Heart failure: The national burden AHA. Heart disease and stroke statistics–2005 update. Koelling TM et al. Am Heart J. 2004;147:74-8. VBWG Affects 1 million Americans >550,000 new cases annually >53,000 deaths in 2002 Leading Medicare hospital diagnosis >1 million hospitalizations annually Direct and indirect costs: $27.9 billion

ACC/AHA: Heart failure stages A and B Hunt SA et al. J Am Coll Cardiol. 2005;46:1-82. VBWG Stage A *Appropriate patients Stage B Hypertension CAD Diabetes Obesity Metabolic syndrome Previous MI LV remodeling LV hypertrophy Low EF Patients No structural heart disease/asymptomatic Structural heart disease/asymptomatic Definition Treat BP, lipids Smoking cessation  Regular exercise  Alcohol/drug use All measures under stage A Goals ACEI or ARB for vascular disease/diabetes* ACEI or ARB*  -Blockers* Therapy

ACC/AHA: Heart failure stages C and D VBWG Stage C *Selected patients Stage D Shortness of breath Fatigue  Exercise capacity Marked symptoms at rest despite maximal therapy Patients Structural heart disease Prior/current symptoms Refractory HF Definition All Stage A and B Dietary salt restriction All Stage A, B, and C Decision re: appropriate level of care Goals Routine drugs Diuretics ACEI  -Blockers Options Compassionate care/hospice Drug therapy Devices* Biventricular pacing Implantable defibrillators Selected patients Aldosterone antagonist ARBs Digitalis Hydralazine/nitrates Extraordinary measures Heart transplant Chronic inotropes Permanent mechanical support Experimental surgery/drugs Hunt SA et al. J Am Coll Cardiol. 2005;46:1-82.

CHARM: HF patients with LV dysfunction VBWG CHARM-AlternativeCHARM-Added Candesartan 32 mg/d vs placebo Candesartan 32 mg/d vs placebo + ACEI and other HF therapy Therapy N = 2028 LVEF ≤40% Intolerant to ACEI N = 2548 LVEF ≤40% Treated with ACEI Patients 41 months33.7 monthsFollow-up 23% RRR (P < 0.001) 7% absolute  Primary outcome* 15% RRR (P < 0.011) 4% absolute  Granger CB et al. Lancet. 2003;362: McMurray JJV et al. Lancet. 2003;362: *CV mortality/HF hospitalization RRR = relative risk reduction

VBWG Pfeffer MA et al. N Engl J Med. 2003;349: VALIANT: Study design *<40% by radionuclide ventriculography (RVG) Valsartan 160 mg 2  /d (n = 4909) Captopril 50 mg 3  /d (n = 4909) Captopril 50 mg 3  /d + valsartan 80 mg 2  /d (n = 4885) Therapy N = 14,703 with MI within ≤10 days HF and/or LVEF <35%* Patients 24.7 monthsFollow-up

VALIANT: Primary outcome— Death from any cause VBWG Months Probability of event Valsartan* Valsartan plus captopril † Captopril *P = 0.98 vs captopril † P = 0.73 vs captopril Pfeffer MA et al. N Engl J Med. 2003;349:

ACC/AHA recommendations: ARBs in patients with LV dysfunction VBWG Alternative therapy: Use ARBs approved for the treatment of HF in patients witih current or prior HF symptoms who are ACEI intolerant I Class A Level of evidence ARBs are reasonable alternatives to ACEI as first-line therapy for patients with mild to moderate HF, especially those already taking ARBs for other indications IIaA ARBs should be administered to post-MI patients without HF symptoms who are intolerant of ACEIs and have a low LVEF IB Added therapy: Consider adding ARBs in persistently symptomatic patients with reduced LVEF who are already treated with conventional therapy IIbB Hunt SA et al. J Am Coll Cardiol. 2005;46:1-82.

CHARM-Added: Effects of adding candesartan to  -blocker and ACEI McMurray JVV et al. Lancet. 2003;362: VBWG Candesartan better Placebo better PlaceboCandesartan  -Blocker 223/702274/ /574264/561 Recommended dose of ACE inhibitor 232/643275/648 Yes No Yes No 251/633263/624 All patients483/ / *For treatment interaction P* Hazard ratio

HF with LV dysfunction: Patients, efficacy, and dosing considerations Adapted from Hunt SA et al. J Am Coll Cardiol. 2005;46:1-82. VBWG ARBPatients Initial dose(s) Efficacy Maximum dose(s) CandesartanHF4–8 mg 1  /d  CV mortality  HF hospitalizations 32 mg 1  /d ValsartanHF Post-MI 20–40 mg 2  /d  CV mortality 160 mg 2  /d

CHARM: Prevention of diabetes with candesartan Yusuf S et al. Circulation. 2005;112: VBWG Proportion of patients (%) Placebo Candesartan RRR = 22% HR = 0.78 (0.64–0.96) P = n = 202 (7.4%) n = 163 (6.0%) Years RRR = relative risk reduction