Treatment of COPD and the TOnado trial: a tempest in a teapot?

Abstract

@ERSpublicationsDespite encouraging results for LABA/LAMA combination therapy in mild COPD, can we justify the additional costs? http://ow.ly/JVNb6The treatment of COPD follows a stepwise approach in practically all clinical practice guidelines and also current strategy documents [1]. Lung function impairment or low forced expiratory volume in 1 s (FEV1), once considered the single most important treatment parameter, now represents one of the target parameters for risk reduction in patients with chronic obstructive pulmonary disease (COPD), alongside exacerbations and respiratory symptoms, dyspnoea in particular. Furthermore, more holistic COPD approaches increasingly recognise the importance of physical activity and multimorbidity for disease outcome, mortality in particular [2].Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β 2 -adrenoceptor agonists (LABAs) are the cornerstone of maintenance therapy for patients with moderate-to-severe COPD whose symptoms are not adequately controlled by short-acting bronchodilators alone [1,3]. The crucial role of these drugs has, in part, been helped by the fact that long-acting bronchodilators, and LAMAs in particular, have demonstrated efficacy in preventing COPD exacerbations, a good safety record and might even decrease mortality [4,5]. Also, the role of inhaled steroids for chronic treatment remains controversial and largely unresolved, despite recent efforts to identify a COPD phenotype that might benefit from this form of treatment [6].Since anticholinergic drugs and β 2 -adrenoceptor agonists differ in their pharmacology and their target receptors, but both act on the level of airway smooth muscle tone, combinations of these drug classes have been used and have been advocated for the treatment of COPD for decades. It comes therefore with little surprise that also the combination of LAMA and LABA is recommended for COPD patients not adequately controlled on a single bronchodilator drug alone [1] resulting in the development of an increasingly confusing variety of LAMA+LABA fixed-dose combinations (FDCs), and their respective generic clones [3].In the current issue of the European Respiratory Journal, a novel candidate of this drug combination principle is presented by BUHL et al. [7]. Two replicate phase III trials aimed to assess the efficacy and safety of inhaled tiotropium+olodaterol FDC 5/5 µg or 2.5/5 µg delivered via the Respimat Soft Mist inhaler compared with their individual mono-components in patients with moderate-to-very-severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage 2-4) over 52 weeks. The authors hypothesised that combination therapy with tiotropium+olodaterol FDC would provide improvements in lung function, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks) and other COPD disease parameters compared to monotherapy with either component alone, and with a comparable safety profile.

Olodaterol + tiotropium bromide for the treatment of chronic obstructive pulmonary disease

“…Only documentation that the addition of olodaterol improves significantly individual patient-reported outcomes would induce NICE to review its COPD guidelines. In any case, we fully agree with Rabe's opinion that what we really must know is whether this drug combination will affect (severe) exacerbations and hospitalizations, and ultimately death [59]. We are confident that the large DYNAGITO study will clarify this question.…”

“…However, TONADO 1 and 2 trials showed significant improvements in lung function but only some improvement of health-related quality of life with olodaterol/tiotropium FDC compared with the monocomponents over 1 year [37]. Rabe [59] correctly questioned the additional benefit of combination of two bronchodilators over the comparator tiotropium in more severe disease, which might have consequences for drug reimbursement not only for olodaterol/tiotropium FDC but also for the entire class of drug combinations in general in the future.…”

Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD

“…Within the context of the TOviTO program, TOnado-1 and TOnado-2 trials globally evaluated the effects of FDC of tiotropium (2.5 or 5 µg) and olodaterol (5 µg), delivered once-daily through the same Respimat device for 52 weeks, which were compared with the mono-components (tiotropium or olodaterol alone). 55 , 56 At both dosages, tiotropium/olodaterol enhanced trough FEV 1 and FEV 1 AUC 0–3 , producing significantly greater effects than each single drug. Moreover, the FDC of tiotropium 5 µg/olodaterol 5 µg improved St George’s Respiratory Questionnaire total score at 24 weeks more than either tiotropium or olodaterol.…”

Die Klassifikationen GOLD I–IV vs. GOLD A–D in der Alltagsversorgung

“…Dies dürfte für eine insgesamt eher höhere Exazerbationsrate verantwortlich sein. Die Gegenüberstellung von tatsächlicher Therapie (Anzahl und Arten der zum Einsatz gebrachten Medikationen) und der Schweregrad-Einteilung zeigt in ernüchternder Weise, dass ganz offensichtlich in niedrigen Schweregraden eine beträchtliche und nicht zuletzt im Hinblick auf die daraus folgenden Kosten kritisch zu betrachtende [19]…”