# Patients' and physicians' perspectives on the burden and management of asthma: Results from the APPaRENT 2 study

Kenneth Chapman, Giorgio Walter Canonica, Kim Lavoie, Natalia Nenasheva, Gabriel Garcia, Sinthia Bosnic-Anticevich, Arnaud Bourdin,

Maria Carmen Del Cano, P.G. Abhijith, Bhumika Aggarwal

► To cite this version:

Kenneth Chapman, Giorgio Walter Canonica, Kim Lavoie, Natalia Nenasheva, Gabriel Garcia, et al. Patients' and physicians' perspectives on the burden and management of asthma: Results from the APPaRENT 2 study. Respiratory Medicine, 2022, 201, pp.106948. 10.1016/j.rmed.2022.106948. hal-03762562

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# Patients' and physicians' perspectives on the burden and management of asthma: Results from the APPaRENT 2 study

Kenneth R. Chapman<sup>a, *</sup>, Giorgio Walter Canonica<sup>b</sup>, Kim L. Lavoie<sup>c</sup>, Natalia Nenasheva<sup>d</sup>, Gabriel Garcia<sup>e</sup>, Sinthia Bosnic-Anticevich<sup>f</sup>, Arnaud Bourdin<sup>g</sup>, Maria Carmen del Cano<sup>h</sup>, P. G. Abhijith<sup>i</sup>, Bhumika Aggarwal<sup>j</sup>

## ARTICLE INFO

**Keywords:**

Asthma symptoms

Global cohort

Patient perspectives

Physician perspectives

Guideline adherence

## ABSTRACT

**Background:** The 2021 Global Initiative for Asthma (GINA) report recommends 2 treatment tracks depending on choice of reliever therapy: either inhaled corticosteroid (ICS)/formoterol, or short-acting β2-agonist (SABA) with ICS to be used whenever a SABA is taken.

**Objective:** The Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma (APPaRENT) 2 study aimed to understand current real-world treatment approaches and their alignment with GINA recommendations.

**Methods:** Patients and physicians were recruited for the online survey from online panels from August-November 2021. Inclusion criteria: adults, physician diagnosis of asthma, ≥6 months prescribed inhaler use (patients); primary care, ≥4 patients with asthma per month, ≥3 years clinical practice (physicians).

**Results:** 1650 patients and 1080 physicians were included. For patients with moderate to severe asthma, physicians prescribed proactive regular dosing (PRD) with ICS/long-acting β2-agonist (LABA) combination with (47%) or without (15%) SABA as initial therapy. Most pulmonologists (75%) and general practitioners (57%) selected a PRD approach. The majority of patients, 85% (79-91%), considered to be using maintenance and reliever therapy (MART), were also prescribed non-ICS rescue inhaler.

**Conclusions:** Physicians preferred a preventive regular dosing approach to achieve symptom control for patients with moderate to severe asthma, which is more aligned with GINA 2021 Track 2 recommendations than Track 1. Many patients on MART request additional rescue inhalers, suggesting that MART is being misapplied in most instances and that patients may perceive their asthma as inadequately controlled with MART therapy.

## 1. Introduction

The decline in asthma mortality rate has plateaued [1]. Global strategies and national guidelines differ in the advice offered to healthcare practitioners seeking best outcomes [2-7]. The Global

Initiative for Asthma (GINA) [4] 2021, a consensus document, postulates that 2 treatment tracks may provide comparable outcomes. The tracks are defined by the choice of reliever (either low-dose inhaled corticosteroid [ICS]/formoterol for Track 1 or short-acting β2-agonist [SABA] for Track 2). The latter track is accompanied by the

<footnote><sup>a</sup> University of Toronto, Toronto, Canada</footnote>

<footnote><sup>b</sup> Department of Biomedical Sciences, Humanitas University, Asthma & Allergy Unit- IRCCS; Humanitas Research Hospital, Milan, Italy</footnote>

<footnote><sup>c</sup> University of Quebec at Montreal and Montreal Behavioural Medicine Centre, CIUSSS-NIM, Hôpital du Sacre-Cœur de Montreal, Montreal, Canada</footnote>

<footnote><sup>d</sup> Department of Allergology and Immunology of the Federal State Budgetary Educational Institution of Further Professional Education "Russian Medical Academy of Continuous Professional Education" of the Ministry of Healthcare of the Russian Federation, Russia</footnote>

<footnote><sup>e</sup> Pneumology Hospital Rossi, La Plata, Argentina</footnote>

<footnote><sup>f</sup> Woolcock Institute of Medical Research, University of Sydney, Australia and Sydney Local Health District, Sydney, Australia</footnote>

<footnote><sup>g</sup> CHU Montpellier, PhyMedExp, INSERM, CNRS, Université de Montpellier, Montpellier, France</footnote>

<footnote><sup>h</sup> National Institute of Respiratory Diseases, Mexico City, Mexico</footnote>

<footnote><sup>i</sup> GSK, General Medicines, Singapore</footnote>

<footnote>* Corresponding author. Asthma & Airway Centre, University Health Network, Rm. 7-451 EW, 399 Bathurst Street, Toronto, Ontario, M5T 2S8

**E-mail addresses:** ken.chapman.airways@gmail.com (K.R. Chapman), canonica.gw@gmail.com (G.W. Canonica), kiml.lavoie@yahoo.ca (K.L. Lavoie), 1444031@gmail.com (N. Nenasheva), gabrielgarcia.cepir@gmail.com (G. Garcia), sinthia.bosnic-anticevich@sydney.edu.au (S. Bosnic-Anticevich), arnaud01009157@gmail.com (A. Bourdin), carmencano09@gmail.com (M.C. Cano), abhijith.x.pg@gsk.com (P.G. Abhijith), bhumika.x.aggarwal@gsk.com (B. Aggarwal).</footnote>
recommendation for ICS to be used whenever a SABA is taken [4]. In the GINA recommendations, the daily maintenance regimen for patients in Steps 3–5 is ICS/formoterol as maintenance therapy with additional ICS/formoterol as needed (maintenance and as-needed reliever therapy [MART]) in Track 1, or regular dosing with ICS/long-acting β2-agonist (LABA) with as-needed SABA for symptom relief in Track 2; further add-on therapies are recommended at Step 5. The former strategy assumes that asthma control and exacerbation reduction will be guided accurately by patient perception of symptoms; the latter strategy places these outcomes in the hands of the physician. Physicians and patients have a long history of familiarity with the regular dosing regimen proposed in Track 2, whereas the flexible dosing approach, first advocated in 2020, was then included in Track 1 in the GINA 2021 report [4].

Proactive regular dosing (PRD) with an ICS-based treatment alongside as-needed SABA for symptom relief has long been a cornerstone of asthma treatment, and its use is associated with benefits including controlling symptoms and reducing mortality, severe exacerbations, and asthma-related hospitalizations [8–12]. Moreover, early intervention with ICS prevents the development of irreversible airway obstruction that occurs over time [13]. This preventive treatment of the underlying pathophysiology of asthma results in reduced inflammation, reduced airway remodeling, and sustained bronchoprotective efficacy, which have been identified as hallmarks of PRD with ICS [10,12,14,15]. With consistent regular dosing, reliance on self-driven symptom tracking is reduced, and therefore the risk of over- or under-treatment by the patient is minimized [16].

The alternative approach for patients with moderate asthma, namely MART, has several limitations that have been described previously; despite two large scale trials comparing MART to usual standard of care, there is no evidence that MART affords better outcomes [17]. Ubiquitous application of this approach is limited by the heterogeneity of disease and patient response to ICS [18–20]. As-needed budesonide/formoterol dosing was inferior to twice-daily low dose budesonide for symptom control of mild asthma in both Symbicort Given as Needed in Mild Asthma (SYGMA) studies [21,22]. The impact on exacerbations was indistinguishable between preventive and intermittent dosing treatment groups in SYGMA 1 [21]. SYGMA 2 failed to test the superiority of exacerbation prevention with the new as-needed strategy as the recruited patients had too few exacerbations [22]. It should be noted that the US Food and Drug Administration and European Medicines Agency have not approved as-needed ICS/formoterol for symptom relief in mild or moderate asthma; therefore the GINA recommendation is currently off-label for many countries [23,24]. Neither the MART strategy nor the SYGMA strategy has been recognized in the National Heart, Lung, and Blood Institute 2020 asthma guidelines and updates [2]. Symptom control was identified as the primary goal for asthma management by both patients and physicians in the Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma (APPaRENT 1) study, and findings indicated that there remains frequent misapplication of MART dosing [25].

The APPaRENT 2 study was undertaken to understand current treatment approaches for patients with asthma and how these align with the latest GINA recommendations in real-world clinical practice. The APPaRENT 2 study includes different participating countries from APPaRENT 1 (Australia, Canada, China, and the Philippines), the broadening of healthcare providers to include pulmonologists in the physician survey, and modifications in both the patient and physician survey questionnaires to investigate deeply the motivations for patients' and physicians' attitudes and management of regular versus flexible dosing.

## 2. Materials and methods

### 2.1. Study design and eligibility criteria

The APPaRENT 2 study was a multi-country, cross-sectional, voluntary, closed online survey-based study of patients with asthma and physicians in 5 countries where MART therapy is approved, Argentina, Brazil, France, Italy, and Mexico. Patients and physicians were recruited via high-quality online nonprobability panels between August and November 2021; see **supplement** for additional details including the Checklist for Reporting Results of Internet E-Surveys (CHERRIES).

Participants were then invited to complete a self-administered online survey in patients' and physicians' local languages. Eligible patients were aged ≥18 years with a self-reported history of a past or current diagnosis of asthma made by a physician and self-reported use of a prescribed inhaler for at least 6 months. Eligible physicians were primary care physicians, internal medicine physicians, or pulmonologists with ≥3 years in clinical practice who treated ≥4 patients with asthma each month on average. Physicians who were responsible for drug formulation decisions or who were employed by a pharmaceutical company at the time of the study were excluded.

### 2.2. Statistical analysis

Sample sizes were based on APPaRENT 1 and selected to be sufficient for within-country regression analyses [25]; for additional details please see **supplement**. Reported p-values were determined using Chi-square testing for categorical data and analysis of variance (ANOVA) means testing for continuous data. Participants who responded that they were not aware of/did not apply treatment approaches were excluded from subsequent analyses surrounding their use.

Respondents were recruited from nonprobability panels; therefore, formal response calculations were not appropriate and cooperation rates were defined as the total number of completed surveys divided by the total number of initial web invitations sent minus the number of cases known to be ineligible. The proportions of patients or physicians with different responses are presented as ranges throughout, indicating the lowest and highest proportions across the 5 countries.

## 3. Results

### 3.1. Study population and cooperation rates

Between 12,000 and 19,000 invitations were sent to patients in Argentina, Brazil, France, Italy, and Mexico, with a total of 1650 patient surveys (330 per country) completed (Supp Table I). Eligibility was unknown for 11,698–12,909 patients, while 259–850 were not eligible. Patient cooperation rates ranged from 2% in Mexico to 3% in Brazil (Supp Table I). For the asthma-treating physician survey, approximately 1100–2100 invitations were sent to physicians in each country, with 1080 physician surveys (216 per country) completed (Supp Table II). Physician eligibility was unknown for 774–1772 physicians, and 52–131 were ineligible; cooperation rates ranged from 12% in Brazil to 23% in Mexico (Supp Table II).

### 3.2. Sociodemographics

Overall, patients had a mean age of 39 years (standard deviation of 14.2 years), and most were female (58%; Table I). Almost half (45%) of patients reported that at least one person in their household currently smoked a tobacco product and/or used a vaping product on a daily basis;
<table><caption>**Table 1**

Patient sociodemographic and health characteristics.</caption><thead><tr><th></th><th>Overall (N = 1650)</th><th>Argentina (N = 330)</th><th>Brazil (N = 330)</th><th>France (N = 330)</th><th>Italy (N = 330)</th><th>Mexico (N = 330)</th></tr></thead><tbody><tr><td><strong>Gender</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>960 (58)</td><td>128 (39)</td><td>236 (72)</td><td>214 (65)</td><td>170 (52)</td><td>212 (64)</td></tr><tr><td><strong>Age, mean years</strong></td><td>38.8</td><td>35.2</td><td>36.2</td><td>47.1</td><td>43.2</td><td>32.4</td></tr><tr><td><strong>Age category, years</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>18-29</td><td>403 (24)</td><td>84 (25)</td><td>106 (32)</td><td>43 (13)</td><td>44 (13)</td><td>126 (38)</td></tr><tr><td>30-39</td><td>587 (36)</td><td>159 (48)</td><td>107 (32)</td><td>77 (23)</td><td>99 (30)</td><td>145 (44)</td></tr><tr><td>40-49</td><td>342 (21)</td><td>62 (19)</td><td>74 (22)</td><td>64 (19)</td><td>95 (29)</td><td>47 (14)</td></tr><tr><td>≥50</td><td>318 (19)</td><td>25 (8)</td><td>43 (13)</td><td>146 (44)</td><td>92 (28)</td><td>12 (4)</td></tr><tr><td><strong>Education</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No education</td><td>5 (0)</td><td>0 (0)</td><td>2 (1)</td><td>2 (1)</td><td>0 (0)</td><td>1 (0)</td></tr><tr><td>Primary school</td><td>10 (1)</td><td>0 (0)</td><td>1 (0)</td><td>2 (1)</td><td>5 (2)</td><td>2 (1)</td></tr><tr><td>Secondary school (to 16 years)</td><td>406 (25)</td><td>42 (13)</td><td>46 (14)</td><td>149 (45)</td><td>132 (40)</td><td>37 (11)</td></tr><tr><td>College/university</td><td>973 (59)</td><td>266 (81)</td><td>217 (66)</td><td>127 (38)</td><td>111 (34)</td><td>252 (76)</td></tr><tr><td>Postgraduate</td><td>256 (16)</td><td>22 (7)</td><td>64 (19)</td><td>50 (15)</td><td>82 (25)</td><td>38 (12)</td></tr><tr><td><strong>Location of residence</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Large city/metropolitan area</td><td>932 (56)</td><td>259 (78)</td><td>233 (71)</td><td>75 (23)</td><td>107 (32)</td><td>258 (78)</td></tr><tr><td>Suburb</td><td>199 (12)</td><td>28 (8)</td><td>21 (6)</td><td>61 (18)</td><td>58 (18)</td><td>31 (9)</td></tr><tr><td>Small city</td><td>272 (16)</td><td>36 (11)</td><td>40 (12)</td><td>81 (25)</td><td>81 (25)</td><td>34 (10)</td></tr><tr><td>Town</td><td>120 (7)</td><td>3 (1)</td><td>22 (10)</td><td>25 (8)</td><td>55 (17)</td><td>4 (1)</td></tr><tr><td>Rural area</td><td>127 (8)</td><td>4 (1)</td><td>3 (1)</td><td>88 (27)</td><td>29 (9)</td><td>3 (1)</td></tr><tr><td><strong>Do you or anyone in your household currently smoke cigarettes, cigars, pipe, and/or vaping product on a daily basis?</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>747 (45)</td><td>179 (54)</td><td>123 (37)</td><td>136 (41)</td><td>159 (48)</td><td>150 (45)</td></tr></tbody></table>

Data presented as n (%) unless otherwise indicated. Chi-square test for differences between countries *p* < 0.001 for all metrics assessed.

<table><caption>**Table 2**

Physician sociodemographic characteristics.</caption><thead><tr><th></th><th>Overall (N = 1080)</th><th>Argentina (N = 216)</th><th>Brazil (N = 216)</th><th>France (N = 216)</th><th>Italy (N = 216)</th><th>Mexico (N = 216)</th></tr></thead><tbody><tr><td><strong>Gender</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>682 (63)</td><td>111 (51)</td><td>117 (54)</td><td>161 (75)</td><td>158 (73)</td><td>135 (63)</td></tr><tr><td><strong>Age, mean years</strong></td><td>45.3</td><td>46.8</td><td>42.4</td><td>48</td><td>46.7</td><td>42.7</td></tr><tr><td><strong>Years in clinical practice, mean</strong></td><td>17.2</td><td>18.9</td><td>14.9</td><td>18.6</td><td>18.2</td><td>15.4</td></tr><tr><td><strong>Age category, years</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>18-29</td><td>25 (2)</td><td>1 (1)</td><td>1 (1)</td><td>1 (0)</td><td>15 (7)</td><td>6 (3)</td></tr><tr><td>30-39</td><td>365 (34)</td><td>40 (19)</td><td>95 (44)</td><td>60 (28)</td><td>81 (38)</td><td>89 (41)</td></tr><tr><td>40-49</td><td>326 (30)</td><td>96 (44)</td><td>76 (35)</td><td>54 (25)</td><td>24 (11)</td><td>76 (35)</td></tr><tr><td>≥50</td><td>364 (34)</td><td>79 (37)</td><td>43 (20)</td><td>101 (47)</td><td>96 (44)</td><td>45 (21)</td></tr><tr><td><strong>Practice setting*</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Government-sponsored clinic or doctor's office</td><td>155 (14)</td><td>19 (9)</td><td>41 (19)</td><td>8 (4)</td><td>62 (29)</td><td>25 (12)</td></tr><tr><td>Government-sponsored hospital</td><td>243 (23)</td><td>40 (19)</td><td>30 (14)</td><td>65 (30)</td><td>71 (33)</td><td>37 (17)</td></tr><tr><td>Private clinic or doctor's office</td><td>552 (51)</td><td>108 (50)</td><td>115 (53)</td><td>115 (62)</td><td>70 (32)</td><td>125 (58)</td></tr><tr><td><strong>Location of treatment facility</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Large city/metropolitan area</td><td>745 (69)</td><td>188 (87)</td><td>175 (81)</td><td>91 (42)</td><td>111 (51)</td><td>180 (83)</td></tr><tr><td>Suburb</td><td>95 (9)</td><td>4 (2)</td><td>6 (3)</td><td>46 (21)</td><td>27 (13)</td><td>12 (6)</td></tr><tr><td>Small city</td><td>177 (16)</td><td>23 (11)</td><td>28 (13)</td><td>51 (24)</td><td>54 (25)</td><td>21 (10)</td></tr><tr><td>Town</td><td>36 (3)</td><td>1 (0)</td><td>7 (3)</td><td>8 (4)</td><td>19 (9)</td><td>1 (0)</td></tr><tr><td>Rural area</td><td>25 (2)</td><td>0</td><td>0</td><td>18 (8)</td><td>5 (2)</td><td>2 (1)</td></tr></tbody></table>

*p-value (determined by Chi-square test for categorical data and analysis of variance (ANOVA) means test for continuous data) did not indicate significant variation (p ≥ 0.05) between countries; significant variation between countries was observed for all other sociodemographic and health characteristics.

Data presented as n (%) unless otherwise indicated.

rates were highest in Argentina (54%) and lowest in Brazil (37%).

The majority of physicians surveyed were male and practiced in a private clinic or doctor's office (51%) or a government-sponsored hospital or hospital-based facility (23%; Table II). Most (56%) were working in primary care (general practitioner of family medicine), and 28% were pulmonologists or chest physicians. Physicians in Argentina, Brazil, and Mexico practiced mainly in a large city or metropolitan area (87%, 81%, and 83%, respectively) while those in France and Italy practiced in more rural areas (the proportions practicing in a large city or metropolitan area were 42% and 51%, respectively).

### 3.3. Asthma status

Most patients described their current level of asthma severity as moderate (55–68%) and reported a mean Asthma Control Test (ACT) score of 16.3 (15.4–17.0; Table IIIA). The proportion of patients who described their asthma control in the previous 4 weeks as not controlled

at all or poorly controlled was <10%. However, 52% of patients reported that their asthma kept them from getting as much done at work, school, or home at least some of the time in the past 4 weeks. The majority of patients (65%) reported using their reliever inhaler ≥2 times/week and 57% of patients reported waking up at night due to their asthma symptoms ≥1 time/week in the previous 4 weeks. There was a statistically significant association between living with a household member who smokes/vapes and the patient describing asthma control as 'poorly controlled' or 'not controlled at all' (p < 0.0001). The mean ACT score was also significantly lower (15.2) among respondents living with household members who smoke/vape compared with those who do not (17.2) (p < 0.0001).

Overall, physicians reported that the majority of their patients (42%) had mild asthma (32–50%), with 31% having moderate asthma (28–32%; Table IIIB). Physicians reported that they would anticipate at least one-third of their patients with mild asthma would have ≥1 exacerbation each year requiring physician care, increasing to around
<table><caption>**Table 3**

Patient asthma status – (A) patient and (B) physician responses.</caption><thead><tr><th></th><th>Overall (N=1650)</th><th>Argentina (N=330)</th><th>Brazil (N=330)</th><th>France (N=330)</th><th>Italy (N=330)</th><th>Mexico (N=330)</th></tr></thead><tbody><tr><td colspan="7"><strong>Overall, how would you describe your current level of asthma severity?</strong></td></tr><tr><td>Mild</td><td>565 (34)</td><td>99 (30)</td><td>111 (34)</td><td>111 (34)</td><td>125 (38)</td><td>109 (36)</td></tr><tr><td>Moderate</td><td>988 (60)</td><td>226 (68)</td><td>188 (57)</td><td>182 (55)</td><td>184 (56)</td><td>208 (63)</td></tr><tr><td>Severe</td><td>97 (6)</td><td>5 (2)</td><td>31 (9)</td><td>37 (11)</td><td>21 (6)</td><td>3 (1)</td></tr><tr><td colspan="7"><strong>Why do you feel this is your current level of asthma severity? (Select all that apply)</strong></td></tr><tr><td>Your doctor told you</td><td>1212(73)</td><td>276 (84)</td><td>221 (67)</td><td>240 (73)</td><td>214 (65)</td><td>261 (79)</td></tr><tr><td>You had tests done and have seen test results</td><td>859 (52)</td><td>196 (59)</td><td>170 (52)</td><td>148 (45)</td><td>164 (50)</td><td>181 (55)</td></tr><tr><td>You take a high dose of controller medications</td><td>342 (21)</td><td>92 (28)</td><td>86 (26)</td><td>74 (22)</td><td>46 (14)</td><td>44 (13)</td></tr><tr><td colspan="7"><strong>Asthma Control Test</strong></td></tr><tr><td>Mean Score</td><td>16.3</td><td>15.4</td><td>16.1</td><td>16.6</td><td>17</td><td>16.3</td></tr><tr><td colspan="7"><strong>In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school, or at home?</strong></td></tr><tr><td>All of the time</td><td>65 (4)</td><td>11 (3)</td><td>21 (6)</td><td>13 (4)</td><td>8 (2)</td><td>12 (4)</td></tr><tr><td>Most of the time</td><td>211 (13)</td><td>74 (22)</td><td>34 (10)</td><td>44 (13)</td><td>33 (10)</td><td>26 (8)</td></tr><tr><td>Some of the time</td><td>580 (35)</td><td>129 (39)</td><td>99 (30)</td><td>119 (36)</td><td>105 (32)</td><td>128 (39)</td></tr><tr><td>A little of the time</td><td>507 (31)</td><td>86 (26)</td><td>104 (32)</td><td>95 (29)</td><td>95 (29)</td><td>127 (38)</td></tr><tr><td>None of the time</td><td>287 (17)</td><td>30 (9)</td><td>72 (22)</td><td>59 (18)</td><td>89 (27)</td><td>37 (11)</td></tr><tr><td colspan="7"><strong>During the past 4 weeks, how often have you had shortness of breath?</strong></td></tr><tr><td>More than once a day</td><td>212 (13)</td><td>18 (5)</td><td>53 (16)</td><td>74 (22)</td><td>38 (12)</td><td>29 (9)</td></tr><tr><td>Once a day</td><td>241 (15)</td><td>58 (18)</td><td>47 (14)</td><td>45 (14)</td><td>48 (15)</td><td>43 (13)</td></tr><tr><td>3 to 6 times a week</td><td>358 (22)</td><td>107 (32)</td><td>57 (17)</td><td>61 (18)</td><td>67 (20)</td><td>66 (20)</td></tr><tr><td>Once or twice a week</td><td>685 (42)</td><td>125 (38)</td><td>133 (40)</td><td>118 (36)</td><td>142 (43)</td><td>167 (51)</td></tr><tr><td>Not at all</td><td>154 (9)</td><td>22 (7)</td><td>40 (12)</td><td>32 (10)</td><td>35 (11)</td><td>25 (8)</td></tr><tr><td colspan="7"><strong>During the past 4 weeks, how often did your asthma symptoms wake you up at night or earlier than usual in the morning?</strong></td></tr><tr><td>4 or more nights a week</td><td>158 (10)</td><td>20 (6)</td><td>54 (16)</td><td>31 (9)</td><td>26 (8)</td><td>27 (8)</td></tr><tr><td>2 to 3 nights a week</td><td>455 (28)</td><td>130 (39)</td><td>89 (27)</td><td>68 (21)</td><td>70 (21)</td><td>98 (30)</td></tr><tr><td>Once a week</td><td>308 (19)</td><td>74 (22)</td><td>43 (13)</td><td>59 (18)</td><td>58 (18)</td><td>74 (22)</td></tr><tr><td>Once or twice</td><td>437 (26)</td><td>67 (20)</td><td>93 (28)</td><td>79 (24)</td><td>99 (30)</td><td>98 (30)</td></tr><tr><td>Not at all</td><td>292 (18)</td><td>39 (12)</td><td>51 (15)</td><td>93 (28)</td><td>76 (23)</td><td>33 (10)</td></tr><tr><td colspan="7"><strong>During the past 4 weeks, how often have you used your rescue inhaler reliever or nebulizer medication?</strong></td></tr><tr><td>3 or more times per day</td><td>135 (8)</td><td>18 (5)</td><td>43 (13)</td><td>26 (8)</td><td>19 (6)</td><td>29 (9)</td></tr><tr><td>1 to 2 times per day</td><td>468 (28)</td><td>108 (33)</td><td>97 (29)</td><td>85 (26)</td><td>86 (26)</td><td>92 (28)</td></tr><tr><td>2 or 3 times per week</td><td>484 (29)</td><td>132 (40)</td><td>75 (23)</td><td>86 (26)</td><td>83 (28)</td><td>98 (30)</td></tr><tr><td>Once a week or less</td><td>404 (24)</td><td>61 (18)</td><td>77 (23)</td><td>84 (25)</td><td>85 (26)</td><td>97 (29)</td></tr><tr><td>Not at all</td><td>158 (10)</td><td>11 (3)</td><td>38 (12)</td><td>49 (15)</td><td>47 (14)</td><td>13 (4)</td></tr><tr><td colspan="7"><strong>How would you rate your asthma control during the past 4 weeks?</strong></td></tr><tr><td>Not controlled at all</td><td>23 (1)</td><td>4 (1)</td><td>7 (2)</td><td>7 (2)</td><td>2 (1)</td><td>3 (1)</td></tr><tr><td>Poorly controlled</td><td>127 (8)</td><td>30 (9)</td><td>24 (7)</td><td>18 (5)</td><td>29 (9)</td><td>26 (8)</td></tr><tr><td>Somewhat controlled</td><td>702 (43)</td><td>192 (58)</td><td>124 (38)</td><td>104 (32)</td><td>144 (44)</td><td>138 (42)</td></tr><tr><td>Well controlled</td><td>603 (37)</td><td>81 (25)</td><td>142 (43)</td><td>140 (42)</td><td>112 (34)</td><td>128 (39)</td></tr><tr><td>Completely controlled</td><td>195 (12)</td><td>23 (7)</td><td>33 (10)</td><td>61 (18)</td><td>43 (13)</td><td>35 (11)</td></tr></tbody><tfoot><tr><td colspan="7">Data presented as n (%). Chi-square test for differences between countries p < 0.001 for all metrics assessed.</td></tr></tfoot></table>

<table><thead><tr><th></th><th>Overall (N=1080)</th><th>Argentina (N=216)</th><th>Brazil (N=216)</th><th>France (N=216)</th><th>Italy (N=216)</th><th>Mexico (N=216)</th></tr></thead><tbody><tr><td colspan="7"><strong>Approximately what percent of your persistent asthma patients have...?</strong></td></tr><tr><td>Mild asthma***</td><td>41.6</td><td>49.8</td><td>43</td><td>31.7</td><td>36.9</td><td>46.7</td></tr><tr><td>Moderate asthma*</td><td>30.5</td><td>29.9</td><td>28</td><td>31.9</td><td>32.1</td><td>30.5</td></tr><tr><td>Severe asthma***</td><td>13.7</td><td>9.2</td><td>14.1</td><td>18.6</td><td>15.1</td><td>11.3</td></tr><tr><td>Severity unclear***</td><td>7.7</td><td>6.7</td><td>8.8</td><td>9.2</td><td>7.6</td><td>6.1</td></tr><tr><td>Severity fluctuates**</td><td>9.8</td><td>8.7</td><td>10.3</td><td>11</td><td>10.6</td><td>8.3</td></tr><tr><td colspan="7"><strong>What percentage of your patients will have at least one exacerbation each year that requires physician care?</strong></td></tr><tr><td>Mild asthma***</td><td>36.9</td><td>31.9</td><td>38.1</td><td>33.3</td><td>37.6</td><td>43.9</td></tr><tr><td>Moderate asthma**</td><td>47.9</td><td>45.3</td><td>49.2</td><td>43.3</td><td>49.8</td><td>51.7</td></tr><tr><td>Severe asthma</td><td>66.7</td><td>64.1</td><td>65.6</td><td>65.2</td><td>71.6</td><td>66.7</td></tr></tbody></table>

(A) Data presented as n (%). Chi-square test for differences between countries *p* < 0.001 for all metrics assessed.

(B) Data presented as average estimated % of patients. Chi-square test for differences between countries: *p* < 0.05; **p* < 0.01; ***p* < 0.001.

one-half of those with moderate asthma and at least two-thirds of those with severe asthma.

### 3.4. Treatment preferences and aims

Overall, physicians cited asthma control (44%) and exacerbation reduction (33%) as the most important goals for patients with asthma of any severity. For patients with mild, moderate, and severe asthma, the most common treatment goal was to achieve symptom control (40%, 46%, and 42%, respectively), followed by exacerbation control (24%, 25%, and 30%, respectively).

Approximately half of patients (53%) reported having had their asthma medication changed by their physician, most commonly due to symptom worsening (39%). If patients' asthma remained uncontrolled on initial therapy, 59% of physicians indicated that they would switch to a PRD approach with ICS/LABA either alone or with SABA, while 36% would switch to a MART regimen. Physicians indicated that the most common reasons for switching patients from one ICS/LABA regimen to another were symptom worsening, inadequate asthma control, and asthma exacerbations. For patients with moderate to severe asthma, 76% of physicians indicated that they often or sometimes switch patients to another ICS/LABA when symptoms do not improve.
### 3.5. Current treatment patterns

Overall, 34% of patients reported they had been prescribed only a SABA reliever inhaler for as-needed use, 28% of patients reported they had been prescribed a regular dosing regimen with daily maintenance inhaler and SABA for use as needed, and 27% of patients reported that they had been prescribed regular dosing with a daily maintenance inhaler only. Twelve percent of patients reported being prescribed one inhaler for both daily use and as a rescue inhaler (Table IV).

Physicians reported their prescribed treatments for asthma patients (Fig. 1); the categories were not mutually exclusive. For patients with moderate to severe or fluctuating severity asthma, physicians most frequently reported prescribing PRD with ICS/LABA combination with SABA (47%); other prescribed therapies included ICS/LABA without SABA (15%), low-dose ICS + SABA (16%), fixed-dose combination ICS/formoterol (9%), MART + SABA (6%), low-dose ICS without SABA (3%), and SABA only (3%).

### 3.6. Proactive regular dosing

Overall, 75% of patients who responded reported familiarity with the PRD approach (68–82%). The proportion of patients who reported ever having followed regular dosing was highest among those with severe asthma (94%). Of those patients who reported ever having followed a daily maintenance approach, 75% said they currently follow this approach; this includes 69%, 77%, and 81% of patients with self-reported mild, moderate, and severe asthma, respectively (Table V). Among patients currently following a regular dosing approach, 85% reported having been prescribed a separate SABA reliever.

The most common factors reported by physicians for the prescribing of SABA alongside ICS/LABA were: patients expressed a desire to have an extra reliever to feel safer (57%), and patient convenience of having an extra reliever in their car, at work, or for travel, etc (50%). The most important factors noted by physicians that influence patient outcomes when prescribing maintenance medications were asthma control (40%), asthma exacerbations (26%), and symptom severity (20%).

As an initial treatment for patients with moderate, severe, or fluctuating severity asthma, physicians most frequently reported selecting regular ICS/LABA dosing alone or with as-needed SABA. ICS/LABA combination with as-needed SABA was prescribed for 47% of patients overall (39–53%); ICS/LABA combination alone without SABA was prescribed for 15% of patients overall (10–28%). If patients remained uncontrolled on initial therapy, ICS/LABA dosing alone or with as-needed SABA was also the most commonly reported follow-up treatment approach for moderate, severe, or fluctuating severity asthma. Overall, ICS/LABA combination + SABA as needed was prescribed as follow-up treatment for 44% of patients (37–50%) and ICS/LABA combination without SABA for 15% of patients (8–22%; Fig. 2).

Pulmonologists selected a PRD approach for their patients more frequently than other general physicians; ICS/LABA combination + SABA as needed was prescribed for 55% of patients (compared with 43% of general practitioners and family medicine physicians and 48% of internal medicine physicians; Fig. 3). Overall, ICS/LABA combination

without SABA was prescribed for 20% of patients treated by pulmonologists (compared with 14% of those treated by general practitioners and family medicine physicians and 7% of those treated by internal medicine physicians).

### 3.7. MART dosing

Around half of patients (56%) reported being aware of MART dosing for the treatment of asthma (47–70%). Of those who reported being aware of MART, most (78%) said they had heard about this approach from their doctor and 66% of patients reported having been prescribed this approach (51–86%). Of patients who had been prescribed this approach, 85% reported also being given a separate rescue inhaler (79–91%); for 67% of these patients (46–75%), the reliever medication was provided at their request.

The majority of physicians (67%) reported awareness of MART. Pulmonologists had greater awareness of MART than other physicians (86% had familiarity compared with 45% of internal medicine physicians and 62% of general practitioners). Physicians reported that, at present, 10% of their patients with mild asthma and 16% with moderate asthma were prescribed a MART regimen + SABA. For patients with moderate, severe, or fluctuating severity asthma, 6% of physicians indicated they would consider MART + as-needed SABA as initial therapy.

When asked about the reasons for prescribing MART, physicians ranked asthma control as the most important factor (41%), followed by exacerbations (27%), symptom severity (18%), lung function impairment (4%), previous poor adherence (3%), co-morbidities (2%), flexibility to change the dose (2%) and patient device preference (2%).

Physicians were asked to identify key patient factors influencing the decision to prescribe a SABA reliever in addition to ICS/formoterol as MART. Patient desire for an extra reliever to feel safer was rated highest (59%) followed by convenience of an extra reliever in the car, at work or for travel (53%), patient familiarity with SABA (48%) and patients accustomed to an extra reliever (42%); categories were not mutually exclusive.

## 4. Discussion

Results from APPaRENT 2 align with those previously reported for APPaRENT 1 and show broad concordance across the 9 participating countries [25]. These findings were also consistent with the Global Asthma Physician Survey (GAPS) and the Asia-Pacific Survey of Physicians on Asthma and Allergic Rhinitis (ASPAIR), in which most patients and physicians communicated that the priority goal of asthma management is symptom control [26,29].

Despite this prioritization of symptom control in asthma management, APPaRENT 2 identified high rates of poor asthma control and SABA use across all participating countries. Rates of smoking and vaping were high across the patient population (45% of patients overall reported that ≥1 person in their household used a tobacco/vaping product on a daily basis) and this was shown to be associated with poor asthma control in this cohort. Physicians anticipated high rates of asthma

<table><caption>**Table 4**

Patient-reported treatment patterns.</caption><thead><tr><th>Overall (N = 1650)</th><th>Argentina (N = 330)</th><th>Brazil (N = 330)</th><th>France (N = 330)</th><th>Italy (N = 330)</th><th>Mexico (N = 330)</th></tr></thead><tbody><tr><td colspan="6"><strong>Thinking about your asthma medication, which of the following best describes your current asthma treatment regimen prescribed by your doctor?</strong></td></tr><tr><td>Only use a daily controller/maintenance inhaler</td><td>440 (27)</td><td>69 (21)</td><td>111 (34)</td><td>88 (27)</td><td>79 (24)</td></tr><tr><td>Only use a rescue inhaler/reliever for use as needed to relieve symptoms</td><td>566 (34)</td><td>150 (45)</td><td>97 (29)</td><td>95 (29)</td><td>114 (35)</td></tr><tr><td>Use both a daily controller/maintenance inhaler and a rescue inhaler/reliever as needed</td><td>454 (28)</td><td>77 (23)</td><td>77 (23)</td><td>111 (34)</td><td>96 (29)</td></tr><tr><td>Use an inhaler for both daily use and as a rescue inhaler/reliever as needed</td><td>190 (12)</td><td>34 (10)</td><td>45 (14)</td><td>36 (11)</td><td>41 (12)</td></tr></tbody></table>

Data presented as n (%). Significant variation (p < 0.001) between countries was observed for all responses shown (Chi-square test).
<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Physician-reported prescribing by asthma severity
ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; MART, maintenance and reliever therapy; SABA, short-acting β2-agonist.</figcaption></figure>

<table><caption>**Table 5**
Patient-reported use of regular dosing and MART.</caption><thead><tr><th></th><th>All patients<br>(N = 1650)</th><th>Mild<br>(N =<br>565)</th><th>Moderate<br>(N = 988)</th><th>Severe<br>(N = 97)</th></tr></thead><tbody><tr><td><strong>Proactive regular dosing</strong><br>Some inhalers are designed to be used every day regardless of having symptoms. This approach is referred to as daily controller/maintenance.</td><td></td><td></td><td></td><td></td></tr><tr><td>Have you ever followed this approach?</td><td>1244 (75)</td><td>378<br>(67)</td><td>775 (79)</td><td>91 (94)</td></tr><tr><td>If yes, do you currently follow a daily maintenance approach?</td><td>933 (75)</td><td>261<br>(69)</td><td>598 (77)</td><td>74 (81)</td></tr><tr><td>When you were prescribed this approach for treating your asthma, were you also prescribed a separate rescue inhaler?</td><td>793 (85)</td><td>210<br>(80)</td><td>522 (87)</td><td>61 (82)</td></tr><tr><td><strong>MART</strong><br>Some inhalers can be used as both your daily combination asthma controller/maintenance inhaler and as your rescue inhaler/reliever as needed, in one inhaler.</td><td></td><td></td><td></td><td></td></tr><tr><td>Are you aware of this approach for treating asthma?</td><td>931 (56)</td><td>270<br>(48)</td><td>602 (61)</td><td>59 (61)</td></tr><tr><td>If yes, has a doctor ever prescribed this approach for you?</td><td>616 (66)</td><td>161<br>(60)</td><td>415 (31)</td><td>40 (32)</td></tr><tr><td>When you were prescribed the MART approach for treating your asthma, were you also prescribed a separate quick relief rescue inhaler?</td><td>521 (85)</td><td>126<br>(78)</td><td>358 (86)</td><td>37 (93)</td></tr></tbody></table>

Data presented as n (%). Chi-square test for differences between countries *p* < 0.001 for all metrics assessed.
MART, maintenance and reliever therapy.

exacerbations, expecting ≥1 exacerbation requiring physician input for 36% of patients with mild asthma, which complements the findings that patients continue to overestimate their level of asthma control, tolerate frequent symptoms, and potentially overly rely on rescue medication. However, the identification of exacerbation reduction as another priority goal for asthma management, alongside these observations, highlights the disparity between the desired outcomes for patients and the current patient experience; improved communication between patients and physicians will be the key to addressing this gap.

It is noteworthy that although the evidence supporting Track 1 was designated Category B by GINA, indicative of scenarios in which randomized controlled trials are few, are small in size, were undertaken in patient populations that differ from those pertaining to the

recommendation, or have data that are inconsistent, the GINA strategy gave preference to Track 1 [4]. Awareness that supporting evidence for a reliever-driven approach is modest may account for the day-to-day preference for the better-established preventive approach with ICS/LABA alone or with SABA reliever. Over half of patients with moderate asthma reported being prescribed regular dosing regimens. For patients who remain uncontrolled on initial therapy, physicians were more likely to prescribe PRD with ICS/LABA with/without as-needed SABA than MART regimens; symptom worsening and exacerbations were the most common reasons for switching asthma medications. The recent review by Fletcher et al. (2022) suggests that optimal asthma management following an exacerbation should, irrespective of care setting, involve prescribing PRD with controller therapy followed by a primary care visit within 2 weeks to evaluate patient response and maintain asthma control [27].

Pulmonologists selected a regular dosing approach for their patients more frequently than other physicians. This may reflect increased adherence to guidelines by pulmonologists. Previous studies have shown that the prescribing behavior and perspectives of asthma specialists can differ from those of general practitioners [28]. Differences in prescribing may in part be attributed to residual concerns among some general practitioners around the side effects of ICS despite guideline recommendations.

APPARENT 2 suggests that most patients with moderate asthma are prescribed PRD regimens, indicating that despite the introduction of the treatment tracks in the GINA 2021 recommendations, there remains a disconnect with real-world practice. The majority of physicians and patients reported a preference for a PRD approach, which aligns with many recent national guidelines (British Thoracic Society, French guidelines [as written by The French Emergency Medicine Society, French Intensive Care Society, and the Pediatric Intensive Care and Emergency Medicine French-Speaking Group], Japanese Society of Allergology, Spanish Asthma Management Guidelines, Agency for Care Effectiveness Singapore clinical guidance, and Thai Asthma Council) that recommend regular dosing with ICS-containing maintenance therapy with SABA as reliever for patients with moderate to severe asthma [3,5–7,30].

The MART approach was approved, and to some extent reimbursed, in all participating countries (for details see *Supp Table 3*). Despite this, awareness of the MART approach was low among patients and prescribing of this regimen by physicians was low for patients with moderate, severe, or fluctuating severity asthma; interestingly, although pulmonologists had the greatest awareness of the MART approach (86%), they also prescribed PRD therapies more frequently than other physicians (75%). Minimal use of the MART approach may be due, in part, to the lack of endorsement in local guidelines. As a result, the
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Physician-reported prescribing for moderate to severe asthma by location</figcaption></figure>

*Chi-square test for differences between countries *p* < 0.001. †Other treatments included: inhaled SABA only (eg, salbutamol), low-dose ICS without inhaled SABA, low-dose ICS with inhaled SABA, ICS/formoterol fixed-dose combination as needed, and MART with inhaled SABA. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; MART, maintenance and reliever therapy; SABA, short-acting β2-agonist.

<figure><img src="image_4.png" /><figcaption>**Fig. 3.** Physician-reported prescribing by specialty</figcaption></figure>

*Chi-square test for differences between practitioners *p* < 0.001. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; MART, maintenance and reliever therapy; SABA, short-acting β2-agonist.

MART approach was also misapplied in most instances, with SABA inappropriately prescribed alongside ICS/formoterol, the presumed obligate reliever. This finding is consistent with results from APPARENT 1 and other previous real-world, survey-based studies among physicians that have highlighted suboptimal adherence to guidelines [31] and high rates of coprescription with a separate rescue/reliever inhaler [25,26]. Patient desire for an additional reliever for perceived safety and convenience, was a key driver for incorrect prescription of MART. There is a need for education of both physicians and patients on the appropriate use of SABA as a reliever in conjunction with regularly dosed ICS-based maintenance, as well as broader awareness of the role of individual medications and potential risks associated with SABA overuse [32].

There are limitations inherent to survey methodology that must be considered when interpreting the data reported here (see Supplement for additional survey methods, including CHERRIES checklist). These

data are likely not universally representative of real-world clinical practice due to the highly specific populations targeted, physician/patient selection bias, recall bias, and the bias associated with the use of surveys and recruitment from nonprobability panels. Cooperation rates were particularly low, especially among patients (2–3%), and not all participants responded to all questions (as indicated in the data tables); this limits the interpretation of these response data. Due to the nature of the survey, responses could not be matched between physicians and patients. Future real-world studies assessing patient adherence to PRD and MART regimens may help refine the framework for which patients may benefit most from either regimen and facilitate the progression to a personalized approach to asthma management.
## 5. Conclusions

Physicians and patients continue to prioritize asthma symptom control over exacerbation reduction, and as such, PRD with ICS/LABA with/without as-needed SABA remains a preferred treatment approach for patients with uncontrolled moderate to severe asthma, particularly among pulmonologists. This suggests that physicians are more aligned with, and more frequently prescribe according to, GINA 2021 Track 2 (PRD) recommendations than Track 1 (MART). A high proportion of patients prescribed MART also reported being inappropriately prescribed rescue inhalers, which were often provided at their request, suggesting patients may perceive their asthma as inadequately controlled on MART therapy. If MART is to be implemented correctly, patient education will be essential to avoid confounding by SABA use. There is confusion between reliever strategies in the real world; correct implementation of "Track 1" or "Track 2" strategies will require both patient and physician education.

## Funding sources

This work was funded by GlaxoSmithKline (GSK study 214325). The funders of the study had a role in the study design, data analysis, data interpretation, and writing of the report.

## Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

## CRediT authorship contribution statement

**Kenneth R. Chapman:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Giorgio Walter Canonica:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Kim L. Lavoie:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Natalia Nenasheva:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Gabriel Garcia:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Sinthia Bosnic-Anticevich:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Arnaud Bourdin:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Maria Carmen del Cano:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Abhijith P.G.:** Conceptualization, Validation, Writing – original draft, Writing – review & editing. **Bhumika Aggarwal:** Conceptualization, Validation, Writing – original draft, Writing – review & editing.

## Declarations of competing interest

KRC has received research grant funding, speaker fees, and consulting fees from AstraZeneca, Grifols, GSK, Novartis, Sanofi, Regeneron, speaker fees and consulting fees from Boehringer Ingelheim, Valero, and Teva; consulting fees from CSL Behring and Inhibrx; research and consulting fees from Takeda and Mereo Biopharma. GWC has received research grants and been a lecturer or received advisory board fees from A. Menarini, ALK-Abelló, Allergy Therapeutics, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, GSK, Hal Allergy, Mylan, Merck, Merck Sharp & Dome, Mundipharma, Novartis, Regeneron, Roche, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes Greer, UCB Pharma, Uriach Pharma, Valeas, and Vibor-Pharma. KLL has received consulting fees/speaker fees from GSK, Abbvie, Boehringer Ingelheim, Janssen, Bausch, Astellas, Novartis, AstraZeneca, X-Facto, and Sojecci Inc. NN has received consulting fees, honoraria for lectures, and/or research funding from AstraZeneca, ALK-Abelló, Boehringer Ingelheim, Glenmark, MSD, Novartis, Sanofi, and Stallergenes Greer. GG

has received research grants from Novartis, GSK, Boehringer Ingelheim, AstraZeneca, and Sanofi, and for acting as a consultant/advisor/speaker for GSK, AstraZeneca, Novartis, and Sanofi. SB-A has received consulting fees, personal fees, speaker fees, and research funding from Teva, AstraZeneca, Boehringer Ingelheim, GSK, and Mylan. AB has received personal fees from GlaxoSmithKline, Regeneron, Chiesi, Teva, and Boehringer Ingelheim; personal fees and other from AstraZeneca and Novartis. MCC has received consultant and speaker fees from AstraZeneca, Boehringer Ingelheim, and GSK; speaker fees from Moksha 8 and Novartis. BA and A-PG are employees of and eligible for/own stocks/ shares in GSK.

## Acknowledgements

Abt Associates were responsible for data collection and analysis, which was funded by GSK. Editorial support was provided by Hayley Ellis, PhD, of Fishawack Communications Ltd, part of Fishawack Health, and was funded by GSK.

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