【高血压英文课件】Alteringthe-Course-of-Renal-Disease

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide,*,Downloaded from,www.cozaar.ae,RENAAL,Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the A,II,Antagonist Losartan,1,RENAAL 1,Angiotensin,II,Drives Pathology in Hypertension,Hypertension,Vascular Dysfunction,Endothelial dysfunctionRemodeling/hypertrophyFibrosisAtherosclerosis,Tissue Dysfunction,Cell loss,Fibrosis,Remodeling,Ischemia,Heart,MI, HF,Kidney,ESRD,Brain,Stroke,Genetics, risk factors (diabetes, hypercholesterolemia) Environment (diet, smoking, stress),MI=myocardial infarction; HF=heart failure; ESRD=end-stage renal disease,Adapted from Weir MR, Dzau VJ,Am J Hypertens,1999;12:205S-235S; Timmermans PB et al,Pharmacol Rev,1993;45(2):205-251; and Jessup M, Brozena S,N Engl J Med,2003;348:2007-2018.,2,Angiotensin II Drives Patholog,Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking,Endpoints Studied,ACE Inhibitor Trials,in Type 2 Diabetics,TotalReduction ofReduction ofReduction in Risk with 1 Year Follow-UpSampleProteinuriaGFR Decline of ESRD,*,Ravid et al,Ann Intern Med,1993,94YesYes,No,Lebovitz et al,Kidney Int,1994,121YesYes,No,Bakris et al,Kidney Int,1996,52YesYes,No,Ahmad et al,Diabetes Care,1996,103YesYes,No,Nielsen et al,Diabetes Care,1997,36YesYes,No,UKPDS et al,Br Med J,1998,758YesNo,No,Fogari et al,J Hum Hypertens,1999,107YesNo,No,ABCD,Diabetes Care,2000,470YesYes,No,Ruggenenti et al,(REIN),352 (27)*,YesYes,Yes*,Am J Kidney Dis,2000,MICRO-HOPE*,Lancet,2000,3577YesNo,Yes*,GFR=glomerular filtration rate,*Reduction in the risk of end-stage renal disease (renal transplant or dialysis),*Only 27 (8%) of the 352 patients in this study were Type 2 diabetics,*In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70),3,Clinical Endpoint Data for ESR,Controlling the Course of Renal Disease with Losartan,Rationale for RENAAL (Losartan Renal Protection Study),:,Losartan significantly lowered BP comparable to other classes of antihypertensive drugs,Losartan demonstrated superior tolerability compared to other classes of antihypertensive drugs (placebo-like side-effect profile),Losartan was a specific antagonist of angiotensin,II,(significant driver of pathology in renal disease),Losartan had significant renoprotective effects in animal models of renal disease,Losartan was well tolerated and lowered BP in hypertensive patients with renal insufficiency,BP=blood pressure,Adapted from Goa KL, Wagstaff AG,Drugs,1996;51(5):820-845; Goldberg AI et al,J Hypertens,1995;13(suppl 1):S77-S80;Lafayette RA et al,J Clin Invest,1992;90:766-771; Remuzzi A et al,J Am Soc Nephrol,1993;4(1):40-49; Toto R et al,Hypertension,1998;31:684-691.,4,Controlling the Course of Ren,Effect of Losartan on Microalbuminuria,Urinary albumin (mg/24 hr),Type 2 diabetes,Type 1 diabetes,Renal transplant,Hypertension,0,50,100,150,200,250,30,22,n=12,37,15,n=9,57,40,n=10,83,39,n=194,92,60,n=103,115,66,n=424,153,55,n=14,188,94,n=8,211,173,n=40,21,15,n=29,5,Effect of Losartan on Microalb,RENAAL,R,eduction of,E,ndpoints in,N,IDDM with the,A,II,A,ntagonist,L,osartan,An investigator-initiated, multicenter, double-blind, randomized, placebo-controlled study to evaluate the renal protective effects of losartan in patients with Type 2 diabetes and nephropathy,1513 Patients; 250 Centers; 28 Countries,Steering CommitteeChairB. M. Brenner, MD,Data and Safety Monitoring CommitteeChairC. E. Mogensen, MD,Clinical Endpoint Adjudication Committee ChairS. Haffner, MD,Coordinating Center: Merck Research LabsStudy DirectorS. Shahinfar, MD,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334; Brenner BM et al,N Engl J Med,2001;345(12):861-869.,6,RENAALReduction of Endpoints,RENAAL Primary Hypothesis,Long-term treatment with losartan versus placebo (alone or in combination with conventional antihypertensive therapy*) in Type 2 diabetic patients with nephropathy will increase the time to first event and decrease the incidence of doubling of sCr, ESRD, or death,*Excluding ACE inhibitors and other A,II,antagonists,sCr=serum creatinine,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,7,RENAAL Primary HypothesisLong,Losartan compared to placebo (alone or in combination with conventional antihypertensive therapy*) in patients with Type 2 diabetes and nephropathy will,Increase the time to first event and decrease the incidence of cardiovascular morbidity/mortality,Reduce proteinuria,Decrease the rate of progression of renal disease,*Excluding ACE inhibitors and other A,II,antagonists,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,RENAAL Secondary Hypothesis,8,Losartan compared to placebo (,RENAAL Study Design,qd=once daily,*CTx=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents.,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,4 wk,Losartan 100 mg qd,(+CTx),Maintain conventional,antihypertensive therapy (CTx)*,(excluding ACE inhibitors, A,II,antagonists),Losartan 100 mg qd (+CTx),Placebo,(+CTx),Goal trough BP:,140/300 mg/g or 24-hr protein 500 mg,sCr: 1.33.0 mg/dl, 115265 mol/L*,Exclusion criteria,Type 1 diabetes,Known non-diabetic renal disease or renal artery stenosis,Recent history of MI, CABG, PTCA, CVA, TIA,History of HF,HbA,1c,12%,CABG=coronary artery bypass graft; PTCA=percutaneous transluminal coronary angioplasty; CVA=cerebral vascular accident; TIA=transient ischemic attacks,*Lower limit 1.5 mg/dl (133,mol/L) in male patients 60 kg,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,10,RENAAL Inclusion/Exclusion Cr,Europe19%,Latin America18%,North America 46%,Asia,17%,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,RENAAL Enrollment by Region,N=1513,11,Europe19%Latin America18%Nor,Losartan (+CTx)Placebo (+CTx)(n=751)(n=762),Age, years 6060,Male, %6265,Female, % 3835,Race, %,Asian1618,Black1714,Caucasian4850,Hispanic1918,Other21,Systolic BP, mmHg 152153,Diastolic BP, mmHg8282,BMI, kg/m,2,3029,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,RENAAL Baseline Characteristics,12,Losartan (+CTx)Placebo (+CTx,RENAAL Primary Composite Endpoint and Components,Losartan (+CTx) Placebo (+CTx),Composite (n=751) (n=762) % Risk and componentsn (%) n (%) p,Value,reduction 95% CI,DsCr, ESRD, Death 327 (43.5) 359 (47.1)0.0216 (2, 28),DsCr 162 (21.6) 198 (26.0) 0.00625 (8, 39),ESRD 147 (19.6) 194 (25.5) 0.00228 (11, 42),Death 158 (21.0) 155 (20.3)0.882 (27, 19),ESRD or death 255 (34.0) 300 (39.4)0.0120 (5, 32),DsCr=doubling of serum creatinine; CI=confidence interval,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869.,13,RENAAL Primary Composite Endp,ESRD,Months,% with event,0,12,24,36,48,0,10,20,30,RR: 28%,p=0.002,ESRD or Death,Months,% with event,sCr=serum creatinine; RR=risk reduction,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,RENAAL Primary Components,Doubling of sCr,Months,% with event,RR: 25%,p=0.006,Placebo (+CTx) 76268955429536,Losartan (+CTx) 75169258332952,RR: 20%,p=0.010,Placebo (+CTx) 76271561034742,Losartan (+CTx) 75171462537569,0,12,24,36,48,0,10,20,30,40,50,0,12,24,36,48,0,10,20,30,Placebo (+CTx) 76271561034742,Losartan (+CTx) 75171462537569,Slide,14,14,ESRDMonths% with event01224364,RENAALPrimary Composite EndpointDoubling of sCr / ESRD / Death,Months,% with event,RR: 16%,p=0.02,Months,0,12,24,36,48,0,10,20,30,40,50,RR: 22%,p=0.008,Placebo (+CTx) 7626895542953676058443121424,Losartan (+CTx) 7516925833295274661247926336,ITT analysis,Per-protocol analysis,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,0,12,24,36,48,0,10,20,30,40,50,15,RENAALPrimary Composite Endpo,RENAAL,Time to ESRD from Doubling of sCr,Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,Months,% with event,0,6,12,18,24,0,20,40,60,80,RR: 30%,p=0.013,Placebo (+CTx) 19811148114,Losartan (+CTx)16210443193,16,RENAALTime to ESRD from Doubl,BaselineYear 1Year 2Study End,Systolic/diastolic,Losartan,(+CTx)152/82146/78143/77140/74,Placebo,(+CTx)153/82150/80144/77142/74,Mean arterial pressure,Losartan,(+CTx)105.5100.999.195.9,Placebo,(+CTx)106.0103.199.796.8,Pulse pressure,Losartan,(+CTx) 69.4 67.866.266.7,Placebo,(+CTx) 70.8 69.867.167.4,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,;,Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,RENAALBP (mmHg),17,BaselineYear 1Year 2Study,RRp Value RRp Value RRp Value,Unadjusted16%0.0228%0.00220%0.01,Adjusted15%0.0326%0.00719%0.016,DsCr/ESRD/DeathESRD ESRD/Death,RENAAL,Risk Reduction for Primary Composite Endpoint and Components After Adjusting for Mean Arterial Pressure,Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,18,RRp Value RRp Value RRp,RENAALDose of Losartan,The daily dose of losartan ranged from 50100 mg,100 mg qd,Losartan*,n=751,%,71,*,Patients who took the dose more than 50% of the time.,Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,19,RENAALDose of Losartan The da,RENAALConcurrent Antihypertensive Medications,LosartanPlaceboTherapeutic Class(n=751)(n=762),Calcium-channel blocker, %77.981.1,Dihydropyridine, %60.763.9,Diuretic, %83.884.0,Alpha blocker, %40.245.7,Beta blocker, %34.136.7,Centrally acting agents ,% 18.021.7,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,20,RENAALConcurrent Antihyperten,RENAAL Secondary Composite Endpointand Components,Losartan (+CTx) Placebo (+CTx),Composite (n=751) (n=762) % Risk and componentsn (%) n (%) p,Value,reduction 95% CI,CV morbidity/mortality 247 (32.9) 268 (35.2)0.255 10 (8, 24),CV death 90 (12.0) 79 (10.4)0.45512 (52, 17),HF,89 (11.9) 127 (16.7)0.005 32 (11, 48),MI 50 (6.7) 68 (8.9)0.079 28 (4, 50),Unstable angina 42 (5.6) 41 (5.4)0.881 3(59, 33),Stroke47 (6.3) 50 (6.6)0.787 5 (41, 36),Revascularization 69 (9.2) 60 (7.9)0.33119 (68, 16),CV=cardiovascular,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,21,RENAAL Secondary Composite E,RENAALFirst Hospitalization for Heart Failure,0,12,24,36,48,Months,0,5,10,15,20,% with event,Risk reduction: 32%,p=0.005,Placebo (+CTx) 76268561637553,Losartan (+CTx)75170163738874,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,22,RENAALFirst Hospitalization f,0,12,24,36,48,Months,Median % change,60,40,20,0,20,40,35% Overall reductionp0.001,RENAALChange from Baseline in Proteinuria,Proteinuria measured as the urine albumin:creatinine ratio from a first morning void.,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,Placebo (+CTx) 762632529390130,Losartan (+CTx)751661558438167,23,012243648MonthsMedian % change,RENAALRate of Progression of Renal Disease,(median 1/sCr slope),Losartan (+CTx),Placebo (+CTx),0,0.02,0.04,0.06,0.08,dl/mg/yr,0.056,0.069,p=0.01,18% reduction,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,24,RENAALRate of Progression of,RENAAL,Most Common Clinical and Laboratory Adverse Experiences Leading to Discontinuation of Study Therapy,Heartfailure,ESRD,MI,Stroke,Worseningrenalinsufficiency,sCr,Hyper-kalemia,Percentage,Clin and Lab AEs bars Apr24 Apr. 25, 2001,Losartan,(+CTx),Placebo,(+CTx),Laboratory,Clinical,6,2,3,1,2,1,1,1,1,2,1,1,0.4,0,2,4,6,3,Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.,25,RENAALMost Common Clinical an,Public Health and Economic Implications of RENAAL (US),For diabetic patients at risk over a 3.5-year period, it is estimated that,Addition of losartan to the treatment regimens of 100 patients with Type 2 diabetes and nephropathy would be expected to lead to a reduction of 6.3 cases of ESRD,In RENAAL, losartan reduced ESRD days by 31%,Reduction in days with ESRD saves $5144 (p=0.003) per treated patient at 3.5 years and $7058 (p=0.002) per patient over 4 years,After accounting for costs of losartan, reduction in ESRD resulted in net savings of $3522 per patient over 3.5 years (95% CI: $143$6900) and $5298 (95% CI: $954$9643) per patient over 4 years,Costs are reported in 2001 US dollars.,Adapted from Herman WH et al,Diabetes Care,2003;26(3):683-687.,26,Public Health and Economic Imp,Public Health and Economic Implications of RENAAL (EU),Extrapolating the addition of losartan to the treatment regimen of patients with Type 2 diabetes and proteinuria in the EU,44,092 cases of ESRD averted (95% CI: 11,89876,286) after 3.5 years,64,383 years with ESRD averted (95% CI: 20,886107,879) after 3.5 years,Reduction in ESRD-related costs of 2.6 billion after 3.5 years, increasing to 3.6 billion after 4 years,Costs based on ESRD costs in Germany in 1999.,Adapted from Gerth WC et al,Kidney Int,2002;62(suppl 82) S68-S72.,27,Public Health and Economic Imp,RENAAL Summary (,I,),In patients with Type 2 diabetes and nephropathy,Losartan delayed onset of the primary composite endpoint (DsCr/ESRD/Death) and delayed progression to ESRD,Losartan reduced proteinuria and the rate of decline in renal function (assessed by the reciprocal of sCr concentration),Losartan reduced the incidence of first hospitalization for heart failure,These benefits were largely independent of BP,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,28,RENAAL Summary (I)In patients,RENAAL Summary (,II,),In patients with Type 2 diabetes and nephropathy,Losartan and placebo, added to CTx, showed no significant difference in all-cause mortality, MI, stroke, revascularization, hospitalizations for unstable angina, and death due to CV disease,Losartan was generally well tolerated in this patient population,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,29,RENAAL Summary (II) In patien,RENAALConclusions,Losartan conferred significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy,Losartan therapy resulted in a significant reduction in first hospitalizations for heart failure,These benefits of losartan were independent of achieved BP control,Losartan was generally well tolerated,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,30,RENAALConclusionsLosartan con,RENAAL results show that losartan + CTx,Provided excellent tolerability,Provided proven renal protection and cardioprotective benefit,28% risk reduction in ESRD,32% risk reduction in incidence of first hospitalization for heart failure,35% reduction in proteinuria,Analysis of the public health implications of RENAAL suggested potential of losartan for substantial healthcare savings,RENAAL Losartan Renal Protection Study,Adapted from Brenner BM et al,N Engl J Med,2001;345(12):861-869; Herman WH et al,Diabetes Care,2003;26(3):683-687;,Gerth WC et al,Kidney Int,2002;62(suppl 82):S68-S72.,31,RENAAL results show that losar,Why Is RENAAL Relevant to the Treatment of Hypertension?,High BP causes increased risk for cardiac, renal and cerebrovascular events (MI, HF, ESRD, stroke),RENAAL provided strong evidence of a need to block the pathological effects of angiotensin,II,beyond BP,RENAAL demonstrated that specific A,II,blockade with losartan in hypertensive patients with Type 2 diabetes and nephropathy helps control the course of disease and delays ESRD,RENAAL demonstrated that losartan provides renal protection and a cardioprotective benefit,Adapted from Whelton PK et al,J Hypertens,1992;10(suppl 7):S77-S84;,MacMahon S et al,Lancet,1990;335:765-774; Kannel WB,JAMA,1996;274(24):1571-1576; Klag MJ et al,N Engl J Med,1996;334:13-18;,Brenner BM et al,N Engl J Med,2001;345(12):861-869,.,32,Why Is RENAAL Relevant to the,Losartan Endpoint Trials,ELITE,II,The losartan heart failure survival study,No significant difference was observed between treatment with losartan or captopril on all-cause mortality in HF patients, but losartan was significantly better tolerated,RENAALThe losartan renal protection study,Losartan provided renal protection and a cardioprotective benefit with excellent tolerability,LIFEThe losartan hypertension survival study,Losartan provided protection against stroke and new-onset diabetes,OPTIMAALThe losartan post-MI survival study,Losartan provided cardiovascular benefits comparable to captopril,ELITE=Evaluation of Losartan in the Elderly; LIFE=Losartan Intervention For Endpoint reduction; OPTIMAAL=Optimal Trial in Myocardial Infarction with the Angiotensin,II,Antagonist Losartan,Adapted from Pitt B et al,Lancet,2000;355:1582-1587; Brenner BM et al,N Engl J Med,2001;,345(12):861-869;,Dahlf B et al,Lancet,2002;359:995-1003;,Dickstein K et al,Lancet,09/01/02; available at Endpoint TrialsELITE,References,Please refer to notes page.,34,ReferencesPlease refer to note,References,(contd),Please refer to notes page.,35,References (contd)Please refe,References,(contd),Please refer to notes page.,36,References (contd)Please refe,Before prescribing, please consult the manufacturers prescribing information.,Merck does not recommend the use of any product in any different manner than as described in the prescribing information.,Copyright 2003-2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.,All rights reserved. 5-05 CZR 2001-W-6747-SS Printed in USA,VISIT US ON THE WORLD WIDE WEB AT ,37,Before prescribing, please con,