The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA

Worldwide, 235 million people are estimated to suffer from asthma, [1] affecting 1–18% of the population in different countries [2]. Asthma is characterized by symptoms such as wheeze, chest tightness and shortness of breath, which can vary in intensity over time [2]. Exacerbations of asthma are acute or sub-acute episodes of increased symptoms and deteriorations in lung function, requiring an intensification of treatment [2]. Exacerbations occur across the spectrum of asthma severity but are more frequent in patients with severe disease and place a great burden on healthcare systems and patients [2‐4].

Guidelines highlight the importance of using preventative therapies to reduce the risk and frequency of asthma exacerbations [2]. In patients with mild-to-moderate asthma, exacerbation frequency can be reduced by maintenance controller therapies such as inhaled corticosteroids (ICS) combined with long-acting β₂-agonists (LABA) [2, 5‐8]. However, in patients with severe asthma and persistent symptoms, a 5-year study has shown that exacerbation frequency remains relatively unchanged, despite intensive therapy with ICS/LABA for a minimum of 4 months per year [9]. Small-scale observational and database studies have demonstrated that the risk of a subsequent exacerbation is increased in patients with a history of frequent events and in patients with eosinophilic inflammation [9‐11]. Healthcare resource utilization (HRU) is reported to be greatest in patients with severe asthma and a history of previous exacerbations, with exacerbations requiring oral corticosteroid (OCS) treatment, and emergency department (ED) visits or hospitalization documented as posing the greatest burden to healthcare systems [2, 12‐15]. Additionally, the average direct costs per patient are reported to be approximately twice as high in patients with severe uncontrolled asthma compared with those that have non-severe uncontrolled asthma [16].

To improve disease management, there is a need to better characterize the burden of asthma exacerbations by disease severity. This report describes the results from two large retrospective cohort studies from the US and UK, which aimed to characterize the overall asthma exacerbation rates, their subsequent reoccurrence, associated HRU, and costs by asthma severity.

In this report of two large database studies in the US and UK, each involving >200,000 patients with asthma, it was demonstrated that increased disease severity defined by GINA Step, medication use, and exacerbation history was associated with higher asthma exacerbation frequency. Furthermore, patients with an asthma-related exacerbation leading to ED/hospital re-admission had a 32–35% increased risk of a subsequent exacerbation during the 12 months after the index date in both countries and healthcare resource use within 30 days of an exacerbation was highest for patients with the most severe disease. While overall trends were similar between the US and UK, US patients demonstrated a higher exacerbation frequency, lower medication use, and higher ED/hospital re-admission rates compared with UK patients.

The trends demonstrated in both the US and UK are similar to previous studies. The smaller-scale TENOR study demonstrated that exacerbation frequency was higher in patients who had a recent history of an exacerbation compared with those who did not [10]. In a study of health insurance claims from approximately 2,500 patients with persistent asthma, the occurrence of an exacerbation in the previous year was found to increase the risk of a subsequent exacerbation nearly 8-fold [9]. Exacerbation severity has also been shown to increase subsequent exacerbation risk. The TENOR study demonstrated that the occurrence of a recent severe exacerbation requiring an ED/hospital admission increased the odds of a future exacerbation nearly 3-fold following adjustment for key covariates, compared with patients with exacerbations not requiring admissions [10]. In the current large database studies, following adjustment for confounding covariates, the risk of a subsequent exacerbation during the following year was increased by 35% (US) and 32% (UK) in patients who had a previous exacerbation requiring an ED/hospital visit compared with patients requiring only OCS treatment. Exacerbation risk has also been demonstrated to increase with eosinophilia [11]. Although in the current study eosinophil counts were not assessed as a risk factor, it was demonstrated that the proportion of patients experiencing ≥1 exacerbations during the follow-up period was higher in patients who had severe uncontrolled asthma (GINA Step 4/5 plus ≥2 exacerbations in the previous year) with eosinophil counts (≥300 cells/μl) than in patients who did not. The current study also demonstrated that females had a higher exacerbation risk than males, a result demonstrated in a previous study, [20] although not all studies are in agreement [21].

As expected, in both countries, the use of ICS/LABA and OCS increased with markers of disease severity including GINA Step, Leidy category, and exacerbation history, and was higher in patients with severe uncontrolled asthma or severe uncontrolled eosinophilic asthma status versus patients who had non-severe asthma. In the current study, despite the increased medication usage in patients with more severe disease, total HRU during the 30 days after an exacerbation was still highest in these patients. Reflecting this, a previous study demonstrated in patients with persistent asthma symptoms that despite high-intensity treatment, the number of asthma exacerbations over a 5-year period remained relatively unchanged [9]. Most strikingly, the proportion of patients with asthma-related ED/hospital re-admissions in the 30-day period following a previous ED/hospital admission approximately doubled between GINA Step 3 and Step 5. Similarly, a history of frequent exacerbations and a severe disease classification increased asthma-related re-admission rates, with up to 23% experiencing an asthma-related re-admission within 30 days of discharge. These trends are reflected in a previous small-scale US-based study, which demonstrated that the majority of ED visits were made by the most severe patients (≥6 ED visits in the previous year) and that markers of severity were independent predictors of high ED use [14]. Together, these results indicate that patients with severe disease are the most likely to require further healthcare utilization after an asthma exacerbation, suggesting that higher levels of step-up care and the use of novel drug classes may be needed [22].

In terms of healthcare costs in the US during the 30 days after an exacerbation, asthma-related costs were higher in patients with a greater history of exacerbations and categorized as having severe uncontrolled asthma or severe uncontrolled eosinophilic asthma compared with patients who did not meet these criteria. Specifically, patients with severe uncontrolled eosinophilic asthma, the asthma-related cost was $1,073 compared with $520 in the overall asthma population during the 30 days after an exacerbation. Similarly, an observational study by Zeiger et al. (2015) demonstrated that the annual asthma-related costs approximately doubled in patients with severe uncontrolled asthma compared with patients with non-severe uncontrolled asthma [16]. Broadly, the results of both studies are in accordance with other small-scale [13] and large-scale population studies [15].

Whilst the overall trends in both databases were similar, some differences were identified between the US and UK. In the UK, the exacerbation frequency for patients at GINA Step 1–3 was approximately half that of the US, despite the frequency of exacerbations being similar between the UK and US for GINA Step 4–5. This may be a reflection of the higher ICS/LABA and OCS use at these lower treatment steps in the UK compared with the US, since ICS/LABA use has been demonstrated to decrease exacerbation frequency [2, 5]. Asthma-related ED/hospital re-admission within 30 days was also higher in the US compared with the UK, which could also be related to medication use or differences in the access to primary care physicians in these countries.

The strength of these studies is that they sample data from a large number of patients (>400,000 across the US and UK), allowing for the characterization of exacerbation frequency and HRU across a wide range of asthma severities and provide insights into the differences between the two populations. However, there are also several limitations, some inherent to the retrospective database methodology. Disease severity was inferred by GINA or BTS Step rather than clinical measurements, which may have led to severity being incorrectly assigned due to fluctuations in physician prescribing behavior over time. Limitations that affect database comparability include differences in the type of data that the US (prescription claims) and UK (medication prescriptions) databases use, which may have led to an underestimated or overestimated medication use. In the US specifically, this may have contributed to an under-reporting of SABA use, as patients may not have required a new SABA prescription if the previous one had not been completely used. Further limitations that may have affected database comparability include: 1) the inclusion of lung cancer as an exclusion criteria in the US but not UK cohort (these data are not well captured and recorded in the CPRD); 2) lack of claims data in the UK CPRD versus US IMPACT database; 3) the inclusion of only patients with commercial health insurance in the US IMPACT versus UK CPRD database potentially reducing representation of the full asthmatic population; and 4) UK database patients were not required to be HES-linked, potentially resulting in the under-reporting of ED visits and HES spells specific for the treatment of exacerbations. This may have also prevented the accurate differentiation of exacerbation severity based on ED visit/hospitalization. However, as BTS and GINA guidelines both recommend treatment with OCS after ED/hospitalization discharge for an exacerbation, it is likely that most exacerbations were captured in the data sources sampled.

Using data from >200,000 patients with asthma in both the US and UK, we demonstrated that the frequency and risk of asthma exacerbations, HRU, and healthcare costs (US only) all increased with disease severity. In particular, these outcomes increased in patients with higher GINA Step, a frequent history of exacerbations, and severe uncontrolled and severe uncontrolled eosinophilic asthma status. Interestingly, the results suggest a higher exacerbation frequency, lower medication use and higher ED/hospital re-admission rates in the US compared with the UK. Appropriate post-discharge medication, healthcare practitioner follow-up, and asthma management plans should be ensured for patients admitted to the ED or hospital for asthma. Patients with severe uncontrolled asthma warrant more attentive post-discharge clinical supervision given their increased risk of a recurrent ED/hospital re-admission.