Estimates suggest that in at least 5% of cases, asthma is severe and uncontrolled.1,2 The Spanish asthma management guidelines (GEMA) define severe uncontrolled asthma (SUA) as asthma that cannot be controlled despite administration of combined high-dose inhaled corticosteroids+long-acting beta-agonists (ICS+LABA) for 1 year, or oral corticosteroids for 6 months.3 Patients with a history of severe asthma have a 6-fold risk of a fatal outcome 3 years after hospital discharge. Furthermore, these patients have a higher risk of disease-related hospitalization, poor quality of life, high costs related to their disease, and mortality.1–4 Nevertheless, severe cases often remain undetected by both primary care and specialist physicians, because being, as they are usually are, confined to specialist asthma units,5 physicians working outside this context need not be skilled in their diagnosis.

Pharmacological asthma therapy has remained practically unchanged for many years. The first anti-IgE monoclonal antibody (omalizumab) has been available in Spain since 2006, and is indicated for SUA. Patients with severe asthma have a higher risk of morbidity and mortality, and absorb most of the asthma healthcare budget (70% of the total funds allocated to the Finnish asthma program, for example).6 Omalizumab has been shown to be effective in the management of severe asthma. Dose and dosing frequency of this drug is calculated from the patient's pretreatment IgE levels (IU/ml) and body weight (kg). Doses range from 75 to 600mg omalizumab every 15 or 30 days, adjusted to serum IgE.7–9

Although omalizumab can be administered in outpatient clinics, in Spain it is usually administered in a hospital, and the administration strategy is adapted to the specific setting, such as day clinics, pharmacy services, or pulmonology units. The method of administration and need for trained personnel add to the cost of the drug and increase the burden on the patient, who must bear the expense of traveling to the hospital to receive treatment. However, the effectiveness of outpatient vs. in-hospital administration, and the difference in cost between these strategies is as yet unknown.

The aim of this study was to compare the clinical outcomes and costs associated with omalizumab treatment in SUA patients in 2 tertiary hospitals. In one hospital, the drug was administered on an outpatient basis in a primary care center, and in the other it was administered in the day hospital.

The study was approved by the clinical trials ethics committee of the Consorcio H. General Universitario of Valencia, and assigned number CHI-OMA-2013-01. It was classified by the Spanish Ministry of Health, Consumer Affairs and Equality as an EPA-OD (post authorization study with a non-prospective follow-up), and being a retrospective study no informed consent from patients was required, although patient details included in the database were encrypted. The study adhered to the guidelines of the Declaration of Helsinki and the revised (Edinburgh 2000) version.

A total of 138 patients were initially included. Five from hospital A and 3 from hospital B were later excluded for the following reasons: lost to follow-up (3 cases), incomplete follow-up (less than 12 months, 3 cases), and dropout due to patient-perceived lack of improvement in 2 cases. The dropout rate (5.3% vs. 6.4%, P=ns) and the baseline characteristics of patients lost-to-follow-up were similar in both hospitals. The final sample included 130 patients, 86 from hospital A and 44 from hospital B.

Table 2 shows the general characteristics of the patient population, together with comorbidities, smoking history, and treatment prior to the start of the study. Four patients from hospital A were diagnosed with allergic bronchopulmonary aspergillosis. Comorbidities and history of atopy were comparable in patients from both hospitals. All patients used short-acting bronchodilators on demand for quick relief; over 75% of patients used more than 4 puffs per week. One patient who was receiving daily oral steroids in combination with anticholinergics and antileukotrienes refused treatment with inhaled corticosteroids.

A comparison of general characteristics of patients in the A vs. the B group before starting omalizumab showed no significant differences in age, sex, FEV1%, BMI, ACT and ACQ score, IgE levels, dose of inhaled corticosteroids, oral or controller steroid cycles, number of hospitalizations and number of visits to the emergency room over the preceding year. However, the aggregate number of days of hospitalization was greater in group A (P<.05) (Table 3).

A comparison of the pre-treatment and post-follow-up (12 months omalizumab) status of both groups (separately and pooled) showed significant differences in ACT (P<.001), ACQ (P<.001) and improved FEV1% (P<.001). In both groups, the total number of admissions fell significantly (P<.001), as did days of hospital stay (P<.001), visits to the emergency room (P<.001) and number of oral steroid cycles (P<.001) with respect to the preceding year. No inter-group post-treatment differences were found in these variables (Table 4).

In both groups, the medication required for asthma control decreased significantly. The number of patients receiving inhaled corticosteroids remained the same, but in overall terms dose was reduced by 40% over pre-treatment levels. The proportion of patients using short-acting bronchodilators was significantly reduced (P<.001), as was use of antileukotrienes (P<.001), anticholinergics (P<.01), antihistamines (P<.05), and xanthines (P<.05). The proportion of patients requiring controller oral steroids was reduced (P<.05) (Fig. 1), together with their mean daily dose (22±12mg vs. 10±5mg, P<.01).

Fig. 1.

Percentage of patients receiving each asthma therapy before and after 1-year treatment with omalizumab.

(0.13MB).

In terms of the safety profile of the study drug, only 10 patients presented initial flu-like syndrome, and 4 presented erythema and local induration, with no significant differences between cohorts. None of these adverse effects led to suspension of treatment or dropout.

In economic terms, costs associated with hospitalization, emergency consultations, unscheduled visits to primary care and the pulmonology department were significantly reduced in both hospitals (Table 5). Mean cost saving with respect to the preceding year (pre-treatment) was €1250 per patient/year.

Table 6 compares costs in group A and B, according to omalizumab administration strategy. Costs stemming from drug administration, nursing and patient travel expenses were lower in group A. No significant inter-group differences were found in other itemized costs, with the exception of travel expenses associated with visits to primary care and the pulmonology department before start of omalizumab treatment, which were lower in group A (Table 6). Mean annual savings per patient in nursing and travel to and from the day clinic or primary care was €100 per patient/year, which in proportional terms is a reduction of 35% between the 2 treatment strategies.

Although omalizumab has been shown to be effective in the treatment of SUA,12 to the best of our knowledge no studies have evaluated and compared the cost and clinical outcomes of in-hospital and outpatient administration of this therapy. Our findings have shown that in 2 comparable populations of patients with severe asthma, outpatient administration of the drug is perfectly feasible. Clinical outcomes in both populations were similar, but the cost of outpatient administration was lower for both the hospital and the patient, and more convenient for the latter. Some cost differences were attributable to the higher cost of stay in the hospital where the drug was administered on an outpatient basis, while the difference in costs derived from visits to the primary care physician and the specialist before starting treatment was less significant. The cost of hospital stay is inherent to the characteristics of each hospital, and depends on various factors such as infrastructure overheads, number of beds, maintenance costs, staff, etc.13 and the cost of the initial and subsequent visits will also depend on structural overheads, staff costs, or the cost of scheduled appointments. All these are intrinsic to hospital management and are usually specific to each hospital; thus, these costs are variable and unlikely to change in the short term.

Omalizumab should only be prescribed by specialists. In Spain, it is usually administered in a hospital setting, probably because it is only available through hospital pharmacies. Omalizumab must be administered by a trained nurse in a controlled setting, although the scarcity of adverse effects does not fully justify these precautions. There is no evidence that in-hospital administration of the drug is safer or more clinically effective than administration in other healthcare settings, such as primary care. In this study, all patients were recruited from a specialist asthma unit where the drug was prescribed, the dosage adjusted and patients followed up in the usual manner. Follow-up of SUA patients receiving omalizumab has not hitherto been evaluated in other centers, such as primary care. The treatment itself is costly, and reducing the cost of administration would benefit the healthcare system. Some authors have estimated the total number of asthmatics in Spain to be 857514 patients, with an overall cost of €1480 million.14 Treating uncontrolled asthma accounts for 70% of this expenditure, including all non-medical costs, and certain direct medical costs (hospitalization, visits to the emergency room, fatality). In our study, the mean direct pre- and post-treatment medical costs per patient (such as visits to the emergency room, hospitalization and non-scheduled visits to primary care and specialist physicians), despite considerable inter-individual variability, was reduced by €1200/year. If prevalence of SUA in the total asthmatic population in Spain is taken to be 5%, 45000 patients in Spain would be affected by the severe, uncontrolled form of this disease, most of whom are candidates for treatment with omalizumab or other biological therapies appearing in the future. Based on our findings, the cost of omalizumab can be reduced by 35% merely by modifying the administration strategy, giving an estimated saving of between €4.5 and €9 million/year.

As other authors have shown, omalizumab significantly reduces the number of hospitalizations for exacerbation, visits to the emergency room, non-scheduled visits to primary care and specialist physicians, and also the dose of inhaled and oral steroids.12,15–18 This was true of both our study groups, irrespective of whether the drug was administered in-hospital or in primary care. This finding supports the clinical benefit of omalizumab in SUA patients, and also suggests that administration in an outpatient setting is equally effective.

Several studies have analyzed omalizumab in terms of pharmoeconomics. Oba et al.19 estimated the cost of each additional successfully controlled day to be $523, and the daily cost of achieving at least a 0.5-point increase in Asthma Quality of Life Questionnaire score to be $378. The authors concluded that, from a pharmoeconomics perspective, omalizumab is more beneficial in SUA patients. They found this therapy to be cost-effective when used in non-smokers that are hospitalized 5 or more times each year, or for more than 20 days in total, despite receiving the best possible treatment.

Dewilde et al.20 estimated the cost-effectiveness of omalizumab to be €56091/quality of life year (QALY), assuming a fatal outcome in 1%–3% of exacerbations, and equating reduction in mortality with reduction of exacerbations. A recent cost-effectiveness study was able to establish a difference in favor of omalizumab in terms of chronic disease, exacerbation-related mortality, price, exacerbations and clinical response, and additional QALYs, even with increased direct medical costs. The authors concluded that the cost-effectiveness of omalizumab was similar to that of other chronic biological treatments.21

Another study showed that omalizumab progressively improved asthma control and quality of life while reducing the cost of medication and hospital treatment. Although costs increased by €450/month, cost effectiveness increased substantially by €23880 per QALY gained, showing the beneficial outcome of investing in omalizumab in developed countries.22 A study carried out in Spain reported an incremental cost-effectiveness ratio of €462.08 per prevented exacerbation, and 26864.89 per QALY gained.23 A recent review study has shown that current asthma treatment is cost-effective in terms of disease control and therapeutic choices, including inhaled steroids, long-acting bronchodilators, and omalizumab.24 It is important to bear in mind that cost-effectiveness measured by QALYs will differ according to the calculation method used, the chronicity and severity of the disease analyzed, and the reference healthcare system. This could explain the difference in results reported in different studies.25

Our study has some important limitations. It is a retrospective study performed in 2 asthma units specializing in patients with SUA. Nevertheless, although some bias may be present in sample selection, all patients completing a course of treatment lasting at least 1 year were included in the study, with very few exclusions. We believe that as our study was performed in a routine clinical practice setting, the results are conclusive. However, it might not be possible to infer results obtained from the group receiving the drug in an outpatient service to other units, due to differences in the geographical extent of the catchment population or the complexity of higher risk patients (severity, frequency, instability of the crisis, comorbidity). Factors such as the impact of the hospital on the local population, its location (central or distant), level of care, and organizational system used can cause major variations in cost.

In conclusion, our study has contributed valuable insights into the cost-effectiveness of omalizumab in SUA patients. We show that this drug can be administered in an outpatient setting, and that this strategy can help reduce the cost of this therapy. Outpatient administration of omalizumab did not compromise safety, achieved the same clinical outcomes, and was more convenient for patients.

This study was partially funded with a Novartis research grant awarded in 2014.

ECHV and EFB designed and planned the study, performed the statistical study, and wrote and revised the manuscript.

PL and LN compiled the database, evaluated the patients, and revised the manuscript.

MR, JNSCH, CS and JB evaluated study patients in their clinical practice, and helped draft and revise the manuscript.

The authors declare they have no conflicts of interest.