PHA223 Literature Review: MART therapy in the management of uncontrolled asthma in adults Due March 5th -5 PDF

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1 Name: Anam Mir Student ID: bh39od PHA 222 Literature Review: Discuss the evidence base for the use of maintenance & reliever therapy management (MART) in the management of uncontrolled asthma in adults. 1. Introduction Asthma is defined as a chronic inflammatory disorder of the airways associated with symptoms of airflow limitation: such as shortness of breath, wheezing, and cough [1]. However, the symptoms are reversible with the use of medication. Approximately, 5.4 million individuals in the UK are currently being treated for asthma, and 250,000 individuals deal with severe uncontrolled asthma that does not respond to guideline-driven usual treatment [1]. Uncontrolled asthma often has a strong impact on an individual’s lifestyle by restricting their daily activities, and increasing the likelihood of exacerbations and hospitalizations. The NICE guidelines define uncontrolled asthma as the following [2]:

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≥ 3 days a week with symptoms and/or the required use of a short-acting beta-agonist (SABA)

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≥ 1 night a week with awakening at night due to asthma In reference to figure 1, the guidelines of the British Thoracic Society (2019)

recommend that a patient be started on a SABA such as salbutamol, as required, for exacerbations, alongside a low dose of inhaled corticosteroids (ICS) [3]. If the asthma remains uncontrolled, t hen the guidelines suggest the addition of a long-acting beta-agonist (LABA) to the low-dose of ICS, as maintenance, OR the initiation of m  aintenance and reliever therapy (MART) [3]. Subsequently, this literature review aims to examine the use of MART in the management of uncontrolled asthma. More specifically, the role of MART in reducing the frequency of patient hospitalizations. MART is defined as a form of combined ICS and LABA treatment administered through a single inhaler [2]. It contains both an ICS and a fast-acting LABA (formoterol) for the daily maintenance and relief of symptoms, as needed [1]. For example, b  eclomethasone with formoterol and budesonide with formoterol.

2 Figure 1: the diagnosis of asthma in adults published by SIGN guidelines in association with the British Thoracic Society [2] pg. 80.

2. Methodology In order to address the aforementioned topic of the literature review, there were numerous sources examined, cross-referenced and filtered to those most relevant to the review. The databases utilised included Science Direct, PubMed-NCBI, and Google Scholar.

In each of the three databases, the following key-words were searched: “uncontrolled asthma” and/or “maintenance and reliever therapy” and/or “adults.” After which, in reference to figure 3, 122 non-duplicate sources were screened, from all three databases combined. After which, numerous filters were applied to all 3 of the databases which included the following: geography, type of therapy, subject specificity, and species (refer to figure 2 for specifics). After this, 87 more resources were removed from all of the databases combined, leaving 35 resources to be screened and reviewed. Subsequently, a last set of inclusion/exclusion criteria were applied to the sources: clinical trials & peer reviewed journals only, resources discussing uncontrolled asthma, and those that investigate the direct effect of MART on the management of uncontrolled asthma (refer to figure 2).

3 Finally, 32 resources were excluded after full-text review, due to irrelevant content in regards to the literature review (refer to figure 3), and statistical insignificance of the data from clinical trials. Conclusively, 3 sources were selected for the literature review.

Figure 2: a summary table of the inclusion/exclusion criterion applied in the 3 databases utilised The inclusion/exclusion criteria applied

The number of sources excluded

The age group of the subjects: Adults ≥ 18

1. Science Direct: 10 sources excluded 2. Google Scholar: 8 sources excluded 3. PubMed-NCBI: 6 sources excluded

The species of the subjects: Human

1. Science Direct: 7 sources excluded 2. Google Scholar: 8 sources excluded 3. PubMed-NCBI: 9 sources excluded

The type of Asthma therapy under investigation: MART regimen

1. Science Direct: 5 sources excluded 2. Google Scholar: 6 sources excluded 3. PubMed-NCBI: 9 sources excluded

The location of the trials: United Kingdom, Europe, Canada and New Zealand

1. Science Direct: 6 sources excluded 2. Google Scholar: 8 sources excluded 3. PubMed-NCBI: 5 sources excluded

The 2nd set of inclusion/exclusion criterion applied (n = 32 excluded) The type of sources: clinical trials and peer-reviewed journals

1. Science Direct: 3 sources excluded 2. Google Scholar: 4 sources excluded 3. PubMed-NCBI: 1 sources excluded

The severity of asthma of the subjects: uncontrolled and/or severe

1. Science Direct: 6 sources excluded 2. Google Scholar: 7 sources excluded 3. PubMed-NCBI: 4 sources excluded

The correlation under investigation: only sources investigating the effect of MART on uncontrolled asthma

1. Science Direct: 3 sources excluded 2. Google Scholar: 3 sources excluded 3. PubMed-NCBI: 1 source excluded

Figure 3: PRISMA diagram of the source filtration process utilised in the literature review

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3. Results & Discussion Article 1: Safety of budesonide/formoterol MART in asthma trials This study was published in a diverse journal geared towards respiratory health entitled Respiratory Medicine. The journal has a low impact factor of 3.237 (2018) in comparison to its competitive counterpart such as the British Medical Journal with an impact factor of 27.6 [5]. Despite this, the content of the journal can be deemed reputable as the research is conducted at Firestone Institute for Respiratory Health, and St Joseph’s Healthcare & McMaster University by Drs. Malcom Sears and Finn Radner [7]. McMaster University in Hamilton, ON, Canada ranks in the top 100 globally for their research and science-programmes. Additionally, statistical expertise and assistance are provided by Dr. Stefan Paterson of AstraZeneca [7]. However, a conflict of interest must be addressed, as Dr. Sears was a speaker and representative of many pharmaceutical companies such as AstraZeneca [7], which can introduce experimenter bias.

Subsequently, this study examines the safety of the ICS and LABA combination (MART) of budesonide/formoterol dry powder inhaler regimen in comparison to other

5 combination treatments based on the Canadian Thoracic Society (CTS) guidelines (refer to figure 4 below) [7]. An evident limitation is that this study does not adhere to SIGN or NICE guidelines, which are prevalent in the UK. Hence, the results of this study cannot directly translate to a UK population; nonetheless, the differences between the guidelines are minor.

In terms of the methodology, all double-blind, randomized, and clinical AstraZeneca trials in subjects with mild to moderate asthma that utilised a budesonide/formoterol inhaler as MART for ≥ 6 months were outlined by the company database. As a point of reference, 14,346 subjects combined were randomized to 6 trials, 5,584 used budesonide/formoterol as MART and 8,762 used comparator treatments (refer to figure 4 below) [7]. In five of the six trials, the patients enrolled were of ages 12-89. However, the mean age of enrolment was 39.4, thus this study is primarily targeted towards adults and pertains to this literature review. Notably, 41% of the patients were male, 74% of the patients were caucasian, and 17% were oritental; thus the results of this study cannot directly translate to all ethnicities [7]. In order to evaluate the safety of MART through the budesonide/formoterol inhaler, two primary endpoints were assessed: 1. Primary endpoint: All-cause mortality and asthma-related serious adverse-events (SAEs) 2. Secondary endpoints: overall SAEs, cardiac-related SAEs, discontinuations due to adverse events (DAEs), and asthma-related and cardiac-related DAE’s

Based on the results, the primary endpoint of asthma-related SAEs was markedly reduced in the MART with budesonide/formoterol versus the comparator therapy: 41 individuals (0.73%) and 121 individuals (1.38%), respectively [7]. Moreover, the Kaplane-Meier survival curves in the results clearly depict a prolonged survival time in the MART regimen patients.

On the other hand, the secondary endpoint of cardiac-related SAEs was significantly lower in the MART group: being 23 individuals (0.41%) [7]. Universally, discontinuations due to asthma-related or cardiac-related adverse effects were prominently reduced with the budesonide/formoterol MART in comparison with alternative treatments. Finally, common adverse effects associated with B2 agonists and ICS treatment were encountered by the patients; however, no noteworthy severe events were witnessed in either of the two treatment groups.

6 In conclusion, this study effectively illustrates that MART therapy, specifically through the use of the budesonide/formoterol inhaler, in the management of asthma, effectively reduces the frequency of all SAE’s: which ultimately decreases the likelihood of hospitalizations and frequency of acute attacks. Figure 4: a flow-chart depicting the randomisation of patients to the experimenter treatment vs. control treatments [7].

Article 2: Budesonide/formoterol MART in primary care asthma management The following research paper is published in the Primary Care Respiratory journal. This journal has a lower impact factor than the aforementioned, being 3.006, which is considered low [5]. Nonetheless, the study was written and conducted by Roland A. Riemersma, Dirkje Postma, and Thys van der Mole from the departments of general practice & pulmonary medicine from the University Medical Center Groningen, Netherlands [6]. The research was funded by AstraZeneca, through an unrestricted educational grant [6]. However, this presents a conflict of interest as the AstraZeneca sponsors were also involved in the study design and interpretation of the data which can unintentionally skew the results in favour of the sponsor’s desired results. Notably, this clinical trial has been registered at: http://www.clinicaltrials.gov (identifier: NCT00235911), meaning the trial was documented in its entirety prior to being conducted [6]. This is advantageous as it limits both publication & selective bias.

Correspondingly, this study investigates the effects of SMART (same as MART) and usual-care on bronchial hyperresponsiveness and clinical asthma severity. The SMART therapy consists of the budesonide/formoterol (Symbicort®) inhaler as both the maintenance

7 and reliever therapy [6]; it must be considered that the Symbicort® inhaler is a product of Astra-Zeneca, which can lead to further experimenter bias. A limitation to this study is that the guidelines for usual-care are not explicitly outlined, and considered common knowledge. It would have also been beneficial had the researchers outlined a renowned society such as the British Thoracic society, as a point of reference.

In terms of the methodology, an advantage to this study is that it was ethically approved by the Medical Ethics Committee of the University Medical Center Groningen, Netherlands (METc2003/111) [6]. In addition to such, all of the patients had signed and provided their written consent which deems the study to be ethically solidified. The study was designed as an open, and multicentre study, suggesting that the patients and the experimenters were aware of the randomization. In reference to figure 5, 102 adult (≥ 18) patients with mild-to-moderate persistent asthma were selected from 32 general hospitals [6]. Eligible patients were then randomized after a 4 week run-in period to receive the SMART regimen (experimental group) (n=54) (budesonide/formoterol 80/4.5μg Turbuhaler®, two puffs, once each day, and additional inhalations, as required) OR the usual-care regimen (control group) (n=48) for 12 months [6]. The method of randomization, and the individuals involved in the randomization are not specified, hence making the study prone to the placebo effect and observer bias.

On the other hand, the usual-care patients were instructed to continue their medication as required, and were treated by their GP as usual [6]. As a safety measure, if any of the patients required >12 puffs on two consecutive days, and/or had a threatening exacerbation, they were instructed to contact their GP [6]. The GP was permitted to treat the exacerbation but not change their maintenance treatment in the SMART group. As a limitation, no records of visits to the GP have been listed in the study: including the number of patients that required additional GP care and the nature of changes, if any, made by the GP for the treatment of exacerbations. This data could have been beneficial in the establishment of after-care for such patients. The following endpoints were measured: 1. Primary outcome: Bronchial hyperresponsiveness: which is measured as the dose of histamine that results in a decrease of 20% in FEV1 (PD  20-histamine), determined at randomisation and after 12 months, using the dosimeter method [6]. 2. Secondary outcomes: daily diary card data of the run-in period and four weeks before each clinic visit from the following two questionnaires [6]: a. Asthma Control Questionnaire scores

8 b. the Satisfaction with Asthma Treatment Questionnaire (SATQ, after one and twelve months of treatment) c. FEV1, and peak expiratory flow (PEF), measured during the run-in period and after 1, 3, 6, and 12 months of treatment, respectively

In terms of the results, out of the 102 recruited patients, only 90 patients completed the study: 46 individuals of the SMART, and 44 individuals of usual care; the reasons are detailed in figure 5 below [6]. Notably, four patients assigned to the SMART regimen discontinued the study due to adverse events such as: pulmonary embolisms, palpitations & tremor, and asthma deterioration. Subsequently, it would have been beneficial had the researchers done a follow-up with the patients that discontinued the study; and asked them questions in relation to their medication compliance, and assurance of safety, as an extension to the efficacy of treatment. Equally, the difference in the PD20-histamine values of treatment groups was minor, being 0.72, with a p-value of 0.25 suggesting that there is a 25% probability the results were obtained due to chance, thus deeming the differences almost negligible.

Furthermore, there were a total of 11 exacerbations; with four in the SMART group, and seven in the UC group, and no asthma-related hospitalisations in either group. In addition, the mean ICS dose decreased by 41% to 326μg/day (BDP equivalents) with SMART and remained almost constant at 798μg/day (BDP equivalent) with UC during the 12-month treatment period [6]. The aforementioned results were extremely significant as they had a p value of p...