# Presentation: 175684

## Evaluation and Management of Heart Failure

- University of Washington
- Medical Resident Conference
- September/October 2004

## Basic Questions

- Initial evaluation
- Is heart failure present?
- What type of heart failure?
- What caused the heart failure?
- What stage/class is the heart failure?
- Treatment
- How do I treat?
- Ongoing evaluation
- How do I follow response to treatment?

## Is Heart Failure Present?

- Non-specific symptoms of heart failure
- Shortness of breath
- Exertional
- Nocturnal
- Fatigue
- Nonspecific signs of heart failure
- Dependent edema
- Rales

## Is Heart Failure Present?

- Specific symptoms of heart failure
- Orthopnea
- Paroxysmal nocturnal dyspnea
- Specific signs of heart failure
- S3 gallop
- Elevated jugular venous pressure

## B-type Natriuretic Peptide(BNP)

- BNP is a neurohormone secreted by the myocardium in response to stretch
- Elevated BNP levels are associated with elevated ventricular filling pressures
- Large variation in “normal” or optimal level
- Obesity
- Age
- Gender

## BNP Levels in Patients With Dyspnea Secondary to COPD or CHF

**N=56****	****	****   N=94****	**

- Dao Q et al, *JACC* 2001

**p < 0.001**

**Notes:**
Pilot Study:  The BNP levels represent the mean levels with the standard error.  The ability to differentiate dyspnea due to COPD vs. CHF is a major diagnostic dilemma in the E.D.  The rapid whole blood assay provides a strong indication of symptom origin.  Patients who presented with dyspnea from pulmonary origin without cardiac involvement had normal BNP levels in the blood, whereas patients with dyspnea as a symptom of congestive heart failure had markedly elevated BNP levels.

## BNP Levels for Types of Lung Disease

**207********272**

- Morrison KL et al, JACC 2002

## What Kind of Heart Failure?

- Up to 40% of all patients with heart failure have intact systolic function with left ventricular ejection fraction >50%

## Diastolic Dysfunction

- Older age
- More women
- Preserved LVEF
- Small LV cavity
- More LVH
- Variable cardiomegaly
- S4 rather than S3

- Greater incidence of
- HTN
- Diabetes
- Obesity
- Equal incidence of
- Sleep apnea
- Atrial fibrillation
- Lesser incidence of
- Coronary disease

## Diastolic Dysfunction

## Echocardiography

- All patients with signs or symptoms suggestive of heart failure should undergo echocardiography
- Ventricular size and systolic function
- Regional wall motion abnormalities
- Wall thickness
- Diastolic properties
- Valvular abnormalities
- Pericardial effusion

## What Caused the Heart Failure?

- Laboratory evaluation
- Chemistry panel
- Thyroid function
- Iron studies
- CBC
- Urinalysis

## What Caused the Heart Failure?

- Laboratory evaluation
- Iron studies and thyroid function tests
- Electrocardiogram
- Rhythm abnormalities
- Atrial fibrillation
- Conduction abnormalities
- Signs of hypertrophy
- Signs of ischemia or infarction

**Notes:**
In addition to the echocardiogram

## Screening for Coronary Disease

- Ischemic heart disease is the underlying cause of heart failure in two thirds of patients with left ventricular systolic dysfunction.
- When to evaluate?
- Invasive or noninvasive evaluation?

## Screening for Coronary Disease

- Indications for cardiac catheterization
- For patients with angina 		Class I
- For patients with chest pain		Class IIa
- With known or suspected CAD	Class IIb
- Non-invasive testing should be reserved for those HF patients without chest pain who have a “reasonable” likelihood of CAD

## Assessing Heart Failure Severity 

- NYHA Classification
- I to IV
- HFSA Stages
- A to D
- Patients can move back and forth through NYHA classes, but not through HFSA stages.

## NYHA Classification

- Class I
- Asymptomatic
- Class II
- Symptoms with moderate exertion
- Class III
- Symptoms with minimal exertion
- Class IV
- Symptoms at rest

## Stages of Heart Failure

- Stage A
- High risk for development of heart failure
- Stage B
- Structural heart disease
- No symptoms of heart failure
- Stage C
- Symptomatic heart failure
- Stage D
- End-stage heart failure

## Heart Failure Classification

| NYHA Class | Symptoms |  HF Stage |
| --- | --- | --- |
| Class I | Asymptomatic | B
 |
| Class II | Moderate exertion | C
 |
| Class III | Minimal exertion | C |
| Class IV | At rest | D |

## How Do I Treat?

## +

_**Control volume**__**  **_

**Diuretic**

_**Slow Progression of Disease**_** **

**ACE**
**inhibition**

**Beta Blocker**

**Treat Residual**
**Symptoms**

**Digoxin**

**+**

**Notes:**
Slide 41
 The current management paradigm for moderate (NYHA Class II and III) heart failure due to left ventricular systolic dysfunction first requires that fluid overload be controlled with a diuretic, since these drugs are the only reliable means of controlling the fluid retention of heart failure. [R1/Consensus 25A] Then, progression of disease must be slowed with the use of ACE inhibitors and beta blockers. [R1/ Consensus 29A] Prior to initiation of beta-blocker therapy, the dosing of diuretics, ACE inhibitors and digitalis (if used) should be stabilized. Patients that remain symptomatic despite treatment should then be treated with digoxin. [R1/ Consensus 45A]

Reference
1. Steering Committee and Membership of the Advisory Council to Improve 	Outcomes Nationwide in Heart Failure. Consensus Recommendations for the 	Management of Chronic Heart Failure. Am J Cardiol. 1999;83:1A-80A

## Sites of Action

## Treatment Strategies

## Treatment Options in Heart Failure

- Digoxin
- Diuretics
- Afterload reduction
- ACE inhibitors: ACEI
- Angiotensin II receptor blockers: ARB
- Nonspecific vasodilators
- Beta blockers
- Aldosterone antagonists

## Digoxin

- Used in heart failure for more than 200 years
- Improves symptoms for patients on diuretic and ACE inhibitor
- No overall impact on survival

## The Digitalis Investigation Group

***NEJM.***** 1997;336:525****.**

**Mortality Due to Worsening HF**

**The Digitalis Investigation Group**

- n=6800 patients, EF <45%, normal sinus rhythm

**Total Mortality**

**18**

**16**

**14**

**12**

**10**

**8**

**6**

**4**

**2**

**0**

**50**

**40**

**30**

**20**

**10**

**0**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**36**

**40**

**44**

**48**

**52**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**36**

**40**

**44**

**48**

**52**

**Placebo**

**Digoxin**

***p=*****0.8**

**Placebo**

**Digoxin**

***p=0.06***

**Mortality Due to Worsening Heart Failure (%)**

**months**

**months**

**Notes:**
 The DIG trial was a randomized, double blind, placebo controlled trial in 6800 patients with heart failure.  Patients were randomized to receive digitalis or placebo, in addition to ACE inhibitors and diuretics. 
 Digoxin had a neutral effect on all cause mortality, insignificantly lowered deaths due to worsening heart failure and significantly reduced hospitalizations due to heart failure.  Digoxin use was also associated with a trend toward increased sudden death.  

## Afterload Reduction 

- Angiotensin Converting Enzyme Inhibitors
- Treatment of choice
- For all patients with ventricular dysfunction
- Angiotensin II Receptor Blockers
- For ACEI intolerant patients
- Non-specific vasodilators
- Hydralazine and Isosorbide
- Calcium channel blockers NOT of benefit

## CONSENSUS and SOLVD:  Effect of ACE Inhibition on Mortality

**CONSENSUS and SOLVD:  Effect of ACE Inhibition on Mortality**

**Placebo****(n = 126)**

**Enalapril**** ****(n = 127)**

**Placebo****(n = 1284)**

**CONSENSUS*****NYHA Class IV**

**SOLVD****** ****NYHA Class II–III**

**Enalapril**** ****(n = 1285)**

**Percent (%)**

**Months**

**Risk reduction 27% (*****p***** = 0.003)****	****	**

**Risk reduction 16% (*****p***** = 0.0036)****	****	**

*******	****The CONSENSUS Trial Study Group. *****N Engl J Med.***** 1987;316:1429-1435. **
********	****The SOLVD Investigators. *****N Engl J Med.***** 1991;325:293-30.**

**Notes:**
This slide illustrates the results of two landmark clinical trials evaluating the effect of ACE inhibitors on mortality in heart failure patients
In the CONSENSUS study, 253 patients with NYHA class IV heart failure received enalapril or placebo in addition to conventional therapy for heart failure for 6 months.
Results showed that treatment with enalapril resulted in a significant 27% reduction in all-cause mortality.  These results provided evidence that enalapril reduced mortality in patients with severe heart failure.

In the SOLVD treatment trial, 2,569 patients with NYHA class II-III were randomized to enalapril or placebo in addition to conventional therapy for heart failure. The primary endpoint of the study was all-cause mortality.
The study had a mean follow-up time of 41 months.
Treatment with enalapril was associated with a 16% reduction in all-cause mortality in NYHA class II-III patients.

## HOPE Study

*P*<0.001.
- Reprinted with permission from Yusuf S, et al. *N Engl J Med.* 2000;342:145-153.

- Composite Outcomes of Death from MI, Stroke, or CV Causes

- 1500

- Days of follow-up

- Ramipril 14.1%

- Placebo 17.7%

- 0

- 10

- 20

- Patients (%)

- 15

- 5

- 0

- 500

- 1000

**Notes:**
	The beneficial effects of ACE-Is are not only limited to patients with LV dysfunction or post-MI but 	are also seen in a wide range of subjects at high risk of CV events. The Heart Outcomes Prevention 	Evaluation (HOPE) study examined high-risk patients with either vascular disease or diabetes plus 	one additional CV risk factor, but with no evidence of LV dysfunction or heart failure. This multi-center, 	randomized, double-blind study randomized 9297 patients who were at least 55 years of age to ramipril, 	10 mg/day, or placebo for five years. At baseline, 88% of the patient population had CV disease, 47% 	had hypertension, and 39% had diabetes. Ramipril decreased the primary composite outcome of acute 	Ml, stroke, or CV death by 22% (P<0.001). Significant reductions were also achieved in each of the 	components of the composite end point; acute Ml by 20% (P<0.001), stroke by 32% (P< 0.001), and 	CV mortality by 26% (P<0.001).

Reference
Yusef S, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):145-153.

## Beta Blockade

- What drug to use?
- Carvedilol
- Toprol XL
- Bisoprolol
- For which patients?
- Compensated heart failure
- When do I start?
- Prior to hospital discharge?

## Properties of selected beta-blockers

**********1**** ****	****       ********2**** ****	****     ********1****                         **** blockade****	****blockade****     ****blockade     ISA    ****	****	**

- Carvedilol*	+++	  +++              +++         -
- Metoprolol	+++	     -	        -	          -
- Bisoprolol	+++	     -	        -	          -
- Bucindolol	+++	  +++                -           ++

*****anti-oxidant, inhibitor of apoptosis, inhibitor of endothelin

**Properties of selected beta-blockers**

## All-Cause Mortality Results

- Relative risk and 95% confidence intervals

**CIBIS-II****	**** **1.3 yearsplacebo 228/1320 (17%)bisoprolol 156/1327 (12%)

**MERIT-HF **12 monthsplacebo 217/2001 (11%)
- TOPROL-XL 145/1990 (7%)

**COPERNICUS****  **~ 12 months
- Placebo 190/1133 (18.5%)carvedilol 130/1156 (11.4%)

**All-Cause Mortality Results**

- 	**BEST** 2 yearsplacebo 449/1354 (17%)bucindolol 411/1354 (15%)

- 

- 

- 

- 

**Notes:**
 Overall, results of the large clinical trials indicate an overwhelming benefit associated with beta blockade (selective and non-selective).  
MERIT-HF, CIBIS II and COPERNICUS all demonstrated a very consistent reduction in overall mortality.
These clinical trial results suggest that ß1 blockade is the important factor in determining clinical outcomes.

## Beta Blockade

- How do I optimize?
- Start low
- Go slow
- Aim high
- What do I do when the patient decompensates?
- For volume overload, diurese
- For hypotension, stagger med schedule

## Primary EP: Mortality

- Mortality (%)

- 0

- 10

- 20

- 30

- 40

- 0

- 1

- 2

- 3

- 4

- 5

- Hazard ratio 0.83
- 95% CI 0.74-0.93, p=0.0017

**Primary EP: Mortality**

**Number at risk**
- Metoprolol	  1518			  1359			1234		    1105		   933			  352
- Carvedilol	  1511			  1367			1259		    1155		   1002		  383

- Metoprolol

- Carvedilol

- Poole-Wilson et al Lancet 2003;362:7-13

- Average follow-up 57.9 months

## Mode of death

**Circulatory Failure**

**Fatal stroke**

- Time (years)

- Hazard ratio: 0.81
- 95% CI: 0.677, 0.97
- p=0.0216

- Hazard ratio: 0.827
- 95% CI: 0.673, 1.016
- p=0.0702

- Hazard ratio: 0.332
- 95% CI: 0.177, 0.624
- p=0.0006

- Mortality (%)

- 0

- 5

- 10

- 15

- 20

- 0

- 1

- 2

- 3

- 4

- 5

- 0

- 5

- 10

- 15

- 20

- 0

- 1

- 2

- 3

- 4

- 5

- 0

- 1

- 2

- 3

- 4

- 0

- 1

- 2

- 3

- 4

- 5

**Mode of death**

- Metoprolol

- Carvedilol

## All Cause Hospitalisation

- Time (years)

- Endpoint (%)

- 0

- 20

- 40

- 60

- 80

- 0

- 1

- 2

- 3

- 4

- 5

- 918

- 689

- 519

- 386

- 115

- 930

- 693

- 554

- 430

- 143

- Metoprolol

- Carvedilol

- Hazard Ratio = 0.967
- 95% CI 0.887 – 1.054, p = 0.4478

- Number at risk
- Metoprolol
- Carvedilol

- 1518

- 1511

## Aldosterone Antagonists

- Non-diuretic doses
- RALES trial
- Spironolactone
- Class III-IV
- EPHESUS trial
- Eplerenone
- Low EF after MI

**Notes:**
Spironolactone is a nonspecific aldosterone inhibitor – side effects include painful gynecomastia in men and menstrual irregularities and libido changes in premenstrual women. 
Eplerenone is a selective aldosterone antagonist with an improved side effect profile.

## Randomized AldactoneEvaluation Study (RALES)

**Pitt et al. *****N Engl J Med.***** 1999;341(10):709-717.**

**Randomized Aldactone****Evaluation Study (RALES)**

**Probability ****of Survival**

**1.00**

**Placebo**

**Months**

**Spironolactone**

**0.95**

**0.90**

**0.85**

**0.80**

**0.75**

**0.70**

**0.65**

**0.60**

**0.55**

**0.50**

**0.45**

**0.00**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**30**

**33**

**36**

**p< 0.001**

**Notes:**
RALES trial NEJM 1999
1663 pts with Class III-IV HF and LVEF <35%
Trial was stopped early after mean f/u of 24 months b/o significant reduction in mortality with aldactone
30% risk reduction
Lower risk of death both due to SCD and progressive HF
35% reduction in hospitalization for worsening HF
Improved HF symptoms
Mean aldactone dose was 26 mg
Only 11% on beta blockers at time of randomization
Pts excluded with creatinine >2,5 and BL K >5.

## EPHESUS

- Total deaths
- 478 eplerenone
- 554 placebo
- CV deaths
- 407 eplerenone
- 483 placebo

**Notes:**
In the EPHESUS trial of over 6600 patients with evidence of symptomatic LVSD post MI, pts were randomized to E or P an average of 7 days after infarction. 
478 deaths with active drug v 554 with placebo
Most of the decrease due to lower risk of SCD with nonsignificant decreases in risk of death due to HF or recurrent MI. Beneficial effect seen in background Rx with ACEI or ARB.

## Options for Intravenous Therapy

- Inotropes
- Dobutamine
- Milrinone
- Vasodilators
- Nitroprusside
- Nesiritide

## Intravenous Inotropes

**DOBUTAMINE**
- Beta agonist
- Positive inotrope
- Rapid onset of action
- Can not be used with beta blockers
- Drug of choice for hypotensive patients

**MILRINONE**
- Phosphodiesterase inhibitor
- “Ino-dilator”
- Can use with beta blockers
- Slower onset of action
- Renal clearance

## Intravenous Vasodilators

**NITROPRUSSIDE**
- Balanced vasodilator
- Inexpensive
- Short half life
- Rapid onset
- Quick offset
- Renal clearance
- Side effects
- Neurologic
- Hypoxia

**NESIRITIDE**
- Balanced vasodilator
- Expensive
- Longer half life
- Fewer side effects

## Nesiritide Versus Other Vasodilators

**Parameters**

**Nitroglycerin**

**Nitroprusside**

**Nesiritide**

- Tachyphylaxis

- Yes

- No

- No

- Toxic Metabolites

- No

- Yes

- No

- Hypotension

- Yes

- Yes

- Yes

**Cost/day**

- $110

- $100

- $380

- Headache

- Yes

- Yes

- Yes

- Action on RAAS

- ?

- 

-  Renin

- 

-  Aldosterone

- Difficult titration

- No

- Yes

- No

**Notes:**
Slide:  Nesiritide may offer benefits in the treatment of HF when compared to currently available vasodilators.  Vasodilators such as nitroglycerin often require dosing adjustments because of tolerance with prolonged use.  Nitroprusside may cause problems due to precipitous drops in blood pressure.  Nesiritide, like the other vasodilators, may cause hypotension and may also cause headache.  The incidence of headache that occurs with nesiritide is substantially less than that which occurs with nitroglycerin.  
Additional costs:  milrinone $220/day

## How do I monitor response to treatment?

## Echocardiography

- Once the diagnosis of heart failure due to systolic dysfunction is established, repeat echocardiography is indicated only
- For significant change in functional status
- To assess response to beta blockade

## Uses of BNP levels

- DIAGNOSIS
- Levels less than 100 pg/ml generally exclude a cardiac cause of dyspnea
- PROGNOSIS
- Failure to lower BNP level during hospitalization suggests an increased risk of early readmission
- Elevation of BNP during hospitalization suggests increased mortality

## Uses of BNP levels

- On admission
- During course of therapy
- When euvolemic
- Clinically
- By right heart catheterization
- On discharge

## BNP Predicts Outcome 

**1506**

**690**

**2**

**2009**

**BNP Level**

**Of the 72 patients admitted with CHF, 22 endpoints occurred**
**In these patients BNP increased by a mean of 233 pg/ml, p<0.001**
**In patients without death or readmission BNP decreased by 215 pg/ml**
**The last BNP level measured was the strongest predictor of events, if the level was <1200 (in this population) 90% chance of no adverse events**

**Notes:**
Each BNP value represents the mean +/- SEM

## BNP Concentration for the Prediction of Clinical Events

- BNP Concentration for the Prediction of Clinical Events

- Harrison A, et al, *Annals of Emergency Medicine* 2002

- 0

- 20

- 40

- 60

- 80

- 100

- 120

- 140

- 160

- 180

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- 45

- BNP < 230 pg/ml

- BNP 230-480 pg/ml

- BNP > 480 pg/ml

- CHF Death, Hospitalization, or ED visit

- Days

- 50%

***RR CHF death 24.1***

**Notes:**
NOTES: Reverse Kaplan Meier Curve for survival.   325 patients presenting to the emergency room with dyspnea were followed after BNP level drawn initially.  Patients with the highest level of BNP had a 50% cumulative probability of an event.  In the lowest risk group the patients had an excellent 6 month prognosis with only 2.5% incidence of CHF events.  The relative risk of 6 month CHF death in patients with BNP levels above 230 was 24 (compared to patients below that level.  The relative risk of noncardiac death was 1.1.  
In 325 patients presenting to the ED with dyspnea, BNP levels were determined. Patients were then followed for 6 months looking for the following endpoints: death (cardiac and non-cardiac), hospital admissions (cardiac), and repeat ED visits for CHF.  Using Kaplan-Meyer plots for all CHF events, patients who left the emergency department with BNP levels >480 pg/ml had a 6-month cumulative probability of a CHF event of (43%). On the other hand, patients who left the emergency department with BNP levels <230 pg/ml had an excellent prognosis with only 2.5% incidence of CHF end-points. The odds ratio for 6-month CHF death in patients with BNP levels > 230 was 46. 
BNP levels measured in patients presenting with dyspnea to the ED are highly predictive of future cardiac events. Utilization of BNP levels in patients presenting with symptoms of CHF should prove to be a cost-effective way to risk-stratify patients with HF. 

## CONCLUSIONS

- Heart failure is not a specific disease entity but a final common pathway of many diverse cardiovascular conditions
- To adequate understand your patient with heart failure you need to know
- The type of heart failure
- The cause of heart failure
- The Stage and Class of heart failure and the volume status

## CONCLUSIONS

- There are multiple treatment options for patients with heart failure
- Polypharmacy is the rule rather than the exception
- Polypharmacy is NOT a dirty word

## Additional Treatment Optionsin Heart Failure

- Devices
- Defibrillators
- Biventricular Pacemakers
- Surgery
- Revascularization
- Valvular reconstruction
- Ventricular support
- IABP/LVAD
- Transplantation

## Mechanical Support

- Intra-aortic balloon pump for short term support

## Mechanical Support

- Intra-aortic balloon pump for short term support
- Ventricular assist device as bridge to transplant or destination therapy

## Cardiac Transplantation

- Consider cardiac transplant for patients
- Less than 65 years
- Class III-IV HF
- Lack of other medical or surgical options
- Limited comorbidities
- Expected survival less than 12 months