1. Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk Joshua Furman, MD Staff Cardiologist Mount Sinai Medical Center Miami Beach, Florida

2. Key Question Which class of agents do you presently consider first-line treatment for patients with hypertension? 1. Diuretics 2. β-Blockers (BBs) 3. Calcium channel blockers (CCBs) 4. Angiotensin-converting enzyme inhibitors (ACEIs) 5. Angiotensin receptor blockers (ARBs) 6. All of the above Use your keypad to vote now! ?

3. Faculty Disclosure  Dr Furman has no relevant financial relationships with any commercial interests to disclose.

4. Learning Objectives  State the prevalence of hypertension and its role in the cardiovascular disease continuum  Formulate hypertension management according to risk stratification  Describe the importance of targeting improvement in vascular function in patients with hypertension

5. Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263. Progression of Cardiovascular Disease: The Cardiovascular Continuum Myocardial infarction Myocardial ischemia Endothelial dysfunction and atherothrombosis Ventricular dysfunction Ventricular dilation and hypertrophy Hyperlipidemia, hypertension, diabetes, smoking, obesity, etc Congestive heart failure and death Peripheral arterial disease Stroke Sudden death

6. Development and Progression of Vascular Disease Dzau V. Hypertension. 2001;37:1047-1052. RISK FACTORS Smoking CLINICAL SEQUELAE Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation  NO  Local Mediators  Tissue ACE, AII Endothelin Catecholamines PAI-1, Platelet Aggregation, Tissue Factor VCAM/ICAM Cytokines Proteolysis Inflammation Growth Factors Cytokines Matrix VasoconstrictionThrombosis InflammationPlaque Rupture Vascular Lesion and Remodeling  BP Diabetes  LDL

7. Time ACS = acute coronary syndrome; HF = heart failure; LVH = left ventricular hypertrophy. Adapted from Vasan RS, Levy D. Arch Intern Med. 1996;156:1789-1796. Death / Sudden Death Obesity Diabetes Smoking Dyslipidemia HF Overt heart failure Systolic dysfunction Diastolic dysfunction Subclinical left ventricular dysfunction Hypertension Risk Factors Atherothrombosis, left ventricular remodeling LVH ACS Progression From Hypertension to Heart Failure/Sudden Death

8. Hypertension and Global CV Risk

9. What Is Global CV Risk?  Treating hypertension to goal is good  Addressing all CV risk factors is better  Achieve optimal BP level  Avoid CV and renal morbidity and mortality Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

10. JNC 7 Cardiovascular Risk Factors  Hypertension  Cigarette smoking  Obesity (BMI ≥30 kg/m 2 )  Physical inactivity  Dyslipidemia  Diabetes mellitus  Microalbuminuria or estimated GFR <60 mL/min  Age (men >55 yr; women >65 yr)  Family history of premature CVD Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

11. In Nearly 2 Out of 3 Adults With Hypertension, Hypertension Is Still Not Controlled *Adults aged 18 to 74 years with hypertension. † Controlled = BP  140/90 mm Hg. ‡ Data were computed (M. Wolz, unpublished data, 2003) from the NHLBI. Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf 30% 41% 66%! 70 59 34 0 10 20 30 40 50 60 70 80 90 100 NHANES (1999-2000) ‡ US Population (%)* Treated Aware Controlled †

12. 4. Chamontin et al. Am J Hypertens. 1998;11(6 Pt 1):759-762. 5. Marques-Vidal et al. J Hum Hypertens. 1997;11:213-220. Patients With BP Controlled Worldwide Adapted from G. Mancia 1. JNC VI. Arch Intern Med. 1997;157:2413-2446. 2. Joffres et al. Am J Hypertens. 1997;10:1097-1102. 3. Colhoun et al. J Hypertens. 1998;16:747-752. USA 1 27% England 3 6% <140/90 mm Hg Canada 2 22% Australia 5 France 4 24% India 5 Scotland 5 17.5% Spain 5 20% Finland 5 20.5% Germany 5 22.5% >65 yr only <160/95 mm Hg 19% 9%

13. Point Total10-Year Risk (%) <0<1 01 11 21 31 41 52 62 73 84 95 106 118 1210 1312 1416 1520 1625  17  30 10-Year NCEP/Framingham Risk Scores for Fatal or Nonfatal CHD in Men* *A separate Framingham risk calculator exists for women. NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/. http://www.nhlbi.nih.gov/guidelines/cholesterol/ Age (y)Points 20-34-9 35-39-4 40-440 45-493 50-546 55-598 60-6410 65-6911 70-7412 75-7913 TC (mg/dL) Age 20-39 y Age 40-49 y Age 50-59 y Age 60-69 y Age 70-79 y <16000000 160-19943210 200-23975310 240-27996421  280 118531 HDL (mg/dL)Points  60 50-590 40-491 <402 SBP (mm Hg)UntreatedTreated <12000 120-12901 130-13912 140-15912  160 23 Smoking status Age (y) 20-3940-4950-5960-6970-79 Nonsmoker00000 Smoker85311

14. Key Question What percentage of patients with hypertension have 2 or more additional CV risk factors? 1. 20% 2. 30% 3. 40% 4. 50% 5. >50% Use your keypad to vote now! ?

15. 26% 25% 8% RF = risk factor. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S. MenWomen 2 RFs 3 RFs 1 RF No Additional RFs 4 or More RFs 27% 24% 12% 2 RFs 3 RFs 1 RF No Additional RFs 4 or More RFs >50% of Hypertension Occurs in Presence of 2 or More Risk Factors CV Risk Factor Clustering With Hypertension: Framingham Offspring, Aged 18 to 74 Years 19% 22% 17% 20%

16. Risk of CHD in Mild Hypertension by Intensity of Associated Risk Factors SBP 150-160 mm Hg++++++ TC 240-262 mg/dL− + ++++ HDL-C 33-35 mg/dL−−++++ Diabetes−−−+++ Cigarette smoking−−−−+ + ECG-LVH−−−−−+ 42 36 30 24 18 12 6 0 4 6 10 14 21 40 10-Year Probability of Event (%) Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S. Risk Factors

17. Arch Intern Med. 1997;157:2413-2446; Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf JNC Reclassification of BP Based on Risk Category SBP (mm Hg) DBP (mm Hg)Category SBP (mm Hg) DBP (mm Hg) Optimal<120and<80Normal<120and<80 Normal120-129and80-84 Prehypertension120-139or80-89 Borderline130-139or85-89 Hypertension Stage 1140-159or90-99Stage 1140-159or90-99 Stage 2160-179or100-109 Stage 2≥160or≥100 Stage 3≥180or≥110 JNC VI JNC 7

18. Adapted from: Stevens VJ et al. Ann Intern Med. 2001;134:1-11; Messerli FH et al. In: Griffin BP et al, eds. 2004. Manual of Cardiovascular Medicine. 2nd ed; Whelton SP et al. Ann Intern Med. 2002;136:493-503; Cutler JA et al. Am J Clin Nutr. 1997;65(suppl):643S-651S; Xin X et al. Hypertension. 2001;38:1112-1117; Whelton PK et al. JAMA. 1997;277:1624-1632. BP Decrease (mm Hg) SBPDBP Exercise Low-Salt Diet Alcohol Reduction Nonpharmacologic Interventions and BP Reduction 5 4 3 2 1 0 6 7 Weight Loss (19.4 lb)

19. NORMAL PREHYPERTENSION STAGE 1 STAGE 2 SBP <120 mm Hg and DBP <80 mm Hg SBP 120-139 mm Hg or DBP 80-89 mm Hg SBP 140-159 mm Hg or DBP 90-99 mm Hg SBP  160 mm Hg or DBP  100 mm Hg Treatment recommended Consider treatment in those with diabetes or renal disease who fail lifestyle modification JNC 7 Classification of Blood Pressure Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

20. RESULTS At 2 years, hypertension had developed in 154 participants in the placebo group and 53 in the candesartan group (RRR 66%, P <.001) At 4 years, hypertension had developed in 240 participants in the placebo group and 208 in the candesartan group (RRR 15.6%, P <.007) TROPHY = Trial of Preventing Hypertension. Julius S, et al. N Engl J Med. 2006;354:1685-1697. Study Design: TROPHY n = 409 2 years candesartan + 2 years placebo When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated STUDY N = 809 Participants had prehypertension: SBP 130-139 mm Hg and DBP  89 mm Hg OR SBP  139 mm Hg and DBP 85-89 mm Hg n = 400 2 years placebo + 2 years placebo

21. TROPHY: Kaplan-Meier Curves of New Onset Clinical Hypertension Years in Study 01234 0 10 20 30 40 50 60 70 80 90 100 Cumulative Incidence (%) Candesartan Placebo TROPHY = Trial of Preventing Hypertension. Julius S et al. N Engl J Med. 2006;354:1685-1697.

22. Key Points for Optimal Hypertension Management JNC 7 recommends: If SBP >20 mm Hg or DBP >10 mm Hg over goal, consider initiating with 2-drug combination <130/80 mm Hg in patients with diabetes or renal disease <140/90 mm Hg JNC 7 BP Goals Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

23. Antihypertensive Medications: Mechanism of Action Drug ClassMechanism of Action Diuretics  Rid body of excess fluids and sodium  May enhance effect of other BP medications ACEIs  Lower levels of angiotensin II  Dilate blood vessels ARBs  Block angiotensin II receptors  Dilate blood vessels BBs  Decrease heart rate and cardiac output CCBs  Interrupt movement of calcium into heart and vessel cells Aldosterone Receptor Blockers  Decrease salt and water retention Renin Inhibitors  Block action of renin, decreasing formation of angiotensin I American Heart Association. December 11, 2006. Available at:http://www.americanheart.org/presenter.jhtml?identifier=3038158.

24. LIFESTYLE MODIFICATIONS Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease) Without Compelling Indications With Compelling Indications Stage 1 Hypertension Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combo Stage 2 Hypertension 2-drug combos for most (usually thiazide-type diuretics and ACEI, or ARB, or BB, or CCB) Compelling Indications Other drugs (diuretic, ACEI, ARB, BB, CCB) as needed If not at goal BP, optimize dosages or add drugs until goal BP achieved; consider consultation with hypertension specialist INITIAL DRUG CHOICES JNC 7: Algorithm for Hypertension Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

25. JNC 7 Highlights: Key Risk-Related Messages  Certain high-risk conditions are compelling indications for the initial use of specific antihypertensive drug classes Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

26. Antihypertensive Agents and Components of Risk Stratification Antihypertensive agents that may not be suitable for patients at higher risk: Dyslipidemia Diuretics,  -blockers Diabetes Diuretics,  -blockers, CCBs (with CHD) CHF with systolic dysfunction Diuretics,  -blockers, CCBs CHDCCBs (with diabetes, post-MI) Kaplan N, Gifford R Jr. JAMA. 1996;275:1577-1580; Estacio R et al. N Engl J Med. 1998;338:645-652.

27. JNC 7: Compelling Indications for Antihypertensive Drug Classes Recommended Drugs Aldo Compelling IndicationDiureticACEI BBARBCCB ANT Heart failure Post MI High coronary disease risk Diabetes Chronic kidney disease Recurrent stroke prevention Aldo ANT = aldosterone antagonist. Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf

28. RESULTS BP  with both treatments Primary end point (composite of cardiac mortality and morbidity) occurred in valsartan 10.6% vs amlodipine 10.4%, HR 1.04 Amlodipine effects were more pronounced in the early period BP  4.0/2.1 mm Hg in the amlodipine group after 1 month VALUE = Valsartan Antihypertensive Long-term Use Evaluation. Julius S, et al. Lancet. 2004;363:2022-2031. Study Design: VALUE Step 1: valsartan 80 mg/day Step 2: valsartan 160 mg/day n = 7649 Both regimens included HCTZ in steps 3 and 4 Further drugs could be given to achieve BP control Randomized, double-blind, parallel group comparison STUDY N = 15,245 Aged  50 years; With treated or untreated hypertension and high risk of cardiac events Step 1: amlodipine 5 mg/day Step 2: amlodipine 10 mg/day n = 7596

29. VALUE: Hazard Ratios for Prespecified Analyses in Patients With Hypertension at High CV Risk Favors ValsartanFavors Amlodipine Hazard Ratio Valsartan/Amlodipine Primary cardiac composite end point Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.512.0 Patients had hypertension and were at high CV risk. VALUE = Valsartan Antihypertensive Long-term Use Evaluation. Julius S et al, for the VALUE trial group. Lancet. 2004;363:2022-2031.

30. Key Question On average, how many drugs will a patient need to control hypertension? 1. 1 2. 2 3. 3 4. 4 Use your keypad to vote now! ?

31. Number of Antihypertensive Agents Needed to Achieve Systolic BP Control *~50% patients required ≥3 medications. † Average per patient. Bakris et al. Am J Kidney Dis. 2000;36:646-661; ALLHAT. JAMA. 2002;288:2981-2997; Berl et al. Ann Intern Med. 2003;138:542-549; Bakris et al. Arch Intern Med. 2003;163:1555-1565; Wright et al. JAMA. 2002;288:2421-2431; Pepine et al. JAMA. 2003;290:2805-2816. SBP achieved (mm Hg) Number of BP Medications † Trial 4321 ALLHAT138 IDNT138 RENAAL141 UKPDS144 ABCD132 MDRD132 HOT138 AASK128 INVEST131 *

32. Hypertension and Diabetes: Global CV Risk Reduction With Evidence-Based Intervention

33. Adapted from Curb JD et al. JAMA. 1996;276:1886-1892; Hansson L et al. Lancet. 1998;351:1755-1762; Tuomilehto J et al. N Engl J Med. 1999:340:677-684. Diabetes Approximately Doubles CVD Risk in Patients With Hypertension Study Patients With Diabetes Patients Without Diabetes Ratio (events per 1000 pt-yr) Systolic Hypertension in the Elderly Program (SHEP) CV events63.036.81.71 Stroke28.815.01.92 CHD events32.215.22.12 Systolic Hypertension in Europe (Syst-Eur) CV events55.028.91.90 Stroke26.612.32.16 CHD events23.112.41.87 Hypertension Optimal Treatment (HOT) (DBP <90 mm Hg) CV events24.09.82.45

34. Patients with hypertension received nitrendipine  enalapril or HCTZ. N = 4695. Diabetes n = 492. Syst-Eur = Systolic Hypertension in Europe; CV = cardiovascular. Adapted from Tuomilehto J et al. N Engl J Med. 1999;340:677-684. Syst-Eur: CV Protection Resulting From BP Lowering Was Greatest in Patients With Diabetes Reduction in Event Rate for Active Treatment Group (%) Overall Mortality CVD Mortality All CV Events Fatal and Nonfatal Stroke Fatal and Nonfatal Cardiac Events 0 –10 –20 –30 –70 –40 –50 41% P =.09 8% P =.55 70% P =.01 16% P =.37 62% P =.002 25% P =.02 69% P =.02 36% P =.02 –60 57% P =.06 22% P =.10 DiabeticNondiabetic

35. Target DBP (mm Hg) Stroke, MI, or CV Death (per 1000 patient-years)  80  85  90 0 5 10 15 20 25 P =.005 Patients with hypertension and diabetes were given baseline felodipine, plus other agents in a 5-step regimen. Study N = 18,790; diabetes n = 1501. HOT = Hypertension Optimal Treatment; MI = myocardial infarction. Adapted from Hansson L et al, for the HOT Study Group. Lancet. 1998;351:1755-1762. HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to Lower BP Goal

36. UKPDS: Tight Glucose Versus Tight BP Control and CV Outcomes Patients had hypertension and Type 2 diabetes. N = 1148. Tight glucose control (goal <6.0 mmol/L or 108 mg/dL) Tight BP control (average 144/82 mm Hg) *P <.05 compared to tight glucose control Stroke Any Diabetic End Point DM Deaths Microvascular Complications -50 -40 -30 -20 -10 0 Relative Risk Reduction (%) 32% 37 % 10% 32% 12% 24 % 5% 44% * * * * UKPDS = United Kingdom Prospective Diabetes Study. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

37. Antihypertensive Medications: Mechanism of Action Drug ClassMechanism of Action Diuretics  Rid body of excess fluids and sodium  May enhance effect of other BP medications ACEIs  Lower levels of angiotensin II  Dilate blood vessels ARBs  Block angiotensin II receptors  Dilate blood vessels BBs  Decrease heart rate and cardiac output CCBs  Interrupt movement of calcium into heart and vessel cells Aldosterone Receptor Blockers  Decrease salt and water retention Renin Inhibitors  Block action of renin, decreasing formation of angiotensin 1 American Heart Association. December 11, 2006. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3038158.

38. Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992. The Renin-Angiotensin-Aldosterone System (RAAS)  Blood Pressure  Vascular Proliferation  Oxidative Stress  Vascular Inflammation  Thrombogenesis  Aldosterone ACE Angiotensinogen Renin Angiotensin I Angiotensin II AT1 Kininogen Kallikrein Bradykinin Inactive Peptides

39. Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992. The Renin-Angiotensin-Aldosterone System (RAAS)  Blood Pressure  Vascular Proliferation  Oxidative Stress  Vascular Inflammation  Thrombogenesis  Aldosterone ACE Angiotensinogen Renin Angiotensin I Angiotensin II AT1 ARBs Kininogen Kallikrein Bradykinin Inactive Peptides  Renin Inhibitors

40. Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992. The Renin-Angiotensin-Aldosterone System (RAAS)  Blood Pressure  Vascular Proliferation  Oxidative Stress  Vascular Inflammation  Thrombogenesis  Aldosterone ACE Angiotensinogen Renin Angiotensin I Angiotensin II AT1 ARBs  Kininogen Kallikrein Bradykinin Inactive Peptides AT2

41. Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992. The Renin-Angiotensin-Aldosterone System (RAAS)  Blood Pressure  Vascular Proliferation  Oxidative Stress  Vascular Inflammation  Thrombogenesis  Aldosterone ACE ACEIs Angiotensinogen Renin Angiotensin I Angiotensin II AT1  Kininogen Kallikrein Bradykinin Kininase II Inactive Peptides Nitric Oxide 

42. EUROPA Investigators. Lancet. 2003;362:782-788; HOPE Study Investigators. N Engl J Med. 2000;342:145-153; PEACE Trial Investigators. N Engl J Med. 2004;351:2058-2068; Pitt B, et al. Am J Cardiol. 2001;87:1058-1063. PEACE: CV Death/MI/CABG/PCI HOPE: CV Death/MI/Stroke 15 5 10 0 20 0 Placebo Ramipril 10 mg Time (years) Percent 241 22% Risk Reduction HR = 0.78 (0.70–0.86) P <.001 3 Time (years) 12 4 10 0 134 14 0 Placebo Perindopril 8 mg 8 6 2 52 EUROPA: CV Death/MI/Cardiac Arrest 20% Risk Reduction HR = 0.80 (0.71–0.91) P =.0003 40 20 30 0 50 0 Placebo Quinapril 20 mg Time (years) 1 4% Risk Increase HR = 1.04 (0.89–1.22) P =.6 10 23 QUIET: All CV Events Time (years) Trandolapril 4 mg Placebo 30 20 10 15 5 12345 25 0 6 4% Risk Reduction HR = 0.96 (0.88–1.06) P =.43 Percent ACEI Trials in CAD Without HF: Primary Outcomes

43. MICRO-HOPE, PERSUADE: CV Events in Patients With Diabetes MICRO-HOPE = Microalbuminuria, Cardiovascular, and Renal Outcomes (Heart Outcomes Prevention Evaluation); PERSUADE = Perindopril Substudy in Coronary Artery Disease and Diabetes. HOPE Study Investigators. Lancet. 2000;355:253-259; Daly CA et al. Eur Heart J. 2005;26:1369-1378. 012345 0 5 10 15 20 25 Follow-Up (years) Primary Outcome (%) MICRO-HOPE (n = 3577) CV death/MI/stroke Ramipril 10 mg Placebo 25% RRR P =.0004 01234 0 5 10 15 20 25 Follow-Up (years) PERSUADE (n = 1502) CV death/MI/cardiac arrest Perindopril 8 mg Placebo 19% RRR P =.13 5

44. Impact of ACE Inhibitors on the Risk of Developing New-Onset Diabetes Mellitus RR = 0.66 (0.51-0.85) P <.001 HOPE Trial: Ramipril 10 mg QD vs placebo; 9297 patients with vascular disease or diabetes plus 1 other CV risk factor, 4355 with hypertension; BP: baseline (139/79 mm Hg); 2 years: ramipril (135/76 mm Hg), placebo (138/78 mm Hg). Yusuf S et al. N Engl J Med. 2000;342:145-153. 5.4 3.6 New Diagnosis of Diabetes (%)

45. HOPE Study: Prevention of Diabetes With Ramipril The occurrence of self-reported diabetes was reduced by 34% (95% CI, 15%-49%; P <.001) in the HOPE study. This effect was observed early and maintained consistently throughout the trial. HOPE Study Investigators. Lancet. 2000;355:253-259. 0.10 0.08 0.06 0.04 0.02 0 2004006008001000120014001600 Days of Follow-Up (no diabetes at baseline) Kaplan-Meier Rates Placebo Ramipril

46. MICRO-HOPE: Albuminuria in Patients With Diabetes 0.0 0.5 1.0 1.5 2.0 2.5 3.0 HOPE Study Investigators. Lancet. 2000;355:253-259. 4-5 1 23 0 P =.001 P =.02 Placebo Ramipril Mean Albumin/Creatinine Ratio (urine) Time (y)

47. LIFE: Secondary End Points No. of Events Total Mortality Angina Pectoris CHF Revascularization New-Onset Diabetes End Points 814 301 314 545 562 0.51 2 Favors Losartan Favors Atenolol Hazard Ratio (95% CI) Dahlof B et al. Lancet. 2002;359:995-1003.

48. LIFE: New-Onset Diabetes Intention-to-Treat Losartan Atenolol Proportion of Patients With First Event (%) 0 1 2 3 4 5 6 7 8 9 10 Adjusted Risk Reduction 25%, P =.001 Unadjusted Risk Reduction 25%, P =.001 0 6 12 18 24 30364248546066 Study Month Dahlof B et al. Lancet. 2002;359:995-1003.

49. CV Pharmacotherapy: Impact on Newly Diagnosed Diabetes CA = calcium antagonist. Pepine CJ, Cooper-DeHoff RM. J Am Coll Cardiol. 2004;44:509-512. Sever PS et al. Lancet. 2003;361:1149-1158. Randomized active treatment vs control (eg, placebo, diuretic, β-blocker  diuretic) 100 30 20 10 0 STOP-2INSIGHT ALLHAT Reduction of New Diabetes (%) INVESTALPINESCOPECHARMANBP2LIFE HOPEALLHAT CAPPPSTOP-2VALUEPEACE ASCOT ACEI or ARB CA + ACEI or ARB CA

50. Multiple Mechanisms of ACEI in Cardiovascular Disease Blood pressure lowering Cardioprotective effects   Preload and afterload   LV mass   Sympathetic stimulation   Reperfusion injury  Improved myocardial remodeling Metabolic syndrome  Lipid neutral  Improved glucose metabolism  Increases adiponectin  Decreased insulin resistance Modified from: Lonn E et al. Eur Heart J Suppl. 2003;5:A43-A48. Vasculoprotective effects  Direct antiatherogenic  Enhance endogenous fibrinolysis  Inhibit platelet aggregation  Antimigratory for mononuclear cells   Matrix formation  Improve endothelial function  Antioxidant  Anti-inflammatory  Protection from plaque rupture  Improved arterial compliance and tone

51. Adherence

52. Monotherapy Is Inadequate in 40%-60% of Patients With Hypertension Materson et al. Am J Hypertens. 1993;8:189-192. Response defined as DBP <95 mm Hg after 1 year of treatment. Response (%) 80 Alpha 2 Agonist CADiureticAlpha 1 Antagonist ACEIPlaceboBB 0 20 60 40 50% Response

53. Factors Contributing to Poor Adherence  Lack of understanding  Dementia/senility  Side effects  Lack of discharge planning  Cost  Lack of symptoms  Complexity of Rx regimen  Poor mobility  Little or no support system Modified from: Vermeire E, et al. J Clin Pharm and Ther. 2001;26:331-342; Cheng JWM, et al. Pharmacotherapy. 2001;21:828-841.

54. Practical Tips to Improve Adherence  Talk to your patient  Explain the condition and why therapy is important  Ask about adherence  Involve the patient as a partner in treatment  Provide clear written and oral instructions  Tailor the regimen to the patient’s lifestyle and needs  Use motivational interviewing techniques  Look for:  Ways to approach patients based on individual attitudes  Allies in patient care—family, friends  Ways to simplify the regimen  Refill dates (no refill = no adherence) Ockene IS et al. J Am Coll Cardiol. 2002;40:630-640.

55. Practical Tips to Improve Adherence  Use systematic approaches  Disease management programs  Periodic review of electronic medical records or manual chart audits  Group/shared medical appointments offering care, education, social support  Other techniques  Follow-up (telephone/mail/e-mail) and reminder cards  Signed agreements/contracts  Self-monitoring tools (eg, tape measure, pedometer)  Patient assistance programs  Support when medication costs are a barrier Fonarow GC et al. Am J Cardiol. 2001;87:819-822; Ockene IS et al. J Am Coll Cardiol. 2002;40: 630-640; NCEP ATP III. September 2002. NIH publication no. 02-5215; Pfizer Helpful Answers Web site. Available at: http://www.pfizerhelpfulanswers.com.

56. Summary: The Case for Global CV Risk Management  CV disease remains the leading cause of death in both men and women in the United States  Data from the Framingham Heart Study have demonstrated clustering of risk factors—and that risk of death from CHD and stroke increases further with each added risk factor  Hypertension, a pivotal risk factor for CV disease, should prompt the search for the presence of additional risk factors  Recent clinical trials have provided evidence supporting a standard of care for the management of global CV risk

57. Case Study

58. Case Study: 55-Year-Old Man From India With Hypertension and Type 2 Diabetes  The patient is in for a checkup  History  Hypertension  Type 2 diabetes  Nonsmoker  No symptoms  Physical examination  BP: 148/96 mm Hg  Height: 64"  Weight: 178 lb  BMI: 30 kg/m 2  Waist circumference: 38"  Cardiac dysfunction status: normal ventricular function (LVEF 68%)  Laboratory values  Glucose: 148 mg/dL (fasting)  A1C: 8.8%  Creatinine: 1.5 mg/dL  Urinalysis: 1+ proteinuria  Lipid profile (mg/dL): TC: 268; LDL-C: 168; HDL-C: 42; TG: 296  Medications  HCTZ 25 mg/d  Glyburide 5 mg/d

59. 10-Year NCEP/Framingham Risk Scores for Fatal or Nonfatal CHD in Men* *A separate Framingham risk calculator exists for women. NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/. http://www.nhlbi.nih.gov/guidelines/cholesterol/ Age (y)Points 20-34-9 35-39-4 40-440 45-493 50-546 55-598 60-6410 65-6911 70-7412 75-7913 TC (mg/dL) Age 20-39 y Age 40-49 y Age 50-59 y Age 60-69 y Age 70-79 y <16000000 160-19943210 200-23975310 240-27996421  280 118531 Point Total10-Year Risk (%) <0<1 01 11 21 31 41 52 62 73 84 95 106 118 1210 1312 1416 1520 1625  17  30 HDL (mg/dL)Points  60 50-590 40-491 <402 SBP (mm Hg)UntreatedTreated <12000 120-12901 130-13912 140-15912  160 23 Smoking status Age (y) 20-3940-4950-5960-6970-79 Nonsmoker00000 Smoker85311

60. Decision Point What is the JNC 7 goal for this patient who has hypertension, diabetes, and renal disease? 1. <120/80 mm Hg 2. <130/80 mm Hg 3. <140/80 mm Hg 4. <140/90 mm Hg Use your keypad to vote now! ?

61. Decision Point The patient’s BP is 148/96 mm Hg while taking HCTZ 25 mg/d and glyburide 5 mg/d. To further lower BP, you would add a(n): 1. BB 2. CCB 3. ARB 4. ACE Use your keypad to vote now! ?

62. Q & A

63. PCE Takeaways

64. 1. Patients with hypertension often present with multiple cardiac risk factors 2. Be vigilant in your investigation of all clinical indicators 3. Creatively address patient adherence; not everyone responds to the same interventions 4. Clinical inertia is the enemy—don't settle for "close enough"

65. Key Question How important is using an antihypertensive agent with proven risk reduction (reducing morbidity and mortality) when choosing medications for your patients with hypertension? 1. Not important 2. Slightly important 3. Somewhat important 4. Extremely important Use your keypad to vote now! ?