ICS/Ultra LABA in the Treatment of Obstructive Airway Diseases: A Consensus of Indian Experts

Citation: Dhar, R.; Talwar, D.; James, P.; Mishra, A.; Vachaparambil, J.; Patil, S.; Khatri, N.; Bhagat, S.; Barkate, H.
- FF/Vi is an effective choice for patients who are uncontrolled on their current Asthma treatment and also for controlled Asthma patients. - SABA or ICS/SABA can be a viable reliever option when personalizing treatment for appropriate sets of patients with FF/Vi.

## What is the implication of the main finding?
- FF/Vi offers a definitive advantage in terms of treatment adherence and compliance benefit as compared to the conventional ICS/LABAs. - Adding LAMA to FF/Vi (100/25 g) in GOLD group D and B COPD patients can be an optimized strategy.
Abstract: Inhaled corticosteroid and ultra-long-acting beta-agonist (ICS/uLABA) combination is a recent advancement in the armamentarium against obstructive airways diseases (OADs). The combination of ICS/uLABA has several advantages, creating a favorable landscape for its utilization. Fluticasone furoate/vilanterol trifenatate (FF/Vi) is one such example of an ICS/uLABA. It offers several benefits from both drugs, such as a convenient once daily dosing schedule; high lipophilicity; high receptor affinity of fluticasone furoate along with high functional selectivity and a quick onset of action of vilanterol. However, the Global Initiative for Asthma (GINA) as well as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines do not clearly define the positioning of ICS/uLABA compared to conventional ICS/LABAs. There are a few areas of uncertainty especially around the appropriate reliever strategy with ICS/uLABA in Asthma. The current consensus was planned with a group of Indian pulmonology experts to provide more clarity on the potential use of FF/Vi in Asthma and COPD. The clinical statements highlighted in this consensus manuscript address crucial clinical questions revolving around the efficacy and safety of FF/Vi as compared to conventional ICS/LABAs and identify the ideal patient profile for its use. This consensus paper also sheds light upon the appropriate reliever to be used along with FF/Vi in Asthma and the utilization of FF/Vi-based triple therapy in OADs. Expert recommendations mentioned in this paper will serve as guidance to pulmonologists as well as consultant physicians who are involved in providing care to OAD patients and will help them weigh the various factors that need to be taken into account while prescribing ICS/uLABA combination.
Keywords: Asthma; COPD; consensus; ICS/ultra LABA; FF/Vi; vilanterol; fluticasone furoate

# Background
Obstructive airway diseases (OAD) are a leading cause of mortality, morbidity, and disability-adjusted life years (DALYs) worldwide. Chronic inflammation and obstruction of the airways are common in all types of OAD. As a result, inhalational corticosteroids and bronchodilators are the mainstay of therapy in the overall management of OAD. Asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases and necessitate daily maintenance medications for management of symptoms and better quality of life. Despite decades-long experience with the current management for Asthma and COPD, treating physicians still face challenges in terms of adherence, compliance, and complete control of symptoms.
Medication non-adherence rates among patients with Asthma and COPD are as high as 30 to 70 percent [bib_ref] Dosing Frequency and Medication Adherence in Chronic Disease, Coleman [/bib_ref]. More than once-daily dosing results in lower adherence rates than medications dosed once daily [bib_ref] Dosing Frequency and Medication Adherence in Chronic Disease, Coleman [/bib_ref]. Until recently, all commercially available inhaled corticosteroid and long-acting beta-agonist (ICS/LABA) fixed-dose combination (FDC) preparations in India were intended for twice-or three-times daily use. With introduction of the first ICS/ultra LABA (ICS/uLABA) FDC in the form of Fluticasone furoate/Vilanterol (FF/Vi), physicians now have the choice of prescribing once-daily ICS/uLABA for their patients.
Vilanterol (Vi), being an ultra LABA, has unique pharmacological properties as compared to other molecules of the same class, as shown in [fig_ref] Table 1: Comparison of distinguishable pharmacological properties of LABAs and uLABAs [/fig_ref] [bib_ref] In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Acting  2 -Adrenoceptor..., Slack [/bib_ref] [bib_ref] LABA/LAMA fixed-dose combinations in patients with COPD: A systematic review, Rogliani [/bib_ref]. Vi is a highly lipophilic 2-agonist with inherent 24-h activity in vitro, which is in development for once-daily administration in combination with fluticasone furoate (FF) for both Asthma and COPD. Vi shows a level of intrinsic efficacy that is significantly greater than that of salmeterol but comparable to indacaterol. Intrinsic efficacy is the extent to which LABAs activate the receptor without regard for drug concentration or receptor numbers. In isolated human small airways, Vi has a significantly faster onset of action and a significantly longer duration of action than salmeterol, with a significant bronchodilator effect observed even at 22 h [bib_ref] Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment..., Calzetta [/bib_ref]. Fluticasone furoate has high lipophilicity, high tissue permeability, low solubility and slow inhaled-drug-particle dissolution. It has high affinity for glucocorticoid receptor (GR) and dissociates slowly from it. Only around half the quantity of FF is needed to occupy the same number of glucocorticoid receptors compared to fluticasone propionate (FP). This allows for greater potency with reduced drug exposure [bib_ref] Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway..., Daley-Yates [/bib_ref] [bib_ref] Efficacy in asthma of once-daily treatment with fluticasone furoate: A randomized, placebo-controlled..., Woodcock [/bib_ref]. FF exhibits greater in-vitro anti-inflammatory potency. It is a stronger inhibitor of NF-B activation and TNF release than mometasone furoate, budesonide and ciclesonide's active metabolite, and has a longer duration of action than FP in inhibiting activation of NF-B and AP-1 [bib_ref] Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment..., Calzetta [/bib_ref].
The fluticasone furoate/vilanterol (FF/Vi) (100/25 g) dry powder inhaler (DPI) has already been approved as maintenance therapy for both COPD and Asthma by the EMA and the US FDA, while the FF/Vi (200/25 g) DPI has been approved for Asthma management. FF/Vi DPI is the first once-daily ICS/uLABA recently commercialized in India for the treatment of COPD (FF/Vi: 100/25 g) and Asthma (FF/Vi: 100/25 g and 200/25 g). Landmark studies for FF/Vi in COPD and Asthma found improved symptom control, improved adherence, and a lower need for rescue medication with FF/Vi than with conventional ICS/LABA, including budesonide/formoterol (BUD/FOR) [bib_ref] A randomised trial of fluticasone furoate/vilanterol (50/25 g; 100/25 g) on lung..., Kerwin [/bib_ref] [bib_ref] Fluticasone furoate/vilanterol (100/25; 200/25 g) improves lung function in COPD: A randomised..., Martinez [/bib_ref] [bib_ref] Once-daily fluticasone furoate/vilanterol combination versus twice-daily budesonide/formoterol combination in the treatment of..., Furuhashi [/bib_ref] [bib_ref] Symptom control in patients with asthma using inhaled corticosteroids/long-acting  2 -agonists..., Averell [/bib_ref].
Global Initiative for Asthma (GINA) guidelines have now shared BUD/FOR as the preferred therapeutic option throughout the management steps in asthmatic patients, but a thorough discussion of the important role of ICS/uLABA in Asthma management is lacking. Similarly, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines do not highlight the benefit of ICS/uLABA vis-a-vis conventional ICS/LABA. The current consensus was conducted by Indian experts with an intent to unlock the full potential of the novel combination of ICS/uLABA in the management of Asthma and COPD.

# Methodology
A roundtable meeting of experts was held to formulate recommendations for the present role of inhaled FF/Vi (ICS/uLABA) treatment in patients with Asthma and COPD. This expert panel consisted of 20 pulmonologists. The panel was invited based on their clinical experience, academic achievements and engagement in clinical research in the area of OAD management. A minimum of ten years of clinical experience in the field was a mandatory requirement.
The expert panel was tasked with examining the reviewed literature around FF/Vi in Asthma and COPD, identifying areas of ambiguity in its use to develop clinical consensus statements and formulating practice recommendations through a roundtable discussion.
After discussion with the faculty members, the following clinical consensus statements were formulated. The statements are depicted in . . Clinical statements formulated for expert recommendations.

## Asthma

## 1.
Comparison of FF/Vi to current Gold Standard (BUD/FOR) in Asthma 2.
Reliever use with FF/Vi in Asthma patients 3.
Addition of once daily (OD) long-acting anti-muscarinic agent (LAMA) to FF/Vi or high-dose (HD) FF/Vi in uncontrolled severe Asthma as optimized strategy 4.
Triple therapy in Asthma-open-triple versus single-inhaler-triple therapy COPD

## 1.
Profiling of the patients for use of FF/Vi in COPD 2.
Pneumonia risk with FF/Vi in COPD 3.
Benefits of FF/Vi (ICS/uLABA) as compared to conventional ICS/LABA combinations 4.
Triple therapy in COPD-open-triple versus single-inhaler-triple therapy
To develop clinical consensus statements, an electronic search of the PubMed and Embase database was undertaken around each scientifically important topic. A thorough literature search was carried out to discover relevant English-language publications published between 1 January 2010 and 31 August 2021.Various combinations of keywords such as "fluticasone furoate/vilanterol," "FF/Vi," "ICS/ultra LABA" and "ultra LABA/ICS" were used. Appropriate variations in search phrases "fluticasone furoate", "vilanterol," and Boolean operators (AND, OR) were used wherever possible.
The findings of the literature searches, including electronic full-text copies, were sent to the panel members. A roundtable meeting was held in September 2021 and the consensus statements were deliberated upon by the moderator. Expert opinion was sought from the panel in the form of agreement (defined as more than 70% panelists agreeing), conditional agreement (defined as 50-70% panelists agreeing) or disagreement (defined as more than 50% panelists disagreeing). The meeting included presentation of the evidence and a debate. Finally, the consensus report was written, peer reviewed (see Acknowledgements), and comments were included as the authors felt suitable. [fig_ref] Figure 1: Stepwise consensus development process [/fig_ref] provides an overview of the consensus development process. the panel in the form of agreement (defined as more than 70% panelists agreeing), conditional agreement (defined as 50-70% panelists agreeing) or disagreement (defined as more than 50% panelists disagreeing). The meeting included presentation of the evidence and a debate.
Finally, the consensus report was written, peer reviewed (see Acknowledgements), and comments were included as the authors felt suitable. [fig_ref] Figure 1: Stepwise consensus development process [/fig_ref] provides an overview of the consensus development process. [bib_ref] ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Knuuti [/bib_ref]. The same has been depicted in [fig_ref] Table 3: Class of recommendation and level of evidence [/fig_ref] below. [bib_ref] ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Knuuti [/bib_ref]. The same has been depicted in [fig_ref] Table 3: Class of recommendation and level of evidence [/fig_ref] below.

# Results and discussion
The combination of FF/Vi is approved by various leading regulatory authorities in two strengths (100/25 g and 200/25 g) as a dry powder inhaler (DPI) formulation. The global approval status and indication of FF/Vi combinations is depicted in [fig_ref] Table 4: List of FF/Vi combinations approved globally [/fig_ref]. [fig_ref] Table 5: Summary of landmark clinical studies of FF/Vi in OAD [/fig_ref] depicts the summary of critically analyzed literature pertaining to FF/Vi including randomized clinical trials, systematic reviews, meta-analysis and observational studies. The current Global Initiative for Asthma (GINA) strategy document recommends using ICS/Formoterol combination both as a daily controller and as a rescue medication (MART) as a preferred strategy. Recommendations by GINA represent a global strategy document but not a guideline; therefore, there is a need for a treatment strategy based on professional judgment, population characteristics and local healthcare systems.
MART regimen rely on patient perceptions to control symptoms. It can be unreliable, as the underlying inflammation may be present despite the absence of symptoms. MART requires a considerable degree of patient education to explain the role of treating inflammation and smooth muscle constriction with the use of a single inhaler [bib_ref] Single maintenance and reliever therapy (SMART) of asthma: A critical appraisal, Chapman [/bib_ref] [bib_ref] Anti-inflammatory reliever therapy for asthma, Lipworth [/bib_ref].
Moreover, use of MART therapy does not rule out the use of SABA completely. The multinational APPaRENT survey conducted in patients and physicians showed that 55-75% of physicians reported awareness towards MART dosing. Yet, the majority of them reported that they prescribed a SABA along with MART at some point in time. As far as the patients are concerned, only 20-50% of the patients were aware about the appropriate MART dosing strategy.
There are some limitations of the MART strategy. Patients have to play a more active role in their disease management. Identification of eligible patients for the MART strategy in clinical practice is complicated, especially when a patient moves up the treatment ladder (step [bib_ref] In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Acting  2 -Adrenoceptor..., Slack [/bib_ref] [bib_ref] LABA/LAMA fixed-dose combinations in patients with COPD: A systematic review, Rogliani [/bib_ref] [bib_ref] Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment..., Calzetta [/bib_ref]. Adjustment of treatment is challenging, with no clarity on when and how much to step up or down. In fact, fewer than 1 out of 5 patients remain well controlled at 1 year with BUD/FOR MART therapy, suggesting the underlying issue remains unresolved [bib_ref] Single maintenance and reliever therapy (SMART) of asthma: A critical appraisal, Chapman [/bib_ref] [bib_ref] Participants of the regional meetings As-needed antiinflammatory reliever therapy for asthma management:..., Bianco [/bib_ref] Therefore, clinicians should assess and personalize treatment plans to ensure adherence and appropriate treatment of the modifiable risk factors.
FF/Vi versus BUD/FOR and conventional ICS/LABA A total of 25% more patients experienced an improvement in their Asthma control with FF/Vi versus conventional ICS/LABAs, including BUD/FOR in the Salford Lung Study (SLS) [bib_ref] Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice:..., Woodcock [/bib_ref].
Asthma control is not just about reducing symptoms:
- FF/Vi can help Asthma patients reduce their rate of exacerbations versus both BUD/FOR and ICS, as seen in real-world and clinical settings. FF/Vi has 13% lower risk of overall exacerbation versus BUD/FOR (p < 0.001) and 22% lower risk of severe exacerbation versus BUD/FOR (p = 0.027) [bib_ref] Symptom control in patients with asthma using inhaled corticosteroids/long-acting  2 -agonists..., Averell [/bib_ref] [bib_ref] Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus..., Bateman [/bib_ref]. - Rescue-medication use is a key indicator of Asthma control. When compared with BUD/FOR, FF/Vi was associated with a 10% reduction in the use of rescue medication (SABA) in real-world settings [bib_ref] Symptom control in patients with asthma using inhaled corticosteroids/long-acting  2 -agonists..., Averell [/bib_ref]. - When measured using the Asthma Quality of Life Questionnaire (AQLQ), 27% more patients improved their quality of life versus conventional ICS/LABAs in everyday practice [bib_ref] Patientreported outcomes with initiation of fluticasone furoate/vilanterol versus continuing usual care in..., Svedsater [/bib_ref].
An estimated 71% of patients with Asthma remain uncontrolled despite treatment [bib_ref] Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD, Lipson [/bib_ref]. The problem lies with many Asthma patients over-perceiving their level of Asthma control when, upon deeper discussion, their symptoms often turn out to be frequent and regular [bib_ref] Continuing discrepancy between patient perception of asthma control and real-world symptoms: A..., Fletcher [/bib_ref].
A high proportion of patients who are thought to have "difficult" or therapy-resistant Asthma are found to have poor adherence to maintenance therapies when investigated. Such individuals are, thus, difficult asthmatics rather than treatment resistant. Nonadherence with such therapies may result in reduced lung function, increased-interval symptoms, and more frequent/severe Asthma attacks [bib_ref] Once daily combined inhaled steroid and ultra long-acting bronchodilator prescribing in pediatric..., Langley [/bib_ref]. Expert panel recommendations on the use of FF/Vi in asthma are depicted in Box 1.

## Box 1. recommendation.

## Recommendation
FF/Vi has shown improved treatment control and lesser SABA dependence compared to other ICS/LABAs including BUD/FOR.

## 1.
For uncontrolled asthma patients (Step 3-4) on BUD/FOR  Switch to FF/Vi (IA) 2.
Stable Asthma (Step 3-4) on BUD/FOR  Shared decision making with patient on choice of treatment (IIC) FF/Vi isn't just an effective choice for patients who are uncontrolled on their current asthma treatment-it can be a considerate choice for controlled asthma patients too.

## Reliever use with ff/vi in asthma patients
An anti-inflammatory and reliever (AIR) approach (BUD/FOR) has been shown to be more effective than SABA-ICS or LABA-ICS plus SABA in reducing risks of severe Asthma exacerbation and providing similar levels of day-to-day Asthma control; however, there is no such evidence vis-a-vis ICS/uLABA to our knowledge.
Limitations of the AIR strategy include difficult identification of eligible patients in clinical practice, especially when a patient moves up the treatment ladder (step 3-5) and challenging adjustment of treatment with no clarity on when and how much to step up or down [bib_ref] Participants of the regional meetings As-needed antiinflammatory reliever therapy for asthma management:..., Bianco [/bib_ref].
The relative airway potency of FF was found to be greater than predicted from its relative glucocorticoid receptor (GR) binding affinity compared to FP and BUD. This may result in enhanced airway potency, prolonged reduction in airway sensitivity and a reduced need for reliever use [bib_ref] Symptom control in patients with asthma using inhaled corticosteroids/long-acting  2 -agonists..., Averell [/bib_ref].
Once-daily dosing with FF/Vi has shown to provide continuous 24-hour efficacy with no drop in effectiveness towards the end of the 24-hour dosing interval [bib_ref] Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg)..., Bernstein [/bib_ref] [bib_ref] Randomised, double-blind, placebo-controlled, cross-over single dose study of the bronchodilator duration of..., Braithwaite [/bib_ref] [bib_ref] Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: A cross-over..., Bardsley [/bib_ref]. Hence, the requirement of a reliever SABA when using FF/Vi would be minimal, if existing at all.
Expert panel recommendations on the appropriate reliever use with FF/Vi are depicted in Box 2.

## Box 2. recommendation.

## Recommendation
Most experts supported the use of SABA as a reliever option when personalizing treatment with FF/Vi for appropriate set of Asthma patients.

## 1.
For treatment naive patients, SABA must be used as a reliever with FF/Vi (IA) 2.
For previously BUD/FOR treated patients switched to FF/Vi as maintenance, ICS-SABA or BUD/FOR to be used as reliever (IIC)

## Adding od lama to ff/vi or high dose ff/vi in uncontrolled severe asthma as optimized strategy
The addition of LAMA to FF/Vi (100/25) resulted in improved lung function and symptom control in moderate or severe uncontrolled Asthma [bib_ref] Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in..., Lee [/bib_ref] [bib_ref] Inhaled long-acting muscarinic antagonists in asthma-A narrative review, Papi [/bib_ref].

## Recommendation

## 1.
Addition of LAMA to FF/Vi should be considered preferentially for patients with persistent airflow limitation and bronchodilator reversibility, independent of blood eosinophil and/or FENO levels (IIA) 2.
Step-up to high-dose ICS should be considered particularly in patients with increased eosinophil (>300 cells/L) and/or FENO levels  A recent network meta-analysis showed that triple-combination therapies with an ICS administered at high dose (HD) were superior (p < 0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with regards to moderate exacerbation (p>0.05).
These findings suggest that triple combinations including an ICS when given at an HD may represent the first treatment choice in patients with a history of severe Asthma exacerbation, whereas in patients with a history of moderate Asthma exacerbation, either MD ICS/LABA/LAMA FDC or HD ICS/LABA FDC may be used as a first-line treatment.
Despite the unpredictable nature of Asthma exacerbations regardless of disease severity, recent evidence indicates that the past history and severity of exacerbations in the year prior may predict the risk and severity of future Asthma exacerbations.
In this respect, the results of the subset analysis on exacerbation severity may provide the rationale for a tailored therapy based on the severity of exacerbation that each patient experienced in the previous year, thus leading to the optimization of the dose of ICS and the number of bronchodilators included in the FDC [bib_ref] Triple therapy in uncontrolled asthma: A network meta-analysis of phase III studies, Rogliani [/bib_ref]. Box 4 depicts the expert panel recommendations on the use of triple therapy in asthma. A recent network meta-analysis showed that triple-combination therapies with an ICS administered at high dose (HD) were superior (p < 0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with regards to moderate exacerbation (p>0.05).
These findings suggest that triple combinations including an ICS when given at an HD may represent the first treatment choice in patients with a history of severe Asthma exacerbation, whereas in patients with a history of moderate Asthma exacerbation, either MD ICS/LABA/LAMA FDC or HD ICS/LABA FDC may be used as a first-line treatment.
Despite the unpredictable nature of Asthma exacerbations regardless of disease severity, recent evidence indicates that the past history and severity of exacerbations in the year prior may predict the risk and severity of future Asthma exacerbations.
In this respect, the results of the subset analysis on exacerbation severity may provide the rationale for a tailored therapy based on the severity of exacerbation that each patient experienced in the previous year, thus leading to the optimization of the dose of ICS and the number of bronchodilators included in the FDC [bib_ref] Triple therapy in uncontrolled asthma: A network meta-analysis of phase III studies, Rogliani [/bib_ref]. Box 4 depicts the expert panel recommendations on the use of triple therapy in asthma.

## Recommendation

## 1.
Poorly

## Copd

## Profiling of the patients for use of ff/vi in copd
Initiating treatment for COPD, similar to Asthma, with the combination of a bronchodilator and an ICS is very common in primary-care settings.
Though ICS use in COPD is limited on account of the inherent differences in the inflammatory process involved in COPD and Asthma, certain patient profiles have superior clinical benefit as oppose to avoiding it. ICS can be added to LABA or to the combination of LABA and LAMA leading to TT. GOLD guidelines strongly suggest the use of ICS in patients with-a history of hospitalization(s) for exacerbation of COPD,  two moderate exacerbations per year, baseline eosinophil count (BEC) 300 cells/L and history of or concomitant Asthma. GOLD also advise to consider the use of ICS in patients with-history of one moderate exacerbation per year, BEC  100-< 300 cells/L. For patients with COPD, in particular those who continue to smoke, the bronchial epithelium and infiltrating immune cell types may be steroid-insensitive, rendering ICS-containing therapies ineffective [bib_ref] The Use of Inhaled Corticosteroids for Patients with COPD Who Continue to..., Adcock [/bib_ref].
In SLS-COPD study with predominant group B, D patients, FF/Vi has shown benefits over and above conventional ICS/LABA. Rates of moderate or severe exacerbation reduced significantly (p = 0.02) with FF/Vi compared to UC. Those patients who were switched from an ICS-containing regimen (mostly FP/SAL or BUD/FOR) showed the greatest exacerbation benefit. An improvement in COPD-related health status (i.e.,  two reduction in CAT score) was experienced by 45% in the FF/Vi group versus 36% in the UC group (OR 1.51, P<0.001). This was further confirmed by a large observational study.
Expert panel recommendations on the appropriate patient profiles for use of FF/Vi in COPD have been depicted in Box 5.

## Box 5. recommendation.

## Panel recommendations

## 1.
ICS use based on clinical and biomarker profiling of COPD patient. FF/Vi has potential to use across clinical spectrum of COPD proposed by experts is as below and in [fig_ref] Box 3: Recommendation. [/fig_ref]. The modelled probabilities of an ECOPD over a 1-year period were considerably higher than those for pneumonia. The seemingly paradoxical observation that ICS reduce

## Pneumonia risk with ff/vi in copd
Acute exacerbation of COPD (ECOPD) and pneumonia often present with similar symptoms. This poses a diagnostic challenge and can significantly impact on patient outcomes. At times, pneumonia and ECOPD can exist simultaneously, making it difficult to understand which superseded the other.
The modelled probabilities of an ECOPD over a 1-year period were considerably higher than those for pneumonia. The seemingly paradoxical observation that ICS reduce exacerbation frequency but increase pneumonia risk suggests that ECOPD and pneumonia may have different underlying aetiologies in individual patients [bib_ref] Risk factors for exacerbations and pneumonia in patients with chronic obstructive pulmonary..., Hartley [/bib_ref] [bib_ref] Pneumonia in exacerbations of COPD: What is the clinical significance?, Trethewey [/bib_ref].
A pooled analysis from five clinical studies showed that the probability of ECOPD was considerably higher than for pneumonia. The above factors must be taken into consideration while assessing treatment-associated pneumonia-risk-exacerbation benefit assessment with ICS [bib_ref] Risk factors for exacerbations and pneumonia in patients with chronic obstructive pulmonary..., Hartley [/bib_ref]. The European Medicines Agency states that there is no conclusive clinical evidence for intra-class differences in the magnitude of the risk among ICS products. Whether one should give due importance to the risk of pneumonia with an individual ICS still remains questionable.
Evidence suggests that ICS may increase the risk of pneumonia and that the same is mainly linked to fluticasone propionate use in moderate to severe COPD patients, as seen in the TORCH study. Nevertheless, an increased risk of pneumonia with ICSs was not seen in more recent large studies conducted in moderate than in severe patients [bib_ref] Risk of Pneumonia with Different Inhaled Corticosteroids in COPD Patients: A Meta-Analysis, Zhang [/bib_ref].

## - 
A real-world effectiveness study in COPD patients showed that there was no increase in the risk of pneumonia in FF/Vi group as compared to the usual care group [bib_ref] Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice, Vestbo [/bib_ref].

## - 
Another large clinical trial conducted in patients with moderate COPD and heightened cardiovascular disease risk showed that the incidence of pneumonia was comparable in the placebo, fluticasone furoate, vilanterol and FF/Vi groups [bib_ref] Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with..., Vestbo [/bib_ref]. - A recent study showed that the risk of pneumonia with fluticasone furoate 100 g (RR = 1.39) was significantly lesser than the 200 g dose (RR = 1.90). The same study also showed that fluticasone furoate 100 g was safer in terms of pneumonia risk as compared to fluticasone propionate 500 g (RR = 1.80) and 1000 g (RR = 1.64) and was closer to 800 g budesonide (RR = 1.26) [bib_ref] Risk of Pneumonia with Different Inhaled Corticosteroids in COPD Patients: A Meta-Analysis, Zhang [/bib_ref].
Box 6 represents the expert panel recommendations on risk of pneumonia with FF/Vi. Box 6. Recommendation.

## Panel recommendations

## 1.
There is a clinical dilemma while diagnosing exacerbation vs pneumonia in COPD patients. Along with clinical signs, radiological diagnosis must be considered for distinctive diagnosis of pneumonia while ruling out exacerbation (IA) 2.
The choice of the ICS prescribed should not solely rely upon background incidence of pneumonia in COPD patients. An individualized risk benefit assessment should be performed considering risk of exacerbation (IA) 3.
There is a lesser risk of pneumonia with fluticasone furoate (100 g) as compared to fluticasone propionate in COPD patients (IA)
However, the panel also mentioned that the clinical significance of the varying incidence of pneumonia with different ICS needs to be explored further

## Benefits of ff/vi (ics/ulaba) as compared to conventional ics/laba combinations (a) exacerbation reduction
Frequent exacerbations in patients with COPD are a major reason for disease progression and mortality [bib_ref] Chronic obstructive pulmonary disease exacerbations: Latest evidence and clinical implications, Qureshi [/bib_ref]. Evidence suggests that patients who had experienced a greater exacerbation burden after initiation of maintenance therapy had a worse lung function at diagnosis as well as a more rapid lung function decline. This emphasizes the need for better treatment options and treatment strategies [bib_ref] The Long-Term Burden of COPD Exacerbations During Maintenance Therapy and Lung Function..., Kerkhof [/bib_ref].

## - 
Real-world evidence suggests that FF/Vi provides a significant exacerbation benefit.
A large-scale effectiveness study showed that the rate of moderate or severe exacerbations is significantly lower, by 8.4% in the FF/Vi group as compared to the usual care group. Patients switched from an ICS-containing regimen (FP/SAL or BUD/FOR) showed the greater benefit [bib_ref] Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice, Vestbo [/bib_ref]. - Further evidence in the form of a clinical trial showed that FF/Vi with or without LAMA had better and consistent protection than LABA/LAMA group against moderate-to-severe exacerbations in patients with increasing baseline eosinophil count [bib_ref] Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD, Lipson [/bib_ref]. - A large observational study showed that FF/Vi was associated with a 14% lower risk of having a COPD-related moderate or severe exacerbation compared to BUD/FOR [bib_ref] Assessment of COPD-related outcomes in patients initiating a once daily or twice..., Stanford [/bib_ref]. - As far as the single inhaler triple combination is concerned, rate ratio for moderate to severe exacerbations in FF/VI/UMEC group was comparable to that of BUD/FORM/Glycopyrronium (rate ratio = 0.99 in both the groups) [bib_ref] Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled..., Ferguson [/bib_ref].
(b) Lung-function improvement COPD is a progressive inflammatory disease causing a gradual decline in expiratory flow and, thereby, a deterioration in lung function [bib_ref] Pantazopoulos, I. Pulmonary function testing in COPD: Looking beyond the curtain of..., Kakavas [/bib_ref]. It is associated with a significant and rapid deterioration of lung function and a great degree of airway obstruction [bib_ref] Predicting Health-Related Quality of Life in Patients with Chronic Obstructive Pulmonary Disease:..., Corlateanu [/bib_ref].
The role of FF/Vi in lung function slowing lung function decline is well-established.
- A clinical trial in COPD patients showed that the rate of lung-function decline decreased by 8 mL/year in the FF/Vi group as compared to the placebo group (p = 0.019) [bib_ref] Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with..., Vestbo [/bib_ref]. - Evidence also shows that weighted mean (wm) FEV1 (mean 130 mL) is greater and time to 100 mL improvement shorter (median 16 min) with FF/Vi as compared to FP/SAL (weighted mean 108 mL, median 28 min) [bib_ref] A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with..., Agusti [/bib_ref].

## - 
A recent study showed that once-daily FF/Vi improved trough FEV1 by about 230 mL as compared to a placebo in COPD patients. However, other trials suggest a more modest increase (100-130 mL) in FEV1 [bib_ref] Combination of Fluticasone Furoate and Vilanterol for the Treatment of Chronic Obstructive..., Bollmeier [/bib_ref].
(c) Symptom control COPD assessment tool (CAT) is often used to gauge the symptom prognosis and health status recovery in COPD patients [bib_ref] Evolution of the COPD Assessment Test Score during Chronic Obstructive Pulmonary Disease..., Feliz-Rodriguez [/bib_ref]. FF/Vi has shown beneficial effects in this aspect. A real-world phase III study showed an improvement in COPD-related health status (a decrease in CAT score of more than or equal to 2): 45% in FF/Vi group versus 36% in UC group (OR 1.51, p < 0.001) [bib_ref] Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice, Vestbo [/bib_ref].
(d) Quality-of-life improvement COPD impairs quality of life and day-to-day functioning of patients. Improvement in the quality of life of COPD patients is an important goal and the same has been emphasized in GOLD guidelines. A systematic review showed that with FF/Vi 100/25 g, FP/SAL 500/50 g and BUD/FORM 400/12 g, all three groups showed significant improvement in mean SGRQ score as compared to a placebo. The mean improvement with FF/Vi (4.6 units) exceeded the minimal clinically important difference (MCID) of 4 units and was numerically higher than that seen with FP/SAL (3.278) or BUD/FORM (3.64) in COPD patients [bib_ref] Once-daily fluticasone furoate/vilanterol 100/25 mcg versus twice daily combination therapies in COPD-Mixed..., Stynes [/bib_ref].
Mortality benefit - IMPACT trial was the first large trial reporting mortality data with the use of triple therapy in the treatment of COPD. The trial showed that triple therapy offered significant mortality benefits as compared to LABA/LAMA (HR = 0.58). The trial also showed that dual therapy with FF/Vi provided a significant mortality benefit versus LABA/LAMA (HR = 0.61) [bib_ref] Inhaled therapy reduces COPD mortality, Andreas [/bib_ref].

## - 
The SUMMIT trial was conducted in patients with moderate COPD and heightened cardiovascular disease risk showed that all-cause mortality with FF/Vi was 12.2% lower as compared to a placebo group but was not statistically significant (p = 0.137). However, the all-cause mortality was significantly lower in the FF/Vi group (HR = 0.76) among subjects with a Summit Score of 14 to 19. The SUMMIT trial is one of the largest randomized controlled COPD trials, with more than 16,000 patients [bib_ref] Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with..., Vestbo [/bib_ref].

## - 
The results of recent network meta-analysis provides high quality evidence that both MD ICS/LABA/LAMA and MD ICS/LABA FDCs were significantly effective in reducing on-treatment all-cause of death, whereas only MD ICS/LABA/LAMA FDC significantly prevented adjudicated cardiovascular mortality. Indeed, the protective effect against mortality was related to the dose of the ICS in the FDC. A total of~125 COPD patients had to be treated for one year with an MD ICS-containing combination to prevent one death compared with LABA/LAMA FDC. Given the importance of the outcome "mortality", the specific context of COPD characterized by a high prevalence, and the safety profile of MD ICS-containing FDCs, an NNT of 125 seems to be more than acceptable and of clinically relevant magnitude [bib_ref] Evaluating triple ICS/LABA/LAMA therapies for COPD patients: A network meta-analysis of ETHOS,..., Calzetta [/bib_ref].
(e) Safety benefits Cardiovascular events are regarded as an important source of morbidity and mortality in COPD patients, regardless of the disease severity. COPD is, in fact, considered a powerful, independent risk factor for cardiovascular morbidity and mortality. Evidence indicates that cardiovascular diseases may account for 25% of all deaths and around 40-50% of all hospitalizations in patients with mild to moderate COPD. Therefore, for therapies positioned to reduce all-cause mortality and hospitalizations in COPD, it is desirable that they have beneficial effects on the cardiovascular system [bib_ref] Pharmacotherapy for Mortality Reduction in Chronic Obstructive Pulmonary Disease, Sin [/bib_ref]. A pilot-randomized controlled trial concluded that the short-term use of FF/Vi led to consistent and physiologically plausible beneficial effects on cardiac structure, function, and pulmonary vasculature [bib_ref] Lung Deflation and Cardiovascular Structure and Function in Chronic Obstructive Pulmonary Disease...., Stone [/bib_ref].
(f) Adherence and compliance benefit A decline in adherence to COPD treatment appears early right from the first year of treatment, with a steep decrease from the beginning, which continues afterwards. Hence, it would be prudent to intervene early to maximize adherence and subsequent benefit from the therapy [bib_ref] Status of and strategies for improving adherence to COPD treatment, Lopez-Campos [/bib_ref]. Patients as well as physicians play a major role in ensuring a good adherence. Physicians can affect treatment adherence in COPD based on the medication class prescribed, method of administration, dosing regimen and polypharmacy [bib_ref] Adherence to COPD treatment: Myth and reality, Rogliani [/bib_ref]. Use of once daily FF/Vi regimen is one such early implementable intervention directed towards improving the dosing regimen taking into account that the BUD/FOR combination has a twice-daily dosing schedule. Along with a favorable safety and efficacy profile, the added convenience of once-daily administration schedule of FF/Vi will prove to be beneficial and improve adherence in COPD patients [bib_ref] Combination of Fluticasone Furoate and Vilanterol for the Treatment of Chronic Obstructive..., Bollmeier [/bib_ref]. Box 7 shows expert panel recommendations on the advantages of FF/Vi. Box 7. Recommendation.

## Panel recommendations

## 1.
The exacerbation and symptom control benefit showed by FF/Vi in the real world studies outweighs the benefit from usual ICS/LABAs (IIA) 2.
FF/Vi to be used over usual ICS/LABAs in patients with cardiovascular morbidity because of its beneficial effects on the cardiovascular system (IB) 3.
FF/Vi offers a definitive advantage in terms of adherence and compliance benefit as compared to the other ICS/LABAs (IA) 4.
Since COPD is a chronic disease and needs long term treatment, experts suggested that once daily dosing would be the greatest advantage offered by FF/Vi (IC)

## Triple therapy in copd-open-triple versus single-inhaler-triple therapy?
There is evidence to validate that triple therapy with FF/Vi/UMEC results in a lower rate of moderate or severe COPD exacerbations than ICS/LABA or LABA/LAMA in symptomatic COPD patients with a previous history of exacerbation [bib_ref] Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive..., Lipson [/bib_ref]. A randomized noninferiority study in COPD patients showed that single-inhaler triple therapy (FF/Vi/UMEC) was non-inferior to ICS/LABA or LABA/LAMA inhalers with respect to trough FEV1 change from baseline at 24 weeks. Similar results were seen on all other measures pertaining to efficacy, quality of life and safety [bib_ref] Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for..., Bremner [/bib_ref]. However, the phenotype of patients who will require an add-on LAMA to FF/Vi in clinical practice is not clearly established.
Open-triple therapy is primarily useful in the patients who prefer flexibility in dose titration and thereby show a preference towards splitting the components. However, for patients predisposed towards poor adherence, single-inhaler triple therapy could be considered. A recent study showed that bronchodilation and lung-function improvement was comparable in the single-inhaler triple therapy and open triple therapy [bib_ref] Efficacy and safety of single-inhaler triple therapy of glycopyrronium, formoterol and fluticasone..., Salvi [/bib_ref]. Box 8 represents expert panel recommendations on the use of triple therapy in COPD.

## Box 8. recommendation.

## Panel recommendations

## 1.
Add LAMA to FF/VI (100/25 g) in group D and B COPD patients as an optimized strategy (IIA) However, the de-escalation strategy needs to be defined while considering an improvement in clinical symptoms.

## 2.
Open triple therapy to be a good strategy in unstable COPD (post exacerbation requiring hospitalization) patients as it allows to titrate the dose of ICS, it also gives flexibility to prescribe ICS/LABA in the morning and LAMA in the evening in those where exacerbation is predominant over dyspnea (IC)
The benefits of both open triple and SITT agreed by experts are same as discussed under asthma section.
Challenges and perspectives of ICS/uLABA approach [bib_ref] Ultra-LABAs for the treatment of asthma, Cazzola [/bib_ref]. Along with Fluticasone furoate/Vilanterol, Indacaterol/Mometasone combination is another example of ICS/uLABA combination which has expanded the armamentarium of OAD treatment. A convenient dosing schedule and compliance benefits are the clear advantages of the ICS/uLABA combinations. Moreover, ICS/uLABAs appear to be better treatment options compared to conventional ICS/LABAs based on several clinical studies in Asthma as well as in COPD. Yet, there are certain challenges associated with the use of ICS/uLABAs in practice. (c) Possibility of using FF/Vi as a SMART strategy considering its quicker onset of action needs to be evaluated.

# Conclusions
Recent evidence indicates that ICS/uLABA have laid the foundation for an optimistic change in the current landscape of OAD management. The current consensus is a sincere effort to understand the evolving role of ICS/uLABA in treatment of OADs. This consensus statement developed from a composite approach of the expert panel will provide a guiding light to pulmonologists and respiratory physicians and will help them weigh the various factors that need to be taken into account while prescribing ICS/uLABA. Experts believe that the recommendations provided here can be considered in the OAD management guidelines. We also indicate the need for the implementation of programs to sensitize pulmonologists and respiratory physicians towards the effective implementation of the recommendations for the utilization of ICS/uLABA. The landscape of ICS/uLABA can be further optimized with clinical experience.
[fig] Figure 1: Stepwise consensus development process. The class of recommendation and level of evidence grading used in this manuscript are based on the grading system used byKnuuti et al. which was modified for suitability in the current study [/fig]
[fig] : Adding LAMA to FF/Vi improved lung function in patients with moderate or severe Asthma uncontrolled on conventional ICS/LABA. There are higher odds of Asthma control when LAMA is added to FF/Vi. The mean annualized rate of exacerbations was found to be 0.31 for both FF/Vi/UMEC (100 and 200) and for FF/Vi (100 and 200), with a 2.6% reduction in rate with FF/Vi/UMEC compared with FF/Vi. ACQ-7 responders at 24 weeks were numerically higher (62%) with LAMA added to FF/Vi (100/25) as compared to higher dose of FF/Vi (200/25) when used alone (58%) Numerically greater improvements in clinic-trough FEV1 were observed with FF/UMEC/Vi 100/62.5/25 g versus FF/Vi 200/25 g across the baseline eosinophil and FeNO ranges. There is now substantial evidence on the efficacy and safety of LAMAs in uncontrolled Asthma notwithstanding treatment with ICS/LABA combinations. This regimen is recommended by GINA as an optimization step for patients with severe Asthma before any biologic or systemic corticosteroid treatment is initiated.Box 3 represents the expert panel recommendations on the addition of LAMA to FF/Vi. Recommendations on stepping up to a higher dose of FF/Vi are also shown in Box 3. [/fig]
[fig] Box 3: Recommendation. [/fig]
[fig] . 4: Triple Therapy in Asthma-Open-Triple versus Single-Inhaler-Triple Therapy? ICS/LABA/LAMA FDCs are effective and safe in uncontrolled Asthma, and the dose of ICS in the combination portrays itself as the discriminating factor while treating patients with a history of moderate or severe exacerbation. This has been depicted inFigure 2. [/fig]
[fig] Figure 2: Various steps of GINA 2021 guidelines where use of uLABA/ICS can be considered. [/fig]
[fig] Box 4: Recommendation. Recommendation 1. Poorly controlled symptomatic patients could be effectively treated with triple combination therapies including different strengths of an ICS according to the severity of previous exacerbations (IA) 2. Physicians may exercise both open triple and SITT options in clinical practice as per the clinical need and patient preference (IC) Open triple therapy advantages in clinical practice  Flexibility for dose titration, especially of ICS  Flexibility for choice of components  Split ICS/LABA & LAMA as am/pm dosing in select patients [/fig]
[fig] Figure 3: Potential use of FF/Vi in the various GOLD 2021 categories of COPD patients. mMRC: Modified Medical Research Council Dyspnea Scale; CAT: COPD Assessment Test. [/fig]
[fig] Author: Contributions: Conceptualization, R.D., S.P. and S.B.; methodology, R.D., D.T., P.J., A.M., J.V., S.P., S.B. and N.K.; writing-original draft preparation, N.K., S.B. and S.P.; writing-review and editing, R.D., D.T., N.K., S.B., S.P. and H.B.; visualization, R.D., S.P., S.B. and N.K.; supervision, R.D., D.T., P.J., A.M., J.V., S.P., and H.B.; project administration, R.D., D.T., P.J., A.M., J.V., S.P., S.B., H.B. and N.K.; funding acquisition, N.K., S.B. and S.P. All authors have read and agreed to the published version of the manuscript. [/fig]
[fig] Funding: The project was funded by Glenmark Pharmaceuticals Ltd.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable. [/fig]
[table] Table 1: Comparison of distinguishable pharmacological properties of LABAs and uLABAs. Vilanterol has a greater functional selectivity and quicker onset of action as compared to other LABAs/uLABA [/table]
[table] Table 3: Class of recommendation and level of evidence. [/table]
[table] Table 4: List of FF/Vi combinations approved globally. [/table]
[table] Table 5: Summary of landmark clinical studies of FF/Vi in OAD. [/table]