Cost-effectiveness of Hydrocortisone Injection, Symbicort Inhaler and Prednisolone Tablets Used in Treatment of Asthma in Alshaab Teaching Hospital Khartoum, Sudan

Asthma is a chronic disease and one of the most familiar long-term respiratory diseases affecting millions of adults worldwide.^1–7 It remains a global public health problem affecting people of all ages.⁸ The most current global prevalence of asthma is estimated to be three hundred and thirty-nine (339) million people.^9,10 The disease burden on governments, healthcare systems, families, and patients is increasing worldwide. At the same time, its morbidity and mortality have become a problem in many countries, especially developing ones,¹¹ where access to healthcare facilities and essential medicines remains a problem.¹² Dramatic increases in the global prevalence of asthma over the last decades were reported, where 1 out of 7 people worldwide is affected by the disease.² The overall global prevalence of asthma was reported as 4.3%,¹³ and the prevalence of asthma symptoms among adults (aged 18-45 years) was 8.6%.⁹

In previous decades asthma was claimed as a disease in high-income countries. Today, this claim is no longer valid; the prevalence of asthma rises in middle and low-income countries more than in high-income countries.¹² The prevalence of asthma in these countries is expected to reach its peak in the nearest future, probably due to the emergence of economic and epidemiologic transitions.^3,14 Moreover, in Africa, only a few studies have been conducted on asthma and related topics because of a lack of data which caused as a result of poor documentation habits among health practitioners and health facilities. Data related to the prevalence of asthma is available only on country-based, where few countries have it while the majority do not have.^15,16

However, in Sudan, no unified figures indicate the overall prevalence of asthma because asthma is not considered a public health priority in the country. The overall prevalence of asthma in Sudan has yet to be indicated.¹⁷ Some studies highlighted that the prevalence of asthma among adult Sudanese in some regions of the country is around 10% of the region’s population.^18,19 However, a survey by Thomson R, et al. in 2020 in Khartoum reported asthma as the “third most common cause of hospitalisation after pneumonia and malaria”.¹³

This study is the first of its kind to be conducted in Sudan, which evaluates the costs and outcomes of three corticosteroid preparations (hydrocortisone injection 100mg, prednisolone tablet 30mg and Symbicort (budesonide/formoterol) inhaler 160/4.5 ug/dose.) use for treating asthmatic patients at Alshaab Teaching Hospital. We used the provider perspective to evaluate the cost and outcomes of these preparations.

The study was conducted after the approvals of the research committee of the faculty of pharmacy and deanship of the post-graduate studies-International University of Africa, Ministry of Health Khartoum state and Alshaab Teaching Hospital. EQ-5D-3L Arabic version questionnaire was used in data collection in this study. Permission to use the instrument from 2015-2016 was obtained from EuroQol Group, United Kingdom.

A hospital-based cross-sectional whereby the cost and outcome of corticosteroid preparations are collected together. This study was conducted at a government hospital specialising in chest and heart diseases, Alshaab Teaching Hospital (ASH), between May and December 2016.

Male and female patients aged 16 to 80 visited Alshaab Teaching Hospital from May to December 2016 were included in the study. A systematic sampling method was used, which allowed the selection of study participants at the regular interval after selecting the first one randomly and devoid of bias. The sample size of this study was calculated to be 139 adult asthmatic patients. Patients with severe or acute exacerbated asthma, patients with age ≥16 to ≤80 years old, admitted to emergency or visited the outpatient clinic of Alshaab Teaching Hospital between May and December of 2016, using hydrocortisone injection 100mg, prednisolone tablet ≥30mg or Symbicort (budesonide/ formoterol) inhaler 160/4.5 ug/dose were included in the study. Severe and acute exacerbated hospitalised asthmatic patients, patients with asthma and other respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and patients with age <16 or >80 years were excluded from the study.

Cost-Effectiveness Analysis (CEA) of corticosteroid preparations were conducted in this study. The costs and outcomes of corticosteroid preparations were determined from a provider’s perspective. Therefore, only direct medical (health service) costs: expenses and services provided are evaluated, while direct non-medical such as costs of transportation costs expenses of non-medical or informal care, and indirect costs, such as costs of patient’s productivity and other non-health service costs were excluded.

Discounting on the costs and effectiveness is optional as the study time horizon was less than one year.

To obtain the Quality Adjusted Life Years (QALYs) related to each Preparation, the Health-Related Life (HRQoL) should be multip by the quantity of life (i.e. time spent by patients in a particular health state obtained from medication or while using a specific drug). In this study, estimating the quantity of life was difficult due to the time factor and the inability of the patients to recall when they start using corticosteroids. Also, there are no documented patient records from which such information can be extracted in the hospital. Therefore, Health-Related Quality of Life (HRQoL) was used instead of the QALY because of its ability to reflect the effectiveness of the medication and one of the parameters used in computing QALYs.²⁰

A bottom-up costing approach was used as a costing approach, in which the costs of medication (corticosteroid preparations), laboratory investigations, and medical personnel services were collected separately and then summed to give a direct medical cost prospectively. This approach was used to compute the following cost categories.

The cost of each corticosteroid preparation was obtained from the pharmacy department of the hospital. To calculate the cost of medication (corticosteroid preparations), the Prescribed Daily Dose (PDD), frequency and duration of treatment were considered. The cost was computed by multiplying the total quantity of medication prescribed by the unit cost of the drug: Medication cost = Total quantity of prescribed medication x Unit cost of the medication.

The medical personnel service cost was calculated by multiplying the number of units per service per 8 months by the price per unit service, then the costs of medical personnel services (doctor, pharmacist, laboratory scientists, nurse) were added together to give medical personnel service cost. Price per unit service was calculated from the salaries of medical personnel, which were obtained from the accounts department of ASH, and the average time taken by medical personnel to deliver a service to the patient:

Cost per unit service = Average salary per month ÷ 22 working days ÷ eight working hours per day ÷ 60 min x Average time taken per service or visit.

Medical personnel service cost = the number of units per service per 8 months x cost per unit service.

The cost of laboratory investigations was obtained from the hospital’s laboratory department. The costs of laboratory investigations are calculated by multiplying the number of each laboratory investigation by its unit cost:

Laboratory investigation cost = Number of the lab. Investigation x laboratory investigation unit cost.

Furthermore, the costs of medication, medical personnel service and laboratory investigation were added to calculate each corticosteroid preparation’s direct medical cost. The cost categories related to each preparation were summed and multiplied by the number of patients prescribed the preparation, then multiplied by eight months to calculate the total direct medical cost for each preparation. The average direct medical cost per patient per 8 months was then calculated.

However, the instruments used in this study’s data collection were: Data collection forms which collected data related to the costs of corticosteroid preparations and the EQ-5D-3L questionnaire.

Due to the time factor and limited resources at the time of data collection, in addition to the dimension (strategy) of measurement of the instrument used, only positive outcomes of the corticosteroid preparations were identified, measured and evaluated, while, the negative outcomes were not evaluated. The EQ-5D-3L questionnaire Arabic version²¹ measured the positive outcome. The questionnaire has two parts: a descriptive system which measures a patient’s health state, and a visual analogue scale. Value sets (UK TTO) were used to value the health states, and the health states were later presented in the form of utilities or health-related quality of life (HRQoL) (refer to Technical Appendix).

The empiric approach, in which all relevant costs and effects were collected in one study, was selected and used in this study. Two types of data related to the use of corticosteroid preparations by the patients were collected.

The direct medical cost of corticosteroid preparations includes medication, laboratory investigations and medical personnel services data, which were collected using data collection forms. The monetary values were attached to each data mentioned earlier to calculate the direct medical cost of each corticosteroid preparation. Moreover, the cost of the preparations was recorded in the Sudanese Currency (SDG) and then converted to the American dollar (US) based on the current average bank exchange rate of 6.7 SDG per 1 $ (Central Bank of Sudan, 2016) at the time of the study.

Data related to the outcome of corticosteroid preparations were collected using the EQ-5D-3L questionnaire Arabic version.²¹ The questionnaire has five dimensions which collectively give health states. Weights were attached to these health states to provide a single patient health index (known as utilities or HRQoL) which was then used to define the outcome of each preparation.

However, the data were assembled and entered into Microsoft excel 2013 and then transferred to SPSS version 24 for analysis. Data analysis was performed for corticosteroid preparations used in treating asthmatic patients. The data on costs and outcomes were collected within eight months. Therefore, the cost and outcomes were not discounted. Statistical significance was defined at p-value ≤0.05.

An Average Cost-Effectiveness Ratio Analysis (ACER) was conducted to determine the most cost-effective corticosteroid.

A deterministic two-way sensitivity analysis was performed to test the uncertainty of the results of the research, where two parameters were varied relative to their base case value. These parameters include an average direct medical cost per patient (SDG) and outcomes (HRQoL). High and low estimates of costs (+20% and -20%) and outcomes (+10% and -10%) were inserted, and ACER were re-calculated. The impact (i.e., change in the ACER from the base case) was interpreted.

The number of asthmatic patients that participated in this study was 139 patients. Of these, 53 patients were prescribed hydrocortisone injection, 51 were prescribed prednisolone tablets, and 35 took Symbicort inhaler (Table 1).

To explore and find the most cost-effective Average Cost-Effectiveness Ratio Analysis (ACER) was conducted. From the Table 2, after considering both the direct medical costs and defined effectiveness (HRQoL) parameters, the direct medical costs per successfully treated patient for each preparation were determined, and prednisolone preparation was marked as the most efficient preparation concerning effectiveness-adjusted expenses with:

An approximate average cost-effectiveness ratio of 643.40 SDG ($96)/HRQoL proved more favourable than Hydrocortisone injection with 2600.00 SDG ($388) /HRQoL after the two preparations were compared.

An approximate average cost-effectiveness ratio of 643.40 SDG ($96)/HRQoL proved more favourable than the Symbicort inhaler with =3283.10 SDG ($490) /HRQoL after the two preparations were compared.

Prednisolone tablet versus Hydrocortisone injection: prednisolone tablet was more effective at a lower price, i.e. prednisolone tablet is dominant.

Prednisolone tablet versus Symbicort inhaler: prednisolone tablet was as effective as Symbicort inhaler at a Lower price, i.e. prednisolone tablet is dominant.

Table 3 illustrates the impact on the ACER for two values of the cost and two values of the outcomes of the corticosteroid preparations. Again, we see how sensitive the ACER is to each parameter and the extensive range of estimates, from SDG 585 to SDG 3641.67.

Health-related quality of life HRQoL is a measure that is commonly used; its uses are not certainly limited to the monitoring of population health state but also extended to measure and compare the effectiveness of different types of medications and their related health care services for a given disease at hospitals level and in clinical trials. Among the generic instruments used for measuring the HRQoL is EQ-5D-3L, the most familiar and straightforward instrument used in almost all kinds of diseases, including asthma.^22–28

Evaluating the cost and effectiveness of asthma medications, particularly the most expensive ones, such as corticosteroid preparations, is essential to ensure the rational and cost-effective use of the preparations in managing severe or acute exacerbated asthma.²⁹

In Sudan and other African countries, little or no studies are conducted in the field of Pharmaco-economics of asthma. The studies published on the economic evaluation of asthma in Africa are more of partial economics evaluation studies.³⁰ There is a need to encourage researchers to conduct researches on economic evaluations of asthma, considering the recent rise in the prevalence of asthma in Sudan and Africa.³¹

These findings clearly show that asthma in ASH is more common in the age group (16-40 years), which is known as the most economically active group, followed by the age group 60-80 (elderly patients). The increase in the prevalence of asthma among the elderly group may be due to the overall decrease in their quality of life seen with ageing.²³ However, out of 139 patients that participated in this study, 58% were females, and 42% were males. Similar results were reported in studies conducted in Ankara, Turkey, by Çelik et al. 2004 ³² and Accordini et al. 2006.³³

In this study, systemic corticosteroids (hydrocortisone injection and prednisolone tablet) were found to be the most prescribed corticosteroid preparations in an emergency department, which are either prescribed alone or in combination with inhaled corticosteroids. This finding was found to be similar to a finding in studies conducted by Raissy et al. 2013³⁴ and Donohue et al. 2004,³⁵ in which they reported the advantage of systemic corticosteroids over inhaled corticosteroids. Also, Rowe et al. 2004³⁶ highlighted in their study that systemic corticosteroids have a high preference in the emergency department than inhaled corticosteroids. However, among the laboratory investigations done by the patients in ASH, chest X-ray was the most systematic.

In this study, the medication cost category was the predominant cost category, accounting for 72% of the total direct medical costs of three preparations. Followed by medical personnel services cost, which accounted for 18% of the total direct medical costs of three preparations, and laboratory investigations, with 10% of the total direct medical costs of three preparations. These findings are found to be similar to the findings of studies conducted in Turkey, Sweden, the Netherlands, the USA, and France, which reported the cost of medication as a critical cost driver among different cost categories of the direct medical cost.^32,37–41 In contrast, this was found to be dissimilar to a finding from a study conducted by Bahadori et al. 2010.²⁹ Also, the fact that the laboratory investigation cost was the lowest cost category in this study was found to be similar to a finding in a study conducted in Turkey by Bavbek et al. (2011).⁴¹ The reason behind which among the cost categories have higher contribution and which have a low contribution to the direct medical cost may be due to but certainly not limited to differences in unit cost, study period, exchange rates and annual inflation rate³² which varies from one study to another or one from country to another. Furthermore, in this study, the most expensive prescribed corticosteroid preparation for treating adult asthmatic patients in ASH was inhaled corticosteroids (Symbicort inhaler). This finding was supported by a study by Rowe et al. 2004.³⁶

Health states reflect the health benefit obtained by a patient as a result of using a particular medication. Adult asthmatic patients in ASH described their health states as a result of using a specific type of corticosteroid preparation using the descriptive system of EQ-5D-3L questionnaire Arabic version, from which we estimated the health benefit (in the form of HRQoL) gained by the patients from a particular corticosteroid preparation using the TTO-UK value sets.^20,42

Corticosteroids are the most effective and widely used medications among the available anti-inflammatory medications for treating severe and acute exacerbated asthma.³⁴ There are many corticosteroids with different efficacy, effectiveness and potency available in various dosage forms. Regarding this, corticosteroids are categorised into systemic and inhaled corticosteroids. These two categories of corticosteroids are shown to have differences in efficacy/effectiveness, potency, safety and cost of their acquisition. Some studies showed that inhaled corticosteroids (such as Symbicort inhaler) have an advantage over systemic corticosteroids due to their high topical potency and low systemic absorption and actions.⁴³ Some argued that systemic corticosteroids (such as hydrocortisone injections and prednisolone tablets) have an advantage over inhaled corticosteroids, especially in the emergency department.³⁵ However, many systemic corticosteroids are available in the market with different efficacy, potency and duration of action.⁴⁴ The difference in efficacy/effectiveness of systemic corticosteroids may be explained by their differences in the glucose-mineralocorticoid property ratio. Corticosteroids with more glucocorticoid properties were shown to have more anti-inflammatory activity in the treatment of asthma, and oral corticosteroids such as prednisolone tablets are shown to have more glucocorticoid properties than parenteral corticosteroids such as hydrocortisone injection and are also preferred over parenteral corticosteroids.^44,45 These claims shed more light on the reason why prednisolone tablet was more effective than hydrocortisone injection in our study.

Moreover, our findings show that the use of a Symbicort inhaler offers additional benefits only when compared with hydrocortisone injection while offering no additional benefits when compared with a prednisolone tablet. Some studies reported the patients’ incorrect use of inhaler devices, poor adherence and steroid phobia as a reason behind the low or no additional benefits shown by Symbicort compared with prednisolone tablets.^38,45 In support of our finding, a study by Rowena et al. 2004 reported that oral corticosteroids, such as prednisolone tablets showed better effectiveness than inhaled corticosteroids.³⁶ However, Kemp et al. 2010 argued that inhaled corticosteroids are a cornerstone of asthma therapy, considering the route it administers.⁴⁶

The Average Cost-Effectiveness Ratio (ACER) is the most suitable and straightforward analysis to use when comparing medications used to treat the same disease but differs only in their route of administration. The cost-effectiveness ratio of corticosteroid preparations identifies how much it will cost ASH to provide a corticosteroid preparation and its related services to the patient to achieve a unit of gain of HRQoL. ACER was performed to find the most cost-effective corticosteroid preparations for treating asthmatic patients at ASH. Prednisolone preparation was found to be the least expensive preparation, also marked as the most reasonable alternative concerning effectiveness (HRQoL) and once again as the most efficient preparation concerning effectiveness-adjusted costs among the available options (preparations) in ASH. This fact was confirmed by the cost-effectiveness plane, which indicated prednisolone tablet as the most efficient (dominated) preparation on effectiveness-adjusted costs compared with hydrocortisone injection and Symbicort inhaler. This result makes prednisolone preparation a non-competitive preparation with no competitor that can necessitate us to do incremental cost-effectiveness ratio (ICER) analysis; hence prednisolone preparation was proved to be the most cost-effective preparation among the available preparations used among the asthmatic patients at ASH.

The absence of the EQ-5D-3L Sudan Arabic version and lack of country value sets let us use the EQ-5D-3L Saudi Arabian Arabic version and UK value sets (TTO-UK). There is a need to reassess the patients’ health states using the Sudan EQ-5D-3L Arabic version and value sets obtained from the Sudanese population.

Health-Related Quality of Life (HRQoL) was used instead of QALY due to time factors and limited resources. Future studies should focus on measuring the patients’ Quality and Quantity of Life to assess QALY gained due to using particular corticosteroid preparation.

Only positive outcomes were evaluated. Asthmatic patients’ comorbidities are not considered when evaluating costs and outcomes.

In conclusion, this study found that the prevalence of asthma and the utilisation of pharmaceutical products and services by asthmatic patients in ASH was more in females than males, also more in the age group 16-40 years. Hydrocortisone injection was the most prescribed preparation, followed by prednisolone tablet, and the least was Symbicort inhaler. Medication cost was seen as the significant cost category of the direct medical cost of preparations, and chest X-rays as the most frequently done laboratory investigation in ASH. The Symbicort inhaler was concluded to be the most expensive preparation, and the prednisolone tablet was the least expensive preparation. Prednisolone was found to be the most reasonable alternative concerning effectiveness (HRQoL) and most cost-effective (efficient preparation concerning effectiveness-adjusted costs) among the available corticosteroid alternatives (preparations) in ASH.

This paper was part of a thesis submitted to the Department of Pharmacy Practice, Faculty of Pharmacy, International University of Africa, Sudan, supervised by Assistant Professor Mohamed Awad Mousnad. The authors thank faculty members and staff for their precious suggestions. Many thanks also go to the Alshaab Teaching Hospital staff for their cooperation. The authors acknowledge the Europol group for the permission to use the EQ-5D-3L Arabic version questionnaire.