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

Highlights What are the main findings? 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 μg) 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.

• 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 µg) 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.

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 [1,2]. More than once-daily dosing results in lower adherence rates than medications dosed once daily [1]. 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 Table 1 [3,4]. Vi is a highly lipophilic β2-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 [5]. 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 [6,7]. FF exhibits greater in-vitro anti-inflammatory potency. It is a stronger inhibitor of NF-κB 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-κB and AP-1 [5].
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 [15,16]. 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 Table 2. Table 2. Clinical statements formulated for expert recommendations.

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.
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. Figure 1 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. Figure 1 provides an overview of the consensus development process.  [17]. The same has been depicted in Table 3 below.  [17]. The same has been depicted in Table 3 below.

Results and Discussion
The combination of FF/Vi is approved by various leading regulatory authorities in two strengths (100/25 µg and 200/25 µg) as a dry powder inhaler (DPI) formulation. The global approval status and indication of FF/Vi combinations is depicted in Table 4. Table 5 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 [24,25].
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 [26].
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 [3][4][5]. 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 [24,27] 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) [22].
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) [14,28]. • 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 [14]. • 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 [29].
An estimated 71% of patients with Asthma remain uncontrolled despite treatment [19]. 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 [30].
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 [31]. Expert panel recommendations on the use of FF/Vi in asthma are depicted in Box 1.

Recommendation
FF/Vi has shown improved treatment control and lesser SABA dependence compared to other ICS/LABAs including BUD/FOR.
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 [27].
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 [14].
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 [32][33][34]. 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.

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 naïve 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 [23,35].

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/µL) 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 [36]. 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 [36]. Box 4 depicts the expert panel recommendations on the use of triple therapy in asthma.

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/µL 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/µL. 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 [37].
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.

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 Figure 3. 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 [38,39].
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 [38]. 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 [40]. 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 [41].

•
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 [18].

•
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 [20]. • A recent study showed that the risk of pneumonia with fluticasone furoate 100 µg (RR = 1.39) was significantly lesser than the 200 µg dose (RR = 1.90). The same study also showed that fluticasone furoate 100 µg was safer in terms of pneumonia risk as compared to fluticasone propionate 500 µg (RR = 1.80) and 1000 µg (RR = 1.64) and was closer to 800 µg budesonide (RR = 1.26) [41].
Box 6 represents the expert panel recommendations on risk of pneumonia with FF/Vi. Box 6. Recommendation.

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 µg) 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 [42]. 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 [43].

•
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 [18]. • 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 [19]. • 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 [21]. • 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) [44].
(b) Lung-function improvement COPD is a progressive inflammatory disease causing a gradual decline in expiratory flow and, thereby, a deterioration in lung function [45]. It is associated with a significant and rapid deterioration of lung function and a great degree of airway obstruction [46].
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) [20]. • 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) [47].

•
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 [48].
(c) Symptom control COPD assessment tool (CAT) is often used to gauge the symptom prognosis and health status recovery in COPD patients [49]. 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) [18].
(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 [16]. A systematic review showed that with FF/Vi 100/25 µg, FP/SAL 500/50 µg and BUD/FORM 400/12 µg, 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 [50].
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) [51].

•
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 [20].

•
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 [52].
(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 [53]. 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 [54].
(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 [55]. 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 [56]. 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 [48]. Box 7 shows expert panel recommendations on the advantages of FF/Vi. Box 7. Recommendation.

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 [57]. 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 [58]. 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 [59]. Box 8 represents expert panel recommendations on the use of triple therapy in COPD.

1.
Add LAMA to FF/VI (100/25 µg) 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 [60]. 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.