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Fall 2007 Symposia Series

St. South San Francisco Conference Center San Francisco, California November 3, 2007. Fall 2007 Symposia Series. Blood Pressure and Beyond: Important Considerations in Managing Your Patient’s Cardiovascular Risk. Joshua Furman, MD, FACC Division of Cardiology Mount Sinai Medical Center

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Fall 2007 Symposia Series

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  1. St South San Francisco Conference Center San Francisco, California November 3, 2007 Fall2007Symposia Series

  2. Blood Pressure and Beyond: Important Considerations in Managing Your Patient’s Cardiovascular Risk Joshua Furman, MD, FACC Division of Cardiology Mount Sinai Medical Center Miami Beach, Florida

  3. ? 7 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

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

  5. 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

  6. 65 Million Americans Require Treatment for Hypertension Nearly1 in 3 adults (31%) in the United States has hypertension Fields LE et al. Hypertension. 2004;44:398-404.

  7. JNC 7 Cardiovascular Risk Factors • Hypertension • Cigarette smoking • Obesity (BMI ≥30 kg/m2) • Physical inactivity • Dyslipidemia • Diabetes mellitus • Microalbuminuria or estimated GFR <60 mL/min • Age (men >55 yr; women >65 yr) • Family history of premature CVD BMI = body mass index; CVD = cardiovascular disease; GFR = glomerular filtration rate. 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. Microalbuminuria and Hypertension Increase the Risk of Ischemic Heart Disease N = 2085, 10-year follow-up Relative Risk of Ischemic Heart Disease Adapted from Borch-Johnsen et al. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

  9. Progression of Cardiovascular Disease: The Cardiovascular Continuum Myocardial infarction Myocardialischemia Ventricular dysfunction Sudden death Peripheral arterial disease Ventricular dilation and hypertrophy Endothelialdysfunctionand atherothrombosis 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.

  10. Development and Progression of CVD HYPERTENSIONAge, gender, smoking, inactivity, obesity, cholesterol, diabetes mellitus Risk factors  Oxidative stress  Endothelial function EPCs Genetic factors Functional alterations Structural alterations Clinical sequelae EPC = endothelial progenitor cell. Adapted from Pepine CJ. Am J Cardiol. 2001;88(suppl):5K-9K.

  11. Development and Progression of Vascular Disease RISK FACTORS LDL BP Diabetes Smoking Oxidative Stress Endothelial Dysfunction andSmooth Muscle Activation NO •  Local Mediators •  Tissue ACE, AII EndothelinCatecholamines PAI-1, PlateletAggregation, Tissue Factor VCAM/ICAMCytokines Proteolysis Inflammation Growth Factors Cytokines Matrix Inflammation PlaqueRupture Vasoconstriction Thrombosis Vascular Lesionand Remodeling CLINICAL SEQUELAE Dzau V. Hypertension. 2001;37:1047-1052.

  12. Renal Continuum of Risk Macro- albuminuria Micro- albuminuria Diabetic Nephropathy Endothelial Dysfunction End-Stage Renal Disease Risk Factors Diabetes Hypertension Death Adapted from Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders; 2001.

  13. US Adult Population at Risk Hypertensive (>139/89 mm Hg) Normal(<120/80 mm Hg) 65 M1 98 M 45 M2 Prehypertensive(120-139/80-89 mm Hg) • Fields LE et al. Hypertension. 2004;44:398-404. • American Heart Association. Heart Disease and Stroke Statistics─2004 Update. 2003.

  14. Lifestyle Modifications to Manage Hypertension The effects of implementing these modifications are dose and time dependent. DASH = Dietary Approaches to Stop Hypertension.1. The Trials of Hypertension Prevention Collaborative Research Group. Arch Intern Med. 1997;157:657-667. 2. He J et al. Hypertension. 2000;35:544-549. 3. Sacks FM et al. N Engl J Med. 2001;344:3-10. 4. Vollmer WM et al. Ann Intern Med. 2001;135:1019-1028. 5. Chobanian AV, Hill M. Hypertension. 2000;35:858-863. 6. Kelley GA, Kelley KS. Hypertension. 2000;35:838-843. 7. Whelton SP et al. Ann Intern Med. 2002;136:493-503. 8. Xin X et al. Hypertension. 2001;38:1112-1117. Table adapted with permission from Chobanian V et al. JAMA. 2003;289:2560-2572.

  15. TROPHY: Kaplan-Meier Curves of New Onset Clinical Hypertension 90 Candesartan Placebo 80 70 60 Cumulative Incidence (%) 50 40 30 20 10 0 0 1 2 3 Years in Study TROPHY = Trial of Preventing Hypertension. Julius S et al. N Engl J Med. 2006;354:1685-1697.

  16. 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.

  17. Increased Stroke Risk With -blockers Shown in Meta-Analysis N = 105,951 RR(95% CI) Favors β-blocker Favors other drug Stroke 1.29 (1.12-1.49) ASCOT-BPLA 0.87 (0.68-1.12) CONVINCE 1.58 (0.69-3.64) ELSA 0.77 (0.49-1.23) HAPPHY 1.14 (0.93-1.39) INVEST 1.34 (1.13-1.58) LIFE 1.22 (0.83-1.79) MRC Old 1.22 (0.99-1.50) NORDIL 1.12 (0.96-1.30) STOP-2 0.90 (0.48-1.69) UKPDS 0.56 (0.21-1.48) Yurenev 2.28 (1.31-3.95) MRC 1.16 (1.04-1.30) Total events Test for heterogeneity:χ2 = 22.39(P =.02) 0.5 0.7 1.0 1.5 2.0 Lindholm LH et al. Lancet. 2005;366:1545-53.

  18. Key Points for Optimal Hypertension Management <140/90 mm Hg <130/80 mm Hg in patients with diabetes or renal disease JNC 7BPGoals • JNC 7 recommends: • If SBP >20 mm Hg or DBP >10 mm Hg over goal, • consider initiating with 2-drug combination 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.

  19. JNC 7 Highlights: Key Risk-Related Messages Certain high-risk conditions arecompelling indicationsfor 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.

  20. Compelling Indications* for Therapy in Complex Hypertension *Compelling indications are based on benefits from outcomes studies or existing clinical guidelines. †High-risk condition is managed simultaneously with BP; combination of agents may be required. 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.

  21. Hypertension and Global CV Risk

  22. Hypertension:The Disease Continuum Natural History of CVD Progression Early Paradigm Elevated BP Target Organ Damage More Recent Paradigm Vascular Dysfunction Elevated BP Target Organ Damage A Proposed Future Paradigm VascularDysfunction Target OrganDamage EndothelialDysfunction Elevated BP Anginapectoris LVH Stroke Renaldamage MI LVH = left ventricular hypertrophy; MI = myocardial infarction.

  23. 160 140 120 100 80 IDNT: Systolic BP, Mean Arterial Pressure, and Diastolic BP Response SBP Irbesartan Amlodipine Control BP (mm Hg) MAP DBP 0 6 12 18 24 30 36 42 48 54 Follow-up Visit (mo) Control defined as placebo plus permitted adjunctive antihypertensive therapy. Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups and 3.3 concomitant agents in the control group. IDNT = Irbesartan Diabetic Nephropathy Trial; MAP = mean arterial pressure. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

  24. IDNT: Primary End Point –Time to Doubling of Serum Creatinine, ESRD, or Death 70 Irbesartan Amlodipine Control RRR 23%P = .006 60 RRR 20%P = .02 P = NS 50 Subjects (%) 40 30 20 0 6 12 18 24 30 36 42 48 54 60 10 Follow-up (mo) Control defined as placebo. ESRD = end-stage renal disease; RRR = relative risk reduction; SeCr = serum creatinine. Lewis EJ et al. N Engl J Med. 2001;345:851-860. 0

  25. 180 160 140 120 100 80 60 40 0 6 12 18 24 30 36 42 48 54 LIFE: Blood Pressure Results – Follow-up Atenolol Losartan Atenolol 145.4 mm Hg Systolic Losartan 144.1 mm Hg BP (mm Hg) Mean Arterial Losartan 81.3 mm Hg Diastolic Atenolol 80.9 mm Hg Study Month Dahlof B et al. Lancet. 2002;359:995-1003.

  26. LIFE: Primary Outcome (CV Death, MI, stroke) 9193 Patients With Hypertension and ECG-LVH 16 13.0% adjusted risk reduction, P =.021(losartan vs atenolol) 14 12 10 Proportion of Patients With First Event (%) 8 Primary Outcome 6 Atenolol Losartan 4 BP from baseline (mm Hg) 29.1/16.8 30.2/16.6 Patients with BP ≤140/90 mm Hg 46% 49% 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (mo) No. at risk Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 LIFE = Losartan Intervention For Endpoint reduction in hypertension study.Dahlof B et al. Lancet. 2002;359:995-1003.

  27. VALUE: Comparison of CCB and ARB Population: 15,245 patients with high-risk hypertension Treatment: Amlodipine 5-10 mg  HCTZ 12.5-25 mgValsartan 80-160 mg  HCTZ 12.5-25 mg Primary outcome:Composite of cardiac mortality, MI, HF Secondary outcomes:MI, HF, stroke Follow-up: 4.2 years VALUE = Valsartan Antihypertensive Long-term Use Evaluation. Julius S et al. Lancet. 2004;363:2022-2031.

  28. VALUE: Similar Treatment Effectson Primary Outcome at Study End N = 15,245 14 HR = 1.03(95% CI, 0.94-1.14) P = .49 12 10 Valsartan-based regimen (n = 7649) Main outcome of cardiac disease did not differ between treatment groups. Unequal reductions in BP might account for differences. 8 Proportion of Patients With First Event (%) 6 4 Amlodipine-based regimen (n = 7596) 2 0 6 18 30 42 54 66 0 Time (mo) Julius S et al. Lancet. 2004;363:2022-2031.

  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. • Julius S et al, for the VALUE trial group. Lancet. 2004;363:2022-2031.

  30. ? 7 What percentage of patients with hypertension have 2 or more additional CV risk factors? • 20% • 30% • 40% • 50% • >50%

  31. 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.

  32. ? 7 On average, how many drugs will a patient need to control hypertension? • 1 • 2 • 3 • 4

  33. ALLHAT 138 IDNT 138 RENAAL 141 UKPDS 144 ABCD 132 MDRD 132 HOT 138 AASK 128 * INVEST 131 1 2 3 4 Number of Antihypertensive Agents Needed to Achieve Systolic BP Control SBP achieved(mm Hg) Trial Number of BP Medications† *~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.

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

  35. 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.

  36. 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 Reduction in Event Rate for Active Treatment Group (%) 22% P = .10 25% P = .02 –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.

  37. 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.

  38. 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.

  39. Adherence

  40. 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.

  41. 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.

  42. 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.

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

  44. Antihypertensive Drugs: Hemodynamic Mechanism of BP Reduction BP (MAP) SVR CO HR SV BB, ARB, ACEI, Central acting, CCB, Diuretic, VasoD Preload Contractility BB Diuretic BB, CCB* *Nondihydropyridine CCBs. CO = cardiac output; HR = heart rate; SV = stroke volume; SVR = systemic vascular resistance. 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; Houston MC. Primary Care. 1991;18:713-753.

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

  46. Deleterious Effects of Angiotensin II PAI-1/thrombosis Abnormalvasoconstriction Angiotensin II Plateletaggregation ActivateSNS Superoxideproduction Vascularsmooth musclegrowth Aldosterone Myocytegrowth Collagen Vasopressin Endothelin Remodeling SNS = sympathetic nervous system. Burnier M et al. Lancet. 2000;355:637-645; Brown NJ et al. Adv Intern Med. 2000;45:419-429.

  47. Possible Consequences of Angiotensin II on Target Organs Stroke Atherosclerosis1* Vasoconstriction2 Vascular hypertrophy2 Endothelial dysfunction2 Hypertension LVH2 Fibrosis2 Remodeling2 Apoptosis3 AII AT1 receptor Heart failure, MI DEATH ↓GFR4 ↑Proteinuria4 ↑Aldosterone release2 Glomerular sclerosis4 Renal failure *Preclinical data. 1. Daugherty A et al. J Clin Invest. 2000;105:1605-1612; 2. Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37-S44; 3. Booz GW et al. Heart Failure Rev. 1998;3:125-130; 4. Anderson S. Exp Nephrol. 1996;4(suppl 1):34-40.

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

  49. 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.

  50. HOPE: Landmark Outcomes With Ramipril Effects Beyond Baseline Therapy • Aspirin • BBs • Lipid-lowering agents • Diuretics • Other antiplatelets • CCBs All-Cause Mortality Stroke CV Death Nonfatal MI 0 -5 -10 -15 %RR 16%† -20 20%* -25 *P = .0001 26%* -30 †P = .005 32%* -35 HOPE = Heart Outcomes Prevention Evaluation.Yusuf et al, for the HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

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