Comment

Chronic obstructive pulmonary disease (COPD) is a large and growing burden on society. Since 1990, the mortality rate from COPD has increased by 58% in the USA, making COPD the second leading cause of mortality in the country.1 Superficially, these alarming data seem paradoxical in the face of falling smoking prevalence in high-income countries and the substantial progress in the pharmacological management of COPD. Whereas 20 years ago the most common drugs for COPD were short-acting bronchodilators, most patients are now treated with three different drugs as maintenance therapy at an annual cost of more than US$32 billion worldwide. In 2012, the bestselling prescription drug in the world was an inhaler for COPD, with annual sales of $9 billion.2 Despite these investments by patients and society, rates of hospital admissions and mortality from COPD keep increasing. Although many reasonable theories have been advanced to account for this paradox, the most obvious yet overlooked explanation is that despite their enormous costs, existing treatment might not be very effective at reducing the morbidity and mortality from COPD. The present mainstays of COPD treatment are longacting muscarinic antagonists (LAMAs). Although they do not reduce the total mortality of COPD, they are believed to be quite effective at mitigating the risk of exacerbation, which is the main cause of hospital admission. However, results from the longest trial to date (4 years)3 suggest that LAMAs reduce exacerbations by 14%, rather than by 20–30% as was suggested by the results of shorter (6–12 month) trials.4 Long-acting β2 agonists (LABAs) are even less effective at reducing exacerbations than LAMAs.5 In clinical practice the most widely prescribed (and the most expensive) drugs for COPD are combination inhalers that contain an inhaled corticosteroid and a LABA. However, despite their expense and the claims made for their effectiveness, these combinations are no more effective at preventing exacerbations than a less costly inhaler containing only a LAMA.6 Furthermore, the small salutary effect on exacerbation frequency from combinations of inhaled corticosteroids and LABAs is countered by the increased risk of pneumonia, particularly related to the use of fluticasone.7 The benefits of these inhalers are further attenuated in real-world settings because of

poor adherence and the substantial technical challenges associated with the proper use of the inhalers. Indeed, investigators of one study,8 which assessed the performance of meter-dosed inhalers and dry powder inhalers, showed that 591 (81%) of 734 patients with COPD made technical errors during inhaler use and 100 (14%) patients made such egregious errors (eg, not removing the cap or not loading the drugs into the inhaler device) that they did not receive any benefit.8 Sadly, despite billions of dollars being spent on inhalers every year, only one in three patients who are seen at respiratory clinics receives inhaler training. Importantly, in one study,9 inhaler training led to significantly improved health outcomes (eg, 0·1 vs 0·4 hospitalisation admissions per patient-year; p=0·003). Against this background, in The Lancet Respiratory Medicine, Marc Decramer and colleagues10 report the findings from two large 6-month studies that assessed the efficacy of combining a LABA (vilanterol) and a LAMA (umeclidinium) in one inhaler compared with the approved LAMA monotherapy tiotropium. The combination was assessed at two different doses of umeclidinium (125 and 62·5 μg), and was also compared with its monotherapy components. Across both studies, the LABA–LAMA combination produced greater bronchodilation than tiotropium alone, as measured by trough forced expiratory volume in 1 s (FEV1), which was increased by 60–90 mL across studies and dose groups. The investigators also showed the superiority of combined umeclidinium plus vilanterol over vilanterol monotherapy; although they did not show a significant difference from umeclidinium monotherapy for this endpoint, they suggest that, when their results for other endpoints are taken together with other findings, the combination seems to be better than both monotherapy components. The strengths of these studies are the large sample sizes, the robust design, and the careful follow-up and assessment of outcomes, and the investigators are correct to conclude that the combination of umeclidinium and vilanterol can be used to improve lung function in patients with moderate to severe COPD. But are these findings clinically relevant? The traditional approach suggests that they are, with FEV1 used as a biomarker for drug approval by regulatory

www.thelancet.com/respiratory Published online May 15, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70043-8

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Wanted: new treatments for COPD

Lancet Respir Med 2014 Published Online May 15, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70043-8 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(14)70065-7

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agencies. However, in these two studies,10 the fairly small increase in FEV1 for umeclidinium plus vilanterol compared with tiotropium did not translate into any meaningful differences in patient-based outcomes, with no significant effect seen on symptoms or health status compared with tiotropium. Similarly, the combination drug had no effect on time to first exacerbation compared with tiotropium. Surprisingly, there were more withdrawals because of adverse effects and serious adverse events in the group that received umeclidinium plus vilanterol than in the group that received tiotropium. Over the past 20 years, drug developments in COPD have been dominated by bronchodilators because smooth-muscle relaxation is an easy therapeutic target and because the threshold for drug approval by regulatory agencies, including the US Food and Drug Administration, is low, with their endorsement contingent on two or more 3–6 month clinical trials that clearly show improvements in FEV1. The data produced by Decramer and colleagues10 and by Wedzicha and colleagues11 suggest that despite significant improvements in FEV1, the addition of a LABA to a LAMA provides marginal (if any) clinical benefits beyond that achieved with a LAMA monotherapy. This year more than 7 million people around the world will die from COPD and more than 700 million days will be spent in hospital by patients with COPD in the USA alone.1 Regrettably, we might have reached the limits of clinical benefit from bronchodilation. There is a pressing need to move beyond me-too bronchodilators and to find truly novel drug targets that will modify disease progression and mitigate rates of exacerbation and hospital admission to combat the growing global burden of COPD. To this end, Decramer and colleagues’ studies10 have reminded us that FEV1 is a fallible biomarker in COPD and might not always be a

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suitable surrogate for patient-based health outcomes; biomarkers that accurately reflect disease activity are thus urgently needed. Don D Sin James Hogg Research Centre, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada; and Division of Respiratory Medicine, Department of Medicine, St Paul’s Hospital, Vancouver, BC, Canada [email protected] The author is a Canada Research Chair in chronic obstructive pulmonary disease and has served on advisory boards of Almirall, AstraZeneca, Takeda, and Novartis. He has received research funding from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim. 1 2

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US Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA 2013; 310: 591–608. IMS Health. Top 20 global products 2012. http://www.imshealth.com/ deployedfiles/ims/Global/Content/Corporate/Press%20Room/TopLine%20Market%20Data%20&%20Trends/Top_20_Global_ Products_2012_2.pdf (accessed March 17, 2014). Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Eng J Med 2008; 359: 1543–54. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003; 290: 2301–12. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364: 1093–103. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, for the INSPIRE investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008; 177: 19–26. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax 2013; 68: 1029–36. Tommelein E, Mehuys E, Van Hees T, et al. Effectiveness of PHARMAceutical care for patients with COPD (PHARMACOP): a randomized controlled trial. Br J Clin Pharmacol 2013; published online Oct 9. DOI:10.1111/bcp.12242. Melani AS, Bonavia M, Cilenti V, et al, for the Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011; 105: 930–38. Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014; published online May 15. http:// dx.doi.org/10.1016/S2213-2600(14)70065-7. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013; 1: 199–209.

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Wanted: new treatments for COPD.

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