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
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
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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