1. Downloaded from www.cozaar.aewww.cozaar.ae Strategy for Reducing the Risk of Stroke in Hypertensive Patients with LVH 1

2. Downloaded from www.cozaar.aewww.cozaar.ae Consequences of Hypertension 1-4 Hypertension Brain Heart Kidney End-stage renal disease MI, heart failure, sudden death Stroke, dementia 1. Weir et al. Am J Hypertens 1999;12:205S-213S. 2. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999:1629-1648. 3. Francis CK. In: Izzo JL Jr, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 2nd ed. 1999:175-176. 4. Hershey LA. In: Izzo JL Jr, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 2nd ed. 1999:188-189. 2

3. Downloaded from www.cozaar.aewww.cozaar.ae Stroke and MI in Hypertension Trials 1-3 1. Kjeldsen SE et al. Blood Pressure 2001;10:190-192. 2. Dalhöf B et al. Lancet 2002;359:995-1003. 3. Wing LMH et al. N Engl J Med 2003;348:583-592. 3 0 1 2 3 4 5 6 7 8 STOP-1 SHEP STONE SYST-EUR SYST-CHINA HOT CAPPP STOP-2 NICS NORDIL INSIGHT Percentage of patients with event Stroke Myocardial Infarction Percentage of fatal and nonfatal strokes, and fatal and nonfatal MIs reported in large, prospective hypertension trials published after 1990. LIFE ANBP2

4. Downloaded from www.cozaar.aewww.cozaar.ae The Consequences of Stroke 5.5 million people worldwide died from stroke in 2001 1 15 million people worldwide survive minor strokes each year 2 —In the United States, up to 30% of stroke survivors are permanently disabled 3 — The consequences of stroke may impact the families of stroke survivors 4 In Western countries, stroke is the second most common cause of neurologic disability 5 1. World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life. 2002. 2. American Heart Association. Statistical fact sheet—populations: International cardiovascular disease statistics. 3. American Heart Association. Heart Disease and Stroke Statistics—2003 Update. 4. Wolf PA. In: Izzo JL Jr, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 2nd ed. 1999:203-207. 5. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999:1417-1427. 4

5. Downloaded from www.cozaar.aewww.cozaar.ae Factors That Can Increase Risk of Stroke 1-4 Untreatable Age >60 years Family history of stroke Male sex Prior TIA or stroke Treatable Hypertension —Worldwide, 62% of strokes are caused by hypertension —Stroke risk increases as blood pressure increases Diabetes Hyperlipidemia Obesity Smoking Atrial fibrillation 1. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999:1417-1427, 1629-1648. 2. American Stroke Association. What are the risk factors for stroke? 3. Law MR, Wald NJ. BMJ 2002;324:1570-1576. 4. American Heart Association. Statistical fact sheet—populations: International cardiovascular disease statistics. 5

6. Downloaded from www.cozaar.aewww.cozaar.ae Stroke Mortality Rate by Age 1 Blood Pressure and Stroke Mortality Stroke mortality rate in each decade of age vs. usual blood pressure at the start of the decade. A meta-analysis involving 1 million participants in 61 cohort studies to determine the relevance of blood pressure to risk of disease in patients of different ages. 1. Prospective Studies Collaboration. Lancet 2002;360:1903-1913. 6

7. Downloaded from www.cozaar.aewww.cozaar.ae A Systematic Review and Meta-analysis of Conventional Therapy vs. Placebo In four separate trials,  blockers and diuretics significantly reduced the risk of stroke compared with placebo TrialNEvents, active treatment/control Relative risk (95% CI) STOP-Hypertension 1 162729/530.53 (0.33, 0.86) p=0.0081 MRC 2 17,35460/1090.45 (0.25, 0.60) p<0.01 MRC-O 3 4396101/1340.25 (0.03-0.42) p=0.04 Coope and Warrender 4 88423/44 (includes TIAs) 0.58 (0.35-0.86) p<0.03 1. Dahlöf B et al. Lancet 1991;338:1281-1285. 2. Medical Research Council Working Party. BMJ 1985;291:97-104. 3. Medical Research Council Working Party. BMJ 1992;304:405-412. 4. Coope J, Warrender TS. BMJ 1986;293:1145-1151. 7

8. Downloaded from www.cozaar.aewww.cozaar.ae Primary Endpoints in Hypertension Trials Mega-trialsCAPPP 1 STOP-2 2 NORDIL 3 ALLHAT 4 Comparator treatments ACE I vs.  blocker/ diuretics ACE Is/CCBs vs.  blockers/diuretics CCB vs.  blockers/ diuretics CCB vs. diuretic ACE I vs. diuretic No. of patients/primary endpoints 10,985/6986614/65910,881/80333,357/2956 Primary combined endpoint MI, stroke, CV death Fatal MI, fatal stroke, fatal CV disease MI, stroke, CV death Fatal CHD, nonfatal MI Differences on primary endpoint NS p = 0.52 NS p = 0.89 NS p = 0.97 NS p = 0.65 (amlodipine) p = 0.81 (lisinopril) 1. Hansson L et al. Lancet 1999;353:611-616. 2. Hansson L et al. Lancet 1999;354:1751-1756. 3. Hansson L et al. Lancet 2000;356:359-365. 4. The ALLHAT Officers and Coordinators. JAMA 2002;288:2981-2997. 8 These were four independent, noncomparative trials.

9. Downloaded from www.cozaar.aewww.cozaar.ae Conclusions from Clinical Trials Treating hypertension with conventional therapy (  blockers and diuretics) can reduce the risk of stroke 1,2 No treatment of hypertension had demonstrated superior benefits vs. conventional therapy for reducing the combined risk of cardiovascular morbidity and mortality beyond lowering of blood pressure 3-6 More can be done to reduce the risk of stroke 9 1. Coope J, Warrender TS. Br Med J 1986;293:1145-1151. 2. Medical Research Council Working Party. Br Med J 1985;291:97-104. 3. Hansson L, et al. Lancet 1999;353:611-616. 4. Hansson L, et al. Lancet 1999;354:1751-1756. 5. The ALLHAT Officers and Coordinators. JAMA 2002;288:2981- 2997. 6. Hansson L, et al. Lancet 2000;356:359-365.

10. Downloaded from www.cozaar.aewww.cozaar.ae L osartan I ntervention F or E ndpoint reduction in hypertension study 1 An investigator-initiated, multinational, double-blind, double-dummy, randomised, active-controlled, parallel-group study from 945 centres 1. Dahlöf B et al. Lancet 2002;359:995-1003. Steering Committee Chair: Cochair: B. Dahlöf R. B. Devereux 10

11. Downloaded from www.cozaar.aewww.cozaar.ae Objective 1 The LIFE investigators set out to evaluate whether losartan was superior to atenolol in reducing combined cardiovascular mortality and morbidity in hypertensive patients with ECG-LVH —To determine if losartan offers a benefit beyond blood-pressure control vs. atenolol in this patient population 1. Dalhöf B et al. Lancet 2002;359:995-1003. 11

12. Downloaded from www.cozaar.aewww.cozaar.ae Study Design 1 A comparative trial between losartan and an established antihypertensive, atenolol: —Primary composite endpoint: stroke, CV death, and MI —9193 hypertensive patients with ECG-LVH —4.8-year mean follow-up —945 study sites in 7 countries 1. Dalhöf B et al. Lancet 2002;359:995-1003. 12

13. Downloaded from www.cozaar.aewww.cozaar.ae Inclusion Criteria 1 Age 55 to 80 years Previously treated or untreated hypertension Diastolic BP 95–115 mmHg and/or Systolic BP 160–200 mmHg ECG-confirmed LVH —Product of QRS duration and Cornell voltage > 2440 mm X ms —Sokolow-Lyon voltage > 38 mm 1. Dalhöf B et al. Lancet 2002;359:995-1003. 13

14. Downloaded from www.cozaar.aewww.cozaar.ae Design/Dosing Titration 1 *Titration upward if SiDBP >90 mmHg or SiSBP >140 mmHg. **Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg, but was mandatory if SiBP >160/95 mmHg. Addition of ACE Is, AII antagonists, or  blockers prohibited. Day  14 Day  7 Day 1 Mth 1 Mth 2 Mth 4 Mth 6 Yr 1 Yr 1.5 Yr 2 Yr 2.5 Yr 3 Yr 3.5 Yr 4 Titration to target blood pressure: <140/90 mmHg Placebo Losartan 50 mg Atenolol 50 mg Losartan 50 mg + HCTZ 12.5 mg* Losartan 100 mg + HCTZ 12.5 mg* Losartan 100 mg + HCTZ 12.5–25.0 mg* + others** Atenolol 50 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5–25.0 mg + others** 14 1. Dalhöf B et al. Lancet 2002;359:995-1003.

15. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in the Risk of the Primary Endpoint: Combined CV Events 1 Number at risk Losartan (n)46054524446043924312424741894112404738971889901 Atenolol (n)4588449444144349 4289 42054135 4066 399238211854876 1. Dahlöf B et al. Lancet 2002;359:995-1003. Risk reduction = relative risk vs. atenolol. No significant difference in CV death and MI vs. atenolol. 15 Atenolol Proportion of patients with first event (%) 10 12 14 16 0 2 4 6 8 06 423012 18 243648 54 60 66 Time (months) Losartan Adjusted risk reduction 13.0%, p = 0.021 Unadjusted risk reduction 14.6%, p = 0.009 Composite of stroke, CV death, and MI

16. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in the Risk of Stroke 1 No significant difference in CV death and MI vs. atenolol.Risk reduction = relative risk vs. atenolol. Losartan (n) 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925 Atenolol (n) 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897 Number at risk 16 1. Dahlöf B et al. Lancet 2002;359:995-1003. Atenolol Proportion of patients with first event (%) 6 7 0 2 3 4 5 06 423012 18 243648 54 60 66 Time (months) Losartan 1 Adjusted risk reduction 24.9%, p = 0.0010 Unadjusted risk reduction 25.8%, p = 0.0006 Fatal and nonfatal stroke 8

17. Downloaded from www.cozaar.aewww.cozaar.ae Comparable Blood-Pressure Reductions 1 1. Dahlöf B et al. Lancet 2002;359:995-1003. 17 Atenolol Losartan Systolic Diastolic Mean arterial Atenolol 145.4 mmHg* Atenolol 102.4 mmHg* Atenolol 80.9 mmHg* Losartan 144.1 mmHg* Losartan 102.2 mmHg* Losartan 81.3 mmHg* *Mean BP at last visit. mmHg 180 170 160 140 150 130 110 120 100 90 40 80 60 70 50 Time (months) 42 362430121860 48 54

18. Downloaded from www.cozaar.aewww.cozaar.ae Important Subgroups Hypertensive patients with ECG-LVH and: Isolated systolic hypertension (ISH) 1 Diabetes mellitus 2 Atrial fibrillation (AF) 3 Without clinically evident vascular disease 4 18 1. Kjeldsen SE et al. JAMA 2002;288:1491-1498. 2. Lindholm LH et al. Lancet 2002;359:1004-1010. 3. Dalhöf B et al. Presented at the European Society of Cardiology Congress; Berlin, Germany; August 31–September 4, 2002. Poster 2163. 4. Devereux RB et al. American Heart Association Scientific Sessions; Chicago, IL, USA; November 17–20, 2002. Oral presentation.

19. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in Risk of Stroke in Patients with ISH 1 1. Kjeldsen SE et al. JAMA 2002;288:1491-1498. Atenolol 666 650 630 621 606 593 579 568 562 536 245 99 Losartan 660 651 640 628 618 605 595 581 577 551 266 108 Number at risk 19 8 10 6 4 0 2 Proportion of patients with first event (%) 06 423012 18 243648 54 60 66 Time (months) Atenolol Losartan Adjusted risk reduction 40%, p = 0.02 Fatal and nonfatal stroke No significant difference in MI vs. atenolol.

20. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in Risk of Stroke in Patients with Diabetes Mellitus 1 1. Lindholm LH et al. Lancet 2002;359:1004-1010. Losartan (n) 586 570 560 554 540 530 524 519 500 477 248 131 Atenolol (n) 609 590 572 561 549 537 521 515 494 456 211 101 Number at risk 20 Proportion of patients with first event (%) 06 4230 12 18 243648 54 60 66 Time (months) Atenolol Losartan 12 10 8 6 4 0 2 Adjusted risk reduction 21.2%, p = 0.204 Unadjusted risk reduction 21.8%, p = 0.190 Fatal and nonfatal stroke

21. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in Risk of Stroke in Patients with AF 1 1. Dalhöf B et al. Presented at the European Society of Cardiology Congress; Berlin, Germany; August 31–September 4, 2002. Poster 2163. 21 Adjusted risk reduction 49%, p = 0.018 Proportion of patients with first event (%) 0 6 4230 12 1824 36 48 54 60 66 Time (months) Atenolol Losartan 20 25 15 10 5 0 Fatal and nonfatal stroke

22. Downloaded from www.cozaar.aewww.cozaar.ae Reduction in Risk of Stroke in Patients without Clinically Evident Vascular Disease 1. Devereux RB et al. American Heart Association Scientific Sessions; Chicago, IL, USA; November 17–20, 2002. Oral presentation. 22 Proportion of patients with first event (%) 0 12 24 3648 60 Time (months) Atenolol Losartan Adjusted risk reduction 34%, p<0.001 Unadjusted risk reduction 34%, p<0.001 6 5 4 1 3 2 0 Fatal and nonfatal stroke

23. Downloaded from www.cozaar.aewww.cozaar.ae Summary of Reduction in Risk of Stroke Total Patient Population 1 ISH Subgroup 2 Diabetes Mellitus Subgroup 3 AF Subgroup 4 No Evident Vascular Disease Subgroup 5 NNT5928511154 Percent reduction in risk of stroke 25%40%21%49%34% p-value0.0010.0200.2040.018<0.001 1. Dalhöf B et al. Lancet 2002;359:995-1003. 2. Kjeldsen SE et al. JAMA 2002;288:1491-1498. 3. Lindholm LH et al. Lancet 2002;359:1004-1010. 4. Dalhöf B et al. Presented at the European Society of Cardiology Congress; Berlin, Germany; August 31–September 4, 2002. Poster 2163. 5. Devereux RB et al. American Heart Association Scientific Sessions; Chicago, IL, USA; November 17–20, 2002. Oral presentation. 23

24. Downloaded from www.cozaar.aewww.cozaar.ae Conclusions 1 In hypertensive patients with ECG-LVH, 25% risk reduction in stroke with losartan vs. atenolol Results suggest that the benefits of losartan vs. atenolol go beyond blood-pressure control “In LIFE, losartan has proven that it matters how you treat patients with hypertension.” There was no significant difference in CV death and MI vs. atenolol 1. Dalhöf B et al. Lancet 2002;359:995-1003. 24

25. Downloaded from www.cozaar.aewww.cozaar.ae Angiotensin II Plays an Important Role in Organ Damage 1-7 GFR Proteinuria Aldosterone release Glomerular sclerosis 1. Willenheimer R et al. Eur Heart J 1999;20:997-1008. 2. Dahlöf B. J Hum Hypertens 1995;9(suppl 5):S37-S44. 3. Daugherty A et al. J Clin Invest 2000;105:1605-1612. 4. Fyhrquist F et al. J Hum Hypertens 1995;9(suppl 5):S19-S24. 5. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999:1682-1704. 6. Anderson S. Exp Nephrol 1996;4(suppl 1):34-40. 7. Fogo AB. Am J Kidney Dis 2000;35:179-188. AII AT 1 receptor Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction LVH Fibrosis Remodeling Stroke DEATH *Preclinical data LV = left ventricular; GFR = glomerular filtration rate Hypertension Heart failure MI Renal failure 25

26. Downloaded from www.cozaar.aewww.cozaar.ae Summary 1 Stroke is a devastating consequence of hypertension Lowering BP can reduce the risk of stroke The LIFE study in hypertensive patients with ECG-LVH demonstrated: —13% risk reduction in primary composite endpoint (stroke, CV death, and MI) vs. atenolol —25% risk reduction in stroke vs. atenolol Losartan offered stroke risk reduction beyond blood-pressure reduction vs. atenolol in hypertensive patients with ECG-LVH “Losartan seems to confer benefits beyond reduction in blood pressure.” 1. Dahlöf B et al. Lancet 2002;359:995-1003. 26

27. Downloaded from www.cozaar.aewww.cozaar.ae Appendix 27

28. Downloaded from www.cozaar.aewww.cozaar.ae Abbreviations Clinical trials: ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ANBP = Australian National Blood Pressure Study CAPPP = Captopril Prevention Project HOT = Hypertension Optimal Treatment INSIGHT = Intervention as a Goal in Hypertension Treatment LIFE = Losartan Intervention For Endpoint reduction in hypertension Study 28

29. Downloaded from www.cozaar.aewww.cozaar.ae Abbreviations Clinical trials: MRC = Medical Research Council MRC-O = Medical Research Council Trial of Treatment of Hypertension in Older Adults NICS = National Intervention Cooperative Study NORDIL = Nordic Diltiazem Study SHEP = Systolic Hypertension in the Elderly Program STONE = Shanghai Trial of Nifedipine in the Elderly STOP = Swedish Trial in Old Patients with Hypertension SYST-CHINA = Systolic Hypertension in China SYST-EUR = Systolic Hypertension in Europe 29

30. Downloaded from www.cozaar.aewww.cozaar.ae Abbreviations ACE I = angiotensin-converting enzyme inhibitor AF = atrial fibrillation CCB = calcium channel blocker CV = cardiovascular ECG-LVH = electrocardiographically-confirmed left ventricular hypertrophy HCTZ = hydrochlorothiazide ISH = isolated systolic hypertension MI = myocardial infarction NNT = number of patients needed to treat NS = not significant TIA = transient ischemic attack 30

31. Downloaded from www.cozaar.aewww.cozaar.ae Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturers’ prescribing information. Merck does not recommend the use of a product in any different manner than as described in the prescribing information. Copyright © 2003-2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 5-05 CZR 2003-W-6953-SS VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com 31