Budesonide/formoterol aseffective as prednisolone plusformoterolin acute exacerbations of COPDA double-blind, randomised,non-inferiority, parallel-group,multicentre studyBudesonide/formoterol aseffective as prednisolone plusformoterolin acute exacerbations of COPDA double-blind, randomised,non-inferiority, parallel-group,multicentre study
Done by:Done by:
Khalid Al-Rashdi R3 Khalid Al-Rashdi R3
Non-inferiority is a kind of similarity within a limit. The limitis the degree of tolerable inferiority of the new drugcompared with the standard treatment .
if the non-inferiority limit is set at 7·5%, an increase in the incidence ofserious events or deaths—say 7% instead of the 5% currentlyestablished for the comparator—is not seen as large enough tomark a difference between the new and the control drug. The newdrug will therefore be considered non-inferior to the old drug.
Introduction:Introduction:
- Chronic obstructive pulmonary disease (COPD) is a- Chronic obstructive pulmonary disease (COPD) is a
major health problem and cause of death and disability.major health problem and cause of death and disability.
- up to 90% of all COPD patients with exacerbations can betreated at primary health care centres and thereafterreturn home with intensified therapy.- up to 90% of all COPD patients with exacerbations can betreated at primary health care centres and thereafterreturn home with intensified therapy.
- oral corticosteroids represent standard treatment forCOPD exacerbations.- oral corticosteroids represent standard treatment forCOPD exacerbations.
- 2-week course of inhale budesonide/formoterol would beequally effective for treatment of acute COPDexacerbations as standard therapy in patients judged bythe investigator not to require hospitalisation.- 2-week course of inhale budesonide/formoterol would beequally effective for treatment of acute COPDexacerbations as standard therapy in patients judged bythe investigator not to require hospitalisation.
-- the initial 2-week treatment would influence the rate ofexacerbations during a subsequent 12-week open-labeltreatment period with the fixed combination ofbudesonide and formoterol at a standard dose of 320/9μg bid.-- the initial 2-week treatment would influence the rate ofexacerbations during a subsequent 12-week open-labeltreatment period with the fixed combination ofbudesonide and formoterol at a standard dose of 320/9μg bid.
-Department of Public Health and Caring Sciences,Family Medicine and Clinical Epidemiology, UppsalaUniversity, 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
Methods:Methods:
-double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatmentstrategies.-double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatmentstrategies.
-two weeks' treatment with inhaledbudesonide/formoterol (320/9 μg, qid) was comparedwith prednisolone (30 mg once daily) plus inhaledformoterol (9 μg bid) in patients with acuteexacerbations of COPD attending a primary health carecentres.-two weeks' treatment with inhaledbudesonide/formoterol (320/9 μg, qid) was comparedwith prednisolone (30 mg once daily) plus inhaledformoterol (9 μg bid) in patients with acuteexacerbations of COPD attending a primary health carecentres.
Inclusion criteria:Inclusion criteria:
- ≥ 10 pack years,aged ≥ 40 years, with moderate COPDcorresponding to GOLD stage IIa or IIb ,COPD for ≥ 6months prior to study entry.- ≥ 10 pack years,aged ≥ 40 years, with moderate COPDcorresponding to GOLD stage IIa or IIb ,COPD for ≥ 6months prior to study entry.
-dyspnoea for less than one week-dyspnoea for less than one week
-FEV1 30–60% of predicted normal after acute-FEV1 30–60% of predicted normal after acute
treatment with a single dose of oral corticosteroid plusnebulised salbutamol/ipratropium bromidetreatment with a single dose of oral corticosteroid plusnebulised salbutamol/ipratropium bromide
-no requirement for subsequent immediate hospitalisation.-no requirement for subsequent immediate hospitalisation.
-subsequent open-label budesonide/formoterol (320/9μg bid) for another 12 week.-subsequent open-label budesonide/formoterol (320/9μg bid) for another 12 week.
Exclusion criteria:Exclusion criteria:
- diagnosis of asthma.- diagnosis of asthma.
- a previous COPD exacerbation within 30 days prior to thestudy.- a previous COPD exacerbation within 30 days prior to thestudy.
- oxygen saturation < 92% after the initial acutetreatment.- oxygen saturation < 92% after the initial acutetreatment.
- Requirement for oxygen therapy.- Requirement for oxygen therapy.
- a need for immediate hospitalisation as judged by theinvestigator.- a need for immediate hospitalisation as judged by theinvestigator.
- treatment with any inhaled corticosteroid in doses > 1000μg/day at study entry.- treatment with any inhaled corticosteroid in doses > 1000μg/day at study entry.
- use of or need for treatment with a non-selective β-receptor.- use of or need for treatment with a non-selective β-receptor.
Assessments:Assessments:
- end of weeks one and two, and at the end of the- end of weeks one and two, and at the end of the
open follow-up period.open follow-up period.
- The primary efficacy variable → change in FEV1 frombaseline to treatment.- The primary efficacy variable → change in FEV1 frombaseline to treatment.
- Other efficacy variables were treatment failures,FEV1measured twice daily at home with a Piko-1® electronicpeak flow meter, the number of patients with an- Other efficacy variables were treatment failures,FEV1measured twice daily at home with a Piko-1® electronicpeak flow meter, the number of patients with an
exacerbation and the time to first exacerbation duringthe follow-up period.exacerbation and the time to first exacerbation duringthe follow-up period.
-A self administered Clinical COPD Questionnaire-A self administered Clinical COPD Questionnaire
(CCQ)was completed at the start of the study,(CCQ)was completed at the start of the study,
after one week and at the end of the double-blind period.after one week and at the end of the double-blind period.
-At all visits serum C-reactive protein (CRP) concentrations.-At all visits serum C-reactive protein (CRP) concentrations.
-Safety was monitored by reporting of adverse events,serious adverse events and discontinuations due toadverse events.-Safety was monitored by reporting of adverse events,serious adverse events and discontinuations due toadverse events.
Results:Results:
-treatment failure:-treatment failure:
2 cases in first group 2 cases in first group
-Use of reliever medication-Use of reliever medication
patients in the budesonide/formoterol andprednisolone plus formoterol groups used 1.8 and 2.1inhalations per day of reliever medication, respectively. patients in the budesonide/formoterol andprednisolone plus formoterol groups used 1.8 and 2.1inhalations per day of reliever medication, respectively.
Critical appraizal:Critical appraizal:
Were the Pts in the two groups similar atthe start of the trial with respect toprognostic factors?Were the Pts in the two groups similar atthe start of the trial with respect toprognostic factors?
Were Pts analysed in the groups to whichthey were randomizedWere Pts analysed in the groups to whichthey were randomized
Blinding :Blinding :
Were Pts aware of group allocation?Were Pts aware of group allocation?
Were clinicians aware of group allocation?Were clinicians aware of group allocation?
Were outcome assessors aware of groupallocation?Were outcome assessors aware of groupallocation?
Were statisticians aware of groupallocation?Were statisticians aware of groupallocation?
Were the follow up of Pts sufficiently long& complete?Were the follow up of Pts sufficiently long& complete?
Absolute Risk Reduction (ARR):Absolute Risk Reduction (ARR):
The absolute arithmetic difference in eventsrate .The absolute arithmetic difference in eventsrate .
ARR= EER – CERARR= EER – CER
after 1 week =6.84 % -2.5% = 4.34% after 1 week =6.84 % -2.5% = 4.34%
after 2 week =8.55 % -7.5% = 1.05% after 2 week =8.55 % -7.5% = 1.05%
Relative Risk Reduction (RRR):Relative Risk Reduction (RRR):
Proportional reduction in rates of bad eventsbetween experimental & control group intrial .Proportional reduction in rates of bad eventsbetween experimental & control group intrial .
RRR =(EER-CER)/CERRRR =(EER-CER)/CER
first week=(6.84 % -2.5 % ) /2.5% =173% first week=(6.84 % -2.5 % ) /2.5% =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 treatedto achieve one additional favourableoutcome.The number of Pts who need to be treatedto achieve one additional favourableoutcome.
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 myPts?Will the results help me in caring for myPts?
Were the study Pts similar to Pts in mycare?Were the study Pts similar to Pts in mycare?
Were all clinically important outcomesconsidered?Were all clinically important outcomesconsidered?
Are the likely benefits worth the potentialharms & costs?Are the likely benefits worth the potentialharms & costs?
discussion:discussion:
- The risk of systemic side effects when using oralprednisolone – even short courses – has been wellrecognised and the total steroid burden may be heavy inpatients with frequent exacerbations.- The risk of systemic side effects when using oralprednisolone – even short courses – has been wellrecognised and the total steroid burden may be heavy inpatients with frequent exacerbations.
- Short-term increases in the doses of inhaledbudesonide have been found safe and well tolerated- Short-term increases in the doses of inhaledbudesonide have been found safe and well tolerated
Limitation:Limitation:
- lack of a placebo.- lack of a placebo.
- this study included only patients who had a deteriorationof their clinical status during the last week prior to entry.- this study included only patients who had a deteriorationof their clinical status during the last week prior to entry.
- all treatment effects were due to the initial single dose oforal steroid plus the nebulisation of bronchodilators.- all treatment effects were due to the initial single dose oforal steroid plus the nebulisation of bronchodilators.
-duration of the prednisolone course (2 weeks)-duration of the prednisolone course (2 weeks)
-3-month follow-up period to be sufficient to evaluate-3-month follow-up period to be sufficient to evaluate
the incidence of further exacerbations.the incidence of further exacerbations.
-coast effective.-coast effective.
Conclusion:Conclusion:
- High dose budesonide/formoterol was as effective asprednisolone plus formoterol for the ambulatorytreatment of acute exacerbations in non-hospitalizedCOPD patients.- High dose budesonide/formoterol was as effective asprednisolone plus formoterol for the ambulatorytreatment of acute exacerbations in non-hospitalizedCOPD patients.
- An early increase in budesonide/formoterol dose maytherefore be tried before oral corticosteroids are used.- An early increase in budesonide/formoterol dose maytherefore be tried before oral corticosteroids are used.
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