The studies described in this protocol are all performed within the framework of PROTECT
(Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Work
Package 2 and Workgroup 1. Primary aim of these studies is to develop, test and disseminate
methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE)
studies applicable to different safety issues and using different data sources. To achieve
this, results from PE studies on five key adverse events (AEs) performed in different
databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the
studies in this protocol and not on the clinical consequences of the association under
investigation .
Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic airway
diseases in the western world. For both, a stepwise treatment to reduce symptoms, improve
lung function, and prevent risk of exacerbation is recommended using several drug classes
according to guidelines published by e.g. the Global Initiative for Asthma [GINA guideline]
and the Global Initiative for Chronic Obstructive Lung Disease [GOLD guideline],
respectively. Beta-2-adrenoceptor agonists (B2A) are therapeutic mainstays in treating asthma
and COPD due to their bronchodilative effects mediated by B2A. This drug class consists of
two types of drugs: short acting B2A (SABA) which are used as a reliever medication and long
acting B2A (LABA) which are used as maintenance / controller medication. Formoterol and
salmeterol are the most frequently used LABA compounds with a half-life between 5-15 hrs and
therefore, these compounds most commonly have labelled indications for use twice a day. .
Focussing on cardiac side effects of B2A one must consider that drugs with an opposite
mechanism of action (beta-adrenoceptor-antagonists) have well-known cardio protective effects
and are widely used in patients suffering from e.g. ischemic heart disease, hypertension and
acute myocardial infarction (AMI)). Conversely, stimulation of cardiac beta-adrenoceptors as
done by B2A may have deleterious cardiovascular effects particularly in patients with cardiac
risk factors. And in fact, tachycardia and arrhythmias are well-known side effects of B2A
confirming a cardiac influence of these drugs particularly after oral therapy (due to a high
systemic exposure) as stated in the respective summary of product characteristics (SPCs),
e.g. clenbuterol (Spiropent(R)). Obviously, inhaled drugs cause much smaller systemic
exposure but cardiac side effects (e.g. arrhythmias, tachycardia) are also described in the
respective SPCs (e.g. formoterol [Foradil(R)). Furthermore, cardiac side were also reported
after exposure with inhaled MA (e.g. ipratropium [Atrovent(R)].
Several observational studies have been performed on the association between the usage of
inhaled B2A and the occurrence of AMI. However, these studies have produced conflicting
results. Reasons for this variation are numerous, e.g. small number of events (AMI) leading
to poor precision of risk estimate, potential misclassification of potential cardiac events
versus airway-related events due to similar clinical complaints, differences in populations
of drug users, measurement of drug exposure, and background risk of AMI. Additionally, a
consensus document was released in 2000, redefining AMI.
To make comparing results possible, this protocol gives guidelines for conducting studies in
the same way in five databases and across 3 designs (cohort, nested case-control,
case-cross-over) on the association between inhaled LABA use and AMI. The main focus is to
evaluate the impact of study design, population and database characteristics on the
association between inhaled LABA and AMI.
Data will be collected from the following databases: The Health Improvement Network (THIN),
the General Practice Research Database (GPRD), the Dutch Mondriaan project, Base de Datos
para la Investigación Farmacoepidemiológica en Atencion Primaria (BIFAP), the National
Databases of Denmark, and the Bavarian statutory health insurance physicians' association
database.