MD Jennifer K Quint
email: j.quint@imperial.ac.uk

PhD, FRCP Sofie Arnetorp
email: sofie.arnetorp@astrazeneca.com

MSc Janwillem W H Kocks
email: janwillem@gpri.nlc

PhD Maciej Kupczyk
email: maciej.kupczyk@umed.lodz.plf

MSc Javier Nuevo
email: javier.nuevo@astrazeneca.com

MSc, eMBA Vicente Plaza
email: vplaza@santpau.cati

PhD Claudia Cabrera
email: claudia.s.cabrera@astrazeneca.com

PhD Chantal Raherison-Semjen

PhD Brandie Walker

SM, MD, MSc Erika Penz
email: erika.penz@usask.cam@n

SM, MD, MSc Ileen Gilbert
email: ileen.gilbert@astrazeneca.como

MD, Njira Lucia Lugogo
email: nlugogo@med.umich.edu

MD Ralf J P Van Der Valk

Javier Arnetorp

Claudia Nuevo

Ileen Cabrera

Ralf J P Gilbert

Van Der Valk

Short-acting β(2)-agonist exposure and severe asthma exacerbations: SABINA findings from Europe and North America

de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

ABSTRACT

Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting β2-agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists.

Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. US-commercial 0.92 [0.91-0.93]; US-Medicare 0.74 [0.71-0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the US datasets was attributable to the large patient population possessing <3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face healthcare provider encounters. In US SABA monotherapy-treated patients, ≥3 SABA was associated with more emergency/outpatient visits and hospitalizations (1.31 [1.29-1.34]). Most GINA 2-5-treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of ≥3 SABA and severe exacerbations persisted (1.32 [1.18-1.49]) after excluding these patients J o u r n a l P r e -p r o o f and the independent effect was further confirmed when UK SABA data was analyzed as a continuous variable in patients with up to 100% annual coverage for ICScontaining medications.

Methods

Conclusions:

Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

. J o u r n a l P r e -p r o o f HIGHLIGHTS Key words: Asthma, Asthma management, Short-acting β2-agonists, Inhaled corticosteroids, Severe exacerbations

What is already known about this topic?

Although the Global Initiative for Asthma (GINA) no longer recommends SABA without concomitant ICS for patients with asthma aged ≥12 years, US guidelines only partially address this concept and continue to recommend SABA-only treatment for intermittent asthma.

What does this article add to our knowledge?

Independent of maintenance therapy, increasing SABA exposure leaves patients across North America and Europe at risk of severe exacerbations. In the US, SABA monotherapytreated patients represented most patients, with over half experiencing ≥1 annual severe exacerbation.

How does this study impact current management guidelines?

These findings indicate possible undertreatment of patients with asthma and highlight potential gaps in US guidelines. As addressed by GINA, our findings underscore the need for symptom-based use of an ICS with a fast-acting bronchodilator as a rescue/reliever to potentially mitigate the occurrence of severe exacerbations across all asthma severities.

J o u r n a l P r e -p r o o f INTRODUCTION Asthma affects ~339,000,000 people worldwide. [START_REF]The Global Asthma Report[END_REF] Across severities, patients remain at risk of exacerbations despite effective treatments targeting underlying inflammation. [START_REF]Global strategy for asthma management and prevention[END_REF][START_REF] Castillo | Asthma exacerbations: pathogenesis, prevention, and treatment[END_REF] When used acutely, short-acting β2-agonists (SABAs) provide rapid symptom relief and can be life-saving. [START_REF] O'byrne | The paradoxes of asthma management: time for a new approach?[END_REF] However, β2-agonists have no inherent antiinflammatory activity, [START_REF] O'byrne | The paradoxes of asthma management: time for a new approach?[END_REF] and their use without concomitant inhaled corticosteroids (ICS) may be proinflammatory. [START_REF] Aldridge | Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma[END_REF] Budesonide-formoterol (ICS and a fast-acting bronchodilator fixed-dose combination) used as a rescue/reliever or as maintenance and rescue/reliever reduces exacerbation risk in patients with asthma aged ≥12 years of all severities compared with as-needed SABA, budesonide maintenance plus as-needed SABA, or budesonide-formoterol maintenance plus as-needed SABA. [START_REF] Beasley | Controlled trial of budesonide-formoterol as needed for mild asthma[END_REF][START_REF] Hardy | Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial[END_REF][START_REF] Kuna | Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations[END_REF][START_REF] O'byrne | Effect of a single day of increased as-needed budesonide-formoterol use on J o u r n a l P r e -p r o o f short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study[END_REF][START_REF] O'byrne | Inhaled combined budesonide-formoterol as needed in mild asthma[END_REF][START_REF] Rabe | Budesonide/formoterol in a single inhaler for maintenance and relief in mild-tomoderate asthma: a randomized, double-blind trial[END_REF][START_REF] Scicchitano | Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma[END_REF] Although not universally adopted, the Global Initiative for Asthma (GINA) has not recommended as-needed SABA without concomitant ICS for patients aged ≥12 years since 2019. [START_REF]Global strategy for asthma management and prevention[END_REF] In adults and adolescents, GINA 2021 recommends as-needed low-dose ICSformoterol as the preferred reliever across all therapy steps (Track 1; controller and preferred reliever). [START_REF]Global strategy for asthma management and prevention[END_REF] Moreover, GINA advises against distinguishing between intermittent and mild persistent asthma, as patients in both groups are at risk of severe exacerbations and this risk is reduced by ICS-containing treatment. [START_REF]Global strategy for asthma management and prevention[END_REF] The 2020 focused updates to the United States (US) National Asthma Education and Prevention Program (NAEPP) guidelines also preferentially recommend use of fastacting bronchodilators with concomitant ICS for patients aged ≥12 years treated as mild, moderate, and severe persistent asthma at steps 2-4. The NAEPP guidelines J o u r n a l P r e -p r o o f continue to distinguish intermittent from mild persistent asthma and recommend asneeded SABA monotherapy for the intermittent population. The use of SABA as rescue/reliever therapy is also a component of preferred therapy for those requiring severe asthma treatment at steps 5 and 6. [START_REF]Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group[END_REF][START_REF]National Asthma Education and Prevention Program (NAEPP) guidelines 2007 working draft[END_REF] Through a series of real-world observational studies, the SABa use IN Asthma (SABINA) program examines patterns of prescription/possession of SABA and ICScontaining medication as a surrogate measure of medication use. [START_REF] Cabrera | SABINA: global programme to evaluate prescriptions and clinical outcomes related to short-acting beta2-agonist use in asthma[END_REF] In the United Kingdom (UK) [START_REF] Bloom | Asthma-related health outcomes associated with short-acting β2-agonist use: an observational UK study as part of the SABINA global program[END_REF] and Sweden, [START_REF] Nwaru | Overuse of short-acting beta2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme[END_REF] prescription/possession of ≥3 SABA canisters/year was associated with increased exacerbation risk and asthma-related healthcare utilization. Moreover, in Sweden, prescription of ≥3 SABA canisters/year increased the risk of all-cause, respiratory, and asthma-related mortality. [START_REF] Nwaru | Overuse of short-acting beta2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme[END_REF] Utilizing an epidemiologic investigation of 10 North American and European datasets in >1,000,000 patients, the present SABINA analyses were undertaken to determine whether the association of SABA exposures and severe asthma exacerbations is universal and to understand how diverse asthma management practices, healthcare systems, and insurance types affect SABA-associated severe exacerbations. Some of the analyses were previously reported in an abstract. [START_REF] Quint | Late Breaking Abstract -Short-acting ß2-agonist use in asthma in Western societies[END_REF] J o u r n a l P r e -p r o o f

METHODS

Study design

Data on medication prescription (sent to pharmacy) or possession (filled prescriptions) were obtained from national or administrative claims, medical records and pharmacy databases (Figure 1A) in the participating SABINA countries who had approval from their scientific committee, including local experts, and performed the analyses by September 1, 2020. Data from Canada, France, the Netherlands, Poland, Spain, UK, and US were included (see Figure E1 and Table E1 in the Online Repository for further details on the methodologies used in each countryspecific analyses). Datasets from Canada (Alberta and Nova Scotia) and the US (commercial, Medicaid, and Medicare) were analyzed separately as they represented populations of differing demographics, healthcare insurance, and/or socioeconomic status. The primary objective was to evaluate how similarities and differences across North American and European healthcare delivery systems affect associations between SABA prescription/possession (exposure) and the number of severe asthma exacerbations (dependent variable as the outcome). Secondary objectives were to determine whether a safe threshold for prescription of SABA canisters/year exists and to understand how maintenance medication mitigates severe exacerbation risk.

Patient populations, exposures, and outcome variables

Patients aged ≥12 years with current asthma according to diagnostic code and prescription/possession of ≥1 SABA canister/year formed the minimum criteria for inclusion in the analyses (Figure 1). As the objective of the analyses was to examine J o u r n a l P r e -p r o o f the association between SABA prescription/possession and the number of severe asthma exacerbations/year, patients without prescription/possession of SABA and potentially on maintenance and reliever therapy (MART) were excluded. SABINA countries with methodological variations deemed to have a serious impact on the prespecified main analysis were excluded (red in Figure 1), while countries with complete alignment (green) or methodological variations having minimal (yellow) or medium (orange) impact were included. SABA prescription/possession was evaluated as a dichotomized variable (≥3 or 1-2 canisters/year) across all countries and additionally as a continuous variable in the UK. To capture the association of SABA monotherapy as a rescue/reliever with severe exacerbations, asthma treatment was classified using GINA 2018 definitions. To further harmonize and compare, we aimed to define severe asthma exacerbations according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines: [START_REF] Reddel | An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice[END_REF] prescription/possession of asthma-related OCS bursts (≥3 days) or emergency department/accident/emergency visit or hospitalization for asthma. Variations from any pre-specified definitions are noted in Figure 1.

Statistical analysis

Patient characteristics, exposures, and outcome data were described as mean (standard deviation [SD]) for continuous variables and absolute and relative frequencies for categorical variables. Negative adjusted binomial models were used to assess the association between SABA prescription/possession (≥3 vs. 1-2 canisters/year) and severe exacerbations. To adjust for potential confounders, the models included the following prespecified covariates which were selected a priori: [START_REF] Bloom | Asthma-related health outcomes associated with short-acting β2-agonist use: an observational UK study as part of the SABINA global program[END_REF] age, sex, comorbidities, prior exacerbations, GINA treatment step (1-2 vs. 3-5), and J o u r n a l P r e -p r o o f maintenance medicine (proportion of days covered [PDC]) (Figure 1B). Using SABA prescription/possession, incidence rate ratios (IRRs) of severe exacerbations were estimated and results presented overall and stratified as GINA 1-2 and GINA 3-5 treatment groups. Multiple comparisons were adjusted by using a conservative Bonferroni correction, with P≤0.0125 as the cut-off. Post hoc sensitivity analyses were performed to further explore the robustness of the association between SABA and severe exacerbations and the potential role of SABA monotherapy in the US GINA 1 dataset by comparing IRRs with GINA 2-5-treated patients. In the US datasets, severe exacerbations requiring OCS bursts without a face-to-face healthcare provider (HCP) evaluation (prescribed over telephonic consultation) and those that were serious enough to necessitate emergency, face-to-face HCP evaluations or hospitalizations were also evaluated in GINA 1-treated patients.

Stratification analyses

A stratification analysis probed the associations between SABA prescription/possession (dichotomized) and severe exacerbations in GINA 2-5treated patients with ≥50% maintenance therapy in datasets of the main analyses.

To further assess the strength of association between SABA and severe exacerbations in these patients, a post hoc meta-analysis of findings from the stratification analysis was performed to obtain a summary estimate across all datasets using a random-effects model based on log IRRs and their standard errors, with the inverse variance method being used for pooling the different data sources.

The interplay between SABA and ICS was further probed by evaluating the association between SABA prescription as a continuous variable and severe exacerbations in the UK dataset using a negative binomial model in all GINA 2-5-J o u r n a l P r e -p r o o f treated patients and at each GINA step separately, with results stratified by ≥50%, ≥75%, and ≥100% maintenance therapy. For patients with ≥12 SABA prescriptions during the baseline year, these were capped at 13 prescriptions and linear representations of cubic splines were used; [START_REF] Harrell | Regression modeling strategies: with applications to linear models, logistic and ordinal regression, and survival analysis[END_REF] the model included all pre-specified selected covariates.

To evaluate the potential recommendation for monitoring SABA prescriptions [START_REF] Mckibben | Tossing a coin:" defining the excessive use of short-acting beta 2-agonists in asthma-the views of general practitioners and asthma experts in primary and secondary care[END_REF][START_REF] Stanford | Short-acting β-agonist use and its ability to predict future asthma-related outcomes[END_REF] and identifying at-risk patients, an additional post hoc analysis determined a data-driven cutoff for the level for SABA canisters associated with a clinically relevant 20% [START_REF] Bonini | Minimal clinically important difference for asthma endpoints: an expert consensus report[END_REF] increased incidence of severe exacerbations. This was performed by modelling the association between SABA prescriptions and the number of severe exacerbations and incrementally plugging-in values for SABA prescriptions starting at 1 canister and recording the corresponding exacerbation rate until a 20% increase in incidence was observed.

J o u r n a l P r e -p r o o f

RESULTS

Patient characteristics and SABA patterns

Data from 1,033,564 patients with asthma were analyzed. Mean (SD) age ranged from 23.2 (13.1) years (US Medicaid) to 72.2 (6.9) years (US Medicare). Patients were predominantly female (ranging from 55.8% in Canada [Alberta] to 68.2% in US Medicare; Table I). Based on prescription/possession, 56.5% of patients were treated as mild asthma (GINA 1-2). However, more patients from Canada (Alberta; 58.6%), the UK (63.4%), Poland (66.7%), the Netherlands (68.8%), and Spain (73.4%) were treated as moderate-to-severe asthma (GINA 3-5). Overall, 40.2% of patients in the main analysis were prescribed/possessed ≥3 SABA canisters/year, ranging between 26.0% (the Netherlands) and 63.2% (Canada [Nova Scotia]).

Associations between SABA and severe asthma exacerbations

All 8 main analysis datasets revealed a numerically lower mean number of severe exacerbations for prescription/possession of 1-2 vs. ≥3 SABA canisters/year for GINA 1-5-and GINA 2-5-treated patients (see Table E2 in the Online Repository).

In GINA 1-5 patients, the lowest mean (SD) number of severe exacerbations in both SABA groups was observed in the Netherlands (0.16 [0.50] vs. 0.23 [0.60]) and the highest in US Medicare (0.95 [1.54] vs. 1.06 [1.59]).

Across GINA 1-5, except for US Medicare, prescription/possession of ≥3 vs. 1-2 SABA canisters/year was associated with an increased incidence of severe exacerbations after adjusting for covariates (Figure 2A). Across all countries and datasets, more severe exacerbations were observed with prescription/possession of ≥3 vs. 1-2 SABA canisters/year among GINA 3-5-treated patients. The highest IRR was observed in Poland, followed by US Medicaid, the Netherlands, the UK, and Canada (Nova Scotia) (Figure 2B). In GINA 1-2-treated patients, results were not uniform. In the UK, Canada (Alberta and Nova Scotia), Poland, and US Medicaid, prescription/possession of ≥3 vs. 1-2 SABA canisters/year was associated with an increased incidence of severe exacerbations. This association was not significant for the Netherlands (1.25 [0.91-1.71]), and a lower IRR of severe exacerbations with possession of ≥3 vs. 1-2 SABA canisters/year was observed in the US Medicare (0.74 [0.71-0.76]) and commercial datasets (0.92 [0.91-0.93]; Figure 2C). Additionally, multiple comparisons revealed that all datasets passed the Bonferroni-corrected threshold of P ≤0.0125, except GINA 1-2-treated patients in the Netherlands (P=0.163), with US Commercial and Medicare datasets (both P<0.001; Table E6) showing an inverse association between SABA and severe asthma exacerbations (Figure 2C).

US GINA 1 sensitivity analysis

J o u r n a l P r e -p r o o f

Patients possessing SABA monotherapy (GINA 1 equivalent) represented the largest treatment group within each US dataset (Table I 3A). Overall, only 16.7% of GINA 1-treated patients experienced exacerbations that were serious enough to necessitate a face-to-face assessment by an HCP, whereas 61.9% experienced any severe exacerbation type (requiring OCS bursts and/or unscheduled clinician or emergency department/urgent care visits or hospitalization). The disproportionate impact of GINA 1 on all US observations is shown by comparing the incidence of severe exacerbations relative to SABA exposure groups for the GINA 1-5-vs. 2-5treated populations. For all US datasets combined, GINA 2-5-treated patients exhibited a higher incidence of severe exacerbations for possession of ≥3 vs. 1-2 SABA canisters/year (1.23 [1.22-1.24]) compared with GINA 1-5 (1.03 [1.02-1.04];

Figure 3B

). However, after excluding OCS bursts from the definition of severe exacerbations, exposure to ≥3 SABA canisters/year was associated with an increased incidence of exacerbations serious enough to necessitate emergency, face-to-face HCP evaluations or hospitalizations (1.31 [1.29-1.34] in US SABA monotherapy-treated patients; Figure 3C). Similarly, for the total US GINA 1-5treated population, the proportion of patients experiencing ≥1 severe exacerbation requiring face-to-face HCP evaluation or hospitalization was also higher among patients possessing ≥3 vs. 1-2 SABA canisters/year (35.5% vs. 25.1%).

J o u r n a l P r e -p r o o f

Association of SABA with severe exacerbations among patients with ≥50% annual ICS coverage

Overall, 60.6% of all GINA 2-5-treated patients did not have prescription/possession of maintenance therapy for up to 50% of the time (Figure 4). Meta-analysis of the incidence rate data (based on Figure 4) showed that prescription/possession of ≥3 vs. 1-2 SABA canisters/year was associated with a 32% (adjusted IRR [95% CI],

1.32 [1.18-1.49]) higher risk of severe exacerbations across all datasets combined, independent of ICS use and other exacerbation risk factors. Although the effect estimates showed increased severe exacerbation risk with higher SABA prescription/possession, marked heterogeneity was observed between datasets (heterogeneity statistic, I 2 =95%). In 6 of the 8 individual datasets, the increased risk associated lower CI did not overlap the null value (IRR=1). In the US Medicare (1.02 [0.97-1.07]) and Canada Nova Scotia (1.29 [0.98-1.70]) populations, ≥3 vs. 1-2 SABA canisters/year was associated with a numerically higher severe exacerbation incidence. All datasets included in the stratification analyses, with the exception of Canada (Nova Scotia; P=0.073) and US Medicare (P=0.435), passed the Bonferronicorrected threshold of P≤0.0125 (Table E6).

Analysis of SABA as a continuous variable in the UK dataset

After adjusting for the main analysis covariates, including ICS PDC, prescription of SABA canisters remained associated with severe exacerbations on a continuous scale in UK GINA 2-5-treated patients. This association persisted even in patients with ≥50%, ≥75%, and ≥100% ICS-containing therapy, showing that the association of SABA prescriptions with severe exacerbations was independent of ICS (Figure 5).

J o u r n a l P r e -p r o o f

after excluding patients with <50% of ICS-containing therapy at each treatment level (see Figures E2A and E2B in the Online Repository). A post hoc analysis of SABA canisters revealed that increasing SABA prescriptions from 1 to 2.7 canisters/year was accompanied by a clinically relevant 20% increased incidence of severe exacerbations (Table E7). Moreover, severe exacerbations increased with increasing prescriptions of ICS-containing therapy, as previously described, [START_REF] Blakey | Identifying risk of future asthma attacks using UK medical record data: a Respiratory Effectiveness Group initiative[END_REF][START_REF] Papi | Relationship of inhaled corticosteroid adherence to asthma exacerbations in patients with moderate-to-severe asthma[END_REF][START_REF] Lugogo | Real-world patterns and implications of short-acting beta2-agonist use in patients with asthma in the USA[END_REF] indicative of confounding by disease severity.

J o u r n a l P r e -p r o o f

DISCUSSION

This analysis in >1,000,000 patients with asthma provides the largest multi-country, real-world evidence exploring how treatment patterns of SABA and maintenance therapy affect the frequency of severe exacerbations. Overarching similarities across countries on the association of SABA prescription/possession with severe exacerbations, combined with several notable inter-and intra-country differences, provide unique insights into the impact that variations in healthcare delivery, insurers, and HCP/patient approaches to asthma management may have on severe exacerbations.

Overall, 40.2% of GINA 1-5-treated patients were prescribed/possessed ≥3 SABA canisters/year, and only 39.4% of GINA 2-5-treated patients received maintenance therapy ≥50% of the time. Across countries, stratifying for ≥50% GINA 2-5 maintenance exposure revealed that prescription/possession of ≥3 vs. 1-2 SABA was associated with a 32% increased incidence of severe exacerbations, independent of ICS-containing medications. In the UK, SABA as a continuous variable further confirmed the association with severe exacerbations, regardless of prescribed ICS. This suggests that patients remain uncontrolled despite potentially reasonable exposure to their prescribed maintenance therapy, [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF] highlighting underestimation of asthma severity, as per GINA treatment steps, and/or the need for timely ICS administration to control worsening airway inflammation.

Similarities and clinically relevant differences across Europe and Canada

The association between prescription/possession of ≥3 SABA canisters/year and severe exacerbations (IRRs across GINA steps [1-5, 1-2, and 3-5] and stratified

Healthcare access and severe asthma exacerbations

Results from Canada highlight the influence of access to healthcare on asthma morbidity. Findings from Alberta, a large representative sample of the Canadian population, demonstrated that possession of ≥3 vs. 1-2 SABA canisters/year was consistently associated with an increased severe exacerbation incidence across GINA steps, which was replicated in the smaller Nova Scotia population. Although Nova Scotia as a province has a lower socioeconomic status than Alberta, 30 associations between possession of ≥3 vs. 1-2 SABA canisters/year and number of severe exacerbations for both Canadian datasets were concordant with those for the UK, another country with similar healthcare accessibility and using comparable methodologies.

J o u r n a l P r e -p r o o f

Clinically relevant similarities and differences for the US Differences in the US patient characteristics and insurance types provide valuable insights. Elderly patients with asthma, as in the Medicare population, have been reported to have poorer perception of declining lung function, less allergy symptoms, and greater comorbidities than younger patients. [START_REF] Battaglia | Asthma in the elderly: a different disease?[END_REF][START_REF] Connolly | Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale[END_REF][START_REF] Mathur | Changes in immune function in asthma in the elderly[END_REF] Therefore, SABA use before the onset of a severe exacerbation may be attenuated, owing to decreased warning signs and/or symptoms of asthma being mistakenly attributed to other comorbid conditions.

Although the US Medicaid and commercial datasets comprised younger patients, the Medicaid population consistently showed the strongest association of severe exacerbations with possession of ≥3 SABA canisters/year. Factors such as lower socioeconomic status, [START_REF] Medicaid | Medicaid: a lower-cost approach to serving a high-cost population[END_REF] limited access to quality care [START_REF] Medicaid | Medicaid: a lower-cost approach to serving a high-cost population[END_REF][START_REF] Cook | Access to specialty care and medical services in community health centers[END_REF] and wide coverage for quick-relief medications [START_REF] Pruitt | Medicaid coverage of guidelinesbased asthma care across 50 states, the District of Columbia, and Puerto Rico, 2016-2017[END_REF] may influence which therapies are used. SABA rescue/reliever medication is the most widely covered asthma treatment in most states' Medicaid programs; [START_REF] Pruitt | Medicaid coverage of guidelinesbased asthma care across 50 states, the District of Columbia, and Puerto Rico, 2016-2017[END_REF] thus, ICS-containing maintenance therapy may be deprioritized or rationed.

A striking difference was observed between the US and other countries for GINA 1-2-treated patients, where possession of ≥3 SABA canisters/year was associated with a lower incidence of severe exacerbations in US commercial and Medicare GINA 1-2-treated patients. Even in US Medicaid GINA 1-2, the significant association of increased severe exacerbations with possession of ≥3 SABA canisters/year showed the lowest IRR across all main analysis datasets. Of note, an overwhelming majority of US GINA 1-2 patients were treated as GINA 1. These SABA monotherapy-treated J o u r n a l P r e -p r o o f patients demonstrated substantial severe exacerbation risk, independent of SABA exposure. Notably, most severe exacerbations in US GINA 1-treated patients were characterized by an OCS burst without a healthcare visit. Consequently, the escalation of SABA for symptom relief without any possession of ICS, even for a week, may have been accompanied by increased airway reactivity, [START_REF] Hancox | Concluding remarks: can we explain the association of betaagonists with asthma mortality? A hypothesis[END_REF][START_REF] Reddel | Reply: About the recommendation of the GINA strategy report on asthma step 1[END_REF] resulting in a severe exacerbation. While OCS burst treatment, likely prescribed over a telephonic consultation, would have quickly reduced the need for additional SABA, the lack of a face-to-face HCP encounter resulted in a missed opportunity for addition of ICS therapy in a presumably mild population. Such scenarios could explain the stronger association between possession of 1-2 vs. ≥3 SABA canisters/year and increased incidence of severe exacerbations in patients treated as having intermittent disease.

However, a higher number of severe exacerbations serious enough to necessitate an emergency, face-to-face HCP outpatient visit or hospitalization was observed for SABA monotherapy-treated patients possessing ≥3 SABAs canisters/year. These data are concordant with observations that US patients and HCPs tend to underestimate the consequences of asthma symptoms, [START_REF] Murphy | Development of the asthma impairment and risk questionnaire (AIRQ): a composite control measure[END_REF] relying predominantly on SABA for rapid relief. [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF][START_REF] Murphy | Asthma management and control in the United States: results of the 2009 Asthma Insight and Management survey[END_REF] These findings suggest the need for ICS administration, either as regular maintenance treatment or intermittently, to address variability in airway inflammation in SABA monotherapy-treated patients and lend support to the GINA recommendation of not distinguishing intermittent from mild persistent asthma.

Both populations experience severe exacerbations, and the use of ICS-containing treatments, either taken as regular maintenance therapy and/or concomitantly with as-needed fast-acting bronchodilators, can reduce this exacerbation risk; 2 with the J o u r n a l P r e -p r o o f latter approach leveraging the inherent relief-seeking behavior of patients when symptomatic.

Defining the threshold for SABA use in asthma management

A threshold for SABA prescription/possession (≥3 canisters/year) can serve as a practical and quantitative measure of reliance on SABA and aid in tracking rescue/reliever use. In view of findings from the UK continuous modeling data and the lack of consensus on appropriate vs. excessive use of rescue/reliever therapy, [START_REF]Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group[END_REF][START_REF] Mckibben | Tossing a coin:" defining the excessive use of short-acting beta 2-agonists in asthma-the views of general practitioners and asthma experts in primary and secondary care[END_REF] an evidence-backed binary classification of SABA (≥3 vs. 1-2 canisters/year) may not fully describe the continuous association between prescription/possession of SABA and severe asthma exacerbations. As increasing SABA prescriptions from 1 to 2.7 canisters/year was associated with a clinically relevant 20% increased incidence of severe exacerbations, careful monitoring of SABA use at any level can help identify at-risk patients. [START_REF] Silver | Quarterly assessment of short-acting β2-adrenergic agonist use as a predictor of subsequent health care use for asthmatic patients in the United States[END_REF] Other exacerbation risk factors, such as seasonal triggers, poor ICS adherence, and incorrect inhaler technique, should also be routinely monitored. [START_REF]Global strategy for asthma management and prevention[END_REF]

Clinical implications

Our results show that widespread SABA use in North America and Europe leaves patients across GINA 1-5 at risk of severe exacerbations and OCS exposures that could lead to acute/chronic complications. [START_REF] Bleecker | Systematic literature review of systemic corticosteroid use for asthma management[END_REF][START_REF] Mcbrien | Time to FOCUS on oral corticosteroid stewardship in asthma management[END_REF] Moreover, prescription/possession of SABA is associated with severe asthma exacerbations independent of whether maintenance therapy is prescribed by an HCP or possessed by a patient. Our results show that for many patients with asthma, adherence to maintenance treatment remains sub-optimal and some may be undertreated and in need of a review of their J o u r n a l P r e -p r o o f current therapeutic regimen. However, given that exacerbations still occurred in those with prescription/possession of maintenance treatment compatible with reasonable and even full adherence, our findings also emphasize the potential need for revisiting the rescue/reliever paradigm to provide ICS concomitantly with a fastacting bronchodilator. Patients often increase SABA use when symptoms first appear and increase ICS use only at the peak of asthma worsening. [START_REF] Tattersfield | Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group[END_REF] However, the period before an exacerbation accompanied by worsening of inflammation-driven symptoms may offer a "window of opportunity" [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF] for intervention. Based on patients' inherent symptom relief-seeking behavior, use of a fast-acting rescue/reliever that provides concomitant ICS may allow treatment to be timed with the onset of increasing inflammation, a management strategy demonstrated to improve outcomes [START_REF] Beasley | Controlled trial of budesonide-formoterol as needed for mild asthma[END_REF][START_REF] Hardy | Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial[END_REF][START_REF] Kuna | Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations[END_REF][START_REF] O'byrne | Effect of a single day of increased as-needed budesonide-formoterol use on J o u r n a l P r e -p r o o f short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study[END_REF][START_REF] O'byrne | Inhaled combined budesonide-formoterol as needed in mild asthma[END_REF][START_REF] Rabe | Budesonide/formoterol in a single inhaler for maintenance and relief in mild-tomoderate asthma: a randomized, double-blind trial[END_REF][START_REF] Scicchitano | Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma[END_REF][START_REF] Bateman | As-needed budesonide-formoterol versus maintenance budesonide in mild asthma[END_REF][START_REF] Rogliani | SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis[END_REF] and currently supported by GINA. [START_REF]Global strategy for asthma management and prevention[END_REF] The concept of avoiding SABA rescue/reliever without concomitant ICS, as outlined by GINA 2019 recommendations, [START_REF]Global strategy for asthma management and prevention[END_REF] was only partially incorporated in the NAEPP 2020 focused updates for asthma management. [START_REF]Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group[END_REF] These guidelines recommend use of a fast-acting bronchodilator with concomitant ICS for patients aged ≥12 years with mild, moderate, and severe persistent asthma at treatment steps 2-4. [START_REF]Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group[END_REF] Unlike the GINA 2019 report, [START_REF]Global strategy for asthma management and prevention[END_REF] the NAEPP Expert Panel Working Group was not charged to address rescue/reliever therapy for patients with intermittent asthma (step 1) or those with severe persistent disease at steps 5 and 6; therefore, data gaps remain within the US asthma management guidelines with respect to whether SABA alone as a rescue/reliever should be considered for these populations. Our SABINA findings may help to inform on these data gaps for patients with intermittent and severe persistent asthma and underscore the need for HCPs to closely monitor both impairment and risk domains of control. Many SABA monotherapy-treated patients J o u r n a l P r e -p r o o f may have met the criteria for persistent asthma, and GINA 3-5-treated patients exhibited more severe exacerbations with greater SABA use, indicating possible undertreatment of patients. However, a potential benefit across all asthma severities might also be gained by employing a fast-acting bronchodilator with concomitant ICS therapy for as-needed symptom relief to address the underlying variability of airway inflammation leading to symptoms and exacerbations.

Limitations

Prescription/possession data do not inform on actual or appropriate medication use.

Although analyses were adjusted for key exacerbation risk factors, other patient characteristics may impact severe exacerbations; however, extensive covariate analyses performed by Bloom et al [START_REF] Bloom | Asthma-related health outcomes associated with short-acting β2-agonist use: an observational UK study as part of the SABINA global program[END_REF] suggested that the model was robust. Data analyses stratified by each individual GINA step could not be performed by all countries; therefore, only the strata of steps 1-2 and 3-5 were prespecified. Given the real-world nature of this study, it was not possible to measure all components of asthma control; therefore, patients were grouped by treatment and not actual disease severity, as suggested in GINA 2021. [START_REF]Global strategy for asthma management and prevention[END_REF] Severe exacerbations were defined per ATS/ERS definitions; 20 however, components of the definitions (OCS burst, hospitalization, and emergency outpatient visit) may have different implications due to differential healthcare practices (eg, OCS over the phone vs. OCS following a face-to-face HCP encounter). Exclusion of patients with no SABA prescription/possession may have precluded assessment of well-controlled asthma patients across disease severities, but it would also have led to inclusion of patients on ICS-formoterol rescue/reliever. Since adherence to ICS-containing treatments is known to be approximately 50% in asthma patients, [START_REF] Williams | Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma[END_REF] an arbitrary threshold of ≥50% J o u r n a l P r e -p r o o f prescription/possession of maintenance therapy was selected to ensure inclusion of sufficient patients for exploring the independent association between SABA prescription/possession and severe exacerbations. While in some countries SABA exposure was assessed during baseline and severe exacerbations during follow-up (preferred by epidemiologists), exposure and outcome assessments were performed in the same year for most datasets (clinically preferred). Our analysis precluded determination of reverse causality (ie, whether SABA prescription/possession is simply a result of severe exacerbations). Finally, our findings are limited to specific countries in North America and Europe; however, further SABINA analyses evaluating the association of SABA exposure with multiple asthma outcomes in an additional 24 countries across 5 continents are now available. [START_REF] Bateman | Short-acting β2-agonist prescriptions are associated with poor clinical outcomes of asthma: the multi-country, cross-sectional SABINA III study[END_REF]

CONCLUSIONS

This multi-country analysis consistently showed that prescription/possession of SABA rescue/reliever was associated with severe asthma exacerbations, independent of ICS across all asthma severities. Moreover, severe exacerbation incidence increased with increasing SABA canisters, independent of maintenance therapy. Even patients with anti-inflammatory maintenance therapy at levels consistent with adequate adherence are prescribed/possess multiple SABA canisters, suggesting that they remain uncontrolled and at risk of severe exacerbations. An ICS-containing rescue/reliever, as suggested by GINA and now recommended for some patients with persistent asthma by NAEPP, rather than asneeded SABA alone, may be needed to control symptoms and prevent severe exacerbations for all patients.

J o u r n a l P r e -p r o o f

Netherlands); M Vervloet (m.vervloet@nivel.nl), PhD (Nivel, Netherlands Institute for Health Services Research, Utrecht, The Netherlands); Michael Pollack (michael.pollack1@astrazeneca.com) (AstraZeneca, US); Paul Hernandez (paul.hernandez@nshealth.ca), MDCM (Dalhousie University, Canada); Silvia Boarino (Silvia.Boarino@astrazeneca.com) (AstraZeneca, Italy); Stephen G Noorduyn (stephen.noorduyn@astrazeneca.com), MSc (AstraZeneca, Canada); Wendy Beekman-Hendricks (Wendy.Beekman@astrazeneca.com) (AstraZeneca, The Netherlands); and YM Weesie (Y.Weesie@nivel.nl), MSc (Nivel, Netherlands Institute for Health Services Research, Utrecht, The Netherlands). The association between SABA prescription/possession and severe asthma exacerbations was evaluated using a negative binomial model. The analyses were adjusted for age, sex, comorbidities, prior exacerbations, GINA treatment step (1-2 vs. 3-5), and maintenance medicine PDC. Prior exacerbations were not included as a covariate in Poland and The Netherlands, while comorbidities were not included as a covariate in Poland. Patients aged ≥65 years and those likely to have COPD were excluded from the Polish dataset. France Study design: This was a cross-sectional survey (ASTHMAPOP) conducted in 2018 to collect up-to-date epidemiological data on asthma prevalence in adults in France, including the burden of disease according to GINA treatment steps, and assess the level of asthma control. A 4-page, self-administered questionnaire was mailed to people aged ≥18 years belonging to the Kantar-TNS panel, which comprised people representative of the French population in terms of age, sex, region, and socioeconomic status; no exclusion criteria were applied. The main population analyzed included all people with asthma, identified based on self-report in the self-administered questionnaire; asthma diagnosis was not based on physicians' assessment. The characteristics of people with asthma were described in comparison with those without asthma. Asthma was classified by treatment steps per the GINA 2017 report, according to prescribed treatments as declared by respondents based on a pre-established list of medications.

J o u r n a l P r e -p r o o f

Data were analyzed using logistic regression and adjusted for the following covariates: age, sex, GINA level, and comorbidities. Comorbidities (categorized as ≥1 vs. none) were self-reported based on a predefined list in the questionnaire and included food allergies, anxiety/depression, obstructive sleep apnea, chronic bronchitis, COPD, emphysema, cataract, diabetes, atopic dermatitis/other skin allergy, glaucoma, hypercholesterolemia, hypertension, osteoporosis, cardiac disease, nasal polyposis, gastroesophageal reflux disease, allergic rhinitis, J o u r n a l P r e -p r o o f nasal allergy, and sinusitis. Statistical analysis was performed using the R software (version 1.2.1355, R Foundation for Statistical Computing, Vienna, Austria).

Spain

Study design: This was a longitudinal, retrospective study conducted in primary and specialized care settings in Spain using the BIGPAC ® Medical Records Database to assess the clinical consequences (severe exacerbations and mortality) in patients with SABA overuse according to GINA treatment steps in usual clinical practice.

Patients with asthma (ICD-10-CM: J45-J46) aged ≥12 years who attended ≥2 healthcare consultations during 2017 and had a 1-year follow-up available in the database were included. Data from Spain were analyzed using a stepwise multivariate linear regression model. Comorbidities included COPD, history of hypertension, diabetes mellitus, obesity, ischemic heart disease (angina, acute myocardial infarction), cerebrovascular accident (stroke, peripheral arterial disease), arrhythmia, heart failure, renal failure, chronic kidney disease, pulmonary vascular disease, depressive syndrome, malignant neoplasms, pneumonia, anemia, bone fractures, and osteoporosis. As summary variables of general comorbidity, the following were used: (a) the CCI as an approximation to severity (categories: 0, 1, 2, and 3+) and (b) the number of chronic comorbidities. These variables were obtained at study initiation. Statistical analyses were performed using SPSS software version 23.0 (IBM Corp., Armonk, NY, USA).

The Netherlands Study design: The aim of the Dutch cohort study was to provide insight into the use of ICS, LABA, and SABA by patients with asthma in daily practice and how this medication use is related to asthma outcomes over the year 2016. Data were derived from the Nivel Primary Care Database (Nivel-PCD), which includes routine care data originating from electronic medical records from GPs across the Netherlands. The participating GPs constitute a representative sample of the total population of Dutch GPs. Within the Dutch healthcare system, all residents are J o u r n a l P r e -p r o o f mandatorily registered with 1 GP, who keeps track of the patient's complete medical record and fulfills a gatekeeper role for access to medical specialists. The database consists of longitudinal information of patient characteristics (age and sex), GP consultations, diagnoses (ICPC-1), and drug prescriptions (ATC).

Comorbidities were categorized as 0, 1, 2, or >2 without R96 asthma and R91, R95 COPD. Maintenance therapy PDC was operationalized as CMA7, which was calculated by dividing the number of days of theoretical use by the number of days between start (January 1, 2016) and end of the observation window (December 31, 2016). Days of theoretical use were calculated by extracting the total number of gap days (days for which no medication was available) from the total time period between start and end of the observation window, accounting for a carryover for all prescriptions within and before the observation window. For the latter, prescriptions issued in Q4 of 2015 for which the duration crosses January 1, 2016, were included. Data analyses were performed using Stata/SE 15.1 for Windows (StataCorp, College Station, TX, USA).

SABINA +

Poland Study design: As national quality standards for asthma have not yet been introduced in Poland, this was the first nationwide study analyzing pharmacy records (drug purchase data). Asthma patients were defined as those who purchased (at least once within 6 months) drugs from R03 class, excluding patients on LABA, LAMA, LABA/LAMA, and LABA/LAMA/ICS (assuming COPD therapy). The accuracy of selection has been confirmed via a subanalysis of patients in the age group of 18-35 years, which revealed the same results as for the entire analyzed population.

Since deidentified retrospective claims data were used, the analysis was considered as "not human subjects research" and therefore exempted from IRB approval. Maintenance medication PDC was based on the number of J o u r n a l P r e -p r o o f canisters of ICS and ICS/LABA per year. Statistical analysis was conducted using the R software (version 3.5.5, R Foundation for Statistical Computing, Vienna, Austria).

US

Study design: This was a retrospective, observational cohort study.

Data source included deidentified claims data from the US contained in the IBM MarketScan Commercial, Medicare Supplemental, and Multistate Medicaid Research databases. Since deidentified retrospective claims data were used, the analysis was considered as "not human subjects research" and therefore exempted from IRB approval.

Comorbidities were assessed based on CCI. PDC was based on the maintenance therapy possession ratio for all therapies (100% for patients at GINA step 1). Patients with the following combinations of systemic corticosteroid claims were assessed: OCS only, injection corticosteroid only, both OCS and injection corticosteroids. All patients were categorized by the presence or absence of maintenance medication during the 12-month post-index period.

At GINA 2, approximately 70% of patients in the US were on leukotriene modifiers. Additionally, patients were indexed on a random SABA prescription fill to ensure that the population comprised a combination of those with newly diagnosed asthma as well as those with long-term asthma. Data were scrutinized 1 year pre-and post-index SABA to ensure that patients with a diagnostic code for COPD were excluded. J o u r n a l P r e -p r o o f The association between SABA prescriptions and severe asthma exacerbations was evaluated using a linear regression model. Spain was unable to provide data to determine IRR, and hence data are reported as regression coefficients (mean delta in linear regression).

CI, confidence interval; GINA, Global Initiative for Asthma; IRR, incidence rate ratio; SABA, short-acting 2-agonist.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

ICS-containing therapy

The association between SABA prescriptions and severe asthma exacerbations was evaluated using a negative binomial model. The analysis was adjusted for age, sex, atopy, depression, anxiety, reflux, pneumonia, COPD, prior exacerbations, and maintenance therapy use PDC.

COPD, chronic obstructive pulmonary disease; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; PDC, proportion of days covered; SABA, short-acting 2-agonist; UK, United Kingdom.

J o u r n a l P r e -p r o o f

:

  Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 years) from Canada, France, the Netherlands, Poland, Spain, United Kingdom (UK), and United States (US). Negative binomial models (incidence rate-ratio [95% confidence interval]) adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. Results: Across severities, 40.2% of patients were prescribed/possessed ≥3 SABA canisters/year. Per GINA-2018 definitions, step 3-5-treated patients prescribed/possessing ≥3 vs. 1-2 SABA experienced more severe exacerbations (between 1.08 [1.04-1.13], US-Medicare; 2.11 [1.96-2.27], Poland). This association was not observed in all step 1-2-treated patients (the Netherlands 1.25 [0.91-1.71];

  J o u r n a l P r e -p r o o f analysis [steps 2-5]) was comparable in the UK (1.30-1.42), Canada (Alberta [1.25- 1.36], Nova Scotia [1.29-1.40]), and the Netherlands (1.25-1.43). The strongest association was consistently reported for Poland (2.11-2.41) and may be attributable to underfunding of the healthcare system,[START_REF]State of Health in the EU -Poland[END_REF] potentially resulting in high use of inexpensive systemic corticosteroids. Poland and the Netherlands used an overall similar methodology, and patients had comparable baseline characteristics; thus, the stronger association between SABA and severe exacerbation rates in Poland may be related to a considerable proportion of patients with uncontrolled symptoms (measured by possession of ≥3 canisters/year) being treated with systemic corticosteroids (proportion of uncontrolled patients with ≥2 oral corticosteroid [OCS] prescriptions was 7.2% in Poland vs. 4.3% in the Netherlands; post hoc calculation).

Figure 1 .

 1 Figure 1. Methodological variations across countries related to (A) study

Figure 2 .

 2 Figure 2. Association between SABA prescription/possession (≥3 vs. 1-2

  J o u r n a l P r e -p r o o f CI, confidence interval; GINA, Global Initiative for Asthma; IRR, incidence rate ratio; PDC, proportion of days covered; SABA, short-acting 2-agonist; SABINA, SABa use IN Asthma; UK, United Kingdom; US, United States.

Figure 3 .

 3 Figure 3. Associations of SABA possession with severe exacerbations during

Figure 4 .

 4 Figure 4. Association between SABA (≥3 vs. 1-2 canisters/year) and severe

Figure 5 .

 5 Figure 5. Association between SABA prescriptions at baseline and severe

  This was a retrospective, longitudinal, open-cohort study utilizing provincial administrative data from Alberta (including pharmacy, hospital and physician billing, and emergency/urgent care) and Nova Scotia J o u r n a l P r e -p r o o f (linked with pharmacy and discharge records). Comorbidities were assessed using the unweighted Elixhauser index score. Maintenance therapy was defined as PDC with an ICS prescription within the first year post-index. Statistical analysis was conducted with the R software (version 3.5.2, R Foundation for Statistical Computing, Vienna, Austria) using the survival package version 2.43-3.

Figure 1 .

 1 Figure 1. Methodological variations across countries related to (A) study design

Figure 2 . 2 JFigure 3 .

 223 Figure 2. Association between SABA prescription/possession (≥3 vs. 1-2

Figure 4 .

 4 Figure 4. Association between SABA (≥3 vs. 1-2 canisters/year) and severe

Figure 5 .

 5 Figure 5. Association between SABA prescriptions at baseline and severe

Figure E1 .

 E1 Figure E1.

Figure E2 .

 E2 Figure E2.

Figure E2 . 5 (

 E25 Figure E2. Association between use of SABA at baseline (prior year) and severe

Table I . Patient characteristics

 I

		SABINA I			SABINA II					SABINA +
		SABINA I	Canada	Canada	SABINA II		The		US	SABINA + US	US
		UK UK	Canada (Alberta)	Canada (Nova (Nova Scotia)	France France	Spain Spain	The Netherlands	Poland Poland	Commercially US Commercially Insured	US Medicaid	US Medicare
	GINA 3-5	119,023	(Alberta) 41,940	Scotia) 2,367	272	29,019	Netherlands 6,514 (68.8)	31,117	161,603 (33.4) Insured	Medicaid 39,723	Medicare 18,004
	Total patients, n Age (years), mean (SD) Female, n (%) Asthma treatment steps, n (%) 187,675 71,629 42.82 (20.43) 38.8 (16.6) 108,266 (57.7) 40,025 (55.8) (63.4) (58.6) GINA 3 65,218 (34.8) 24,278 (33.9) GINA 4 52,191 (27.8) 10,145 (14.2) 1,614 (0.9) 7,517 (10.5) GINA 5	5,009 42.8 (18.0) 2,964 (59.2) (47.3) 1,434 (28.6) 704 (14.1) 229 (4.6)	673 44.4 (17.0) 401 (59.6) (40.4) n/a n/a J o u r n a l P r e -p r o o f 39,555 9,474 46,628 49.8 (20.7) 44.1 (18.9) 44.1 (15.7) 25,394 (64.2) 5,546 (58.5) 26,081 (55.9) (73.4) (66.7) 15,884 (40.2) 2,877 (30.4) n/a 10,104 (25.5) 3,449 (36.4) n/a 3,031 (7.7) n/a 188 (2.0) n/a	483,874 37.8 (16.3) 294,837 (60.9) 42,193 (8.7) GINA 4/5: 119,410 (24.7)	151,439 23.2 (13.1) 90,904 (60.0) (26.2) 12,422 (8.2) GINA 4/5: 27,301 (18.0)	37,608 72.2 (6.9) 25,662 (68.2) (47.9) 4,359 (11.6) GINA 4/5: 13,645 (36.3)
		68,652	29,689	2,642	401	10,536		15,511			111,716	19,604
	GINA 1-2						2,960 (31.2)		322,271 (66.6)
		(36.6)	(41.4)	(52.7)	(59.6)	(26.6)		(33.3)			(73.8)	(52.1)
		37,118	17,942	1,629	n/a	6,030		9,806			90,392	14,122
	GINA 1						1,669 (17.6)		244,303 (50.5)
		(19.8)	(25.0)	(32.5)		(15.3)		(21.0)			(59.7)	(37.6)
		31,534	11,747	1,013	n/a	4,506		5,705			21,324
	GINA 2						1,291 (13.6)		77,968 (16.1)		5,482 (14.6)
		(16.8)	(16.4)	(20.2)		(11.4)		(12.2)			(14.1)

SABA prescription/possession (canisters/year), n (%) 1-2

	SABINA I ONLINE REPOSITORY		SABINA II			SABINA +
				Canada				US
			Canada			The			US	US
		UK		(Nova	France	Spain	Poland	Commercially
			(Alberta)			Netherlands			Medicaid	Medicare
				Scotia)				Insured
	Prior-year exacerbation history (year prior to the study), n (%)
	0 ≥1 Mean (SD)	143,063 (76.2) 44,612 (23.8) 0.41 (1.03)	60,458 (84.4) 11,171 (15.6) 0.32 (1.14)	3,747 (74.8) 1,262 (25.2) 0.44 (1.02)	n/a 341 (50.6) J o u r n a l P r e -p r o o f 18,433 (46.6) n/a n/a 21,122 (53.4) n/a n/a n/a 0.8 (1.0) n/a n/a	277,182 (57.3) 206,692 (42.7) 0.8 (1.3)	86,988 (57.4) 64,451 (42.6) 0.8 (1.3)	19,875 (52.8) 17,733 (47.2) 1.0 (1.6)
		91,920	38,259	1,842	423	28,203	29,167		80,405	23,005
						7,015 (74.0)		322,052 (66.6) †
		(49.0)	(53.4)	(36.8)	(62.8)	(71.3)*	(62.6)		(53.1) †	(61.2) †
		95,755	33,370	3,167	250	11,352	17,461		71,034	14,603
	≥3					2,459 (26.0)		161,822 (33.4)
		(51.0)	(46.6)	(63.2)	(37.2)	(28.7)	(37.4)		(46.9)	(38.8)
	Mean
		4.1 (4.0)	3.9 (4.4)	7.2 (7.4)	n/a	3.3 (3.6) 2.3 (1.9)	3.5 (5.2)	2.77 (2.92)	3.72 (3.72)	3.05 (3.18)
	(SD)

*Data presented for ≤2 SABA canisters/year. † In the US, patients at GINA 1 were required to have ≥2 SABA fills to be included in the analyses.

GINA, Global Initiative for Asthma; n/a, not available; SABA, short-acting β2-agonist; SABINA, SABa use IN Asthma; SD, standard deviation; UK, United Kingdom; US, United States.

J o u r n a l P r e -p r o o f

Table E1 . Additional details about the countries included in the analyses

 E1 The SABINA UK study was a retrospective, longitudinal, open-cohort study that used primary care electronic healthcare records from patients with asthma aged ≥12 years. Linked hospital admission data were obtained from the Hospital Episode Statistics database. Baseline year was 12 months before the index date. The index date was set as the latest date of any of the following: asthma diagnosis, 12th birthday, start of the study

	UK	Study design:
	SABINA I

period (April 1, 2008), 1 year after the GP practice began recording research quality data (CPRD quality control), or 1 year after their continuous CPRD practice registration date. The incidence rate of severe exacerbations was calculated during the total study follow-up of 1 year. The patient follow-up ended at the earliest date of death, the end of the study period (December 31, 2019), the last CPRD data collection date, or the date transferred out of a CPRD practice. Linked pseudonymized data were provided for this study by CPRD. Data were linked by NHS Digital, the statutory trusted third party for linking data, using identifiable data held only by NHS Digital. Select practices consented to this process at a practice level, with individual patients having the right to opt out.

Comorbidities considered were pneumonia, atopy, COPD, anxiety, depression, and reflux. Maintenance therapy (PDC) was based on the annual coverage of ICS-containing therapy for eligible patients.

Table E2 . Outcome: mean (SD) severe exacerbations and IRR values during the year of analysis

 E2 Global Initiative for Asthma; GP, general practitioner; ICD, International Classification of Diseases; ICPC, International Classification of Primary Care; ICS, inhaled corticosteroid; IRB, institutional review board; LABA, long-acting 2-agonist; LAMA, long-acting muscarinic antagonist; NHS, National Health Service; OCS, oral corticosteroid; PDC, proportion of days covered; SABA, short-acting 2-agonist; SABINA, SABa use IN Asthma; UK,

	SABINA I	SABINA II			SABINA +
	United Kingdom; US, United States.	Canada	The		US
	Canada				US
	UK	(Nova	Netherland	Poland	Commerciall	US Medicare
	(Alberta)				Medicaid
		Scotia)	s		y Insured
	Programming was conducted using WPS version 4.1 (World Programming, UK), while statistical analyses were conducted with the R software (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria). Where applicable, studies were approved by each country's IRB or ethics committee. ATC, anatomical therapeutic chemical; CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research J o u r n a l P r e -p r o o f GINA steps 1-5 1-2 SABA canisters/year 0.19 (0.67) (N = 91,920) 0.23 (0.94) (N = 38,259) 0.32 (0.92) (N = 1,842) 0.16 (0.50) (N = 7,015) 0.17 (0.7) (N = 29,167) 0.72 (1.23) (N = 322,052) 0.63 (1.11) (N = 80,405) 0.95 (1.54) (N = 23,005) ≥3 SABA canisters/year 0.50 (1.28) (N = 95,755) 0.36 (1.21) (N = 33,370) 0.46 (1.11) (N = 3,167) 0.23 (0.60) (N = 2,459) 0.36 (1.2) (N = 17,461) 0.98 (1.51) (N = 161,822) 0.94 (1.49) (N = 71,034) 1.06 (1.59) (N = 14,603) IRR (95% CI) 2.63 (2.59-2.68) 1.57 (1.52-1.61) 1.44 (1.31-1.58) 1.44 (1.30-1.59) 2.12 (2.04-2.20) 1.36 (1.35-1.37) 1.49 (1.47-1.51) 1.12 (1.09-1.14) GINA steps 2-5 1-2 SABA canisters/year 0.22 (0.73) (N = 65,184) 0.27 (1.07) (N = 27,650) 0.38 (1.05) (N = 1,247) 0.18 (0.53) (N = 5,930) 0.17 (0.7) (N = 24,284) 0.73 (1.28) (N = 131,698) 0.63 (1.15) (N = 19,726) 0.89 (1.48) (N = 12,555) ≥3 SABA canisters/year 0.54 (1.33) (N = 85,373) 0.41 (1.32) (N = 26,037 0.53 (1.22) (N = 2,133) 0.28 (0.66) (N = 1,875) 0.38 (1.2) (N = 12,538) 0.99 (1.57) (N = 107,873) 0.99 (1.60) (N = 41,321) 1.05 (1.59) (N = 10,931) IRR (95% CI) 2.45 (2.41-2.50) 1.52 (1.47-1.56) 1.39 (1.25-1.55) 1.56 (1.40-1.73) 2.24 (2.14-2.33) 1.36 (1.34-1.37) 1.57 (1.54-1.60) 1.18 (1.15-1.21) A meta-analysis revealed that prescription/possession of ≥3 vs. 1-2 SABA canisters/year was associated with increased unadjusted IRR (95% CI) Datalink; GINA, J o u r n a l P r e -p r o o f of severe exacerbations in patients at GINA steps 1-5 (1.59 [1.33-1.91]) and 2-5 (1.61 [1.33-1.96]).

Table E3 . Association between SABA prescriptions and asthma severe exacerbations in the year of analysis in patients from France ≥3 vs. 1-2 SABA canisters/year Across all GINA treatment steps

 E3

	Number of patients	673
	Number of events	341
	Person follow-up years	n/a
	OR (95% CI)	2.09 (1.47-2.99)
	P value Split by GINA treatment steps GINA steps 1-2 Number of patients Number of events Person follow-up years OR (95% CI) P value GINA steps 3-5 Number of patients J o u r n a l P r e -p r o o f <.000001 401 178 n/a 2.26 (1.39-3.72) .00114 272
	Number of events	163
	Person follow-up years	n/a
	OR (95% CI)	1.82 (1.08-3.06)
	P value	.0244
	France was unable to provide data to determine IRR and hence data are reported as OR. The association
	between SABA prescriptions and severe asthma exacerbations was evaluated using a logistic regression
	model.

CI, confidence interval; GINA, Global Initiative for Asthma; IRR, incidence rate ratio; n/a, not available; OR, odds ratio; SABA, short-acting 2-agonist.

Table E4 . Severe exacerbations at baseline and follow-up (at month 12) by SABA use (canisters/year) for patients from Spain

 E4

		<3 SABA	≥3 SABA	Total
	Exacerbations
		canisters/year	canisters/year
	1 previous exacerbation, n (%)	10,002 (47.4)	11,116 (52.6)	21,118 (100.0)
	1 follow-up exacerbation, n (%)	6,565 (36.9)	11,230 (63.1)	17,795 (100.0)
	Number of previous severe exacerbations,	0.4 (0.5)	2.0 (0.6)	0.9 (0.9)
	mean (SD) Number of follow-up severe exacerbations, mean (SD) SABA, short-acting 2-agonist; SD, standard deviation. 0.2 (0.4) J o u r n a l P r e -p r o o f 1.9 (0.7)	0.7 (0.9)

Table E5 . Association between SABA prescriptions (≥3 vs. <3 canisters/year) and severe asthma exacerbations at 1-year follow-up in patients from Spain Variables in the final model Coefficients P

 E5

						95% CI
		Regression	Standard	value	Lower	Upper
		coefficient	error		limit	limit
	Constant	0.118	0.008	<.001	0.102	0.135
	SABA overuse (≥3 canisters/year)	1.523	0.010	<.001	1.504	1.543
	Charlson Comorbidity Index	0.072	0.003	<.001	0.067	0.078
	Previous severe exacerbations	0.068	0.005	<.001	0.059	0.077
	(number)
	Sex (female)	0.060	0.006	<.001	0.048	0.071
	GINA steps	0.007	0.002	.004	0.002	0.012

Table E6 .

 E6 Association between SABA prescription/possession (≥3 vs. 1-2 canisters/year) and severe asthma exacerbations/year in (A) GINA 1-5-treated patients, (B)

	US Medicaid	1.02 (1.01─1.04)	0.007
	US Medicare	0.74 (0.71─0.76)	<0.001
	GINA 3─5-treated patients, (C) GINA 1─2-treated patients, and (D) GINA 2-5-treated patients (D) GINA 2─5-treated patients prescribed/possessing maintenance therapy ≥50% of the
	prescribed/possessing maintenance therapy ≥50% of the time time
	Dataset UK	IRR (CI) 1.30 (1.25─1.36)	P-value <0.001
	(A) GINA 1-5-treated patients Canada (Alberta)	1.25 (1.15─1.37)	<0.001
	UK Canada (Nova Scotia)	1.41 (1.38─1.45) 1.29 (0.98─1.70)	<0.001 0.073
	Canada (Alberta) Netherlands	1.32 (1.27─1.38) 1.43 (1.22─1.68)	<0.001 <0.001
	Canada (Nova Scotia) Poland	1.38 (1.21─1.58) 2.11 (1.93─2.31)	<0.001 <0.001
	Netherlands Poland US Overall US Commercial US Medicaid US Medicare (B) GINA 3─5-treated patients UK Canada (Alberta) Canada (Nova Scotia) Netherlands Poland US Commercial US Medicaid J o u r n a l P r e -p r o o f 1.40 (1.23─1.58) 2.15 (2.01─2.30) 1.03 (1.02─1.04) 1.02 (1.01─1.03) 1.09 (1.07─1.10) 0.89 (0.86─0.91) 1.42 (1.38─1.46) 1.29 (1.23─1.36) 1.40 (1.17─1.66) 1.42 (1.24─1.63) 2.11 (1.96─2.27) 1.14 (1.12─1.17) 1.30 (1.23─1.37) US Medicare 1.02 (0.97─1.07)	<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.435
	US Commercial	1.24 (1.23─1.26)	<0.001
	US Medicaid	1.48 (1.43─1.53)	<0.001
	US Medicare	1.08 (1.04─1.13)	<0.001
	(C) GINA 1─2-treated patients
	UK	1.38 (1.31─1.45)	<0.001
	Canada (Alberta)	1.36 (1.26─1.48)	<0.001
	Canada (Nova Scotia)	1.35 (1.10─1.67)	0.005
	Netherlands	1.25 (0.91─1.71)	0.163
	Poland	2.41 (2.09─2.79)	<0.001
	US Commercial	0.92 (0.91─0.93)	<0.001

The association between SABA prescription/possession and severe asthma exacerbations was evaluated using a negative binomial model. The analyses were adjusted for age, sex, comorbidities, prior exacerbations, GINA treatment step (1-2 vs. 3-5), and maintenance medicine PDC. Prior exacerbations were not included as a covariate in Poland and The Netherlands, while comorbidities were not included as a covariate in Poland. Patients aged ≥65 years and those likely to have COPD were excluded from the Polish dataset. Multiple comparisons were adjusted by using conservative Bonferroni correction, with P ≤0.0125 as the cut-off for patients treated per GINA steps 1-5, 3-5, 1-2, and 2-5 with prescription/possession of maintenance therapy ≥50% of the time. CI, confidence interval; GINA, Global Initiative for Asthma; IRR, incidence rate ratio; PDC, proportion of days covered; SABA, short-acting 2-agonist; UK, United Kingdom; US, United States.

J o u r n a l P r e -p r o o f

Table E7 . Determination of data-driven cutoff for the level for SABA canisters associated with a clinically relevant 20% increased incidence of severe exacerbations SABA canisters

 E7

		Severe exacerbations (year 1)	SE	Lower CI	Upper CI	Type (ICS coverage)	%change
	1	0.224	0.003	0.218	0.229	Overall/any ICS PDC	0%
	1.2	0.231	0.003	0.226	0.236	Overall/any ICS PDC	3%
	1.5	0.238	0.002	0.233	0.243	Overall/any ICS PDC	6%
	1.7	0.245	0.002	0.241	0.249	Overall/any ICS PDC	9%
	2.0	0.252	0.002	0.248	0.256	Overall/any ICS PDC	12%
	2.2	0.258	0.002	0.254	0.262	Overall/any ICS PDC	15%
	2.5	0.265	0.002	0.260	0.269	Overall/any ICS PDC	18%
	2.7	0.271	0.002	0.266	0.275	Overall/any ICS PDC	21%

CI, confidence interval; ICS, inhaled corticosteroid; PDC, proportion of days covered; SABA, short-acting 2-agonist; SE, standard error.

  ). France and Spain were excluded from the main analyses due to methodological variations being incompatible with the prespecified analysis. Data from countries with methodological variations incompatible with the analyses (shown in red) are presented in the Online Repository. The Spanish dataset included patients with no SABA prescriptions, representing 0.1% of the population. In the US, maintenance therapy for patients at GINA step 2 also included leukotriene modifiers (prescribed in two-thirds of patients).

A&E, accident and emergency; COPD, chronic obstructive pulmonary disease; ED, emergency department; GINA, Global Initiative for Asthma; OCS, oral corticosteroid; PDC, proportion of days covered; SABA, short-acting 2-agonist; SABINA, SABa use IN Asthma; UK, United Kingdom; US, United States.

ACKNOWLEDGMENTS

The authors acknowledge Tamsin Morris and Yang Xu (AstraZeneca, UK) for their insights on the UK analyses, Mena Soliman (AstraZeneca, Canada) for his assistance with interpreting the Canada data, and Dr. Antonio Valero (Barcelona, Spain) and Dr. Jesús Molina (Madrid, Spain) for their assistance with interpreting the Spanish dataset. The authors are grateful to Eleni Rapsomaniki (AstraZeneca, UK) for her assistance with designing and running the stratification analyses. The authors also thank Laura Pillot (AstraZeneca, France) and Delphine Leynaud (AstraZeneca, France) for their assistance in coordinating data collection from France, and Mieke Bastiaanse (AstraZeneca, The Netherlands) for supporting data collection from the Netherlands. The authors also thank the Scientific Committee of the ASTHMAPOP study (France): Alain Didier, Armine Izadifar, Maud Russier, Jean-Pierre Aubert, and Christine Rolland.

Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) and fully funded by AstraZeneca.

Funding/Support: This work was funded by AstraZeneca.

J o u r n a l P r e -p r o o f

Role of the Funder/Sponsor: AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Jennifer K. Quint's research group received funds from AstraZeneca for some of this work, and Jennifer K. Quint has received fees for speaking from AstraZeneca. Janwillem W.H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca, Boehringer Ingelheim, COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution.

He also holds 72.5% of shares in the General Practitioners Research Institute. Maciej Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. Vicente Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, MSD, and Chiesi; received travel assistance from AstraZeneca, Chiesi, and Novartis; served as a consultant for ALK, AstraZeneca, Boehringer Ingelheim, MSD, MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and Menarini. Chantal Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Walker has received honoraria and served on advisory boards for AstraZeneca, and Sanofi. Erika Penz has served on advisory boards, received honoraria and consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Genzyme and Boehringer Ingelheim. Njira Lucia Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and Astra Zeneca; and travel support from Astra Zeneca; her institution received research support from Amgen,

//astrazenecagrouptrials.pharmacm.com/

Supervision: Jennifer K. Quint, Ileen Gilbert, and Ralf J.P. van der Valk.

All authors were involved in the writing of the manuscript and the decision to submit the manuscript for publication.

SABINA North American and European Study Contributors:

Andrew Fong (Andrew.Fong@albertahealthservices.ca), MSc (Alberta Health Services, Canada); Christina Qian (cqian@broadstreetheor.com), MSc (Broadstreet HEOR, Canada); Caroline Fabry-Vendrand (caroline.fabry@astrazeneca.com), PhD (AstraZeneca, France); Chantal Touboul (chantal.touboul@Kantarhealth.com) (Kantar Health, France); Dorota Brzostek (dorota.brzostek@astrazeneca.com), PhD (AstraZeneca, Poland); Ekaterina Maslova (ekaterina.maslova@astrazeneca.com) (AstraZeneca, UK); Filip Surmont (Filip.Surmont@astrazeneca.com) (AstraZeneca, UK); Helena Goike (Helena.Goike@astrazeneca.com), PhD (AstraZeneca, Sweden); Hitesh Gandhi (hitesh.gandhi@astrazeneca.com), MASc, MHA, MBBS (AstraZeneca, US); JC Korevaar (j.korevaar@nivel.nl), PhD (Nivel, Netherlands Institute for Health Services Research, Utrecht, The Netherlands); Joseph Tkacz (Joseph.Tkacz@ibm.com), MSc (IBM Watson Health, US); Karissa Johnston (kjohnston@broadstreetheor.com), PhD (Broadstreet HEOR, Canada); Keith Peres da Costa (keith.peresdacosta1@astrazeneca.com), BTech (ZS Associates, UK); L van Dijk (l.vandijk@nivel.


S Chettibi
email: s.chettibi@yahoo.fr

M Benmohamed

A Multipath Energy-Aware On demand Source Routing Protocol for Mobile Ad-Hoc Networks

Keywords: Routing Protocols, Mobile Ad-Hoc Networks, Energy Consumption

Energy consumption is the most challenging issue in routing protocol design for mobile ad-hoc networks (MANETs), since mobile nodes are battery powered. Furthermore, replacing or recharging batteries is often impossible in critical environments such as in military or rescue missions. In a MANET, the energy depletion of a node does not affect the node itself only, but the overall network lifetime. In this paper, we present multipath and energy-aware on demand source routing (MEA-DSR) protocol, which exploits route diversity and information about batteries-energy levels for balancing energy consumption between mobile nodes. Simulation results, have shown that MEA-DSR protocol is more energy efficient than DSR in almost mobility scenarios.

Introduction

A mobile ad-hoc network (MANET) is a collection of mobile devices communicating in a multi-hop fashion, without relying on any fixed infrastructure or centralized authority. MANETs are very attractive for applications where establishment of a communication infrastructure is impossible (e.g. in battlefields), or even when there is just a need for a transient communication (e.g. in conferences).

There are three current areas of research in energy efficient routing in ad-hoc networks: 1) Power control [START_REF] Xue | A Location-aided Power-aware Routing Protocol in Mobile Ad Hoc Networks[END_REF][START_REF] Doshi | An On-demand Minimum Energy Routing Protocol for a wireless Ad hoc Network[END_REF], increases network capacity and reduces energy consumption by allowing nodes to determine the minimum transmit power level required to maintain network connectivity and forward traffic with least energy cost; 2) Maximum lifetime routing [START_REF] Woo | Power-aware Routing in mobile ad hoc networks[END_REF][START_REF] Woo | Non-Blocking, Localized Routing Algorithm for Balanced Energy Consumption in Mobile Ad Hoc Networks[END_REF][START_REF] Kim | Routing Mechanisms for Mobile Ad Hoc Networks based on the Energy Drain Rate[END_REF], selects paths that maximize network lifetime by balancing energy consumption across the nodes of the network; 3) Power save protocols [START_REF] Xu | Adaptive energy conserving routing for multihop ad hoc networks[END_REF][START_REF] Xu | Geography-informed Energy Conservation for Ad-hoc Routing[END_REF][START_REF] Chen | Span: an energy-efficient coordination algorithm for topology maintenance in ad hoc wireless networks[END_REF], attack the problem of high idle state energy consumption by maximizing the amount of time nodes spend in the sleep state. Other works like [START_REF] Toh | Maximum battery life routing to support ubiquitous mobile computing in wireless ad hoc networks[END_REF][START_REF] Tarique | Energy saving dynamic source routing for ad hoc wireless networks[END_REF], have combined both maximum lifetime routing and power control approaches.

In this paper, we present MEA-DSR a multipath and energy aware on demand source routing protocol for MANETs, based on DSR [START_REF] Johnson | DSR: The Dynamic Source Routing Protocol for Multi-hop Wireless Ad hoc Networks[END_REF]. The remainder of this paper is organized as follows: in section 2, we give motivations to our work and we describe in some detail MEA-DSR protocol. We also evaluate MEA-DSR performances by simulations. Section 3 concludes the paper.

MEA-DSR protocol

Motivations

Routes failure is a norm rather than an exception in MANETs. Frequent route discoveries are needed to re-establish broken routes. Thus, a considerable global energy gain can be achieved by minimizing the frequency of route discoveries. In addition, although frequent topology changes permit some kind of load distribution by forcing nodes to discover new routes, but there is no guarantee that new routes be completely disjoint from the broken ones. Thus, some nodes still used, just because they have critical positions. Hence, an additional energy saving can be acquired by: 1) using node disjoint routes and 2) by taking into account battery levels of nodes when making routing decisions.

MEA-DSR protocol

MEA-DSR protocol is based on DSR [START_REF] Johnson | DSR: The Dynamic Source Routing Protocol for Multi-hop Wireless Ad hoc Networks[END_REF]. In fact, DSR is a multipath routing protocol. However, in DSR multiple routes are stored in a trivial manner with no constraint on number or quality. MEA-DSR, limits the number of routes that a destination node provides to a source node to two. It was shown in [START_REF] Nasipuri | Performance of multipath routing for On-demand protocols in mobile ad hoc networks[END_REF] that the performance advantage from using more than one or two alternate routes is minimal.

The choice of the primary route in MEA-DSR is conditioned by two factors: 1) the residual energy of nodes belonging to the route; 2) the total transmission power required to transmit data on this route. If we consider that nodes transmit all with their maximal transmission power (adjusting transmission power feature is not supported by all network interface cards), the later factor is equivalent to that of hops number in the route. Concerning the choice of the second route, the disjunction ratio from the primary route comes in first order. If several routes present the same disjunction ratio, one will be chosen via the same criterion as for the primary route.

Instead of splitting traffic on several routes, only one route is used in MEA-DSR, during a communication session until its breakage. This permits to avoid problems of: route coupling [START_REF] Pearlman | On the impact of alternate path routing for load balancing in mobile ad hoc networks[END_REF], congestion of common nodes and out of order arrival of data packets to their destinations.

Control packets and data structures used in MEA-DSR protocol

Mobile nodes using MEA-DSR, exchange three types of control packets: route requests (RREQs), route replies (RREPs) and route errors (RRERs). The same format of RRER and RREP defined in [START_REF] Johnson | The Dynamic Source Routing Protocol for Mobile Ad Hoc Networks (DSR)[END_REF] for DSR is used in MEA-DSR, whereas RREQ format has been slightly modified. MEA-DSR utilises three data structures: routes cache, route requests table and routes table. The same structure defined in [START_REF] Johnson | The Dynamic Source Routing Protocol for Mobile Ad Hoc Networks (DSR)[END_REF] for routes cache is reutilised in MEA-DSR. Route requests table format has been enriched by additional fields; routes table is a new data structure specific to MEA-DSR.

RREQ Packet

A field called « min_bat_lev» has been added to RREQ packets. It takes as value the minimum of residual energies of nodes traversed by the RREQ packet.

RREQs table

The format defined in [START_REF] Johnson | The Dynamic Source Routing Protocol for Mobile Ad Hoc Networks (DSR)[END_REF] has been augmented by the following fields: 1) «nb_hops» indicates the number of nodes traversed by the RREQ; 2) « last_node» maintains the identifier of the neighbor who transmitted the RREQ.

Routes table

Description of MEA-DSR protocol operation

MEA-DSR is composed of three phases: 1) route discovery; 2) route selection and ; 3) route maintenance phase.

Route discovery

If a source node needs a route toward a destination and no one is stored in its cache, it broadcasts a RREQ to all its neighbors. In MEA-DSR, only destination nodes can respond to a RREQ packet, because it will be difficult to control route disjunction if intermediate nodes reply directly from their caches as it is the case in DSR.

In order to avoid overlapped route problem [START_REF] Lee | Split multipath routing with maximally disjoint paths in ad hoc networks[END_REF], intermediate nodes do not drop every duplicate RREQs and forward duplicate packets coming on a different link than the link from which the first RREQ is received, whose hop count is not larger than that of the first received RREQ. However, forwarding all duplicates satisfying this criterion generates a very high overhead. Thus, we have limited the number of copies to be forwarded to one.

When an intermediate node situated in the neighborhood of source node, receives the RREQ packet it includes its residual energy value in «min_bat_lev» field. Otherwise, any intermediate node compares its residual energy to the value of «min_bat_lev» field; if it is lower, it changes the value of «min_bat_lev» by its proper value. After the end of above procedure, the intermediate node appends its identifier to the RREQ packet and rebroadcasts it to its neighbors. This process will be continued until that the RREQ packet arrives to destination.

Route selection

After reception of the first RREQ packet, the destination node waits for a certain period of time "Wait_time" before starting route selection procedure. When this period of time expires, destination node selects as a primary route 'route i ', satisfying the following condition:

          j length route j lev bat n j i length route i lev bat _ _ min_ , 1 max _ _ min_ (1)
Where, n is the number of candidate routes stored in the routes table.

After the selection of the primary route, destination node sends immediately a route reply to the source node. The alternative route must be maximally node disjoint than the primary route. If there exist several routes with a same disjunction ratio, one that satisfies equation (1) will be chosen and included in a RREP to be send to the source node.

Route maintenance

In MEA-DSR, if an intermediate node detects a link failure, it transmits a RERR message to the upstream direction of the route. Every node receiving the RERR message, removes every entry in its route cache that uses the broken link, and forwards RERR message to the next node toward the source node. If the source node has no valid route in its cache, then it reinitiates a new route discovery phase.

Simulation

Simulation environment

We have used NS-2 simulator [START_REF]Network simulator -ns2[END_REF], for MEA-DSR performance evaluation. The studied network is a collection of 50 nodes deployed on square area of 1000mx1000m. Each node has a transmission range of 250 m. The medium access control (MAC) protocol was based on IEEE 802.11 with 2 Megabits per second raw capacity. For radio propagation model, a two-ray ground reflection model was used. In all simulations, we have utilized the RWP (Random waypoint) mobility model [START_REF] Broch | A Performance Comparison of Multihop Wireless Ad Hoc Network Routing Protocols[END_REF]. Each node moves with a maximum speed randomly chosen from the interval [5 m/s, 10 m/s]. The duration of every simulation was 600 seconds, executed with different mobility scenarios characterised by different pause times.

Communication between nodes was modelled by CBR (Constant Bit Rate) traffic over UDP. A source generates packets of 512 bytes with a rate of four packets per second. A total of 10 connections were generated. They start at a time randomly chosen from the interval [0s, 120s] and still active until the end of simulation.

It was shown in [START_REF] Kim | Routing Mechanisms for Mobile Ad Hoc Networks based on the Energy Drain Rate[END_REF], that no real optimisation can be achieved in the presence of overhearing. For this reason, we have only considered energy consumed in transmission and reception modes. As value we have utilised those obtained trough experiments in previous works [START_REF] Feeney | Investigating the energy consumption of a wireless network interface in an ad hoc network[END_REF] (1.4 W for transmission mode and 1 W for reception mode).

MEA-DSR, was compared with DSR. Furthermore, it was simulated for different value of "Wait_time".

Performance metrics

In simulations, we are interested in the following performance metrics Packet delivery fraction (PDF)-the ratio of data packets well received by destination nodes to those generated by source nodes. Average end to end delay (AD)-the average time that takes a data packet from the source node to the destination node.

Normalized routing overhead (NRO)-the ratio of the number of routing protocol control packets (RREQs, RREPs, and RRERs) transmitted to the number of data packets received.  Consumed energy per packet (CEP) -the ratio of global consumed energy to the number of data packets received Standard deviation of consumed energy per node (SDCEN)-square root of the average of the squares of the difference between the energy consumed at each node and the average energy consumed per node.

Simulation results

We use the notation "MEA-DSR-nWT" to indicate MEA-DSR protocol with any value for "Wait_Time". Under high mobility scenarios, MEA-DSR-nWT presents a higher packet delivery fraction than DSR. The reason is that intermediate nodes in DSR, are authorized to answer from their caches. However, in such mobility conditions stored routes are more likely to be stale. Thus, data packets forwarded on those routes will be dropped, as soon as they reach broken links, since also salvaging mechanism becomes less efficient. In addition, data packets are more likely to expire because of the additional latency introduced by frequent retransmissions and repetitive salvaging attempts. For lower mobility scenarios, the packet delivery fraction of DSR increases to surpass MEA-DSR-nWT one, because routes tend to be more robust and both responding from cache and salvaging mechanisms become more efficient. In MEA-DSR-nWT, intermediate nodes are not authorized to use their caches to salvage data packets. Thus, data packets probability to be dropped is greater than it is in DSR.

Packet delivery fraction

Packet delivery fraction

MEA-DSR-nWT shows its maximum packet delivery fraction in the case of constant motion (pause time=0), this can be explained by routes variety imposed by mobility. This variety decreases the risk of queue congestion and thus of data packets expiration. For moderate to low mobility scenarios, MEA-DSR-nWT presents approximately the same behaviour, because it uses relatively long stable routes. Long routes are more stable than short ones, since the average ratio of physical link distance to the transmission range of a hop in a short route is greater than it is in a long route. Thus, shortest routes tend to break earlier.

For increased values of WT, MEA-DSR shows a lower packet delivery fraction. The reason is that MEA-DSR tends to use longer routes. Packets traversing longer routes spend more time when forwarded from one interface queue to another, which can lead to their expiration.

Average end-to-end delay (AD)

Average end-to-end delay Average end to end delay in DSR and under all mobility scenarios, is always higher than it is in MEA-DSR-nWT. In high mobility conditions, data packets in DSR spend more time in interface queues due to frequent retransmissions and repetitive salvaging attempts. In low mobility scenarios, intermediate nodes in DSR respond from their caches. Their replies tend to contain long routes since they make concatenations. Thus, data packets are queuing several times before reaching their destinations.

It is very clear on fig. 2, that average end-to-end delay in MEA-DSR-nWT is independent of mobility. This is because MEA-DSR-nWT tends to use relatively stable routes of approximately same length. For growing values of WT, the average end to end delay in MEA-DSR has slightly increased. This was expected, because a destination node takes more time to reply. Under high mobility scenarios, DSR generates more routing overhead than MEA-DSR-nWT, because DSR reinitiates route discoveries repeatedly and consequently generates more RREQs. In lower mobility scenarios, routes become more stable. Thus, the need to reinitiate new route discoveries is diminished for both protocols. However, MEA-DSR-nWT stills generate high overhead. This is because MEA-DSR-nWT permits intermediate nodes to propagate duplicates of RREQs, whereas in DSR intermediate nodes drop every duplicate RREQ packet.

For growing values of WT, routing overhead in MEA-DSR decreases because greater is WT, greater is the number of RREQs received at destination nodes. Hence, it is more likely to discover alternate routes with higher disjunction ratio, diminishing the risk of simultaneous failure of both primaries and alternates routes. Consumed energy per packet gives an idea about the global energy consumption in the network; it is clear that is proportional to the generated routing overhead. For high mobility scenarios, DSR generates more overhead than MEA-DSR-nWT thus it consumes more energy. For lower mobility scenarios, although DSR generates less overhead but it does not present an important improvement in energy consumption because it tends to use longer routes (total transmission power of a packet stills high).

Consumed energy per packet

Standard deviation of consumed energy per node

Standard deviation of consumed energy per node Standard energy deviation of consumed energy per node gives an idea about the fairness of node usage by routing protocols, and so about routing protocol tendency to maximize network lifetime. Under all mobility scenarios, standard energy deviation of consumed energy per node in MEA-DSR-nWT is always lower than that of DSR, which confirms the efficiency of load distribution policy adopted in MEA-DSR-nWT (choice of routes having nodes rich in energy and the use of maximally node disjoint routes). For both protocols, network stability provokes standard deviation of consumed energy increase. This was expected, since routes still in use in a communication session while they are valid.

The higher is WT, the higher is the efficiency of load distribution policy of MEA-DSR since destination nodes receive more RREQs. Therefore, it is more likely to discover routes with higher minimal residual energy and to discover alternate routes with higher disjunction ratio.

Conclusions

Node-disjoint routes are exploited in MEA-DSR to 1) achieve a global energy gain by minimizing frequent route discoveries; and to 2) balance energy consumption of mobile nodes. The choice of the primary route in MEA-DSR is dictated by minimal residual node energy to route length ratio, whereas disjunction ratio from primary route comes in first order in alternate route choice. Simulation results have shown that under high mobility scenarios, MEA-DSR is better than DSR that is in network operation performances or in energy efficiency. For lower mobility scenarios, MEA-DSR stills more energy efficient than DSR, whereas it presented lower packet delivery fraction and higher routing overhead. It was also shown that the higher is WT (wait_time) the higher is energy efficiency and the lower is packet delivery fraction and vice-versa.

Figure 1 .

 1 Figure 1. Packet delivery fraction vs. pause time

Figure 2 .

 2 Figure 2. Average end-to-end delay vs pause time

Figure 3 .

 3 Figure 3. Normalized routing overhead vs pause time

Figure 4 .

 4 Figure 4. Consumed energy per packet vs pause time

Figure 5 .

 5 Figure 5. Standard deviation of consumed energy vs pause time

  This structure is utilised to store every candidate route in destination nodes, indexed by source node identifier. Every entry in the routes table contains the following fields:

Src: maintains the identifier of source node who initiated the route discovery procedure. Seq: maintains the RREQ sequence number. Route: contains the nodes sequence traversed by RREQ packet. Min_bat_lev: keeps the minimal residual energy of nodes traversed by RREQ packet. Arrival_time: keeps the arrival time of RREQ packet at the destination node. Content of the first four fields is directly extracted from arriving RREQ packets.