of clinical prediction rules to a decision tool while recognising the importance of other factors in clinical decision making, such as clinicians’ experience and parents’ preference. Perhaps as this ﬁeld moves forward to assessment of the eﬀect of the rules on physicians’ behaviour and clinical outcomes (impact analysis),6 clinicians and investigators might consider involving patients in the decision-making process.10 Then, when asking the question “should my head-injured child have a CT scan?”, parents can weigh the probability of a clinically important traumatic brain injury with the probability of harm from ionising radiation from the CT scan. *Patricia C Parkin, Jonathon L Maguire Division of Pediatric Medicine and the Pediatric Outcomes Research Team, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8 (PCP, JLM); Department of Pediatrics, Toronto, ON, Canada (PCP, JLM); Department of Health Policy, Management and Evaluation, University of Toronto Faculty of Medicine, Toronto, ON, Canada (PCP); Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, ON, Canada (PCP); and Keenan Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, ON, Canada (JLM) [email protected]
We declare that we have no conﬂicts of interest. 1
Kuppermann N, Holmes JF, Dayan PS, et al, for the Pediatric Emergency Care Applied Research Network (PECARN). Identiﬁcation of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet 2009; published online Sept 15. DOI:10.1016/S0140-6736(09)61558-0. Gill CJ, Sabin L, Schmid CH. Why clinicians are natural Bayesians. BMJ 2005; 330: 1080–03. McGinn TG, Guyatt GH, Wyer PC, et al. Users’ guides to the medical literature XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA 2000; 284: 79–84. Laupacis A, Sekar N, Stiell IG. Clinical prediction rules. A review and suggested modiﬁcations of methodological standards. JAMA 1997; 277: 488–94. Wasson JH, Sox HC, Neﬀ RK, Goldman L. Clinical prediction rules. Applications and methodological standards. N Engl J Med 1985; 313: 793–99. Reilly BM, Evans AT. Translating clinical research into clinical practice: impact of using prediction rules to make decisions. Ann Intern Med 2006; 144: 201–09. Stiell IG, Wells GA. Methodologic standards for the development of clinical decision rules in emergency medicine. Ann Emerg Med 1999; 33: 437–47. Maguire JL, Boutis K, Elizabeth M. Uleryk EM, Laupacis A, Parkin PC. Should a head-injured child receive a head CT scan? A systematic review of clinical prediction rules. Pediatrics 2009; 124: e145–54. Guyatt G, Cook D, Haynes B. Evidence based medicine has come a long way: the second decade will be as exciting as the ﬁrst. BMJ 2004; 329: 990–91. O’Connor AM, Legare F, Stacey D. Risk communication in practice: the contribution of decision aids. BMJ 2003; 327: 736–40.
UPLIFTing care for chronic obstructive pulmonary disease Large clinical trials can answer many important questions. The UPLIFT study, in which nearly 6000 patients with chronic obstructive pulmonary disease (COPD) were followed up for 4 years in a double-blind, randomised comparison of tiotropium and placebo, is a good illustration.1 In The Lancet today, Marc Decramer and colleagues2 report a prespeciﬁed subgroup analysis of the 2739 (46%) patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease, deﬁned for this study as a forced expiratory volume in 1 s (FEV1) after bronchodilator of between 50% and 70% of predicted. Perhaps unsurprisingly, in view of the sample size, the data reﬂect those of the parent study. Tiotropium produced a small but signiﬁcant reduction in the rate of decline of postbronchodilator FEV1. Although exacerbations in patients in this analysis were less frequent than they are in patients with more severe disease, treatment with tiotropium still reduced the rate of exacerbations, improved health status, and was associated with a lower all-cause mortality compared with placebo. However, www.thelancet.com Vol 374 October 3, 2009
because of the low incidence of death, this last diﬀerence did not reach statistical signiﬁcance. So why are these ﬁndings important? Until very recently, there have been few data about the beneﬁts of treatment in the earlier stages of COPD, because most trials recruit patients with an FEV1 of less than 50% of predicted.3–6 The UPLIFT data remedy this deﬁciency, and suggest that therapy is at least as eﬀective in patients with mild disease as it is in those with more severe illness. The increase in prebronchodilator and postbronchodilator FEV1 is larger than that seen in the later stages of COPD, and is suﬃciently large to be clinically signiﬁcant.7 Several factors could explain why tiotropium reduced the rate of decline of FEV1 in these patients. Lung-function decline is more rapid in GOLD stage II than later in the disease and so it is easier to detect an eﬀect of treatment. Analysis of the TORCH data has shown that all forms of therapy can reduce the decline in FEV1 relative to placebo and that there was little variation in eﬀect between the diﬀerent treatments.8 As rather fewer patients were using concomitant medication in this subpopulation, it should
Published Online August 28, 2009 DOI:10.1016/S01406736(09)61518-X See Articles page 1171
symptoms. The presence of symptoms, even in earliest stages of the disease, is associated with a more rapid decline in lung function.12 As the UPLIFT investigators comment, there are still substantial numbers of symptomatic patients in GOLD stage II without a clinical diagnosis. Their data should encourage those developing plans for the early identiﬁcation of COPD, which includes the UK Department of Health, that identifying such patients is indeed worthwhile and can provide the patient with better symptomatic control of their condition and improvements in their overall wellbeing. Science Photo Library
Lisa Davies,*Peter M A Calverley Aintree Chest Centre, University Hospital Aintree, Liverpool, UK (LD); and School of Clinical Sciences, University of Liverpool, Liverpool L9 7AL, UK (PMAC) [email protected]
be easier to show a treatment eﬀect. The change in health status suggests that important gains in wellbeing can be produced and maintained in the earlier stages of COPD, which might reﬂect an eﬀect on frequency of exacerbations as seems to be the case in more severely aﬀected patients.9 The latest UPLIFT report is not explicit about how smoking status was handled in the analyses. Because smoking status has not previously altered the eﬀects of treatment,10 it seems unlikely that it would do so for these data. Although more patients avoided concomitant medication, there were still a substantial number using inhaled corticosteroids, or longacting β agonists, or both, while around a third took some form of anticholinergic drug during the trial. A recent report of a similar group of patients in the TORCH study showed the clinical eﬀectiveness of the combination of a longacting β agonist and inhaled corticosteroid in terms of improvements in health status and decreases in rate of exacerbations, rate of decline of lung function, and even mortality.11 In view of the substantial number of patients who used these treatments in the UPLIFT report, the further improvements in function seen here represent an important further gain in terms of disease control. Thus we can have more conﬁdence that use of our existing drugs improves patients’ wellbeing, at least in those individuals who participate in large clinical trials. The patients here were symptomatic, as reﬂected by their impaired health status, and we should not extrapolate the data to patients with airﬂow obstruction without 1130
LD declares that she has no conﬂicts of interest. PMAC has served on advisory boards for AstraZeneca, GlaxoSmithKline, Nycomed, and Novartis; received research funding from GlaxoSmithKline, Nycomed, and Boehringer Ingelheim; and spoken at meetings supported by AstraZeneca, GlaxoSmithKline, and Nycomed. 1
Tashkin DP, Celli B, Senn S, et al, for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359: 1543–54. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, for the UPLIFT investigators. Eﬀect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespeciﬁed subgroup analysis of a randomised controlled trial. Lancet 2009; published online Aug 28. DOI:10.1016/S0140-6736(09)61298-8. Calverley P, Pauwels R, Vestbo J, et al, for the TRISTAN (TRial of Inhaled STeroids ANd long-acting β2 agonists) study group. Combined salmeterol and ﬂuticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361: 449–56. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003; 22: 912–19. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005; 143: 317–26. 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. Donohue JF. Minimal clinically important diﬀerences in COPD lung function. COPD 2005; 2: 111–24. Celli BR, Thomas NE, Anderson JA, et al. Eﬀect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008; 178: 332–38. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004; 23: 698–702. Calverley PM, Anderson JA, Celli B, et al, for the TORCH investigators. Salmeterol and ﬂuticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89. Jenkins CR, Jones PW, Calverley PM, et al. Eﬃcacy of salmeterol/ﬂuticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009; 10: 59. Bridevaux PO, Gerbase MW, Probst-Hensch NM, et al. Long-term decline in lung function, utilisation of care and quality of life in modiﬁed GOLD stage 1 COPD. Thorax 2008; 63: 768–74.
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