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 Titrate up every 2-4 weeks as tolerated Monitor fluid balance Unless replacing another beta blocker
Daily weights Continue even if clinical improvement is not evident Avoid abrupt withdrawal Adverse Effects of Beta blockers Worsening CHF and fluid retention Fatigue
Often resolves in a few days or weeks Reduce dose or change to a different drug Hypotension Increase diuretics Can usually continue beta blockers 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
Dont delay beta blockers while titrating up Avoid NSAIDs No data supporting ACEIs and ARBs in same patient-some data against it ACEIs and ARBsPrecautions 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 IIIIV 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 Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com 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 Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Baseline characteristics Ivabradine Placebo n=2052 n=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 Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Baseline background treatment Ivabradine Placebo n=2052 n=2098 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 -Blockers, %Blockers, % Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Effect of ivabradine on primary outcome CV death or hospitalization for HF Patients with primary composite end point (%)
Hazard ratio=0.76 P<0.0001 40 Placebo 30 Ivabradine 20 10 0 0 6 12
18 24 30 Time (months) Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Effect of ivabradine on cardiovascular death Hazard ratio=0.83 Patients with cardiovascular death (%) 30 P=0.0166 Placebo
20 Ivabradine 10 0 0 6 12 18 24 30 Time (months)
Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Effect of ivabradine on hospital admission for worsening heart failure Hazard ratio=0.70 Patients with cardiovascular death (%) 30 Placebo P<0.0001 20 Ivabradine 10
0 0 6 12 18 24 30 Time (months) Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Effect of ivabradine on major outcomes Hazard
ratio Primary composite end point Cardiovascular mortality Hospitalization for worsening HF Death from HF All-cause mortality All-cause hospitalization Any cardiovascular hospitalization P P 95% CI 0.76 0.85 0.68- <0.00
01 0.83 0.97 0.71- 0.016 6 0.70 0.80 0.61- <0.00 01 0.61 0.81
0.46- 0.000 6 0.83 0.96 0.72- 0.010 9 1.20 0.82 0.90 Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 0.20 0.40
0.60 Favors ivabradine 0.75- 0.80 1.00 Favors placebo <0.00 01 www.shift-study.com Effect of ivabradine on outcomes according to HR achieved at 28 days Patients with primary composite end point (%)
40 75 bpm 30 70 to <75 bpm 65 to <70 bpm 60 to <65 bpm 20 <60 bpm 10 0 0Day 28 6 12
18 24 Time (months) Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Effect of ivabradine on outcomes according to magnitude of HR reduction Patients with primary composite end point (%) 40 0 bpm -10 to <0 bpm 30 < -10 bpm
20 10 0 0Day 28 6 12 18 24 Time (months) Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com Conclusions
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 Bhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22 www.shift-study.com 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? KaplanMeier Curves for Key Study Outcomes, According to Study Group.
McMurray JJV et al. N Engl J Med 2014;371:993-1004 KaplanMeier Curves for Key Study Outcomes, According to Study Group. McMurray JJV et al. N Engl J Med 2014;371:993-1004 KaplanMeier Curves for Key Study Outcomes, According to Study Group. McMurray JJV et al. N Engl J Med 2014;371:993-1004 KaplanMeier 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 Blocks neurohormonal activation Appropriate for most patients with HF
Beta blockers ACEI, ARB 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 dont prevent anything, we merely postpone-Anonymous
