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1、New advances in COPD between 2007 and 2008(starting from 2006),Paul Jones MD,PhDProfessor of Respiratory MedicineSt Georges,University of London,COPD staging(FEV1/FVC 0.70),GOLD treatment guidelines 2007,GOLD 2006 treatment aims,Relieve symptomsImprove exercise tolerance Improve health status Preven
2、t and treat exacerbationsPrevent disease progressionReduce mortalityMinimize side-effects,Inflammation in COPD,CD8+T-Lymphocytes,*Adjusted for multiplicity(p=0.004 unadjusted),Placebo(n=68),Seretide(n=55),0,40,80,120,160,200,240,280,320,Median cells/mm2,Baseline,Week 12,Baseline,Week 12,Barnes et al
3、 AJRCCM 2006;173:736,SFC reduces a range of inflammatory cells and markers,Barnes et al AJRCCM 2006;173:736,Comparison of effect of 3 months treatment with SFC,FP or placebo on airway cellularity in COPD(total n=60),Difference in cell counts,Bourbeau et al Thorax 2007;62:938,TORCH:Study Design,SFC 5
4、00/50 bd,FP 500 bd,Salmeterol 50 bd,Placebo,Duration=3 years,1,533,1,534,1,524,1,521,6112 patients,2 week run-in,ITT population,(any PRN or regular short-acting bronchodliator and/or theophyline),Regions,*Australia,New Zealand,Argentina,Brazil,Chile,Mexico,South Africa&Canada,RandomisedN=6184,FEV1,D
5、istribution of Severity by Post-bronchodilator FEV1,0,1,0,2,0,3,0,4,0,5,0,6,0,Severe,50,30 to 50,Very Severe,30,%of Subjects,%Predicted,Moderate,Post Bronchodilator FEV1(mL),Adj.Mean Change FEV1,0,24,48,72,96,120,156,Time(Weeks),-150,-100,-50,0,50,100,Plc,SAL,FP,SFC,Vertical bars represent standard
6、errors,Calverley et al NEJM 2007;356:775,GOLD 2006 COPD treatment aims,Relieve symptomsImprove exercise tolerance Improve health status Prevent and treat exacerbationsPrevent disease progressionReduce mortalityMinimize side-effects,Rate of decline of FEV1,-60,-50,-40,-30,-20,-10,0,Celli et al(ATS Ab
7、stract May 07),Change in FEV1(ml/yr),Neversmokers,0,0.5,1.0,1.5,2.0,2.5,3.0,Years,0,2,4,6,8,10,12,Change in SGRQScore,(Worse),Weighted RegressionSlope=3.4 units/year,Spencer et al.Am J Respir Crit Care Med 2001;163:122-8.,3-year health status changes in patients receiving short-acting bronchodilator
8、s,Health status and FEV1 worsen together over 3 years,-6,-4,-2,0,2,4,6,8,10,12,14,-0.3,-0.2,-0.1,0,0.1,SGRQ(units/yr),FEV1 slope(l/yr),r=0.24,Spencer et al Eur Respir J 2004;23:1-5,Worse,Better,Exacerbations,GOLD treatment guidelines 2007,0,5,10,15,20,25,30,zero,0-1,1-2,2-3,3-4,4-6,6-8,8,%patients,A
9、nnualised rate of exacerbations,ATS Moderate-Severe(FEV1 50%pred),Exacerbations of COPD(needing antibiotics steroids),Jones et al ERJ 2003;21:1-6,30,35,40,45,50,55,60,SGRQ score,4 wks,12 wks,26 wks,65,No further exacerbation,Baseline(at presentation with acute exacerbation),Spencer 58:589,COPD:time
10、course of recovery from an exacerbation,Exacerbations and worsening in health status over 3 years,Exacerbation Category,0,0.5,1.0,1.5,2.0,2.5,3.0,Nonein 3 years,SGRQ slope(units/yr),Getting worsefaster,Spencer et al.Eur Respir J 2004;23:1-5.,TORCH:Rate of moderate and severe exacerbations over three
11、 years,*p 0.001 vs placebo;p=0.002 vs SALp=0.024 vs FP,1.13,0.97*,0.93*,0.85*,0,0.2,0.4,0.6,0.8,1.2,Placebo,SAL,FP,SFC,Mean number ofexacerbations/year,Calverley et al NEJM 2007;356:775,1.0,Carbocisteine in COPD,Patients baseline demographic and characteristics,Repeat exacerbation-free,P0.05,Carboci
12、steine reduces COPD exacerbations,Exacerbation-free,Risk Ratio 0.74(95%CI 0.61,0.89)p=0.002,Carbocisteine,Carbocisteine,Placebo,Placebo,Zheng J-P et al,Lancet 2008;371:2013,Carbocisteine improves health status,Zheng J-P et al,Lancet 2008;371:2013,GOLD 2006 COPD treatment aims,Relieve symptomsImprove
13、 exercise tolerance Improve health status Prevent exacerbationsPrevent disease progressionReduce mortalityMinimize side-effects,0,20,40,60,80,100,10,20,30,40,50,60,70,80,90,Upper limitof normal,COPD:Quality of life and FEV1,SGRQ score,Poor Health,Good Health,Jones Thorax 2001;56:880,FEV1(%predicted)
14、,TORCH-SGRQ Total Score,-5,-4,-3,-2,-1,0,1,2,3,0,24,48,72,96,120,156,Adjusted mean Change SGRQTotal Score(Units),Weeks,Vertical bars represent standard errors,Calverley et al NEJM 2007;356:775,Getting worse,Change in SGRQ score in China(n=445),JP Zheng et al.Chest 2007;132:1756,Placebo,SFC,-5,-4,-3,
15、-2,-1,0,1,2,3,0,24,48,72,96,120,156,Adjusted mean Change SGRQTotal Score(Units),Weeks,TORCH-SGRQ Total Score,Placebo,SFC,“The treatment is no longer working”,Without treatment would be here,GOLD 2006 COPD treatment aims,Relieve symptomsImprove exercise tolerance Improve health status Prevent exacerb
16、ationsPrevent disease progressionReduce mortalityMinimize side-effects,TORCH:All cause mortality at 3 years,0,2,4,6,8,10,12,14,16,18,3-yearmortality(%),Log rank test p=0.052Coxs Proportional Hazard p=0.03,15.2,12.6,Calverley et al NEJM 2007;356:775,Placebo,SFC,Cause of Death(Adjudicated by CEC),0,1,
17、2,3,4,5,6,7,Cardio-vascular,Pulmonary,Cancer,Other,Unknown,Deaths(%of ITT Pop),All-cause mortality by GOLD Stage,*Kaplan-Meier estimate,All-cause mortality by GOLD Stage,*Kaplan-Meier estimate,All-cause mortality by GOLD Stage,*Kaplan-Meier estimate,All-cause mortality by GOLD Stage,*Kaplan-Meier es
18、timate,Other trials,2 weekRun-in,2-years treatment,Prednisolone 30mg/day+salmeterol 50mg b.d.,Tiotropium bromide 18mg o.d.via Handihaler(n=665),SFC 50/500mg b.d.via DISKUS(n=658),INSPIRE:Study design,Seemungal et al.J COPD 2007,(FEV1 39%pred,n=1323),Inspire:Exacerbation rate and FEV1,Wedzicha et al
19、AJRCCM 2008;177:19,Inspire:Difference in response of SGRQ(SFC vs tiotropum),MCID=minimal clinically important difference,-5,-4,-3,-2,-1,0,1,Mean Change in SGRQ Total ScoreSFC vs tiotropium,Week,MCID,SFCmoreeffective,34,-2,10,22,46,58,70,82,94,106,Wedzicha et al AJRCCM 2008;177:19,No difference,Mean9
20、5%CI,Inspire:Mortality,On-treatment Comparison from Coxs Proportional Hazards Model,013263952657891104,0,1,2,3,4,5,6,7,Probability of Event(%),Time to Event(Weeks),Tiotropium,Wedzicha et al AJRCCM 2008;177:19,8,250 COPD patients with history of exacerbationsWeaned off previous therapy and put on tio
21、tropiumRandomised to either:PlaceboSalmeterolSFC,Aaron et al.Ann Int Med.2007;146:545,Optimal:trial design,Optimal Study-exacerbations,Tio+SFC,Tio+Salmeterol,Tio+Placebo,p0.1,Aaron et al.Ann Int Med.2007;146:545,Change in FEV1(ml),4,36,20,52,Time(weeks),0,180,120,90,60,30,0,150,Optimal Study FEV1,Aa
22、ron et al.Ann Int Med.2007;146:545,0,-2,-4,-6,-10,-8,4,36,20,52,Change inSGRQ Totalscore,Time(weeks),Tiotropium+Placebo,Aaron et al.Ann Int Med.2007;146:545,0,Tiotropium+Salmeterol,Optimal Study health status,GOLD 2006 treatment aims,Relieve symptomsImprove exercise tolerance Improve health status P
23、revent and treat exacerbationsPrevent disease progressionReduce mortalityMinimize side-effects,TORCH:Expected Adverse Events starting during treatment-rate per 1000 treatment years,SFCN=1546,FPN=1552,SALN=1542,PlcN=1544,Change in total hip BMD(sub-study),Vertical bars represent standard errors,0,48,
24、108,158,Plc,SAL,FP,SFC,-5,-4,-3,-2,-1,0,1,Adj.Mean Percent ChangeBMD Hip,161162158162,87105112118,Numberof Subjects,72828095,52786582,Time(Weeks),Summary,All aspects of COPD respond to SFC treatmentSFC slows disease progressionFEV1 maintained longer and rate of declined slowedFewer exacerbationsHeal
25、th status maintained longerSFC:effective in patients with milder diseaseFEV1 50-60%predictedLess frequent exacerbations(ie 0-1 per year)SFC:some additive effects on top of tiotropiumSFC:minimal detectable side-effects after 3 years,Alternative treatment to Lung Volume Reduction Surgery for severe up
26、per lobe emphysema,IBVTM Valve System,Bilateral UL Selection and Treatment,Chest X-Ray with valves in place,SGRQ in Major COPD Trials,LVRS,Intra-bronchialvalve,Drugs,Conclusions,COPD is a treatable diseaseSalmeterol+fluticasone combination(Seretide)provides clear benefits for milder patients than are currently recommended in guidelinesNew devices may place a role in managing very severe disease instead of lung volume reduction surgery,
