1. Mechanism of superior cardiovascular protection: Clinical perspective on LIFE Tony ABDEL - MASSIH, MD. Cardiologist Hotel-Dieu de France

2. ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg) ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg) 6254 M CategoryOptimalNormal High normal Grade 1 hypertension (mild) Grade 2 hypertension (moderate) Grade 3 hypertension (severe) Isolated systolic hypertension Systolic < 120 120-129130-139140-159160-179 ≥ 180 ≥ 140 Diastolic < 80 80-8485-8990-99100-109 ≥ 110 < 90 < 90 When a patient’s SBP and DBP fall into different categories, the higher category should apply. Isolated systolic hypertension can also be graded (grades 1, 2, 3) according to SBP values in the ranges indicated, provided diastolic values are < 90

3. ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis 7772 M Very high added risk Very high added risk Very high added risk High Very high added risk Very high added risk High High Moderate Moderate Moderate Low Blood Pressure (mmHg) Other Risk Factors and Disease History No other risk factors 1-2 risk factors Associated Clinical Conditions Grade 1 SBP 140-159 or DBP 90-99 Grade 2 SBP 160-179 or DBP 100-109 Grade 3 SBP ≥ 180 or DBP ≥ 110 3 or more risk factors or TOD or diabetes Very high added risk High High Moderate Averagerisk Low Low Averagerisk Normal SBP 120-129 or DBP 80-84 High Normal SBP 130-139 or DBP 85-89 Low risk: 30%

4. Cuspidi et al, J Hypertens 2002 Echocardiography and US TSA in Low Risk Hypertensives APROS STUDY RISK RE-CLASSIFICATION

5. 2313 Association of Hypertension with Other CAD Risk Factors: Framingham Study Kannel, Am J Hypertens 2000; 13: 3S-10S Two25% One26% None19% Four or more 8% Three22% Two24% One27% None17% 12% Three20% MenMenWomenWomen

6. 8175 = 6397 alt. M StrokeMorevs less CHDMorevs less Heart failure Morevs less Major CV events Morevs less CV death Morevs less Total mortality Morevs less Mean BP  (mmHg) -4 / -3 Relative Risk (95% CI) 0.77 (0.63-0.95) 0.86 (0.72-1.03) 0.84 (0.59-1.18) 0.86 (0.77-0.96) 0.93 (0.77-1.11) 0.96 (0.84-1.09) FavoursactiveFavourscontrol 0.51.02.0 Relative risk

7. ESH/ESC Position statement: Choice of antihypertensive drugs The main benefits of antihypertensive therapy are due to lowering of blood pressure per se. There is also evidence that specific drug classes may differ in some effect, or in special groups of patients. Drugs are not equal in terms of adverse disturbances, particularly in individual patients. The major classes of antihypertensive agents - diuretics, β-blockers, calcium antagonists, ACE inhibitors, angiotensin receptor antagonists - are suitable for the initiation and maintenance of therapy.

8. Weighted Average Change in DBP at Trough Losartan Valsartan Irbesartan Candesartan 2359 1455 582 336 2217 855 610 593 1605 190 181 298 N = -2 -4 -6 -8 -10 -12 -14 -16 Los 50 mg Val 80 mg Irb 150 mg Can 8 mg Los 50 - 100 mg Val 80 - 160 mg Irb 150 - 300 mg Can 8 - 16 mg Los 50 ± Hctz 12.5 mg Val 80 ± Hctz 12.5 mg Irb 150 ± Hctz 12.5 mg Can 8 ± Hctz 12.5 mg Conlin et al. Am J Hypertens 2000

9. Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACE I vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ß blockers/Diur Number of Patients 10,98510,8816614 Number of Primary Endpoints 698803659 Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 No Hypertension Trial Has Shown Superiority on Combined CV Morbidity and Mortality vs. an Active Comparator Hansson L et al Lancet 1999; Hannson L et al Lancet 2000;356:359-365; Hannson L et al Lancet 1999;354(9192):1751-1756.

10. 5487 M Trials on “New” vs “Old” Treatments Primary Endpoints (RR + 95% CI) Mancia G. et al., 2003 CAPPP*STOP2*ANBP2*ALLHAT°STOP2*NORDIL*INSIGHT*ALLHAT°INVEST*ALLHAT°SCOPE*LIFE*ACE-IACE-IACE-IACE-ICCBCCBCCBCCBCCB  B ARBARB n = 10985 n = 4418 n = 6083 n = 9054 n = 4209 n = 10881 n = 6321 n = 9048 n = 22599 n = 24335 n = 4506 n = 9193 0.51.02.0 New better Old better 1.05 (0.90-1.22) 1.01 (0.84-1.22) 0.89 (0.79-1.00) 0.99 (0.91-1.08) 0.97 (0.80-1.17) 1.00 (0.87-1.15) 1.10 (0.91-1.34) 0.98 (0.90-1.07) 0.98 (0.90-1.06) 1.03 (0.90-1.17) 0.89 (0.75-1.06) 0.87 (0.77-0.98) * CVD; ° CHD

11. ANBP2: Primary End-Points among All, Male, and Female Subjects 5370 M Wing et al., N Engl J Med 2003; 348: 583-92 All Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Male Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Female Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Hazard Ratio (95% CI) 0.89 (0.79-1.00) 0.89 (0.79-1.01) 0.90 (0.75-1.09) Hazard Ratio (95% CI) 0.83 (0.71-0.97) 0.83 (0.66-1.06) Hazard Ratio (95% CI) 1.00 (0.83-1.21) 1.00 (0.83-1.20) 1.01 (0.76-1.35) P Value 0.050.060.27 0.020.020.14 0.980.980.94 ACE-I superior Diuretics superior 0.21.05.0 ACE-I superior Diuretics superior 0.21.05.0 ACE-I superior Diuretics superior 0.21.05.0

12. LIFE Study: Blood Pressure During Follow-up Study Month Systolic Diastolic Mean Arterial mmHg Atenolol Losartan 6 54 123018243642 48 0

13. LIFE Study Primary Composite Endpoint 0612182430364248546066 Losartan (n)46054524446043924312424741894112404738971889901 Atenolol (n)45884494441443494289420541354066399238211854876 Study Month Proportion of patients with first event (%) Intention-to-treat Losartan Atenolol 2 4 6 8 10 12 14 16 Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009

14. LIFE Study Fatal and Non-Fatal Myocardial Infarction Intention-to-treat 1 2 3 4 5 6 7 Proportion of patients with first event (%) Atenolol Losartan Adjusted Risk Reduction -7·3%, P=0·49 Unadjusted Risk Reduction -5·0%, P=0·63 Study Month 06121824364248546066 30

15. LIFE Study Fatal and Non-Fatal Stroke Proportion of patients with first event (%) Intention-to-treat Losartan Atenolol Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 Study Month 1 2 3 4 5 6 7 8 06121824364248546066 30

16. Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003. SBPDBPPP mm Hg ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSION

17. LIFE Study ISH Subgroup Composite of CV Death, Stroke, and MI 0612182430364248546066 Study month 0 2 4 6 8 10 12 14 16 18 Endpoint rate (%) Atenolol Losartan Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 CV=cardiovascular MI=myocardial infarction

18. LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 24 20 16 12 8 4 Proportion of patients with first event (%) Losartan Atenolol 06121824364248546066 30 Losartan (n)586569558548532520513501484459237127 Atenolol (n)609588562552540527507486472434204 99 Study Month

19. Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death -60 -50 -40 -30 -20 -10 0 0 10 # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

20. 12,1 7,2 0 5 10 15 Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

21. Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510,88166149193 Number of Primary Endpoints 6988036591096 Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 13% RR p = 0.021 Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

22. LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

23. How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Ref 3, p 831, C1, ¶1, L1 Ref 4, p 469, C2, L4 Ref 9, p 493, C1, ¶3, L1; p 496, C1, ¶3, L10 Ref 5, p 1439, Fig 74-1 Ref 27, p 1653, ¶2 Please refer to notes page for reference citations.

24. LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 24 20 16 12 8 4 Proportion of patients with first event (%) Losartan Atenolol 06121824364248546066 30 Losartan (n)586569558548532520513501484459237127 Atenolol (n)609588562552540527507486472434204 99 Study Month

25. Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death -60 -50 -40 -30 -20 -10 0 0 10 # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

26. 12,1 7,2 0 5 10 15 Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

27. Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510,88166149193 Number of Primary Endpoints 6988036591096 Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 13% RR p = 0.021 Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

28. LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

29. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

30. Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Please refer to notes page for reference citations. Plaque fragments Plaque rupture

31. LIFE: Losartan vs. Atenolol Reduced ECG–LVH –18 –16 –14 –12 –10 –8 –6 –4 –2 0 Cornell productSokolow-Lyon Change from baseline (%) p<0.0001 Losartan Atenolol Adapted from Dalhöf B et al Lancet 2002;359:995–1003. Ref 25, p 1001, Fig 7

32. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

33. Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Stroke by Altering Vascular Remodeling and Atherosclerosis Please refer to notes page for reference citations. Plaque fragments Plaque rupture

34. Losartan Reduced Atherosclerosis (Fatty Streaks) in Nonhuman Primates Control Losartan Simian thoracic aorta dissected after 6-month exposure to a high-cholesterol diet (n=4) Adapted from Strawn WB et al Circulation 2000;101:1586–1593. Ref 28, p 1586, C2, ¶1, L1, ¶2, L1,7; p 1590, Fig 4

35. LIFE: Losartan vs. Atenolol Reduced Carotid Artery Hypertrophy % Change in intima-medial cross-sectional area Intima-medial thickness—change from baseline at year 3 –7.9 % –1.7 % p<0.05 –9 –8 –7 –6 –5 –4 –3 –2 –1 0 Atenolol (n=22) Losartan (n=23) Ref 26, Source C, p 34, Table 5

36. Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003. SBPDBPPP mm Hg ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSION

37. LIFE Study ISH Subgroup Composite of CV Death, Stroke, and MI 0612182430364248546066 Study month 0 2 4 6 8 10 12 14 16 18 Endpoint rate (%) Atenolol Losartan Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 CV=cardiovascular MI=myocardial infarction

38. LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 24 20 16 12 8 4 Proportion of patients with first event (%) Losartan Atenolol 06121824364248546066 30 Losartan (n)586569558548532520513501484459237127 Atenolol (n)609588562552540527507486472434204 99 Study Month

39. Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death -60 -50 -40 -30 -20 -10 0 0 10 # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

40. 12,1 7,2 0 5 10 15 Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

41. Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510,88166149193 Number of Primary Endpoints 6988036591096 Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 13% RR p = 0.021 Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

42. LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

43. How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Ref 3, p 831, C1, ¶1, L1 Ref 4, p 469, C2, L4 Ref 9, p 493, C1, ¶3, L1; p 496, C1, ¶3, L10 Ref 5, p 1439, Fig 74-1 Ref 27, p 1653, ¶2 Please refer to notes page for reference citations.

44. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

45. Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Please refer to notes page for reference citations. Plaque fragments Plaque rupture

46. LIFE: Losartan vs. Atenolol Reduced ECG–LVH –18 –16 –14 –12 –10 –8 –6 –4 –2 0 Cornell productSokolow-Lyon Change from baseline (%) p<0.0001 Losartan Atenolol Adapted from Dalhöf B et al Lancet 2002;359:995–1003. Ref 25, p 1001, Fig 7

47. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

48. Losartan vs. Atenolol Improved Structure of Small Gluteal Arteries Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659. Structure Media/lumen ratio (%) 0 2 4 6 8 10 Before 1 year Before 1 year LosartanAtenolol Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4

49. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

50. Losartan vs. Atenolol Improved Endothelial Function of Small Gluteal Arteries Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659. Endothelium-dependent relaxation 0 20 40 60 80 100 * Maximal acetylcholine response (%) Before 1 year Before 1 year LosartanAtenolol Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4; p 1657, Fig 3

51. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

52. Losartan Had Effects on Platelet Aggregation and Thrombus Formation Losartan –Reduced TXA 2 –dependent platelet activation (platelets from 15 healthy men) –Reduced plasma levels of PAI-1 antigen, PAI-1 activity, and sTM level in 12 hypertensive patients –Increased the concentration of thrombin receptor- activating peptide (SRLRRN-NH2) required to induce platelet aggregation in 10 hypertensive patients –Reduced plasma PAI-1 levels in hypertensive postmenopausal women –Reduced the aggregatory response to thromboxane but not thrombin in hypertensive patients Please refer to notes page for reference citations.

53. Losartan Inhibited Platelet Aggregation in Man (via EXP3179) Adapted from Krämer C et al Circ Res 2002;90:770–776. Ref 36, p 774, Fig 4A 0 20 40 60 80 100 Platelet aggregation (%) Time (months) 42068 * * *p<0.0001 vs. placebo Placebo Losartan

54. Hemodynamic factors (central and peripheral, blood pressure) Circulating factors (Glucose, Insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque Emboli formation Thrombus formation Embolic occlusion Thrombotic occlusion Ischemic stroke Plaque fragments Plaque rupture Hemorrhagic stroke Vascular hemorrhage Losartan May Reduce the Risk of CV events by Molecular-Specific Effects Please refer to notes page for reference citations. Losartan reduces uric acid

55. LIFE: Losartan vs. Atenolol Reduced the Rise in Serum Uric Acid without Affecting Renal Function Adapted from Høieggen A et al Kidney Int 2004;65:1–9. NS µmol/L 0 5 10 15 20 25 30 35 40 45 Atenolol Losartan p<0.0001 Ref 40, p 4, C2, ¶2, L1,3; p 5, C1, ¶1, L1, ¶2, L1 + calc Calc: 96.9–87.4=9.5 96.1–86.5=9.6

56. CRP -at Concentrations Known to Predict CV Events- Upregulates AT-1 Receptors in Vascular Smooth Muscle Wang CH et al, Circulation. 2003;107:1783

57. CRP stimulates VSM cell migration. This effect was inhibited by losartan. Losartan per se did not affect VSM migration in the basal state. Ang II increased VSM migration; this effect was potentiated in the presence of CRP and attenuated by N-acetylcysteine (an anti- oxidant) Wang CH et al, Circulation. 2003;107:1783

58. Conclusions Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

59. Atherogenesis Atherogenesis Inflammation Insulin Resistance Thrombogenesis Conditions Associated with CV Disease Obesity/MS/Diabetes, PCOS, HTN, Dyslipidemias, COPD, Systemic Inflammatory Disorders, CRF, Chronic Infections, Homocystenemia, Pschyosocial Stress CV DISEASES CHD, PVD, CVD, Cardiomyopathy, Arrhythmias, Restenosis, Valvular HD, Vein Graft failure, Cardiac Allograft Vasculopathy, Pulmonary Arterial Hypertension