1. Hypertension: New Concepts, Guidelines, and Clinical Management Nathan D. Wong, PhD, FACC Associate Professor and Director Heart Disease Prevention Program Division of Cardiology, Department of Medicine College of Medicine, University of California, Irvine

3. Age Distribution of Hypertensives in US Population (NHANES III and the 1991 Census) 3.7 9.5 13 21.3 23.7 19.2 9.6 Hypertensives Within Age Group (%) Franklin SS. J Hypertension. 1999;17(suppl 5):S29-S36. Age Groups (y) 47.4 million hypertensives 26.0% of US population 26% 74% 0 5 10 15 20 25 30 18-29 30-39 40-49 50-59 60-69 70-79 80+

4. <40 40-49 50-59 60-69 70-79 80+ Age (y) 17% 16% 16% 20% 20% 11% Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by Age Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874 . Frequency of hypertension subtypes in all untreated hypertensives (%) ISH (SBP  140 mm Hg and DBP <90 mm Hg) SDH (SBP  140 mm Hg and DBP  90 mm Hg) IDH (SBP <140 mm Hg and DBP  90 mm Hg) 0 20 40 60 80 100

5. Hypertension: A Significant CV and Renal Disease Risk Factor Peripheral vascular disease  Morbidity  Disability Renal disease CAD CHF LVH Stroke Hypertension National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.

6. Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50%

7. Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: 888-95) PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%

9. BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74 Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6. 34 27 29 10 Control 59 54 55 31 Treatment 70 68 73 51 Awareness 1999–2000 II (Phase 2) 1991–94 II (Phase 1) 1988–91 II 1976–80 National Health and Nutrition Examination Survey, Percent

10. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) National Heart, Lung, and Blood Institute National High Blood Pressure Education Program U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute

11. Blood Pressure Classification <80 and <120 Normal 80–89 or 120–139 Prehypertension 90–99 or 140–159 Stage 1 Hypertension > 100 or > 160 Stage 2 Hypertension DBP mmHg SBP mmHg BP Classification

13. 4-Year Progression To Hypertension: The Framingham Heart Study (<120/80 mm Hg) (130/85 mm Hg) (130-139/85-89 mm Hg) Vasan, et al. Lancet 2001;358:1682-86 Participants age 36 and older

14. Impact of High-Normal BP on Risk of Major CV Events* in Men * Defined as death due to CV disease; recognized myocardial infarction (MI), stroke, or congestive heart failure (CHF). Adapted from Vasan RS. N Engl J Med. 2001;345:1291-1297. Cumulative Incidence (%) of Major CV Events Time (y) Optimal BP (<120/80 mm Hg) Normal BP (120-129/80-84 mm Hg) High-normal BP (130-139/85-89 mm Hg) 16 12 10 8 6 4 2 0 14 0 2 4 6 8 10 12

15. HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25  90  85  80 Major cardiovascular events/1,000 patient-years p =0.005 for trend mm Hg Target Diastolic Blood Pressure

16. SBP-Associated Risks: MRFIT Adapted from Neaton JD et al. Arch Intern Med . 1992;152:56-64 . SBP versus DBP in Risk of CHD Mortality Diastolic BP (mm Hg) Systolic BP (mm Hg) CHD Death Rate 100+ 90–99 80–89 75–79 70–74 <70 <120 120–139 140–159 160+ 48.3 20.6 10.3 11.8 8.8 8.5 9.2 23.8 16.9 13.9 12.8 12.6 11.8 31.0 25.5 24.6 25.3 25.2 24.9 37.4 34.7 43.8 38.1 80.6

19. SHEP: Outcomes * P =.0003 vs placebo. Adapted from SHEP Cooperative Research Group. JAMA . 1991;265:3255-3264. Risk Reduction Risk Reduction (%) 0 – 10 – 20 – 30 – 40 – 50 – 36* Total Mortality – 13 Stroke

21. Syst-Eur: Outcomes * P =.003; † P =.03; ‡ P =.12; § P <.001. Adapted from Staessen JA et al. Lancet . 1997;350:757-764 . Percent Reduction 0 – 5 – 10 – 15 – 20 – 25 – 30 – 35 – 40 – 45 – 42* Heart Failure Stroke All Cardiac Endpoints All Fatal/Nonfatal Cardiac Endpoints MI – 26 † – 29 ‡ – 30 ‡ – 31 § Risk Reduction

24. ATP III: The Metabolic Syndrome* *Diagnosis is established when  3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is  BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497. © 2001, Professional Postgraduate Services ® www.lipidhealth.org <40 mg/dL <50 mg/dL Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women  110 mg/dL Fasting glucose  130/  85 mm Hg Blood pressure HDL-C  150 mg/dL TG Abdominal obesity † (Waist circumference ‡ ) Defining Level Risk Factor

25. Prevalence of Selected Risk Factors in US Adults with the Metabolic Syndrome (without Diabetes) (Wong et al., Am J Cardiol 2003, in press)

26. Estimated Proportion of CHD Events Preventable by Control of Blood Pressure, HDL-C, LDL-C, and All 3 Factors to “Optimal” Levels in Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003, in press) ** * * p<0.05, ** p<0.01 compared to men

28. Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 0.81 0.99 (0.91-1.08) L/C 0.65 0.98 (0.90-1.07) A/C p value RR (95% CI) ALLHAT

29. Cumulative Event Rates for Stroke by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Cumulative Stroke Rate Years to Stroke 0 1 2 3 4 5 6 7 0 .02 .04 .06 .08 .1 0.02 1.15 (1.02-1.30) L/C 0.28 0.93 (0.81-1.06) A/C p value RR (95% CI) ALLHAT

30. Cumulative CHF Rate Years to HF 0 1 2 3 4 5 6 7 0 .03 .06 .09 .12 .15 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril <.001 1.19 (1.07-1.31) L/C <.001 1.38 (1.25-1.52) A/C p value HR (95% CI) ALLHAT

31. Overall Conclusions Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. ALLHAT

35. BP Measurement Techniques Provides information on response to therapy. May help improve adherence to therapy and evaluate “white-coat” HTN. Self-measurement Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep may indicate increased CVD risk. Ambulatory BP monitoring Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm. In-office Brief Description Method

41. Lifestyle Modification Approximate SBP reduction (range) Modification 5–20 mmHg/10 kg weight loss Weight reduction 8–14 mmHg Adopt DASH eating plan 2–8 mmHg Dietary sodium reduction 4–9 mmHg Physical activity 2–4 mmHg Moderation of alcohol consumption

44. Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease ) Initial Drug Choices Lifestyle Modifications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Stage 2 Hypertension (SBP > 160 or DBP > 100 m mHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140 –159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

45. Classification and Management of BP for adults *Treatment determined by highest BP category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡ Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. Two-drug combination for most † (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Yes or > 100 > 160 Stage 2 Hypertension Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Yes or 90–99 140–159 Stage 1 Hypertension Drug(s) for compelling indications. ‡ No antihypertensive drug indicated. Yes or 80–89 120–139 Prehypertension Encourage <80 <120 & Normal With compelling indications Without compelling indication Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification

49. Compelling Indications for Individual Drug Classes Clinical Trial Basis Initial Therapy Compelling Indication ALLHAT, HOPE, ANBP2, LIFE, CONVINCE ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES THIAZ, BB, ACE, CCB BB, ACEI, ALDO ANT THIAZ, BB, ACEI, ARB, ALDO ANT High CAD risk Postmyocardial infarction Heart failure

50. Compelling Indications for Individual Drug Classes Recurrent stroke prevention Chronic kidney disease Diabetes Clinical Trial Basis Initial Therapy Options Compelling Indication PROGRESS NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK NKF-ADA Guideline, UKPDS, ALLHAT THIAZ, ACEI ACEI, ARB THIAZ, BB, ACE, ARB, CCB

53. Relative Risk of CV Events and Mortality: CCBs vs Diuretics or Beta Blockers CCBs, calcium channel blockers. CHD, coronary heart disease. * Includes INSIGHT, NICS-EH, STOP-2, NORDIL, and VHAS. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet . 2000;356:1955-1964. Stroke 456 529 0.87 (0.77-0.98) CHD 567 510 1.12 (1.00-1.26) Heart Failure 278 250 1.12 (0.95-1.33) Major CV Events 1,251 1,234 1.02 (0.95-1.10) CV Death 425 405 1.05 (0.92-1.20) Total Mortality 776 776 1.01 (0.92-1.11) Relative Risk Favors CCBs Favors diuretics or beta blockers CCBs (n=11,685) Diuretics or Beta Blockers (n=11,769) 0.5 1.0 2.0 No. of Events* Relative Risk (95% CI)

54. HOPE: Risk Reduction of CV Events Associated with ACEI (RAS Inhibition) Treatment Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. -22 ( P <.001) MI, Stroke, CV Death (primary end point) -26 ( P <.001) CV Death -20 ( P <.001) MI -32 ( P <.001) Stroke -16 ( P =.005) All-cause Death -35 -30 -25 -20 -15 -10 -5 0 Risk Reduction (%)

55. Relative Risk of CV Events and Mortality: ACE Inhibitors vs Diuretics or Beta Blockers CHD, coronary heart disease. * Includes STOP-2, UKPDS-HDS, and CAPPP. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet . 2000;356:1955-1964. Stroke 425 402 1.05 (0.92-1.19) CHD 423 420 1.00 (0.88-1.14) Heart Failure 223 250 0.92 (0.77-1.09) Major CV Events 1,018 1,004 1.00 (0.93-1.08) CV Death 350 348 1.00 (0.87-1.15) Total Mortality 639 618 1.03 (0.93-1.14) Relative Risk Favors ACE inhibitors Favors diuretics or beta blockers No. of Events* ACE Inhibitors (n=8,097) Diuretics or Beta Blockers (n=8,064) 0.5 1.0 2.0 Relative Risk (95% CI)

56. Reversal of LV Hypertrophy By Antihypertensive Treatment Schmieder RE et al. JAMA. 1996;275:1507-1513. Change in LV mass index (%) Diuretics  -blockers Calcium channel blockers ACE inhibitors p <.01 p <.01 7% 6% 9% 13% 0 -5 -10 -15 -20 -25

57. Regression of LV Hypertrophy Predicts Prognosis LV, left ventricular. Nonregressors defined as baseline and follow-up left ventricular mass index (LVMI) >125 g/m 2 ; regressors defined as baseline LVMI >125 g/m 2 and follow-up LVMI <125 g/m 2 . Adapted from Verdecchia P et al. Circulation. 1998;97:48-54. Probability of event-free survival (%) Rate of events (per 100 patient-yrs) Time to event (wk) P =.002 Regressors (n=285) Nonregressors (n=145) Regressors (n=52) Nonregressors (n=50) 0 100 200 300 400 500 100 90 80 70 0 60 50 7 6 5 4 1 3 2 0

58. Irbesartan and Atenolol in Hypertension and LVH Study Design Single-blind Placebo Irbesartan 150-300 mg Atenolol 50-100 mg Addition of HCTZ 12.5-25 mg if SeDBP  90 mm Hg Addition of Felodipine 5-10 mg if SeDBP  90 mm Hg Wk: -4 0 12 24 48 * BP, echocardiography, neurohormone measurements. Malmqvist K et al. J Hypertens. 2001;19:1167-1176. * Double Blind * * *

59. Irbesartan vs Atenolol in Hypertension and LVH: SeDBP Reduction -20 -15 -10 -5 0 12 wk 24 wk 48 wk % reduction in SeDBP Irbesartan Atenolol * * † * * * * * p <.001 vs baseline. † p <.028 irbesartan vs atenolol. Malmqvist K et al. J Hypertens. 2001;19:1167-1176.

60. Irbesartan vs Atenolol in Hypertension and LVH: LVMI Reduction -18 -16 -14 -12 -10 -8 -6 -4 -2 0 % change in LVMI (g/m 2 ) * p <.001 vs baseline; † p =.024 irbesartan vs atenolol. Malmqvist K et al. J Hypertens. 2001;19:1167-1176. Irbesartan Atenolol 12 wk * 24 wk * * 48 wk * * †

62. LIFE: Dosing * Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers. Adapted from Dahlöf B et al. Am J Hypertens. 1997;10:705-713. Titration to target blood pressure: <140 / <90 mmHg Placebo Run-in Losartan 50 mg Atenolol 50 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5-25 mg + others* Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* Average follow up 4.7 years

63. LIFE: Blood Pressure Results – Follow-up Study Month Systolic Diastolic Mean Arterial mmHg Atenolol Losartan Atenolol 145.4 mmHg Losartan 144.1 mmHg Atenolol 80.9 mmHg Losartan 81.3 mmHg B Dahl ö f et al. Lancet. 2002;359:995-1003. 0 6 12 18 24 30 36 42 48 54 40 60 80 100 120 140 160 180

67. Web site www.nhlbi.nih.gov/

68. DASH Fact Sheet

69. Your Guide to Lowering Blood Pressure

70. Reference Card

74. MRFIT: Association of Systolic BP and Cardiovascular Death in Type 2 Diabetes < 120 120–139 140–159 160–179 180–199  200 Systolic blood pressure (mm Hg) Cardiovascular mortality rate/10,000 person-yr Nondiabetic Diabetic Stamler J et al. Diabetes Care. 1993;16:434-444. 250 225 200 175 150 125 100 75 50 0 25

75. Veterans Administration Hypertension and Screening Clinics 15-Year ESRD Rates and Risk Ratios by Baseline Systolic Blood Pressure SBP (mm Hg) Risk Ratio < 140 > 140 but < 151 > 151 but < 165 > 165 but < 180 > 180 1.00 1.00 1.08 2.07 5.62 Number of screenees: 11,912 (5,730 black; 6,182 white) Source: Perry HM, et al. Hypertension. 1995;25:587-594

76. Veterans Administration Hypertension and Screening Clinics 15-Year ESRD Rates and Risk Ratios by Baseline Diastolic Blood Pressure DBP (mm Hg) Risk Ratio < 94 > 94 but < 100 > 100 but < 106 > 106 but < 118 > 118 1.00 1.05 0.89 1.54 4.18 Number of screenees: 11,912 (5,730 black; 6,182 white) Source: Perry HM, et al. Hypertension. 1995;25:587-594

80. Correlation Between MAP & Renal Function GFR, glomerular filtration rate; HTN, hypertension; MAP, mean arterial pressure. Adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. GFR Decline (mL/min/y) MAP (mm Hg) 95 98 101 107 104 110 113 116 119 r=0.69; P <.05 Untreated HTN 130/85 140/90 0 -2 -4 -6 -8 -10 -12 -14

81. Microalbuminuria as a Risk Factor for Death in Type 2 Diabetes UAC, urinary albumin concentration. Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134. Years after Diagnosis Survival UAC  15  g/mL UAC 16-40  g/mL UAC 41-200  g/mL 0.0 0.4 1.0 0.8 0.6 0.2 0 5 10 2 1 3 4 7 6 8 9 11

82. Proteinuria & Risk of CV Mortality,Stroke, & CHD Events in Type 2 Diabetes CHD, coronary heart disease; UPC, urinary protein concentration. * Defined as CHD death or nonfatal MI. Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039. A: UPC <150 mg/L B: UPC 150-300 mg/L C: UPC >300 mg/L 1.0 0.9 0.8 0.7 0.6 0.5 0 0 10 20 30 40 50 60 70 80 90 Stroke CHD Events* P <.001 for trends Incidence (%) Reduction in Survival due to CV Mortality Months A B C P -values: Overall <.001 A vs B =.013 A vs C <.001 B vs C <.001 0 10 20 30 40

83. Risk Reduction of Diabetes-Related End Points with Tight BP Control * Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or hypoglycemia. † Fatal or nonfatal. ‡ Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure. Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs 154/87 mm Hg (less tight BP control). Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. Risk Reduction (%) Diabetes-related Mortality* Stroke † Microvascular End Points ‡ Myocardial Infarction 32 44 37 21 0 10 20 30 40 50

84. HOT: Significant Benefit From Intensive Antihypertensive Treatment in Diabetes * Defined as fatal and nonfatal MI, fatal and nonfatal stroke, and all other CV death. Adapted from Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25  90  85  80 Major CV Events*/1000 Patient-yrs in Hypertensive Patients with Diabetes P =.005 for trend Target DBP (mm Hg)

85. Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes * P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462. Progression to Death, Dialysis, or Transplant (%) Captopril Placebo Follow-up (y) * 0 1 2 3 4 0 10 20 30 40

86. IRMA 2: Blood Pressure Response SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% in the irbesartan 300-mg group were receiving concomitant antihypertensive agents. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878. Control SeDBP* Irbesartan 150 mg SeDBP* Irbesartan 300 mg SeDBP* Control SeSBP* Irbesartan 150 mg SeSBP* Irbesartan 300 mg SeSBP* Mean SeSBP and SeDBP (mm Hg) Months 0 3 6 9 12 15 18 21 24 27 0 70 130 160 80 90 100 110 120 140 150

87. IRMA 2 Primary Endpoint Development of Overt Proteinuria Subjects (%) Control (n=201) 150 mg (n=195) 300 mg (n=194) Irbesartan 9.7 5.2 14.9 RRR=39% P =0.08 RRR=70% P<0.001 Parving H-H, et al. N Engl J Med 2001;345:870-878. 14 18 16 12 10 8 6 4 2 0

88. IDNT: Systolic BP, Mean Arterial Pressure, & Diastolic BP Response Control defined as placebo. Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups, and 3.3 concomitant agents in the control group. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Irbesartan Amlodipine Control Follow-up Visit (mo) SBP MAP DBP BP (mm Hg) 0 6 12 18 24 30 36 42 48 54 80 100 120 140 160

89. IDNT Primary Endpoint: Time to Doubling of Serum Creatinine, ESRD, or Death Subjects (%) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) 60 Irbesartan Amlodipine Control Lewis EJ et al. N Engl J Med 2001;345:851-860. RRR 20% P =0.02 P =NS RRR 23% P =0.006 0 10 20 30 40 50 60 70

90. IDNT & RENAAL: Study Design SeCr, serum creatinine; ESRD, end-stage renal disease. † Lewis EJ et al. N Engl J Med. 2001;345:851-860. ‡ Brenner BM et al. N Engl J Med. 2001;345:861-869. Patients: 1,715 HTN patients with type 2 1,513 HTN patients with diabetes & nephropathy type 2 diabetes & nephropathy Treatment arms: irbesartan, amlodipine, losartan, placebo placebo Target BP: 135/85 mm Hg 140/90 mm Hg Adjunctive therapy: Permitted except ARBs, Permitted including ACE inhibitors, or CCBs CCBs, except ARBs or ACE inhibitors Primary outcome: Composite of doubling of Composite of doubling of SeCr, ESRD, or death SeCr, ESRD, or death Secondary outcomes: CV events CV events Mean Follow-up: 2.6 years 3.4 years RENAAL ‡ IDNT †

91. IDNT and RENAAL Trial Results Doubling of Creat, 16 ( P =0.02) 20 ( P =0.02) 23 ( P =0.006) -4 ( P =0.69) ESRD, or death Doubling of Creat 25 ( P =0.006) 33 ( P =0.003) 37 ( P< 0.001) -6 ( P =0.60) ESRD 28 ( P =0.002) 23 ( P =0.07) 23 ( P =0.07) 0 ( P =0.99) Death -2 ( P =0.88) 8 ( P =0.57) -4 ( P =0.8) 12 ( P =0.4) CV Morbidity 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12 (P=0.29) & Mortality Losartan vs control Irbesartan vs control Irbesartan vs amlodipine Amlodipine vs control RRR (%) Comparison of Major Endpoints RENAAL IDNT Lewis EJ et al. N Engl J Med 2001;345:851-860. Brenner B et al. N Engl J Med 2001;345:861-869.

116. Antihypertensive Drugs Used in Pregnancy These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105 mm Hg). Central  -agonists Methyldopa is the drug of choice.  -blockers and  -  -blockers Atenolol, metoprolol, and labetalol appear safe and effective in late pregnancy. Calcium antagonists Potential synergism with magnesium sulfate may lead to precipitous hypotension. *Limited or no controlled trials in pregnant women.

117. Antihypertensive Drugs Used in Pregnancy (continued) These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105). Diuretics Diuretics are recommended for chronic hypertension if prescribed before gestation, but they are not recommended for preeclampsia. Direct vasodilators Hydralazine is the parenteral drug of choice based on its long history of safety and efficacy. *Limited or no controlled trials in pregnant women. ACE inhibitors and angiotensin II receptor blockers are contraindicated.

120. Combined Results of Five Randomized Trials of Antihypertensive Treatment in the Elderly Stroke 0 100 200 300 400 500 600 78 288 T T = Treatment C = Control = Fatal events 120 438 C CHD 208 346 T 279 438 C Vascular deaths Total numbers of individuals affected 383 T 494 C All other deaths 34% (6) 2P <0.0001 % (SD) reduction in odds 19% (7) 2P <0.05 23% (6) 2P <0.001 – 7% (8) 2P >0.5 344 362 T C

123. Mechanism of Action of Angiotensin II Receptor Antagonists Angiotensinogen Angiotensin I Angiotensin II AT 2 receptor AT 1 receptor Other AT receptors Bradykinin Inactive peptides Vasodilation Attenuate growth and disease progression ACE inhibitors Alternate pathways AIIRAs ? ?

130. IRMA 2: Mean Baseline Characteristics N Age (y) Male (%) BMI (kg/m 2 ) BP (mm Hg) HbA 1c (%) SeCr (mg/dL) Irbesartan 150 mg/d 195 58 66 29.9 153/90 7.3 1.0 Irbesartan 300 mg/d 194 57 71 30.0 153/91 7.1 1.1 Control 201 58 69 30.3 153/90 7.1 1.0 UAER (µg/min) 58 53 55 Duration of diabetes (y) 9.5 9.2 10.4 Control defined as placebo. BMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbA 1c , glycosylated hemoglobin. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.

131. IRMA 2 Primary End Point: Time to Overt Proteinuria RRR, relative risk reduction. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878. Follow-up (mo) Control (n=201)* Irbesartan 150 mg/d (n=195)* Irbesartan 300 mg/d (n=194)* RRR=39% P =.08 RRR=70% P <.001 Patients (%) 0 3 6 12 18 22 24 0 5 10 15 20

132. IRMA 2: Normalization * of UAER UAER, urinary albumin excretion rate. Control defined as placebo. * Normoalbuminuria defined as UAER of <20 mg/min. † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Parving H-H et al. N Engl J Med. 2001;345:870-878. Control † (n=201) 150 mg/d † (n=195) 300 mg/d † (n=194) Irbesartan 24 34 21 P =.006 Patients (%) 35 45 40 30 25 20 15 10 5 0

133. IRMA 2: Adverse Events Cardiovascular events 18 (8.7) 1 14 (6.9) 2 9 (4.5) 1 Serious AE 47 (22.8) 1 32 (15.8) 2 30 (15.0) 2 Discontinuations due to AE 19 (9.2) 2 18 (8.9) 2 11 (5.5) 2 Control group* (n=201) Irbesartan 150 mg* (n=195) Irbesartan 300 mg* (n=194) No. of Adverse Events (%) Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. 1. Parving H-H, et al. N Engl J Med. 2001;345:870-878. 2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.

135. IDNT: Study Design 1,715 patients with hypertension, type 2 diabetes, & proteinuria  900 mg/d Double-blind treatment Up to 5 weeks Screening/enrollment Control* Amlodipine* Minimum follow-up: approximately 2 years (average follow-up, 2.6 years) Irbesartan* Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to help achieve target BP. Lewis EJ et al. N Engl J Med. 2001;345:851-860.

137. IDNT: Mean Baseline Demographics N Age (y) Male (%) Non-white (%) BMI (kg/m 2 ) History of CV disease (%) Retinopathy (%) Irbesartan 579 59 65 24 31.0 27 69 Amlodipine 567 59 63 31 30.9 30 64 Control 569 58 71 28 30.5 29 67 Control defined as placebo. BMI, body mass index. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Duration of diabetes (y) 15 14 15

138. IDNT: Baseline Exam & Laboratory Characteristics Irbesartan Amlodipine Control SBP (mm Hg)* 160 159 158 Control defined as placebo. SeCr, serum creatinine; HbA 1c , glycosylated hemoglobin. * Mean. † Median. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. DBP (mm Hg)* 87 87 87 SeCr (mg/dL)* 1.67 1.65 1.69 Urine protein (g/24 h) † 2.9 2.9 2.9 HbA 1c (%)* 8.1 8.2 8.2

139. IDNT Primary End Point: Time to Doubling of SeCr, ESRD, or Death Control defined as placebo. SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Irbesartan (n=579) Amlodipine (n=565) Control (n=568) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) Patients (%) RRR=20% P =.02 P =NS RRR=23% P =.006 0 10 20 30 40 50 60 70

140. IDNT: Time to Doubling of SeCr Control defined as placebo. SeCr, serum creatinine; RRR, relative risk reduction. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Patients (%) Follow-up (mo) Irbesartan (n=579) Amlodipine (n=567) Control (n=569) RRR=33% P =.003 P =NS RRR=37% P <.001 0 6 12 18 24 30 36 42 48 54 0 10 20 30 40 50 60 70

141. IDNT Secondary End Point: CV Events * No significant differences between groups. Control defined as placebo. * Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in hospitalization, a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Control (n=569) Irbesartan (n=579) Amlodipine (n=567) 25.3 23.8 22.6 Patients (%) 0 10 20 30 5 15 25

142. IDNT: Adverse Events Early SeCr rise (n) 2 0 0 1 Discontinuations due to hyperkalemia [n (%)] 1 11 (1.9) 3 (0.5) 2 (0.4) Stopped study medicine [n (%)] 2 134 (23) 133 (23) 140 (25) SAEs/1000 days on drug (%) 2 2.0 2.5 2.3 Irbesartan Amlodipine Control No. of AEs AE, adverse event; SAE, serious adverse event. Control defined as placebo. 1. Lewis EJ et al. N Engl J Med. 2001;345:851-860. 2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.