David W Kabel MD FACC

 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

 Pump failure is sensed as hypovolemia  RAS activation leads to increases levels of angiotensin II  ANS activation leads to increased circulating catecholamines  Hyperaldosteronism

 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

 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

 Pharmacologic  Diuretics  Neurohormonal inhibitors  Antiarrhythmic drugs  Device therapies  AICD  Resynchronization therapy  LV assist devices  Adjunctive measures  Diet  Fluid restriction  Home monitoring

 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

 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

 First goal is to achieve euvolemia  Initiate therapy to block neurohormonal activation  Treat comorbidities  Most patients can be treated effectively with inexpensive generics

 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

 Increase sodium excretion by 20-25%  Enhance free water clearance  Maintain efficacy in reduced GFR

 Increase sodium excretion 5-10%  Reduce free water clearance  Lose effectiveness with decreased GFR  Better antihypertensive drugs than loop diuretics  Longer duration of action

 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

 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

 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

 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

 Electrolyte imbalance-sodium, potassium, and magnesium  Volume contraction  Hypotension  Azotemia  Hearing loss  Hypotension, fluid retention, and azotemia together have a poor prognosis

 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

 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

 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

 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

 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 1 st hours  Decrease diuretic dose  Give beta blocker and ACEI at different times of day  Bradycardia and heart block  May require pacemaker

 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?

 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

 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

 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

 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

 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

 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

 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

 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

 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

 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 mg daily-less if decreased GFR  Followup to AFFIRM trial showed 40% increased all cause mortality for AF patients on digoxin

 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

 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

 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

 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

 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

 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

 Novel agent designed to slow HR in systolic HF and EF<40% already on beta blockers.  Sinus rhythm  Target HR bpm  Demostrated that lower resting HR correlated with improved prognosis  Does not lower BP

S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial 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 Effect of ivabradine on outcomes in patients with chronic heart failure and HR  75 bpm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

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

Ivabradinen=2052Placebon=2098 Mean age, years Mean age, years6060 Male, % Male, %7777 BMI, kg/m 2 BMI, kg/m Mean HF duration, years Mean HF duration, years HF ischemic cause, % HF ischemic cause, %6665 NYHA class III, % NYHA class III, %5051 NYHA class IV, % NYHA class IV, %22 Mean LVEF, % Mean LVEF, % Mean HR, bpm Mean HR, bpm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

Ivabradinen=2052Placebon=2098 β-Blockers, % β-Blockers, %8788 At least half target dose At least half target dose5556 At target dose At target dose2626 ACE inhibitors/ARBs, % ACE inhibitors/ARBs, %9090 Diuretics (excludes AAs), % Diuretics (excludes AAs), %8583 Aldosterone antagonists, % Aldosterone antagonists, % M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

Effect of ivabradine on primary outcome CV death or hospitalization for HF Hazard ratio=0.76 P < Patients with primary composite end point (%) Time (months) Placebo Ivabradine 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 = Patients with cardiovascular death (%) Time (months) Placebo Ivabradine M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

Patients with cardiovascular death (%) Time (months) Placebo Ivabradine Hazard ratio=0.70 P < Effect of ivabradine on hospital admission for worsening heart failure 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 < < < P P Hazard ratio Effect of ivabradine on major outcomes Favors ivabradineFavors placebo 95% CI 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 Time (months) Patients with primary composite end point (%) Day 28  75 bpm 70 to <75 bpm 65 to <70 bpm 60 to <65 bpm <60 bpm 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 Day 28 Time (months) Patients with primary composite end point (%)  0 bpm -10 to <0 bpm < -10 bpm 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 10 bpm reduction have the best prognosis Conclusions M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

 Younger than normal patient population  Less that optimal doses of beta blockers  Ivabradine can cause atrial fibrillation  Useful in limited number of patients  Cost

 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:

Kaplan–Meier Curves for Key Study Outcomes, According to Study Group. McMurray JJV et al. N Engl J Med 2014;371:

Kaplan–Meier Curves for Key Study Outcomes, According to Study Group. McMurray JJV et al. N Engl J Med 2014;371:

Kaplan–Meier Curves for Key Study Outcomes, According to Study Group. McMurray JJV et al. N Engl J Med 2014;371:

Adverse Events during Randomized Treatment. McMurray JJV et al. N Engl J Med 2014;371:

Primary and Secondary Outcomes. McMurray JJV et al. N Engl J Med 2014;371:

Conclusions

 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

 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

 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

 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

 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

 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 2 nd opinion if necessary  May benefit from Hospice or Palliative Care  Timing is difficult  Prognosis less certain than with cancers and neurologic diseases

 World Health Organization reports worldwide mortality rate holding steady at 100%- The Onion  We physicians don’t prevent anything, we merely postpone-Anonymous