1. Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk Kenneth A. Jamerson, MD Professor of Internal Medicine University of Michigan Medical Director Program for Multicultural Health University of Michigan Health Systems Ann Arbor, Michigan

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 Jamerson: consultant: King Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, sanofi-aventis Group, Sankyo Co., Ltd.; grants/research support: King Pharmaceuticals, Inc., National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases, Novartis Pharmaceuticals Corporation, Speedel; speakers bureau: Abbott Laboratories, GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals Corporation.

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. Hypertension and Global CV Risk

7. 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

8. 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

9. 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! ?

10. 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%

11. 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

12. 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

13. 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! ?

14. Multiple Antihypertensive Agents Frequently Required to Achieve BP Goal Patients had either diabetes or renal impairment. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661; Brenner BM et al. N Engl J Med. 2001;345:861- 869; Lewis EJ et al. N Engl J Med. 2001;345:851-860. Average No. of BP Medications UKPDS (<150/85 mm Hg) MDRD (<92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) RENAAL (<140/90 mm Hg) IDNT (  135/85 mm Hg) 4321

15. 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

16. 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)

17. 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

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

19. 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

20. 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

21. 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 Endpoint 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.

22. 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.

23. Adapted from Willenheimer R et al. Eur Heart J. 1999;20:997-1008; Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37-S44; Fyhrquist F et al. J Hum Hypertens. 1995;9(suppl 5):S19-S24; Booz GW et al. Heart Fail Rev. 1998;3:125-130; Beers MH, Berkow R, eds. In: The Merck Manual of Diagnosis and Therapy. 1999:1417-1427; Anderson S. Exp Nephrol. 1996;4(suppl 1):34-40. Role of Angiotensin II in the Progression of Cardiovascular Disease The Renin System, Angiotensin II, and End-Organ Damage  Glomerular capillary pressure  Proteinuria  Aldosterone release Glomerular sclerosis Atherosclerosis Vasoconstriction Vascular inflammation and hypertrophy Endothelial dysfunction Left ventricular hypertrophy Fibrosis Remodeling Apoptosis Stroke Death Hypertension Heart Failure Myocardial Infarction Renal Failure Brain Vessels Heart Kidney Angiotensin II

24. Physiology and Pathophysiology of the Renin System AT 1 Receptor Feedback Loop ACE Angiotensinogen Ang II Renin Ang I Angiotensinogen Renin ACE Ang I Ang = angiotensin. Adapted from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

25. Most Agents Work After the Point of Activation Feedback Loop Ang I Angiotensinogen Renin ACE ACEIs AT 1 Receptor Ang II ARBs Renin activates the system by converting angiotensinogen to angiotensin 1 Ang II binds to the AT1 receptor ARBs work at this point ACE cleaves Ang I to form Ang II ACEIs work at this point Adapted from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

26. Direct Renin Inhibitors  Direct renin inhibitors (DRIs) are currently in development  To date, there is no clinical evidence that DRIs have a benefit in morbidity and mortality

27. DRIs Target the Point of Activation AT 1 Receptor Feedback Loop Renin ACE Angiotensinogen DRI DRIs prevent renin from converting angiotensinogen to angiotensin 1 Adapted from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

28. Definition of the Metabolic Syndrome Risk factor * Categorical Cut-points ↑ Waist circumference ≥102 cm (≥40 in) in men † ≥88 cm (≥35 in) in women † ↑ TG≥150 mg/dL (or drug treatment for) ↓ HDL-C<40 mg/dL in men (or drug treatment for) <50 mg/dL in women (or drug treatment for) ↑ BP≥130 mm Hg SBP or ≥85 mm Hg DBP (or drug treatment for) ↑ Fasting glucose≥100 mg/dL (or drug treatment for) *Presence of 3 or more of these factors identifies the metabolic syndrome. † Lower threshold can be used for patients especially prone to insulin resistance, particularly Asian Americans. Grundy SM, et al. Circulation. 2005;112:2735-2752. NOTE: The ADA recently issued a statement calling for a critical appraisal of the metabolic syndrome. Kahn R, et al. Diabetologia. 2005;48:1684-1699.

29. Characteristics of the Metabolic Syndrome: NCEP ATP III National Cholesterol Educational Program (NCEP); Adult Treatment Panel (ATP) III; 2001. Abdominal obesity Glucose intolerance/ Insulin resistance Hypertension Atherogenic dyslipidemia Proinflammatory/ Prothrombotic state Diabetes CVD

30. Management of the Metabolic Syndrome  Weight reduction  Increased physical activity  Modification of atherogenic diet  Drug therapy for dyslipidemia  Drug therapy for hypertension  Aspirin or clopidogrel for prothrombotic state  Lifestyle changes to lower serum glucose (if diabetes has developed, drug therapy may also be needed to reduce A1C to ADA goal of <7%) Grundy SM, et al. Circulation. 2005;112:2735-2752.

31. Adherence

32. CV Risk Factor Control Among Adults With Diagnosed Diabetes *LDL-C and TG not evaluated. Saydah SH, et al. JAMA. 2004;291:335-342. Fewer than half of adults with diabetes achieve treatment goals for CV risk factors A1C Level <7% Blood Pressure <130/80 mm Hg Total Cholesterol* <200 mg/dL Achieved All 3 Treatment Goals 44.3 37.0 29.0 35.8 33.9 48.2 5.2 7.3 0 10 20 30 40 50 60 Adults (%) NHANES III, 1988-1994 (n = 1204) NHANES 1999-2000 (n = 370)

33. 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.

34. 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.

35. 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.

36. 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

37. Case Study

38. 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

39. 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

40. 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! ?

41. 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! ?

42. Q & A

43. PCE Takeaways

44. 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"

45. 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! ?

46. Supporting Studies

47. 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

48. 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.

49. 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

50. 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

51. 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)

52. 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