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Benefit of ACE Inhibitors in Diabetes:Benefit of ACE Inhibitors in Diabetes:Important Findings of 5 Major Clinical TrialsImportant Findings of 5 Major Clinical TrialsUKPDS(1998)Tight blood pressure control with captopril or atenolol compared to less tight control lowered the rates of stroke,any diabetes endpoint,microvascular outcomes,and deathIntensive compared to conventional glucose control lowered risk of any diabetes-related endpoint,microvascular endpoints and myocardial infarction HOPE&MICRO-HOPE Substudy(2000)Ramipril compared to placebo added to usual care reduces the occurrence of death,myocardial infarction,and stroke in both diabetics and nondiabeticsRamipril decreased progression of proteinuria in diabetics ABCD(1998)Enalapril compared to nisoldipine provided comparable blood pressure control and better protection against myocardial infarctionABCD,CAPPP,FACET and UKPDS meta-analysis(2000)ACEIs compared to other agents significantly reduced the frequency of acute myocardial infarction,cardiovascular events,and all-cause mortality Benefit of ACE Inhibitors in DRelative risk for tight control(95%CI)P ValueRelative risk reduction(95%CI)Any DM-related endpoint0.76(0.620.92)0.005DM-related deaths0.68(0.490.94)0.02All-cause mortality0.82(0.631.08)0.17Myocardial infarction0.79(0.591.07)0.13Stroke0.56(0.350.89)0.01Peripheral vascular disease0.51(0.191.37)0.17Microvascular complications0.63(0.440.89)0.009UKPDS Impact of Tight*UKPDS Impact of Tight*vs Less Tightvs Less Tight Blood Blood Pressure Control on Diabetes-Related EndpointsPressure Control on Diabetes-Related Endpoints0.1110Favors tightcontrolFavors less tight control*n=758(mean achieved blood pressure of 144/82 mmHg)n=390(mean achieved blood pressure of 154/87 mmHg)Adapted from UKPDS Group.BMJ.1998;317:703713.Reprinted with permission from the BMJ Publishing Group.Relative risk P ValueRelative UKPDS UKPDS Event Rates for Select Event Rates for Select Endpoints With Endpoints With Tight vs Less Tight Blood Pressure ControlTight vs Less Tight Blood Pressure ControlAny diabetes-related endpointDiabetes-related deathStrokeMicrovascular complicationsEvents per 1000 patient yrsP=0.005P=0.02P=0.01P=0.009Less tight(n=390)mean achieved BP 154/87 mmHgTight(n=758)mean achieved BP 144/82 mmHgUKPDS Group.BMJ.1998;317:703713.UKPDS Event Rates for Select EUKPDS UKPDS Relative Risk Reduction for Relative Risk Reduction for Tight*vs Less TightTight*vs Less Tight Blood Pressure Control Blood Pressure ControlEndpoint%Relative risk reductionP valueAny diabetes-related endpoint Diabetes-related deaths24 25320.0050.02Heart failureStrokeMyocardial infarction5644210.0040.01NSMicrovascular complicationsRetinopathy progressionDeterioration of vision3734470.0090.0040.004*n=758(mean achieved blood pressure of 144/82 mmHg)n=390(mean achieved blood pressure of 154/87 mmHg)UKPDS Group.BMJ.1998;317:703713.UKPDS Relative Risk Reduction UKPDS Outcomes by Treatment UKPDS Outcomes by Treatment Group for Patients Randomized to Group for Patients Randomized to Tight Blood Pressure Control*Tight Blood Pressure Control*UKPDS Group.BMJ.1998;317:713720.Captopril(n=400)Atenolol(n=358)Relative Risk(95%CI)Any DM-related endpoint1411181.10(0.86-1.41)Diabetes-related death48341.27(0.82-1.97)All-cause mortality75591.14(0.81-1.61)Myocardial infarction61461.20(0.82-1.76)Stroke21171.12(0.59-2.12)Peripheral vascular disease531.48(0.35-6.19)Microvascular complications40281.29(0.80-2.10)*the differences between the treatment groups were not statistically significantfor captopril compared to atenololUKPDS Outcomes by Treatment GUKPDS Kaplan-Meier Plots of Proportion of UKPDS Kaplan-Meier Plots of Proportion of Patients with Any Diabetes-Related EndpointPatients with Any Diabetes-Related EndpointPatients with events(%)Years from randomization1241120213546879257237327314400358CaptoprilAtenololN.o of patients at risk:Less tight blood pressure controlCaptoprilAtenololP=0.43UKPDS Group.BMJ.1998;317:713720.Reprinted with permission from the BMJ Publishing Group.UKPDS Kaplan-Meier Plots of PrUKPDS Kaplan-Meier Plots of Proportion of UKPDS Kaplan-Meier Plots of Proportion of Patients Who Died of Disease Related to Diabetes Patients Who Died of Disease Related to Diabetes Patients with events(%)Years from randomization172154Less tight blood pressure controlCaptoprilAtenolol0213546879328303383346400358CaptoprilAtenololNo.of patients at risk:P=0.28UKPDS Group.BMJ.1998;317:713720.Reprinted with permission from the BMJ Publishing Group.UKPDS Kaplan-Meier Plots of PrFavorsconventional0.512FavorsintensiveUKPDS Group.Lancet.1998;352:837-853.Reprinted with permission from Elsevier Science.UKPDS Relative Risk Reduction for UKPDS Relative Risk Reduction for Intensive vs Less Intensive Glucose ControlIntensive vs Less Intensive Glucose Control%Relative riskreductionP valueRelative risk reduction(95%CI)Any DM-related endpoint120.03DM-related deaths100.34All-cause mortality60.44Myocardial infarction160.05Microvascular complications250.01Over 10 years,HbA1c was 7.0%(6.2-8.2)in the intensive group(n=2,729)compared with 7.9%(6.9-8.8)in the conventional group(n=1,138).Favors0.512FavorsUKPDS Group.%relative risk reductionP=0.03P0.01P0.01P=0.05P=0.02UKPDS Group.Lancet.1998;352:837-853.UKPDS Relative Risk Reduction for UKPDS Relative Risk Reduction for Intensive vs Less Intensive Glucose ControlIntensive vs Less Intensive Glucose ControlOver 10 years,HbA1c was 7.0%(6.2-8.2)in the intensive group(n=2,729)compared with 7.9%(6.9-8.8)in the conventional group(n=1,138).%relative risk reductionP=0.0UKPDS Findings on Tight Blood Pressure UKPDS Findings on Tight Blood Pressure Control and Intensive Glucose ControlControl and Intensive Glucose ControlTight vs less tight blood pressure control reduces risk ofAny diabetes-related endpoint 24%P=0.005Microvascular complications37%P=0.009Stroke 44%P=0.01An intensive compared to conventional glucose control policy reduces risk of Any diabetes-related endpoint 12%P=0.03Microvascular complications 25%P0.01Myocardial infarction 16%P=0.05UKPDS Group.BMJ.1998;317:703712.UKPDS Group.Lancet.1998;352:837-853.Tight control(using captopril or atenolol)mean achieved BP 144/82 mmHg(n=758)Less tight control(avoiding ACEIs and-blockers)mean achieved BP 154/87 mmHg(n=390)Over 10 years,HbA1c was 7.0%(6.2-8.2)in the intensive group treated with sulfonylurea or insulin(n=2,729)compared with 7.9%(6.9-8.8)in the conventional group(n=1,138)with diet modificationsUKPDS Findings on Tight Blood Benefit of ACE Inhibitors in Diabetes:Benefit of ACE Inhibitors in Diabetes:Important Findings of 5 Major Clinical TrialsImportant Findings of 5 Major Clinical TrialsUKPDS(1998)Tight blood pressure control with captopril or atenolol compared to less tight control lowered the rate of stroke,any diabetes endpoint,microvascular outcomes,and deathIntensive compared to conventional glucose control lowered risk of any diabetes-related endpoint,microvascular endpoints and myocardial infarction HOPE&MICRO-HOPE Substudy(2000)Ramipril compared to placebo added to usual care reduces the occurrence of death,myocardial infarction,and stroke in both diabetics and nondiabeticsRamipril decreased progression of proteinuria in diabetics ABCD(1998)Enalapril compared to nisoldipine provided comparable blood pressure control and better protection against myocardial infarctionABCD,CAPPP,FACET and UKPDS meta-analysis(2000)ACEIs compared to other agents significantly reduced the frequency of acute myocardial infarction,cardiovascular events,and all-cause mortality Benefit of ACE Inhibitors in DHOPE StudyThe Heart Outcomes Prevention Evaluation(HOPE)Study was a multicenter,randomized trial enrolling 9,297 patients 55 years old with a history of cardiovascular disease,or diabetes plus at least one other cardiovascular risk factorPatients were treated with ramipril or placebo and vitamin E or placebo for an average of 4.5 years Combined primary endpoint was the development of myocardial infarction,stroke,or cardiovascular deathSecondary endpoints were total mortality,admission to hospital for congestive heart failure or unstable angina,complications related to diabetes,and cardiovascular revascularizationYusuf S,et al.N Engl J Med.2000;342:145-153.HOPE StudyThe Heart Outcomes PHOPE Study Outcomes:Events Per Patient GroupCombined Primary Outcome*Cardio-vascular DeathMyocardial InfarctionStrokeNon-Cardiovascular DeathTotal MortalityYusuf S,et al.N Engl J Med.2000;342:145-153.RR=22%P0.001RR=26%P0.001RR=20%P0.001RR=32%P0.001RR=16%P=0.005RR=0%P=NSRR=Relative risk reductionEvents per patient group(%)*The occurrence of myocardial infarction,stroke or cardiovascular deathHOPE Study Outcomes:Events PMICRO-HOPE SubstudyThe MIcroalbuminuria,Cardiovascular,and Renal Outomes HOPE Study enrolled 3,577 diabetics who participated in the larger HOPE Study(n=9,541)MICRO-HOPE had the same study design,duration and endpoints as HOPE,with the addition of the development of overt nephropathy as an endpointHOPE Study Investigators.Lancet.2000;355:253-259.MICRO-HOPE SubstudyThe MIcroalMICRO-HOPE Baseline Characteristics HOPE Study Investigators.Lancet.2000;355:253-259.Ramipriln=1,808Placebon=1,769Mean age(yrs)65.365.6Males(n)1,1121,143Type 2 diabetes(n)Mean duration of diabetes(years)1,77411.11,72211.8Therapy for hyperglycemia(n)Dietary therapy alone Insulin therapy alone Oral agents alone Insulin+oral agents3314329578830048289592Microalbuminuria(n)555587Mean HbA1C(%of ULN*)Mean serum creatinine(mol/L)123 93.812494.0*Measured at local laboratories;HbA1C is reported as percentage above ULN(upper limit of normal)for local laboratory.Conversion factor of 88.4 mol/L=1 milligram per deciliterMICRO-HOPE Baseline CharacteriMICRO-HOPE Events Per Patient Group for MICRO-HOPE Events Per Patient Group for PrimaryPrimary Endpoint*and Components Endpoint*and ComponentsHOPE Study Investigators.Lancet.2000;355:253-259.Combined primary endpoint*Myocardial infarctionStrokeCardiovascular deathRR=25%P0.001RR=22%P=0.01RR=33%P=0.007RR=37%P0.001Events per patient group(%)RR=Relative risk reduction*The occurrence of myocardial infarction,stroke or cardiovascular deathMICRO-HOPE Events Per Patient 0.2 0.4 0.6 0.8 1.0 1.2Adapted from HOPE Study Investigators.Lancet.2000;355:253-259.Reprinted with permission from Elsevier Science.MICRO-HOPE Combined Primary Endpoint*in SubgroupsTotal#%in placebo groupRelative risk reduction(95%CI)Dietary hyperglycemic control63119.0Insulin1,85219.3Oral hypoglycemics91421.6Insulin and oral hypoglycemics18018.5Microalbuminuria1,14028.6Cardiovascular disease2,45823.9*The occurrence of myocardial infarction,stroke or cardiovascular deathDuring studyAt baseline0.20.4 0.6 0.8 1.0 1.2AdaptedMICRO-HOPE Events Per Patient Group for Secondary EndpointsEvents per patient group(%)Total mortalityRevascularizationOvertnephropathy*Heart failureUnstable anginaHOPE Study Investigators.Lancet.2000;355:253-259.*Based on positive 24h urine collection or albumin/creatinine ratio 36 mg/mmol Requiring hospital admissionRR=24%P=0.004RR=17%P=0.03RR=24%P=0.03NSNSRR=Relative risk reductionNS 0.05MICRO-HOPE Events Per Patient MICRO-HOPE Combined Primary MICRO-HOPE Combined Primary Endpoint*Event RatesEndpoint*Event Rates020040060080010001200 140018001600HOPE Study Investigators.Lancet.2000;355:253-259.Reprinted with permission from Elsevier Science.RR=25%P0.001PlaceboRamiprilDuration of follow-up(days)Kaplan-Meier rates*The occurrence of myocardial infarction,stroke or cardiovascular deathRR=Relative risk reductionMICRO-HOPE Combined Primary EnMICRO-HOPEChange in Systolic Blood Pressure*P0.001 Study duration was 4.5 yearsHOPE Study Investigators.Lancet.2000;355:253-259.Change from baseline(mmHg)MICRO-HOPEChange in Systolic Benefit of ACE Inhibitors in Diabetes:Benefit of ACE Inhibitors in Diabetes:Important Findings of 5 Major Clinical TrialsImportant Findings of 5 Major Clinical TrialsUKPDS(1998)Tight blood pressure control with captopril or atenolol compared to less tight control lowered the rate of stroke,any diabetes endpoint,microvascular outcomes,and deathIntensive compared to conventional glucose control lowered risk of any diabetes-related endpoint,microvascular endpoints and myocardial infarction HOPE&MICRO-HOPE Substudy(2000)Ramipril compared to placebo added to usual care reduces the occurrence of death,myocardial infarction,and stroke in both diabetics and nondiabeticsRamipril decreased progression of proteinuria in diabetics ABCD(1998)Enalapril compared to nisoldipine provided comparable blood pressure control and better protection against myocardial infarctionABCD,CAPPP,FACET and UKPDS meta-analysis(2000)ACEIs compared to other agents significantly reduced the frequency of acute myocardial infarction,cardiovascular events,and all-cause mortality Benefit of ACE Inhibitors in DABCD TrialThe Appropriate Blood Pressure Control in Diabetes(ABCD)Trial enrolled 950 non-insulin-dependent diabetics with minimally reduced renal function to compare the effect of moderate BP control(target diastolic BP of 80 to 89 mmHg)to intensive BP control(target diastolic BP of 75 mmHg)over 5.3 years of follow-upNisoldipine and enalapril also were compared as first-line antihypertensive agents in the prevention and progression of complications of diabetesPrimary outcome measure was glomerular filtration rate as assessed by 24hr creatinine clearanceSecondary outcome measures were urinary albumin excretion,left ventricular hypertrophy,retinopathy,and neuropathyIn hypertensive subgroup(n=470),the endpoint of the incidence of myocardial infarction was analyzedEstacio RO,et al.N Eng J Med.1998;338:645-652.ABCD TrialThe Appropriate BlooABCD Hypertensive Subgroup Change in ABCD Hypertensive Subgroup Change in Blood Pressure by Treatment GroupBlood Pressure by Treatment Group708090100110120130140150160Blood pressure(mmHg)MonthNisoldipineIntensive-Treatment GroupIntensive-Treatment GroupModerate-Treatment GroupModerate-Treatment Group618304254618304254SystolicSystolicDiastolicDiastolicSystolicSystolicDiastolicDiastolicEstacio RO,et al.N Engl J Med.1998;338:645-652.1998 Massachusetts Medical Society.All rights reserved.EnalaprilABCD Hypertensive Subgroup ChaABCD Trial CV Outcomes and Death in Hypertensive SubgroupFatal or non-fatal MINon-fatal MICongestive heart failureDeath from CV causesDeath from any causeMI=myocardial infarctionCV=cardiovascular Estacio RO,et al.N Engl J Med.1998;338:645-652.Schrier RW,Estacio RO.N Engl J Med.2000;343:1969.P=0.03P=0.03Number of eventsP=NSP=NSP=NSNisoldipine(n=235)Enalapril(n=235)ABCD Trial CV Outcomes and DeaBenefit of ACE Inhibitors in Diabetes:Benefit of ACE Inhibitors in Diabetes:Important Findings of 5 Major Clinical TrialsImportant Findings of 5 Major Clinical TrialsUKPDS(1998)Tight blood pressure control with captopril or atenolol compared to less tight control lowered the rate of stroke,any diabetes endpoint,microvascular outcomes,and deathIntensive compared to conventional glucose control lowered risk of any diabetes-related endpoint,microvascular endpoints and myocardial infarction HOPE&MICRO-HOPE Substudy(2000)Ramipril compared to placebo added to usual care reduces the occurrence of death,myocardial infarction,and stroke in both diabetics and nondiabeticsRamipril decreased progression of proteinuria in diabetics ABCD(1998)Enalapril compared to nisoldipine provided comparable blood pressure control and better protection against myocardial infarctionABCD,CAPPP,FACET and UKPDS meta-analysis(2000)ACEIs compared to other agents significantly reduced the frequency of acute myocardial infarction,cardiovascular events,and all-cause mortality Benefit of ACE Inhibitors in DABCD,CAPPP,FACET ABCD,CAPPP,FACET and UKPDS Meta-Analysisand UKPDS Meta-AnalysisTo assess whether ACE inhibitors are superior to other agents in the prevention of cardiovascular events in hypertensive type 2 diabeticsReview and meta-analysis of randomized controlled trials of patients treated with ACEIs or other agents,followed for 2 years,with adjudicated cardiovascular events4 trials eligible ABCD(n=470)compared enalapril with nisoldipineCAPPP(n=572)compared captopril with diuretic or beta-blockersFACET(n=380)compared fosinopril with amlodipineUKPDS(n=758)compared captopril with atenololPahor M,et al.Diabetes Care.2000;23:888-892.ABCD,CAPPP,FACET and UKPDS Relative Risk Reduction With ACEIs Relative Risk Reduction With ACEIs in ABCD,CAPPP and FACETin ABCD,CAPPP and FACET%relative risk reductionPahor M,et al.Diabetes Care.2000;23:888-892.Acute Myocardial InfarctionCardiovascular EventStrokeAll-cause MortalityP0.001P60 kg)Brenner BM,et al.N Engl J Med.2001;345(12):861-869.The Reduction of Endpoints in RENAAL Study Design*Open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,or centrally acting agentIn combination with open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,and/or centrally acting agentLosartan100 mg qdMaintain antihypertensive therapy*(excluding ACE inhibitors&angiotensin II receptor antagonists)Losartan 100 mg qdPlaceboTrough Blood Pressure Goal 140/90 mmHgn=1,513 PlaceboLosartan50 mg qdPlaceboWeek 10Week146 week screening phaseAverage follow-up 3.4 yearsBrenner BM,et al.J Renin Angiotens Aldo System.2000;1:329335.RENAAL Study Design*Open-labelRENAAL EndpointsPrimary EndpointComposite of a doubling of serum creatinine,end stage renal disease,or deathSecondary Endpoints1.Composite of morbidity&mortality from cardiovascular causesMyocardial infarctionStrokeFirst hospitalization for heart failure or unstable angina,coronary or peripheral revascularizationDeath from cardiovascular causes2.Proteinuria3.Rate of progression of renal diseaseBrenner BM,et al.N Engl J Med.2001;345(12):861-869.RENAAL EndpointsPrimary Endpoi*The differences between the treatment groups were not statistically significantRENAAL Baseline Characteristics*RENAAL Baseline Characteristics*Losartan Group n=751Placebo Groupn=762Mean Age(yrs)6060Male(%)62 65Mean Systolic BP(mmHg)Mean Diastolic BP(mmHg)1528215382Mean BMI(kg/m2)3029 Median urinary albumin:creatinine ratio(mg/g)12371261Mean serum creatinine(mg/dL)1.91.9Mean glycosylated hemoglobin(%)8.58.4In combination with open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,and/or centrally acting agentBrenner BM,et al.N Engl J Med.2001;345(12):861-869.*The differences between the tRENAAL Trends in Blood Pressure and Pulse PressureMonths75167356237110176265853231371SystolicDiastolicMean arterial pressure(P0.001 at 12 months)0122436486080100120140160Pulse pressureBlood Pressure and Pulse Pressure(mmHg)Placebo*(n)Losartan*(n)Brenner BM,et al.N Engl J Med.2001;345(12):861-869.*In combination with open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,and/or centrally acting agentRENAAL Trends in Blood PressurRENAAL Impact of Losartan RENAAL Impact of Losartan on Primary Composite Endpoint*on Primary Composite Endpoint*Losartan Group n=751Placebo Group n=762P value%Relative riskreduction(95%CI)n%n%Primary composite endpoint*32743.535947.10.0216(2 to 28)Doubling of serum creatinine ESRD Death16214715821.619.621.0198194155 26.025.520.3 0.0060.0020.8825(8 to 39)28(11 to 42)-2(-27 to 19)ESRD or Death25534.030039.40.0120(5 to 32)Doubling of serum creatinine and ESRD22630.126334.50.0121(5 to 34)*Composite of a doubling of serum creatinine,end stage renal disease(ESRD),or deathBrenner BM,et al.N Engl J Med.2001;345(12):861-869.In combination with open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,and/or centrally acting agentRENAAL Impact of Losartan on Brenner BM,et al.N Engl J Med.2001;345(12):861-869.2001 Massachusetts Medical Society.All rights reserved.In combination with open-label diuretic,calcium channel blocker,beta-blocker,alpha-blocker,and/or centrally acting agent*doubling of serum creatinine,end stage renal disease,deathRENAAL Patients Reaching RENAAL Patients Reaching the Primary Composite Endpoint
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