David W Kabel MD FACC. NH activation is an acute adaptation that initially allows BP and cardiac...

TREATMENT OF CHRONIC HEART FAILURE

David W Kabel MD FACC

CHF-Neurohormonal Activation

NH activation is an acute adaptation that initially allows BP and cardiac output to be maintained

NH activation rapidly becomes detrimental

Vasoconstriction is a hallmark of untreated LV dysfunction

Starts a self perpetuating cycle of cell death and remodelling with further NH activation

CHF-Neurohormonal Activation

Pump failure is sensed as hypovolemia

RAS activation leads to increases levels of angiotensin II

ANS activation leads to increased circulating catecholamines

Hyperaldosteronism

CHF-Pathophysiology

CHF-Ventricular Remodeling

Myocyte dysfunction and cell death Remodeling occurs

LV dilatation Increased wall stress Ischemia Energy depletion Interstitial fibrosis More NH activation Mitral regurgitation Change from ellipsoid to spherical shape

HF-Goals of Treatment

Relieve Symptoms Improve LV function-both systolic &

diastolic Reduce hospitalizations Improve prognosis

Increased ejection fraction is associated with improved prognosis

Diastolic function can also improve Manage expectations

Types of HF Therapy

Pharmacologic Diuretics Neurohormonal inhibitors Antiarrhythmic drugs

Device therapies AICD Resynchronization therapy LV assist devices

Adjunctive measures Diet Fluid restriction Home monitoring

General measures in HF Treat co-morbidities according to guidelines

Hypertension!-Systolic BP<120 Diabetes-some hypoglycemic drugs may worsen HF Lipid abnormalities Sleep apnea! Atrial fibrillation

Avoid drugs which may exacerbate HF Anti-arrhythmic drugs other than amiodarone and

dofetilide Calcium blockers-verapamil, diltiazem NSAIDS

Sodium retention Inhibit effects of diuretics, ACEIs and ARBs Renal toxicity

General Measures in HF

Monitor Weight Blood pressure Renal function Home health monitoring can reduce hospital

admissions Regular low to moderate physical activity

Medicare now pays for Cardiac Rehab for CHF Avoid dietary indiscretion Stop smoking

Pharmacologic therapy in HF

First goal is to achieve euvolemia

Initiate therapy to block neurohormonal activation

Treat comorbidities

Most patients can be treated effectively with inexpensive generics

Diuretics in HF

Relieve symptoms faster than any other drugs Relieve dyspnea Reduce edema Improve exercise tolerance

Only drugs that control fluid retention

Should not be used alone in symptomatic patients

Loop Diuretics

Increase sodium excretion by 20-25%

Enhance free water clearance

Maintain efficacy in reduced GFR

Thiazides in HF

Increase sodium excretion 5-10%

Reduce free water clearance

Lose effectiveness with decreased GFR

Better antihypertensive drugs than loop diuretics Longer duration of action

Diuretics- appropriate dosage

Too little Fluid retention Reduced effectiveness of other therapies

Too much Volume contraction Hypotension Hyponatremia Renal insufficiency

Right dose may be difficult to determine Dosage requirements change with change

in clinical status

Practical use of diuretics in Chronic HF

Initiate with loop diuretics Furosemide most common Torsemide or butenamide may work better

in a few patients, especially with deteriorating renal function

Start low dose once a day Titrate up and go to BID dosage as needed

I like AM and noon schedule Reduces nocturia

Restrict dietary sodium

Practical use of diuretics in chronic HF

Maintenance therapy may require lower doses than at initiation

Monitor electrolytes frequently Some class I and II patients may not need

any diuretics for a time Consider lower dose while up-titrating

other drugs, especially if BP is low

Diuretic resistance

Fluid retention may result in poor absorption from GI tract

Reduced GFR requires increased dose of loop diuretics

Intermittent IV loop diuretics Combination therapy

Add metolazone

Risks of diuretic therapy

Electrolyte imbalance-sodium, potassium, and magnesium

Volume contraction Hypotension Azotemia Hearing loss Hypotension, fluid retention, and

azotemia together have a poor prognosis

Beta Blockers in Chronic HF

Block effects of circulating catecholamines Sympathetic activation initially beneficial to

increase cardiac output Long term ANS activation is deleterious

Increased LV volume and pressure overload Vasoconstriction Impaired renal sodium excretion LV hypertrophy and dilatation Myocardial fibrosis Arrhythmias

Benefits outweigh negative inotropic effects

Beta Blockers in Chronic HF

Three drugs are approved for use in HF Carvedilol Metoprolol succinate Bucindolol

All patients with reduced EF should receive beta blockers unless contraindicated Reduced mortality Increased EF Symptomatic relief

Practical Use of Beta Blockers

Do not start until vascular congestion is relieved

Start at same time as ACEI or ARB Effects are additive Small doses of both are more effective than

higher dose of a single drug Even a small dose is better than none

Use with caution with COPD or bradycardia

Practical Use of Beta Blockers

Initiate at small doses Unless replacing another beta blocker

Titrate up every 2-4 weeks as tolerated Monitor fluid balance

Daily weights Continue even if clinical improvement is

not evident Avoid abrupt withdrawal

Adverse Effects of Beta blockers

Worsening CHF and fluid retention Increase diuretics Can usually continue beta blockers

Fatigue Often resolves in a few days or weeks Reduce dose or change to a different drug

Hypotension Often occurs for 1st 24-48 hours Decrease diuretic dose Give beta blocker and ACEI at different times of day

Bradycardia and heart block May require pacemaker

ACE Inhibitors in HF

Best studied of RAS inhibitors First class of drugs shown to improve EF

and prognosis Prevent conversion of Angiotensin I to

Angiotensin II Modifies LV remodelling possibly more

than ARBs All ACEIs equivalent

Tissue ACEI?

ACEIs-Clinical Effects

Improve symptoms and clinical class Reduce SCD Reduce combined risk of hospitalization

and death Improve outcomes in presence or

absence of CAD Improvement occurs in all NYHA classes

Angiotensin Receptor Blockers in HF

Prevent Angiotensin II from attaching to vascular receptors-Prevents vasoconstriction

Modify LV remodelling perhaps less than ACEIs

Less data than ACEIs but clinical effects are similar Fewer hospitalizations and deaths Seen in all NYHA classes

May be better than ACEIs in preventing atrial fibrillation

Most commonly used for patients who develop cough while taking ACEIs

Practical Use of ACEIs and ARBs

Use in all patients with reduced EF unless contraindicated Even Class I

Use with beta blockers Use with diuretics if fluid retention Start at low doses and titrate up unless

hypertensive Check BMP at 1-2 weeks and q3-6

months after that

Long Term Rx with ACEIs and ARBs

Tolerated by 85-90% of patients Try to achieve maximum dose Symptomatic relief may come in a few

days or several months Continue treatment even in absence of

symptomatic improvement Don’t delay beta blockers while titrating up Avoid NSAIDs No data supporting ACEIs and ARBs in

same patient-some data against it

ACEIs and ARBs-Precautions

Avoid in: Hx of angioneurotic edema-high incidence of

cross-reactivity between ACEIs and ARBs Oliguric renal failure Pregnancy

Use with caution in: Hypotension Creatinine>2.0 Bilateral renal artery stenosis Serum potassium >5.0

Aldosterone Antagonists in HF

Spironolactone and Elperenone (Inspra) Main advantage of Inspra is decrease in side

effects-breast pain, GI, but much more costly Block effects of aldosterone in renal

tubule Enhance effects of loop diuretics Increased sodium excretion Potassium retention Most difficult drugs to use in HF Under-utilized even by experts who

advocate increased usage

Aldosterone Antagonists in HF

Added after beta blockers and ACEIs, ARBs Should be used with caution in absence of

loop diuretic or thiazide Monitoring aldosterone antagonists-AHA

recommendations for K+ and renal monitoring 3 days 7days Monthly for 3 months 3-6 months after that

Hydralazine-Nitrates in HF

Both venous (nitrate) and arterial (hydralazine) vasodilatation Both preload and afterload reduction

Reduce mortality but not hospitalizations Inferior to ACEIs, ARBs Frequent side effects

Headache GI symptoms Lupus like syndrome

Hydralazine-Nitrates in HF

Most effective in African-American patients when added to standard therapy

Suitable alternative for patients intolerant to ACEIs and ARBs Angioneurotic edema Azotemia

May be added to standard therapy if patient remains hypertensive

Compliance may be an issue Large number of pills TID dosage Nitrate tolerance

Digoxin In HF

Only indication is for rate control in atrial fibrillation If beta blockers are ineffective Should consider pacemaker & AV node ablation

instead Has mild positive inotropic effects Dosage-Never exceed 0.125 mg daily-less

if decreased GFR Followup to AFFIRM trial showed 40%

increased all cause mortality for AF patients on digoxin

Digoxin in HF

Look for reasons to DC the drug Avoid in patients with recent MI or

ischemia Toxicity enhanced by hypokalemia,

hypoxia, thyroid disease Side effects

Bradycardia and heart block Re-entrant tachycardias Anorexia, weight loss, nausea Visual disturbances-yellow vision, hoarfrost Mental status change

Initiation of Therapy in HF

Achieve euvolemia Start beta blockers and ACEIs, ARBs at low

doses Push beta blockers faster-more effect on

prognosis May increase both at once depending on BP

Titrate up q2-4 weeks BMP on each visit May have to go slowly in elderly Maximum dose determined by BP, renal function

Initiation of Therapy in HF

Inform patient of possible side effects Fatigue

May disappear after several days Ask patient to stick with therapy

Lightheadedness Hypotension may require dose reduction

Drug specific side effects Increase meds to maximum tolerated

dosage

Maintenance Therapy in HF

Check LV function after 3-4 months of maintenance therapy

Add spironolactone If little or no improvement in EF If loop diuretics and metolazone ineffective

Add hydralazine-nitrates In African-American patients If response to standard Rx inadequate

Add additional antihypertensives to achieve systolic BP of <120 If BP not controlled with standard Rx Hydralazine Amlodipine-Only calcium blocker to use in LV dysfunction Clonidine

Resynchronization Therapy in HF

30% of patients with low EF and Class III-IV symptoms have QRS>120 msec

Mechanical consequences of dysynchrony

Suboptimal LV filling Reduced rate of rise of LV contractility Prolonged duration of mitral regurgitation Paradoxical septal motion

Dysynchrony increases mortality

What Is CRT?

Pacemaker therapy-Biventricular Three leads

Right atrium if in sinus rhythm Right ventricular apex Coronary sinus for left ventricular pacing

LV and RV are paced in synchronous fashion Septum contracts with rest of LV May require echo guided adjustments

Ivabridine-Corlanor-SHIFT Study

Novel agent designed to slow HR in systolic HF and EF<40% already on beta blockers.

Sinus rhythm

Target HR 50-60 bpm

Demostrated that lower resting HR correlated with improved prognosis

Does not lower BP

Systolic Heart failure treatment with

the If inhibitor ivabradine Trial

Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure:

analysis from the SHIFT study Effect of ivabradine on outcomes in patients with chronic heart failure and HR 75 bpm

www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

Aim

To assess the effect of ivabradine on outcomes in heart failure patients on recommended background therapies with heart rates ≥75 bpm in the SHIFT trial


Baseline characteristics

Ivabradinen=2052

Placebon=2098

Mean age, years 60 60

Male, % 77 77

BMI, kg/m2 28 28

Mean HF duration, years 3.4 3.4

HF ischemic cause, % 66 65

NYHA class III, % 50 51

NYHA class IV, % 2 2

Mean LVEF, % 28.7 28.5

Mean HR, bpm 84.3 84.6


Baseline background treatment

Ivabradinen=2052

Placebon=2098

β-Blockers, % 87 88

At least half target dose 55 56

At target dose 26 26

ACE inhibitors/ARBs, % 90 90

Diuretics (excludes AAs), % 85 83

Aldosterone antagonists, % 63 61


Effect of ivabradine on primary outcomeCV death or hospitalization for HF

0 6 12 18 24 30

40

10

0

Hazard ratio=0.76

P<0.0001

Pati

ents

wit

h p

rim

ary

com

posi

te e

nd p

oin

t (%

)

Time (months)

20

30

Placebo

Ivabradine


Effect of ivabradine on cardiovascular death

Hazard ratio=0.83 P=0.0166

Pati

ents

wit

h c

ard

iovasc

ula

r death

(%

)

0 6 12 18 24 30

10

0

20

30

Time (months)

Placebo

Ivabradine


Pati

ents

wit

h c

ard

iovasc

ula

r death

(%

)

0 6 12 18 24 30

10

0

20

30

Time (months)

Placebo

Ivabradine

Hazard ratio=0.70

P<0.0001

Effect of ivabradine on hospital admission for worsening heart failure


1.00

Primary composite end point

Cardiovascular mortality

Hospitalization for worsening HF

Death from HF

All-cause mortality

All-cause hospitalization

Any cardiovascular hospitalization

0.76 0.68-0.85

0.83 0.71-0.97

0.70 0.61-0.80

0.61 0.46-0.81

0.83 0.72-0.96

0.82 0.75-0.90

0.79 0.71-0.88

0.20

<0.0001

0.0166

<0.0001

0.0006

0.0109

<0.0001

<0.0001

PPHazard ratio

1.200.40 0.60 0.80

Effect of ivabradine on major outcomes

Favors ivabradine Favors placebo

95% CI


Effect of ivabradine on outcomes according to HR achieved at 28 days

0 6 12 18 24

40

10

0

Time (months)

20

30

Patients with primary composite end point (%)

Day 28

75 bpm

70 to <75 bpm

65 to <70 bpm

60 to <65 bpm

<60 bpm


Effect of ivabradine on outcomes according to magnitude of HR reduction

0 6 12 18 24

40

10

0

20

30

Day 28

Time (months)

Patients with primary composite end point (%)

0 bpm

-10 to <0 bpm

< -10 bpm


In HF in sinus rhythm with HR ≥75 bpm heart rate

reduction with ivabradine improves outcomes,

including all-cause death and cardiovascular death

reduces

Ivabradine-associated risk reductions are related to

both HR achieved and magnitude of HR reduction

Patients achieving <60 bpm or with >10 bpm

reduction have the best prognosis

Conclusions


SHIFT Study-Limitations of Ivabradine

Younger than normal patient population

Less that optimal doses of beta blockers

Ivabradine can cause atrial fibrillation

Useful in limited number of patients

Cost

PARADIGM-HF Study-Effects of Neprilysin Inhibition

Neprilysin degrades several vasoactive peptides BNP,bradykinin, adrenomedullin

Neprilysin inhibition increases levels of natiuretic peptides, thus counteracting RAS activation

LCZ696 compared to enalapril Combination of valsartan with neprilysin

inhibitor sacubitril Would LCZ696 improve outcomes over

enalapril?

Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.

McMurray JJV et al. N Engl J Med 2014;371:993-1004







Adverse Events during Randomized Treatment.


Primary and Secondary Outcomes.


Conclusions

• LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.

PARADIGM-HF

Neprilysin inhibition is similar to other effective therapies Beta blockers ACEI, ARB

Blocks neurohormonal activation Appropriate for most patients with HF

Elderly Atrial fibrillation

Will probably become part of standard CHF regimen

Cost will be a factor

Indications for CRT

EF less than 35% LBBB with QRS >150 msec

HFSA recommends for QRS >120 RV pacing with EF <35% should be

upgraded to CRT MADIT II trial showed benefit for Class I-II

patients Usually combined with AICD

Depends on patient preferences and prognosis

CRT-Biventricular Pacing

Benefits of CRT

Improves LV contraction Increases EF by 5-10% (or more) Reduces mitral regurgitation Improves hemodynamics Clinical improvement

Symptoms may improve by 1-2 classes QOL improvement Improved exercise tolerance and O2

comsumption Reduced hospitalizations Improved survival

Volume Monitoring in HF

New generation of ICDs can monitor volume status by measuring thoracic impedance

Can be measured in office with a programmer

Optivol by Medtronic Detects fluid retention before clinical

signs and symptoms Can help to determine if symptoms are

due to fluid retention


Allows early intervention Prevents hospitalizations Outpatient IV diuretics Enhances standard therapy Devices have alarms but FDA requires

them to be turned off


LV Assist Devices and Transplant

Strict criteria for implantation-Eligibility limited

Indications EF< 35% with Class IV symptoms refractory to

standard therapy Refractory VT and VF

LVAD used to be considered bridge to transplant

LVAD now may be destination therapy for some patients

LVAD-Types

Managing Expectations in HF

Often the most difficult aspect of therapy Disease is progressive

Therapy tends to become less effective over time Most patients with HF will die of it Need to be honest with patient and family Get 2nd opinion if necessary May benefit from Hospice or Palliative Care

Timing is difficult Prognosis less certain than with cancers and

neurologic diseases

Managing Expectations in HF

World Health Organization reports worldwide mortality rate holding steady at 100%- The Onion

We physicians don’t prevent anything, we merely postpone-Anonymous

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David W Kabel MD FACC. NH activation is an acute adaptation that initially allows BP and cardiac...

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