Roflumilast for chronic obstructive pulmonary disease

Roflumilast for chronic obstructive pulmonary disease

Roflumilast for chronic obstructive pulmonary disease I disagree with Klaus F Rabe and colleagues (Aug 13, p 563)1 when they conclude that roflumilast f...

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Roflumilast for chronic obstructive pulmonary disease I disagree with Klaus F Rabe and colleagues (Aug 13, p 563)1 when they conclude that roflumilast for the treatment of chronic obstructive pulmonary disease “improved lung function and reduced exacerbations”. Lung function results are given as changes from baseline, with a 0·051 L mean improvement in forced expiratory volume in 1 s (FEV1, the primary endpoint) after 24 weeks of the higher dose of roflumilast. In the placebo group, an FEV1 decrease of 0·045 L was seen. But the reader has to go back to the baseline characteristics to note that the mean FEV1 before treatment was 1·57 L (SD 0·48) in the placebo group and 1·50 L (0·48) in the roflumilast group. Therefore, this 3·4% improvement in FEV1 for the patients treated with roflumilast leads to a mean absolute value for FEV1 at the end of the trial of 1·55 L in the roflumilast group and of 1·53 L in the placebo group, with an SD of 0·48. There is no significant difference when the comparison is done, as it has to be done, with absolute numbers.2 Rabe and colleagues state that the number of patients with exacerbations is significantly different between groups: 157 of 555 patients in the roflumilast group and 97 of 280 patients in the placebo group. But a classic 2 test gives a non-significant p value of 0·48, with a relative risk reduction of 0·076 (–0·143 to 0·252). Health-related quality of life, a coprimary variable, improved with placebo and roflumilast treatment, with no statistical difference. The mean number of moderate or severe exacerbations per patient was 0·30 (SD 0·64) in the placebo group and 0·28 (0·62) in the roflumilast group. In my view, the clinical benefit of this treatment remains doubtful. Evidencebased decisions are made on the basis of randomised controlled trials,3 but the conclusions of these trials have to be faithful to the observed results. www.thelancet.com Vol 366 November 26, 2005

I declare that I have no conflict of interest.

Jean-François Bergmann [email protected] Department of Internal Medicine A, University Paris 7 Denis Diderot, Hopital Lariboisiere, 2 rue Ambroise Paré, 75010 Paris, France 1

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Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005; 366: 563–71. Hugues EG. Randomized clinical trials: the meeting place of medical practice and clinical research. Semin Reprod Med 2003; 21: 55–64. Devereaux PJ, Yusuf S. The evolution of the randomized controlled trial and its role in evidence-based decision making. Intern Med 2003; 254: 105–13.

Klaus Rabe and colleagues1 show modest bronchodilation in chronic obstructive pulmonary disease (COPD) with the novel phosphodiesterase-4 inhibitor roflumilast. They extrapolate from this finding a claim that roflumilast is anti-inflammatory but do not provide any evidence to support this assertion. The hypothesis that inflammation is the cornerstone of the pathological process in COPD has gained substantial sway in recent years; however, much evidence does not support this contention. Indeed the idea that inflammation might be an epiphenomenon consequent on the true pathological process—airflow obstruction—is given credence by the failure of the archetypal anti-inflammatory agents, inhaled corticosteroids, to modify disease progression in large long-term studies.2 It has been argued that inflammation in COPD is the wrong (CD8) sort of inflammation. However, inflammatory cell infiltrate is correlated with the degree of airflow obstruction and not the presence or absence of the supposed precipitant of inflammation, cigarette smoking.3 Thus inflammation seems to follow obstruction, not vice versa. The idea that airflow obstruction, as measured by forced expiratory volume in 1 s (FEV1) or end expiratory lung volume, is the key variable in COPD is shown by its close relation to prognosis and morbidity. The results of large studies show that improvement in symptom scores, quality of life, and exacerbation

rates are independent of the pharmacological class of agent used. Thus tiotropium, long-acting  agonists and inhaled corticosteroids are all active in proportion to the degree of bronchodilation produced. In combination they are even more effective.4,5 The effects of roflumilast on these variables seen by Rabe and colleagues are entirely consistent with the degree of bronchodilation observed. It is misleading to invoke, particularly in the title, an anti-inflammatory activity which is both unnecessary and unproven.

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I have consulted for, participated in advisory board meetings with, and received lecturing fees from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and MSD. My institution is in receipt of a research grant from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, and Novartis.

Alyn H Morice [email protected] University of Hull, Division of Academic Medicine, Castle Hill Hospital, Cottingham HU16 5JQ, UK 1

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Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005; 366: 563–71. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320: 1297–303. O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8 T lymphocytes with FEV1. Am J Respir Crit Care Med 1997; 155: 852–57. Van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005; 26: 214–22. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361: 449–56.

We miss mortality data in Klaus Rabe and colleagues’ randomised trial of the phosphodiesterase inhibitor roflumilast in chronic obstructive pulmonary disease.1 This finding is particularly important because phosphodiesterase inhibitors have been consistently associated with higher mortality when studied in patients with heart failure.2 We declare that we have no conflict of interest.

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