Correction to the FIELD study report by swl18050

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									                                                                                                                                  Correspondence




Correction to the FIELD                      coronary heart disease 1·27, 1·00–1·61;              1   The FIELD Study Investigators. Effects of long-   See Department of Error
                                                                                                      term fenofibrate therapy on cardiovascular        page 1420
                                             p=0·05; for cardiovascular disease
study report                                 2·06, 1·78–2·39; p<0·0001). Both the
                                                                                                      events in 9795 people with type 2 diabetes
                                                                                                      mellitus (the FIELD study): randomised
In undertaking further analyses of the       fixed and time-dependent adjusted                         controlled trial. Lancet 2005; 366: 1849–61.

FIELD study,1 we recently detected           analyses are complex to interpret;
that the reported effects of fenofibrate       they are confounded by the selection
adjusted for on-study use of other           of particular patients from each study               Asthma as a disease
lipid-lowering therapy are not time-         treatment group at different levels
dependent as was stated. The aim of the      of risk to be prescribed other lipid-
                                                                                                  concept                                                 The printed
analysis was to account for the higher       lowering therapy by their doctors—                   The suggestion in your Aug 26                           journal
rate of use of other lipid-lowering          according to higher levels of risk, more             Editorial (p 705)1 that the time has                    includes an
therapy (mostly statins) during the          adverse lipid profiles, and changes in                come to get rid of “asthma” as a




                                                                                                                                                                                        Science Photo Library
                                                                                                                                                          image merely
study in the placebo group (average          clinical course of disease.                          disease might be understandable, but
17%) than in the fenofibrate group               All other previously reported                     it does not take into account how                       for illustration
(average 8%). A programming mis-             analyses have been rechecked and                     diseases are defined and is therefore
specification meant that this secondary       found to be correct, and the main                    inappropriate.
analysis used drop-in to other lipid-        conclusions remain unchanged. The                      Implicit in your Editorial is that the
lowering therapy as a fixed, rather than      intention-to-treat estimates of the                  word asthma has been displaced by
as a time-dependent, covariate in the        effects of fenofibrate were an 11%                     the concept of asthma as a disease.
Cox regression model.                        (25 to –5; p=0·16) risk reduction for                This change can be viewed as the
   The net effect is that, for patients       coronary heart disease events and                    adoption of an essentialist rather than
who started lipid-lowering treatment         11% (20 to 1; p=0·035) risk reduction                a nominalist philosophy.2 The Editorial
during the trial without a prior on-         for cardiovascular disease events. The               correctly identifies the heterogeneity
study event, all their trial experience      corrected time-dependent analyses                    in patients with asthma, which
from the date of randomisation was           do not help in evaluating sensibly                   includes heterogeneity of cause,
grouped separately in the analysis for       the extent to which the higher rate of               airway hyper-responsiveness, airway
the comparisons of fenofibrate versus         drop-in to other lipid-lowering therapy              inflammation, and relations between
placebo (fixed covariate model). In           in the placebo group has led to an                   the physiological and inflammatory
this sense, subsequent lipid-lowering        underestimation in the primary results               components. Nominalists recognise
therapy was modelled like a baseline         of the real effects of fenofibrate. By                 that asthma has no existence apart
covariate. By contrast, the time-            contrast with these Cox’s regression                 from the patients who have it, and
dependent model groups only the              analyses, our previous analysis1 of the              that the causal implications of a
patients’ experience after drop-in           effect of drop-ins, which assumed                     diagnosis of asthma are widely varied.
separately in the analysis.                  that statin therapy reduced the risk                   The Editorial does not discuss
   The time-dependent adjusted results       of subsequent events by a third,                     the need, in defining a disease,
for fenofibrate should have been              estimated crudely that the intention-                for a primary definition based on
reported as a 9% risk reduction (95%         to-treat results might have masked a                 symptoms, abnormality of function
CI 23 to –8; p=0·27) for coronary heart      real underlying effect of fenofibrate of               or pathology, or cause. For half a
disease events and 4% (14 to –7; p=0·45)     around 17–20%.                                       century, J G Scadding was a lone voice
for total cardiovascular events. These          Further analyses will be necessary                arguing that we should abandon
adjusted results are counterintuitive,       to explore the confounding effects of                 essentialism and define asthma
being less than the intention-to-treat       differential drop-in to lipid-lowering                mainly as an abnormality of function,
estimates, and reflect the over-riding        therapy in this trial.                               as “a disease characterized by wide
selection effects of being prescribed         All authors have had the costs of participating in   variations over short periods of time
statin therapy. Patients at higher           scientific meetings or contributing to advisory       in resistance to flow in intrapulmonary
                                             boards reimbursed by, or received research grants
baseline risk of cardiovascular disease                                                           airways”.3 This is no different from
                                             from, the pharmaceutical industry.
were selected by treating physicians                                                              how chronic obstructive pulmonary
to receive non-randomised lipid-             *Anthony Keech, John Simes,                          disease4 or some other disorders—eg,
lowering therapy over the course of the      Philip Barter, James Best, Russell Scott,            hypertension or diabetes are primarily
study. Further, despite this additional      Marja-Riitta Taskinen, on behalf of the              defined.
treatment, these patients experienced        FIELD Management Committee                             These definitions do not exclude the
higher cardiovascular event rates than       tony@ctc.usyd.edu.au                                 fact that there will be different causes
patients who did not receive additional      NHMRC Clinical Trials Centre, Mallett St Campus,     which have different inflammatory                      e-mail submissions to
                                             University of Sydney, New South Wales 2006,
lipid-lowering therapy (relative risk for    Australia
                                                                                                  and other physiological effects                       correspondence@lancet.com



www.thelancet.com Vol 368 October 21, 2006                                                                                                                                       1415
                               Correspondence




                                                        and which need to be identified to                        of as many different diseases as any                       any aristolochic acid. We have several
                                                        optimise treatment.5 Hence, the term                     word in medicine.”3 In his translation                    other concerns.
                                                        asthma remains useful, provided we                       of the fourth edition of the book,                           First, long dan xie gan wan is used
                                                        have an understanding of how we use                      Forbes, in a footnote, insightfully                       in Chinese medicine to “drain liver-
                                                        the word. It needs to be maintained,                     went on, “As in every other case, a                       gallbladder replete heat”.3 It is
                                                        but physicians and researchers need                      more correct pathology in this disease                    extremely unusual and doubtful that
                                                        to appreciate that it describes an                       will put us in the way of a more                          a healthy person would have taken it
                                                        abnormality of function and not a                        rational practice. Instead of wasting                     for 5 successive years “to enhance the
                                                        specific phenotype defined as a set                        our efforts in attempting to ward                          liver”.
                                                        of observable characteristics of an                      off paroxysms of a purely spasmodic                           Second, interstitial fibrosis is a
                                                        individual or group.                                     nature, by measures directed to the                       non-specific morphological change
                                                        We declare that we have no conflict of interest.          nervous system, our attention will                        in the kidney. It can be associated
                                                                                                                 be directed to the removal of the                         with the use of various analgesics,
                                                        *F E Hargreave, R Leigh,                                 real disease, the structural alteration                   antimicrobial agents, non-steroidal
                                                        K Parameswaran
                                                                                                                 and preternatural sensibility of the                      anti-inflammatory drugs, and diuretics4
                                                        hargreav@mcmaster.ca
                                                                                                                 bronchial membrane.”4                                     as well as with ingestion of aristolochic
                                                        McMaster University, St Joseph’s Healthcare
                                                        Hamilton, Hamilton, Ontario L8N 4A6, Canada
                                                                                                                   Airway inflammation, remodelling,                        acid.
                                                        (FEH, KP); and University of Calgary, Calgary,           and hyper-responsiveness are not                             Third, some references Laing
                                                        Alberta, Canada (RL)                                     recent concepts in asthma.                                and colleagues cite, such as the
                                                        1    The Lancet. A plea to abandon asthma as a           I declare that I have no conflict of interest.             one from a newspaper, are based
                                                             disease concept. Lancet 2006; 368: 705.
                                                                                                                                                                           on supposition. Finally, the title
                                                        2    Scadding JG. Essentialism and nominalism in         Peter Warren                                              “Chinese herbal uropathy and
                                                             medicine: logic of diagnosis in disease
                                                                                                                 warrencp@ms.umanitoba.ca
                                                             terminology. Lancet 1996; 348: 594–96.                                                                        nephropathy” is unscientific and
                                                        3    Scadding JG. Definition and clinical categories      History of Medicine/Respiratory Centre, University
                                                             of asthma. In: Clark TJH, Godfrey S, eds. Asthma.
                                                                                                                                                                           unfair: the nephropathy associated
                                                                                                                 of Manitoba, 810 Sherbrook St, Winnipeg R3A 1R8,
                                                             London, Chapman and Hall, 1983: 1–11.               Canada                                                    with aristolochic acid should no
                                                        4    Global Initiative for Chronic Obstructive Lung      1    The Lancet. A plea to abandon asthma as a            longer be related to Chinese herbal
                                                             Disease (GOLD), WHO, National Heart, Lung
                                                             and Blood Institute (NHLBI). Global strategy
                                                                                                                      disease concept. Lancet 2006; 368: 705.              medicines because they are no longer
                                                             for the diagnosis, management, and                  2    Laennec RTH. De l’auscultation médiate; ou,          permitted to contain it.2,5
                                                             prevention of chronic obstructive pulmonary              Traité du diagnostic des maladies des
                                                             disease. Bethesda: Global Initiative for Chronic         poumons et du coeur, fondé principalement            We declare that we have no conflict of interest.
                                                             Obstructive Lung Disease, World Health                   sur ce nouveau moyen d’exploration. Paris:
                                                             Organization, National Heart, Lung and Blood             Chez J-A Brosson et J-S Chande, 1819.                *Alicia Grant, Bo-Ying Ma,
                                                             Institute, 2005. http://www.guideline.gov/          3    Forbes J. A treatise on the diseases of the chest.   Han Yuan Chen
                                                             summary/summary.aspx?ss=15&doc_                          London: T and C Underwood, 1821: 75.
                                                                                                                 4    Forbes J. A treatise on the diseases of the chest,
                                                                                                                                                                           collegexpct@btconnect.com
                                                             id=8128&nbr=4530 (accessed Oct 2, 2006).
                                                        5    Hargreave FE, Parameswaran K. Asthma, COPD               4th edn. London: T and C Underwood, 1834: 90.        21 Upeer Mulgrave Road, Cheam SM2 7AY, UK
                                                             and bronchitis are just components of airway
                                                                                                                                                                           1      Laing C, Hamour S, Sheaff M, Miller R,
                                                             disease. Eur Respir J 2006; 2: 264–67.
                                                                                                                                                                                  Woolfson R. Chinese herbal uropathy and
                                                                                                                                                                                  nephropathy. Lancet 2006; 368: 338.
                                                        May I comment from the past on                           “Chinese herbal                                           2      Cosyns JP. Aristolochic acid and ‘Chinese herbs
                                                                                                                                                                                  nephropathy’: a review of the evidence to date.
                           The printed                  your timely Editorial on asthma,1
                                                        which asks “Is it not time to step out
                                                                                                                 uropathy and                                                     Drug Saf 2003; 26: 33–48.
                                                                                                                                                                           3      Flaw B. 160 essential Chinese herbal patent
                           journal                      of the [straitjacket] of a seemingly                     nephropathy”?                                                    medicines, 1st edn. Boulder, CO: Blue Poppy
                                                                                                                                                                                  Press, 1999: 53.
                           includes an                  unifying name for asthma that has                                                                                  4      Davison AM, Cameron JS, Grünfeld J-P, Kerr DNS,
                                                        outlived its usefulness?”                                In their Case Report (July 22, p 338),
Science Photo Library




                           image merely                                                                                                                                           Ritz E, Winearls CG, eds. Oxford textbook of
                                                          Laennec, in his grave in Doauarnez,                    Chris Laing and colleagues1 relate                               clinical nephrology, 2nd edn. Oxford: Oxford
                           for illustration                                                                                                                                       Medical Publications, 1998: 1638.
                                                        would be pleased, for he wrote in                        the development of cancer and                             5      Chen HY, Ma B-Y, Grant A. Time to abandon
                                                        his seminal book: “Le mot asthme                         renal failure to having taken long                               the term “Chinese herbs nephropathy”.
                                                                                                                                                                                  Kidney Int 2001; 60: 2039–40.
                                                        signifie proprement difficulté de                           dan xie gan wan without showing
                                                        respirer. Il y a peu de termes dont on                   that the patient had aristolochic-
                                                        ait plus abusé en médecine et par                        acid-related DNA adducts in the                           We read with concern the Case Report
                                                        lesquels on ait désigné autant de                        tissues.2 Aristolochic acid containing                    by Chris Laing and colleagues (July 22,
                                                        maladies différentes.”2 John Forbes                       herbs was banned worldwide as an                          p 338).1 Such cases are appalling and
                                                        translated it thus: “Asthma. The word,                   ingredient in Chinese medicines in                        only emphasise the urgent need for
                                                        which properly signifies difficulty of                      2001. The case report did not present                     regulation of Chinese herbal medicine.
                              For further information
                         on the work of the RCHM, see   breathing, has been as much misused,                     any evidence that the long dan xie gan                      The Register of Chinese Herbal
                                http://www.rchm.co.uk   and has been made the cognomen                           wan taken by the patient contained                        Medicine (RCHM) was set up nearly


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