A CV Risk Education Symposium

1. A CV Risk Education Symposium Integrating Total CV Risk Management Into Clinical Practice

2. Welcome and Opening Remarks

3. What Is the PCE? • The Practicing Clinicians Exchange (PCE) is an innovative network of live educational activities and home study materials designed for NPs and PAs. This unique CME/CE format will provide NPs and PAs with educational opportunities built to meet real-world clinical needs • The PCE’s goal is to provide practicing clinicians with comprehensive CME/CE programs in a variety of therapeutic areas, with opportunities to earn multiple CME/CE credits

4. What Makes PCE Unique? • Developed for NPs and PAs • Symposium series integrated with live teleconference series and home study workbook • Today’s symposium: • Is case based • Has been developed to meet your needs • Includes case studies led by NPs and PAs (in concert with expert physician faculty) • Includes full-panel Q&A sessions led by NPs and PAs

5. Scientific Agenda

6. ? Why Are You Here Today? • Which of today’s learning objectives are you most interested in? 1. Explain the rationale for a global approach to CV risk management 2. Distinguish between primary and secondary CV risk management 3. Extrapolate data from recent clinical trials to select appropriate pharmacologic and nonpharmacologic treatment for CV risk factors in clinical practice 4. Apply current CV risk guidelines to clinical practice 5. Employ techniques to help patients achieve CV risk management goals Use your keypad to vote now!

7. The Case for TotalCV Risk Management

8. CV Risk: The Scope of the Problem

9. Leading Causes of Death for All Males and Females: United States, 2002 Total CVD (preliminary) Cancer Accidents Chronic Lower Respiratory Diseases Diabetes Mellitus Alzheimer’s Disease 494 500 434 400 289 300 269 Deaths (thousands) 200 100 69 61 64 42 39 34 0 Males Females CVD = cardiovascular disease. CDC/NCHS.

10. Prevalence of CHD by Age and Sex:NHANES, 1999-2002 Males Females 18 16.8 16 14 11.6 11.5 12 10.3 10 Percent of Population 8 6.3 6 3.6 4 3.0 1.6 1.4 2 0.2 0.3 0.0 0 20-34 35-44 45-54 55-64 65-74 75+ Ages NHANES = National Health and Nutrition Examination Survey.CDC/NCHS and NHLBI.

11. Prevalence of Stroke by Age and Sex: NHANES, 1999-2002 Males Females 14 12.0 11.5 12 10 8 Percent of Population 6.6 6.3 6 4 3.1 3.0 2.1 2 1.2 1.1 0.8 0.4 0.3 0 20-34 35-44 45-54 55-64 65-74 75+ Ages CDC/NCHS and NHLBI.

12. Estimated Direct and Indirect Costs of Cardiovascular Diseases and Stroke: United States, 2005 450 400 350 300 250 Billions of Dollars 200 150 100 50 0 HeartDisease CoronaryHeartDisease Stroke Hyper- tensiveDisease Congestive HeartFailure Total CVD AHA. Heart Disease and Stroke Statistics—2005 Update.

13. CV Risk Factors: An Intimate Interrelationship

14. 64% lower risk 59% lower risk 91% lower risk Impact of Elevated SBP and Total Cholesterol on CHD Mortality: MRFIT 33.7 n = 202,620 Age-Adjusted CHD Death Rates Per 10,000 Person-years 21 22.6 17.1 12.7 12.2 17.7 12.3 9.6 8.3 245 16.7 5.9 10.9 8.5 221–244 6.3 5.5 13.7 7.9 7.9 203–220 Cholesterol Quintile (mg/dL) 6 4.3 182–202 5.6 5 3.4 3.1 <182 142 <118 132–141 125–131 118–124 SBP Quintile (mm Hg) MRFIT= Multiple Risk Factor Intervention Trial;SBP = systolic blood pressure. Adapted from Neaton JD, et al. Arch Intern Med. 1992;152:56-64.

15. 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.

16. Integrated Cellular Mechanisms of CVD Hypertension Dyslipidemia Diabetes Endothelial Dysfunction  COX Activity  Endothelin  Inflammation  NO Synthesis • Vasoconstriction • Thrombosis • Superoxide • Leukocyte adhesion • Endothelial permeability • Foam cell formation • T-cell activation • Vasoconstriction • Calcium mobilization • Thromboxane A2 • Prostaglandin H2 • Prostacyclin NO = nitric oxide; COX = cyclooxygenase. Liao JK. Clin Chem. 1998;44:1799-1808. Libby P. J Intern Med. 2000;247:349-358. Mason RP. Cerebrovasc Dis. 2003;16(suppl 3):11-17.

17. Examples of Clinical Trials That Are Studying Multiple CV Risk Factors

18. ASCOT-BPLA Results reported in 2005 19,257 hypertensive patients (BPLA) amlodipine ±perindopril atenolol ± bendroflumethiazide PROBE design ASCOT-LLA Results reported in 2003 10,305 patients (LLA) TC ≤6.5 mmol/L (251 mg/dL) 5168 patients atorvastatin 10 mg 5137 patients placebo Double-blind ASCOT: Study Design Investigator-led, multinational randomized controlled trial ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; BPLA = blood pressure–lowering arm; LLA = lipid-lowering arm; PROBE = prospective randomized open blinded end points. Adapted from Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.

19. Hypertension Aged ≥55 years Male Microalbuminuria/proteinuria Smoker Family history of CHD Plasma TC:HDL-C ≥6 Type 2 diabetes Certain ECG abnormalities LVH Prior cerebrovascular events Peripheral vascular disease 0 10 20 30 40 50 60 70 80 90 100 Patients With Risk Factor (%) ASCOT: Patient Population Risk Factor Profile All patients in ASCOT had hypertension plus ≥3 risk factors for CHD ECG = electrocardiogram; LVH = left ventricular hypertrophy; TC = total cholesterol. Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.

20. ASCOT: Main Outcome Measure • Combination of nonfatal MI and fatal CHD • Results to be discussed later today MI = myocardial infarction. Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.

21. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial • Randomized, multicenter clinical trial (75 sites in US and Canada), 2x2 factorial design • 10,000 patients with type 2 diabetes (with and without existing CVD) at high risk for CVD events • Will independently test 3 medical strategies to reduce CVD in patients with diabetes A1C = glycosylated hemoglobin. Available at: www.accordtrial.org/public/purpose.cfm.

22. ACCORD: Main Outcome Measure • First occurrence after randomization of a major CVD event • Nonfatal MI • Nonfatal stroke • CV death • Results to be published in 2010 Available at:www.accordtrial.org/public/purpose.cfm.

23. CV Risk Management: What We Should Be Doing

24. Primary and Secondary Prevention: Definitions • Primary prevention • Modification of risk factors or prevention of their development to prevent or delay the onset of CHD • Secondary prevention • Initiation of therapy to reduce recurrent CHD events and decrease cardiac mortality in patients with established CHD • “Primary and a half prevention”* • As patients with subclinical CHD are identified, the distinction between primary and secondary prevention becomes blurred *Celermajer DS. JACC. 2005;45:1994-1996.

25. Key Goals: JNC 7, NCEP, ADA, and AHA Guidelines *For patients with diabetes. †Therapeutic option <100 mg/dL for patients at moderately high risk. ‡Therapeutic option <70 mg/dL for patients at very high risk. American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35;S65-S67;S68-S71; Chobanian AV, et al. JNC 7: Complete Report. 2003. Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206; Grundy SM et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication No. 02-5215; Pearson TA, et al. Circulation. 2002;106:388-391.

26. ACC/AHA ABC Approach to Primary and Secondary Prevention Complete sets of ACC/AHA guidelines available at www.acc.org and www.americanheart.org.Gluckman TJ, et al. Arch Intern Med. 2004;164:1490-1500.

27. CV Risk Factor Evaluation: What to Consider • “Traditional” risk factors • Framingham risk analysis • Metabolic syndrome • Atherosclerotic disease (or equivalence) • “Emerging” risk factors? More on these in the presentations to come!

28. Conclusions: The Case for Total CV Risk Management • CV disease remains the leading cause of death in both men and women in the US • 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 total CV risk and have led to updates of major clinical guidelines

29. Full Panel Q&A

30. The Hypertension Component: JNC 7 and Beyond

31. Hypertension Affects Approximately 65 Million Americans: 28% of Adults 50 Males Females 40% 38% 40 29% 28% 27% 27% 30 Population With Hypertension (%) 20 10 0 Non-Hispanic White Non-Hispanic Black Mexican American Fields LE, et al. Hypertension. 2004;44:398-404.

32. 256 256 128 128 64 64 32 32 16 16 8 8 4 4 2 2 1 1 0 0 120 140 160 180 70 80 90 100 110 Blood Pressure: Lower Is Better Ischemic Heart Disease Mortality Age at Risk (Y) Age at Risk (Y) 80-89 80-89 70-79 70-79 60-69 60-69 50-59 50-59 40-49 40-49 Ischemic Heart Disease Mortality Ischemic Heart Disease Mortality Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) BP = blood pressure. Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

33. JNC 7 Blood Pressure Classification SBP DBP (mm Hg) (mm Hg) Normal <120 and <80 Prehypertension 120-139 or 80-89 Stage 1 hypertension 140-159 or 90-99 Stage 2 hypertension ≥160 or ≥100 DBP = diastolic blood pressure. Chobanian AV, et al. JNC 7: Complete Report. 2003.Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.

34. JNC 7 Goal Blood Pressures • Most patients • <140/90 mm Hg • Patients with diabetes or chronic kidney disease • <130/80 mm Hg • Based mostly on observational data, not prospective clinical trials • Patients with metabolic syndrome • No specific recommendation Chobanian AV, et al. JNC 7: Complete Report. 2003.Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.

35. Stage 2 Hypertension 2-drug combinations for most (usually thiazide-type diuretics and ACEI, or ARB, or BB, or CCB). Drug(s) for Compelling Indications Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combination. 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 If not at goal BP, optimize dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist. Chobanian AV, et al. JNC 7: Complete Report. 2004. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

36. Practicing Clinicians Case Study 1: A 33-Year-Old White Man Who Presents With Acute Back Pain • Presents with acute low back pain following weekend racquetball game • No other complaints • “Weekend warrior” lifestyle; nonsmoker; occasional ETOH • Using this presentation to perform a CV risk assessment, you find • BP: • 148/90 mm Hg (first reading) • 146/88 mm Hg (second reading) • Height: 6' 0"; weight: 218 lb; waist: 39" • You treat the acute low back pain and ask the patient to return for a more thorough evaluation of CV status

37. Practicing Clinicians Case Study 1: Findings During Return Visit • Family history not significant for CV disease • High-sodium, high-fat diet • Laboratory findings • TC: 170 mg/dL • LDL-C: 102 mg/dL • HDL-C: 48 mg/dL • TG: 100 mg/dL • Fasting glucose: 96 mg/dL • Serum creatinine: 0.9 mg/dL (GFR: 128 mL/min/1.73 m2) • Dipstick: negative for protein GFR = glomerular filtration rate.

38. ? Practicing Clinicians Case Study 1: Decision Point • Given the patient’s risk factor profile, how would you treat him? 1. Prescribe diet/exercise regimen and determine in 3 to 4 months whether drug therapy is indicated 2. Start a diuretic 3. Start a diuretic and an ACE inhibitor 4. Start a dihydropyridineCCB Use your keypad to vote now! ACE = angiotensin-converting enzyme; CCB = calcium channel blocker.

39. JNC 7: Lifestyle Modifications to Prevent and Manage Hypertension DASH = Dietary Approaches to Stop Hypertension. Chobanian AV, et al. JNC 7: Complete Report. 2003. Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.

40. ? Practicing Clinicians Case Study 1: Decision Point • The patient tells you he has been toostressed with work and family obligations to seriously follow his diet/exercise regimen. What would you do next? 1. Start a -blocker 2. Start a diuretic 3. Start a diuretic and an ACE inhibitor 4. Start a dihydropyridineCCB Use your keypad to vote now!

41. Practicing Clinicians Case Study 1: CV Risk Management Pearls • Lifestyle modifications alone may be sufficient for a young patient with stage 1 hypertension and no other CV risk factors (expert opinion) • If lifestyle modifications do not achieve goal BP within 3-4 months, pharmacologic therapy can be prescribed (expert opinion) • Excellent clinical trial outcome data prove that lowering BP with several classes of drugs, including ACEIs, ARBs, β-blockers, CCBs, and thiazide-type diuretics, will all reduce the complications of hypertension (JNC 7) ARB = angiotensin receptor blocker.

42. Newer Versus Older Agents: ALLHAT Primary End Point: Fatal CHD or Nonfatal MI 16 Chlorthalidone Amlodipine Lisinopril N = 33,357 12 Cumulative Event Rate (%) 8 4 0 0 1 2 3 4 5 6 7 Time to Event (years) ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.

43. Newer Versus Older Antihypertensive Agents: ASCOT-BPLA Primary End Point: Nonfatal MI and Fatal CHD Atenolol-based regimen No. of events: 474 Amlodipine-based regimen No. of events: 429 5.0 4.0 Proportion of Events (%) 3.0 2.0 HR = 0.90 (0.79­1.02)P = .1052* N = 19,257 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years *Trial stopped early, after 5.5 years’ median follow-up Dahlöf B, et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.

44. ASCOT-BPLA: Summary of All End Points Unadjusted Hazard Ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-0.78) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) Primary Nonfatal MI (including silent) + fatal CHD SecondaryNonfatal MI (excluding silent) + fatal CHD Total coronary end pointTotal CV events and proceduresAll-cause mortalityCV mortalityFatal and nonfatal strokeFatal and nonfatal heart failure Tertiary Silent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol-based regimen better Amlodipine-based regimen better Area of the yellow squares is proportional to the amount of statistical information. Dahlöf B, et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.

45. Practicing Clinicians Case Study 2: 49-Year-Old White Woman With “Resistant” Hypertension • Presents for routine follow-up of BP • Family history: type 2 diabetes; father had MI (age 45) • Nonsmoker; no ETOH use; history of cystic renal disease • Physical examination • BP: 158/95 mm Hg • Height: 5' 6"; weight: 142 lb; waist: 34" • Laboratory values • Lipid profile: within normal limits • TG: 144 mg/dL • Fasting glucose: 98 mg/dL • Serum creatinine: 1.3 mg/dL (GFR: 44 mL/min/1.73 m2) • Dipstick: negative for protein • Medication • Enalapril 40 mg/d

46. ? Practicing Clinicians Case Study 2: Decision Point • Given this patient’s risk factor profile, what goal would you have for her BP? 1. <140/90 mm Hg 2. <130/85 mm Hg 3. <130/80 mm Hg 4. <120/80 mm Hg Use your keypad to vote now!

47. ? Practicing Clinicians Case Study 2: Decision Point • Because the patient has chronic renal disease, the BP goal is <130/80 mm Hg. What would you do to get this patient there? 1. Reemphasize diet/exercise therapy and reevaluate in 3 months 2. Switch from an ACE inhibitor to an ARB 3. Add a thiazide diuretic 4. Add a dihydropyridine CCB Use your keypad to vote now!

48. Practicing Clinicians Case Study 2: CV Risk Management Pearls • If BP is >20/10 mm Hg above goal, consider starting with 2 agents, perhaps in a combination pill • If patient still not at goal BP, optimize dosages or add additional drugs until goal is achieved • “Compelling indications” may dictate treatment choices Chobanian AV, et al. JNC 7: Complete Report. 2003. Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.

49. ESH-ESC Guidelines: Effective Combinations of Antihypertensive Agents Diuretics Angiotensin ReceptorAntagonists β-Blockers CalciumAntagonists α-Blockers ACE Inhibitors ESH = European Society of Hypertension; ESC = European Society of Cardiology. Adapted from ESH-ESC Guidelines Committee. J Hypertens. 2003;21:1011-1053.

50. JNC 7: Compelling Indications for Antihypertensive Drug Classes Recommended Drugs AldoCompelling Indication Diuretic BB ACEI 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. JNC 7: Complete Report. 2004. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.