Mechanism of superior cardiovascular protection: Clinical perspective on LIFE

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

ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg) Category Optimal Normal High normal Grade 1 hypertension (mild) Grade 2 hypertension (moderate) Grade 3 hypertension (severe) Isolated systolic hypertension Systolic < 120 120-129 130-139 140-159 160-179 ≥ 180 ≥ 140 Diastolic < 80 80-84 85-89 90-99 100-109 ≥ 110 < 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 6254 M

ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis Blood Pressure (mmHg) Normal SBP 120-129 or DBP 80-84 High Normal SBP 130-139 or DBP 85-89 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 Other Risk Factors and Disease History No other risk factors 1-2 risk factors Associated Clinical Conditions Average risk Average risk Low added risk Moderate added risk High added risk Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk Moderate added risk High added risk High added risk High added risk Very high added risk 3 or more risk factors or TOD or diabetes Very high added risk Very high added risk High added risk Very high added risk Very high added risk Low risk: < 15%; Medium risk: 15-20%; High risk: 20-30%; Very high risk: > 30% 7772 M

Echocardiography and US TSA in Low Risk HypertensivesAPROS STUDY RISK RE-CLASSIFICATION Cuspidi et al, J Hypertens 2002

Association of Hypertension with Other CAD Risk Factors: Framingham Study One 26% One 27% Two 25% Two 24% None 19% None 17% Three 22% Three 20% Four or more 8% Four or more 12% Men Women Kannel, Am J Hypertens 2000; 13: 3S-10S 2313

Stroke More vs less CHD More vs less Heart failure More vs less Major CV events More vs less CV death More vs less Total mortality More vs less Mean BP  (mmHg) -4 / -3 -4 / -3 -4 / -3 -4 / -3 -4 / -3 -4 / -3 Favours active Favours control 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) 0.5 1.0 2.0 Relative risk 8175 = 6397 alt. M

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

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

Mega-trials CAPPP NORDIL STOP-2 Comparator ACE I CCB ACE Is/CCBs Treatments vs. vs. vs. ß blockers/ Diur ß blockers/ Diur ß blockers/ Diur Number of Patients 10,985 10,881 6614 Number of Primary 698 803 659 Endpoints MI, MI, Fatal MI, Fatal Composite Primary Stroke, CV Stroke, CV Death Stroke, Fatal Endpoint Death CV Disease Differences on NS NS NS Primary Endpoint p = 0.52 p = 0.97 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.

Trials on “New” vs “Old” TreatmentsPrimary Endpoints (RR + 95% CI) CAPPP* STOP2* ANBP2* ALLHAT° STOP2* NORDIL* INSIGHT* ALLHAT° INVEST* ALLHAT° SCOPE* LIFE* ACE-I ACE-I ACE-I ACE-I CCB CCB CCB CCB CCB B ARB ARB 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) n = 10985 n = 4418 n = 6083 n = 9054 n = 4209 n = 10881 n = 6321 n = 9048 n = 22599 n = 24335 n = 4506 n = 9193 0.5 1.0 2.0 * CVD; ° CHD New better Old better Mancia G. et al., 2003 5487 M

ANBP2: Primary End-Points among All, Male, and Female Subjects 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 (0.71-0.97) 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 0.05 0.06 0.27 P Value 0.02 0.02 0.14 P Value 0.98 0.98 0.94 ACE-I superior Diuretics superior 0.2 1.0 5.0 ACE-I superior Diuretics superior 0.2 1.0 5.0 ACE-I superior Diuretics superior 0.2 1.0 5.0 Wing et al., N Engl J Med 2003; 348: 583-92 5370 M

LIFE Study: Blood Pressure During Follow-up Systolic Mean Arterial mmHg Diastolic Losartan Atenolol 54 48 0 6 12 18 24 30 36 42 Study Month

Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 LIFE Study Primary Composite Endpoint 16 Intention-to-treat 14 Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009 12 10 Atenolol Proportion of patients with first event (%) 8 Losartan 6 4 2 Study Month 0 6 12 18 24 30 36 42 48 54 60 66

LIFE Study Fatal and Non-Fatal Myocardial Infarction 7 Intention-to-treat Adjusted Risk Reduction -7·3%, P=0·49 Unadjusted Risk Reduction -5·0%, P=0·63 6 5 Losartan 4 Proportion of patients with first event (%) Atenolol 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 Study Month

8 Intention-to-treat Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 7 6 Atenolol 5 Losartan 4 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 Study Month LIFE Study Fatal and Non-Fatal Stroke Proportion of patients with first event (%)

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

LIFE StudyISH SubgroupComposite of CV Death, Stroke, and MI Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 18 16 14 12 10 Endpoint rate (%) 8 6 Atenolol 4 Losartan 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Study month CV=cardiovascular MI=myocardial infarction

Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127 0 6 12 18 24 36 42 48 54 60 66 30 Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99 LIFE StudyDiabetesSubgroupPrimary Composite CV Endpoint 24 Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 20 16 Atenolol Losartan Proportion of patients with first event (%) 12 8 4 Study Month

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

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

Mega-trials CAPPP NORDIL STOP-2 Comparator ACEI CCB ACEIs/ CCBs Losartan Treatments vs. vs. vs. vs. ß blockers/ Diur ß blockers/ Diur ß bockers/ Diur Atenolol Number of Patients 10,985 10,881 6614 9193 Number of Primary 698 803 659 1096 Endpoints MI, MI, Fatal MI, Fatal MI, Composite Primary Stroke, CV Stroke, CV Death Stroke, Fatal Stroke, CV Endpoint Death CV Disease Death Differences on NS NS NS 13% RR Primary Endpoint p = 0.52 p = 0.97 p = 0.89 p = 0.021 Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

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 * Defined as composite of CV death, MI, and stroke

How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/enlargement 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 Vascular remodeling Endothelial dysfunction Prothrombotic state Please refer to notes page for reference citations.

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

Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Cardiac remodeling/enlargement Hemodynamic factors (central and peripheral blood pressure) Emboli formation Vascular remodeling Embolic occlusion Plaque fragments Atherosclerotic plaque formation Ischemic stroke Plaque rupture Endothelialdysfunction Thrombotic occlusion Circulating factors (glucose, insulin, RBCs, PAI, TXA2, uric acid) Thrombus/ platelet aggregation Prothrombotic state Hemorrhagic stroke Vascular hemorrhage Please refer to notes page for reference citations.

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

Hypothesis: Losartan May Reduce the Risk of Stroke by Altering Vascular Remodeling and Atherosclerosis Cardiac remodeling/enlargement Hemodynamic factors (central and peripheral blood pressure) Emboli formation Vascular remodeling Embolic occlusion Atherosclerotic plaque formation Plaque fragments Ischemic stroke Plaque rupture Endothelial dysfunction Thrombotic occlusion Circulating factors (glucose, insulin, RBCs, PAI, TXA2, uric acid) Thrombus/ platelet aggregation Prothrombotic state Hemorrhagic stroke Vascular hemorrhage Please refer to notes page for reference citations.

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

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

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

LIFE StudyISH SubgroupComposite of CV Death, Stroke, and MI Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 18 16 14 12 10 Endpoint rate (%) 8 6 Atenolol 4 Losartan 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Study month CV=cardiovascular MI=myocardial infarction

How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/enlargement 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 Vascular remodeling Endothelial dysfunction Prothrombotic state Please refer to notes page for reference citations.

Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Cardiac remodeling/enlargement Hemodynamic factors (central and peripheral blood pressure) Emboli formation Vascular remodeling Embolic occlusion Plaque fragments Atherosclerotic plaque formation Ischemic stroke Plaque rupture Endothelialdysfunction Thrombotic occlusion Circulating factors (glucose, insulin, RBCs, PAI, TXA2, uric acid) Thrombus/ platelet aggregation Prothrombotic state Hemorrhagic stroke Vascular hemorrhage Please refer to notes page for reference citations.

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

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

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

Mechanism of superior cardiovascular protection: Clinical perspective on LIFE