Advanced Therapies in Chronic Heart Failure By Susan George, DNP, APRN- CNP, CCNS, CCRN, CHFN Objectives
Briefly review various pharmacologic agents used to manage heart failure (HF) Define advanced HF Identify warning signs of advanced HF Discuss inotropes used in chronic HF Review indication and contraindication for transplant. Describe mechanical circulatory support in the management of chronic HF Oklahoma Heart Failure
More deaths from HF than all forms of cancer combined 10% within 1st year & 50% within 5yrs 300,000 to 800,000 advance HF patients in US 60,000 patients are younger than 65yrs old High morbidity, mortality, and poor quality of life Cost
In 2012 the estimated was $30.7 billion. $21 billion direct and $10 billion indirect cost Hospitalization accounts for 80% of the direct cost Heidenreich et al. (2013) Definition of Systolic HF It is a complex clinical syndrome that can result from any structural or functional cardiac disorders that impairs ability of the
left ventricle to ejects blood. Classification of Heart Failure Functional classification: NYHA class (I-IV) - Based on clinical signs Staging of HF: ACC/AHA stages (A,B,C,D) Management of HF HF tool box Life style modification Medications Electrical Therapy Advanced HF therapy (Transplant/ MCS)
Goals of HF Management Primary prevention Control of day to day symptoms -Volume management -Congestive symptoms Prevent disease progression -Decrease hospitalization -Decrease mortality
-Prevent ventricular remodeling, vascular remodeling, and activation of neurohormones (norepinephrine, angiotensin II, and aldosterone) Pharmacotherapy for Heart Failure Diuretics
Neurohormonal antagonists (ACEI, ARB, MRA, ARNI) Digoxin Ivabradine Inotropics: (Phosphodiesterase InhibitorsMilrinone and dobutamine) Vasodilators (Hydralazine, Nitroglycerine & Nesiritide) Yancy et al. 2013 ACC/AHA Guideline for Management of Heart Failure Volume Management c Diuretics
Cortex Thiazides K Sparing Medulla Loop LoopofofHenle Henle Loop Diuretics
Neurohormonal Antagonist Neurohormonal antagonists (ACEI, ARB, MRA, ARNI) Change the natural history HF disease process by blocking activation of RAAS and SNS. Arrest, prevent, and may even reverse the process of progressive ventricular remodeling. Decrease morbidity and mortality associated with HF
Angiotensin Receptor Blockers Sartans Angiotensin II AT I receptor Oxidative Stress Free Radicals Cell Growth
(-) Vascular remodeling LV remodeling Proteinuria Angiotensin receptor neprilysin inhibitor (ARNI) ARNI Entresto (Combintion of Sacubitril and Valsartan) Sacubitril: Prodrug that inhibits neprilysin leading to increased levels of natriuretic peptides Valsartan: Angiotensin II receptor blocker
Side Effects Angioedema, hypotension, impaired renal function, and hyperkalemia. Should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACEI. 2016 ACC/AHA Update on New Pharmacological therapy for Heart Failure Beta-blockers Sympathetic Activation in Heart Failure CNS sympathetic outflow Cardiac sympathetic activity 12 1receptors receptors receptors
Myocardial toxicity Increased arrhythmias Sympathetic activity to kidneys + peripheral vasculature 1- Activation of RAS Vasoconstriction Sodium retention
Effects of RAAS activation is also mediated through aldosterone. Increase in aldosterone level persist in the circulation even in the presence of angiotensin II inhibition. It is associated with increased myocardial fibrosis, inflammation, myocyte hypertrophy, and apoptosis. MRAs inhibit aldosterone Ivabradine (Corlanor)
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker. Reduces diastolic depolarization slope in the SA node, thereby decreasing heart rate via direct sinus node inhibition without direct effects on myocardial contractility and intracardiac conduction Indicated to reduce the risk of HF hospitalization in patients with stable, symptomatic chronic HF with LVEF 35%, who are in sinus rhythm with resting heart rate 70 bpm and either are on maximally tolerated doses of betablockers or have a contraindication to beta-blocker use
2016 ACC/AHA Update on New Pharmacological therapy for Heart Failure Hydralazine and Isordil The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for African Americans patients with LVEF <40%, NYHA class IIIIV symptoms receiving optimal therapy with ACE inhibitors and beta blockers. Indicated for patients with LVEF <40% who can
not tolerate ACEI/ARB secondary to renal insufficiency/impairment. Benefits of Medical Therapy Demonstrated in RCTs 2013 ACC/AHA Guideline for Management of Heart Failure Digoxin No mortality benefit Decrease hospitalization Increase exercise tolerance May help for rate control in patients with
Afib Drugs to Avoid in HF Nonsteroidal anti-inflammatory drugs (NSAIDs) Thiazolidinediones Calcium channel blockers nondihydropyridine Dietary supplements Mann & Felker, 2016 ACC/AHA HF Management Algorithm
Yancy et al. 2013 ACC/AHA Guideline for Management of Heart Failure Advanced/End Stage HF Inability to tolerate HF medication or reduction of dose Recurrent hospitalization
Severe exercise intolerance Heart failure wasting syndrome Cardiorenal syndrome
Right heart failure Inotrope dependence Definition of Advanced Heart Failure GDMT: Guideline Directed Medical Therapy CRT: Cardiac Resynchronization Therapy
Prognostic Models in HF Ambulatory Model Key Covariates Outcome Heart Failure Survival Score Peak VO2, LVEF, O2, LVEF, serum sodium, mean BP, HR, ischemic
etiology, QRS duration/morphology All-cause mortality Seattle Heart Failure ModelAllen et al. Circulation. (2012). 125(15). 1928-1952 NYHA function class, All-cause mortality, urgent ischemic etiology, transplantation, or LVAD
diuretic dose, LVEF, implantation SBP, sodium, hemoglobin, percent lymphocytes, uric acid, and cholesterol Allen et al. Circulation. (2012). 125(15). 1928-1952 Seattle Heart Failure Model VO2 Max
Exercise testing has been used for prognostic purposes and exercise capacity has been demonstrated to be an important component to the risk profile in chronic heart failure. VO2 max refers to the maximum amount of oxygen that an individual can utilize during intense or maximal exercise. It is shown to be a strong predictor of hospitalization and death and a predictor of survival in patients with more advanced HF considered for advanced HF therapy.
HF Progression Transition to Advanced HF Allen et al. Circulation. (2012). 125(15). 1928-1952 Advanced Heart Failure Limited treatment option - Heart transplantation - Mechanical circulatory support (MCS) - Long-term inotropic therapy - Palliative care
Inotropes Indicated in the presence of acute or chronic hemodynamic compromise with end organ dysfunction. Bridge to mechanical circulatory support (MCS) Bridge to transplant Palliative
Inotropes in Advanced HF Milrinone and Dobutamine are currently the only two inotropes approved for use in the US. Both increase cardiac output by increasing the intracellular level of cyclic adenosine monophosphate (cAMP) Dobutamine increases cAMP indirectly through
adrenergic agonism. Milrinone, a phosphodiesterase inhibitor, directly blocks cAMP breakdown Dobutamine Sympathomimetic amine, which acts on beta-1, beta-2, and alpha-1 adrenergic receptors. Strong inotropic effect and relatively weak
chronotropic effect No significant change in BP due to its alpha-1 agonist activity causing vasoconstriction, that balances the beta-2 vasodilatory effect. The use is problematic in patients who take beta blockers due to its adrenergic properties Milrinone
Milrinone inhibits phosphodiesterase 3 (PDE3), which prevents the degradation of cAMP and ultimately leads to an increase in protein kinase A (PKA). It is an inodilator, both increasing cardiac contractility and reducing afterload with a consequent reduction in left ventricular filling pressures. PKA increases contractility of the left ventricle and cardiac output through cAMP dependent-PKA Milrinone
Less myocardial oxygen consumption with milrinone when compared to dobutamine. Can be used in patients on beta blockers, because its effects are not dependent on beta adrenoreceptors. Milrinone not only acts as a systemic but also a pulmonary vasodilator. It is the preferred agent in patients with pulmonary hypertension and HF. Similarities
Most of the hemodynamic effects of dobutamine and milrinone are similar. Increase cardiac output Cause peripheral vasodilation Decrease pulmonary capillary wedge pressure Differences Dobutamine Milrinone
Greater increase in heart rate More hypotension Greater increase in myocardial oxygen consumption Greater reduction in left and right heart filling pressures Greater proarrhythmic effect, including Greater reduction in MAP and PAP ventricular tachycardia Effects are attenuated in patients who
receive beta blockers Greater hemodynamic effects in general when the patient is on beta blockers Less expensive: US $380 $533 (for a Expensive: US $16,270 $1,334 (for a course of in-hospital inotrope therapy) course of in-hospital inotrope therapy) Longer duration of action after discontinuation, especially in the presence of renal dysfunction Mortality on Inotropic Support Rogers JG, Butler J, Lansman SL, et al. 2007;50(8):741-47
Advanced HF therapies Cardiac Transplantation Mechanical Circulatory support Time to Transition: Red Flags
Repeated (2) hospitalizations or ED visits for HF in the past year Progressive deterioration in renal function Weight loss without other cause (e.g. cardiac cachexia) Intolerance to ACE inhibitors due to hypotension and/or worsening renal function Intolerance to beta blockers due to worsening HF or hypotension Frequent systolic blood pressure < 90 mmHg Persistent dyspnea with dressing or bathing requiring rest
Inability to walk 1 block on the level ground due to dyspnea or fatigue Recent need to escalate diuretics to maintain volume status, often reaching daily furosemide equivalent dose > 160 mg/d and/or use of supplemental metolazone therapy Progressive decline in serum sodium, usually to < 133 mEq/L Frequent ICD shocks Yancy et al. 2013 ACC/AHA Guideline for Management of Heart Failure Cardiac Transplantation Ideal treatment for advanced HF Provides increased longevity and symptomatic relief
Approximately 3,000 people are on waiting list at any given time In 2015, there was only 2804 donors in US United Network for Organ Sharing [UNOS] (2017) Listing criteria for Heart transplantation
Cardiopulmonary exercise testing: VO2 max <14ml/kg/min if patients intolerant to BB; <12ml/kg/min in the presence f BB; or <50% of predicted VO2 in young patients (50yrs) and women. Acceptable pulmonary artery pressure Age <70 Diabetes well controlled Absence on neoplasm Psychosocial support Contraindication
Noncompliance with medical regimen Active substance abuse Severe symptomatic cerebrovascular disease
Severe organ dysfunction (lung, kidney, liver, coagulopathy) Active infection Active mental illness Inadequate social support Fixed, severe pulmonary hypertension Morbid obesity (BMI > 35 kg/m2) Age > 70 years Recent or uncured malignancy Transplant Listing
Each US transplant center is part of the nationwide United Network of Organ Sharing (UNOS), which is divided into eleven regions, each with specific local organ procurement organizations (OPO) Patients are listed by OPO, transplant center, and ABO blood type, and prioritized by medical urgency (UNOS Status). Medical urgency status: 1A, 1B, 2, 7 Post Transplant Care Immunosuppression
Prednisolone Prophylactic antimicrobials Agents to treat post-transplant complications and comorbidities Survival After Transplant Katz, N. J et al. 2015 Mechanical Circulatory Support MCS with left ventricular assist device (LVAD) is a treatment option.
- Bridge to transplant (BTT) - Destination therapy (DT) - Bridge to decision (BTD) - Bridge to recovery Improves Survival and QOL It is a rapidly evolving field Indication
NYHA IV functional class Life expectancy <2 years Failure to respond to optimal medical management LVEF 25% Refractory cardiogenic shock or cardiac failure VO2 14 mL/kg/min
Need for IV inotropes therapy Recurrent symptomatic sustained VT or VF in the presence of an untreatable arrhythmogenic substrate Exclusion Criteria Active systemic infection Uncorrectable aortic insufficiency Renal insufficiency that may require dialysis in
the near future History of cardiac transplant Any condition, other than heart failure, which is expected to limit survival to less than 2 years INTERMACS Profiles of Advanced Heart Failure
Profile 1: Critical cardiogenic shock Profile 2: Progressive decline- sliding on inotrope Profile 3: Stable but inotrope dependent Profile 4: Resting symptoms Profile 5: Exertion Intolerant Profile 6: Exertion Limited Profile 7: Advanced NYHA Class 3 Types of MCS Left ventricular assist device (LVAD) Biventricular support (BiVAD) Total artificial heart (TAH)
Types of LVADs First generation pumps - Pulsatile pumps Second generation pumps - Continuous axial flow pumps Third generation pumps
- Magnetically levitated pump rotor Commonly Used Durable LVADs HVAD Centrifugal LVAD Magnetic Drive Hemodynamic Bearing HeartMate II Axial Flow LVAD Ruby Bearing HeartMate 3
Centrifugal LVAD Magnetic Levitation No Bearing Comparison of Devices First-Generation Second-Generation Third-Generation Flow Profile Pulsatile
Continuous (Axial) Continuous (Centrifugal) Device Example HeartMate XVE HeartMate II HeartMate III, HeartWare HVAD
BTT (HVAD) BTT, DT (HM 3) Improved Survival with MCS Miller L W et al. Circulation. 2013;127:743-748 LVAD Survival Survival significantly greater (up to 7 times) than that reported with medical therapy for inotrope dependent heart failure based on multiple trials Landmark trial: REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive
Heart Failure) trial. Jorde, S.S., et al. 2013 LVAD Survival HM 3 LVAD Trial Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) ongoing trial. Mehra, M.R. et al. 2017
Improved Outcomes Improvements in patient selection Improvements in technology Improvements in patient management Anti-Coagulation Guidelines Medications Aspirin prevents platelet aggregation Persantine prevents platelet aggregation Plavix/Effient- occasionally used for platelet aggregation Coumadin- required, goal INR depends on patients underlying comorbidities
Patient management Multidisciplinary approach Psychosocial support Total artificial heart (TAH) Biventricular support (BiVAD) Paracorporeal VAD (P-VAD) Summary
Advanced heart failure patients has limited treatment options. Timely referral of end stage HF patients to advanced HF center is essential for success. Heart transplantation is the ideal therapy for refractory end stage HF. However organ shortage limits the therapy. RCTs have demonstrated benefits LVADs in reducing mortality and improving QOL.
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