LABA

Salmeterol-fluticasone combo as safe as inhaled corticosteroid monotherapy for asthma

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AUSTRI: salmeterol fluticasone asthma exacerbation

Asthma patients on salmeterol, a long-acting beta-agonist (LABA), plus fluticasone inhaled corticosteroid (ICS) combination therapy did not have a greater risk of serious asthma-related events compared with patients receiving fluticasone alone, according to the recent AUSTRI* study.

While previous studies have raised doubts about the safety of salmeterol for asthma treatment due to increased death risk, the current findings suggest it is safe as an add-on therapy to ICS.

“Not only was there no difference in the safety profile between the two arms of study, there was [also] less incidence of severe asthma exacerbation in the [LABA/ICS] combination arm compared to steroid alone arm,” said Dr. Ong Kian Chung, a consultant respiratory specialist from the KC Ong Chest & Medical Clinic in Mount Elizabeth Medical Centre, Singapore, who was unaffiliated with the study.

“The combination arm was more efficacious in controlling asthma in this manner, as is currently known.”

The debate about the safety of salmeterol arose from two large clinical trials that showed more asthma-related deaths among patients receiving salmeterol than those on placebo. [Chest2006;129:15-26; BMJ 1993;306:1034-1037; N Engl J Med 2016;374:1887-1888]

The results prompted the US Food and Drug Administration to mandate LABA manufacturers to include a black box warning in their product inserts. [N Engl J Med 2016;374:1887-1888]

However, a meta-analysis suggested that the risk of asthma-related deaths increased only when salmeterol was dispensed in a separate casing and not necessarily when used as a combination therapy with an ICS. [Thorax 2010; 65:39-43]

To address this issue, the multicenter double-blind AUSTRI study randomized 11,679 patients (aged ≥12 years) with persistent asthma to receive either fluticasone propionate plus salmeterol in combination or fluticasone propionate alone in a single masked inhaler twice daily for 26 weeks. [N Engl J Med 2016;374:1822-1830]

The frequency of serious asthma-related events, including hospitalization, endotracheal intubation, or death, was similar in both arms (36 events in 34 patients for fluticasone-salmeterol versus 38 events in 33 patients for fluticasone alone).

The risk of developing serious asthma-related events in the fluticasone-salmeterol arm was no greater than the fluticasone alone arm (hazard ratio [HR], 1.03, 95 percent confidence interval [CI], 0.64-1.66, p=0.003), which demonstrated noninferiority.

Adherence to medications was high in each treatment arm (95.1 percent for both).

Furthermore, patients receiving fluticasone-salmeterol had 21 percent lower risk of a severe asthma exacerbation compared with patients treated with fluticasone only (HR, 0.79, 95 percent CI, 0.70-0.89), with 8 percent of the patients on fluticasone-salmeterol experiencing at least one severe exacerbation episode compared with 10 percent in the fluticasone alone arm (p<0.001).

“It is clear that among patients with asthma who have not had life-threatening episodes in the past and are highly adherent to their drug regimen, it is likely that the use of salmeterol together with fluticasone in a single inhaler is safe,” said Dr. Fernando Martinez, a paediatric pulmonologist from the Arizona Respiratory Center at the University of Arizona in Tuscon, Arizona, US, who was unaffiliated with the study, in a separate commentary. [N Engl J Med 2016;374:1887-1888]

He also suggested that the black-box warning on LABA should be lifted for this group of patients.

Ong agreed, noting that negative reaction to LABA was uncommon in his clinical experience and the adverse effects known to be associated with LABA such as palpitations or hand tremors were rare among his patients.

“This is an important result, and it stresses once again that most patients with asthma, and especially those without serious episodes, can reach high levels of symptom control and avoid frequent exacerbations by simply using their inhalers every day,” said Martinez.

But not all patients may benefit. Martinez noted that patients with life-threatening asthma were excluded from the patient group, although the reasons for this were not explained in the study.

“It is bewildering that the patients at highest risk for the composite primary outcome were purposely left out,” he said, and cautioned that the same precautions should still be maintained when using fluticasone-salmeterol in patients with life-threatening or unstable asthma.

Novartis first in class once-daily dual bronchodilator Ultibro® Breezhaler® (QVA149) gains positive CHMP opinion for the treatment of COPD.

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  • QVA149 (indacaterol/glycopyrronium) is the first once-daily fixed-dose combination of both a LABA and a LAMA bronchodilator to gain positive CHMP opinion 
  • Pivotal Phase III IGNITE data showed QVA149 significantly improved lung function and patient-reported outcomes including breathlessness and rescue medication use, compared to current standard of care[1] 

  • QVA149 demonstrated significantly reduced rates of COPD exacerbations and improved health-related quality of life compared to open-label tiotropium 18 mcg and glycopyrronium 50 mcg[2],[3]

Basel, July 26, 2013 – Novartis announced today that the European Medicines Agency‘s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for approval of once-daily Ultibro® Breezhaler® (indacaterol 85 mcg/glycopyrronium 43 mcg delivered dose, equivalent to 110 mcg/50 mcg metered dose per capsule), as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Ultibro Breezhaler was developed under the name of QVA149.

“The CHMP’s positive opinion supports a major breakthrough in the treatment of COPD, where many patients do not have adequate treatment options,” commented David Epstein, Division Head, Novartis Pharmaceuticals. “QVA149 has shown significant improvements compared with some of the most commonly used treatment options for COPD, which is projected to be the third leading cause of death by 2020.”

QVA149 is an investigational fixed dose combination of two bronchodilators, indacaterol, a long-acting beta2-adrenergic agonist (LABA) and glycopyrronium, a long-acting muscarinic antagonist (LAMA).

QVA149 significantly improved the rate of all exacerbations compared to open-label (OL) tiotropium 18 mcg, glycopyrronium 50 mcg and was comparable to salmeterol/fluticasone (SFC) 50 mcg/500 mcg[3]. The rate of moderate or severe exacerbations was significantly lower compared to glycopyrronium 50 mcg and numerically lower compared to OL tiotropium 18 mcg[2],[3].

In clinical studies, QVA149 demonstrated an acceptable safety profile with no meaningful differences between the treatment groups (placebo, indacaterol 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg, SFC 50 mcg/500 mcg) in the incidence of adverse and serious adverse events[2],[4],[5].

The European Commission generally follows the recommendations of the CHMP and normally grants a marketing authorization within three months of the opinion. Worldwide submissions and reviews of QVA149 are ongoing with US filing expected at the end of 2014.

About the IGNITE clinical trial program
In the Phase III IGNITE clinical trial program, QVA149 is being investigated for the treatment of COPD patients as an inhaled, once-daily, fixed-dose combination of indacaterol maleate and glycopyrronium bromide. IGNITE is one of the largest international clinical trial programs in COPD comprising 11 studies in total (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON, RADIATE, LANTERN, FLAME) with more than 10,000* patients across 52 countries[3],[6]-[9],[10]-[17]. The first eight studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON) completed in 2012. The studies were designed to investigate the efficacy, safety and tolerability, lung function, exercise endurance, exacerbations, shortness of breath and quality of life in patients treated with QVA149.

Results from five of the Phase III IGNITE trials[3],[6]-[9]supported the CHMP’s positive opinion for QVA149 which demonstrated statistically significant improvements in bronchodilation versus treatments widely used as current standards of care[1]. Data showed that QVA149 significantly improved bronchodilation compared to OL tiotropium 18 mcg, SFC 50 mcg/500 mcg, indacaterol maleate 150 mcg, glycopyrronium 50 mcg and placebo providing a rapid onset within five minutes, and sustained bronchodilation during a 24 hour period which was maintained for up to 26 weeks, along with symptomatic improvements[1],[3],[7],[8]. These symptomatic improvements included breathlessness, exercise tolerance, rescue medication use and health-related quality of life[3],[4],[5],[6].

*Total refers to all 11 IGNITE studies.

About the Novartis COPD portfolio
Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

Onbrez® Breezhaler® (indacaterol maleate) is a long-acting beta2-agonist (LABA) that offers clinically relevant 24 hour bronchodilation combined with a rapid onset of action within five minutes at first dose, as demonstrated in the INERGIZE Phase III trial program[18]-[32]. Onbrez Breezhaler 150 mcg once-daily provided greater clinical benefit in terms of reduced shortness of breath, lower use of rescue medication and improved health status, compared with blinded tiotropium bromide 18 mcg[28]. Onbrez Breezhalerwas first approved and launched in the EU (150 mcg and 300 mcg once-daily doses) for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD[33]. It has now received approvals in approximately 100 countries around the world including Japan (as Onbrez® Inhalation Capsules 150 mcg once-daily) and USA (as ArcaptaTM NeohalerTM 75 mcg once-daily).

Once-daily Seebri® Breezhaler® (glycopyrronium bromide) is a novel inhaled long-acting muscarinic antagonist (LAMA; also referred to as a long-acting anticholinergic) indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD[34]. Glycopyrronium bromide was exclusively licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. In Phase III studies (GLOW 1, 2 and 3) Seebri Breezhaler (glycopyrronium 50 mcg) once-daily demonstrated rapid improvements in lung function after first dose on Day 1 which was sustained for 24 hours and maintained over the 52 week study period compared with placebo. Glycopyrronium 50 mcg also significantly improved shortness of breath, health-related quality of life, exacerbation risk, and exercise endurance versus placebo[35].[36],[37]. Seebri Breezhaler is approved in the EU, Japan, Switzerland, Canada, Australia and a number of other countries.

Novartis continues development of respiratory products for delivery via a single-dose dry powder inhaler (SDDPI) called the Breezhaler® device which has low air flow resistance, making it suitable for patients with airflow limitation[38]. The Breezhaler® device allows patients to hear, feel and see that they have taken the full dose correctly[34].

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

References:

[1] Vogelmeier C et al. Once-daily QVA149 provides clinically meaningful improvements in lung function and clinical outcomes versus placebo, indacaterol, glycopyrronium, tiotropium and salmeterol/fluticasone in patients with COPD. [ATS abstract 40759; Session C45; Date: May 21, 2013 Time: 8:15 -10:45].
[2] Decramer M et al. Safety and tolerability of QVA149, glycopyrronium and tiotropium in patients with severe to very severe COPD: the SPARK study. [ATS abstract 41616; Session A43; Date: May 19, 2013 Time:10:45-12:30].
[3] Wedzicha JA et al. Analysis of Chronic Obstructive Pulmonary Disease Exacerbations with the Dual Bronchodilator QVA149 Compared with Glycopyrronium and Tiotropium (SPARK): a Randomized, Double-blind, Parallel-group Study. Lancet Respir Med 2013 http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70052-3/abstract [Accessed 18 July 2013]
[4] Welte T et al. QVA149 once daily is safe and well tolerated in patients with COPD: the SHINE study. [ATS abstract 41616; Session A43; Date: May 19, 2013, 8:15-16.30].
[5]Vogelmeier C et al. QVA149 once daily is safe and well tolerated in patients with COPD: the ILLUMINATE study. [ATS abstract 41633; Session A43; Date: May 19, 2013, 8:15-16.30].
[6] Beeh et al. QVA149 once daily improves exercise tolerance and lung function in patients with COPD: the BRIGHT study. [BTS Winter Meeting 2012, Poster presentation P191; Date: 6 December; Time: 16:00-17:30].
[7] Vogelmeier CF et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with COPD (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respiratory Medicine. 2013; 1 (1): 51-60.
[8] Bateman ED et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. European Respiratory Journalhttp://erj.ersjournals.com/content/early/2013/05/30/09031936.00200212.full.pdf [Accessed 18 July 2013].
[9] Dahl et al, 2012. QVA administered once daily provides significant improvements in lung function over 1 year in patients with COPD: The ENLIGHTEN study. Volume abstract 853405.
[10] Mahler D et al. Superior lung function with once-daily QVA149 translates into improvements in patient reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study. [ATS abstract 45308; Session C20; Date: May 21, 2013 Time: 8:15-10:45].
[11] ClinicalTrials.gov, November 2012. Long Term Safety and Tolerability of QVA149 Versus Tiotropium in Japanese Patients With Chronic Obstructive Pulmonary Disease (COPD) (ARISE). [Online] Available at: http://www.clinicaltrials.gov/ct2/show/NCT01285492?term=%28ARISE%29&rank=4 . [Accessed 18 July 2013].
[12] ClinicalTrials.gov, n.d. Comparison of Safety and Efficacy of the Combination Product QVA149A Against the Concurrent Administration of the Individual Components, QAB149 and NVA237, in Patients With Chronic Obstructive Pulmonary Disease (COPD) (BEACON). [Online]
Available at: www.clinicaltrials.gov/ct2/show/NCT01529632?term=BEACON&rank=6.
[Accessed 18 July 2013].
[13] ClinicalTrials.gov, n.d. Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation (RADIATE). [Online] Available at: www.clinicaltrials.gov/ct2/show/NCT01610037?term=GLISTEN&rank=1 .[Accessed 18 July 2013].
[14] ClinicalTrials.gov, n.d. A 26-week Treatment Randomized, Double-blind, Double Dummy, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of QVA149 (Indacaterol / Glycopyrronium Bromide) Compared to Fluticasone/Salmeterol in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease. [Online]. Available at: www.clinicaltrials.gov/ct2/show/NCT01709903?id=01709903&rank=1.[Accessed 18 July 2013].
[15] FDA Access Data, n.d.Spiriva Medical Review Part 2. [Online]
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-395_Spiriva.cfm.[Accessed 18 July 2013].
[16] FDA Access Data, 2003.Advair Medical Review. [Online]
Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021077_S003_ADVAIR_DISKUS.pdf. [Accessed 18 July 2013].
[17] ClinicalTrial.gov, n.d. A 52-week Treatment, Multi-center, Randomized, Double-blind, Double Dummy, Parallel-group, Active Controlled Study to Compare the Effect of QVA149 (Indacaterol Maleate / Glycopyrronium Bromide) With Salmeterol/Futicasone on the Rate of Exacerbations in Subjects With Moderate to Very Severe COPD (FLAME). [Online] Available at: http://clinicaltrials.gov/ct2/show/NCT01782326?term=COPD+novartis+52&rank=2 .[Accessed 18 July 2013].
[18] Vogelmeier K et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010;11:135.
[19] Balint B et al. Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol- fluticasone. Int J Chron Obstruct Pulmon Dis2010; 5:311-8.
[20] La Force C et al. Sustained 24-hour efficacy of once-daily indacaterol (300 Mu g) in patients with chronic obstructive pulmonary disease: a randomized, crossover study. Pulm Pharmacol Ther 2011; 24:162-8.
[21] Beeh et al. Effect of indacaterol maleate on dynamic lung hyperinflation in patients with COPD.  Eur Respir J 2009; 34 (suppl 53): E4357.  Entire results are also included at: http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult=2737 [Accessed 18 July 2013]
[22] O’ Donnell DE et al. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD.  Respir Med 2011; 105(7): 1030-6.
[23] Magnussen H et al. Indacaterol once-daily is equally effective dosed in the evening or morning in COPD.  Respir Med 2010; 104:1869-76.
[24] Feldman G et al. Efficacy and safety of indacaterol 150 µg once-daily in COPD: a double-blind, randomised, 12-week study. BMC Pulm Med 2010;10:11.
[25] Barnes PJ et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther 2010;23:165-71.
[26] Donohue JF et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155-62.
[27] Kornmann O et al. Once-daily indacaterol vs twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011; 37:273-279.
[28] Dahl R et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist, indacaterol, versus twice-daily formoterol in COPD. Thorax 2010;65:473-9.
[29] Buhl R et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD.  Eur Respir J 2011; 38:797-803.
[30] Chapman KR et al. Long-term safety and efficacy of indacaterol, a novel long-acting ß2-agonist, in subjects with COPD: a randomized, placebo-controlled study.Chest 2011 140;68-75.
[31] Korn S et al. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study. Respir Med 2011; 105:719-26
[32] Mahler DA et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised double-blind comparison. Thorax 2012. Doi:10.1136/thorax8jnl-2011-201140.
[33] EMA, 2012. Onbrez® Breezhaler® (indacaterol) EU Summary of Product Characteristics. [Online] July 26, 2012 Available at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001114/human_med_001219.jsp&mid=WC0b01ac058001d124. [Accessed 18 July 2013].
[34] EMA. 2012. Seebri Breezhaler EU Summary of Product Characteristics. [Online] 17 October 2012. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002430/WC500133769.pdf. [Accessed 18 July 2013].
[35] D’Urzo A et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respiratory Research 2011;12:156.
[36] Kerwin E et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: The GLOW2 study. Eur Resp J 2012;40(5):1106-1114.
[37] Beeh K et al. Once-daily NVA237 improves exercise endurance from first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis2012;7:503-513.
[38] Pavkov et al. Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol. CMRO 2010; 26; 11:2527-2533. doi:10.1185/03007995.2010.518916.
[39] Joshi  M et al. Symptom burden in chronic obstructive pulmonary disease and cancer. Obstructive, occupational and environmental diseases. 2012;18(2).
[40] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2013. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. [Accessed 18 July 2013].
[41] Global Alliance Against Chronic Respiratory Diseases (GARD). Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Available at: http://www.who.int/gard/publications/GARD%20Book%202007.pdf. [Accessed 18 July 2013].
[42] Fletcher MJ et al. COPD Uncovered: An International survey on the impact of chronic obstructive pulmonary disease (COPD) on a working age population. BMC Public Health 2011;11:612.

Source: Novartis Newsletter.

Are inhaled longacting β2 agonists detrimental to asthma?

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Possible adverse effects of adrenergic bronchodilators in asthma have been the subject of discussion for more than half a century, with recent intense debate about the safety of longacting β agonists (LABAs). In this Debate, we consider the issues of bronchodilator and bronchoprotective tolerance resulting from the frequent use of bronchodilators, which is noted particularly with shortacting drugs, but has also been shown to occur quicker and to a greater extent with LABAs. Increased allergen responsiveness and masking allowing inflammation to increase, while symptoms and lung function remain apparently controlled, have also been observed. Studies in which LABAs were used as monotherapy were associated with increased mortality. However, several studies have shown the benefits of adding LABAs to inhaled corticosteroids (ICS). Meta-analyses of asthma clinical trials involving LABAs showed that, when given with mandatory ICS, LABAs were not associated with an increased risk of death, intubations, or hospital admission for exacerbations when compared with use of the same dose of ICS only. Withdrawal of LABA therapy once symptom control is achieved is often associated with subsequent loss of symptom control. When used for appropriate indications, LABAs should be combined with ICS in one inhaler so that monotherapy is not possible.

Source: lancet

 

COPD treatment: time to change our algorithm?

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puff

For the past decade, clinicians have largely followed a set of similar algorithms for chronic obstructive pulmonary disease (COPD) therapy, initiating treatment with an inhaled longacting antimuscarinic (LAMA) and adding combination therapy with a longacting β agonist (LABA) plus an inhaled corticosteroid when symptom or exacerbation control is inadequate. This algorithm is also in accordance with the Global initiative for chronic Obstructive Lung Disease (GOLD) 2007 consensus statement.1 However, the GOLD 2013 consensus statement challenges clinicians to rethink this routine.2 A wide range of treatment options are proposed including LAMA/LABA dual therapy, which is recommended as a treatment alternative for group B (high symptoms/low risk), C (low symptoms/high risk), and D (high symptom/high risk) patients. However, few data have been available to support the efficacy of this combination therapy over single agent bronchodilator therapy. Good data already exist for the efficacy of LAMA monotherapy for symptom control and exacerbation reduction3 as well as for the efficacy of LABA monotherapy for symptom control,4 but scarce data have been available for whether dual agent therapy has additional benefit in terms of either symptom control or exacerbation reduction.

In The Lancet Respiratory Medicine, Jadwiga Wedzicha and colleagues5 present data from the SPARK study, a randomised, three-group, double-blind study in COPD comparing once-daily indacaterol plus glycopyrronium combination therapy (QVA149) versus glycopyrronium alone versus open-label tiotropium. The primary endpoint examined was superiority of QVA149 versus glycopyrronium in reducing the frequency of moderate to severe COPD exacerbations, with the comparison of QVA149 versus tiotropium as a major secondary endpoint. Inclusion criteria were post-bronchodilator forced expiratory volume in 1 s (FEV1) less than 50% and at least one exacerbation in the previous 12 months. This study showed a 12% reduction in the rate of moderate to severe exacerbations for QVA149 compared with glycopyrronium (rate ratio [RR] 0·88, 95% CI 0·77—0·99, p=0·038). The 10% reduction in moderate to severe exacerbations for QVA149 compared with tiotropium was not significant (RR 0·90, 95% CI 0·79—1·02, p=0·096). QVA149 also resulted in significantly higher trough FEV1 as compared to glycopyrronium (differences 70—80 mL, p<0·0001) and tiotropium (differences 60—80 mL, p<0·0001) and resulted in 8—9 unit improvements in St George’s Respiratory Questionnaire score (SGRQ) total score as opposed to 6 units with glycopyrronium and 5—6 units with tiotropium, both significant differences.

The real question is how these data should influence prescribing practices for COPD. These data support better lung function improvement, better symptom control, and greater exacerbation reduction with LAMA/LABA therapy as opposed to LAMA therapy alone in patients with severe to very severe disease. In reality, such patients are likely to be on some form of therapy before they progress to this level of disease severity. Hence for the patient already on LAMA therapy, the addition of a LABA, particularly if exacerbation reduction is a goal, as a next step in therapy is supported by these data.

These data must be interpreted in light of the fact that about 75% of patients were on concomitant inhaled corticosteroids, which has several implications. First, the magnitude of exacerbation reduction seen was 12%, which is arguably clinically significant but might have been attenuated owing to concomitant inhaled corticosteroid use. These results mirror the magnitude of reduction seen with tiotropium in the UPLIFT study,3 in which concomitant inhaled corticosteroid plus LABA therapy was allowed. Second, the high rates of concomitant inhaled corticosteroid use also mean that these data perhaps provide less support for the GOLD recommendation of LABA/LAMA as dual therapy for either groups C or D and perhaps provide greater support for triple therapy (addition of LABA to LAMA plus inhaled corticosteroids) for C and D patients.

In further thinking about how these data inform prescribing practices, one should also note that 22% of patients studied had two or more moderate or severe exacerbations in the previous year. Previous data suggest that group D patients who are judged to be at high risk by both FEV1 and exacerbation criteria are at even greater risk of moderate and severe exacerbations than are those meeting a single criterion, suggesting good efficacy in a relatively high risk population.6 On the other hand, another interesting finding of the study was that the greatest reduction was seen in mild exacerbations—15% with QVA149 compared with glycopyrronium and 16% compared with tiotropium—with mild exacerbations defined as an event with increase in symptoms but self-managed by the patient. Although exacerbation events requiring therapy are more frequently studied, the importance of untreated events should not be underestimated. Even events unreported to a health-care provider have been shown to be associated with significantly worse health status,7 which might explain the improvements in SGRQ score seen with QVA149 therapy.

Overall, these data support greater efficacy for dual bronchodilator therapy with QVA149 as compared with LAMA monotherapy. In view of the lack of data in the past, the use of combination LABA/LAMA therapy has not been embraced by medical practitioners for use in COPD, but these new data suggest dual therapy is an important therapeutic option when trying to maximise symptom improvement and exacerbation reduction.

Source: Lancet