genetics and environmental factors combine to produce different asthma phenotypes and various responses to controller medications .
the global initiative for asthma ( gina ) updated in 20161 is an ongoing international effort to provide a unified approach to the diagnosis and treatment of asthma .
table 1 summarizes the gina general treatment approach to asthma that uses a stepwise function based on the severity of asthma symptoms .
the table shows that inhaled corticosteroids ( icss ) play a major role as maintenance or preventative treatments in this stepwise approach to asthma .
table 2 summarizes the currently available and approved handheld inhalers by the us food and drug administration ( fda ) and several others not available in the usa .
fluticasone furoate ( ff ) is a potent corticosteroid that is dosed once daily due to its long half - life when inhaled .
it was approved by the fda as a once - daily ics for the maintenance treatment of asthma as a dry powder inhaler ( dpi ) in august 2014 with the brand name arnuity ellipta ( gsk , usa).2 controversy exists as to the role of long - acting beta2 agonists ( labas ) in the maintenance treatment of moderate to severe asthmatics .
early clinical trials of the laba salmeterol ( sal ) noted a nonstatistically significant increase in all - cause mortality in asthmatic patients treated over 16 weeks when compared to those using the short - acting beta2 agonist ( saba ) , albuterol.3 a large 2006 clinical trial of 26,355 asthmatics named the salmeterol multicenter asthma research trial ( smart ) evaluated sal by metered dose inhaler ( mdi ) compared to placebo mdi over 28 weeks.4 the use of ics and leukotriene modifiers was equal in both groups ( 47% and 11% , respectively ) .
the primary outcome included respiratory - related deaths or life - threatening events , and both were infrequent for the sal group ( 50 patients ) and placebo group ( 36 patients ) .
this difference did not reach statistical significance ( relative risk [ rr ] = 1.40 , 95% confidence interval [ ci ] = 0.912.14 ) . when secondary outcomes were explored , a small but significant increase in respiratory - related deaths was found in the sal group ( sal 24 vs placebo 11 ; rr = 2.16 , 95% ci = 1.064.41 ) along with specific asthma - related deaths ( sal 13 vs placebo 3 ; rr = 4.37 , 95% ci = 1.2515.4 ) .
the secondary outcome imbalances were largely related to the effects on the african - american subpopulation ( 20 sal vs 5 placebo ; rr = 4.92 , 95% ci = 1.5410.90).4 this study and a few others resulted in the fda requiring a  black box 
warning for all inhaled laba agents based on the  risk  of their use in asthma .
recent studies have called into question if there is an increase in risk to asthmatic patients treated with a combination ics / laba inhaler . in 2016 , peters et al5 studied 11,693 adult and adolescent asthmatic patients 12 years of age for 26 weeks .
they were randomized to the ics budesonide alone or a fixed - dose combination of budesonide and the laba formoterol given twice daily by mdi .
the budesonide / formoterol ( bud / f ) combination was found to be noninferior to budesonide alone with 43 patients having a serious asthma - related event in the bud / f group and 40 patients in the budesonide - alone - treated group ( hazard ratio [ hr ] = 1.07 , 95% ci = 0.701.65 ) . the risk of an asthma exacerbation was 16.5% lower in the bud / f - treated group compared to the budesonide - alone - treated group ( hr = 0.84 , 95% ci = 0.740.94).5 a similarly designed study in 11,679 asthmatic patients 12 years of age treated for 26 weeks also found that the combined fixed - dose fluticasone propionate ( fp)/sal did not have a significantly higher risk of serious asthma - related events and did have a 21% reduction in severe asthma exacerbations than those treated with fluticasone alone.6 similarly , when a fixed combination inhaler of sal and fp was compared to inhaled fp alone in 6,208 asthmatic children aged 411 years , non - inferiority for serious asthma - related events was seen ( hr = 1.28 , 95% ci = 0.732.27).7 these and other data suggest that the combination of an ics with laba is a safe and an effective treatment for asthma . furthermore , the use of both an ics and a laba is an integral part of the gina guidelines ( table 1 ) for the asthma patient at the step 3step 5 levels.1 
 table 2 summarizes the multiple handheld inhalers available in the usa . at this time
, laba monotherapy without the simultaneous use of an ics is still discouraged and has recently been described as  medical negligence  in children with asthma.8 the fixed combination of ff ( 100 or 200 g ) combined with the laba vilanterol trifenatate ( vi ; 25 g ) was approved in the usa in may 2013 for the maintenance treatment of chronic obstructive pulmonary disease ( copd ) as the once - daily dpi breo ellipta ( gsk , usa ) .
the same year , the same combination of drugs , doses and delivery system ( relvar ellipta ; gsk , uk ) was approved in japan and the european union for the treatment of asthma.9 breo ellipta ( ff [ 100 or 200 g]/vi [ 25 g ] ) was approved by the fda for the maintenance treatment of asthma in april 2015.2 this article reviews the data that support the use of the fixed - dose combination of dpi ff with vi as a once - daily asthma maintenance treatment .
the inhaled use of ff in asthma is in part based on its long half - life in the lung that allows once - daily dosing for asthma maintenance therapy.10 as given in table 1 , ics therapy plays a major role in the current gina guidelines .
when as - needed sabas become inadequate to control asthma symptoms , the use of low - dose ics should be considered as early as step 1 and used through step 2 into step 3 as medium- to high - dose ics .
the 100 g daily dpi dose of ff is considered low - dose ics therapy for asthmatics aged 12 years and older.1 after the addition of a laba to low - dose ics therapy at step 3 , higher medium- or high - dose ics therapy is recommended by the gina guidelines for asthmatic patients that remain symptomatic .
high - dose  ics and can be used for symptomatic step 35 asthmatic patients.1 table 3 summarizes the major clinical trials that have examined the use of ff as an ics maintenance asthma therapy .
efficacy and safety have been verified with once - daily ff dosing in asthmatic patients in several studies .
an 8-week study of 545 adolescent and adult asthmatic patients demonstrated significant ( all p0.033 ) improvements with ff in pre - dose and placebo - adjusted forced expiratory volume at 1 second ( fev1 ) .
once - daily evening - dosed ff ( 400 g ) was also as effective as twice - daily dosing ( 200 g ) of the same total daily ff dose in improving placebo - adjusted fev1 ( 200 ml).11 in this study , the morning - dosed ff ( 400 g ) was found to be less effective than an equal dose of ff ( 200 g ) given twice daily ( 202 ml improvement , 95% ci = 96307 vs 315 ml improvement , 95% ci = 208421 ml).11 a randomized , double - blind , double - dummy and placebo - controlled study further evaluated once - daily ff ( 100 g ) given in the morning compared to the evening over a 2-week trial in asthmatics aged 1870 years who required an ics to control symptoms.12 inhaled ff ( 100 g ) daily increased 24-hour weighted mean fev1 relative to placebo ( for am dosing , 77 ml ; 90% ci = 1152 ml and for pm dosing , 105 ml ; 90% ci = 29180 ml)13 and found that the difference in the increase when ff was given in the morning or evening was negligible ( adjusted differences , 28 ml ; 90% ci = 10245 ml).12 a longer 24-week multicenter , double - blind , parallel - group study compared once - daily evening doses of ff ( 100 g ) to ff ( 200 g).13 both ff doses improved least - squares mean trough fev1 from baseline by 208 ml in the ff ( 100 g ) group and 284 ml in the ff ( 200 g ) group ( treatment difference , 77 ml ; 95% ci = 39192 ml).13 similar improvements were seen in rescue- and symptom - free days , morning and evening peak expiratory flow ( pef ) and reported adverse events with the two ff doses .
the 200 g ff - treated group was 42% more likely to have well - controlled symptoms than the 100 g ff - treated group .
there were no safety concerns , and no clinically relevant effects on 24-hour urinary cortisol levels with either of the doses of inhaled ff were found.13 when inhaled ff ( 100 g ) daily for 2 weeks was compared to ff ( 100 g ) combined with the long - acting muscarinic antagonist ( lama ) , umeclidinium ( umec ; 15.6 , 31.25 , 62.5 , 125 or 250 g ) , in adult asthmatics , trough fev1 was improved with ff ( 100 g ) alone ( by 87 ml ) compared to baseline , but they increased even more when ff ( 100 g ) was combined with umec doses ( 141214 ml).14 when least - squares mean change in trough fev1 was evaluated , statistically significant differences were seen with ff ( 100 g)/umec ( 125 and 250 g ; both 55 ml , p=0.018 ) compared to ff ( 100 g ) alone.14 in addition , both morning and evening pef improved more with the combination of ff with umec daily inhalation compared to ff alone .
the ff serum concentrations peaked at half an hour when given alone , and this did not change when combined with umec.15 the use of daily ff given by dpi has a proven efficacy in asthmatic patients requiring an ics for symptom control .
the combination of ff with lama appears to increase the efficacy compared to ff alone in asthmatic patients .
several new laba agents designed for once - daily dosing are available or under study including indacaterol , olodaterol , abediterol and vi.16 appropriate concern for the use of laba agents alone as maintenance therapy has mandated that asthmatic subjects in most clinical studies evaluating the use of the inhaled laba vi be currently on an ics ( table 4 ) .
an exception is the study by kempsford et al.17 inhaled vi was given once daily ( 25100 g ) for 14 days to healthy volunteers and once to patients with either asthma or copd .
inhaled vi was rapidly absorbed with a median time to maximal serum concentrations of 5 minutes in healthy subjects and 10 minutes for asthma and copd patients .
all vi doses improved fev1 by 5 minutes and maintained increased fev1 up to 24 hours after inhalation in patients with asthma or copd.17 no clinically significant adverse effects were found including evaluations of vital signs , 12-lead electrocardiogram ( ecg ) , holter ecg , blood glucose or potassium levels .
table 4 summarizes five placebo - controlled clinical trials in asthmatics on an ics that evaluated inhaled vi using a dpi device lasting between 1 and 12 weeks .
doses between 3 and 50 g daily of inhaled vi were tried , and the bronchodilator effect lasted at least 24 hours for vi doses 12.550 g.18 the efficacy and safety of once - daily vi dosing in asthmatics were established by sterling et al19 who evaluated 72 adult ( 18 years old ) asthmatics on an ics with a 7-day treatment of daily inhaled vi ( 6.25 , 12.5 and 25 g ) , twice - daily inhaled vi ( 6.25 g ) or placebo using a dpi . the vi treatment in asthmatics resulted in a statistically significant ( p<0.001 for all doses ) increase on day 7 in trough fev1 and weighted mean 24-hour fev1 versus placebo .
the differences from placebo for trough fev1 with once - daily vi were 94 ml ( 95% ci = 49140 ml ) , 102 ml ( 95% ci = 57147 ml ) and 125 ml ( 95% ci = 80170
the 6.25 g vi twice - daily dose resulted in 140 ml ( 95% ci = 95185 ml ) improvement in trough fev1 compared to placebo.19 non - inferiority between once - daily versus twice - daily vi dosing was also shown.19 a recent large trial children aged 511 years ( n=456 ) with persistent asthma symptoms inadequately controlled on an ics were randomized to once - daily inhaled vi ( 6.25 , 12.5 or 25 g ) , and this was compared to placebo over 4 weeks .
it demonstrated safety but failed to show an improvement from baseline in trough fev1 for any of the vi doses tested.20 adult asthmatic patients uncontrolled on an ics ( n=347 ) were given once - daily vi ( 25 g ) for 12 weeks and were compared to those given twice - daily sal or placebo .
researchers noted the improvement in fev1 of 35942.9 ml with vi , 28341.9 ml with sal and 28942.9 ml for placebo.21 the increase in fev1 was not statistically significantly different between vi and placebo .
overall , these data suggest that there is a variable response to inhaled vi in adult patients with persistent symptoms already on an ics and even less efficacy of vi in asthmatic children on an ics .
pharmacodynamic , pharmacokinetic and safety data have been tested with inhaled ff / vi in several populations , including healthy chinese and japanese , in patients simultaneously on ketoconazole and in patients with renal and hepatic impairment.2225 stable pharmacokinetics and pharmacodynamics and no safety concerns over the use of inhaled ff / vi were found in these studies .
allergen and methacholine challenge tests were used in 27 patients randomized to inhaled ff ( 100 g ) , vi ( 25 g ) , ff ( 100 g)/vi ( 25 g ) or placebo.26 using the allergen challenge to test early asthmatic response ( ear ) and airway hyperresponsiveness ( ahr ) , researchers found a decrease in fev1 . using the mean 02 hours post allergen challenge fev1 ,
the least decrease was reported with the pre - challenge dosing of the combination ff / vi inhaler ( 0.614 l , 95% ci = 0.858 to 0.370 ) and the greatest decrease was after placebo inhaler ( 1.091 l , 95% ci = 1.344 to 0.837 ) .
the methacholine challenge test was used in these patients to model late asthmatic response ( lar ) and ahr at 24 hours . weighted mean
fev1 410 hours post challenge was reduced after placebo ( 466 ml , 95% ci = 589 to 343 ) but actually increased with ff ( 100 g ; 18 ml , 95% ci = 89 to 125 ) and with ff ( 100 g)/vi ( 25 g ; 18 ml , 95% ci = 89 to 124 ) . it was also improved compared to placebo with vi ( 25 g ; 298 ml , 95% ci = 415 to 181).26 the use of the combined ff / vi provided statistically significant protection against the ear of ahr compared to its components alone and to placebo .
there was also statistically significant protection with combination ff / vi therapy when compared to placebo and vi alone against the lar of ahr .
cytochrome p450 3a4 ( cyp3a4 ) is the major hepatic enzyme responsible for metabolizing ff by ester hydrolysis with the formation of the 17 beta - carboxylic acid and loss of the s - fluoro - methyl - carbothioate.24,27 ff is also believed to be a substrate for the p - glycoprotein ( pgp ) efflux transporter , and enterocytes may have a major metabolic effect on ff in the gastrointestinal track.27 the hepatic enzyme cyp3a4 also plays a major role in the metabolism of vi by o - dealkylation.28 it is also believed to be a substrate for pgp when in the gastrointestinal system.24 ketoconazole is a probe used to assess the potential effect of cyp3a4 metabolic inhibition , and it also has inhibitory effects on pgp.24 coadministration of repeat doses of ketoconazole 400 mg daily and inhaled vi ( 25 g ) alone had no pharmacodynamic or pharmacokinetic effect on vi .
when 11 days of 400 mg oral ketoconazole daily was coadministered with inhaled ff ( 200 g)/vi ( 25 g ) from days 5 to 11 , no statistical or clinical effect was seen on heart rate or minimal potassium levels.24 there was a 27% decrease in 24-hour weighted mean serum cortisol levels ( treatment ratio = 0.73 , 90% ci = 0.620.86 ) .
an increase in the ff area under the plasma concentration 024-hour curve by 36% with ketoconazole ( 90% ci = 16%59% ) was reported .
the area under the plasma concentration 024-hour vi curve increased by 65% ( 90% ci = 38%97%).24 
 table 5 summarizes the major pharmacokinetic parameters of ff and vi that allow once - daily dosing for this inhaled fixed combination medication .
table 6 summarizes the major clinical trials evaluating pharmacokinetics , safety and efficacy of ff / vi given by dpi in asthmatic patients .
large randomized double - blind clinical trials have shown improved fev1 and pef measures by treatment with ff / vi compared to placebo or the same or better measures with active control agents such as inhaled fp and fp with the laba sal twice daily.2936 these clinical trials lasted from 2 to 52 weeks and evaluated efficacy and safety . two trials
each of 12-week duration have confirmed the efficacy of ff ( 100200 g)/vi ( 25 g ) given daily by dpi in asian asthmatic patients compared to placebo37 and compared to the active comparator fp using pef measures of efficacy.38 an observational study from italian national health service data used propensity score matching on baseline covariates of gender , age , fev1 and comorbidities on 40 adult asthmatic patients .
they were treated with ff ( 100 g)/vi ( 25 g ) by dpi once daily or beclomethasone dipropionate / formoterol ( bec / f ) inhalation twice daily.39 the bec / f - treated group had 0.28 ( 0.12 ) days of hospitalization , and those treated with ff / vi had 0.08 ( 0.04 ) days of hospitalization ( p=0.09 ) during the 12-week analysis period .
both the number of physician visits and the number of specialist visits were statistically reduced in the ff / vi - treated group compared to the bec / f - treated group.39 another small comparison study ( n=30 ) in japan evaluated bud ( 160 g)/f ( 4.5 g ) two puffs twice daily and one additional inhalation as needed of bud / f each day versus ff ( 100 g)/vi ( 25 g ) by dpi daily over 4 weeks in asthmatics 20 years who required an ics.40 both drug combinations showed statistically significant ( p<0.001 ) improvement in the asthma control questionnaire during the 4 weeks with greater improvement in the scores with the bud / f - treated group .
both groups also showed decreases ( p<0.001 ) in fractional exhaled nitric oxide ( feno ) from baseline to week 4 with the levels in the bud / f group reduced greater ( p<0.001 ) than the ff / vi - treated group .
the use of a fixed - dose ics / laba as a rescue medication in this study goes against historical dogma of using saba agents as rescue medication in asthma but is in the gina guidelines ( table 1 ) .
in addition , direct comparisons between different combinations of ics / laba beg the question of dosage equivalence . in this study ,
perhaps the comparator should have been ff ( 200 g)/vi ( 25 g ) as a high - dose ics as opposed to the low - dose ff ( 100 g)/vi ( 25 g ) combination . the asthma  copd overlap syndrome ( acos ) is an asthma phenotype that shares features of both asthma and traditional copd.1,41 a small ( n=16 ) open - label , randomized , crossover study of patients with acos in japan compared once - daily ff ( 200 g)/vi ( 25 g ) versus fp ( 500 g)/sal ( 50 g ) twice daily for 4-week treatment periods.42 the mean value of fev1 was 1.33 l ( 1.29 ) during the run - in period , 138 l ( 0.39 ) after the fp / sal treatment and 1.47 ( 0.38 ) l after the ff / vi treatment .
the mean value of fev1 was significantly ( p<0.01 ) greater in the ff / vi treatment group compared to the run - in period in these patients with acos .
although a small trial of short duration , it is one of the few pharmacological trials in patients with acos and the only randomized trial evaluating the ff / vi combination inhaler in patients with acos phenotype . a large pragmatic study evaluating ff ( 100 or 200 g)/vi ( 25 g )
the salford lung study is a randomized and controlled trial started before ff / vi inhalers were approved for asthma treatment .
it utilizes the salford electronic medical record to give near real - time data collection and monitoring of safety data at 66 primary care sites in and around salford and south manchester , england.43 the data from this study when available will complement the more standard double - blind , randomized , controlled trials evaluating real - world efficacy and obtaining risk / benefit information on inhaled ff / vi . when east asian patients were compared to non - east asian patients from the large randomized , double - blind , multicenter clinical trials in a prespecified subgroup analysis ,
both ff ( 100 or 200 g)/vi ( 25 g ) dose combinations were as effective in improving fev1 compared to placebo as in non - east asian patients.44 a systematic review with meta - analysis of seven published trials ( n=5,668 ) evaluating inhaled ff / vi in asthmatic patients was recently performed.45 the combination therapy of ff ( 100 or 200 g)/vi ( 25 g ) daily increased trough fev1 in asthmatics treated longer than 8 weeks compared to either fp twice daily or ff daily alone .
three of the seven trials compared ff ( 100 or 200 g)/vi ( 25 g ) doses to ff ( 100 g ) once daily and showed a significant ( p0.001 ) increase in trough fev1 of 90 ml ( 95% ci = 60120 ml ) with the combination inhaler compared to ff alone.45
medication adherence or following the medication plan is a significant problem and factor in the treatment of chronic diseases.46 dosing frequency has a major effect on the rate of nonadherence of medication in chronic diseases.47 when medications are given twice daily compared to once daily , the adherence rates were significantly lower , with regimen adherence reduced by 13.1% and timing adherence reduced by 26.7% compared to once daily.47 the adherence rates fall 23.1% for regimen adherence and 54.2% for timing adherence when medications are given four times daily compared to daily dosing .
nonadherence to treatment is associated with poor baseline asthma control.48,49 the nonadherence rates among asthmatic patients range between 30% and 70% , and because of this the assessment of medication adherence is a critical part of evaluating the difficult to treat asthma patient.50,51 integrated and innovative approaches to patients are needed to improve medication adherence in difficult asthmatic patients.52 once - daily medications and the combination of an ics with a laba in a single inhaler are associated with improved medication adherence compared to that of an ics alone.53,54 better medication adherence must be addressed and will improve health outcomes and asthma disease control.55,56 in addition to being a daily combination dosing asthma maintenance medication , breo ellipta ( gsk ) utilizes the ellipta delivery system .
the ellipta dry powder system ( gsk , uk and japan ) has been shown to be easy to use and preferred over the breezhaler ( novartis pharma uk , japan ) in device - naive japanese volunteers.57 when semi - structured , in - depth , qualitative interviews were conducted on asthma and copd patients after using ellipta ( gsk , germany ) dry powder inhalation systems , the ellipta device was associated with the highest patient satisfaction and preference.58 patient preference for the ellipta device was also demonstrated in 287 copd patients randomized to the ellipta or diskus dpis.59 the ellipta device was significantly preferred ( p<0.001 ) over the diskus device in all categories .
overall inhaler preference was 67% for the ellipta device and 31% for the diskus.59 once - daily dosing with the ff / vi ellipta device and its high patient preference are also likely to contribute to improved asthma medication adherence .
to date , a large amount of clinical trial data exists supporting the efficacy and safety of the use of inhaled ff / vi by dpi for asthma maintenance treatment .
the combination ics / laba of ff / vi fits well into the gina guidelines starting as early as step 3.1 studies looking at a fixed - dose triple - combination inhaler with ff , vi and the lama umec are ongoing in healthy volunteers , being developed for copd indication and could be evaluated in asthmatic patients.60
the dpi inhaler , ff / vi , is a fixed combination of two strengths of ff ( 100 or 200 g ) both with vi ( 25 g ) used as a maintenance treatment in asthmatic patients not controlled on just an ics therapy alone .
the doses of ff cover low- and high - dose ics categories and fit nicely into the current gina asthma treatment guidelines .
similarly , efficacy and safety were demonstrated in clinical trials in adolescent and adult asthmatic patients on an ics with adding inhaled vi but not in children aged 511 years .
the data supporting the combined use of ff / vi in asthmatic patients requiring ics are strong and document its efficacy and safety in long - term , large and randomized clinical trials in adolescents and adults .
pharmacokinetics and pharmacodynamics have been well studied and have demonstrated limited clinically important drug interactions ( eg , ketoconazole ) and minimal alterations from renal and liver impairments .
limited efficacy data with inhaled ff / vi exist for asthmatic children ( < 12 years ) .
further studies on asthmatic children and various asthma phenotypes such as patients with acos are needed to better understand the full spectrum of the use of inhaled fixed combination ff / vi in the maintenance treatment of asthma .
 the use of inhaled corticosteroids ( icss ) plays a key role in the treatment of asthmatic patients , and international guidelines have designated icss as an early maintenance therapy in controlling asthma symptoms . 
 when asthmatic patients remain symptomatic on icss , one common option is to add a long - acting beta2 agonist ( laba ) to the maintenance treatment . 
 fixed combination inhalers that contain both an ics and a laba have been popular for both chronic obstructive pulmonary disease ( copd ) and asthma . 
 historically , these inhalers have been dosed twice daily . 
 however , currently , there is a once - daily combination therapy with the ics fluticasone furoate ( ff ) and the laba vilanterol trifenatate ( vi ) with indications for use in both copd and asthma . 
 this dry powder inhaler ( dpi ) comes in two doses of ff ( 100 or 200 g ) both combined with vi ( 25 g ) . 
 this article reviews the clinical trial data for ff , vi and ff / vi combination inhalers and documents the efficacy and safety of once - daily inhaled maintenance therapy by dpi in asthmatic patients . 
Introduction
FF in asthma
The use of VI in asthma
The use of FF and VI in asthma
Medication adherence with inhalers
Conclusion