Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

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? • Diuretics • β-Blockers (BBs) • Calcium channel blockers (CCBs) • Angiotensin-converting enzyme inhibitors (ACEIs) • Angiotensin receptor blockers (ARBs) • 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. Progression of Cardiovascular Disease: The Cardiovascular Continuum Myocardial infarction Myocardialischemia Ventricular dysfunction Sudden death Peripheral arterial disease Endothelialdysfunction and atherothrombosis Ventricular dilation and hypertrophy Stroke Congestive heart failure and death Hyperlipidemia,hypertension, diabetes, smoking, obesity, etc Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

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.

8. JNC 7 Cardiovascular Risk Factors • Microalbuminuria or estimated GFR <60 mL/min • Age (men >55 yr; women >65 yr) • Family history of premature CVD • Hypertension • Cigarette smoking • Obesity (BMI ≥30 kg/m2) • Physical inactivity • Dyslipidemia • Diabetes mellitus 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.

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

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

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

12. STAGE 2 SBP 160 mm Hg or DBP 100 mm Hg Treatment recommended STAGE 1 SBP 140-159 mm Hg or DBP 90-99 mm Hg Consider treatment in those with diabetes or renal disease who fail lifestyle modification PREHYPERTENSION SBP 120-139 mm Hg or DBP 80-89 mm Hg NORMAL SBP <120 mm Hg and DBP <80 mm Hg 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.

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

14. Multiple Antihypertensive Agents Frequently Required to Achieve BP Goal 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) 1 2 3 4 Average No. of BP Medications 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.

15. JNC 7: Algorithm for Hypertension LIFESTYLE MODIFICATIONS Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease) INITIAL DRUG CHOICES With Compelling Indications Without Compelling Indications 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 Stage 1 Hypertension Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combo If not at goal BP, optimize dosages or add drugs until goal BP achieved; consider consultation with hypertension specialist 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.

16. Nonpharmacologic Interventionsand BP Reduction Low-SaltDiet Weight Loss(19.4 lb) Alcohol Reduction Exercise 0 1 2 3 BP Decrease(mm Hg) 4 5 6 SBP DBP 7 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.

17. JNC 7: Compelling Indications for Antihypertensive Drug Classes Recommended Drugs AldoCompelling Indication Diuretic ACEI BB ARB CCB 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.

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

19. Diabetes ApproximatelyDoubles CVD Risk in Patients With Hypertension 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.

20. HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to Lower BP Goal P = .005 25 20 15 Stroke, MI, or CV Death (per 1000 patient-years) 10 5 0 80 90 85 Target DBP (mm Hg) 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.

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

22. Antihypertensive Medications: Mechanism of Action American Heart Association. December 11, 2006. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3038158.

23. The Renin System, Angiotensin II, and End-Organ Damage Role of Angiotensin II in the Progression of Cardiovascular Disease Atherosclerosis Vasoconstriction Vascular inflammation and hypertrophy Endothelial dysfunction Stroke Brain Hypertension Vessels Angiotensin II Left ventricular hypertrophy Fibrosis Remodeling Apoptosis Death Heart Failure Myocardial Infarction Heart Glomerular capillary pressure Proteinuria Aldosterone release Glomerular sclerosis Renal Failure Kidney 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.

24. AT1 Receptor Physiology and Pathophysiology of the Renin System Renin Renin Angiotensinogen Angiotensinogen Feedback Loop Ang I Ang I ACE ACE Ang II Ang = angiotensin. Adapted from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

25. ACEIs Most Agents Work After the Point of Activation Renin activates the system by converting angiotensinogen to angiotensin 1 Renin Angiotensinogen Feedback Loop Ang I AT1 Receptor ACE ARBs • ACE cleaves Ang I to form Ang II • ACEIs work at this point Ang II • Ang II binds to the AT1 receptor • ARBs 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. AT1 Receptor DRIs Target the Point of Activation DRIs prevent renin from converting angiotensinogen to angiotensin 1 Renin Angiotensinogen DRI Feedback Loop ACE 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 *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. Abdominal obesity Glucose intolerance/ Insulin resistance Hypertension Atherogenic dyslipidemia Proinflammatory/ Prothrombotic state Diabetes CVD Characteristics of the Metabolic Syndrome: NCEP ATP III National Cholesterol Educational Program (NCEP); Adult Treatment Panel (ATP) III; 2001.

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. 48.2 44.3 37.0 35.8 33.9 29.0 7.3 5.2 CV Risk Factor Control Among Adults With Diagnosed Diabetes Fewer than half of adults with diabetes achieve treatment goals for CV risk factors NHANES III, 1988-1994 (n = 1204) 60 NHANES 1999-2000 (n = 370) 50 40 Adults (%) 30 20 10 0 Blood Pressure <130/80 mm Hg Total Cholesterol* <200 mg/dL Achieved All 3 Treatment Goals A1CLevel<7% *LDL-C and TG not evaluated. Saydah SH, et al. JAMA. 2004;291:335-342.

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/m2 • 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/.

40. ? Decision Point What is the JNC 7 goal for this patient who has hypertension, diabetes, and renal disease? • <120/80 mm Hg • <130/80 mm Hg • <140/80 mm Hg • <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): • BB • CCB • ARB • ACE Use your keypad to vote now!

42. Q & A

43. PCE Takeaways

44. PCE Takeaways • Patients with hypertension often present with multiple cardiac risk factors • Be vigilant in your investigation of all clinical indicators • Creatively address patient adherence; not everyone responds to the same interventions • 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? • Not important • Slightly important • Somewhat important • Extremely important Use your keypad to vote now!