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Improving Outcomes in Heart Failure: New Insights From Vascular Biology

Improving Outcomes in Heart Failure: New Insights From Vascular Biology. Heart Failure: A Public Health Concern. 20% Lifetime risk for HF after age 40. Framingham Heart Study. Men. Women. 25. 25. 20. 20. 15. 15. Cumulative risk (%). 10. 10. 5. 5. 0. 0. 0. 40. 50. 50. 60.

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Improving Outcomes in Heart Failure: New Insights From Vascular Biology

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

  2. Heart Failure: A Public Health Concern

  3. 20% Lifetime risk for HF after age 40 Framingham Heart Study Men Women 25 25 20 20 15 15 Cumulative risk (%) 10 10 5 5 0 0 0 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;106:3068-72.

  4. Hypertension is the No. 1 risk factor for HF Framingham Heart Study 60 40 Population-attributable risk (%) 20 0 HTN MI Angina VHD LVH Diabetes Men Women VHD = valvular heart disease Levy D at al. JAMA. 1996;275:1557-62.

  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 Bell DSH. Diabetes Care. 2003;26:2433-41. Bertoni AG et al. Diabetes Care. 2004;27:699-703. Adams KF et al. Am Heart J. 2005;149:209-16.

  6. Diabetes is the No. 1 risk factor for HF in women with coronary disease HERS study Diabetes 3.1 Atrial fibrillation 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 0.5 1 1.5 2 2.5 3 3.5 Adjusted hazard ratio Bibbins-Domingo K Jr et al. Circulation.2004;110:1424-30.

  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 12 10 Annual HF incidence (%) 8 7.0 6 4 2.8 2 1.2 0 CHD CHD + DM CHD + DM + BMI >36 CHD + DM + CrCl <42.8 CrCl (ml/min) = creatinine clearance Bibbons-Domingo K et al. Circulation.2004;110:1424-30.

  8. Heart Failure Pathophysiology

  9. Important pathophysiologic mechanisms in HF (1) Cardiac abnormalities Structural Functional Coronary arteries • Obstruction • Inflammation • Left ventricular chamber • Remodeling – Dilation – Increased sphericity – Aneurysmal dilatation or wall thinning – Concentric hypertrophy • Mitral regurgitation Intermittent ischemia or hibernating myocardium Induced arterial and ventricular arrhythmias Altered ventricular interaction • Myocardium or myocyte • Myocardial relaxation • Abnormal excitation- contraction coupling • -Adrenergic desensitization • Hypertrophy • Necrosis • Fibrosis • Apoptosis Modified from Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

  10. Important pathophysiologic mechanisms in HF (2) Biologically active tissue and circulating substances • 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;348:2007-18.

  11. Important pathophysiologic mechanisms in HF (3) Patient factors Coexisting conditions • Hypertension • Diabetes • Renal disease • Coronary artery disease • Anemia • Obesity • Sleep apnea • Depression • Genetics, ethnicity, sex • Age • Use of alcohol, tobacco, toxic drugs Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

  12. Neurohormonal model of HF Injury to myocytes and extracellular matrix • Neurohormonal activation – RAAS, SNS • Increased cytokine expression • Immune and inflammatory changes • Altered fibrinolysis • 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;105:2099-106.

  13. Diabetes pathogenesis accelerates HF Diabetes Activated RAAS Activated sympathoadrenal system Hyperglycemia Activation of protein kinase C Cardiomyocyte death Cardiac fibrosis Decreased intracellular calcium removal Decreased myocardial contractile strength Diastolic dysfunction Systolic dysfunction Heart failure Kirpichnikov D et al. J Card Fail. 2003;9:333-44.

  14. RAAS in CV continuum: Pivotal role of AT1 receptors in the failing heart Angiotensinogen Bradykinin/Kinins Renin Angiotensin I Degradation ACE Angiotensin II AT2 receptor AT1 receptor B1/B2 receptor NO ? Clinical significance Reactive oxygen species Pro-inflammatory process Vasoconstriction Cellular growth/proliferation Apoptosis Neurohormonal activation Vasodilation Growth inhibition Apoptosis Adapted from Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9.

  15. Primary targets of treatment in HF Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

  16. Angiotensin receptor blockade in the CVD continuum Coronary heart disease ARB Plaque rupture ARB  ARB Atherosclerosis  Myocardial infarction Dilation/ Remodeling Endothelial dysfunction ARB  ARB   Heart failure ARB  End-stage heart failure Risk factors Hypertension Hyperlipidemia Diabetes Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9.

  17. Clinical Trial Update

  18. Survival studies of -blockade in HF Total mortality Placebo/-blocker Patients (N) Favors -blocker EF mean NYHA class P CIBIS-II Bisoprolol 2647 228/156 III/IV 28% 0.0001 MERIT-HF Metoprolol succinate CR/XL 3991 217/145 II-IV 28% 0.00009 COPERNICUS Carvedilol 2289 190/130 III/IV* 20% 0.00013 8927 635/431 All pooled 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;353:2001-7. Packer M et al. N Engl J Med. 2001;344:1651-8. *not recorded in COPERNICUS, but placebo mortality indicates III/IV

  19. MERIT-HF: Metoprolol succinate CR/XL lowers risk of hospitalization with/without diabetes NYHA III/IV, EF <25% All randomized Diabetes No diabetes Diabetes No diabetes 70 50 50 Total # hospitaliz/patient-yrs (%) 26 30 25 25 16 15 13 9 10 –37% P = 0.0026 –35% P = 0.0002 –53% P = 0.0087 –44% P = 0.0039 Metoprolol succinate CR/XL (n = 495) Placebo (n = 490) Deedwania PC et al. Am Heart J. 2005;149:159-67.

  20. MERIT-HF: Benefit of -blockade with/without diabetes Events (n) Favors metoprolol succinate CR/XL Favorsplacebo Metoprolol succinate CR/XL All-cause mortality Placebo 217 145 All patients randomized 61 50 Diabetes 24 14 Diabetes, severe HF No diabetes 156 95 No diabetes, severe HF 48 31 Hospitalization for CHF All patients randomized 200 294 Diabetes 108 72 Diabetes, severe HF 40 20 No diabetes 128 186 No diabetes, severe HF* 40 64 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;149:159-67.

  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 2647 All 228/156 MERIT-HF 985 Diabetes 61/50 3006 No diabetes 156/95 3991 217/145 All COPERNICUS Diabetes 589 No diabetes 1700 190/130 2289 All All 3 studies Diabetes 1886 No diabetes 7041 All 635/431 8927 0.0 1.0 1.8 Relative risk (95% CI) Deedwania PC et al. Am Heart J. 2005;149:159-67.

  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 Bakris GL et al. JAMA. 2004;292:2227-36.

  23. GEMINI: Change in HbA1cand insulin sensitivity Endpoint (mean ) Bakris GL et al. JAMA. 2004;292:2227-36.

  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 Demers C et al. Canadian Cardiovascular Congress; 2004. Calgary. *Phase 2 regimen

  25. RESOLVD substudy: No effect on glucose and insulin with metoprolol succinate CR/XL 17 weeks* 43 weeks *Phase 2: Start metoprolol succinate CR/XL †P = NS vs placebo Demers C et al. Canadian Cardiovascular Congress; 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 Deedwania PC et al. Am Heart J. 2005;149:159-67.

  27. MERIT-HF: Mortality benefit of -blockade in the elderly Sudden death All-cause mortality 20 12 Risk reduction 37% Risk reduction 43% Placebo Placebo P = 0.0008 9 15 P = 0.0032 Metoprolol succinate CR/XL Metoprolol succinate CR/XL % Patients % Patients 6 10 3 5 HF mortality 0 0 6 Risk reduction 61% Placebo 3 6 9 12 15 18 0 3 6 9 12 15 18 0 Months Months P = 0.0005 4 % Patients Metoprolol succinate CR/XL 2 0 0 3 6 9 12 15 18 Deedwania PC et al. Eur Heart J. 2004;25:1300-9. Months N = 1982 age ≥65 years

  28. Meta-analysis: -Blockade improves survival in elderly HF patients Hazard ratio Placebo better -blocker better 0.75 (0.58–0.98) COPERNICUS 0.45 (0.24–0.86) Carvedilol (U.S.) 0.70 (0.49–0.99) CIBIS-II 0.70 (0.52–0.95) MERIT-HF BEST 0.91 (0.78–1.05) 0.76 (0.64–0.90) Overall P = 0.002 –1 1 10 Risk ratio (95% CI) Dulin BR et al. Am J Cardiol.2005;95:896-8.

  29. SENIORS: Design 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 Flather MD et al. Eur Heart J. 2005;26:215-25.

  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 90 90 HR 0.86 (0.74–0.99) P = 0.039 Nebivolol Event- free survival (%) 80 80 Placebo Nebivolol 70 70 60 60 Placebo 50 50 0 6 12 18 24 30 0 6 12 18 24 30 Time (months) Time (months) No. of events: 169 (15.8%) 192 (18.1%) Nebivolol 332 (31.1%) Placebo 375 (35.3%) Flather MD et al. Eur Heart J. 2005;26:215-25. HR = hazard ratio

  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 Flather MD et al. Eur Heart J. 2005;26:215-25.

  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 17% No -blockers Death at 1 year (%) 10 P < 0.001 4% -blockers 0 0 6 12 Months No -blocker 132 115 100 -blocker 239 229 212 Estep JD et al. Am Heart J. 2004;148:958-63.

  33. Not all -blockers are the same Generic name Brand name* AB-rated generic equiv available Properties Dose for HF * see prescribing information †COPERNICUS; other trials 50 mg bid for >75 kg

  34. 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 1 200 Plasmaconcentration (mmol/L) Metoprolol tartrate 50 mg x 3 100 Metoprolol succinate CR/XL 100 mg x 1 0 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.

  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 160 190 Placebo Placebo 180 140 Meanexercise SBP (mm Hg) Meanexercise 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 0 0 0 2 4 8 12 24 0 2 4 8 12 24 Time (hours) Time (hours) Blomqvist I et al. Eur J Clin Pharmacol. 1988;33(suppl):S19-24.

  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 25 † * 20 ACEI  Radial artery systolic pressure (mm Hg) † * 15 10 ACEI + valsartan 5 0 100 0 10 200 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.

  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 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 Median follow-up, 37 months Pfeffer MA et al. Lancet. 2003;362:759-66. Granger CB et al. Lancet. 2003;362:772-6. McMurray JJV et al. Lancet. 2003;362:767-71. Yusuf S et al. Lancet. 2003;362:777-81.

  38. CHARM Program: Reduction in mortality and morbidity CV death or HF hospitalization All-cause mortality Alternative (LVEF ≤40%; ACEI intolerant) Added (LVEF ≤40%; ACEI treated) Preserved (LVEF >40%; ACEI treated/not treated) Overall 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.1 0.7 0.8 0.9 1.0 1.2 Adjusted hazard ratio P heterogeneity = 0.37 Adjusted hazard ratio P heterogeneity = 0.33 Pfeffer MA et al. Lancet. 2003;362:759-66.

  39. CHARM-Overall: CV death and non-CV death—Secondary endpoints 35 13% Relative risk reduction(95% CI 4%–22%) P = 0.006 25 CV death 20 % Patients 15 10 Non-CV death 5 P = 0.45 0 Years 0.0 1.0 2.0 3.0 3.5 Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 Pfeffer MA et al. Lancet. 2003;362:759-66.

  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 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;110:2180-83. Demers C et al. Circulation. 2004;110(suppl):Abstract.

  41. CHARM—Low LVEF trials: Risk reductions at 1 and 2 years with candesartan LVEF ≤40% CV death/HF hospitalization All-cause mortality 0 10 20 20 % Reduction 23 P = 0.001 P < 0.001 30 30 33 P < 0.001 1 year P = 0.001 40 2 years 50 Young JB et al. Circulation. 2004;110:2618-26.

  42. CHARM Program: Outcomes overview Candesartan vs placebo Gleiter CH et al. Cardiovasc Drug Rev. 2004;22:263-84. *statistically significant

  43. CHARM-Overall: Reduction in new-onset diabetes n = new-onset diabetes N = total patients Pfeffer MA et al. Lancet. 2003;362:759-66.

  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 Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

  45. VALIANT: Treatments show similar effect on outcome Death from any cause Combined CV endpoint* 0.4 0.4 0.3 0.3 Probability of event 0.2 0.2 0.1 0.1 0.0 0.0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months Valsartan Valsartan/captopril Captopril *CV death, reinfarction, or hospitalization for HF Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

  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 0.3 0.3 New DM 0.2 0.2 Probability of event Previous DM No DM New DM 0.1 0.1 No DM 0.0 0.0 0 3 6 9 12 3 6 9 12 0 Months Months Previous vs new diabetes diagnosis Previous vs no diabetes New vs no diabetes diagnosis P = 0.43 P < 0.001 P < 0.001 P < 0.005 P < 0.001 P < 0.001 Aguilar D et al. Circulation. 2004;110:1572-8.

  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 Lee VC et al. Ann Intern Med. 2004;141:693-704. McClellen MB et al. Ann Intern Med. 2005;142:386-7. ACC/AHA. www.acc.org

  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 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.

  49. ARBs in LV dysfunction: Before/after CHARM and VALIANT Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

  50. Difference in target dosing among ARB trials Pfeffer MA et al. Lancet. 2003;362:759-66. Pitt B et al. Lancet. 2000;355:1582-7. Dickstein K et al. Lancet. 2002;360:752-60. Cohn JN et al. N Engl J Med. 2001;345:1667-75. Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

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