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Université d'Ottawa University of Ottawa
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ControUd Trirl of Oril Glucoeortiroi& in Outpatients witb Acute COPD warbatioa
Who P m n t to the Ewrgency Departnient
A Ruidombcd, DoubbBUnd, PiacebControUed Püot Study
O Shan Ozvid AARON M.D.F.R.C.P
Thesis submitted to the School of Graduate Studies and Research
in partial fiMment of the rquirernents for the MSc degree in Epiderniology
Thesis supavisors:
Drs. Paul H M and Robert Dales
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1 would iike to express my gratitude to my W s supeniisors, Dn. Paul H e k t and Robert
Dales for th& induable inst~ction, guidance lad m e n i e n t throughout al1 phases of the
ddopment of the piiot study and the thesis. Thiinlo is dso due to Dr. George Wells who
provideci vaiuaôle advice concerthg a d y design and swistical anaiysis, and to Dr. Ian Stiel who
advisai me on how to seaire bding for the shidy.
M. Mary Lunau assisted me with the Emergency Department chart review and Ms.
Luenne Caicutt helped with logistical organization ofthe pilot shidy.
The mperation of the entire Ernergency Department madical staff of The Ottawa General
and Civic Hospitals was indispensable and was gnatly appreciated.
Finally, 1 am gratefùl to my mfe Karen for ali of the patience, good humour, and
encouragement which she has exhibiteci throughout the years of my postgraduate studies.
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Ba&punh. In North Amerka, the p r d a i a of cbronic obstructive puimomy di- (COPD)
arnongst dddy patients is inCfClCSjIlg, and COPD uwda!ion is now a cornmon cause for
Emergency Department (ED) patient visits. ûva 900 patient visits were log@ at the ûttawa
Geaaa and CMC Hospital's Enmgclicy Depertmmts in 19% because of COPD exacerbation. F i -
two percent ofthese ED patient visits for COPD nsulted in a discharge home.
Although exacerbations of COPD occur commonly, the optimal therapy of this condition
ranamS udmown. Inhaled bro- ad d o t i c s have been proven to be effecive, however
the use of sysieniic gluaxdcoids for trcatmmt of COPD d t i o n ranaOu controvcfsial sincc
then is a lack of controIIed uials demonstrating theù efficacy . A review of 19% ED records suggests that 49% of COPD patients are being discharged fiom the ED with a p d p t i o n for orai
prednisone. Given this wide pmctiœ vuiation, it was felt that a state of clinical equipoise atists
which justifies the need for a randomized, double-blind, placebo-controlled trial exarnining whether
oral glucocorticoids should be used to treat patients with COPD cx~~cerbation who are dischargcd
home âom the ED. This theas wül report on the results of the pilot study which wss undertaken to
estabiish the feasibility of a larger, def'uiitive clinical trial.
Objectives: The primss, objective of the pilot study was to ensure that a larger cünical triai will bc
faible. Secondary objectives of the pilot study were: to assess the rate of patient relapse h order
to detennine whether this clinical variable coukl m e as the primary outcorne variable for the
definitive study, to ver@ the sample size cstimates for the îarger trial, to cvaluate patient r e f d rates
and trial reauitrnent, and to ver@ the enroîiment process and alow for pretesting of the data
collection and data -sis process.
Design: Randomioed, double-bünd, placebo-contrdled pilot trial. Patients who pnsented to the
Emergency Departments at The ûttawa General or Ottawa Civic Hospital with acute COPD
emœdwion wae randomized to trutmait with a 10 âay cuurse of prednisone or placebo prior to
hein$ disdiiuged home hm the ED. M patients rcccivcd 8 10 day course of oral uitibiotics and 30
days of inhalai bronchodilators.
éhkoms: The primary outcorne mkbIe was the percent irnprovement in for& expiratory volume
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in oae secad (PEV,) ova tbe 10 &y mament paiod. Seoonbiy outcoaier included i m p m v ~ t s
in oxygamtion, improvana&~ in aibjective dyspma roorsr (d by The b d i m uxi
Tnnsitiod Dycpnca Indsxes), Ùnprovements in diraraspecific quility of life (usesred by the
CiiniicRespiraory DUeueIadar~onnaire),~iaasa10d30&pdadv~rs~eneot
ntes. Al1 ordcoaies wae d 10 dtys a i k domization, wi t i ~ the exception of patient nlapse
which wrc d at 10 ad 30 days ifta mdomivltion.
b u h k Atotal of67 rsfards to the study wim r d v d over the four rnonth piiot paiod, of these
twenty eligiie patients wae domized into the shidy. Nineteen patients suca~&Ny wmpleted
the study, &en in the placebo group anâ ught io the prednjsone group. Racniitment ntes were
appfoxbatdy Wh of that antiupated. Bucd on the d t s of the pilot data, s dculation of the
sample sk needed for the definitive dinid trial aiggested that 3-y rdapsc d d be used as the
primary outcorne variable if212 patients w a e to be awoild in the deMtive study.
Patients tnated with ptednisone in the pilot mdy improved their FEV, by a mean of 40.3 * 44.4% over the 10 âay rwssment pexiod comparai to a mean improvement of 13.9 23.8% in the
placebo-tnated patients v . 1 4 ) . The mean percent oxygen satwation in the ptednisone group
Uiaeassd by 1.6* 1.W in the pfednkmgroup cmpad to aO.18 î 2.8% increese in mean oxygen
saturation in the placebo group (~4.38). Patients reported simiiar Day 1 dyspnea scores on the
B d e Dyspnea Index, bowever by Day 10 the 'fûnctionai impainnent' and 'magnitude of effort'
components of the Transitional Dyspnea Index trended towrrds greater improvernents for the
prednisonatnated patients than for placebo-trcated prtients @ = 0.08 and p= 0.06 respectively).
OVaPU, the total Transitional Dyspnea Inda mean score was 2.44 points higher in the prednisone-
treated group, reflecfing a greater improvement in subjective seKreported dyspnei from Day 1 to
Day 10 in those treated with prednisone, however this improvement was not statisticaüy sisnifiant
(95% CI, - 1.36 to 6.24, fl. 19). Both treatment grcn~ps showed net uiiprovemetlt in disase-specific quality of We as Iissessed
by hpmvements in nie Chronic Reqirat~ry Di- Index Questionnaire scores measwed on Day
i and Day 10 of the triai. The pfddnisone-treatad group consistdy soored greater 10 &y improvemcnts t h the pllrrhrtreatcd groups across aü four domiiiis of tbe quaJity of üfe inâm however none of the differences between the two goups rmched statistidy signifiant levels.
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Patientrrlspsedatagratantetliuiapscted. Rdrpse0~~~ntdbyDaylOin45%
of pkdmmaW pitienfs ud 12% of prednisonetreated patiats @=O. 181, ud by Day 30 in 45%
of pLcebo ad 25% of pradniso~lbtrieated paîicnts (p10.63). ICaplaa-Muer airvivil curver did not
p 4.29). A logistic tegrdon mDdd ushg rislc of 30 day relapse as the outoome variable waa
corrihucted in ordato cittaiip to d i hr the infhrencc of suspecteci ciinidy significant covariates
on the treaûnent &'kt. The adjusted oâds ratio for the treaûmnt effèct was found to be 0.15,
h o w m this rpparais proteetivie &kt of steroid treaûnent was not statistidy si@cant ( 95% CI
of the odds ratio, 0.002- 13.70). The o v e d fiequency of sdf-reporteci dverse events was Smüar
in the two treatment groups.
Co~~~lrrsioonc In summary, the pilot study was complded successfiily and dernoll~tlllfed that a
larger, d e W k triel U f d e . Reiqse ~dapseed at a gr- nte than was acpeaed in the plardvr
group, and it was shown that the rate of 30aay relapse could be used as the primary outcome
variable for the definitive clinid triai. The pilot study involved a relatively s d number of patients,
and thedore did not have &tristical power to Shaw any ciiffixeme in results between the two groups.
Nevertheiess, the pilot data suggests a trend towards improved expiratory airflow, dyspnea scores,
dkw-speciûc quality of Wk, and relapse rates in the prednisonetreated patients compand to those
patienîs on placebo. Naturally, this trend could d y be r e v d in a larger study, and therefon a
larger trial wiü k needed in order to definitively establish whether prednisone is superior to placebo
for outpatient therapy of COPD exacerbation.
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TABLE OF CONTENTS
Item Pa@
List of Tables .............................................................................................. Mü List of Figures ............................................................................................. x 1 . Introduction ..................................................................................... 1 2 . Background ...................................................................................
2.1 Definition of COPD ....................... ................................ 2.2 Epidemiology of COPD .................................................... 2.3 Natural History of COPD .................................................. 2.4 Etiology of COPD Exacerbations ....................................... 2.5 Aimay Inflammation in COPD ........................................... 2.6 Treatment of COPD Exacerbation ...................................... 2.7 Rationale for Use of G i u ~ ~ ~ ~ r t i c o i d s for COPD ................. 2.8 Potential Adverse Effects of Glucocorticoids in
Patients with COPD ........................................................... 2.8 1 Short-term Adverse Effects ................................... 2.82 Long-tenn Adverse Effècts ..................................
2.9 Glucocortioids for COPD Exacerbation-
Evidence f?om the Literatwe ............................................... 10 2.9 1 Giucocorticoids for Hospitaiized Patients ............... 11 2.92 Glucocorticoids for Ambulatory Patients ................. 12
2.10 Glucocorticoids for COPD Exocerbotion-
Clinid Guiddines .............................................................. 16 2.11Summary ............................................................................. 16
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2.12 Rcsuits of the Emergency Department COPD Chrrt R e v i e ~ . 2.13 Codusiom Derived âom the Chrt Review .........................
................................................................................................ Objectives ............................................................................. Expaimtntal Mctbods
4.1 Saidy Design .......................................................................... 4.2 Patient Sdection .....................................................................
. 4.2 1 Inclusion Cnteria .......................................................
...................................................... 4.22 Exclusion Criteria 4.3 Treatment Protocols ................................................................
4.3 1 Expaimentai Manoeuvre ............................................ ................... 4.32 Otha Swdy Manoa~n~ .... ................
4.33 Protocol for Dealing with Patients who Refapsed ........ ........................................................... 4.4 Memues of Cornpliana 27
................................................................. 4.5 Baseiine Assessrnent 27 ................................................................... 4.6 Outcorne Measures 27
4.6 1 Primary Outcorne Measure ............................. ... ...... 27 .................................................. 4.62 Secondary Outcornes 28
............................................. 4.7 Randornimion and StmiScation 31 ................................................................................... 4.8 Blinding 31
..................................................... 4.9 Sample Size Considerations 31 4.10 Sample Size Cddations ....................................................... 33 4.11 FinJ Analysis ...................................................................... 36
4.1 1.1 P ~ c i p a î Analysis of the Primary Outcorne Variable . 36 ......... 4.1 1.2 Analysis of the Seconrlary Outcorne Variables 38
4.1 2 Ethical Considerations ........................................................... 39 5 . Results ...................................................................................................... 40
5.1 Trial Profle ............................................ 40 5.2 P a t i a Characteristics .............................................................. 40
....................................... 5.3 Improvements in Airflow Obstruction 40
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5.4 Improv~en& Oxygen Saturation .................................. 5.5 ANCOVA Mjustment for the Effcct of Stable FEV,
................................................ on Percent Change in FEV. 5.6 The Basciine and Transitionai Dyspnea Indexes .................. 5.7 The Cbronic Respiratory Index Questionnaire ............... ..... . 5.8 Relapse .............................................................................. 5.9 Logistic Regression Modei of 30 Day Relapse ..................... 5.10 Profile of Adverse EBects ..................................................
6 . Discussioa ............................................................................................ 6.1 Summrry ad Interpretation of the Results of
..................................................................... the Pilot Study ................... 6.2 Dctermination of the Primary Outcorne Variaôle
6.3 Verifidon of the Sample Size Estirnates for the
Largei Trial ......................................................................... 6.4 Nad for an Interim Analysis and OrganiZation of a
.................................................. Data Monitoring Committee
....................................... 6.5 Randornizstion and Data Collection 6.6 Ciasdication of Patients ........................................................ 6.7 Referral and Recniitment Rates .............................................
6.71 Pilot Sady R e f d Rates ........................................ 6.72 Measures to Improve Study R d t m e n t .................
7 Conclusion ............................................................................................. Appendices:
Appendix 1 . Patient C o m t ancl Infodon Form ......................................... Appendix II Doctor and Patient Information Letters ........................................
Appendix II . The Study Data Collection Fonn ............... .... ....................... Appendix Iü . The Badine and Transitionai Dyspwr Indexes ........................... Appendor IV . The Chronic Respiratory Discase Questio&e ................ .. ....
........................................................................................................... Re fer ences
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List of Tables
Table P4e
1 . Glucocorticoids for COPD Exacdation Sunimery of Pubiished and Unpubüshed RandomW, ControUeû,
.............................................................................................. CMd Trials
2 . of COPD Admission and Relapse Rates ....................................
3 . Emergency Department Therapy for Patients Discharged FoUowing Acute COPD Exacerbation ..........................................................
4 . Summary of the Data CoUection Schedule ................................................
5 . Simulateci ANCOVA and Power Analysis of Treament Effect ...................... .. .................................................................
6 . BaseLine Characteristics of AU Patients Randornid to the Pilot Saidy .....................................................................................................
7 . Basehe Dyspnea Index Scores @ay 1) ......................................................
8 . Transitionai Dyspnea Index Scores (Day 10) ............................................
9 . Baseline CRQ Scores (Day 1) ......................................................................
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................................................... 10 . Changes in CRQ Scores @ay 10 . Day 1)
1 1 . Ten and Thirty-Day Relapse Proportions in the Two ....................................................................................... TrCILtment Groups
12 . Unhdate Logistic Regmuion Mdels For 30 ................................................................................................ Day Relapse
.......................................................................... 14 . The Main Effects Model
15 . Summary: Impact of the Pilot Study on the Larger
Definitive Chical Triai ..................................................................................
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List of Figures
1. Tbirty Day Relapse Rates Vs. Treatment Received
Ottawa General Hospital 19%. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - . . . . . . . . . . .
2. Trial Profile ..............................................................................................
3. Absolute Change in FEV, From Day 1 to Day 10
Placebo and Prednisone-Treateâ Groups ... .. . . .. . . . .. . . . ... . . . . . . . . . . . . . . .. -. . . .. . . . . . -. -. . . . .
4. Percent Change in FEV, From Day 1 to Day 10
Placebo and Prednisoae-Treated Groups. .......... ..... .. .. ... ... ... . . ..... .... ...... . .. . . . .. ..
5. Distribution of m g e n Saturation Responses for
the Preûnisone and Placebtreated Groups ....................................................
6. Kaplan-Meier Sumival C w e Showing the Probability
of Ranainllig Relapse-Free for Patients Receiving Prednisone
and Those Receiving Placebo ................................................................ ... ..... .
7. Graphitai Representation of Power as a Function of
Sample Size for the Definitive Triai.. . ... ........ . -. . -. . . . -. . . . .. . . . ........ .. .. .. . .. .. . . ..-. . . . . -. . . . . .. . .
8. Power to Detect Absolute Diffaences
Total Sample of 2 12.. .. . . . . . . . . . . . . . . . . . . .. . . ................ .. . . . . . . . . . . . -. -. . . -. . .. . . . . . .+ - . . . . . . . . . . . . .. .
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1.0 Introduction
and public heaith pmblem which results in hudreds of Emergency patient visits to
Ottawa-arca hospitais each year. The optirml tbenpy for acute COPD acacerbation ranaiao
unknown. Onl g l m m k d s a hquedy, but Uieoasistaidy, prescribed for COPD m o n ,
despite a lack of aimnt available evidence demonstrciting their efliicacy, and despite practicc
guidelines wtiich do not support the routine use of glucoc~rticoids for managing outpatient COPD
aacdmtiotl 42 . As a rcsuit, tbere is thedore a nacl to objedively determine whether outpatients with COPD apesbition b e d t h m tnshncat widi a course of oral ghcocortimidd fouowhg that
acute pmtation.
In orda to best answer tbis important clinid question a three-stciged plan ofresearch was
developed. nie p h of research bcgan with a litentwe ud chart review to document the adent of
the clinicai problem, and was foilowed by a pilot study which 1 designcd in wllaboration with
coiîeagues h m Tbe Division of Respiratocy Medicine. The pilot sîudy consisted of a randornized,
double-blind, pk&aantroUed, clinid trial of pfednisone for treatment of outpatients who present
to the Emagency Department with COPD exacerbation. The last stage of the research plan, which
is d y in prosrrss, Win consJt of the definitive, larger ciinid trial. This thesis WU describe the
process, and the results, of the pilot study whicb w u conducted fiom January 5 to May 4,1998.
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The dcnmtion of clm,nic obstructive puimoaary disease has evolved considaably since The
BI.itish Medicai Resesrch Cound tint defined chtonic bronchitis in 1965 as a disease charactented
by "chroaic cough and sputum production for three months in two successive years in the absence
ofother diserisss recognised to cause sputum production."
Today, the deMion of COPD ha9 ban refined to dect its haümark characteristic of chronic
d o w obstniction. Airflow obstiuction rden to a diminished expiratoly flow of air through the
airways of the lung, and is objectively meesured by means of spirometry. The degree of airflow
obstruction is quantifiecl by detennining the forad expiratory volume in one second (the FEV,). in
relation to referenœ values.
In 1997 The British Thoracic Society dehed COPD as "a chronic, slowly progressive
disorder characteid by airflow obstniction that does not change markedly over several months.
Most of the lung finction impairment is fixed, although some reversibility can be produced by
bronchodilator (or o h ) therapy."' Accurding ta British guidelines a diagnosis of COPD in clinical
practice requires: "1) a history of chronic progressive symptoms (cough a d o r wheeze andlor
bdessriess) Md 2) objective evidence of airways obstruction that does not retum to normal with
treatrnent".
In contrast, The 1995 American Thoracic Society (ATS) definition of COPD is somewhat
different and hader to operationalize. The ATS definition States that "chronic obstructive pulmonary
disease is a disease state cfiaracterkd by the presence of chronic airfiow obstruction due to chro~c
bronchitis or emphysema or a combination of the two." ' Chronic bronchitis is ciinically defimd as the presence of chronic productive cough for 3
months in eadi oftwo successive years in a patient in whom other causes of chronic cou& have been
excludedl However, it sbwld be mted that the presence of chronic bronchitis does not n e c e s d y
si* the pnsaice of &wqa obstruction or a diagnosis of COPD. Patients with chronic bronchitis
who do not show spirometric evidence of airflow obstruction are not classified as having COPD
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according to 1997 British, * or 1995 American Thodc Societies ddnitions.'
of tbe a h p x a c l i d to îhe taminal bmtlcbioles, rocompanied by dcsüuction of bronchiolar wrllq
without obvious &rosis.l In raûiây, moat pa!ients do not d a g o lung biopsy in order to maire a
diagnosis of emphyremi, so cliaicdiy patients are ususlly diagnoseci with cmphysema brsed on a
typical history of smoking, cbroiiic progressive dyspnea, ci~onic d o w obstruction, and cbest
radiograph andlor Ci' sari eviûetyx of anphysanatais lung destniction.' This highüghts a weakness
of the American da t ion , since technicaiiy it relies on prtbologic widence to d e a d@osis of
emphysemq whereas the British denaition allows for dinid aad physiologie aiteria for m a h g a
âiagnosis of COPD without requiring pathotogic evidenœ.
The M o w obstruction of COPD, unljkc that of asthme, is chronic, progressive, and is by
definition, largely irreversible.' Reversibility of ürtlow obstruction is deterxnined by testing the
patient's expiratory flow rate response to inheled bronchodilator. Classidy, patients with COPD.
unlike asthmatics, are said to be relatively unresponsive to bronchodilator (ie. relative percent
increase in FEV, of < 15%)', although several studies have show that patients with COPD cm
exhibit widely varying levels of revetsibiüty pst-bronchodilator making them difnailt to distinguish
fiom asthmatic patients based on this aiteria al~ne.~*
Patients wah asthma, wbse airflow obstruction and whose symptoms of breathlessness are
reversible, are not considerd to have COPD.' Often the most dicuit diagnostic problem is
distinguishing COPD âom the persistent airfîow limitation of chronic asthma in older subjects.
Although the distinction rnay be diflcidt, a history of heavy smoking, midace of emphysema
radiologically, and chronic hypoxemia favour the âiagnosis of COPD. In contrsst, onset in
childhood, atopy and marked improvement on spùometry with administration of bronchdiators
favour the âiagnosis of asthma.'
Dkth&h@ patients with asthma fiom those with COPD wül be important for the validity
of this shidy. Previous Large chicai trials have already established the efficacy of using steroids to
treat =te rsthma m o n , and have demonstrateû that Emergency Department patients 4 t h
acute rsthma mwhation treated with outpatient gluoacorticoids have rduced rdapse mes,
reduced use of bar-agoaist bronchodilators, and reduced hospitalisation rates." It would thus be
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2.2 Epiri;cntiOlOg)r of COPD
COPD is a major oaire of morbidity anâ mortality in North Amaica. In 1985 in the United
States, COPD acc~unted for 5% of office visits to physicians and 13% of ho spi ta lido^.' In
Canaâa, COPD nmains a siemificnnt puôiic health burdai; more than 50,000 patients am admittcd
to hospitd every year for tnatment ofemphysam and chronic broncbitis, rind mmy more require
outpatient therapy for Bans of their dwase."
Am@& of morbidity data abstracted fiom the US National Health Interview S w y shows
that in 1985 the agdjusted prdence rate of COPD in persons aged 55 to 84 was 1 10 per 1,000
for males Md 120 per 1,000 for femrilesmiU2 This estimate may be somewhat infiateci however, siuce
the datri fepfe~tnts ~e~rcported pliovljencc of COPD, and h n ait& for the diagnosis of COPD
were not employed. Estimates of Cadian health-professional~sed COPD prdence mes,
derived from the 1994-95 National Health Swey, indiate a COPD pievalence rate of 47% in
persons aged 55-64, 5.4% in those 65-74 and 8.3% in persons 2 75.'' In 1985, accordhg to US
National Center for Health Statistics (NCHS) National Hospital Discharge Sunrey Data, the tige-
adjusted rate for hospital discharges for COPD was 14 per 1,000 and 10 per 1,000 for maks and
fernales respectively over age 55.11* " In Canada, the number of hospitel sepmtions with COPD as
the prllnary discharge diagnosis increased fiom 42,102 in 198 1-82 to 55,782 in 1993-94." Recent
trends suggest that disease prevaienct and hospital discharge rote is stable in men, but increasing
among womea, rd- a 40 year soQetai trad towards increaseû smoking among fernales.' In f k t
in Canada, the rate of age-specific hospital separations in women z 75 increased fiom 504 per
100,000 in 1981 to 1033 per 100,000 in 1994."
Mortality rates for COPD have been increasing. In 1991 COPD caused more than 85,500
deaths in the US, mkhg the disease the fourth leading cause of death in the country.' In the United
States, accordhg to death d c a t t Sormation compileci by the NCHS, the 1985 age-adjusfed
death rate fiom COPD amongst persons 55-84 years old w u 200 per 100,000 and 70 per 100,000
amongst males and f d e s rcspectively." in the US, age-adjusteci death rates for COPD rose 47?%
bawan 1979 and 1993,'. In cwdr. the totd numk of dcrths fkom COPD increased £rom 4438 in 1980 to 8583 in 1995. Age-qmific mortJity ntss runainai stable in aü groups except amon@
those aged 2 75 in which it increased from 2.5 per 1,000 in 1980 to 3.8 per 1,000 in 1995." The
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importuice of COPD-associsteû mortality wiU ükely continue to increase given the aging popuiation
and the hervy srnoLing history of the aureat cohort.
Approxhately 90YI of al1 COPD patients bave a history of Although ntes of
cigarette smoking dtcihed amongst d e s in Cinada bom 1970 to 199016, ovaiill morbidiîy ad
morirlity b m COPD amtinuc to incrcasc due to the long laterrcy period before the devdopment of
clinid diSmse."
2.3 N&dHàisbq of COPD
COPD is a disease characttrized by duonic symptoms of COU& and breathicsmcss which
progrear over time. The &case, by debition, is ch.rnciedzed by chtonic, progressive Uaow
obstruction Reports on the MIunl hUtory of patients with COPD show acceferattd rates of decline
in hmg W o n In COPD patients who smolce, the f i , d expiratory volumes in one sccond (FEV,)
dedines by 50.75 mi per year le, versus an expected declhe in FEV, of 15-25 ml pa year in aga
matched controfs who do not have COPD. Patients with a d d COPD are at ri& of dying of their
disease; five year suNival rates for patients with an initial FEV, of less than 1 .O litre am 45 to 50
percent. '& ".
Individuals with COPD are prone to -te exacerbations of th& üiness. These acute
exacerbations of COPD are characterized ciinicaliy by symptoms of worsening dyspnea, cou&
sputum production and sputum pudence, as weU as by worsening of airflow It is
dficult to predict arpeaed exacerbation rates for individuai patients, however most patients with
COPD -ence one to faa aacdations per year? As aidow obstruction becornes more severe,
exllcerbations ofken ocair more fiequently. Age-adjusted US data suggests t h COPD
exacerbations iccount for an average 1.2 office visits and 0.1 to 0.23 h o s p i ~ o n s per year per
prevaient case.'
Acute acacerbaton of COPD can predict a poorer than expected patient outcorne. A recent
prospective cohort study of 1,016 patients who were admitted to hospital for acute COPD
m o n and who had an wtdaî PaC02 2 50 mm Hg, r m d c d that 11% of patients died durhg
the index hospital stay, and that 60 day and 2 year mortality was 2(W. and 49?% respecti~ely.~
A l t h g h dis study did not indude a contrd group, the reiatively high 2 year mortality nte sugpts
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tbat rade COPD apoabrition with hypercarbh may be wwiated with a greater short-tam risL of
subsequent derth.
2.4 Biblogg of COPD ~ ~ l l s
Worsaing of pihmiary fundi011 during a COPD d î i o n is most commonly caused by
respiratory infedion, but can also occur seconâary to environmental triggers (e.g.. humidity.
pdlution, cxposurc to smoke or ocaipationa1 Mtants). car& dydbnction, or prognssion of the
dedying diseaseu Studies using Wal cuitures and serology have establishd that v i a and, to a
lesser extent, mycoplasana infèctions, are arrociaeû with approxiInaîely one third of acute
exacabatons of chronic br~ncbitis.~ Thnc bacterial pathogerrs, S~reptaroccrcs pmmmioe,
Hhernophilus influellzoe unàMwaxefIrr mkvrhalis, an âequently implicated in flans of COPD,
however these bacteria can be found in the upper respiratory tracts of healthy people, and are oftai
fwnd in the sputum of patients with COPD during periods of clinid quiescena, crs wel as during
periods of disease exacerbation." Deteminhg whether these bacteria are slmply commensals or
whetha they are respotlsl%le for clinid deterioration is therefon di£Ecult. However, severai clinicai
trials have supporteci the use ofantibiotics for treatment of COPD exacerbation, suggesting that in
some patients, bacterial infection of the airways may play a causai role in provoking COPD
exacerbation.
2.5 Ai- i n m i o n in COPD
Histologie and immunohistochemicat studies of the airways of patients with stable COPD have
revealed evidence of chronic infiammation. Lobar branchial biopsy specimens fiom patients with
COPD show infiltration of the airway wall with lymphocytes, and macrophages and increased
expression of marks of lymphocyte Recent studies have also shown that patients with
COPD have sigdcantly increased numks of CD3+ and CD8+ T-lymphocy~es in subepithelial
branchial biopsies as compared to control srnokm and non-srnoken." Similady, levels of the
in8animatorycyto~tumwne~0sisbdaud~.rrede~lltediatbespuhunofstable
COPD patients cornparcd to controls, aiggesting that COPD is assochaî with a dironic
inflammatory response within the airways? Ahhough it stems reasonable to assume thnt Urwry
-
inflammation plays a similar mle in the pathogenesis of worsening of airfiow obstruction seen during
acute exacerbations of COPD, there is to date suprisingly little data which exists characterizhg the
inflarnmatory responses seen in acute COPD exacerbation.
2.6 Treutment of COPD Exacerbaiion
Current Canadian, U.S., and European Thoracic Society guidelines recommend that
exacerbations of COPD be treated with appropriate supplemental oxygen therapy, plus
bronchodilator therapy with beta,-agonists and anticholinergic aerosols. '9 '* *' Antibiotics are usually prescribed since it has been show that they may be of help in resolving an acute exacerbation and
are valuable at decreasing the risk of fùrther deteri~ration.~' The most comprehensive study of
antibiotic therap y for COPD exacerbation showed that treatrnent wi th a broad-spectrum antibiotic
increased the 21 day successful recovery rate fiom 55% to 68% in the antibiotic-treated group (p
-
and release of inflammatory mediators, may thus have theoretic benefits in COPD exacerbation.j3
2.8 Potentiai Adverse Effects of Glucocorticoids in Patients with COPD
2.81 Short-term adverse effects:
A prospective randomized controlled trial evaluating the complication rate of a short course
of glucocorticoids (1-3 weeks) in patients with COPD has not been published. Albert et al reported
that the fkquency of side effects in COPD patients with acute respiratory failure treated with 3 days
of N methylprednisolone was similar to placebo." Unpublished results fiom the SCCOPE trial
(Systemic Corticosteroids in COPD Exa~erbations)'~, a trial using htravenous and oral steroids in
the treatrnent of hospitalized patients with COPD exacerbation, demonstrated that hyperglycemia
was the only short-terni side-effect seen more fkquently in the steroid-treated group.
However, short courses of glucocorticoids cm be associated with side effects which may be
important to patients with COPD exacerbation. Short courses of glucocorticoids can increase the
nsk of infection. The strongest evidence for this cornes fkom a meta-analysis of 71 controlled
clinical trials in which patients were randomized to treatment of their illness with steroids or
placebo? When al1 diagnostic groups were considered, systemic steroids were found to be
associated with a relative risk of 1.6 (95% CI, 1.3 to 1.9) of lethal and nonlethal idections. However
an increase in the incidence of infection was not seen in the subgroup of patients with puimonary
disease ( ~ 3 6 4 ) .
Short-term steroid use is also associated with acute psychiatnc side-effects. A prospective
study of 676 patients treated with short-term steroids for a variety of illnesses showed that 3.1 %
developed acute psychosis or inappropriate euphona. 37 Finally, atrophy and myopathy of skeletal
and respiratory muscles are well-known side-effects which may occur with short term administration
of glucocorticoids. Short courses of supra therapeutic doses of glucocorticoids in rats and hamsters
have been shown to cause reduction in diaphragm weight and atrophy of type IIb diaphragmatic
muscle fibres.38*
2.82 Long-tenn adverse effects:
A clinical study involving 21 consecutive patients admitted to hospital with acute
-
exacerbations of COPD or asthma has suggested that patients who have been treated with nwnerous
courses of systemic steroid are more at risk for generalized and respiratory muscle weakness than
those patients who have not received steroids. A multiple regression analysis of the relationship
between maximal inspiratory muscle strength (Pimax) and quadriceps force (QF) and steroid dose
in these patients, showed that the average daily dose of steroids used over the previous 6 month
period independently accounted for 32% of the variance in Pimax and for 5 1% of the variance of
QF? This potential contribution of steroids to reduced respiratory muscle strength in COPD
patients is of great clinical significance since respiratory muscle f'unction of many patients with
COPD is already compromised due to hyperinflation, malnutrition, and detraining. Any additional
steroid-induced reduction of respiratory muscle force could theoretically cause M e r respiratory
c~mpromise.~ l
Finally, epidemiological data exists which suggests that long-terni use of glucocorticoids in
patients with COPD may be hannfûl. When data fiom the Swedish Long-Term Home Oxygen
Registry were analysed using multivariate regression analysis models to determine predictors of
survival in COPD patients, oral steroid usage showed no tendency to improve swival in men and
steroid use was associated with an increased mortality rate in women with COPD (relative risk of
death 2.13; 95% CI, 1.38 to 3.29)." Similar studies fiom The Netherlands assessing the
independent contribution of corticosteroids on mortality using a Cox proportional hazards mode1 and
adjusting for age, FEV,, smoking and sex, has shown that the chronic use of oral steroids was
associated with increased risk of mortality (RR =1.33, p=0.002)."
2.9 Glucocorticoid9 for COPD Exucerbation- Evidence fron, the Literuture
A MEDLINE search of the published literature was undertaken to look for trials which
exarnined the use of oral or parenteral steroids for acute management of COPD exacerbation. The
search ternis used were the following: (exp lung diseases, obstructive or chronic bronchitis tw. or
emphysema tw.) and (exp steroids or prednisone.tw.). The reference lists of retrieved studies were
manually searched in order to try to find M e r studies. Three published clinical trials, as well as
one study published in abstract fiom only were found. Preliminary data h m two unpublished trials
recently presented at an international meeting are also summarized below. A summary of the
-
retrieved clinical trials is found in table 1.
2.91 G f u ~ ~ ~ ~ r t i ~ ~ i à s for LospUalized patients:
Albert et ai studied 44 patients admitted to hospital with COPD exacerbation and randomized
them to either methylprednisolone 0.5 mgkg every 6 hours for 72 hours, or to p l a ~ e b o . ~ They
found that 12 of 22 steroid treated patients had prebronchodilator FEV, increases of 40% or more
at the end of 72 hours of therapy compared to. 3 of 2 1 placebo treated patients @+.O 1 ). They did
not h d a difference in oxygenation, and mortality and hospital duration time were not assessed.
A large trial, which has not yet been published, was recently presented at the 1998 Amencan
Thoracic Society annual meeting.'' The SCCOPE ûial was a multicenter, placebo-controlled study
which randomized patients admitted to hospital with COPD exacerbation to treatment with placebo,
or to treatment with 3 days intravenous methylprednisolone and then either 2 weeks or 8 weeks of
oral prednisone. Al1 patients received antibiotics and inhaled bmnchodilators. The trial's primary
endpoint was treatment failure within 6 months of entry (a composite outcome defined as death,
intubation, readmission for COPD, or need for pharmacologie intensification of treatment). The
study was designed as an equivalence trial and actually required 1200 patients to show a 25%
difference in failure rates between the two groups. Unfominately the trial only enrolled 27 1 patients.
The study showed that the 30 day and 90 day failure rate was 10% higher in the placebo group as
compared to the active group. However, at 6 months the two groups had identical failure rates.
Mean hospital stay was slightly lower in the steroid-treated groups (8.4 vs. 9.7 days, p=0.03). FEV,
was significanily greater on days 2 and 3 in the steroid-treated groups, however this efFect was lost
by 14 days (although it shouid be noted that the analysis was by intention-to-treat and a significant
proportion of patients had crossed over from placebo to open-label prednisone by day 14).
Another recent trial, published in abstract fom only, randomized 57 hospitalised COPD
patients to treatment with 30 rng/day of prednisolone for 14 days or placebo.* Seven patients
withdrew due to treatment failure, 2 in the steroid-treated group and 5 in the placebo-treated group.
Lung function was marginally better in the steroid-treated goup at discharge from hospital; FEV,
was 42% predicted in the treatment group compared to 34% predicted in control group, however
statistical tests were lacking. The rate of M e r exacerbations afier discharge fiom hospital was
similar in both groups. The authon concluded that steroids were associated with fewer dropouts but
-
did not prevent M e r exacerbations after discharge and were therefore of little benefit. However,
it is âifficult to judge the valiâity of this conciusion in the absence of a more complete presentation
of the study data.
A similar trial, published only in abstract fonn randomized 30 inpatients with acute COPD
exacerbation to therapy with either steroids or placebo for an 1 1 day course? The authors observed
a statistically significant improvement in pulmonary fûnction in both groups, however there was no
additional improvement in the pulmonary fùnction of the steroid-treated group over that of the
placebo-treated group afler one month of follow-up. The authors concluded that steroids were of
little benefit.
2.92 Glucocorticoids for ambulatory patients:
Emerrnan et al studied patients with acute COPD exacerbation in the- emergency
department." They randomized 96 patients to 100 mg of methyl-prednisolone or placebo within 30
minutes of arriva1 to the ED. They did not hd a significant treatment effect. Change in FEV, was
similar at 4.5 hours in both groups (37% improvement in the steroid treated group compareâ to 43%
improvement in the control group), and there was no difference in percent of patients admitted to
hospital(33% vs. 30%), or the number who relapsed within 24 hours (1 0% vs. 1 5%). It should be
noted however, that this trial studied the acute effects of therapy over only 4.5 hours following only
one dose of systemic steroids. Therefore inferences from this study may be limited, since the
duration of therapy and follow-up may have been too bnef to discem a treatment effect.
The only longitudinal trial studying steroid use in outpatients with COPD exacerbation was
performed by Thompson et al!' Twenty-seven outpatients with COPD exacerbation were recmited
fiom the emergency department and f?om outpatient clinics. Patients were randomized to receive a
9 day taper of prednisone (60 mg, 40 mg, then 20 mglday each for 3 days). Unfortunately, because
of the small numbers of patients randomized, the baseline characteristics of the prednisone and the
placebo groups were somewhat different, and suggest that the placebo treated group may have been
more chronically il1 before entering the trial (the placebo group had a baseline FEV,, before
exacerbation of 1.15 0.49 litres compared to 1.59 * 0.67 litres in the prednisone-treated group). This may have biased the resuits in favour of the prednisone-treated group, since obviously the
prednisone-treated group had more potential for improvement back to their higher previous baseline
-
status. Results from this small trial showed Chat patients in the prednisone-treated group had a
significant improvement in FEV, on day 10 but not day 3 of the trial. Overall, patients in the
prednisone-treated group hproved their FEVl by 0.05 litres per day VS. 0.00 litres per day for
control patients (p4.006). Prednisone treated patients also had a more rapid improvement in arterial
oxygenation , but no significant change in dyspnea scale scores when compared to placebo-treated
patients. Eight of the 14 placebo treated patients required hospital admission or open-label
prednisone compared to none of the 13 actively-treated patients (p4.002).
In addition to data fiom these three clinical trials, several retrospective studies have been
published suggesting a possible benefit to glucocorticoids for COPD exacerbation. Murata and
colleagues conducted a retrospective review of 352 patients with COPD exacerbation who were
treated and released fiom the emergency department." Thirty-two percent of ED visits resulted in
relapse, defined as an unscheduled revisit to the ED within 14 days of treatment. A multiple logistic
regression mode1 comparing visits that resulted in relapse versus those that did not showed that
patients who had visits which resulted in relapse had lower entry and discharge FEV,'s, required
greater number of treatments with nebulized bronchodilators in the ED, had more fiequent use of
parenteral adrenergic h g s , and had less fiequent use of oral prednisone on discharge. The same
investigators have also published a retrospective case-control study of 30 COPD patients with a
history of multiple relapsed9 They compared 45 emergency department visits in which steroids
were prescnbed to an equal nurnber of matched visits in which they were withheld and found that
the 48 hour relapse rate for steroid-treated visits was 9% compared to 3 3% for the non-steroid treated
visits (~~0.005).
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ble 1.
Glucocorticoids for COPD Exacerbation
Summary of Published and Unoublished Randomized. Controlled. m a l Trials;
- --- - - - --
Author, year n Patient Treatment Protocol Outcome Results Author's Commen ts
( refertnce) Population Measures Conclusions
lben, 1980 '4 44 Inpatients IV methyl- FEV,. Control group: mean FEV, Stcroids improvcd Clinical outcornes not
prcdnisolonc x 72 PaO,. improved 20%. airflow more than asstsstd.
hours or placebo Sttroid group: mean FEV, placebo
improved 40% (p
-
-- -
Author, year n Patient Treatment Protocol Outcome Results Author's Comments
( reference) Population Measures Conclusions
Rostom, 1994 '5 30 Inpatients IV methyl- FEV,. No improvement of FEV, in Steroids of no bencfit Many patients lost to
prednisolone x 72 steroid group compared to follow-up, data is
hours followtd by 1 1 controls. incomplete.
days of oral
prendnisone, or
placebo
Emcrman, 1989& 96 Emtrgency IV methyl- FEVl at 4.5 Control group: 43% Steroids of no bmcfit Duration of therapy and
Deparanent prednisolonc 125 hours. improvement in FEV, . F/U may have k n too patients mg. x 1 dose No, of patients Steroid group: 37% bdef to disceru treamcnt
admitted. improvernent in FEV,. (p = NS), t ffect.
Relapse rates. No difference in relapse or
admission rates betwetn thc two
groups.
Thornpson, 1996 " 27 Outpatients- Nine days of tapering FEV,. Conîrol group: FEV, improvcd Steroids improve airflow Groups unbalanccd with
clinics and oral prednisone Failure rate. 0.00 Lld. Failure rate 8/14. obstruction and prevent respect to baselhc
ED Dyspnea scale, Steraid group: FEV , improved trtatment failwes charactcristics, mal1 0.05 Wd (p=0.006), numbtr of patients
Failure rate 011 3. randomized.
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2.10 G- for COPD 4!xadhhn- awcal GY*
Current American Thoncic Society GuiAdincli for cve of @am with COPD state that "corticostwiâsxan k useful ifthere h an ;isthmatic compoamt in a patient who dembnstmtcs
responsivcntss to Ma-agoaist thmpy, although tbat h limited informafion supporthg the use of
intnvenous rad oral staoids in the m e n n e n t of COPD cxacctbatioll~."~
Cumnt British Thoracic Society Guiddines state thaî for trrrtmmt of amte COPD
exacerbations "W corticosteroi& may be prtscll'bed in some cases. These shodd not be used
uniess: the prtimt h rilruuïy on orai wrticosiaoids; &ere is a previoudy d~cumeated respoase to
o d c m b s t d Q ; rirflow obstniction to respoad to an inamse in broncbodilator dosage; this
is the first prescntation of airflow obstruction." The guideLines conclude by stating "therc is a necd
for further research into the place of oral corticosteroids in the conta of an raite exacerbation of
COPDw . l6
2.1 1 Suinnuiip
COPD acacabaton npresents an important ciinid and public health problem. The optimal
treatment of aate COPD exacerbation remaiflS unknown. Although experimental data strongly
supports the use of oral gluco«>rtiwids for treathg outpatient exacerbations of rsthma, the data is
weak to aupport the same trecitment in the COPD population. The ridrs and benefits of short courses
of prednisone are unclear for COPD a d nimnt available evidaia is inConc1usive. There is therefore
a n d to objecrivdy study tbis issue and detenaine whether patients who present to the Emergsncy
Depatmiait with COPD mcdation shaild be dischiuged home on oral prednisom. A randoniizcd,
d d d - phabcoirtroIIed dinicai trial is warranted and offas a unique opportunity to answer
this Unportant clinid question.
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made for COPD etaddm to the ûttawa OeMJ and C i Hospital m m c y in
1996. Datawasrcassedthtough t b e O C H ~ a q E P l S Databue and throu~T&eOOH EmeqeaylXdwgeCodjngDatabgse. DatawascdledtdonthemimbaofEDvisits,disposition
of tbe patient fdowhg eadi visit, lad nLpse rates. Red& rn aumrarirrd bdow, ad are ptesented
in Tables 2 and 3.
Table 2 depicts a summary of 19% COPDdaîeû admission, discharge and relapse rates for
The ûttawa Gavnl and Civic Hospitais. In 1996, The Ottawa G a d Hospitai recorded 368 ED
vUits f a COPD m o n . Of these visits, 187 (5 1%) r d t e d iu U i s i o n to hospitrl rad 18 1
(490h) resdtnsutttd in disdrvge h m the Department. Excluding repeat visits, 142 individuai
patients at OGH were dkhargad fhm the ED in 1996. At The Ottawa Civic Hospital 546 ED visits
were recorded; 252 (46%) r d t e d in admission to hospital and 294 (54%) r d t e d in discharge
fiom the ED. Excluding qxat nsits, 2 16 individual patients at OCH were discharged fiom the ED
in 1996.
Relapse rates, defineci as a repeat visit to the same Emergency Department for symptoms of
COPD exaddon , an outlined in table 2. Ofthe 475 ED visits that resuheâ in discharge âom both
hospitais, 12.W d t e d in a rdapse w i t h 10 days, and 18.9Lh resuited in relapse within 30 days.
Tabk 3 depicts data rebieved fiom a more d d e d d y s i s ofthe charts of the 142 patients
who wae dischargai home fiom the W H ED in 1996. Data h m these patient charts wu coUected
in orda to deterrnine Emergency Deparment therapy of the patients' COPD exacerbation. Patient
characteristics were also abstracted ftom the entire chart in order to determine whether the patient
would meet the criteria for trial eiigibility.
One hwdrrd and thirty4ght of 142 charts were retrieved (97.2%)- four patients had charts
which had gone misshg from Medicd Records d data on these patients w u not adable. 70 of
138 patients (5 1%) haci had recentîy p l a d on pradnisone or had d v e d a prescription for
prednisone on d k h g e fhm the Emwpcy Depvtmcnt. 54 of 138 patients (39%) hd bœn
recently placeci on mtiiiotics or had raceiveci a prescription for mtibiotics on discharge fkom the
Emergency Department.
-
F i p 1 depicta r flow diagram of 3ûday rdapse events W. artmeDt tdccived. ûftbore
patients who dapd witbin 30 days of thir Virit to the Emergmq oaly 3% were
p r r s a a s d ~ u p o a ~ ~ ~ m ( o r ~ i I r r r d y b e a a p c e a c i i i p ~ n e b s f o r e
pnseptation to The Emergw Depcvrment). In contrast, 51% of those patients who did not
a 3-y relapse were p d ô a i , or were already taking, pdnisonc on dischuge âom
nie ED, (x2 = 1.13, p = 0.29). Finally, a feasibility miew wrr da taken to detamiae that a d u e n t naumba of @%le
patiarts would be avaüabk at the two ho~pitrlr in orda to support the definitive hger study. Tbe
charts of 138 of the 142 COPD patients who wae dischargexi fiom The OGH ED in 19% wac
aiulymd (Eair cbsrrr wae unadable h m Medical Records) in orda to detamine the proportion
of patients wbo would fit the digiiiiüity aiteria for the proposed clinical triai. In total, 41 of 138
patients (30%) definitely met aii study eligiiility criteria and an a d d i t i d 19 of 138 patients (14%)
werepiged to possiiiy Wii shdy digibii aiteria according to information contaimû in the chart.
Assuming the COPD patients who present to the OGH ED are similar to those who present to the
OCH ED, then approximately 35% of the 358 individual patients who presented to both hospitals
with COPD araCabation in 1996 would have been etigible for the trial. B d on this estimate, 125
efigible patients would have b a n adable in 1996 for potentiai recniitment into the triai.
1) A diderit nmikr of patients with amte COPD e m d a t b n shaild be aniable for the definitive
shidy .
2) niae appeius to be a wide practia variation c o n d g the veatment of COPD exacerbation in
the ED- only 49% of ED patients were prescribed staoids on discharge. Given this wide practice
variation, a statc of ciinid equipoise exists *ch cthiully justifies the necd for the pilot study and
definitive trial.
3) Relapse is M y ammon and can save u an objective clinicai outame variable.
-
RESULTS OF THE 1996 EMERGENCY DEPARTMENT COPD RECORDS REVIEW:
Table 2: Summvy of COPD Admission and Rates:
HorpiW lYEDVWb UAdmbrioiu #Dischargea 18d.y 30 diy
for COPD for COPD home relapserate rdipcerrtc
Both 914 439 (48%) 475 (52%) 12.00/0 18.9%
* 18 1 discharges /l42 wüviduai patients ** 294 discharges / 216 individual patients
Table 3: Ernergeacy Departmart Therapy for Patients Discharged Fdowing Acute COPD
Exacerbation.
-
T h i r t y d a y r s l i p r c a t e s v s . ~ & e d
Ottriwa Gaieral Hospital 1996.
142 COPD patient8 diichargcd in 1996
23 patients relapaed within 30 days
1 19 patienta did not relapse
unknown (9% (5 2%) (5 1%) (47%)
2 therapy unknown
(2%)
-
This thesis Win describe the pmess, and the r&s, of the pilot study wbich 1 designed
in wiib d l c q ~ ~ ftoai The Ottawa Hoqbl, Division of Respiratory Medicine, and
wbich wrs canductcd from January 5 to May 4, 1998. This pilot study was a rsndonnzed,
placebocon~olled cünid triai, and was designed to k a pdude to a larger, debitive, clinid
trial. The dehitive ciinid trial wdi attanpt to rscatlrin whctha o d gluoocorticoids are effectm at t r d n g anite aP#rbition ofchronic obstrucrM pibnoaiiry direare in patients discharged fkom
Spteifi Objd~~l~yics u f t k Hlbt Su&:
Pn'rmvy Objcc~l~vc:
The primiiry objective of the pilot study was to ensure that a larger cihical triai wül be
feasible.
The specific secondary objectives of the pilot study were:
1) To cissess the proportion of patients who relapse in the two treatment groups, in order
to ddamine whetba thU clinicai variabie d d serve as the p h m y outcorne variable for
the definitive study.
2) To verify the sample size estimates for the larger trial.
3) To d u a t c patient r e f d rat- and triai recruitment.
4) To verify the emoUmcnt proass- did the iacIusion/exciusion aiteria Jlow for the
intendeci group of patients to be entacd into the study?
5) To aUow for prc-testing of the ditr coildcfion d data anaiysW procas.
Ine h e e mcrjoy objectîws of thc definithe clinical bicil will & :
1) To detaalnc whether r 10 dry anux of o d glucocorticoids wüi improve airflow obstruction
-
in paîients with raite mmrbtion of chronic obsüuctive puimomy diseue (COPD) who are
discharged from The Emergency Dqwtment.
2) To compare tbe fhquc~lcy of 10 dry ad 30 day relapse events in patients rccciving oral
gluoocorticoids cornparcd to controls rfta the tmtmaii of w t e COPD auCabiton in the
Em=%=Y - 0
3) To compare rates of patientlcc~lfc~ed outcornes, including improvements in subjective dyspnea
scores and irnprovemaits in disease-specific q d t y of life measured at day 10 following an
Emergency Department visit.
nie pVwy aitanne variable of the definitive triai win be either percent improvement in
akfiow obstruction (objective 1 above) or relapse rate (objective 2 above). The choice of primary
outcome variable w i l depend on the results of the pilot study.
-
41 wgal
niispbr~wasaMdomurd,daiblabüad,p~ntroUadclinicalüiai. Patients
were randomized to artmeat with oral prednisonc or to treatrnent with identidy kbelled
pleoebo apsules. nie shdy was nm out of The Emergency Departmm of The ûttawa Gaiarl
and Ottawa CMC Hospitais lad recruited patients &om January 5,1998 to May 4, 1998. Data
coMecfion was completed on June 4,1998.
4.2 PafUnii3&&11
4.21 Inclusina C&&
Inclusion criteria wae chosen to wnform to wrent ATS definitions of COPD. The
aiteria were also dected to ensure that the shidy population was refledjve of those patients in
the ED who are ordinarily identifid and diagnosed as having COPD exacerbation.
Patients were considerd to fiilfill the diagnosis of COPD if they met the foliowing criteria:
1) Patients with a previais dirignosis of dironic bronchitis, ernphysema or COPD estabiished
by th& physician In the e ~ i r that the patient had not been previously labelleci as havhg
COPD, hdshe was di eligible for the study if the tnating emergency department
physQM felt that the clinical history was complti'blc with a diagnosis of COPD, and not
asthma.
Chicil history n e c a a q to support a new diagnosis of COPD:
a) Patient must have a history of cbroaic shortness of breath or chronic cough with sputum
production.
b) Symptorns should be constant Md chonic and wt fluctuate on a day-today basis.
2) Patients must have had evidence of airflow obstruction on prescatrtion at the emergency
deputmcnt. d e h d as an FEV, r 7P? of p d d e d and a FEV, 1 FVC d o r 703C.
3) Patients mut have cbronic Mow obstniction, defincd as an FEV, s 7W of predided
-
and a FE& 1 FVC Rbjo s 7Wh. The FEV, ad FVC d fk tbis aitaion wrr takm h m spirometry d t s otmhd at r t h e of ciinid staôiüty eitba before,
or1 moathi&rtheanqaxyroomvirit.
4) Patiam anirr be 1 35 y e ~ old.
5) Patients must bave a minimum history of 15 padc-ycars smoking.
6) Patients mus& be an acute uadmtion of COPD and must mtet at lcast one of the foUowing tbree clinid criteria for acute COPD exacdwion as defiaed by
Anbisena: hmasd chronic baseline dyspnea , increased sputum volume or hmasai sputum punilencc. The above cornplaints hid to have n d t a t e d the cmctgency
department visit.
Patients excluded were those with:
Signifiant reversible aidow obstruction in the ernergency rwm: Signifiant reversible
akfiow obshuction was defined as at Ieast a r 200/r and a 22ûû ml irnprovernent in FEV,
fiom bwiine after inhalation of bronchodilator.
Physician diagnosed rpthme, cczema, ;iuagic rhinitis or nasal polyposis.
Use of oral or injectable corticosteroi& (but not inhaled steroids) during the month
preceâing trial aitry.
History of chronic lune disease ot&er than COPD. Patients with a bistory of
broncbiectads, cystic fibrosis, and interstitial lung disuise were excluded. P a b t s with
lung cancer were excluded, unless the cancer has ban complete1y resected with no
evidence of residual di-.
Pneunonia or congestive hem faüure on anergency room CXR.
Patients not able to paform an FEV, rrsessmsnt.
Patients with h w n adverse d o n or intoleru~ce to systemic steroids.
Patients with severe uncontroUed dllbeia mdüau (emet.gc~~cy ioom b l d sugar > 15
nimolli), sevae mul (Cr > 200, or cm âhlyis), hcprtic (ôiopsy proven cinhosis or chronic
-
bepatitis), or cadac Mwe (echocsrdiogmrnd0~~lle~1ted paâe ï l I or IV le& vatriEUllV
d y s 8 m e r i a i r a d y m p a m i t i c ~ ~ ~ N Y H A ~ ~ o r T V ) , p a t i ~ 1 1 ~ w i t h o ~ o ~
&isirointeStinalbl-.
9) Iaiibüay to provide inforneci consent or wmply with the study protocol duc to cognitive
impairment, ianguagc barri@, or distance > 100 Hometres fiom the study centre.
10) Patients admitted to hospitai.
1 1) Patient has ptCViOUSly participateci in the shrdy.
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4.31 eig,m'mcnlOl M-m:
Eiigible patients wae d o d y rllocated to receive ather:
Oral pmdnisone, 40 mg cspaiks to takc once M y for 10 days, or
placebo capsuies identicai in taste and appeamnce, to be Eaken daily for 10 days.
Uedications were preparad by one centrai pharmacy and labeîled only with a saidy nwnbef so as
to easure concealmerit of docation.
This dose and duration of administration of prednisone was chosen ôaseâ on previous
stucïies in astbmatics which demonstrateci that a 10 âay course of 40 mg/day of preânisone was
as d e and was as effective as a taperllig prednisone coune in achieving relief of ainlow
obstruction and prevention of asthmatic rela~se.~"
4.32 Oiher adj, manueuncc
1) A standsrdized emergency department pmtocoI and order sheet for treatment of COPD
exacerbation was distnbuted - the order sbeets specified that patients should not receive intravenous or oral giucocorticoids in the anergaicy department. AU other decisions regarding
treatment and care of the patients were left to the treating emergency physician.
2) Both groups of patients were placed on an antibiotic. Patients were prescribed
trimethoprim-~ethoxaso1c (septra) 2 tablets twice daily for 10 days, or in the event of a
sulfa allergy, they received doxycyciine 100 mg twice daiiy for 10 days.
3) Both groups of patients were provideû with inhaled salbutamol and inhaled
ipratropium m e t d dose inhalers. Education concerning use of the M e r s wss provided to
al patients and inhalation technique was verified. Patients were adnsed to use ipratropium 3
p u 5 fair times diUly and sslkitrund 2 pifn f i timeJ M y for the duration of the triai period
of 30 days.
4) Those patic~ns taking hbdd corticosteroi& d o r thsophyhe preparatiom More
aiteMg the trial were advised to continue on these &CIltiom.
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4.33 mwud fw dciibiiy MW padirnlr wko *se& The patient's EMily doctor wu notifiai by fix the patieat eritaed the sîudy.
Patients who d e an umcheddcd nsl to the anergmcy d e p t t m t or to the famiiy doctor
on or More &y 10 bcccpise of seKreported woneniag of dyspnea wcrc considemi to have
relapsed ad wae cbdïed treatment Wwes. In tbe case of treabnat Mures, the
physician tredng the patient w u advised to take the patient 08 the study medication, ad to
treatthepitYntwithopatJawlprsdmaone. ~waes&nbystudypersonneioathesime
day of their reiapse, or u soon as possible thmafk, anâ they wera asked to c~mplete the
saidy m-ts which hd kea scheduied for dry 10.
Cornpliance with the trial medication and antibiotic reg- w u ursessed through
patient questionnaire and pi11 counts. Patients were asked to retm u n u d pus and pül
containers on study day 10 to ver@ cornpliance with the drug regimen. Udortunately, there
is no wrnrnercially available assay to monitor for blood levels of prednisone, and Urnefore
laboratory testhg for cornpliance was not feasible.
4.5 Bascüne Assessment
Recorded infiormation for al patients on admission into the trial inciuded: age, gaider,
height, weipis WC ongin, past medicai history, duntion of COPD, srnohg history, aimnt
medication use, aliergies, md reani respiratory symptoms. M o u s pulmonary function tests
were rlso d e d favailable. A CXR, brsdine rnd podm&xWor spirometry, and pulse
oximetry was obtahed on ail patients as part of routine tmergency room care.
4.6 Outcome M i =
4.61 t i r m y y outCome nteasum
The primery outcome me8SUre was improvement in airflow obstruction. This w u
determined by assessin8 the percent change in the postbronchodilator FEV, at study day 10
h m the postbronehodilator FEV, oôtaiaed before discharge from the cmetgency department.
FEV, was chosen as the primiary outwme variable 9na it is a direct, sensitive,
r m m e of the u n d m physioIogic abnocmality'. FE& is an objective rneasurement ad k
-
bishly reprOdcIc~'ble.~~ l percent change in FE& h9 prcviously bcen shown in the diaicd
trials of Albert Y and Thompson " to k a sensitive mcuun of improvmmt in airfiow obstruction in a simikr patient popdation.
AIthough -t in FEV, hs b c~~feiated with cbangm h patients' of
dyspner and quality of üfé a a, we chose not to use dyspatr iadac or @ty of He as the
Pimuy autcome variables, since patient reporting ofqwlity of afe anâ dyspnea Y aeccssuily
subjective, ad patient scores on these questionnaires mry ûe affkctcd by the douad l l i g
effécts of steroids on mood and a€Fect, inclepcndcnt of the dects of stcroid on the acaul
dimue pmcess.
In the event that we wae unable to oôtain spirometric meJlQUles on dry 10, then
in the sitting position rccording to esâablisbtd Amaican Tboncic Society aiteria.'' A
minimum of two forcd flow-volume loops of g d quJity wae obtained. If the FEV, and
FVC dues wen not within 1W of one amthet, an additionai rneasuramt was taken. The
flow-volume loop with the ôest FEV, and FVC wu, used.
4 62 S c c o ~ ouikomes
Secondary outcornes were asssed at day IO, with the exception of relapse mes which were
assesscd a! 10 days and 30 days der dornization. Secondary outcornes inciudcd:
1) The absolute change in postbronchodilator FEV, on study day 10 complrcd to day 1.
2) Absdute improvuncnt in oxygenation measund by pulse oximetry done on room Ur,
or if the patient was on home oxygm, O- wu performeû on the patient's usurl oxygen
prescription.
3) The poporrion of patients Wb0 rdapse within 10 ud 30 dry+ rdrpse wu defined, as paCbiiparnetd)uaiimdisdukdWatoaphys9ui'so~ora~tothe~cllcy
department kcruw of a patient's perception of worsening dyspnea.
4) Improvement in subjective dyspacr score as d ôy The Mahler Badine rad Truuitiod Dyspma Indexes. 5s T h W e r inciex ïs a two-part, intenimua-idministd
dyspnea iada tht ntes dyspnea rccordhg to th= crtegories: iùnctionai impainnait,
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mgnitu& of tasic, rad mgnitude of &ort. The h.adinc idex @DI) Y usai to rate
the~~~aityof~~~~aita~epoinSintimedthetriingtiondylp~ind~Oursd~
u s e a s ~ a O m t h a b a s d l l i e . Atbaseüiie,dyspneain&oftl ira~on~~~ntedon
a 5 p o i a t c a l e â o m O ( r e v a e ) t o 4 ( ~ ) . ~foruchofthethrescategoriesare adûedtoEormabasdiaetocjdyspaer~(~û-12). Thetnnsitiondyspneaindar(TDI)
is useû to rate changes in each of the thrœ utegories using a 7-point d e f?om -3 (major
detaioration) to +3 (major improvement). Ratmgs form the transition index csn be added to
fom a dyspna transition total score (range, -9 to +9).
Interobasmr cigrranait for the baJdine index has ban obscfvd at Wh, whüe the
agreement for the tnnation index was W A . ~ A cornlition of r = 0.60 @ 4l.001) was
rrportsd betweai the basdine totai score ad the 12 minute wak test, anâ the transition totaî
score has km signiiicz~lltly correlatecl with the cbange in 12 minite wallc (r = 0.33, p < 0.05).
TheBDIhasJsokaiscaito comktestroi lglywidiotha~ofdyspnea(the MRC and
Oxygen Cost Diagram), (r = 0.53 - 0.83). and moderately with the FEV, (r = 0.43)." 5 ) Improvement in disease-specific quaiity of life as rssessod by the Chronic Respiratory
Disease Index Questionnaire (CRQ)? The CRQ evaiuates fm aspects of quality of We in
p a t i e r r t s w a h ~ ~ ~ : dyspnea, &igue, etnotionai oaslon, and mastery. Each domain includes fiiur to mm items, d each item U scored on a d e of t to 7 (1- extmnely
short of breath to 7- not at ali short of breath). This questionnaire has been demonstrated in
the COPD population to be reiiabie, vaîïd, and responsive to change. " " In previous clinid trials evaluating dmg trament protocois, changes in the CRQ correiated with changes in
spirometric values, acacise paforrnance, Md subjective ratings of hprovement by both the
patients ud phy9cians. " CmeMons improvd fûrther when patients wae given information abcut tbeir pmiiais C~CS~OI ISC~, and the dwdopers of the CRQ recommcnd providing pa!ients
with feedback on th& previous responses whai they r e p t the test more than one the.*
6) Adverse e f f i rates uwvA at 10 days by patient questionnaire.
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Table 4: Summary of the Data Coiiection Schaduie:
-
Pd- with wte COPD arroerbition wac rneaed by the v c l l c y depuimnt
p ~ a d i f ~ ~ w a e ~ t ~ o d ~ y p e r s o d w h o r u i e a x d t h c patient rad determincd ifthe patient fiilfiud digibüity aiteria. Study pasonad wae on cali
by page systan 24 hain a day, sevm days a wak in a rotathg oabin-five cill scbeduie. The
priaapai inveatgator (rnyseif) wu on continuous s a m d ull to handle quaies Born the study
employees or patients. Atta informed consent was obtained Born digib1e patients
randocnidon was pafonncd. 'Ibe randoniiution process aonsisted of a computer-generated
random iisthg of tbe two treatmcnt aîiocafiolls blockd by groups of four and sbritifid by
emergency dqwîmmt. Randomization was tbrough central allocafion of r domiauion
~ e a n d w a s coordiaiitedbythcOttawiGasaJHosptilWumrcyRcstirJiDepPrtmait.
Physichm and nscardi M w e n unaware of die treatmsnt docation prior to randomization. 4.8 Blinùïng
The sbdy was doubleblinded. Medidons wae pnpared by one central pharmacy and
labellecl only with a study number so as to ensure concealment of allocation. The prednisone
and placebo were packaged in capsule form and had identicel taste and appearance.
49~kiR1ZLÇolLSCICCrafiOns
Patients were r d t e d for the pilot study over a four month peiod. AU consecutive
patients randornized over the four month pilot period were included in the study . Twenty patients wen randomind fiom Jan. 5 1998 to April5 1998.
Befm die pilot was pedonned a totai of 124 patients (62 per group) were estimated to be requireû for the larga cünicai trial. This sampk was caiailated to provide a power of
8% to d e t a a 2W difference ôetween improvement in FEV, in the placebo and matment
groups, with a probabii oftype 1 error (two-taüd aiph) of 5%.
A 20 % âi fkace in i m p m m in FEV, wss choseri as the s d e s t difference having
dinicd importance hiai on Americm and Camdian lhoraQc Society recommendatiom stating
tbat a 2O?h mip0VmWiit in FEV, in cbronic COPD patients is a sisnificant bnprovement w&kh
iustifies bng-tenn staoid use in these patients In addition, 1 conductecl a ~umy of 10
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4.19 ScuiipIc rjzC c&nWns
The sunple size e s t h m was basai upon the foiiowhg ~ t i o ~ :
Theaitcoiaemeisunuced topiantheraidywasthe~b~geinFEVl rtDay 1Ofirom
~ . T b s ~ ~ , r n d b M n b r d ~ n w a e ~ ~ o m d r c a b o m t h e s t u d y
by Thompron et ai. to be 0.90 * 0.26 litres. At Day 10, placebo patients wae assumeû to improve by 15% h m basdine and prednisone patients by 35% for a hypothesbd a h b i
cllnicaiiy important diffttcact of 20%. As patients improved, both groups were asamad to
have a large straQrd devhiion of0.49 at Day 10 as per Thompson's study.
kpanaw a conrkSion of .8 ktmai Badine d Day 10 FEVl measms, the standard
deviation of the change âom baseiine wu aimami to be 0.32. In a prdiminiry estimate, a
ample of 104 patients (52 pa groupa) were needed to detect a 2VA improvement (ie. an
absolute miprowmnt of 0.18 litres ) bastd on the twdded t-test for two independent groups
with an 8û% power and a 5% fàlsapositive rate; using the formula
where ZN = total sample size
Ze= 1 .% (standard nonnal deviate for a two-tailed a = 0.05)
Z04.84 (standard normal deviate for P = 0.20) O = standard deviation around the mean of the outcorne measurernent. The
standard deviation is estmiated at .32 ütres
b = A 2W differetlce between improvement in FEV, in the placebo and prednisoae
groups on Day 10 of tbe triai. A 2W diftierenct comsponds to an absolute greater
improvemcnt in FEV, of O. 18 litres in the ueatment group fiom badine, as compared to the
placeôo group. Substituthg the values of the wiow parametas hto the fonnula yields
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'Ibtis, lO4prtia1tsuenseded to6daUW.dinaaicebetweenUnptovemeat inFEV,
in the placebo rad pdnbone groups 4 t h r two-tadeci a = 0.05 and W h powa. S W c d
FEV, chta wae thm andysd using an ANCOVA modd to ver@ the adequacy of the plannad
sample size for the large clinid triai:
prednisone and piacebo) rnd ucluunait (i.~. BUdjllt ud Day 10). fwr oohorts wcre
ge11Cr(lfed. The sinnilitcd FEVl changes wae subjcctad to an acllilysis of cowisnce
(ANCOVA) mode1 hcluding the foiiowing arplanaîory mors: treatrnent, centre, baPdine
FEVl and by centre interaction. For snipücity, we llssumed FEVl change c o d a i d
with baseîine leveI with equal slope between the two treatment groups. Imbalance between
cenins at baseline was chancterized according to the mean levd difference equal to O, .25 of
baseJine dandard deviation, .S SD, 1 SD Md 1.5 SD (whae the baseîine standard deviation wes
0.26). Test of ûeatmmt &kt in the ANCOVA mode1 w u then subjected to a power anaiysis.
Table 5 sunnaentd the rrsubs the simiiirrni ANCOVA (pva&es of various effects) Md of the
power analysis of treatment effect.
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Table 5: S i ANCOVA ad Powa hdysb of Tnrtmait E&ct
rEntrc 2N haru W mut Difft~cooc Signifiant RxA ame" FEIV,"
Numba (N)@ -A
A- an rimition rate of 2Wh, a total of 124 patients (104 + (.20 104)), are needed for the study.
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4 D l l . l P n ' ~ r i l ~ s U of tkpn'ntoly O U l C O m e ~
The fiaril uulygs wiü be p d o d on an " M o n to trcata basis. Us@ uiir appmach,
patients wül be inchcied in the d y s i s accorcüug to tbe group to which thy were d o m i d .
Tbosepatiest~whorrlapsewitbindieQst 10dayrofthe~winhnnthcpost-koncbodürtorFEV,
vaiue dont on the day of relapse oountui as the Day 10 Mhie for puposes of the adysis W. endpoint llIISlysY, with the hst observation canieû forward).
The principal d y s i s of the dinerem between the petcent improvement in
poBtbroadiodilator FEV, m the plicebo ancl pradnisanc p u p s fiom day 1 to dry 10 of the trial wüi
be rssessed ushg patamdric proCCdures (Mependent t tests) iiiitUUy. Student's t-test with eqwû
Varwces wÿl be usai foc these analyses if the p-vJue of Leverie's test for homo8dty of wiaace
k graata that O. 10, otherwise Students t-test with unequai wiances wüi ôe used. Howcver, if the
Kolmogorov-SnWwrv test of d t y suggests that the data is not normally disbibuted (p < 0. IO),
a nonparametric test (Wdcoxon Rank Sum) wiii also be monned.
In the event that the two treatment groups appear to be imbalanced at baseline with respect
to a major badine covuiate, aich as stable FEV, or Day 1 FEV,, then an analysis of covariance
mode1 4 t h the imbalanced variable as the covariate wiU be conducted. The adysis of cuvariance
wül be done ifthe stable FEV, is imbaland betweca the two groups sincc bigha stable FEVL)s in
one group compared to the otha couid bias the results in tiivour of thaî group. In theory, patients
in the group with high stable FEVI)s d d have more m m for improvement bidr to their becdine
iung fiuiction rnd d d therefore show proportionately greater changes in % improvement in FEV,
from day 1 to day 10. The anaiysis of covariance wül thus sewe to adjust for the possible
confoundiag &ed of diffaait subie FEV, or Doy 1 FE&, distnhtions in the two treatment gmups.
Tbe ANCOVA mU k pafonned as per methods dcsaiibtd by Kleinbaum a al? Fint. the two sbajght line nlgesaon equations of percent change in FEV, on the covariate wül be genented.
T h e t w o s t r a i ~ ü a e s w ü l b e c o m p M I S u s i ~ a p u t i r l F t c s t f ~ r p u i l l ~ ~ t h e m o d d Y = ~ ~
+ ~ l X + ~ + ~ x Z + ~ , w t i a e ~ b a A i n i m y M n i b l e i d ~ t i f y i n s t b c treatmentgroup(0ifplaccb0, 1 if trea!ment) and with the n d hypothesis for the test for paraiielism Ho: P, = O. Afta the
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nr t t A- o f a l n n d a r ~ , O Y ~ C O ~ C Absolute changes in FE& and oxygen Saniration for the two tmûment lgoups wül be
camparsd us@ piinmetric procebres (idependent t tests) initiallys or with noqmamtdc mctbods
ifdie daîa is mt normaiiy distributad. Diaamces in scores of the Tnnsitiod Dyspnca Indexes in
the two graips, ad diffhnces fiom day 1 to day 10 in the scores of the four cbmpoaaits of the
C W Respintory Questonnaire, wili be compareû u s i ~ independent t tests. Relapse rates at 10
and 30 days wül be comparai ushg Fisba's exact cbi-quart tests.
ofal the outcorne variables d for thb study, the wt«wie variable wbich is arguably
the most coiroi9y imptant is tbe pm9orim of ppoiems who arpaiaia a 30-day rolipsc. A logistic
regesdon d e l will be developed using the pilot with 3ûday relapse as the dependent
variable. The logistic regrcssion will be done in an rttempt to a d j ~ for the influase of suspected
climcaliy asiiifiaint coviniites on the tmtmmt &kt. Variables which wül be assesed for potaitiil inchision m the mode1 wiN k those that arc wnsidered: 1) ciinidy Unportant variables that could
potaii;ahr ducllcc tbe outame; d o r 2) variables which are maldistributad in the two trcatmc11t
groups at baseline.
The sdection of variables for the logistic mode1 wül begh with a univariate uialysis of t ich
variable. nie indepadent variables will then be screened for inclusion into the final modd by adding
each variable individuaiiy to the basic logistic m d containhg the constant tenn and the vuUbk
'treatment'. Any vahable which appears to apprearbly change the btta d c i e n t for the variable
'treatment' wül be consided to be a possible confoundct rad wiü be rdained in the d. In
addition, uiy relevant variable wbidi h w s a signifiant nLtionship with the treatment variaôlt
~ b y a ~ n t i o t e s t f w t i i e ~ p < O . l O ) w ü l b e r M . Usingthisapproachafiniil
logistic modd wdî be gaiartcd and an adjusted od& d o for the tr-t &dct wül k obtwid.
S u ~ v a i aaalysU w i l be uwd to compue number of days to reiapse in the two trtafmmt
gmups. ~~ smhd auves wül be oonstnicred to dcscn'be time to relapse and the ames wiN be oompared ushg the log-nnlt test stritisiic.
Allp values will be reportcd as two-sided. AU data wül be presu~ted as iileuu * stindsrd deviatiom unltss othembe sta!Cd. Od& d o s win be rrported with 95% confidc~lcc intemis.
Ali analyses wül be pdonacd with SPSS software (n3 vemion mimba 8.0.
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health problan. Tbas L nimntly no oonvkhq &dam tbt t rdqg aitpotid COPD aracabrition with oorticostcroi& provides MY sipifiant M t to patiw Wb0 are rlrsidy ô c i q
trcated with stradrrd thaipy of antibiotics and broacbodilatom. the uaoatYnty mgadhg tnihnaitappnmhmthispopihtioaddietditive~ofclllncrlWin thisfield, Ibeiieve
that a state of ciinid quipise &sts which cthicaîly justifies the nced for a trial.
A S & i Data Monitoring Conmittee wiii k m e d for the luga trial for the putpose of
irdaimPialysi,rndpossiôleeariytanmgtionofthetrnl. A s a b i r i b a s a f k t y ~ t h o s e p a t i ~
who compLm of worsaiing dyspnea during the fust 10 days of the trial win k withcûawn fiom the
Jaidy, and th& physician WU k o f f i the option of placing the patient on opai-labd preQUone.
This will e n m that assignment to the placebo um will not k bazardous to the patient. Ethical
approvai for the plot rad the îarger study was granted fiom the Ottawa G e n d and Civic Hospitals
Research Ethics Cornmittees.
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i l W P C g k
SBdy-mm patients wae r e f d to the study d* the four month pilot phase, oftberc,
23 patients fhltibd digibüity criteria for admission h o the triai (Fiw 2). Tweniy ofthe eligiiiile
23 pathts wae amllcd inio tbe trial, tbrce pcticiu &sui c a m t . Nieen of twmty completad
the 3o.dry study. Oae patient in the prcdnisone-treated grwp withârew affer 3 days on the advice
of ber W y physician and rrfiised fûrther attenipts at foliow-up. Complete chta was thdore
available for 1 1 patients in the placebo group rad 8 patients in the prednisone group.
Thae wae two protocol violations reiated to irnpmper ~ ~ l ~ o h c n t of patients iado the pilot
study. ûne patiait (Who died 6 drys rffa enrollmeat) was dialysisdependant and shodd have beai
excludeci bpsed ai aekision critaia 118, and the second patient was discovered on day 10 of the trial
to have been on pndiiisone 21 days More triai entry whem be brought in his old piîl bottles to the
study imestigaton. Both patients were retained in the intention-to-treat dys i s .
5.2 P&nt . Age, sex, smoking history, presenting symptoms, and mean study Day 1 FEV, were
comparable ktween groups (Table 6). Becaw of the smpll numbers of patients enroUed in the püot
study tbae wae imbiknco wah rrspect to rncan stable FEV,, history of ooronary iirtery diseasc, and
use of inhaled stsroids b a n the two groups (Table 6).
$3 InilproocHcnrrnb in A ÿ l a u Obstm&n
Figure 3 depicts tk aûsolute changes in FEV, âom day 1 to day 10 for the placebo and
prednisone-treated patients. The mem improverneat in FEV, was 0.15 * .27 Litres for the placebo- treated group uwl0.26 * -25 litres for the prednisone-treated group. The data were not nonnally disvibuted (KoImogorov-Smimov (KS) test p=.M for placebo group and r . 2 0 for predaisone
group) and the &ta were thttefore anaiyscd using the Wdcoxon rank-sum test. The mean absolute
improvement in FEV, was not si@cantly Mema b a n the two groups @=0.20). The percent change in FEV, h m base& K. (Dry 10 FEV, - Day 1 FEV,) 1 Day 1 FEV,,
is depicteû in F i p 4. Phcebtrortad patiam improvd th& FEV, by r mean of 13.9 * 23.8% over the 10 dry paiod comparai to an improvcment of 4.3 * 44.4% in the prednisone-treated
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group. K S t e s t r n W a o r m a ü ( y w e r e ~ d ~ p = 0 . 1 1 rnd0.12forthetworrspedivs~ps),
d d i t i w u e ~ ~ ~ û o t h p M m a r i c u d ~ ~ ) n - p ; r n m C r r i c ~ . Ltvcae'stsrtfor
eqdty of lmimccs was SiSmfiCant p= 0.05, rnd M o r t the two groups wae a!mlmed to bave
w q u d w l i i e c s f o r t h ~ o f t h e ~ t e s t . T h e m e r n p a a n t i m p m ~ i n F E V ,
was not aigniûcrntly ktweea the two ~pwips Çdepenâent t-tem amunhg umqud
wirnces pt 0.16, Wilcoxon rank-aun tert p= 0.14).
Figure 5 dcpîcts the distriion of oxygc11 situntion responses for the prednisonc and
placebo-treatd groups. The mean cbange in orna sanuation (Day 10 - Day 1) wu rliehdy, kit of the Qghc patients tnated wiui prednisoae improd tbeir oxygm saturation ove the 10 day period
comparedto6ofthe 11 pb#boarritedpa!ic~lfs. nieph#bolpoup siK,weda0.18t2.8%inctease
in mean oxygen saturation cumpared to a 1.6 1.PA increase in mean oxygen saniration in the
prednisone group (Wiicoxon p = 0.38).
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Figure 2: Trial Profiie
1 67 patients refemd to the study during pilot phase
1 23 patients fûlfillcd eligibility critena 1 1 _ 1 3 patients refiscd 1
I consent I
20 patients randomized
I l rcceived
I l completed trial
44 patients excluded due to failurt to meet eligibility
cntcna
( 9 received 1 I prednisone 1 ,-,
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Table 6: Badine Charaderistics of AU Patients Randomhd to the Hot Sady:
Mcin rtrbk FEVfIFVC (Va) SD 53 14% 43 9%
MM dudy day 1 FEV, (L) * SD 0.82 .27 0.85 .30
Mcin rtridy dry 1 F E V W C (Y.) f SD 47 10% 45 10%
COPD m d c a t h we ~~ 5 (4%) 8 (8%) IpntroQim 7 (6w s (%%) Aatibiotics 5 (45%) 2 (2%) TbWhyline 1 (9% 2 (2%) Home oxyw 1 O (0%)
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Figure 3 : Absolute Cbange in FEV, From Day 1 to Day 10
Piacebo a d Prednisanc-Treatd Gmups:
Placebo-treated group (n = 1 1 ) : mean change = .15 2.27 litres
Prednisone-treated group (n = 8) : mean chan