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

? 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!

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.

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

Hypertension and Global CV Risk

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.

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 Chobanian AV, Bakris GL, Black HR, et al, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Complete Report. Bethesda, Md: National Heart, Lung, and Blood Institute; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. 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.

? 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!

>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 >50% of Hypertension Occurs in Presence of 2 or More Risk Factors Men Women 1 RF 2 RFs 1 RF 2 RFs 26% 25% 27% 24% 19% 22% 17% 20% 8% 12% Epidemiologic research confirms the phenomenon of risk factor clustering. Data based on the Framingham Study, which examined the occurrence of hypertension in isolation or in combination with other major risk factors (ie, hyperlipidemia, glucose intolerance, hyperinsulinemia, obesity, and LVH), demonstrate that hypertension usually coexists with other cardiovascular risk factors. Less than 20% of hypertension occurs in the absence of 1 or more major risk factors. Clusters of 2 to 3 cardiovascular risk factors occur in about half of all patients with hypertension. These data highlight the need to more aggressively diagnose comorbid risk factors among patients with hypertension. Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens. 2000;13:3S-10S. 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. 9

10-Year Probability of Event (%) Risk of CHD in Mild Hypertension by Intensity of Associated Risk Factors 40 42 36 30 10-Year Probability of Event (%) 21 24 18 14 10 12 6 4 6 Risk Factors SBP 150-160 mm Hg + + + + + + TC 240-262 mg/dL − + + + + + HDL-C 33-35 mg/dL − − + + + + Diabetes − − − + + + Cigarette smoking − − − − + + ECG-LVH − − − − − + The risk of CHD in patients with hypertension—particularly elevated SBP—is a significant predictor of death from coronary heart disease (CHD). Risk for CHD is exacerbated by the intensity of associated risk factors (eg, elevated total cholesterol [TC], low high-density lipoprotein cholesterol [HDL-C], diabetes, cigarette smoking, and left ventricular hypertrophy). Each additional CHD risk factor or CHD risk equivalent, whatever its degree, can increase the overall 10-year risk of coronary death in both men and women. In addition to these risk factors shown above, obesity, physical inactivity, and elevated low-density lipoprotein cholesterol [LDL-C] increase the overall risk for CHD in patients with mild hypertension.   Reference Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens. 2000;13:3S-10S. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

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 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 Pharmacologic therapy is usually needed to treat high blood pressure. Recent clinical trials (eg, ALLHAT) have shown that blood pressure control can be achieved in most patients with hypertension. The majority of patients require 2 antihypertensive agents to achieve goal blood pressure (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease). A thiazide-type diuretic is recommended as initial therapy for uncomplicated hypertension, either alone or in combination with an antihypertensive agent from another class (ACE inhibitor, angiotensin receptor blocker [ARB], β-blocker, or CCB). A drug from a different class should be added if the first drug is insufficient for achieving goal blood pressure. Patients whose blood pressure is >20/10 mm Hg above goal should receive pharmacologic therapy, either singly or in a fixed-dose combination.    National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, Md: National Heart, Lung, and Blood Institute; 2003. NIH Publication No. 03-5233. 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.

Nonpharmacologic Interventions and BP Reduction Weight Loss (19.4 lb) Low-Salt Diet Alcohol Reduction Potassium Supplement Exercise 1 2 3 BP Decrease (mm Hg) Meta-analyses of lifestyle changes indicate BP reductions Meta-analyses of data from 54 randomized, controlled trials (N = 2419) indicate aerobic exercise significantly decreases systolic and diastolic blood pressure in overweight, normal-weight, hypertensive, and nonhypertensive people. Comparing exercise results to 3 other meta-analyses, Messerli et al found that the decrease in blood pressure due to exercise exceeded the magnitude of the reduction due to low-salt diet (32 trials, N = 2635), alcohol reduction (15 trials, N = 2234), and potassium supplements (33 trials, N = 2609). 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.

JNC 7 Classification of Blood Pressure 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 Key Take-Aways In the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) published in 2003, Stage I hypertension was defined as in JNC 6, while Stage 2 hypertension was consolidated into a single category (vs Stages 2 and 3 in JNC iag6). (JNC7, p.11, 2nd paragraph) JNC 7 also added a prehypertension category, formerly termed normal and borderline in JNC 6. (JNC7, p.12, Table 3) Although not a disease category, the classification of prehypertension is used to identify persons at risk of developing hypertension so that both patients and clinicians will be encouraged to make the necessary lifestyle changes to prevent or delay the disease from developing. (JNC 7, p.12, 1st column, 2nd paragraph) Although drug therapy is not for prehypertensive persons based on their level of BP, drug therapy should be considered in prehypertensive patients with concomitant diabetes or renal disease in whom lifestyle modification has failed to reduce their BP to ≤130/80 mm Hg. (JNC7, p.12, 1st column, 2nd paragraph) Additional Background Information  ≈ 28% of American adults 18 years (≈59 million) have prehypertension (AHA Update, page 18). 1. National Institutes of Health. National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 04-5230. August 2004:1-86. 2. AHA Statistical Update. Heart disease and stroke statistics—2006 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Committee. Circulation. 2006;113:e85-e151. 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.

Goal BP Recommendations for Patients With DM or Renal Disease Organization Year Goal BP (mm Hg) Canadian Hypertension Society 2007 <130/80 American Diabetes Association 2006 National Kidney Foundation 2004 British Hypertension Society 130/80 JNC 7 2003 World Health Organization/ International Society of 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.

JNC 7: Compelling Indications for Antihypertensive Drug Classes Recommended Drugs Aldo Compelling Indication Diuretic ACEI BB ARB CCB Ant Heart failure • • • •   • Post MI   • •     • High coronary disease risk • • •   •   Diabetes • • • • •   Chronic kidney disease   •   •     Recurrent stroke prevention • and •         Patients with prehypertension or hypertension who have compelling indications (specific high-risk conditions) require therapy with specific antihypertensive agents (ACE inhibitors, ARBs, β-blockers, CCBs). Compelling indications include heart failure, post myocardial infarction (MI), high CHD risk, diabetes, chronic kidney disease, and prevention of recurrent stroke. The selections of agents for patients with these high-risk conditions are based on favorable outcome data from clinical trials. Also in these patients, however, a combination of agents may be required to lower BP. Other management considerations include medications already being taken by the patient, tolerability, and desired BP targets. National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 Express). Bethesda, Md: National Heart, Lung, and Blood Institute; 2003. NIH Publication No. 03-5233. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. 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.

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

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

Multiple Antihypertensive Agents Needed to Achieve BP Goal: ALLHAT 1 Drug 2 Drugs 3 Drugs % Controlled <140/90 mm Hg 100 80 60 Patients (%) 40 20 Baseline 6 Months 1 Year 3 Years 5 Years 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.

Average No. of BP Medications 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) When patients have hypertension and diabetes, these comorbidities contribute strongly to both renal and CV injury. Diabetes is the most common cause of end-stage renal disease (ESRD) in the United States. More than 11 million Americans have both diabetes and hypertension. Bakris and colleagues reviewed clinical trials in which patients with either diabetes or renal impairment were randomized to 2 BP reduction targets. Among these trials were the United Kingdom Prospective Diabetes Study (UKPDS), Modification of Diet in Renal Disease (MDRD), Hypertension Optimal Treatment (HOT), and the African American Study of Kidney Disease (AASK). The authors demonstrated that patients assigned to the lower BP target required an average of 3.2 daily antihypertensive medications to achieve goal. As shown in the graph, patients in 2 other studies (RENAAL and IDNT) required >3 nonstudy medications to achieve BP goals. These data further emphasize the importance of using multiple antihypertensive agents in the treatment of high-risk patients with hypertension. References Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661. Brenner BM, Cooper ME, de Zeeuw D et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. Cushman WC, Ford CE, Cutler JA et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens. 2002;4:393-404. Lewis EJ, Hunsicker LG, Clarke WR et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. 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.

DM Approximately Doubles CVD Risk in Patients With Hypertension Study Patients With Diabetes Patients Without Diabetes Ratio (events per 1000 pt-yr) SHEP CV events 63.0 36.8 1.71 Stroke 28.8 15.0 1.92 CHD events 32.2 15.2 2.12 Syst-Eur 55.0 28.9 1.90 26.6 12.3 2.16 23.1 12.4 1.87 HOT (DBP <90 mm Hg) 24.0 9.8 2.45 Patients with both hypertension and diabetes are at higher risk for CV events, stroke, and CHD events. In the Systolic Hypertension in the Elderly Program (SHEP) study, 4736 subjects aged 60 years and older with isolated systolic hypertension (ISH), defined as a SBP >160 mm Hg and DBP <90 mm Hg, were randomized to receive placebo or active antihypertensive therapy.1 A total of 583 of the subjects had type 2 diabetes. While all subjects who received active treatment experienced a significant reduction in major CVD events, the overall absolute reduction was twice as high in patients with diabetes compared with their nondiabetic counterparts, reflecting the higher risk associated with diabetes. In the Systolic Hypertension in Europe (Sys-Eur) trial, 2398 elderly patients (age >60 years) with ISH received active treatment beginning with a dihydropyridine calcium antagonist or placebo.2 Major CVD events were more common, nearly double, in patients with diabetes than in those without diabetes. Lastly, in the Hypertension Optimal Treatment (HOT) study,3 18,790 subjects were randomized to 1 of 3 BP goals: <90 mm Hg, <85 mm Hg, and <80 mm Hg. In those in the lowest BP goal group who had diabetes, the risk for major CVD events was reduced by 51% compared with those without diabetes in the highest group. The ADA and NKF recommend a BP goal of <130/80 mm Hg for persons with diabetes to reduce the risk for CVD events.4 1. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA. 1996;276:1886-1892. 2. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999;340:677-684. 3. Hansson L, Zanchetti A, Carruthers SG, et al for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762. 4. American Diabetes Association. Treatment of hypertension in adults with diabetes. Position statement. Diabetes Care. 2002;25(suppl 1):S71-S73. 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.

HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to Lower BP Goal 25 P = .005 20 15 Stroke, MI, or CV Death (per 1000 patient-years) 10 5 In the Hypertension Optimal Treatment (HOT) study, 18,790 patients were randomized to 3 DBP targets: 80, 85, or 90 mm Hg in a 3.8-year study. All patients received a dihydropyridine calcium channel antagonist initially. Approximately 70% also received an ACE inhibitor or ß-blocker, and then a diuretic, as necessary to achieve DBP goal. Active lowering of blood pressure was particularly beneficial in the subgroup of 1501 patients with diabetes mellitus. In the group randomized to the DBP target 80 mm Hg, the risk of a major cardiovascular event* was 51% lower than in the group randomized to the DBP target of 90 mm Hg. *Major cardiovascular events defined as all MIs, all strokes, and all other cardiovascular deaths. Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762. 80 85 90 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.

Reduction in Event Rate for Active Treatment Group (%) 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 Overall Mortality CVD Mortality All CV Events –10 8% P = .55 –20 16% P = .37 Reduction in Event Rate for Active Treatment Group (%) –30 25% P = .02 22% P = .10 –40 36% P = .02 41% P = .09 –50 Patients with hypertension and diabetes can benefit greatly from antihypertensive therapy. In a post hoc analysis of data from the Syst-Eur trial, Tuomilehto and colleagues compared the effects of BP lowering on long-term outcome in patients with and without diabetes. In Syst-Eur, 4695 patients older than 60 years who had SBP of 160-219 mm Hg and DBP <95 mm Hg were randomly assigned to active treatment with the calcium channel blocker (CCB) nitrendipine 10 to 40 mg/day (with the possible addition or substitution of enalapril or hydrochlorothiazide [HCTZ] to attain the study’s SBP goal) or to placebo. Approximately 10% of the population (492 patients) had diabetes at baseline. At 2 years, in the 492 patients with diabetes, the mean SBP and DPB were lower by 8.6 mm Hg and 3.9 mm Hg, respectively, in those receiving active treatment relative to those receiving placebo. These BP levels were comparable to the relative BP reductions in nondiabetic patients: 10.3 mm Hg systolic and 4.5 mm Hg diastolic. As shown in this slide of patients receiving active treatment, risk reductions for all endpoints were greater in the diabetic subgroup. In patients with diabetes, active treatment reduced overall mortality by 41%, cardiovascular disease (CVD) mortality by 70%, all cardiovascular (CV) events combined by 62%, fatal and nonfatal stroke by 69%, and all cardiac events combined by 57%. The reductions in CVD mortality, all CV events, fatal and nonfatal stroke, and fatal and nonfatal cardiac events were significantly greater among those with diabetes than among those without diabetes. Tuomilehto J, Rastenyte D, Birkenhager WH, et al, for the Systolic Hypertension in Europe Trial Investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340:677-684. –60 57% P = .06 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.

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 5% -10 10% 12% -20 Relative Risk Reduction (%) 24% -30 * The results of the UKPDS suggest that reducing BP in patients with hypertension and type 2 diabetes is critical not only for preserving renal function but for reducing total CV risk. In a comparison of tight glucose control vs tight BP control, tight BP control had a relatively greater impact on CV outcomes than did tight blood glucose control.   References: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-713. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):713-720. 32% 32% * -40 37% *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.

Currently Available Antihypertensive Medications: Mechanism of Action Drug Class Mechanism of Action Diuretics Rid the body of excess fluids and sodium through urination May enhance the effect of other BP medications ACEIs Lower levels of angiotensin II Expand blood vessels ARBs Block angiotensin II receptors BBs Decrease heart rate and cardiac output CCBs Interrupt movement of calcium into heart and vessel cells American Heart Association. December 11, 2006. Available at: http://americanheart.org/presenter.jhtml?identifier=159.

The Renin-Angiotensin-Aldosterone System (RAAS) Kininogen Kallikrein Bradykinin Inactive Peptides Nitric Oxide  Angiotensinogen Renin ACEIs Angiotensin I ACE  Angiotensin II  ARBs ARBs ¯ Blood Pressure ¯ Vascular Proliferation ¯ Oxidative Stress ¯ Vascular Inflammation ¯ Thrombogenesis AT1 The renin angiotensin aldosterone system (RAAS) is a series of metabolic pathways that regulates blood pressure and endothelial function. ACEIs and angiotensin receptor blockers (ARBs) both impact the enzymatic cascade that affects blood pressure control. This is accomplished at different points for ACEIs versus ARBs (as observed on the right side of the diagram). ACEIs inhibit the degradation of bradykinin (as observed on the left side of the diagram). Bradykinin stimulates the production of nitric oxide, which acts as a vasodilator. ACE regulates the balance between the vasodilatory and salt-wasting properties of bradykinin and the vasoconstrictive and salt-retentive properties of angiotensin II. Bradykinin promotes vasodilation by stimulating the production of arachidonic acid metabolites, nitric oxide, and endothelium-derived hyperpolarizing factor in vascular endothelium. In the kidney, bradykinin causes natriuresis through direct tubular effects. Ang II is a potent vasoconstrictor, acting directly on vascular smooth muscle cells. In addition, Ang II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular tone. Ang II causes volume expansion through sodium retention (via aldosterone and renal vasoconstriction) and fluid retention (via antidiuretic hormone). Brown NJ, et al. Circulation. 1998;97:1411-1420. Burnier M. Circulation. 2001;103:904-912. Endemann DH. J Am Soc Nephrol. 2004;15(8):1983-1992. 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.

The Renin-Angiotensin-Aldosterone System (RAAS) Kininogen Angiotensinogen Renin Inhibitors Kallikrein Renin  Bradykinin Angiotensin I ACE Inactive Peptides Angiotensin II ARBs ¯ Blood Pressure ¯ Vascular Proliferation ¯ Oxidative Stress ¯ Vascular Inflammation Thrombogenesis AT1 The renin angiotensin aldosterone system (RAAS) is a series of metabolic pathways that regulates blood pressure and endothelial function. ACEIs and angiotensin receptor blockers (ARBs) both impact the enzymatic cascade that affects blood pressure control. This is accomplished at different points for ACEIs versus ARBs (as observed on the right side of the diagram). ACEIs inhibit the degradation of bradykinin (as observed on the left side of the diagram). Bradykinin stimulates the production of nitric oxide, which acts as a vasodilator. ACE regulates the balance between the vasodilatory and salt-wasting properties of bradykinin and the vasoconstrictive and salt-retentive properties of angiotensin II. Bradykinin promotes vasodilation by stimulating the production of arachidonic acid metabolites, nitric oxide, and endothelium-derived hyperpolarizing factor in vascular endothelium. In the kidney, bradykinin causes natriuresis through direct tubular effects. Ang II is a potent vasoconstrictor, acting directly on vascular smooth muscle cells. In addition, Ang II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular tone. Ang II causes volume expansion through sodium retention (via aldosterone and renal vasoconstriction) and fluid retention (via antidiuretic hormone). Brown NJ, et al. Circulation. 1998;97:1411-1420. Burnier M. Circulation. 2001;103:904-912. Endemann DH. J Am Soc Nephrol. 2004;15(8):1983-1992. Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

Valsartan/Amlodipine VALUE: Hazard Ratios for Prespecified Analyses in Patients With Hypertension at High CV Risk Favors Valsartan Favors Amlodipine 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 An analysis of risk ratios for various endpoints reveals that overall cardiac morbidity was not different in the valsartan and amlodipine groups. However, patients receiving valsartan had more heart attacks and strokes.1 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363:2022-2031. 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.

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 Val-HeFT clearly showed the benefits of valsartan in the small subgroup (7%) who were not receiving an angiotensin-converting enzyme inhibitor. In this subgroup, Diovan reduced the risk of achieving the morbidity/mortality endpoint by a dramatic 44% (P<0.001).1 1. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414–1421. 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.

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 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.

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 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.

ACEI Versus Placebo: Effect on MI CONSENSUS II SOLVD-Treatment SOLVD-Prevention Total (95% CL) 1.5 AIRE TRACE 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.

ACEI Trials in CAD Without HF: Primary Outcomes 14 EUROPA: CV Death/MI/Cardiac Arrest HOPE: CV Death/MI/Stroke 20 Placebo 12 Placebo 10 20% Risk Reduction HR = 0.80 (0.71–0.91) P = .0003 15 22% Risk Reduction HR = 0.78 (0.70–0.86) P <.001 8 Percent Ramipril 10 mg 6 10 Percent Perindopril 8 mg 4 5 2 Time (years) Time (years) 1 2 3 4 5 1 2 3 4 PEACE: CV Death/MI/CABG/PCI QUIET: All CV Events 30 50 Quinapril 20 mg Placebo 25 40 4% Risk Increase HR = 1.04 (0.89–1.22) P = .6 4% Risk Reduction HR = 0.96 (0.88–1.06) P = .43 20 Percent 30 Percent 15 Trandolapril 4 mg 20 Placebo 10 10 Key Summary: Four major trials have studied the effect of long-term ACE inhibition in CAD patients with normal LV function. EUROPA: Perindopril 8 mg demonstrated a 20% reduction in the primary outcome (CV death, MI, and cardiac arrest) in relatively low-risk patients. (EUROPA 2003, 784) HOPE: ramipril 10 mg demonstrated a 22% reduction in the primary outcome (CV death, MI, and stroke) in high-risk patients. (Yusuf 2000, page 148) EUROPA and HOPE achieved comparable benefits, even though EUROPA patients were at lower risk and more intensively treated. (20% vs 22%) PEACE: In contrast, trandolapril 4 mg demonstrated a neutral effect on the primary outcome (CV death, MI, and revascularization) in lower-risk patients. (PEACE 2004, page 2062) QUIET: This trial also demonstrated a neutral effect of ACE inhibition on a composite of all major CV outcomes. Quinapril 20 mg was administered to 1750 patients who had undergone coronary angioplasty or atherectomy. Subjects were randomized to treatment or placebo and followed for a mean of 27 months. (Pitt 2001, page 1060) The proposed reasons for the differences among the trial findings include: a low-risk population; the drug or dosage; too brief a study period (QUIET); or underpowered (PEACE) to demonstrate a reduction in MI and CV death. (Pitt 2001, page 1061) (PEACE 2004, page 2063) 5 Time (years) Time (years) 1 2 3 4 5 6 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. 1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788. 2. HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ALTACE® (ramipril), on cardiovascular high-risk patients. N Engl J Med. 2000;342:145-153. 3. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068. 4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACEI therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.

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 20 20 Placebo 25% RRR P = .0004 19% RRR P = .13 15 15 Primary Outcome (%) 10 10 Perindopril 8 mg Ramipril 10 mg 5 5 1 2 3 4 5 1 2 3 4 5 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.

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 Key Take-Aways Ramipril lowered the risk of overt nephropathy in diabetic people who did and did not have baseline microalbuminuria (relative risk reduction 24% [95% CI 3 to 40], P = 0.027).1 (MICRO-HOPE substudy 2000, p.255, Table 3) Treatment with ramipril resulted in a lower albumin/creatinine ratio than placebo at 1 year and at the end of the study.1 (MICRO-HOPE substudy 2000, p.256, Figure 3) If albuminuria is present, patient should be seen by a nephrologist. Additional Background Information 3,577 people with diabetes included in the HOPE study were randomized to ramipril 10 mg/d or placebo and vitamin E or placebo for a median follow-up of 4.5 years.1 (MICRO-HOPE substudy 2000, p.253, Abstract, Methods; p.254, 2nd column, last paragraph) 225 (20%) participants with and 41 (2%) without baseline microalbuminuria developed overt nephropathy (relative risk 14.0 [95% CI 10-19], P<.0001).1 (MICRO-HOPE substudy 2000, p.256, 2nd column, 2nd to last paragraph) Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. 0.0 1 2 3 4-5 Time (y) HOPE Study Investigators. Lancet. 2000;355:253-259.

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

Adherence

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 33.9 48.2 44.3 37.0 40 29.0 35.8 Adults (%) 30 20 Encouraging adherence—and understanding what undermines it—is critical to therapeutic success. 10 5.2 7.3 A1C Level <7% Blood Pressure <130/80 mm Hg Total Cholesterol* <200 mg/dL Achieved All 3 Treatment Goals *LDL-C and TG not evaluated. Saydah SH, et al. JAMA. 2004;291:335-342.

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) There are several steps the health care provider can take to help ensure patient adherence to therapy.1 The cornerstone of any patient–health care provider relationship is communication. There is no substitute for talking to your patient. Discussions should include action items such as the patient’s view on adherence and/or specific adherence patterns, an explanation of the condition, and the reason and importance of specific treatments selected. Goals should include simplifying the therapeutic drug regimen when possible, asking about adherence at every visit, and checking refill dates.1 Patient’s adherence rates may improve if they realize that their provider is interested in when and how they take their medicine and if they refill it on time, thus strengthening the patient-provider relationship. Other studies have shown benefits by involving the patient as a partner and tailoring the medication to meet the patient’s lifestyle and needs, as well as their willingness and desire to change. Another successful approach is to always provide clear written and oral instructions and use behavioral strategies as reminders to take medication. Encouraging a patient support system, such as involving family and/or friends as allies in the treatment process, can also improve adherence.1 Background Motivational interviewing can also be used to improve patient adherence. Motivational interviewing is a patient-centered therapeutic technique designed to increase a patient’s intrinsic motivation for change by exploring what is causing ambivalence to therapy and then resolving these issues. Open questions should be asked rather than a series of questions that will evoke short answers and leave little room for expansion. The four primary principles of motivational interviewing are: 1) express empathy (focus on patients’ awareness of their own thoughts and abilities in an effort to increase confidence in, and reliance on, their own decision-making skills) 2) develop discrepancy (elicit from patients those aspects of his/her life that are important and at odds with current behavioral patterns) 3) roll with resistance (rather than meeting consumer resistance with confrontation, providers are encouraged to utilize reflection in an effort to decrease it whenever possible) 4) support self-efficacy (encouraging patient based on the abilities and resources they possess) Ockene et al, Pg 633, table 1 Ockene et al. Pg. 635, Col. 2, Para. 3, Lines 6-11 & Bullets 1-4; Pg. 636, Col. 1, Bullets 1-3; Pg. 633, Table 1 Ockene et al. Pg. 635, Col. 2, Para. 3, Lines 6-11 & Bullets 1-4; Pg. 636, Col. 1, Bullets 1-3; Pg. 633, Table 1 Squires. P.3, para.1 Ockene IS et al. J Am Coll Cardiol. 2002;40:630-640. Squires. P.12, para.4 Squires. P.9, para.2, Lines 2-4 Squires. P.9, para.4, last line; P.10, first line Squires. P.10, para.3, lines 1-2 Squires. P.11, para.2, lines 4-5 References 1. Ockene IS, Hayman LL, Pasternak RC, Schron E, Dunbar-Jacob J. Task force #4—adherence issues and behavior changes: achieving a long-term solution. J Am Coll Cardiol. 2002;40:630-640. 2. Squires DD, Moyers TB. Motivational interviewing. Available at: http:www.bhrm.org/guideline/motiveint.pdf. Accessed August 31, 2005.

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 Practical approaches to improving adherence include the use of systematic approaches, such as disease management programs1 and regular reviews of medical records.2 In addition, having individuals participate in group appointments with patients with similar medical conditions not only provides social support but also the advantage of patients seeing first-hand how educational approaches have worked for others.3 Other techniques include reminder follow-ups, the implementation of an informal agreement between the health care provider and the patient, and use of self-monitoring tools (eg, pedometer, home testing devices, BP monitors, and scales).3 Patient assistance programs are available to support patients when costs are a barrier to adherence.4 Fonarow et al, Pg 819, Abstract, Col 2, Lines 9-15 NCEP ATP III, p. IX-5, col.2, para.4, lines1-4 Ockene et al. Pg 633, Table 1 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. References 1. Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treatment of coronary heart disease by implementation of a cardiac hospitalization atherosclerosis management program (CHAMP). Am J Cardiol. 2001;87:819-822. 2. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Bethesda, Md: National Heart, Lung, and Blood Institute; September 2002. NIH publication no. 02-5215. 3. Ockene IS, Hayman LL, Pasternak RC, Schron E, Dunbar-Jacob J. Task force #4—adherence issues and behavior changes: achieving a long-term solution. J Am Coll Cardiol. 2002;40:630-640. 4. Pfizer Helpful Answers Web site. Available at http://www.pfizerhelpfulanswers.com.

Case Study

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

? 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!

? 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!

Q & A

PCE Takeaways

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"

? 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!