KSC2017 Inotrope and vasodilator in ADHF Seonghoon Choi Cardiology Hallym University Epidemiology and economic burden of HF 2012 USA 2030(est) Korea Incidence 825,000/yr Prevalence 5.1 million(2.1%) 8 million 750,000 (1.5%) 2013 NHIS Hospitalization ~ 1million/yr 60-70% at 5 yr Mortality 57,757(58% F) 30-40% at 1 yr Cost $30.7 billion $69.7 billion 1065억 (2016) Cost in HF Admission Lifetime Costs of Medical Care After Heart Failure Diagnosis. Circulation: Cardiovascular Quality and Outcomes. 2011; 4: 68-75. Typical presentation of ADHF • Median age 75 • Comorbidity : HTN 72%, DM 44%, COPD 31%, CKD 30%, Atrial fibrillation 31%. • Reduced EF ~ 50% • NYHA class @admission I 2%, II 11%, III 40%, IV 47% • SBP @admission < 90 mmHg 2%, 90-140mmHg 48%, >140 mmHg 50% ADHERE Registry Background Neuro-hormonal effects on cardiac function In ADHF AHF therapy 1970-2010 Congestion Renal impairment Low output Vasoconstriction Diuresis Reno protection Inotrope Vasodilator Loop < 5% 10-15% Diuretics >90% Levosmiendan* Nitro-vasodilator Dobutamine Natriuretic Milrinone† peptide* * Not available in Korea † post cardiac operation low CO HF, drug resistant ADHF Current IV treatment for ADHF • Diuretics Preload • Inotropes – β agonist (dobutamine, dopamine) – PDE inhibitors (milrinone) Contractility • Vasodilator Afterload Starlings Law of the Heart and Contractility SV Dobutamine NTG Furosemide Preload Bed side assessment of patient hemodynamic profile Evidence of Congestion(↑filling pressure) : Orthopnea, High jugular venous pressure, Increasing S4. Loud P2, edema. Ascites, Rales, Abdominojugular reflux, Valsalva square Wave Evidence of low perfusion Narrow Pulse pressure Pulsus alterans Cool forearms and legs Sleepy or obtuned ACE inhibition-Related Symptomatic hypotension Low serum Na Worsening renal function JAMA 2002:287;628-40 Forrest classification Primary strategy Continue PO OPD Diuretics treatment Vasodilators (GDMT) Inotropes Diuretics +/- IV fluids Inotropes General therapeutic approach Algorithm for management of acute decompensated heart failure SNP; Na nitroprusside When does we use other than diuretics? • Inadequate response to initial diuretics dose with symptomatic hypotension inotropes • Inadequate response to initial diuretics dose without symptomatic hypotension, severe volume overload or hypertension vasodilators (+ inotropes if inadequate response) Hemodynamic monitoring • Routine invasive hemodynamic monitoring not recommended • Invasive hemodynamic monitoring to be considered in 1. Patient refractory to initial therapy 2. Patient whose volume status and cardiac filling pressures are unclear 3. Patient with clinically significant hypotension (SBP <80mmHg) or worsening renal failure during therapy 4. Patient in whom documentation of an adequate hemodynamic response to the inotropic agent is necessary when chronic outpatient infusion is being considered Inotropes Inotropes • “In patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures, intravenous inotropic or vasopressor drugs should be administered to maintain systemic perfusion and preserve end- organ performance while more definitive therapy is considered.” 2013 ACC/AHA Heart Failure Guidelines: Inotropes Usually effective in patients with • Marginal SBP <90mmHg • Symptomatic hypotension despite adequate filling pressure • Unresponsive to/or intolerant IV vasodilators Patients with fluid overload Poor response to intravenous diuretics Worsening renal function Inotropes Inotropes in ADHF traditional Novel Int J Mol Sci. 2015 Dec; 16(12): 29060–29068. Positive inotropes for acute HF Hemodynamic profile of inotropes Pro-arrhythmic effect Probably increase mortality in ischemic patients Ischemic/injured myocardium may “hibernate” as a protective mechanism and Inotropes recruit hibernating myocytes and may hasten cell injury or apoptosis Short-term gains appear to be offset by higher mid and long- term mortality Dobutamine • Beta 1,2 receptor agonist (3:1) – positive inotropic and chronotropic effect and secondary vasodilatory effects • Tachyphylaxis, increased risk of arrhythmia • For β-blocker users, usually higher dose is required (15-20mcg/kg/min) • Combination with milrinon: hemodynamically additive effects Dopamine • At low doses ≤ 2mcg/kg/min vascular D1 receptors in the coronary, renal and mesenteric beds with vasodilation and natriuresis • At intermediate doses: 2-5mcg/kg/min myocardial beta1 receptors with positive inotropic effects. Increase SBP and heart rate No change in diastolic pressure and peripheral vascular resistance. • ≥5mcg/kg/min : triggers vasoconstriction. • Low-dose dopamine (1-2mcg/kg/min) with dobutamine(↓ renal perfusion(?)) : no proven effect Milrinone • Increased myocardial contractility and decreased systemic and pulmonary vascular tone • Less chronotropic effects (Milirone < dobutamine) • Less interaction with beta blocker • IV bolus – associated with hypotension (10%) • Initially 0.1 mcg/kg/min and titrate to 0.2 to 0.3 mcg/kg/min, • up to 0.75 mcg/kg/min • Effects on HF symptom and sign - uncertain • Not indicated for routine use as an adjunct to standard therapy in patients with an exacerbation of HF. • Increase mortality in patients with CAD extreme caution in patients with CAD and should be used only in patients with a low cardiac output state not responding to other non-inotropic therapy KHF guideline Inotropes 1. Patients with cardiogenic shock should receive intravenous inotropic support temporarily to maintain systemic perfusion and preserve other end-organ functions (class of recommendation I, level of evidence C). 2. Continuous usage of intravenous inotropic support is reasonable in patients with advanced HF who are waiting for mechanical circulatory support (MCS) or cardiac transplantation (class of recommendation IIa, level of evidence B). 3. Use of intravenous inotropic support is harmful in patients without documented severe systolic dysfunction, low blood pressure, or hypoperfusion (class of recommendation III, level of evidence A). Vasodilator Vasodilator • Afterload reduction by decreasing oxygen myocardial demand and improving forward flow Mechanisms of action of selected vasodilators Relaxin binds RXFP1, a G-coupled protein receptor, to activate NOS3 and increase intracellular NO. cGMP, cyclic guanosine monophosphate; Ga, guanine nucleotide-binding protein; GTP, guanosine triphosphate; NPs, natriuretic peptides; NO, nitric oxide; NOS3, endothelial nitric oxide synthase; PDE, phosphodiesterase; pGC, particular guanylyl cyclase; RXFP1, relaxin/insulin-like family pepide receptor 1; sGC, soluble guanylyl cyclase. Vasodilator • Class IIB recommendation for treatment of ADHF Hypertensive patients Pulmonary congestion not responsive to initial diuretics and standard HF therapy • Beneficial effects: Decrease BP and improve the efficiency of cardiac work Speed symptom relief Possibly decrease risk for CCU, mechanical ventilation No proven change in mortality • Nitroglycerin, Nitroprusside, Nesiritide Vasodilators to treat acute heart failure Nitroglycerin Primarily venodilation • decreased preload decreased pulmonary congestion • May get rebound tachycardia and 20% patients develop resistance • Preferred in ischemia • Tolerance within 24 hrs Less potent arteriolar dilator than nitroprusside Advantages Effective, high comfort level, established safety profile, cost Disadvantaged Rapid tachyphylaxis, frequently under-dosed, requires titration in CCU/MICU, dose-limiting sx(20%) Nitroprusside Primary arteriolar dilator Most useful in marked hypertension/ hypertensive emergency Improves symptoms of pulmonary congestion, and signs of peripheral perfusion Titration of infusion rate (invasive hemodynamic monitoring) Nitroprusside toxicities: Cyanide intoxication: metabolic acidosis Thiocyanate toxicity: Hyper-reflexia, seizures, altered mental status. Serum concentration assay Advantages Potent, Fine titration Disadvantaged ICU and arterial line, thiocyanate toxicity (esp in renal/hepatic insufficiency), no RCT Nesiritide Recombinant brain natriuretic peptide (BNP) Significant vasodilator effect (venous and arterial) balanced Natriuretic effect Suppression of RAS and catecholamines Indirect increase of CO Reduces LV filling pressure, variable effect on CO, urine output, sodium excretion Better than diuretics for dyspnea Longer t ½ than nitroglycerin or nitroprusside Advantage : Faster than NTG, Easy dosing, Few side effects, Disadvantage : Hypotension, cost $380/day Negative Clinical outcome 2011 Nesiritide Initial trials: Improved PCWP and symptoms c/w placebo Lower PCWP than NTG, but similar dyspnea No difference in hard outcomes NTG vs nesiritide Subsequent retrospective analysis: worsened renal function Meta analysis: trend toward increased mortality at 30 days Colucci W, et al. NEJM 2000; 343(4): 246-53 JAMA 2002; 287(12): 1531-40 JAMA 2005;293(15) 1900-1905. Circulation 2005. 29; 111(12): 1487-91. Summary • ADHF is basically hemodynamic condition with perfusion and filling pressure presented by volume status and afterload with underlying contractility. • Both inotropes and vasodilator can be used in appropriate effect of initial IV diuretics therapy. • Inotropic agent should be applied to patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures • Vasodilator is effective in hypertensive HF and diuretics resistant HF but there is no proven drug which have long term survival gain. • As all inotrope and vasodilator have its own characteristics especially on adverse effect, we should consider underlying patients medical situation like as CKD, b-blocker or RAAS blocker user. • Concern on turning point to move on mechanical treatment .