Advanced Heart Failure: My Approach Feb 4, 2011 Advanced Heart Failure: My Approach J.L. Mehta, MD, PhD Stebbins Chair in Cardiology Professor of Internal Medicine, Physiology and Biophysics University of Arkansas for Medical Sciences Little Rock, AR

Topics to be Discussed Burden of heart failure Causes of heart failure, morbidity and mortality Pathophsiology Role of RAAS and SNS blockers, and diuretics When to use defibrillators/biventricular pacing

Burden of Heart Failure CHF affects more than 4.5 million people in the USA and 0.5 million new cases are diagnosed each year 1.2-2% of the population has CHF, with 75-80% of the group are above the age of 65 years Nearly 20 million people have unsuspected disease and likely to develop CHF in the next 1- 5 years CHF is responsible for >11 million visits to a physician's office and result in 3.5 million hospitalizations per year Median survival following onset is 1.7 years for men and 3.2 years for women- worse than lung cancer

Causes of Heart Failure, Morbidity and Mortality - Ischemic heart disease - Hypertension - Cardiomyopathies (viral, alcohol) Causes of Hospitalization - Non-compliance with drugs - Excessive salt and alcohol intake - Infections - Anemia - Co-morbidity (e.g. renal dz, Liver dz, depression)

Myocardial ischemia and Low Cardiac Output State Angiotensin - Angiotensin - Angiotensin Inflammation Release of Catecholamines, ANP, BNP and ET-1 TGFb1, PAI-1, ROS expression Release of MMPs and collagen degradation Myocyte apoptosis, Fibroblast growth Myocyte hypertrophy Myocyte slippage Collagen formation Cardiac enlargement and fibrosis Wall thinning and regional dilatation  Wall stress Local Ang II release Early Stage Intermediate Stage Late Stage Mehta JL, 2010

Neurohormonal Activation in Heart Failure Myocardial injury to the heart Initial fall in LV performance,  wall stress Activation of SNS Fibrosis, apoptosis, hypertrophy, cellular, alterations, myotoxicity Remodeling and progressive worsening of LV function Peripheral vasoconstriction Hemodynamic alterations CHF symptoms Morbidity and mortality Arrhythmias Pump failure Renal dysfn Fatigue Chest congestion Edema SOB RAS, renin-angiotensin system; SNS, sympathetic nervous system.

Mortality by Baseline Plasma Norepinephrine Level 100 > 900 pg/mL 80 60 > 600 and < 900 pg/mL Cumulative Mortality (%) 40 < 600 pg/mL Heart failure patients demonstrate long-term activation of the sympathetic nervous system. The level of adrenergic nervous system activation correlates with the concentration of plasma norepinephrine, as well as with levels of left ventricular filling pressures and mean right atrial pressure.1 The extent of elevation of plasma norepinephrine concentration occurring in patients with heart failure correlates directly with the severity of left ventricular dysfunction,2 and with cardiac mortality.3 Measurements of plasma norepinephrine and plasma renin activity were performed in the Vasodilator-Heart Failure Trial II (V-HeFT II) to assess the effect of therapy on neuroendocrine activation and examine the response to therapy among patients with different degrees of activation. Baseline plasma norepinephrine data were grouped into three relatively homogeneous strata for analysis. Cumulative mortality between the three strata was significantly different (P < .0001). The patients with plasma norepinephrine > 900 pg/mL had a higher mortality than those with corresponding values < 600 pg/mL or from 601 to 900 pg/mL. In these three groups mortality was directly related to increased plasma norepinephrine levels. This study thus confirms the relationship between baseline PNE values and cumulative mortality in heart failure patients.4 Slide and Notes References 1. Leimbach WN Jr, Wallin G, Victor RG, et al. Direct evidence from intrarenal recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986;73:913-919. 2. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978;41:233-243. 3. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. 4. Francis GS, Cohn JN, Johnson G, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation. 1993;87(suppl VI):VI-40–VI-48. 20 Overall P < .0001 6 12 18 24 30 36 42 48 54 60 Months Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48. 10

When to Use ß-blockers and RAS Inhibitors It dose not matter which agent is started first, but early ß-blockade reduces the risk of sudden death in the first year The usual practice of starting the ACE inhibitor first may lead to under-treatment with ß-blockers The CIBIS III trial Willenheimer, Eur Heart J Suppl 2009;11:A15-A20

Treatment of Advanced of Heart Failure Part 1 Hospitalize early Treat first with usual drugs- if patient not responsive, then change Rx Limit salt intake Treat hypertension Treat infections- usually UTI or pulmonary Treat anemia to hemoglobin to ~10 g/100 ml Treat co-morbidity (e.g. renal dz- may need fluids) Treat abnormal thyroid function If patient has angina, use anti-ischemic therapy If patient has valvular dz, may consider surgery when patient is stable

Treatment of Advanced Heart Failure Part 2 ACE inhibitors, ARBs, Hydralazine and Nitrates Use maximal dose of ACE inhibitors, if not tolerated then use ARBs May combine the two groups of drugs If patient is already taking ACE inhibitors/ARBs, switch to hydralazine + nitrates- use adequate dose, response is quick Dose of hydrazine- 50-100 mg TID and ISD- 40 mg TID

Treatment of Advanced Heart Failure Part 3 Diuretics Excessive diuresis can cause metabolic alkalosis and poor renal perfusion- if present hold diuretics If no alkalosis, use IV lasix or metalazone If alkalosis present, use K+ and Mg+ supplementation Patient may have acute renal failure from excessive diuresis, consider gentle fluid administration If patient has hyponatremia, consider half or normal saline (250 ml per hr until urine output improves or patient develops rales when diuresis may be begun)

RALES: Probability of Survival Patients with Class II-IV CHF 30% reduction in risk of death 31% reduction in cardiac death, P<0.001 Kaplan-Meier Analysis of the Probability of Survival among Patients in the Placebo Group and Patients in the Spironolactone Group Pitt, B. et al. N Engl J Med 1999;341:709-717

Eplerenone in Mild CHF- EMPHASIS-HF Patients with class I-II CHF NNT-19 Zannad F et al. N Engl J Med 2011;364:11-21.

Treatment of Advanced Heart Failure Part 4 Other therapies Digitalis- increases CO and makes patient feel better Dobutamine / milrinone- use short course only- no long tem benefit Nasiritide - no role in the therapy of CHF CCBs – no role in the therapy of CHF Ultra-filtration - no better than diuresis

Cardiac Resynchronization Therapy: Treatment of Advanced Heart Failure Part 5 CRT improves functional capacity, quality of life, and reduces hospitalization in patients with advanced symptomatic CHF, and evidence of a ventricular conduction abnormality. Appropriate method patient selection for CRT is not clear. Issues about the placement of LV lead remain.

Treatment of Advanced Heart Failure Part 6 ICD Therapy: Treatment of Advanced Heart Failure Part 6 Implantable defibrillators reduce the risk of sudden death in patients with CHF, with and without prolonged QRS duration Patients with Class II-III benefit more than Class IV patients Issues: - Who are the best candidates for defibrillators? - Is the cost of implanting and maintaining these devices worth the benefit? - How can side effects and risks be minimized?

CRT / ICD and Death or Hospitalization for CHF In class II or III CHF patients, with wide QRS complex, and EF <30%, the addition of CRT to ICD reduced rates of death and hospitalization for CHF. This improvement was accompanied by more adverse events in 1 month (pneumothorax, hematoma and infections). Tang AS et al. N Engl J Med 2010;363:2385-2395.

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