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Transcript of 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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22
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
Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
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.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Primary and Secondary Outcomes.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
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
Volume Monitoring in HF
Allows early intervention Prevents hospitalizations Outpatient IV diuretics Enhances standard therapy Devices have alarms but FDA requires
them to be turned off
Volume Monitoring in HF
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