ARBs in Cardiovascular Disease

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

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; 363:2022 31; 2. Pfeffer et al. N Engl J Med 2003;349:1893 906 3. Cohn et al. N Engl J Med 2001; 345:1667 75; 4. Sawada et al. Eur Heart J 2009;30:2461 69 5. Califf et al. Am Heart J 2008;156:623 32; 6. Mochizuki et al. Lancet 2007;369:1431 9

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

Plasma A II (pg/ml) Plasma ACE (nmol/ml/min) AII escape with ACEI therapy 100 80 60 40 20 0 30 Enalapril 20mg * * * * * * * * 20 10 * 0 Placebo 4h 24h 1 2 3 4 5 6 Hospital Months *P < 0.001 vs placebo. Adapted with permission from Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966 972.

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

Number of patients Angiotensin Receptor Blockers Have a Wealth of Outcomes Data 60,000 50,000 40,000 30,000 20,000 10,000 0 57,046 10 8 6 5 4 3 2 1 9 7 53,247 13 12 11 15 14 25,019 21 20 19 18 17 16 1. VALUE 2. VALIANT 3. NAVIGATOR 4. Val-HeFT 5. JIKEI HEART 6. KYOTO HEART 7. VART 36,940 30 29 28 27 25 24 23 22 8. VALISH* 9. NAGOYA-HEART* 10. V-CARD* 11. ONTARGET 12. PRoFESS 13. TRANSCEND 14. HALT-PKD* 15,693 15. NCT00490958* 16. LIFE 17. OPTIMAAL 18. ELITE II 19. RENAAL 20. NCT00090259* 21. VA NEPHRON-D* 22. CHARM 23. SCOPE 24. SCAST* 25. CASE-J 26. ACCOST 6,777 27. HIJ-CREATE 28. E-COST 29. HOPE-3* 30. 4C* 31. I-PRESERVE 32. IDNT 33. ACTIVE-I* 34. NID-2 35. SUPPORT* 36. COLM* 37. OSCAR* 38. ORIENT 39. MOSES 1,405 Diovan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan 26 33 32 31 34 36 38 37 35 39 *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 2009 1. 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. 2009 [abstract at ESC]; 8. http://clinicaltrials.gov (NCT00151229); 9. http://clinicaltrials.gov (NCT00129233 ); 10. http://clinicaltrials.gov (NCT00140790); 11. ONTARGET Investigators 2008; 12. Yusuf et al 2008; 13. TRANSCEND Investigators 2008; 14. http://clinicaltrials.gov (NCT00283686); 15. http://clinicaltrials.gov (NCT00490958); 16. Dahlöf et al. 2002; 17. Dickstein et al. 2002; 18. Pitt et al. 2000; 19. Brenner et al. 2001; 20. http://clinicaltrials.gov (NCT00090259); 21. Fried et al 2009; 22. Pfeffer et al 2003; 23. Papademetriou et al. 2004; 24. http://clinicaltrials.gov (NCT00120003); 25. Ogihara et al. 2008; 26. http://clinicaltrials.gov (NCT00108706); 27. Laufs et al. 2008; 28. Suzuki et al. 2005; 29. http://clinicaltrials.gov (NCT00468923); 30. http://clinicaltrials.gov (NCT00139386); 31. Massie et al 2008; 32. Lewis et al. 2001; 33. http://clinicaltrials.gov (NCT00249795); 34. http://clinicaltrials.gov (NCT00535925); 35. http://clinicaltrials.gov (NCT00417222); 36. Ogihara et al 2009; 37. Ogawa et al 2009; 38. Imai et al. 2009 (Abstract F-FC313 at ASN 2009); 39. Schrader et al. 2005

ARBs in CHF ELITE II Val-HeFT CHARM Losartan 50 OD vs Captopril 25 tid Valsartan 40-160 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

Evolution of HF management Ancient Compensatory Hemodynamic Neurohormonal Cupping & leaching Rotating tourniquets Phlebotomy Trephine Vasodilators ACEIs -blockade ARBs 1555 B.C. 1785 A.D. 1846 1888 1898 1908 1948 1960s 1970s Symptom improvement 1990s Survival improvement 9

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;5:155-160

Survival probability (%) Kaplan-Meier analysis of survival 1.0 Valsartan p = 0.80 0.9 Placebo 0.8 0.7 0 3 6 9 12 15 18 21 24 27 Cohn et al. NEJM 2001;345:1667 Time since randomization (months)

Val-HeFT: Effect of Valsartan on Combined Mortality and Morbidity End Point* Probability of Event- Free Survival 100 95 90 85 80 75 70 65 0 0 3 6 9 12 15 18 21 24 27 30 Months Valsartan (n = 2511) Placebo (n = 2499) 13.2% risk reduction P = 0.009 *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;345:1667-1675.

Event-free probability Primary endpoint: greatest benefits in patients not on ACE inhibitor therapy Combined all-cause mortality / morbidity 1.0 0.8 44.5% risk reduction p = 0.0002 0.6 0.4 0 Placebo (n = 181) Valsartan (n = 185) Time since randomization (months) 3 6 9 12 15 18 21 24 27 Cohn et al. AHA Scientific Sessions 2000

Probability of Event-Free Survival Val-HeFT: AT 1 -Receptor Blockers Reduce Mortality in ACE Inhibitor Intolerant Patients 100 90 80 70 Combined Morbidity/Mortality Valsartan (n = 185) Placebo (n = 181) 60 44.0% risk reduction 50 P = 0.0002 40 0 3 6 9 12 15 18 21 24 27 30 Months 100 90 80 70 60 50 Mortality 33.1% risk reduction P = 0.0171 0 3 6 9 12 15 18 21 24 27 30 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):1414 1421

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

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 50 40 % Placebo 406 (40.0%) 334 (33.0%) 30 Candesartan 20 10 0 Number at risk HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 0 1 2 3 3.5 years Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126 16

CHARM-Alternative Secondary outcomes Candesartan Placebo CV death 219 252 CHF hosp. 207 286 CV death, CHF hosp, 353 420 MI CV death, CHF hosp, 369 432 MI, stroke CV death, CHF hosp, 396 456 MI, stroke, revasc 0.85 0.68 0.78 0.80 0.81 p-value 0.072 <0.0001 0.0007 0.001 0.002 0.6 0.8 1.0 1.2 1.4 candesartan better Hazard ratio placebo better 17

CHARM-Added: Primary outcome CV death or CHF hospitalisation % 50 40 Placebo 538 (42.3%) 483 (37.9%) 30 Candesartan 20 10 0 Number at risk HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 0 1 2 3 3.5 years Candesartan 1276 1176 1063 948 457 Placebo 1272 1136 1013 906 422 18

CHARM-Added Secondary outcomes Candesartan Placebo CV death 302 347 CHF hosp. 309 356 CV death, CHF hosp, 495 550 MI CV death,chf hosp, 512 559 MI, stroke CV death,chf hosp, 548 596 MI, stroke, revasc 0.84 0.83 0.85 0.87 0.87 p-value 0.029 0.014 0.010 0.020 0.015 0.6 0.8 1.0 1.2 1.4 candesartan better Hazard ratio placebo better 19

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 30 25 20 15 10 % Placebo Candesartan 366 (24.3%) 333 (22.0%) 5 0 Number at risk HR 0.89 (95% CI 0.77-1.03), p=0.118 Adjusted HR 0.86, p=0.051 0 1 2 3 3.5 years Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 20

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

i-preserve: Study Design Randomized, double-blind, placebo controlled trial Irbesartan (mean dose 275 mg) N=4,128 75 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

Cumulative Incidence of Primary Events (%) i-preserve: Primary Endpoint Death or protocol specified CV hospitalization (Mean follow-up 49.5 months) 40-30 - 20 - HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35 Placebo Irbesartan 10-0 - No. at Risk Irbesartan Placebo 0 6 12 18 24 30 36 42 48 54 60 Months from Randomization 2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497 2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446 23

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; 0.99 1.28) p = 0.069 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 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

Probability of Event 0.4 0.35 SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF All-Cause Mortality TRACE Echocardiographic EF 35% 0.3 0.25 0.2 Placebo ACE-I 0.15 0.1 0.05 Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) OR: 0.74 (0.66 0.83) Years 0 0 1 2 3 4 ACE-I 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Flather MD, et al. Lancet. 2000;355:1575 1581

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* (0.67 0.83) 30 20 0.73* (0.63 0.85) 0.80* (0.69 0.95) 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;355:1575 1581

Acute MI (0.5 10 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

Probability of Event Mortality by Treatment 0.3 0.25 Captopril Valsartan Valsartan + Captopril 0.2 0.15 0.1 0.05 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 0 Months 0 6 12 18 24 30 36 Captopril 4909 4428 4241 4018 2635 1432 364 Valsartan 4909 4464 4272 4007 2648 1437 357 Valsartan + Cap4885 4414 4265 3994 2648 1435 382 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

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) 0.004 Per Protocol Patient Population (n = 14,285) 0.002 Noninferiority Noninferiority not Demonstrated Val Superior to Cap Cap Superior to Val 0.8 1 1.13 1.2 Favors Valsartan Favors Captopril

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

Probability of Event CV Death, MI, or HF by Treatment 0.4 Captopril 0.3 Valsartan Valsartan + Captopril 0.2 0.1 Valsartan vs. Captopril: HR = 0.96; P = 0.198 Months 0 Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369 0 6 12 18 24 30 36 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

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 (0.94-1.09), p = 0.02 Telmisartan + Ramipril vs. Ramipril RR 0.99 (0.92-1.07) The ONTARGET Trial Programme (N=31,546) ACEI intolerant patients TRANSCEND (N=5,926) Telmisartan vs. Placebo HR=0.92 (0.81-1.05), P=0.2158 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

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 4 8 22% 26% 20% 32% 12 p<0.001 p<0.001 p<0.001 p<0.001 16 20 24 28 32 36 40 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;342:145 153

mmhg LIFE: Comparable BP Reductions 180 170 160 150 140 130 120 110 100 90 80 70 60 50 Systolic Mean Arterial Diastolic 40 0 6 12 18 24 30 36 42 48 54 * Mean BP at last visit Dahlöf B et al Lancet 2002;359:995-1003. Study Month Atenolol 145.4 mmhg* Losartan 144.1 mmhg* Atenolol 102.4 mmhg* Losartan 102.2 mmhg* Losartan 81.3 mmhg* Atenolol 80.9 mmhg*

Proportion of patients with first event (%) LIFE: Primary Composite Endpoint Composite of CV death, stroke and MI 16 14 12 Atenolol 10 Losartan 8 6 4 35 Number at Risk 2 Adjusted Risk Reduction Unadjusted Risk Reduction 13.0%, p=0.021 14.6%, p=0.009 0 0 6 12 18 24 30 36 42 48 54 60 66 Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf B et al Lancet 2002;359:995-1003. Study Month

Proportion of patients with first event (%) LIFE: Stroke Fatal and nonfatal stroke 8 7 6 Atenolol 5 4 Losartan 3 2 Number at Risk 1 Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 0 0 6 12 18 24 30 36 42 48 54 60 66 Study Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 Month 925 Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 Dahlöf B et al Lancet 897 2002;359:995-1003.

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;358:1547 1559

Telmisartan 80mg as effective as ramipril 10mg in reducing CV risk CV Death MI Stroke CHF Hosp All Death Telmisartan better Ramipril better 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 RR (95% CI)

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;358:1547 1559

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 0.5 0 1 2 3 4 6 * 72 Screening Randomisation *Patient visits every 6 months for months 6-72. Julius S et al. Lancet. June 2004;363. End of treatment adjustment period SNUH Cardiovascular Center

Proportion of Patients With First Event (%) VALUE: Primary Composite Cardiac Endpoint 14 12 10 8 6 4 2 Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = 0.94 1.14; P = 0.49 Number at risk Valsartan Amlodipine 7596 Julius S et al. Lancet. June 2004;363. 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474

New-onset Diabetes (% of Patients in Treatment Group) VALUE: Incidence of New-onset Diabetes (Not Prespecified in Design Paper) 18 16 14 12 10 8 6 4 2 0 Julius S et al. Lancet. June 2004;363. 23% Risk Reduction With Valsartan P<0.0001 13.1% Valsartan-based Regimen (n=5094) 16.4% Amlodipine besylatebased Regimen (n=5074)

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

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

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 15245 Valsartan Vs. Amlodipine 4.2 년 3.67% Vs. 4.34% 16% (p=0.044) LIFE study: Watchtell K et al., JACC 2005;45:712-719 VALUE trial: Schmieder R et al., J Hypertens 2006;24 (Suppl):S3 SNUH Cardiovascular Center

Proportion of patients with first event (%) LIFE: New Onset AF 8 7 RR: 0.67 [95% CI: 0.55 0.85], p<0.001 Adjusted RR: 0.67 [95% CI: 0.55 0.85], p<0.001 6 5 4 3 2 1 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Atenolol (n=4182) Losartan (n=4298) Wachtell K, et al. JACC, 2005;45:712-9 SNUH Cardiovascular Center

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: 0.707-0.995], p=0.044 Incidence of persistent AF 1.35% in the valsartan 1.97% in the amlodipine Odds ratio 0.681 [95% CI: 0.522-0.889], p=0.005 Schmieder R et al., J Hypertens 2006;24 (Suppl):S3 SNUH Cardiovascular Center

Prevention of AF with ACEI & ARB: Meta-Analysis Healey et al. JACC 2005;45:1832-9 SNUH Cardiovascular Center

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 0.66-0.97), P=0.02 Amlodipine vs Placebo RR=1.04(95%CI 0.86-1.25), P=0.69 Irbesartan vs Amlodipine RR=0.77(95%CI 0.63-0.93), 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

Survival (all-cause mortality) Proteinuria: Independent Risk Factor for Mortality in Type 2 Diabetes 1.0 0.9 0.8 0.7 0.6 Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) 0.5 Gall, MA et al. Diabetes 1995;44:1303 0 1 2 3 4 5 6 Years P<0.01 normo vs. micro- and macroalbum P<0.05 micro vs. macroalbuminuria

Incidence (%) CV Outcomes and Renal Disease 20 18 16 14 12 10 8 6 4 2 0 14.4 18.5 * Primary outcome 9.3 14.8 Total mortality Mann J. et al. Ann Intern Med 2001;134:629 * 5.8 9.4 * CV mortality Cr (cl) >65 ml/min (n=5888 Cr (cl) 65 ml/min (n=3394 10.3 MI 12.5 * 2.5 4.5 * Hospitalization for CHF *P<0.05. Combined CV death, MI, or stroke.

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) 635-638.

% with event % with event % with event RENAAL TIIDM with Nephropathy Doubling of Serum Creatinine 30 20 10 ESRD Risk Reduction: 28% p=0.002 P L 30 20 10 Risk Reduction: 25% p=0.006 0 0 12 24 36 48 Months P (+ CT) 762 689 554 295 L (+ CT) 751 692 583 329 36 52 Brenner BM et al New Engl J Med 2001;345(12):861-869. P L 0 0 12 24 36 48 Months P (+ CT) 762 715 610 347 42 L (+ CT) 751 714 625 375 69 50 40 30 20 10 ESRD or Death Risk Reduction: 20% p=0.010 0 0 12 24 36 Months 48 P (+ CT) 762 715 610 347 42 L (+ CT) 751 714 625 375 69 P L

Median Percent Change RENAAL: Change of Proteinuria 40 20 0-20 -40 P p<0.001 35% Overall Reduction L -60 0 12 24 36 48 Months P (+CT) 762 632 529 390 130 L (+CT) 751 661 558 438 167 Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. Brenner BM et al New Engl J Med 2001;345(12):861-869.

Proportion With Primary End Point IDNT: Cumulative Proportions of Patients With the Primary Composite End Point* 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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 0 6 12 18 24 30 36 42 48 54 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;345:851-860.

Incidence of Diabetic Nephropathy (%) IRMA 2 20 15 10 5 Placebo 150 mg of irbesartan 300 mg of irbesartan 44% Risk reduction 68% * Risk reduction 0 0 3 6 Adapted from Parving, HH et al. NEJM 2001;345: 870-878 12 18 Months of Follow-up 22 24 *P<0.001 vs. placebo

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 -20-30 -40-30 -33-25 ALLHAT Officers and Collaborators. JAMA. 2002;288:2981-2997. Yusuf S et al. JAMA. 2001;286:1882-1885. Dählof B et al. Lancet. 2002;359:995-1003. Lithell H et al. J Hypertens. 2003;21:875-886. Julius S et al. Lancet. 2004;363:2022-2031. Pfeffer MA et al. Lancet. 2003;362:759-766. -19-23 -22

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 -6-8 -10-12 -14-6 -8 *P<0.05 vs beta-blockers. Klingbeil AU et al. Am J Med. 2003;115:41- -11 * -10 * -13 *

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) 0.5 1.0 2.0 Relative Risk Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.