Advanced Heart Failure: My Approach J.L. Mehta, MD, PhD Stebbins Chair in Cardiology

1. 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

2. 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

3. 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

4. Causes of Heart Failure, Morbidity and Mortality • Causes of heart failure - 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)

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

6. 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 FatigueChest congestionEdemaSOB RAS, renin-angiotensin system; SNS, sympathetic nervous system.

7. Mortality by Baseline Plasma Norepinephrine Level 100 > 900 pg/mL 80 60 > 600 and < 900 pg/mL Cumulative Mortality (%) 40 < 600 pg/mL 20 Overall P < .0001 0 0 6 12 18 24 30 36 42 48 54 60 Months Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48.

8. 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

9. 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

10. 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

11. 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)

12. RALES: Probability of Survival • Patients with Class II-IV CHF • 30% reduction in risk of death • 31% reduction in cardiac death, P<0.001 Pitt, B. et al. N Engl J Med 1999;341:709-717

13. 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.

14. 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

15. 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.

16. 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?

17. 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.

18. Thank you