Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

1. Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk Randall M. Zusman, MD Associate Professor of Medicine Harvard Medical School Director Division of Hypertension and Vascular Medicine Massachusetts General Hospital Boston, Massachusetts

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 Zusman:advisory board member, research support, speakers bureau: AstraZeneca,Bristol-Myers Squibb Company, Forest Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc, sanofi-aventis Group, Sankyo Co., Ltd.

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. Hypertension and Global CV Risk

6. 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.

7. 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.

8. ? 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!

9. 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.

10. 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.

11. 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.

12. Nonpharmacologic Interventionsand BP Reduction Low-SaltDiet Weight Loss(19.4 lb) Alcohol Reduction PotassiumSupplement 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.

13. 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.

14. Goal BP Recommendations for Patients With DM or Renal Disease 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.

15. 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 •and • 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.

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

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

18. Clinical Trials • AASK = The African American Study of Kidney Disease and Hypertension • AIRE = Acute Infarction Ramipril Efficacy • ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial • COMET = Carvedilol or Metoprolol European Trial • CONSENSUS = Cooperative North Scandinavian Enalapril Survival • EUROPA = European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease • HOPE = Heart Outcomes Prevention Evaluation • HOT = Hypertension Optimal Treatment • IDNT = Irbesartan in Diabetic Nephropathy Trial • MDRD = Modification of Diet in Renal Disease • MICRO-HOPE = Microalbuminuria, Cardiovascular, and Renal Outcomes (Heart Outcomes Prevention Evaluation)

19. Clinical Trials (cont’d) • PEACE = Prevention of Events With Angiotensin-Converting Enzyme Inhibition • PERSUADE = Perindopril Substudy in Coronary Artery Disease and Diabetes • QUIET = Quinapril Ischemic Event Trial • RENAAL = Reduction in Endpoints With the Angiotensin Antagonist Losartan • SAVE = Survival and Ventricular Enlargement • SHEP = Systolic Hypertension in the Elderly Program • SOLVD = Studies of Left Ventricular Dysfunction • Syst-Eur = Systolic Hypertension in Europe • TRACE = Trandolapril Cardiac Elevation • UKPDS = United Kingdom Prospective Diabetes Study • Val-HeFT = Valsartan Heart Failure Trial • VALIANT = Valsartan in Acute Myocardial Infarction Trial • VALUE = Valsartan Antihypertensive Long-term Use Evaluation

20. Multiple Antihypertensive Agents Needed to Achieve BP Goal: ALLHAT % Controlled <140/90 mm Hg 1 Drug 2 Drugs 3 Drugs 100 80 60 Patients (%) 40 20 0 Baseline 6 Months 3 Years 5 Years 1 Year Patients had hypertension and at least 1 other CHD risk factor. N = 33357. Adapted from Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

21. Multiple Antihypertensive Agents Needed to Achieve BP Goal: Diabetes/Renal Impairment 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.

22. DM 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.

23. 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 = 18790; 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.

24. Syst-Eur: CV Protection Resulting From BP Lowering Was Greatest in Patients With Diabetes With Diabetes Without Diabetes Fatal and Nonfatal Stroke Fatal and Nonfatal Cardiac Events All CV Events Overall Mortality CVD Mortality 0 –10 8% P = .55 16% P = .37 –20 22% P = .10 25% P = .02 Reduction in Event Rate for Active Treatment Group (%) –30 36% P = .02 –40 41% P = .09 –50 57% P = .06 –60 62% P = .002 –70 69% P = .02 70% P = .01 Patients with hypertension received nitrendipine  enalapril or HCTZ. N = 4695. Syst-Eur = Systolic Hypertension in Europe; CV = cardiovascular. Adapted from Tuomilehto J et al. N Engl J Med. 1999;340:677-684.

25. 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% -20 Relative Risk Reduction (%) 24% * -30 32% 32% * 37% -40 * *P <.05 compared to tight glucose control 44% * -50 Patients had hypertension and type 2 diabetes. N = 1148. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

26. Currently Available Antihypertensive Medications: Mechanism of Action American Heart Association. December 11, 2006. Available at: http://americanheart.org/presenter.jhtml?identifier=159.

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

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

29. Hazard Ratio Valsartan/Amlodipine Primary cardiac composite endpoint Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2.0 Favors Valsartan Favors Amlodipine VALUE: Hazard Ratios for Prespecified Analyses in Patients With Hypertension at High CV Risk • 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. Val-HeFT: HF Morbidity With ARB in Patients Not Receiving ACEIs 100 Valsartan (n = 185) Placebo (n = 181) 80 60 Event-Free Probability (%) 40 Risk Reduction 44% (P <.001) 20 0 0 3 6 9 12 15 18 21 24 27 Months ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure. Maggioni AP et al. J Am Coll Cardiol. 2002;40:1414-1421.

31. VALIANT: ARBs in Secondary Prevention Acute dual RAS blockade provides no significant benefit 0.4 Captopril Valsartan 0.3 Valsartan and captopril All-Cause Mortality (probability) 0.2 0.1 Valsartan vs captopril: HR = 1.00; P = .982 Valsartan + captopril vs captopril: HR = 0.98; P = .726 0.0 0 6 12 18 24 30 36 Months Patients had post-MI HF or LVSD (EF <0.40). N = 14703. EF = ejection fraction; LVSD = left ventricular systolic dysfunction; MI = myocardial infarction; RAS = renin-angiotensin system; VALIANT = Valsartan in Acute Myocardial Infarction Trial. Pfeffer M et al. N Engl J Med. 2003;349:1893-1906.

32. COMET: Primary Endpoint of Mortality 40 Metoprolol Carvedilol 30 All-Cause Mortality (%) 20 HR = 0.83 95% CI, 0.74-0.93 P = .0017 10 0 0 1 2 3 4 5 Time (years) Carvedilol n = 1511; metoprolol n = 1518. COMET = Carvedilol or Metoprolol European Trial. Poole-Wilson PA et al. Lancet. 2003;362:7-13.

33. ACEI Versus Placebo: Effect on MI CONSENSUS II SOLVD-Prevention SOLVD-Treatment Total (95% CL) 1.5 TRACE AIRE SAVE OR (95% CL) for the Occurrence of MI 1.0 0.7 0.5 1.3 3.0 3.1 3.4 3.5 Years Patients had HF and/or LVD. Strauss MD, Hall A. Circulation. 2006;114:838-854.

34. ACEI Trials in CAD Without HF: Primary Outcomes EUROPA: CV Death/MI/Cardiac Arrest HOPE: CV Death/MI/Stroke 14 20 Placebo Placebo 12 20% Risk Reduction HR = 0.80 (0.71–0.91) P = .0003 22% Risk Reduction HR = 0.78 (0.70–0.86) P <.001 15 10 Percent 8 Ramipril 10 mg 10 6 Perindopril 8 mg Percent 4 5 2 Time (years) Time (years) 0 0 0 1 2 3 4 5 0 1 2 3 4 QUIET: All CV Events PEACE: CV Death/MI/CABG/PCI 50 30 Quinapril 20 mg Placebo 4% Risk Increase HR = 1.04 (0.89–1.22) P = .6 40 25 4% Risk Reduction HR = 0.96 (0.88–1.06) P = .43 20 30 Percent Percent Trandolapril 4 mg 15 Placebo 20 10 10 Time (years) Time (years) 5 0 0 1 2 3 4 5 6 0 1 2 3 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.

35. MICRO-HOPE, PERSUADE: CV Events in Patients With Diabetes MICRO-HOPE(n = 3577)CV death/MI/stroke PERSUADE(n = 1502)CV death/MI/cardiac arrest 25 25 Placebo Placebo 20 20 25% RRRP = .0004 19% RRRP = .13 15 15 Primary Outcome (%) Perindopril8 mg 10 10 Ramipril10 mg 5 5 0 0 5 0 1 2 3 4 5 0 1 2 3 4 Follow-Up (years) Follow-Up (years) HOPE Study Investigators. Lancet. 2000;355:253-259; Daly CA et al. Eur Heart J. 2005;26:1369-1378.

36. MICRO-HOPE: Albuminuria in Patients With Diabetes 3.0 Placebo 2.5 Ramipril 2.0 P = .02 Mean Albumin/Creatinine Ratio (urine) 1.5 P = .001 1.0 0.5 0.0 1 0 4-5 2 3 Time (y) HOPE Study Investigators. Lancet. 2000;355:253-259.

37. The Data Support Global CV Risk Management • CV disease remains the leading cause of death in both men and women in the United States • Framingham data show that CV risk factors tend to cluster—and that risk of death from CHD and stroke increases proportionately • Endothelial dysfunction seems to be a key factor in the development of CV disease • Recent clinical trials have given us a wealth of information with which to manage global CV risk

38. Adherence

39. 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 (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.

40. Practical Tips to Improve Adherence • Talk to your patient • Explain the condition and why specific 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: • Different ways to approach patients based on individual patient attitudes • Allies in patient care—family, friends • Ways to simplify the regimen • Refill dates (if the patient has not refilled the prescription, the medication is not being taken) Ockene IS et al. J Am Coll Cardiol. 2002;40:630-640.

41. 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—blend 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, home testing devices) • Patient assistance programs • Support patients where medication costs are a barrier to adherence 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.

42. Case Study

43. Case Study: 55-Year-Old Asian Man With Hypertension and Type 2 Diabetes • 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

44. ? 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!

45. ? Decision Point The patient’s BP is 148/96 mm Hg while taking HCTZ 25 mg/d and glyburide 5 mg/d. To bring BP down to <130/80 mm Hg, you would add a(n): • BB • CCB • ARB • ACE Use your keypad to vote now!

46. PCE Takeaways

47. 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"

48. ? 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!