ARBs in Cardiovascular Disease

Transcription

1 ARBs in Cardiovascular Disease Yong-Jin Kim, MD Seoul National University Hospital

2 Cardiovascular Continuum Ventricular remodelling Remodelling Myocardial infarction Myocardial infarction Ventricular dilation Ventricular Dilation 2 Heart Failure Heart failure Atherosclerosis Atherosclerosis and LVH and LVH 1 End-stage Heart Disease End-stage heart disease Risk factors Diabetes Hypertension Risk factors Diabetes Hypertension 3 Death Death 1. Julius et al. Lancet 2004; 363: ; 2. Pfeffer et al. N Engl J Med 2003;349: Cohn et al. N Engl J Med 2001; 345: ; 4. Sawada et al. Eur Heart J 2009;30: Califf et al. Am Heart J 2008;156:623 32; 6. Mochizuki et al. Lancet 2007;369:1431 9

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4 Clinical trials with ACE inhibitors Vascular and CAD HOPE, PEACE EUROPA MI CONSENSUS, ISIS-4, GISSI-4 SMILE, SAVE AIRE, TRACE Myocardial Infarction Pathological Remodeling CAD Ventricular Enlargement Atherosclerosis Hypertrophy Risk Factors: Diabetes Hypertension Hyperlipidemia Hypertension CAPPP, ALLHAT DM ABCD, REIN, AASK HF SOLVD V-HeFT II SAVE, ATLAS Heart Failure Death

5 Plasma A II (pg/ml) Plasma ACE (nmol/ml/min) AII escape with ACEI therapy Enalapril 20mg * * * * * * * * * 0 Placebo 4h 24h Hospital Months *P < vs placebo. Adapted with permission from Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:

6 Clinical trials with ARB DM/Renal RENAAL, IDNT IRMAII, MARVAL ABCD-2V, NAVIGATOR Myocardial Infarction Pathological Remodeling CAD/MI VALIANT, OPTIMAL VAL-PREST CAD, Nephropathy Atherosclerosis Hypertrophy Ventricular Enlargement Heart Failure Risk Factors: Diabetes Hypertension Hyperlipidemia Hypertension VALUE, SCOPE, TROPHY, LIFE HF ELITE I&II Val-HeFT CHARM Death

7 Number of patients Angiotensin Receptor Blockers Have a Wealth of Outcomes Data 60,000 50,000 40,000 30,000 20,000 10, , , , VALUE 2. VALIANT 3. NAVIGATOR 4. Val-HeFT 5. JIKEI HEART 6. KYOTO HEART 7. VART 36, VALISH* 9. NAGOYA-HEART* 10. V-CARD* 11. ONTARGET 12. PRoFESS 13. TRANSCEND 14. HALT-PKD* 15, NCT * 16. LIFE 17. OPTIMAAL 18. ELITE II 19. RENAAL 20. NCT * 21. VA NEPHRON-D* 22. CHARM 23. SCOPE 24. SCAST* 25. CASE-J 26. ACCOST 6, HIJ-CREATE 28. E-COST 29. HOPE-3* 30. 4C* 31. I-PRESERVE 32. IDNT 33. ACTIVE-I* 34. NID SUPPORT* 36. COLM* 37. OSCAR* 38. ORIENT 39. MOSES 1,405 Diovan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan *Expected enrolment Ongoing and completed randomized controlled trials with death or hard CV events as or part of the primary endpoint Valid as of December Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007; 6. Sawada et al 2009; 7. Narumi et al [abstract at ESC]; 8. (NCT ); 9. (NCT ); (NCT ); 11. ONTARGET Investigators 2008; 12. Yusuf et al 2008; 13. TRANSCEND Investigators 2008; (NCT ); (NCT ); 16. Dahlöf et al. 2002; 17. Dickstein et al. 2002; 18. Pitt et al. 2000; 19. Brenner et al. 2001; (NCT ); 21. Fried et al 2009; 22. Pfeffer et al 2003; 23. Papademetriou et al. 2004; (NCT ); 25. Ogihara et al. 2008; (NCT ); 27. Laufs et al. 2008; 28. Suzuki et al. 2005; (NCT ); (NCT ); 31. Massie et al 2008; 32. Lewis et al. 2001; (NCT ); (NCT ); (NCT ); 36. Ogihara et al 2009; 37. Ogawa et al 2009; 38. Imai et al (Abstract F-FC313 at ASN 2009); 39. Schrader et al. 2005

8 ARBs in CHF ELITE II Val-HeFT CHARM Losartan 50 OD vs Captopril 25 tid Valsartan BID add on Standard Tx vs Standard Tx Candesartan 8-32 OD add on Stardard Tx vs Standard Tx N 3,152 5,010 7,601 Primary endpoint All-cause mortality: NS All-cause mortality: NS All-cause mortality: NS No Approved Indication All-cause M/M: - Overall population : ACEI+ARB = -13.2% - Subgroup w/o ACEI: ARB = -44.5% Approved Indication CV death or HF hospitalization: - CHARM Added: ACEI+ARB = -15% - CHARM Alternative: ARB = -30% - CHARM Preserved: NS Approved Indication

9 Evolution of HF management Ancient Compensatory Hemodynamic Neurohormonal Cupping & leaching Rotating tourniquets Phlebotomy Trephine Vasodilators ACEIs -blockade ARBs 1555 B.C A.D s 1970s Symptom improvement 1990s Survival improvement 9

10 Val-HeFT: valsartan added to usual therapy for HF 5,010 HF patients >18 yr; EF <40%; NYHA II-IV Randomized to Valsartan 40 mg bid titrated to 160 mg bid Placebo 906 deaths (events recorded) Cohn et al. J Card Fail 1999;5:

11 Survival probability (%) Kaplan-Meier analysis of survival 1.0 Valsartan p = Placebo Cohn et al. NEJM 2001;345:1667 Time since randomization (months)

12 Val-HeFT: Effect of Valsartan on Combined Mortality and Morbidity End Point* Probability of Event- Free Survival Months Valsartan (n = 2511) Placebo (n = 2499) 13.2% risk reduction P = *All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators. Cohn JN et al. N Engl J Med. 2001;345:

13 Event-free probability Primary endpoint: greatest benefits in patients not on ACE inhibitor therapy Combined all-cause mortality / morbidity % risk reduction p = Placebo (n = 181) Valsartan (n = 185) Time since randomization (months) Cohn et al. AHA Scientific Sessions 2000

14 Probability of Event-Free Survival Val-HeFT: AT 1 -Receptor Blockers Reduce Mortality in ACE Inhibitor Intolerant Patients Combined Morbidity/Mortality Valsartan (n = 185) Placebo (n = 181) % risk reduction 50 P = Months Mortality 33.1% risk reduction P = Months Valsartan significantly reduced all-cause mortality in a subgroup (n = 366) of ACE inhibitor intolerant CHF patients Adapted from Maggioni AP et al. J Am Coll Cardiol. 2002;40(8):

15 CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARM Alternative n=2028 LVEF 40% ACE inhibitor intolerant CHARM Added n=2548 LVEF 40% ACE inhibitor treated CHARM Preserved n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death 15

16 CHARM-Alternative: Primary outcome CV death or CHF hospitalisation % Placebo 406 (40.0%) 334 (33.0%) 30 Candesartan Number at risk HR 0.77 (95% CI ), p= Adjusted HR 0.70, p< years Candesartan Placebo

17 CHARM-Alternative Secondary outcomes Candesartan Placebo CV death CHF hosp CV death, CHF hosp, MI CV death, CHF hosp, MI, stroke CV death, CHF hosp, MI, stroke, revasc p-value < candesartan better Hazard ratio placebo better 17

18 CHARM-Added: Primary outcome CV death or CHF hospitalisation % Placebo 538 (42.3%) 483 (37.9%) 30 Candesartan Number at risk HR 0.85 (95% CI ), p=0.011 Adjusted HR 0.85, p= years Candesartan Placebo

19 CHARM-Added Secondary outcomes Candesartan Placebo CV death CHF hosp CV death, CHF hosp, MI CV death,chf hosp, MI, stroke CV death,chf hosp, MI, stroke, revasc p-value candesartan better Hazard ratio placebo better 19

20 CHARM-Preserved: Primary outcome CV death or CHF hospitalisation % Placebo Candesartan 366 (24.3%) 333 (22.0%) 5 0 Number at risk HR 0.89 (95% CI ), p=0.118 Adjusted HR 0.86, p= years Candesartan Placebo

21 i-preserve: Entry Criteria Age 60 years Current HF symptoms LVEF 0.45 NYHA class II - IV CHF hosp. 6 months NYHA Class III/IV CXR congestion ECG (LVH, LBBB) Echo (LVH, LAE) Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke 3m; hypertrophic or restrictive CM, pericardial or valvular disease; significant pulmonary disease, creatinine >2.5mg/dl, Hb <11g/dL Only 1/3 pts could enter on an ACEI at baseline LBBB = left bundle branch block LAE = left atrium enlargement CHF = congestive heart failure 21

22 i-preserve: Study Design Randomized, double-blind, placebo controlled trial Irbesartan (mean dose 275 mg) N=4, mg 150 mg 300 mg (n=2,067) Enrollment Single-blind 2 weeks R Forced titration Maintenance (n=2,061) W 2 W 4 W 8 M 6 M 10 M 14 to end Every 4 months Placebo Follow-up continued until 1,440 primary endpoints occurred 22

23 Cumulative Incidence of Primary Events (%) i-preserve: Primary Endpoint Death or protocol specified CV hospitalization (Mean follow-up 49.5 months) HR (95% CI) = 0.95 ( ) Log-rank p=0.35 Placebo Irbesartan No. at Risk Irbesartan Placebo Months from Randomization

24 ARBs in Post MI OPTIMAAL VALIANT Captopril vs. Losartan Captopril vs. Valsartan vs. Combination N 5,477 14,703 Primary endpoint: All-cause mortality Captopril vs. Losartan RR 1.13 (95% CI; ) p = Valsartan vs. Captopril: HR = 1.00; P = Valsartan + Captopril vs. Captopril: HR = 0.98; P = Conclusion Study revealed that losartan was not superior to captopril, and losartan was not shown to be equivalent to captopril No Approved Indication Valsartan is as effective as a proven dose of captopril in reducing the risk of: - Death - CV death or nonfatal MI or heart failure admission Approved Indication

25 Probability of Event SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF All-Cause Mortality TRACE Echocardiographic EF 35% Placebo ACE-I Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) OR: 0.74 ( ) Years ACE-I Placebo Flather MD, et al. Lancet. 2000;355:

26 Events (%) SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiographic EF 35% 40 ACE-I (n = 2995) Death and Major CV Events Placebo (n = 2971) 0.75* ( ) * ( ) 0.80* ( ) 10 0 n = 355 n = 460 Readmission for HF n = 324 n = 391 Reinfarction n = 1049 n = 1244 Death/MI or Readmission for HF *odds ratio (95% CI) Flather MD, et al. Lancet. 2000;355:

27 Acute MI ( days) SAVE, AIRE or TRACE eligible (either clinical/radiologic signs of HF or LV systolic dysfunction) Major Exclusion Criteria: Serum creatinine > 2.5 mg/dl BP < 100 mm Hg Prior intolerance of an ARB or ACE-I Nonconsent double-blind active-controlled Captopril 50 mg tid (n = 4909) Valsartan 160 mg bid (n = 4909) Captopril 50 mg tid + Valsartan 80 mg bid (n = 4885) median duration: 24.7 months event-driven Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability

28 Probability of Event Mortality by Treatment Captopril Valsartan Valsartan + Captopril Valsartan vs. Captopril: HR = 1.00; P = Valsartan + Captopril vs. Captopril: HR = 0.98; P = Months Captopril Valsartan Valsartan + Cap Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

29 All-Cause Mortality: Non-Inferiority Analyses Hazard Ratio (97.5% CI) noninferior ity margin P-value (noninferiority) Intention-to-Treat Patient Population (n = 14,703) Per Protocol Patient Population (n = 14,285) Noninferiority Noninferiority not Demonstrated Val Superior to Cap Cap Superior to Val Favors Valsartan Favors Captopril

30 Mortality in SAVE, TRACE, AIRE, and VALIANT SAVE Hazard Ratio for Mortality TRACE AIRE Combined VALIANT (imputed placebo) Valsartan preserves 99.6% of mortality benefit of captopril. 0.5 Favors 1 Favors 2 Active Drug Placebo Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

31 Probability of Event CV Death, MI, or HF by Treatment 0.4 Captopril 0.3 Valsartan Valsartan + Captopril Valsartan vs. Captopril: HR = 0.96; P = Months 0 Valsartan + Captopril vs. Captopril: HR = 0.97; P = Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

32 ARBs in High CV risk ONTARGET TRANSCEND N 25,620 5,926 Primary endpoint: CV death, MI, stroke, CHF hosp ONTARGET (N=25,620) Telmisartan vs. Ramipril RR 1.01 ( ), p = 0.02 Telmisartan + Ramipril vs. Ramipril RR 0.99 ( ) The ONTARGET Trial Programme (N=31,546) ACEI intolerant patients TRANSCEND (N=5,926) Telmisartan vs. Placebo HR=0.92 ( ), P= Conclusion In patients who have vascular disease or high-risk diabetes but do not have HF, Telmisartan is as effective as Ramipril There is no additional advantage(and there is some harm) from the combination of Telmisartan and Ramipril compared with Ramipril alone. Telmisartan was well tolerated in patients unable to tolerate ACE inhibitor. Although the drug had no significant effect on primary outcome of this study

33 ACEI in reducing CV mortality and morbidity The HOPE study % risk reduction ramipril (n=4,645) vs placebo (n=4,652) in preventing major CV events in high-risk pt 0 Composite Death from CV endpoint* CV causes MI Stroke % 26% 20% 32% 12 p<0.001 p<0.001 p<0.001 p< Ramipril, n=4,645 Placebo, n=4,652 * Composite CV endpoint = death from CV causes + MI + stroke ACE = angiotensin-converting enzyme; CV = cardiovascular; HOPE = Heart Outcomes Prevention Evaluation; MI = myocardial infarction Yusuf S, et al. N Engl J Med 2000;342:

34 mmhg LIFE: Comparable BP Reductions Systolic Mean Arterial Diastolic * Mean BP at last visit Dahlöf B et al Lancet 2002;359: Study Month Atenolol mmhg* Losartan mmhg* Atenolol mmhg* Losartan mmhg* Losartan 81.3 mmhg* Atenolol 80.9 mmhg*

35 Proportion of patients with first event (%) LIFE: Primary Composite Endpoint Composite of CV death, stroke and MI Atenolol 10 Losartan Number at Risk 2 Adjusted Risk Reduction Unadjusted Risk Reduction 13.0%, p= %, p= Losartan Atenolol Dahlöf B et al Lancet 2002;359: Study Month

36 Proportion of patients with first event (%) LIFE: Stroke Fatal and nonfatal stroke Atenolol 5 4 Losartan 3 2 Number at Risk 1 Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p= Study Losartan Month 925 Atenolol Dahlöf B et al Lancet ;359:

37 ONTARGET: Telmisartan is as protective as ramipril in CV protection Reduction in composite CV risk Composite CV risk = cardiovascular mortality + non-fatal myocardial infarction + hospitalisation for congestive heart failure + non-fatal stroke The ONTARGET Investigators. N Engl J Med 2008;358:

38 Telmisartan 80mg as effective as ramipril 10mg in reducing CV risk CV Death MI Stroke CHF Hosp All Death Telmisartan better Ramipril better RR (95% CI)

39 Telmisartan 80mg added to ramipril 10mg: as effective as ramipril alone Reduction in composite CV risk Composite CV risk = cardiovascular mortality + non-fatal myocardial infarction + hospitalisation for congestive heart failure + non-fatal stroke The ONTARGET Investigators. N Engl J Med 2008;358:

40 VALUE: Design Rollover from previous therapy (92%) Elective titration to target BP (<140/90 mm Hg) Valsartanbased regimen V 80 mg A 5 mg Amlodipinebased regimen V 160 mg A 10 mg V 160 mg + HCTZ 12.5 mg A 10 mg + HCTZ 12.5 mg V 160 mg + HCTZ 25 mg A 10 mg + HCTZ 25 mg V 160 mg + HCTZ 25 mg + "Free" add-on A 10 mg + HCTZ 25 mg + "Free" add-on Month * 72 Screening Randomisation *Patient visits every 6 months for months Julius S et al. Lancet. June 2004;363. End of treatment adjustment period SNUH Cardiovascular Center

41 Proportion of Patients With First Event (%) VALUE: Primary Composite Cardiac Endpoint Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = ; P = 0.49 Number at risk Valsartan Amlodipine 7596 Julius S et al. Lancet. June 2004; Time (months)

42 New-onset Diabetes (% of Patients in Treatment Group) VALUE: Incidence of New-onset Diabetes (Not Prespecified in Design Paper) Julius S et al. Lancet. June 2004; % Risk Reduction With Valsartan P< % Valsartan-based Regimen (n=5094) 16.4% Amlodipine besylatebased Regimen (n=5074)

43 Possible Mechanisms of ARB in AF Prevention Inflammation Atrium: Angiotensin Collagen Synthesis LVEDP Pressure Dilatation Remodeling Fibrosis Conduction Δ AF Systemic BP SNUH Cardiovascular Center

44 Clinical Evidence: ARB 제제의심방세동예방효과 Aksnes TA et al., J Hypertens 2007;25:15-23 SNUH Cardiovascular Center

45 심방세동발생률을보고한대규모고혈압연구 대상 환자수 약제 관찰 기간 발생률 RR 감소율 LIFE 8851 Losartan Vs. Atenolol 4.8 년 3.5% Vs. 5.3% 33% (p<0.001) VALUE Valsartan Vs. Amlodipine 4.2 년 3.67% Vs. 4.34% 16% (p=0.044) LIFE study: Watchtell K et al., JACC 2005;45: VALUE trial: Schmieder R et al., J Hypertens 2006;24 (Suppl):S3 SNUH Cardiovascular Center

46 Proportion of patients with first event (%) LIFE: New Onset AF 8 7 RR: 0.67 [95% CI: ], p<0.001 Adjusted RR: 0.67 [95% CI: ], p< Time (months) Atenolol (n=4182) Losartan (n=4298) Wachtell K, et al. JACC, 2005;45:712-9 SNUH Cardiovascular Center

47 VALUE Trial: Reduced Incidence of New AF with ARB Incidence of new onset AF 3.67% in the valsartan 4.34% in the amlodipine Odds ratio 0.84 [95% CI: ], p=0.044 Incidence of persistent AF 1.35% in the valsartan 1.97% in the amlodipine Odds ratio [95% CI: ], p=0.005 Schmieder R et al., J Hypertens 2006;24 (Suppl):S3 SNUH Cardiovascular Center

48 Prevention of AF with ACEI & ARB: Meta-Analysis Healey et al. JACC 2005;45: SNUH Cardiovascular Center

49 Prevention of AF with ACEI & ARB: Meta-Analysis Healey et al. JACC 2005;45: SNUH Cardiovascular Center

50 ARBs in DN RENAAL IDNT Losartan vs Placebo Irbesartan vs Amlodipine vs Placebo N 1,513 1,715 Primary endpoint: The composite of a doubling of the base-line serum creatinine concentration, ESRD, or death Risk reduction 16%, p=0.02 Irbesartan vs Placebo RR=0.80(95%CI ), P=0.02 Amlodipine vs Placebo RR=1.04(95%CI ), P=0.69 Irbesartan vs Amlodipine RR=0.77(95%CI ), P=0.006 Conclusion Losartan conferred significant renal benefits in patients with T2DM and nephropathy Approved Indication Irbesartan is effective in protecting against the progression of nephropathy due to T2DM Approved Indication

51 Survival (all-cause mortality) Proteinuria: Independent Risk Factor for Mortality in Type 2 Diabetes Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) 0.5 Gall, MA et al. Diabetes 1995;44: Years P<0.01 normo vs. micro- and macroalbum P<0.05 micro vs. macroalbuminuria

52 Incidence (%) CV Outcomes and Renal Disease * Primary outcome Total mortality Mann J. et al. Ann Intern Med 2001;134:629 * * CV mortality Cr (cl) >65 ml/min (n=5888 Cr (cl) 65 ml/min (n= MI 12.5 * * Hospitalization for CHF *P<0.05. Combined CV death, MI, or stroke.

53 Angiotensin II Induced Renal Fibrosis Ang Il Renal Cells (mesangial, tubuloepithelial interstitial fibroblasts) Inflammatory Cells Growth factors: TGFß, PDGF, CTGF Cytokines: IL-6, TNFa Chemokines: MCP-1, RANTES, OPN Other: PA1, Metalloproteinases Activation and recruitment of inflammatory cells Chemotaxis Chemokines - MCP-1, RANTES Adhesion molecules - VCAM-1 Cytokines, growth factors ECM production and degradation Proteinuria ECM accumulation Cell proliferation Inflammation Renal Fibrosis Mezzano, S.A. Hypertension 2001; 38(2)

54 % with event % with event % with event RENAAL TIIDM with Nephropathy Doubling of Serum Creatinine ESRD Risk Reduction: 28% p=0.002 P L Risk Reduction: 25% p= Months P (+ CT) L (+ CT) Brenner BM et al New Engl J Med 2001;345(12): P L Months P (+ CT) L (+ CT) ESRD or Death Risk Reduction: 20% p= Months 48 P (+ CT) L (+ CT) P L

55 Median Percent Change RENAAL: Change of Proteinuria P p< % Overall Reduction L Months P (+CT) L (+CT) Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. Brenner BM et al New Engl J Med 2001;345(12):

56 Proportion With Primary End Point IDNT: Cumulative Proportions of Patients With the Primary Composite End Point* Irbesartan, 300 mg (n=579) Amlodipine, 10 mg (n=567) Placebo (n=569) Relative Risk Reductions Irbesartan vs placebo: 20% (P=.02) Irbesartan vs amlodipine: 23% (P=.006) Amlodipine vs placebo: NS Months of Follow-up 1,715 patients with HTN, DM II and proteinuria > 900 mg/d for 2 year follow-up *Composite of the doubling of baseline SCr, onset of ESRD, or death from any cause. The end point difference was driven by differences in doubling of SCr and ESRD; there was no difference in mortality. Lewis et al. N Engl J Med. 2001;345:

57 Incidence of Diabetic Nephropathy (%) IRMA Placebo 150 mg of irbesartan 300 mg of irbesartan 44% Risk reduction 68% * Risk reduction Adapted from Parving, HH et al. NEJM 2001;345: Months of Follow-up *P<0.001 vs. placebo

58 New-Onset DM With RAS Blockade 0 Lisinopril (ALLHAT) Ramipril (HOPE) Losartan (LIFE) Candesartan (SCOPE) Valsartan (VALUE) Candesartan (CHARM) -10 % Reduction in New-Onset DM ALLHAT Officers and Collaborators. JAMA. 2002;288: Yusuf S et al. JAMA. 2001;286: Dählof B et al. Lancet. 2002;359: Lithell H et al. J Hypertens. 2003;21: Julius S et al. Lancet. 2004;363: Pfeffer MA et al. Lancet. 2003;362:

59 Regression of Left Ventricular Hypertrophy Meta-Analysis of 80 Studies Involving 3767 Patients With Equivalent Blood Pressure Lowering 0-2 Beta blockers Diuretics CCBs ACEIs ARBs -4 % Reduction in Left Ventricular Mass Index *P<0.05 vs beta-blockers. Klingbeil AU et al. Am J Med. 2003;115: * -10 * -13 *

60 BP-Lowering Treatment Trialists: ARB vs Other Outcome Favors ARB Favors Other RR (95% CI) Stroke 0.79 (0.69, 0.90) CHD 0.96 (0.85, 1.09) Heart failure 0.84 (0.72, 0.97) Major CV events 0.90 (0.83, 0.96) CV death 0.96 (0.85, 1.08) Total mortality 0.94 (0.86, 1.02) Relative Risk Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:

61 Clinical trials with ARB DM/Renal RENAAL, IDNT IRMAII, MARVAL ABCD-2V, NAVIGATOR Myocardial Infarction Pathological Remodeling CAD/MI VALIANT, OPTIMAL VAL-PREST CAD, Nephropathy Atherosclerosis Hypertrophy Ventricular Enlargement Heart Failure Risk Factors: Diabetes Hypertension Hyperlipidemia Hypertension VALUE, SCOPE, TROPHY, LIFE HF ELITE I&II Val-HeFT CHARM Death

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