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.
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).
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.
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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The research leading to these results was conducted as part of the PROTECT consortium (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium, www.imi-protect.eu) which is a public-private partnership coordinated by the European Medicines Agency.
The authors thank the excellent collaboration of physicians in the participating countries, whose contribution in recording their professional practice with high quality standards enables the availability of databases used in this research.
The paper is on behalf of the members of work-package 2 (WP2) and work-package 6 (WP6) of PROTECT.
Conflict of interest
AA, PS, JK, JH, and MR have no conflicts of interest; CB reports that her department at the University of Basel received payment from Novartis Pharma AG, Basel, Switzerland, during the conduct of the study for statistical analyses; MdG reports grants from Top Institute Pharma (NL) www.tipharma.com; SS reports personal fees from Rottapharm Madaus (Cologne, Germany) and travel costs for an investigator meeting reimbursed by Bayer HealthCare AG (Leverkusen, Germany), the division of Pharmacoepidemiology & Clinical Pharmacology employing O.H. Klungel received Top Institute Pharma Grant T6.101 Mondriaan unrestricted grant for pharmacoepidemiological research. STL, PP, EP, YW, RR, and RS belong to EFPIA (European Federation of Pharmaceutical Industries and Association) member companies in the IMI JU and costs related to their part in the research were carried by the respective company as in-kind contribution under the IMI JU scheme. EP was previously employed at Novartis when this work was carried out. EP is publishing as a Novartis former employee.
The PROTECT project has received support from the Innovative Medicine Initiative Joint Undertaking (IMI JU; www.imi.europa.eu) under Grant Agreement no. 115004, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA (European Federation of Pharmaceutical Industries and Association) companies’ in-kind contribution. In the context of the IMI JU, the Department of Pharmacoepidemiology, Utrecht University, also received a direct financial contribution from Pfizer. The views expressed in this article are those of the authors only and not of their respective institution or company.
A. Afonso and S. Schmiedl contributed equally to this work.
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Afonso, A., Schmiedl, S., Becker, C. et al. 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. Eur J Clin Pharmacol 72, 1105–1116 (2016). https://doi.org/10.1007/s00228-016-2071-8
- Secondary data analysis
- Methodological comparison
- Long-acting beta-2-agonists
- Acute myocardial infarction