Budesonide/formoterol as Budesonide/formoterol as effective as prednisolone plus effective as prednisolone plus

formoterolformoterolin acute exacerbations of COPD in acute exacerbations of COPD

A double-blind, randomised,A double-blind, randomised,non-inferiority, parallel-group, non-inferiority, parallel-group,

multicentre studymulticentre study

Done by:Done by:

Khalid Al-Rashdi R3Khalid Al-Rashdi R3

Non-inferiority is a kind of similarity within a limit. The limit is the degree of tolerable inferiority of the new drug compared with the standard treatment.

if the non-inferiority limit is set at 7·5%, an increase in the incidence of serious events or deaths—say 7% instead of the 5% currently established for the comparator—is not seen as large enough to mark a difference between the new and the control drug. The new drug will therefore be considered non-inferior to the old drug.

IntroductionIntroduction::

- -Chronic obstructive pulmonary disease (COPD) is Chronic obstructive pulmonary disease (COPD) is aa

major health problem and cause of death and major health problem and cause of death and disabilitydisability..

- -up to 90% of all COPD patients with exacerbations up to 90% of all COPD patients with exacerbations can be treated at primary health care centres and can be treated at primary health care centres and thereafter return home with intensified therapythereafter return home with intensified therapy..

- -oral corticosteroids represent standard treatment oral corticosteroids represent standard treatment for COPD exacerbationsfor COPD exacerbations..

- -22--week course of inhale budesonide/formoterol week course of inhale budesonide/formoterol would be equally effective for treatment of acute would be equally effective for treatment of acute COPD exacerbations as standard therapy in COPD exacerbations as standard therapy in patients judged by the investigator not to require patients judged by the investigator not to require hospitalisationhospitalisation..

- - -the initial 2-week treatment would influence the the initial 2-week treatment would influence the rate of exacerbations during a subsequent 12-rate of exacerbations during a subsequent 12-week open-label treatment period with the fixed week open-label treatment period with the fixed combination of budesonide and formoterol at a combination of budesonide and formoterol at a standard dose of 320/9 μg bidstandard dose of 320/9 μg bid . .

-Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology, Uppsala University, Sweden.

-done in one hospital and 29 health centers.

Published: 19 February 2009

Respiratory Research 2009, 10:11 doi:10.1186/1465-9921-10-11

This article is available from: http://respiratory-research.com/content/10/1/11

MethodsMethods::

--double-blind, randomised, non-inferiority, double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two parallel-group, multicentre study comparing two treatment strategiestreatment strategies..

--two weeks' treatment with inhaled two weeks' treatment with inhaled budesonide/formoterol (320/9 μg, qid) was budesonide/formoterol (320/9 μg, qid) was compared with prednisolone (30 mg once daily) compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 μg bid) in patients with plus inhaled formoterol (9 μg bid) in patients with acute exacerbations of COPD attending a primary acute exacerbations of COPD attending a primary health care centreshealth care centres..

Inclusion criteriaInclusion criteria::

≥ - ≥ -1010 pack years,aged ≥ 40 years, with moderate pack years,aged ≥ 40 years, with moderate COPD corresponding to GOLD stage IIa or COPD corresponding to GOLD stage IIa or IIb ,COPD for ≥ 6 months prior to study entryIIb ,COPD for ≥ 6 months prior to study entry..

--dyspnoea for less than one weekdyspnoea for less than one week

--FEV1 30–60% of predicted normal after acuteFEV1 30–60% of predicted normal after acute

treatment with a single dose of oral corticosteroid treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromideplus nebulised salbutamol/ipratropium bromide

--no requirement for subsequent immediate no requirement for subsequent immediate hospitalisationhospitalisation..

--subsequent open-label budesonide/formoterol subsequent open-label budesonide/formoterol (320/9 μg bid) for another 12 week(320/9 μg bid) for another 12 week..

Exclusion criteriaExclusion criteria::

- -diagnosis of asthmadiagnosis of asthma.. - -a previous COPD exacerbation within 30 days prior a previous COPD exacerbation within 30 days prior

to the studyto the study . . - -oxygen saturation < 92% after the initial acute oxygen saturation < 92% after the initial acute

treatmenttreatment . . - -Requirement for oxygen therapyRequirement for oxygen therapy..

- -a need for immediate hospitalisation as judged by a need for immediate hospitalisation as judged by the investigatorthe investigator . .

- -treatment with any inhaled corticosteroid in doses treatment with any inhaled corticosteroid in doses > 1000 μg/day at study entry> 1000 μg/day at study entry..

- -use of or need for treatment with a non-selective use of or need for treatment with a non-selective β-receptorβ-receptor..

AssessmentsAssessments:: - -end of weeks one and two, and at the end of theend of weeks one and two, and at the end of the

open follow-up periodopen follow-up period..

- -The primary efficacy variable → change in FEV1 The primary efficacy variable → change in FEV1 from baseline to treatmentfrom baseline to treatment..

- -Other efficacy variables were treatment Other efficacy variables were treatment failures,FEV1 measured twice daily at home with failures,FEV1 measured twice daily at home with a Piko-1® electronic peak flow meter, the number a Piko-1® electronic peak flow meter, the number of patients with anof patients with an

exacerbation and the time to first exacerbation exacerbation and the time to first exacerbation during the follow-up periodduring the follow-up period..

--A self administered Clinical COPD QuestionnaireA self administered Clinical COPD Questionnaire

((CCQCCQ))was completed at the start of the studywas completed at the start of the study,,

after one week and at the end of the double-blind after one week and at the end of the double-blind periodperiod..

--At all visits serum C-reactive protein (CRP) At all visits serum C-reactive protein (CRP) concentrationsconcentrations..

--Safety was monitored by reporting of adverse Safety was monitored by reporting of adverse events, serious adverse events and events, serious adverse events and discontinuations due to adverse eventsdiscontinuations due to adverse events..

ResultsResults::

--treatment failuretreatment failure:: 22 cases in first groupcases in first group

--Use of reliever medicationUse of reliever medication patients in the budesonide/formoterol and patients in the budesonide/formoterol and

prednisolone plus formoterol groups used 1.8 and prednisolone plus formoterol groups used 1.8 and 2.1 inhalations per day of reliever medication, 2.1 inhalations per day of reliever medication, respectivelyrespectively..

Critical appraizalCritical appraizal::

Were the Pts in the two groups Were the Pts in the two groups similar at the start of the trial with similar at the start of the trial with respect to prognostic factors?respect to prognostic factors?

Were Pts analysed in the groups to Were Pts analysed in the groups to which they were randomizedwhich they were randomized

BlindingBlinding: :

Were Pts aware of group allocation?Were Pts aware of group allocation? Were clinicians aware of group Were clinicians aware of group

allocation?allocation? Were outcome assessors aware of Were outcome assessors aware of

group allocation?group allocation? Were statisticians aware of group Were statisticians aware of group

allocation?allocation?

Were the follow up of Pts sufficiently Were the follow up of Pts sufficiently long & completelong & complete??

Absolute Risk Reduction (ARR):Absolute Risk Reduction (ARR):

The absolute arithmetic difference in The absolute arithmetic difference in events rate .events rate .

ARR= EER – CERARR= EER – CER

after 1 week =6.84 % -2.5% = after 1 week =6.84 % -2.5% = 4.34%4.34%

after 2 week =8.55 % -7.5% = after 2 week =8.55 % -7.5% = 1.05%1.05%

Relative Risk Reduction (RRR):Relative Risk Reduction (RRR):

Proportional reduction in rates of bad Proportional reduction in rates of bad events between experimental & events between experimental & control group in trial .control group in trial .

RRR =(EER-CER)/CER RRR =(EER-CER)/CER

first week=(6.84 % -2.5 % ) /2.5% first week=(6.84 % -2.5 % ) /2.5% =173% =173%

second =(8.55% -7.50)/7.50 =14%second =(8.55% -7.50)/7.50 =14%

Number Need to Treat ( NNT ):Number Need to Treat ( NNT ):

The number of Pts who need to be The number of Pts who need to be treated to achieve one additional treated to achieve one additional favourable outcome.favourable outcome.

NNT = 1/ ARRNNT = 1/ ARR

=1/4.34% = 23.04=1/4.34% = 23.04

=1/1.05%=95.24=1/1.05%=95.24

Will the results help me in caring for Will the results help me in caring for my Pts?my Pts?

Were the study Pts similar to Pts in Were the study Pts similar to Pts in my care?my care?

Were all clinically important Were all clinically important outcomes considered?outcomes considered?

Are the likely benefits worth the Are the likely benefits worth the potential harms & costs?potential harms & costs?

discussiondiscussion::

- -The risk of systemic side effects when using oral The risk of systemic side effects when using oral prednisolone – even short courses – has been well prednisolone – even short courses – has been well recognised and the total steroid burden may be recognised and the total steroid burden may be heavy in patients with frequent exacerbationsheavy in patients with frequent exacerbations . .

- -Short-term increases in the doses of inhaled Short-term increases in the doses of inhaled budesonide have been found safe and well budesonide have been found safe and well toleratedtolerated

LimitationLimitation::

- lack of a placebo.- lack of a placebo.

- -this study included only patients who had a this study included only patients who had a deterioration of their clinical status during the last deterioration of their clinical status during the last week prior to entryweek prior to entry..

- -all treatment effects were due to the initial single all treatment effects were due to the initial single dose of oral steroid plus the nebulisation of dose of oral steroid plus the nebulisation of bronchodilatorsbronchodilators..

--duration of the prednisolone course (2 weeks)duration of the prednisolone course (2 weeks)

--33--month follow-up period to be sufficient to evaluatemonth follow-up period to be sufficient to evaluate

the incidence of further exacerbationsthe incidence of further exacerbations..

--coast effectivecoast effective..

ConclusionConclusion::

- -High dose budesonide/formoterol was as effective High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in ambulatory treatment of acute exacerbations in non-hospitalized COPD patientsnon-hospitalized COPD patients . .

- -An early increase in budesonide/formoterol dose An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids may therefore be tried before oral corticosteroids are usedare used..

ENDEND