Prescribing of long-acting beta-2-agonists/inhaled corticosteroids after the SMART trial

For formoterol we found a PPR increase between 2004 and 2007 followed by a slight decrease in 2008 whereas for salmeterol, a distinct year-by-year decrease was found between 2004 and 2008. Despite the fact, that the German drug regulatory authority has been discussed LABA in general as a drug class for which concomitant ICS prescribing is needed [7], our data cannot exclude a shift in LABA prescriptions in terms of stopping salmeterol and initiating formoterol prescribing (without ICS) in individual patients. For formoterol, an earlier onset of bronchodilative effects compared to salmeterol is well-known [20] and might explain a switch from salmeterol to formoterol. However, a lacking prescribing of ICS to asthma patients receiving formoterol has to be considered as guideline-violating prescription behaviour, too. By conducting a combined analysis of formoterol and salmeterol, we found a PPR increase between 2004 (45.2 per 10,000 persons) and 2008 (50.6 per 10,000 persons; data not shown). Furthermore, only a small proportion of patients received LABA without ICS (“switchers”, “non-concomitant LABA and ICS users” and “LABA users without ICS”) and the proportion of patients classified into these categories decreased between 2004 and 2008.

Similar to our combined analysis of formoterol and salmeterol, [19] a slight increase of the absolute number of LABA prescriptions was found in Italian asthma patients between 2006 and 2008. On the other hand, the proportion of asthmatic children receiving LABA decreased distinctly between 2001 and 2006 in a Scottish study [13]. Regarding the United States, the proportion of treatment visits with a LABA prescription without concomitant steroids decreased between 2004 and 2008 and reached less than 1% in 2008 [25]. Our data suggest a higher proportion of patients receiving LABA without ICS but methodological differences might have contributed to these discrepant results. Whereas Higashi et al. [25] calculated the proportion of visits for a particular prescription category out of all visits (including visits without LABA or ICS prescriptions) we analysed the proportion of a particular patient category based on prescriptions within one year out of all patients having at least one prescription of interest not mentioning the number of treatment visits.

In our study, the proportion of concomitant LABA/ICS users increased from 52.0% to 57.6% between 2004 and 2008. The observed increase could be related to an increased prescribing of i.) ICS to patients receiving LABA, ii.) LABA to patients receiving ICS, or iii.) fixed LABA/ICS combinations. It is worth mentioning, that all three potential changes in prescription behaviour would be in accordance to guidelines [3]. Regarding the proportion of patients with fixed LABA/ICS combination, we found an increase between 2004 and 2008 (82.2% versus 85.7%) out of all “concomitant LABA and ICS users”. In comparison [25], LABA and ICS were prescribed concomitantly (fixed combination drug and separate compounds) in the United States in approximately 20% to 30% of asthma treatment visits. Out of these patients, 99% received a fixed combination of LABA/ICS [25].

Regarding a compound specific analysis of fixed combination drugs, we found a PPR increase of between 12.1% (salmeterol/fluticasone) and 49.8% (formoterol/beclometasone [2007–2008]) within the study period. In comparison, prescriptions of fixed salmeterol/fluticasone combination for Italian asthma patients increased between 2006 and 2008 by 45% whereas for formoterol-containing fixed combinations, a much more pronounced increase by 137% was found [19]. In a combined analysis of salmeterol- and formoterol-containing fixed combinations, more than a doubling was found for the proportion of children receiving LABA/ICS in Scotland between 2001 and 2006 [13]. On a European level [26], a 50% increase of fixed LABA/ICS combination drug prescriptions was found between 2005 and 2009.

Regarding age- and sex-stratified analyses (year 2008), the highest proportion of patients with at least one LABA prescription without concomitant ICS (combined analysis of “LABA users without ICS”, “non-concomitant LABA and ICS users”, “switchers”) was found in elderly men. The “lack” of ICS prescribing in these elderly men receiving LABA might be related to a relevant COPD drug burden (i.e. asthma-COPD overlap syndrome). However, not prescribing ICS to ACOS patients on a regular base might be reasonable regarding most recent data [27].

The knowledge gap between research and clinical practice is a well-known problem and a wide range of interventions has been evaluated. To sum up the available evidence, multifaceted, interactive approaches (e.g. audits and feedback, workshops, reminders) seems to be more effective than passive, single interventions (e.g. educational materials [28,29]). For asthma, several strategies for improving knowledge translation have been evaluated. For example, a multiple level intervention was conducted in Canada including the individual patient, the practice, and the health system level. By implementing six guideline-based care elements including e.g. spirometry measurement, asthma controller therapy, and self-management action plans, a significant improvement of relevant clinical endpoints (e.g. reduced number of urgent / emergent healthcare visits [30]) was found. Furthermore, the proportion of patients receiving LABA/ICS combination therapy increased, but unfortunately, results for LABA monotherapy were not reported in this study. Most recently, electronic tools were examined to promote knowledge translation at physician and patient level, but further studies are needed to clarify the impact of these approaches [31,32] in particular regarding their impact on improving guideline-adherent prescription behaviour.

In Germany, a nationwide disease management program (DMP) for patients with asthma was implemented in 2006 including e.g. regular visits, individual action plans, and regular feedback to coordinating general practitioners [33]. By analysing annual trends of asthma treatment for patients included in this DMP between 2006 and 2010, a guideline-adherent prescribing was found in the majority of patients. Nevertheless, a small but slightly increasing proportion of patients has received LABA monotherapy (2006: 2.1%, 2010: 3.5%). As already discussed for our study, this finding could be related to a concomitant diagnosis of COPD which was present in 2.8% to 5.2% of DMP patients [33].

Regarding the impact of regulatory actions on prescribing behaviour in daily practice, only a few well-conducted studies are available. In a systematic review, no final conclusion regarding the impact of safety-related regulatory actions could be made due to inadequate study designs and heterogeneity in analyses and outcome measures [34]. In particular, confounding factors are of outstanding importance but difficult to adjust for hampering a valid estimate of the actual impact of a particular regulatory action. By comparing the impact of different information included in a “Dear doctor” letter, “simple” information (dose limit) has been considered by physicians more frequently compared to “complex” information (QT prolongation due to drug-drug interactions) [35]. Taken into account the more or less “simple” message of asthma guidelines and SMART-related regulatory actions, a guideline adherent prescribing of LABA and ICS seems achievable. Due to confounding factors (e.g. disease management program for asthma patients) and the complexity of treatment decision making, we were unable to quantify the actual impact of the SMART trial publication and/or SMART-related drug regulatory actions on prescribing behaviour.

Our study has several strengths worth noting. First, the database covers a population of about 10.5 million people and represents 85% of the inhabitants of Bavarian (the largest federal state of Germany). In addition, we were able to perform detailed analyses focusing on the presence or absence of concomitant ICS prescriptions in asthma patients receiving LABA. Furthermore, due to a 5-year period, we could analyse trends in PPRs as well as in LABA- and ICS-related prescription behaviour after the SMART trial. Despite these strengths, there are also several limitations regarding our study. Firstly, our analysis was limited to the years 2004 to 2008 and more recent changes in prescription behaviour should be taken into account. By comparing nationwide drug prescription data for the years 2008 and 2013 (irrespective of indication), for salmeterol a 72.5% decrease (2008: 9.1 Mio. DDD, 2013: 2.5 Mio. DDD), for formoterol a 22.2% increase (2008: 99.1 Mio. DDD, 2013: 121.1 Mio. DDD), for ICS a slight decrease of 4.0% (2008: 167.6 Mio. DDD, 2013: 160.9 Mio. DDD), and for fixed combinations of LABA/ICS a distinct increase of 28.7% (2008: 255.8 Mio. DDD, 2013: 329.2 Mio. DDD) were found [36,37]. Since our main aim was to conduct a comprehensive and more detailed analysis of LABA- and ICS-prescribing in asthma patients after the SMART trial, we decided to use a period covering most factors potentially influencing drug prescribing including publication and dissemination of SMART results and SMART-related drug regulatory actions. Secondly, the prescriptions are documented on a quarterly basis in the database meaning that all LABA and ICS prescriptions were counted as concomitant if they occurred in the same quarter irrespective of the actual prescription date. Hence, the proportion of concomitant LABA/ICS users is likely to be overestimated in our study. Thirdly, only patients with compulsory insurance are covered in our analyses and thus, by excluding patients with a private health insurance, a socioeconomic bias on our study results cannot be excluded. Fourthly, this study covers a Southern region of Germany and hence, generalizability of results to other German regions or to other countries is limited as reported for several other studies, too [38,39]. However, by taking into account methodological differences, PPRs for LABA, ICS, and fixed combination of LABA/ICS found in our study showed a similar pattern and trend compared to national drug consumption data [36,40]. Fifthly, by using prescription data only, prescribing quality can only roughly assessed due to missing individual data important for a clinical decision (e.g. lacking lung function parameter, detailed clinical history) and a substantial proportion of patients potentially given an incorrect diagnosis (i.e. asthma instead of COPD) [41,42].