1. 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

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
- 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. 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

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
Fatigue Chest congestion Edema SOB
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
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:
2. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978;41:
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:
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 VI-48. 10

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 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
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:

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. 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?

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:

18. Thank you