPDpatients, 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.
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