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A Public Health Concern

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Presentation on theme: "A Public Health Concern"— Presentation transcript:

1 Improving Outcomes in Heart Failure: New Insights From Vascular Biology

2 A Public Health Concern
Heart Failure: A Public Health Concern Heart failure (HF) is a major chronic condition in the United States that is likely to increase in the coming decades. The slides in this section examine current epidemiologic trends in HF.

3 20% Lifetime risk for HF after age 40
Framingham Heart Study Men Women 25 25 Framingham Heart Study investigators determined the lifetime risk (up to age 94 years) for developing overt HF at selected index ages in a 25-year follow-up of a population-based sample of men and women who were free of HF at baseline.1 At age 40 years, the lifetime risk for HF was 21% for men and 20% for women. Remaining lifetime risk did not change with advancing index age because of the rapidly increasing HF incidence rate: at age 80 years, the lifetime risk was 20% for men and 19% for women. Overall, when established clinical criteria are used to define overt HF, the lifetime risk is 20% (or 1 in 5) for both men and women. 20 20 15 15 Cumulative risk (%) 10 10 5 5 40 50 50 60 70 80 90 40 50 50 60 70 80 90 Attained age (years) Lifetime risk for HF for given index age is cumulative through age 94 years Lloyd-Jones DM et al. Circulation. 2002;106: 1. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB, Kannel WB, et al. Lifetime risk for developing congestive heart failure: The Framingham Heart Study. Circulation. 2002;106:

4 Hypertension is the No. 1 risk factor for HF
Framingham Heart Study 60 Hypertension is the most common risk factor for HF. In a population-based sample followed for up to 20 years, investigators for the Framingham Heart Study determined that hypertension antedated the development of HF in 91% of cases.1 Hypertension carried the greatest population-attributable risk for development of HF of all risk factors: 39% in men and 59% in women. The risk for developing HF is ~2 greater in hypertensive men and ~3 greater in hypertensive women compared with normotensive subjects. Overall, hypertension is present in ~60% of men and women with HF. In addition, the risk of HF is ~6 greater in men and women who have had a myocardial infarction (MI). Angina, valvular heart disease, left ventricular (LV) hypertrophy, and diabetes also were predictive of increased risk for HF in both sexes. 40 Population- attributable risk (%) 20 HTN MI Angina VHD LVH Diabetes Hazard ratio M 2.1 6.3 1.4 2.5 2.2 1.8 W 3.3 6.0 1.7 2.8 3.7 Men Women VHD = valvular heart disease Levy D at al. JAMA. 1996;275: 1. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KKL. The progression from hypertension to congestive heart failure. JAMA. 1996;275:

5 Diabetes: A frequent comorbidity with HF
Framingham data show  HF in diabetic adults age 45 to 74 years – 2x  in men; 5x  in women Medicare sample of diabetic adults age ≥65 years (1994–1999): – HF prevalence in 1994: 22.4% – Annual HF incidence: 7.9% – Similar incidence by sex and race – Significant ↑ with age and diabetes-related comorbidities National registry of >100,000 patients hospitalized with HF (mean age 72.4 years) – 44% had diabetes Epidemiologic studies have established that HF is a common condition in people with diabetes.1-3 Framingham Heart Study data show that HF is 2 as common in men with diabetes and 5 as common in women with diabetes than in those without diabetes.1 Among Medicare beneficiaries ≥65 years of age with diabetes sampled in 1994–1999, 22.3% had diabetes at baseline (1994); new cases developed at an annual rate of 7.9%. Rates were similar by sex and race.2 Diabetes is present in 44% of patients hospitalized with HF (mean age, 72.4 years) according to data (as of January 2004) on 105,388 patients in 274 US hospitals included in the Acute Decompensated Heart Failure National Registry. Bell DSH. Diabetes Care. 2003;26: Bertoni AG et al. Diabetes Care. 2004;27: Adams KF et al. Am Heart J. 2005;149: 1. Bell DSH. Heart failure: The frequent, forgotten, and often fatal complication of diabetes. Diabetes Care. 2003;26: Bertoni AG, Hundley WG, Mossing MW, Bonds DE, Burke GI, Goff DC. Heart failure incidence, prevalence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27: Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:

6 Diabetes is the No. 1 risk factor for HF in women with coronary disease
HERS study Diabetes 3.1 Atrial fibrillation Investigators in the Heart and Estrogen/progestin Replacement Study (HERS) evaluated risk factors for developing HF in 2391 postmenopausal women with coronary disease who did not have HF at baseline.1 Of the nine predictors of HF among postmenopausal women with coronary disease, diabetes was the strongest risk factor (adjusted hazard ratio [HR], 3.1; 95% confidence interval [CI], 2.3–4.2). 2.9 Myocardial infarction >1 event 2.5 Creatinine clearance <40 2.3 Systolic BP ≥140 2.1 Current smoking 1.9 BMI >35 1.9 Left bundle branch block 1.6 LV hypertrophy 1.5 0.5 1 1.5 2 2.5 3 3.5 Adjusted hazard ratio Bibbins-Domingo K Jr et al. Circulation.2004;110: 1. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, Shlipak MG. Predictors of heart failure among women with coronary disease. Circulation. 2004;110:

7 Increasing risk for HF in women with CHD: Impact of diabetes, renal insufficiency, obesity
HERS study; 2391 women with CHD and no HF at baseline 14 12.8 The HERS study demonstrated that women with coronary heart disease (CHD) and diabetes who also have an elevated body mass index (BMI) or depressed creatinine clearance were at highest risk for developing HF, with an annual incidence of 7% and 12.8%, respectively.1 Diabetic women with CHD who did not have renal insufficiency and were not obese had a 2.8% annual incidence of HF, which was more than double the rate for women with CHD who were not diabetic. 12 10 Annual HF incidence (%) 8 7.0 6 4 2.8 2 1.2 CHD CHD + DM CHD + DM + BMI >36 CHD + DM + CrCl <42.8 CrCl (ml/min) = creatinine clearance Bibbons-Domingo K et al. Circulation.2004;110: 1. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, Shlipak MG. Predictors of heart failure among women with coronary disease. Circulation. 2004;110:

8 Heart Failure Pathophysiology
HF can be thought of as a state of neurohormonal imbalance in which activity of potentially harmful neurohormonal pathways outweighs that of favorable pathways.1 Slides in this section focus on the neurohormonal model of HF as the pathophysiologic basis of treatment. 1. McMurray J, Pfeffer MA. New therapeutic options in congestive heart failure. Part I. Circulation. 2002;105:

9 Important pathophysiologic mechanisms in HF (1)
Cardiac abnormalities The traditional view that HF is a constellation of signs and symptoms caused by inadequate performance of the heart focuses on only one aspect of the pathophysiology of the HF syndrome. We now recognize that a complex of alterations that affect the heart are important in the progressive nature of HF. This slide summarizes structural and functional cardiac abnormalities that comprise a key aspect of HF pathophysiology.1 The next two slides, respectively, detail the biologic alterations and individual patient factors that contribute to the HF syndrome as it is currently understood. . Structural Functional Myocardium or myocyte Myocardial relaxation Abnormal excitation- contraction coupling -Adrenergic desensitization Hypertrophy Necrosis Fibrosis Apoptosis Left ventricular chamber Remodeling – Dilation – Increased sphericity – Aneurysmal dilatation or wall thinning – Concentric hypertrophy Coronary arteries Obstruction Inflammation Mitral regurgitation Intermittent ischemia or hibernating myocardium Induced arterial and ventricular arrhythmias Altered ventricular interaction Modified from Jessup M, Brozena S. N Engl J Med. 2003;348: 1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:

10 Important pathophysiologic mechanisms in HF (2)
Biologically active tissue and circulating substances The deleterious effects of biologically active tissue and circulatory substances play a major role in HF pathophysiology.1 The neurohormonal model of HF recognized the importance of activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) in the progression of cardiac dysfunction, and led to efforts to antagonize circulating norepinephrine, angiotensin (Ang) II, and aldosterone to slow HF progression. RAAS SNS (norepinephrine) Vasodilators (bradykinin, nitric oxide, prostaglandins) Natriuretic peptides Cytokines (endothelin, tumor necrosis factor, interleukins) Vasopressin Matrix metalloproteinases Jessup M, Brozena S. N Engl J Med. 2003;348: 1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:

11 Important pathophysiologic mechanisms in HF (3)
Patient factors Other individual patient factors can influence the progression of HF; among these factors are genetic background, including sex and ethnicity; age; and use of alcohol, tobacco, or toxic substances. Coexisting conditions—notably hypertension, diabetes, renal disease, coronary artery disease (CAD), anemia, obesity, sleep apnea, and depression—have all been associated with increased HF progression.1 Genetics, ethnicity, sex Age Use of alcohol, tobacco, toxic drugs Coexisting conditions Hypertension Diabetes Renal disease Coronary artery disease Anemia Obesity Sleep apnea Depression Jessup M, Brozena S. N Engl J Med. 2003;348: 1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:

12 Neurohormonal model of HF
Injury to myocytes and extracellular matrix Neurohormonal activation – RAAS, SNS Increased cytokine expression Immune and inflammatory changes Altered fibrinolysis Chronic HF can be thought of as a state of neurohormonal imbalance in which the activity of potentially harmful pathways outweighs that of favorable pathways.1 The pathophysiologic basis of therapy in HF currently involves blunting progression through the use of neurohumoral antagonists that inhibit undesirable pathways, notably the SNS and the RAAS in patients with low LV ejection fraction (LVEF). New peptides, such as endothelins, and other mediators, such as cytokines and free radicals, may also play a role in HF. These pathways, in turn, are now thought to activate pathophysiologic processes, such as apoptosis. Potentially, therapeutic interventions might be targeted not just at inhibiting undesirable pathways, but also at augmenting neurohormonal pathways with potentially favorable actions in HF (eg, natriuretic pathways). Oxidative stress Apoptosis Altered gene expression Energy starvation Ventricular remodeling Electrical, vascular, renal, pulmonary muscle, and other effects Heart failure McMurray J, Pfeffer MA. Circulation. 2002;105: 1. McMurray J, Pfeffer MA. New therapeutic options in congestive heart failure. Part I. Circulation. 2002;105:

13 Diabetes pathogenesis accelerates HF
Activated sympathoadrenal system Activated RAAS Hyperglycemia Alterations in multiple signaling pathways and metabolic processes (including activation of the RAAS and SNS), as well as insulin resistance, hyperglycemia, and dyslipidemia, contribute to the pathogenesis of diabetic cardiomyopathies.1 The high incidence of HF in individuals with diabetes results from an increased number of pathophysiologic activities working in synergy to decrease LV function. Activation of protein kinase C Cardiomyocyte death Cardiac fibrosis Decreased intracellular calcium removal Decreased myocardial contractile strength Systolic dysfunction Diastolic dysfunction Heart failure Kirpichnikov D et al. J Card Fail. 2003;9: 1. Kirpichnikov D, McFarlane SI, Sowers JR. Heart failure in diabetic patients: Utility of -blockade. J Card Fail. 2003;9:

14 RAAS in CV continuum: Pivotal role of AT1 receptors in the failing heart
Angiotensinogen Bradykinin/Kinins Renin Angiotensin I The RAAS plays a pivotal role in cardiovascular (CV) disease. Increasing evidence shows that Ang II is involved in the pathogenesis of atherosclerosis, vascular and myocardial remodeling, and HF. The effects of Ang II are mediated by the Ang II type-1 (AT1) and type-2 (AT2) receptors.1 Most of the known biological effects of Ang II are mediated by activation of the AT1 receptor—which underlies the potential importance of AT1 receptor blockers as protective drugs in nearly all stages of the CV continuum. AT2 receptor stimulation leads to vasodilation and inhibition of vascular smooth muscle growth, but other effects are the subject of ongoing investigation. ACE Degradation Angiotensin II AT1 receptor AT2 receptor B1/B2 receptor NO Reactive oxygen species Pro-inflammatory process Vasoconstriction Cellular growth/proliferation Apoptosis Neurohormonal activation ? Clinical significance Vasodilation Growth inhibition Apoptosis Adapted from Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9. 1. Wassmann S, Nickenig G. The role of the AT1 receptor in the cardiovascular continuum. Eur Heart J Suppl. 2004;6(Suppl H):H3-H9.

15 Primary targets of treatment in HF
• Treatment options for HF patients affect the pathophysiologic mechanisms stimulated in HF.1 This slide summarizes effects of HF therapies on the heart, kidney, and peripheral arteries. • Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease afterload by interfering with the RAAS, resulting in peripheral vasodilation. They also favorably affect LV hypertrophy and remodeling, and renal blood flow. • Aldosterone antagonists counteract the multiple effects of increased aldosterone production in HF (ie, increased sodium retention and potassium excretion, promotion of ventricular and vascular hypertrophy). • Diuretics decrease preload by stimulating natriuresis in the kidney. • Digoxin affects the Na+/K+–ATPase pump in the myocardial cell, increasing contractility; inotropes also increase myocardial contractility. • Beta-blockers inhibit the SNS and adrenergic receptors, slowing heart rate, decreasing blood pressure (BP), and having a direct beneficial effect on the myocardium; they also enhance reverse remodeling. • Vasodilators decrease afterload by counteracting peripheral vasoconstriction. • Cardiac resynchronization therapy with biventricular pacing improves LV function and favors reverse remodeling. • Nesiritide (brain natriuretic peptide) decreases preload and afterload. • Exercise improves peripheral blood flow by eventually counteracting peripheral vasoconstriction. It also improves skeletal muscle physiology. Jessup M, Brozena S. N Engl J Med. 2003;348: 1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:

16 Angiotensin receptor blockade in the CVD continuum
Coronary heart disease ARB Plaque rupture ARB The progression of disease in the CV continuum has its inception with risk factors that induce endothelial dysfunction and initiate atherosclerotic disease in the coronary arteries.1 Plaque rupture and thrombosis leads to coronary artery occlusion and MI, which is followed by remodeling. Finally, HF develops, signaling the endpoint of the continuum. Basic, animal, and human studies have shown that angiotensin receptor blockade may exert protective effects on the CV continuum at various stages of pathologic progression. ARB Atherosclerosis Myocardial infarction Endothelial dysfunction Dilation/ Remodeling ARB ARB Heart failure ARB End-stage heart failure Hypertension Hyperlipidemia Diabetes Risk factors Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9. 1. Wassmann S, Nickenig G. The role of the AT1 receptor in the cardiovascular continuum. Eur Heart J Suppl. 2004;6(Suppl H):H3-H9.

17 This section includes slides on recent clinical trials of beta-blockade and angiotensin receptor blockade in the treatment of HF. This section also contains slides on the use of these evidence-based therapies in special populations where their use continues to be suboptimal.1 Clinical Trial Update 1. Cleland JG, Cohen-Solal A, Aguilar JC, Dietz R, Eastaugh J, Follath F, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): An international survey. Lancet. 2002;360:

18 Survival studies of -blockade in HF
Total mortality Placebo/ -blocker Favors -blocker Patients (N) NYHA class EF mean P CIBIS-II Bisoprolol • These major randomized, placebo-controlled trials studied the effect on survival of beta-blockade added to baseline therapy with ACE inhibition and diuretics in patients with HF. • CIBIS-II: The Cardiac Insufficiency Bisoprolol Study II enrolled 2647 patients with New York Heart Association (NYHA) class III–IV HF who were treated with bisoprolol, a 1-adrenergic receptor blocker.1 • MERIT-HF: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure enrolled 3991 patients with NYHA class II–IV HF who received treatment with metoprolol succinate CR/XL, a 1-adrenergic receptor blocker.2 • COPERNICUS: The Carvedilol Prospective Randomized Cumulative Survival Trial enrolled 2289 patients with NYHA class III–IV HF who received treatment with carvedilol, a 1-, 2-, 1-adrenergic receptor blocker.3 • The individual and pooled results of these studies show that beta-blockade consistently improves survival rates in patients with NYHA class II to class IV HF. 2647 228/156 III/IV 28% 0.0001 MERIT-HF Metoprolol succinate CR/XL 3991 217/145 II-IV 28% COPERNICUS Carvedilol 2289 190/130 III/IV* 20% All pooled 8927 635/431 0.0 0.5 1.0 Relative risk and 95% CI CIBIS-II Investigators. Lancet. 1999;353:9-13. MERIT-HF Study Group. Lancet. 1999;353: Packer M et al. N Engl J Med. 2001;344: *not recorded in COPERNICUS, but placebo mortality indicates III/IV 1. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet. 1999;353:9-13. 2. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353: 3. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:

19 Total # hospitaliz/ patient-yrs
MERIT-HF: Metoprolol succinate CR/XL lowers risk of hospitalization with/without diabetes NYHA III/IV, EF <25% All randomized In MERIT-HF, treatment with metoprolol succinate CR/XL produced highly significant risk reductions in hospitalizations for HF in both diabetic (n = 985) and nondiabetic (n = 3006) patients.1 Hospitalizations for HF were reduced by 37% in the diabetic group and by 35% in the nondiabetic group. In patients with severe HF, treatment with metoprolol succinate CR/XL reduced HF hospitalizations by 53% in the diabetic cohort and by 44% in the nondiabetic group. Diabetes No diabetes Diabetes No diabetes 70 50 50 Total # hospitaliz/ patient-yrs (%) 30 25 25 26 16 13 15 10 9 –37% P = –35% P = –53% P = –44% P = Placebo (n = 490) Metoprolol succinate CR/XL (n = 495) Deedwania PC et al. Am Heart J. 2005;149: 1. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences from MERIT-HF. Am Heart J. 2005;149:

20 MERIT-HF: Benefit of -blockade with/without diabetes
Events (n) Favors metoprolol succinate CR/XL Favors placebo Metoprolol succinate CR/XL All-cause mortality Placebo All patients randomized 217 145 Diabetes 61 50 MERIT-HF demonstrated reductions in all-cause mortality and hospitalizations for worsening HF (time to first event) for all HF patients randomized to metoprolol succinate CR/XL. Further analysis showed benefit in subgroups with and without diabetes.1 Metoprolol succinate CR/XL also improved outcomes in HF patients with and without diabetes who had severe HF (NYHA class III/IV and ejection fraction <25%). Diabetes, severe HF 24 14 No diabetes 156 95 No diabetes, severe HF 48 31 Hospitalization for CHF All patients randomized 294 200 Diabetes 108 72 Diabetes, severe HF 40 20 No diabetes 186 128 No diabetes, severe HF* 64 40 0.0 1.0 Relative risk (95% CI) *Severe HF = NYHA class III/IV, EF<0.25 Deedwania PC et al. Am Heart J. 2005;149: 1. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences from MERIT-HF. Am Heart J. 2005;149:

21 Pooled HF trials: Effect of -blockade on survival in diabetic patients
Total (n) randomized Deaths (n) Placebo/-blockade CIBIS II Diabetes 312 33/27 No diabetes 2335 195/129 Pooled mortality data from three major beta-blocker trials, including CIBIS-II, COPERNICUS, and MERIT-HF, showed similar survival benefits with beta-blockade in patients with or without diabetes.1 Treatment with beta-blockade reduced the risk of death by 25% in patients with diabetes and by 36% in patients without diabetes (data not shown). All 2647 228/156 MERIT-HF Diabetes 985 61/50 No diabetes 3006 156/95 All 3991 217/145 COPERNICUS Diabetes 589 No diabetes 1700 All 2289 190/130 All 3 studies Diabetes 1886 No diabetes 7041 All 8927 635/431 0.0 1.0 1.8 Relative risk (95% CI) Deedwania PC et al. Am Heart J. 2005;149: 1. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences from MERIT-HF. Am Heart J. 2005;149:

22 GEMINI: Design Glycemic Effects in diabetes Mellitus: carvedilol-metoprolol comparison IN hypertensIves study Objective: Compare effects of -blockers with different pharmacologic properties on glycemic and metabolic control in patients with diabetes and hypertension receiving RAAS blockade Participants: 1235 patients Randomized to treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or Metoprolol tartrate 50 mg to 200 mg bid (n = 737) Follow-up: 35 weeks The Glycemic Effects in diabetes Mellitus: carvedilol-metoprolol comparison IN hypertensIves (GEMINI) compared the effects of carvedilol and metoprolol tartrate on glycemic control in patients with hypertension and type 2 diabetes who were receiving RAAS blockade.1 Patients were randomized to receive a 6.25-mg to 25-mg dose of carvedilol or 50-mg to 200-mg dose of metoprolol tartrate, each 2/day, and followed-up for 35 weeks. Bakris GL et al. JAMA. 2004;292: 1. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. JAMA. 2004;292:

23 GEMINI: Change in HbA1c and insulin sensitivity
Metoprolol tartrate Carvedilol % (SD) P HbA1c 0.15 (0.04) <0.001 0.02 (0.04) 0.65 Insulin sensitivity –2.0 0.48 –9.1 0.004 In GEMINI, carvedilol demonstrated better glycemic control compared with metoprolol tartrate. However, the clinical relevance of these differences is unclear, as the study was not powered to show any difference in clinical outcomes.1 A larger trial would be needed to determine whether observed metabolic improvement would translate into clinical benefit. Endpoint (mean ) Bakris GL et al. JAMA. 2004;292: 1. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. JAMA. 2004;292:

24 RESOLVD substudy: Effect of metoprolol succinate CR/XL on glucose and insulin
Randomized Evaluation of Strategies fOr Left Ventricular Dysfunction 247 patients with heart failure Mean LVEF 28% 18% female 26% with diabetes At 17 weeks, patients taking enalapril  candesartan were randomized to – Metoprolol succinate CR/XL ≤200 mg/d* (n = 130) or – Placebo (n = 117) Blood samples analyzed at 17 weeks and after 43 weeks The Randomized Evaluation of Strategies fOr Left Ventricular Dysfunction (RESOLVD) pilot study was a 43-week clinical trial comparing the effect of enalapril, candesartan, and metoprolol succinate CR/XL, alone or in combination, on ventricular remodeling in patients with HF. In Phase 2 of the study (initiated at 17 weeks), patients who were receiving enalapril ± candesartan were randomized to treatment with metoprolol succinate CR/XL or placebo. The two-phase design provided a unique opportunity to evaluate the effects of metoprolol succinate CR/XL on plasma glucose and insulin in patients taking enalapril ± candesartan.1 Plasma glucose and insulin levels were measured at 17 weeks and again at 43 weeks. *Phase 2 regimen Demers C et al. Canadian Cardiovascular Congress; Calgary. 1. Demers C, McKelvie RS, Azad A, Afzal R, Malmberg K, Rouleau JL, et al. Effect of metoprolol CR vs placebo on plasma glucose and insulin levels: Results from the RESOLVD pilot study. Presented at: Canadian Cardiovascular Congress; October , 2004; Calgary.

25 RESOLVD substudy: No effect on glucose and insulin with metoprolol succinate CR/XL
Glucose (mmol/L) Insulin (mmol/L) Insulin (mmol/L) Metoprolol succinate CR/XL 8.26 107 8.31† 108† Placebo 8.28 116 8.38 139 17 weeks* 43 weeks RESOLVD results showed that in patients receiving enalapril ± candesartan, additional treatment with metoprolol succinate CR/XL for ~6 months had no effect on plasma glucose and insulin levels.1 *Phase 2: Start metoprolol succinate CR/XL †P = NS vs placebo Demers C et al. Canadian Cardiovascular Congress; Calgary. 1. Demers C, McKelvie RS, Azad A, Afzal R, Malmberg K, Rouleau JL, et al. Effect of metoprolol CR vs placebo on plasma glucose and insulin levels: Results from the RESOLVD pilot study. Presented at: Canadian Cardiovascular Congress; October 23-27, 2004; Calgary.

26 Implications for -blockade in diabetes and HF
HF is a frequent, often fatal complication of diabetes -Blockers are safe and well tolerated by patients with HF and diabetes -Blockade benefits diabetic patients by decreasing hospitalizations for HF and improving survival It is time to remove existing barriers for use of -blockers in patients with HF and diabetes HF is a frequent complication of diabetes that is associated with a much higher risk of hospitalizations and adverse events.1 Regardless of diabetes status and HF severity, beta-blockade significantly reduces HF hospitalizations and improves survival. It is time to remove existing barriers and to provide beta-blockers to the large number of diabetic patients who would benefit from this therapy.1 Deedwania PC et al. Am Heart J. 2005;149: 1. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences from MERIT-HF. Am Heart J. 2005;149:

27 MERIT-HF: Mortality benefit of -blockade in the elderly
Sudden death All-cause mortality 12 20 Risk reduction 43% Risk reduction 37% Placebo Placebo P = 9 15 P = Metoprolol succinate CR/XL Beta-blockers are underused, particularly in the elderly, who make up 90% of HF cases.1 MERIT-HF studied the effects of treatment in 1982 patients who were ≥65 years of age at randomization.1 This subgroup analysis showed that metoprolol succinate CR/XL reduced total mortality by 37% (P = ), sudden death by 43% (P = ), and death from worsening HF by 61% (P = ). % Patients Metoprolol succinate CR/XL % Patients 6 10 3 5 HF mortality 6 Risk reduction 61% Placebo 3 6 9 12 15 18 3 6 9 12 15 18 Months Months P = 4 % Patients Metoprolol succinate CR/XL 2 3 6 9 12 15 18 Months Deedwania PC et al. Eur Heart J ;25: N = 1982 age ≥65 years 1. Deedwania PC, Gottlieb S, Ghali JK, Waagstein F, Wikstrand JC. Efficacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. Eur Heart J. 2004;25:

28 Meta-analysis: -Blockade improves survival in elderly HF patients
-blocker better Placebo better Hazard ratio COPERNICUS 0.75 (0.58–0.98) A meta-analysis of all-cause mortality data in elderly and non-elderly patients with HF from five major beta-blocker trials showed that elderly HF patients derived considerable benefit from treatment.1 These five trials included >12,000 HF patients, including 4617 patients (36%) who were elderly. Patients classified as elderly ranged in age from 59 years in the Carvedilol US study, to 65 years in COPERNICUS and BEST, and 71 years in CIBIS-II. In MERIT-HF, patients in the upper-age tertile were classified as elderly. The composite data show that elderly patients who received beta-blocker therapy had a significant 24% reduction in total mortality (P = 0.002). There was no significant difference in mortality reduction between elderly and younger patients. The analysis challenges the idea that beta-blocker therapy should be withheld from patients on the basis of age. The findings suggest that all patients with systolic HF should receive beta-blockers, unless absolutely contraindicated or not tolerated by the patient. Carvedilol (U.S.) 0.45 (0.24–0.86) CIBIS-II 0.70 (0.49–0.99) MERIT-HF 0.70 (0.52–0.95) BEST 0.91 (0.78–1.05) Overall 0.76 (0.64–0.90) P = 0.002 –1 1 10 Risk ratio (95% CI) Dulin BR et al. Am J Cardiol.2005;95:896-8. 1. Dulin BR, Haas SJ, Abraham WT, Krum H. Do elderly systolic heart failure patients benefit from beta blockers to the same extent as the non-elderly? Meta-analysis of >12,000 patients in large-scale clinical trials. Am J Cardiol. 2005;95:

29 SENIORS: Design 2128 patients with HF or LVEF ≤35%
Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure 2128 patients with HF or LVEF ≤35% ≥70 years of age (mean, 76 years) Randomly assigned to − Nebivolol titrated to 10 mg once daily over 16-week maximum (n = 1067) − Placebo (n = 1061) Primary outcome: Composite of all-cause mortality or CV hospital admission (time to first event) Follow-up: median 21 months The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure (SENIORS) was a large, randomized trial to assess the effect of the beta-blocker nebivolol in patients ≥70 years, regardless of ejection fraction.1 Investigators randomly assigned patients to nebivolol (titrated from 1.25 mg to 10 mg once daily over 16 weeks) or placebo. The primary outcome was a composite of all-cause mortality or CV hospital admission (time to first event). The mean duration of follow-up was 21 months. Flather MD et al. Eur Heart J. 2005;26: 1. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:

30 SENIORS: Primary and secondary outcomes
All-cause mortality or CV hospital admission (primary outcome) All-cause mortality (main secondary outcome) 100 100 HR 0.88 (0.71–1.08) P = 0.214 The SENIORS study shows that treating elderly HF patients with nebivolol reduced the composite risk of all-cause mortality or CV hospitalization compared with placebo.1 The beneficial effects appeared after 6 months, and the risk reduction continued to increase with longer treatment. Although the 0.86 hazard ratio for the primary outcome suggests a lesser degree of risk reduction compared with previous large trials, both components of the primary outcome show a similar and consistent effect, with a 15% proportional and a 4% absolute reduction in risk. . 90 90 HR 0.86 (0.74–0.99) P = 0.039 Nebivolol Event- free survival (%) 80 80 70 Nebivolol Placebo 70 60 60 Placebo 50 50 6 12 18 24 30 6 12 18 24 30 Time (months) Time (months) No. of events: 169 (15.8%) (18.1%) Nebivolol (31.1%) Placebo (35.3%) HR = hazard ratio Flather MD et al. Eur Heart J. 2005;26: 1. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:

31 SENIORS: Clinical relevance
Confirms data indicating -blockade benefits elderly HF patients Extends evidence for benefit of -blockade to a broad range of elderly patients (age >70 years) with HF, including those with mild or preserved LV function As in previous large trials, both all-cause mortality and CV hospital admissions show a similar and consistent effect with -blockade The SENIORS study confirms and extends the evidence that beta-blockade is beneficial to a broad range of elderly patients with HF, including those with mild LV dysfunction or preserved ventricular function.1 Patients in the SENIORS study more closely resemble HF patients in the general population, where the mean age is 76 years. As has been the case in previous trials of beta-blocker therapy in HF patients, all-cause mortality and hospital admissions for CV causes show similar and consistent benefits from treatment. Flather MD et al. Eur Heart J. 2005;26: 1. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:

32 Benefit of -blockade on mortality in urban patients with HF
N = 551; 62% African American, 20% White, 15% Hispanic NYHA class III/IV HF: No -blocker group 60%; -blocker group 45% 20 This impact of beta-blocker therapy in urban patients with HF was examined in a retrospective chart review of 551 consecutive patients with systolic dysfunction referred to a HF clinic in an urban public hospital.1 In the group, 62% were African American, 20% were white, and 15% were Hispanic. The majority of patients were male (59%) and >75% had severe LV dysfunction. The group that did not receive beta-blockers had a larger proportion with NYHA class III or IV HF than the group receiving beta-blockers (60% vs 45%, P = 0.002). Approximately two thirds of the patients tolerated beta-blockade (as assessed by the need to permanently discontinue therapy). Patients who did not receive beta-blocker therapy had significantly higher 1-year mortality than those who did receive beta-blockers (17% vs 4%, P < 0.001); they also had higher 1-year hospitalization rates (29% vs 16%, P = 0.004). 17% No -blockers Death at 1 year (%) 10 P < 0.001 4% -blockers 6 12 Months No -blocker -blocker Estep JD et al. Am Heart J. 2004;148: 1. Estep JD, Mehta SK, Uddin F, King K, Toto KH, Nelson LL, et al. -Blocker therapy in patients with heart failure in an urban setting: Moving beyond clinical trials. Am Heart J. 2004;148:

33 Not all -blockers are the same
Generic name Brand name* AB-rated generic equiv available Properties Dose for HF Atenolol Tenormin 1 selective Yes Not FDA- approved for HF Bisoprolol Zebeta N/A Not FDA- approved for HF Metoprolol tartrate Lopressor or generic Metoprolol succinate CR/XL TOPROL-XL No 200 mg qd Carvedilol Coreg Non-selective (1, 1, 2) 25 mg bid† Labetalol Normodyne Non-selective (1, 1, 2) There are six beta-blockers that are available for prescription, of which only two have received FDA approval for the treatment of patients with HF.1-6 Metoprolol (metoprolol tartrate and metoprolol succinate CR/XL), atenolol, and bisoprolol are selective for 1-adrenergic receptors. Carvedilol and labetalol are non-selective, blocking 1-, 1-, and 2-receptors. The only beta-blockers that are currently approved by the FDA for treatment of HF are metoprolol succinate CR/XL and carvedilol. †COPERNICUS; other trials 50 mg bid for >75 kg * see prescribing information 1. Tenormin [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2000. 2. Zebeta [package insert]. Pearl River, NY: Lederle Pharmaceutical Division, American Cyanamid Co; 1999. 3. Lopressor [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2003. 4. TOPROL-XL [package insert]. Wilmington, DE: AstraZeneca LP; 2002. 5. Coreg [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2003. 6. Normodyne [package insert]. Kenilworth, NJ: Key Pharmaceuticals Inc; 1994.

34 Metoprolol tartrate 50 mg
Metoprolol tartrate vs metoprolol succinate CR/XL: Significant pharmacokinetic differences Three-way crossover in patients with HF; N = 15 300 Metoprolol succinate CR/XL 200 mg x 1 The pharmacokinetics of metoprolol tartrate 3 daily were compared with once-daily doses of metoprolol succinate CR/XL.1 Patients with HF (N = 15) were randomized in an open 3-way crossover study in which each study period lasted 7 days. The doses in each period were: metoprolol tartrate 50 mg 3 daily or metoprolol succinate CR/XL 100 mg or 200 mg once daily. On day 7, blood samples for assay of metoprolol in plasma were drawn immediately before intake of the morning tablet and at various time points thereafter to 24 hours. The median peak plasma concentration of metoprolol succinate CR/XL 200 mg (263 nmol/L) was similar to that of metoprolol tartrate 50 mg (285 nmol/L). Metoprolol succinate CR/XL 100 mg gave a lower median peak plasma concentration. Comparison of the curves for metoprolol succinate CR/XL 200 mg and metoprolol tartrate 50 mg shows that plasma levels of metoprolol succinate CR/XL exhibit less variation than those of metoprolol tartrate over a 24-hour dosing interval.1 The data also suggest that there is an increased risk of suboptimal beta-blockade if a dose of metoprolol tartrate 50 mg is missed or only taken 2 daily. 200 Plasma concentration (mmol/L) Metoprolol tartrate 50 mg x 3 100 Metoprolol succinate CR/XL 100 mg x 1 08 14 22 08 Time (h) Metoprolol succinate CR/XL 100 mg Metoprolol succinate CR/XL 200 mg Metoprolol tartrate 50 mg Metoprolol tartrate 50 mg Andersson B et al. J Card Fail. 2001;7:311-7. 1. Andersson B, Åberg J, Lindelöw B, Täng MS, Wikstrand J. Dose-related effects of metoprolol on heart rate and pharmacokinetics in heart failure. J Card Fail. 2001;7:

35 Effect of metoprolol succinate CR/XL vs atenolol on exercise heart rate/SBP over 24 h
N = 10 healthy men Systolic BP Exercise heart rate Metoprolol succinate CR/XL, atenolol, and placebo were administrated on successive days to 10 healthy men to compare their pharmacokinetic and pharmacodynamic properties.1 Plasma concentration-time profiles were more even with metoprolol succinate CR/XL than with atenolol over the 24-h dose interval. Reductions in both exercise heart rate and systolic BP over the 24-h period were more even with metoprolol succinate CR/XL than with atenolol. 160 190 Placebo Placebo 180 140 Mean exercise SBP (mm Hg) Mean exercise heart rate (bpm) 170 Atenolol 50 mg 120 Atenolol 50 mg 160 Metoprolol succinate CR/XL 100 mg Metoprolol succinate CR/XL 100 mg 100 150 2 4 8 12 24 2 4 8 12 24 Time (hours) Time (hours) Blomqvist I et al. Eur J Clin Pharmacol. 1988;33(suppl):S19-24. 1. Blomqvist I, Westergren G, Sandberg A, Jonsson UE, Lundborg P. Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: A comparison with atenolol. Eur J Clin Pharmacol. 1988;33(Suppl):S19-S24.

36 Recommended ACEI doses do not completely halt Ang II formation in HF
42 HF patients on 40 mg long-acting ACEI (fosinopril, lisinopril, enalapril) or captopril 150 mg The added benefits of ARBs in patients receiving ACE inhibitors (ACEI) suggests that recommended doses provide only partial suppression of ACE in chronic HF patients. This phenomenon has been termed “angiotensin escape.” Jorde and coworkers evaluated BP responses to doses of Ang I that were administered before and after valsartan in 42 HF patients who were receiving maximally recommended doses of an ACE inhibitor.1 Before valsartan, radial artery systolic pressure increased linearly with increasing doses of Ang I despite treatment with an ACE inhibitor, which indicates persistent Ang II formation. The BP response to Ang I was blunted significantly by valsartan—providing further evidence of persistent Ang II formation. In patients who had their ACE inhibitor dose doubled, the response to Ang I was no longer different from that noted after valsartan (data not shown). The therapeutic implications of ACE escape include evaluation of higher-than-standard doses of ACEI and routine addition of ARB to ACE inhibitors in patients with severe HF.2 25 * 20 ACEI Radial artery systolic pressure (mm Hg) * 15 10 ACEI + valsartan 5 10 100 200 Angiotensin I (ng/Kg) *P < 0.05 vs after valsartan †P < 0.05 vs 10 ng/kg Ang I Jorde UP et al. Circulation. 2000;101:844-6. 1. Jorde UP, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, et al. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation. 2000;101: 2. Ennezat PV, Berlowitz M, Sonnenblick RH, Le Jemtel TH. Therapeutic implications of escape from angiotensin-converting enzyme inhibition in patients with severe chronic heart failure. Curr Cardiol Rep. 2000;2:

37 CHARM Program: 3 Component trials comparing candesartan with placebo
Target dose, candesartan 32 mg Primary outcome: CV death or CHF hospitalization Overall trial: All-cause death • The CHARM Program (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) included three parallel, independent, randomized, double-blind comparisons of the ARB candesartan versus placebo.1 • Three distinct groups with symptomatic HF (NYHA class II–IV) were studied: – CHARM-Alternative: patients with LVEF ≤40% not receiving ACE inhibitors due to intolerance (n = 2028).2 – CHARM-Added: patients with LVEF ≤40% receiving ACE inhibitors (n = 2548).3 – CHARM-Preserved: patients with LVEF >40% (n = 3023), treated or not treated with ACE inhibitors.4 • The primary outcome for each component trial2–4 was CV death or HF hospitalization, and all-cause death in CHARM-Overall.1 CHARM- Alternative CHARM- Added CHARM- Preserved n = 2028 LVEF ≤40% ACE inhibitor intolerant n = 2548 LVEF ≤40% ACE inhibitor treated n = 3023 LVEF >40% ACE inhibitor treated/not treated 1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362: 2. Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet. 2003;362: 3. McMurray JJV, Östergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet. 2003;362: 4. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved trial. Lancet. 2003;362: Median follow-up, 37 months Pfeffer MA et al. Lancet. 2003;362: Granger CB et al. Lancet. 2003;362:772-6. McMurray JJV et al. Lancet. 2003;362: Yusuf S et al. Lancet. 2003;362:

38 CHARM Program: Reduction in mortality and morbidity
CV death or HF hospitalization All-cause mortality • There was no significant heterogeneity across the three trials in the impact of candesartan on either all-cause mortality or CV death or HF hospitalization (interaction test P = 0.37 and P = 0.33, respectively). • The adjusted reduction in all-cause mortality for CHARM-Overall was 10% (HR, 0.90; 95% CI, 0.82–0.99; P = 0.032). • The adjusted reductions in CV death or HF hospitalization were (data not shown)1-4: – CHARM-Alternative: 30% (P = ) – CHARM-Added: 15% (P = 0.010) – CHARM-Preserved: 14% (P = 0.051) – CHARM-Overall: 18% (P < ) Alternative (LVEF ≤40%; ACEI intolerant) Added (LVEF ≤40%; ACEI treated) Preserved (LVEF >40%; ACEI treated/ not treated) Overall 0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362: 2. Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet. 2003;362: 3. McMurray JJV, Östergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet. 2003;362: 4. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved trial. Lancet. 2003;362: Adjusted hazard ratio P heterogeneity = 0.37 Adjusted hazard ratio P heterogeneity = 0.33 Pfeffer MA et al. Lancet. 2003;362:

39 CHARM-Overall: CV death and non-CV death—Secondary endpoints
35 13% Relative risk reduction (95% CI 4%–22%) P = 0.006 25 • In CHARM-Overall, candesartan reduced the rate of CV death, a secondary endpoint, compared with placebo (unadjusted HR, 0.88; 95% CI, 0.79–0.97; P = 0.012; adjusted HR, 0.87; P = 0.006).1 • The treatment difference in CV death was striking in the first year and was maintained without additional divergence in subsequent years. • The rate of non-CV death was not affected by candesartan treatment compared with placebo (P = 0.45). CV death 20 % Patients 15 10 Non-CV death 5 P = 0.45 Years 0.0 1.0 2.0 3.0 3.5 Number at risk Candesartan Placebo Pfeffer MA et al. Lancet. 2003;362: 1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362:

40 CHARM-Overall: Reduction in mortality and nonfatal MI with candesartan
Events (n) Placebo/candesartan Risk reduction P Sudden death 344/299 15% 0.036 Patients with HF are at increased risk of sudden death and death attributed to progressive pump failure. In CHARM, candesartan reduced sudden death and death from worsening HF in patients with symptomatic HF, although this reduction was most apparent in patients with LVEF ≥40%.1 The occurrence of both nonfatal MI and the combined outcome of nonfatal MI and CV death were significantly reduced with candesartan.2 The effect of candesartan was similar with or without concomitant use of ACE inhibition. HF death 260/209 22% 0.008 CV death 769/691 12% 0.012 Nonfatal MI 148/116 23% 0.032 Nonfatal MI/CV death 868/775 21% 0.004 All deaths 945/886 9% 0.055 0.5 0.6 0.7 8.0 9.0 1.0 0.5 Solomon SD et al. Circulation. 2004;110: Demers C et al. Circulation. 2004;110(suppl):Abstract. 1. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJ, et al. Effect of candesartan on cause-specific mortality in heart failure patients: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2004;110: Demers C, McMurray JJV, Swedberg K, McKelvie RS, Olofsson B, Östergren J, et al. Impact of candesartan in preventing myocardial infarction: Results of the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity (CHARM) Programme. Circulation. 2004;110(suppl III)III-514.

41 CHARM—Low LVEF trials: Risk reductions at 1 and 2 years with candesartan
CV death/HF hospitalization All-cause mortality The low LVEF trials in the CHARM Program demonstrate the effects of candesartan versus placebo in 4576 patients with HF and LVEF ≤40% who participated in either CHARM-Alternative (participants who could not tolerate ACE inhibition) or CHARM-Added (participants already treated with an ACE inhibitor).1 The analysis demonstrates that adding candesartan to standard treatment (an ACE inhibitor, beta-blocker, aldosterone antagonist; or even all three) in HF patients with LVEF ≤40% decreases the risk of: – CV death – Admission to the hospital for worsening HF – All-cause mortality The benefits of candesartan were evident early, including a 33% reduction in all-cause mortality and a 30% reduction in CV death and hospitalizations for HF at 1 year. The results provide additional findings that support a wider use of ARBs (specifically, candesartan) in HF. 10 20 20 % Reduction 23 P = 0.001 P < 0.001 30 30 P < 0.001 33 1 year P = 0.001 40 2 years 50 Young JB et al. Circulation. 2004;110: 1. Young JB, Dunlap ME, Pfeffer MA, Probstfield JL, Cohen-Solal A, Dietz R, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: Results of the CHARM low-left ventricular ejection fraction trials. Circulation.2004;110:

42 CHARM Program: Outcomes overview
Candesartan vs placebo Parameter CHARM Added CHARM Alternative CHARM Preserved CHARM Overall Follow-up (months) 41 34 37 38 CV deaths (%) 23.7 vs 27.3* 21.6 vs 24.8 11.2 vs 11.3 18.2 vs 20.3* HF hospitalization (%) 24.2 vs 28* 20.4 vs 28.2* 15.9* vs 18.3 19.9 vs 24.2* Combined endpoint (%) 37.9 vs 42.3* 33 vs 40* 22 vs 24.3 30.2 vs 34.5* NNT/year to prevent 1 CV death/HF hospitalization 85 40 132 73 This slide provides an overview of the outcomes of the CHARM Program, comparing the effects of candesartan with placebo in each of the studies.1 The CHARM program results suggest that ARBs can be a meaningful replacement therapy in cases of ACE inhibition intolerance. In the CHARM-Added trial, the addition of candesartan improved prognosis substantially in patients already on an ACE inhibitor.1 The CHARM Program showed that in patients with HF and LV dysfunction, the addition of candesartan has the potential for a major therapeutic impact. *statistically significant Gleiter CH et al. Cardiovasc Drug Rev. 2004;22: 1. Gleiter CH, Jagle C, Gresser U, Morike K. Candesartan. Cardiovasc Drug Rev ;22:

43 CHARM-Overall: Reduction in new-onset diabetes
Candesartan n/N Placebo Hazard ratio (95% CI) P 163/2715 (6%) 202/2721 (7.4%) 0.78 (0.64–0.96) 0.02 In CHARM-Overall, the number of new cases of diabetes was significantly lower in the candesartan group (6%) compared with placebo (7.4%) (HR, 0.78; 95% CI, 0.64–0.96; P = 0.02).1 This confirms findings of other large clinical trials with ACE inhibitors and ARBs that have demonstrated a reduction in new-onset diabetes. n = new-onset diabetes N = total patients Pfeffer MA et al. Lancet. 2003;362: 1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362:

44 VALIANT: Design 14,800 patients with acute MI + HF/LV dysfunction
Receiving conventional therapy Randomly assigned (0.5 days to 10 days after acute MI) – Valsartan 160 mg bid (n = 4909) – Valsartan 80 mg bid + captopril 25 mg tid (n = 4885) – Captopril 50 mg tid (n = 4909) Primary outcome: death from any cause Follow-up: median 24.7 months • The VALsartan In Acute myocardial iNfarction Trial (VALIANT) enrolled 14,800 patients with acute MI complicated by LV dysfunction, HF, or both.1 • Patients were permitted to have received conventional therapy with ACE inhibitors or ARBs. • The study population was randomized (0.5 days to 10 days after acute MI) to treatment with: – Valsartan 160 mg 2 daily (n = 4909) – Valsartan 80 mg 2 daily + captopril 25 mg 3 daily (n = 4885) – Captopril 50 mg 3 daily (n = 4909) • Medications were uptitrated to the study dosage in four steps. • The primary outcome was death from any cause, and the median follow-up was 24.7 months. Pfeffer MA et al. N Engl J Med. 2003;349: 1. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau J-L, Køber L, Maggioni AP, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:

45 VALIANT: Treatments show similar effect on outcome
Death from any cause Combined CV endpoint* 0.4 0.4 • The rate of all-cause death (primary outcome) in the VALIANT trial was similar in the treatment groups1: – Valsartan versus captopril, P = 0.98 – Valsartan/captopril versus captopril, P = 0.73 • The combined endpoint of CV death, reinfarction, or hospitalization for HF (a secondary outcome) was also similar: – Valsartan versus captopril, P = 0.20 – Valsartan/captopril versus captopril, P = 0.37 0.3 0.3 Probability of event 0.2 0.2 0.1 0.1 0.0 0.0 6 12 18 24 30 36 6 12 18 24 30 36 Months Months *CV death, reinfarction, or hospitalization for HF Valsartan Valsartan/captopril Captopril Pfeffer MA et al. N Engl J Med. 2003;349: 1. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau J-L, Køber L, Maggioni AP, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:

46 VALIANT: Poorer 1-year outcomes in patients with new-onset or previous diabetes
All-cause mortality Adverse CV events 0.4 0.4 Previous DM The VALIANT investigators studied the impact of diabetes on prognosis in high-risk patients with acute MI and LV dysfunction or HF.1 Diabetes was present at baseline in 3400 patients (23%); diabetes was newly diagnosed in 580 patients (4%) shortly after MI; 10,719 patients did not have diabetes. Despite similarities in characteristics between patients with newly diagnosed diabetes and those without diabetes, the rate of death was greater in patients with newly diagnosed diabetes and was similar to the rate in patients with previous diabetes. Patients with previously known diabetes and those with newly diagnosed diabetes also had higher rates of the composite CV outcome than those without diabetes. Adverse CV events include CV death, reinfarction, HF, resuscitated sudden death, and stroke. Diabetes, whether previously known or newly diagnosed, is associated with poorer long-term outcomes after MI than in patients without diabetes. 0.3 0.3 New DM Probability of event 0.2 0.2 Previous DM No DM New DM 0.1 0.1 No DM 0.0 0.0 3 6 9 12 3 6 9 12 Months Months P = 0.43 P < 0.001 Previous vs new diabetes diagnosis Previous vs no diabetes New vs no diabetes diagnosis P < 0.005 P < 0.001 Aguilar D et al. Circulation. 2004;110: 1. Aguilar D, Solomon SD, Køber L, Rouleau J-L, Skali H, McMurray JJV, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation. 2004;110:

47 Clinical implications of CHARM and VALIANT
In HF patients and in patients with acute MI and LV dysfunction, evidence supports – ARBs as alternative to ACEIs (in ACEI–intolerant patients) – Benefit from addition of ARBs to ACEI-based regimens ARBs and ACEIs similarly reduce all-cause mortality and HF hospitalizations in patients with HF or high-risk MI Discharge prescription of ACEI or ARB meets new Medicare/Medicaid quality performance measures for HF/MI with LV dysfunction In HF patients with acute MI and LV dysfunction, evidence supports: – ARBs as an alternative in patients intolerant to ACE inhibitors – Adding ARBs to treatment in patients who are already receiving an ACE inhibitor. ACE inhibitors and ARBs similarly reduce all-cause mortality and HF hospitalizations in patients with HF or high-risk MI.1 Prescribing of either an ACE inhibitor or an ARB at discharge now (as of January 1, 2005) meets quality performance measures for HF and acute MI as defined by the Centers for Medicare and Medicaid Services (CMS) and Joint Commission on Accreditation of Healthcare Organizations (JCAHO).2,3 Lee VC et al. Ann Intern Med. 2004;141: McClellen MB et al. Ann Intern Med. 2005;142:386-7. ACC/AHA. 1. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: Angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med. 2004;141: 2. McClellan MB, Loeb JM, Clancy CM, Francis GS, Jacobs AK, Kizer KW, et al. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in chronic heart failure. Ann Intern Med. 2005;142: 3. ACC, AHA, Physician Consortium for Performance Improvement. Clinical Performance Measures: Tools Developed by Physicians for Physicians. Available at: Accessed April 28, 2005.

48 Benefit of ARB + ACE inhibitor in HF
HF hospitalization All-cause mortality ARB+ ACEI better ACEI alone better ARB+ ACEI better ACEI alone better The CHARM and VALIANT studies have substantially increased our knowledge on the role of ARBs in patients with HF and post-MI LV dysfunction.1 Results from both studies support previous findings that ARBs are a good alternative to ACE inhibitors in the minority of patients who cannot tolerate ACE inhibitors, both after acute MI and in HF. ARBs consistently reduced HF hospitalizations in CHARM and VALIANT, as was also shown in Val-HeFT. Whereas no effect on all-cause mortality was demonstrated in either Val-HeFT or VALIANT, a reduction in CV mortality was shown in CHARM.1 CHARM (HF) VALIANT (post MI + HF/LV dysfunction) Val-HeFT (HF) 0.6 0.8 1.0 1.2 1.4 0.6 0.8 1.0 1.2 1.4 Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8. 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:

49 ARBs in LV dysfunction: Before/after CHARM and VALIANT
Before CHARM, VALIANT After CHARM, VALIANT ARBs superior to ACEI? No (ELITE II, OPTIMAAL) No ARBs non-inferior to ACEI? ? (ELITE II, OPTIMAAL) Yes ARBs additive on top of ACEI? ? (Val-HeFT) Yes, HF No, post-MI Combination ARB, ACEI, and -blocker dangerous? ? (ELITE II, Val-HeFT) This slide summarizes questions and answers before and after the CHARM and VALIANT studies about the role of ARBs in patients with LV dysfunction.1 ARBs superior to ACE inhibitors? There is no evidence that ARBs are superior to ACE inhibitors, either in acute MI or HF; however when adequately dosed, ARBs may be equivalent to ACE inhibitors. ARBs non-inferior to ACE inhibitors? It is now well established that an ARB is a good alternative for the ACE inhibitor, both in CHF and in acute MI with signs of HF or LV dysfunction. ARBs additive on top of ACE inhibitors? VALIANT showed that in patients with acute MI, adding an ARB to an adequate-dose ACE inhibitor has no benefit. In contrast, CHARM showed that in patients with chronic HF, adding an ARB to an ACE inhibitor (and a beta-blocker) might reduce CV mortality. Moreover, a reduction in HF hospitalizations can be anticipated in both HF and after acute MI. Is the combination of ARB, ACE inhibitor, and beta-blocker dangerous? No, it is not. However, the benefits of triple therapy might be less pronounced following adequate and high doses of both the ACE inhibitor and beta-blocker. Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8. 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:

50 Difference in target dosing among ARB trials
Patients Study drug Outcome CHARM Overall HF LVEF ≤40% LVEF >40% Candesartan 32 mg qd vs Placebo 10%  mortality 13%  CV death 23%  HF hosp ELITE II ≥ 60 years Losartan 50 mg qd vs Captopril 50 mg tid Similar  morbidity/mortality OPTIMAAL Post-MI + HF Mortality trend favors captopril No difference in morbidity Val-HeFT Valsartan 160 mg bid vs Placebo + conventional HF Rx No  mortality 13.2%  morbidity/mortality 28%  HF hosp VALIANT Acute MI + HF/LV dysfunction Valsartan 160 mg bid or Captopril 50 mg tid or Valsartan 80 mg bid + captopril 50 mg tid Similar  mortality/morbidity No added benefit with ACEI+ARB • ARB trials demonstrate the importance of dose to achieve optimal benefits from therapies that modulate the RAAS. • CHARM1: The target dose of candesartan (32 mg qd) reduced mortality, CV death, and hospitalization in HF patients with or without LV systolic dysfunction. • ELITE II2 and OPTIMAAL3: Losartan 50 mg qd versus captopril 50 mg tid showed trends in favor of the ACE inhibitor. It is argued that the losartan dose was suboptimal.4 • Val-HeFT5: 93% of patients were taking ACE inhibitors, but doses were suboptimal. Although there was no mortality reduction, valsartan 60 mg bid showed benefits in combined morbidity/mortality and HF hospitalization. • VALIANT6: Valsartan 160 mg bid, captopril 60 mg tid, or valsartan 80 mg bid + captopril 50 mg tid resulted in similar reductions in mortality/morbidity, with no additional benefit from an ACE inhibitor plus an ARB. 1. Pfeffer MA, Swedberg K, Granger CB, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362: 2. Pitt B, Poole-Wilson PA, Segal R, et al, on behalf of the ELITE II Investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355: 3. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomised trial. Lancet. 2002;360: 4. Mann DL, Deswal A. Angiotensin-receptor blockade in acute myocardial infarction–A matter of dose. N Engl J Med. 2003;349: 5. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345: 6. Pfeffer MA, McMurray JJV, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349: Pfeffer MA et al. Lancet. 2003;362: Pitt B et al. Lancet. 2000;355: Dickstein K et al. Lancet. 2002;360: Cohn JN et al. N Engl J Med. 2001;345: Pfeffer MA et al. N Engl J Med. 2003;349:

51 Impact of RAAS modulation on mortality in HF patients with renal insufficiency
Minnesota Heart Survey Post-discharge mortality (mean follow-up 15 mo) ACEI/ARB Rx at discharge Berger et al tested the hypothesis that the survival benefit of RAAS modulation among patients with HF is greatest for those with severe renal insufficiency.1 The study used data from the Minnesota Heart Survey database, which retrospectively sampled medical records of 4926 patients who were hospitalized with HF in 2000 in the Minneapolis/St Paul metropolitan area. Patients were stratified into four categories of renal impairment; post-discharge mortality (mean follow-up, 15 months) was assessed according to renal function and use of ACE inhibitors/ARBs. The discharge prescribing rate for ACE inhibitors/ARBs was lowest (48%) in patients with more severe renal dysfunction. Nevertheless, the results show that RAAS modulation provided a survival benefit, particularly among patients with moderately impaired renal function. 7 P = 0.17 6 80 68 64 63 5 60 Odds ratio (95% CI) 48 4 P = 0.002 % 40 3 P = 0.04 P = 0.65 20 2 1 ≥90 60–89 30–59 <30 ≥90 60–89 30–59 <30 GFR (mL/min) GFR (mL/min) No ACEI/ARB at discharge ACEI and/or ARB at discharge 4926 patients hospitalized with HF Berger AK et al. Circulation. 2004;110 (suppl III):III-749. 1. Berger AK, Duval SJ, Barber CA, Luepker RV. ACE inhibitors and angiotensin receptor blockers in patients with renal insufficiency and congestive heart failure: An interesting paradox. Circulation. 2004;110(Suppl III):III-749.

52 Physicians are now challenged to incorporate evidence-based information from major clinical trials into rational treatment plans for patients with HF and LV dysfunction.1 Summary 1. McMurray JJV, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation. 2004;110:

53 ACC/AHA stages of systolic HF and treatment options
Current ACC/AHA chronic HF guidelines emphasize that each stage of HF is associated with unique options for treatment.1,2 Stage A: Treatment should include risk-factor reduction and patient and family education. Hypertension, dyslipidemia, and diabetes should be targeted, and ACE inhibitors or ARBs are also recommended in appropriate patients. Stage B: ACE inhibitors or ARBs are recommended in all patients; -blockers are recommended in appropriate patients. Stage C: All patients should receive ACE inhibitors and -blockers. Other treatments may include dietary sodium restriction, diuretics, and digoxin. – Additional options in appropriate patients include cardiac resynchronization (if bundle-branch block is present), revascularization and mitral-valve surgery, and aldosterone antagonists and nesiritide. – A multidisciplinary team approach may be useful. Stage D: Refractory symptoms require special interventions, which may include inotropes, ventricular assist device (VAD), heart transplantation, and hospice care. *In appropriate patients Jessup M, Brozena S. N Engl J Med. 2003;348: 1. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38: 2. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:


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