Management of Acute Decompensated Heart Failure Washington Metropolitan

Management of Acute Decompensated Heart Failure Washington Metropolitan Society of Health-System Pharmacists September 28, 2013 Rockville Maryland David S. Roffman, Pharm. D, BCPS/AQ Cardiology Professor Pharmacy Practice and Science School of Pharmacy University of Maryland

Financial Disclosures for David S. Roffman, Pharm. D Nothing to disclose

Learning Objectives At the completion of the lecture, the participants will be able to: 1. Describe the typical presentation of acute decompensated heart failure (ADHF) 2. List therapeutic objectives associated with pharmacologic therapy for ADHF 3. State the indications, adverse effects, and monitoring parameters for the use of inotropes, vasodilators, pressors, and loop diuretics in the treatment of ADHF 4. Describe emerging pharmacotherapeutic options for ADHF

Heart Failure Guidelines 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

Applying Classification of Recommendations and Level of Evidence Class IIa Class IIb Class III Benefit >>> Risk Benefit >> Risk Additional studies with focused objectives needed Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Risk ≥ Benefit No additional studies needed Procedure/ Treatment SHOULD be performed/ administered IT IS REASONABLE to perform procedure/administer treatment Procedure/Treatment MAY BE CONSIDERED Level of Evidence: Level A: Data derived from multiple randomized clinical trials or meta-analyses Multiple populations evaluated Level B: Data derived from a single randomized trial or nonrandomized studies Limited populations evaluated Level C: Only consensus of experts opinion, case studies, or standard of care Very limited populations evaluated Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

Definitions of HFr. EF and HFp. EF http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

Clinical Profiles of Hospitalized HF Patients n Volume overload – pulmonary/systemic vascular congestion – precipitated by acute BP increase n Profound depression of CO – hypotension – renal insufficiency – shock syndrome n Signs/symptoms of both

The Hospitalized Patient Diagnosis of HF The diagnosis of heart failure is primarily based on signs and symptoms derived from a thorough history and physical exam. Clinicians should determine the following: New a. adequacy of systemic perfusion; b. volume status; c. the contribution of precipitating factors and/or comorbidities d. if the heart failure is new onset or an exacerbation of chronic disease; and e. whether it is associated with preserved, normal, or reduced ejection fraction. Chest radiographs, echocardiogram, and New echocardiography are key tests in this assessment.

The Hospitalized Patient Precipitating Factors for Acute HF It is recommended that the following common potential precipitating factors for acute HF be identified as recognition of these Newtherapy: comorbidities, is critical to guide • acute coronary syndromes/coronary ischemia • severe hypertension • atrial and ventricular arrhythmias • infections • pulmonary emboli • renal failure • medical or dietary noncompliance

The Hospitalized Patients Being Evaluated for Dyspnea Concentrations of BNP or NT-pro. BNP should be measured in patients being evaluated for dyspnea in which the contribution of HF is not known. Final diagnosis requires interpreting these results in the context of all available clinical data and ought not to be considered a stand-alone test. New Acute coronary syndrome precipitating HF hospitalization should be promptly identified by electrocardiogram and cardiac troponin testing, and treated, as appropriate to the overall New condition and prognosis of the patient.

Therapeutic Objectives for Acute Decompensated Heart Failure n n n Improve survival? Resolve pulmonary vascular congestion Preserve end organ performance Achieve previous baseline heart failure status (NYHA Classification) Reduce the risk of rehospitalization

Recommended Therapies for Hospitalized HF Patients http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

Recommended Therapies for Hospitalized HF Patients http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

The Hospitalized Patient Treatment With Intravenous Loop Diuretics Patients admitted with HF and with evidence of significant fluid overload should be treated with intravenous loop diuretics. Therapy should begin in the emergency department or outpatient clinic without delay, as early intervention may be associated with better outcomes for patients hospitalized with decompensated HF (Level of Evidence: B). If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose. Urine output and signs and symptoms of congestion should be serially assessed, and diuretic dose should be titrated accordingly to relieve symptoms and to reduce New extracellular fluid volume excess. (Level of Evidence: C).

Diuretic Therapy in ADHF Hunt et. al. 2009. J Am Coll Cardiol 53; 15: 1 -90

The Hospitalized Patient Intensifying the Diuretic Regimen When diuresis is inadequate to relieve congestion, as evidence by clinical evaluation, the diuretic regimen should be intensified using either: New a. higher doses of loop diuretics; b. addition of a second diuretic (such as metolazone, spironolactone or intravenous chlorthiazide) or c. Continuous infusion of a loop diuretic.

The Hospitalized Patient I IIa IIb III Ultrafiltration and Intravenous Inoptropic Drugs Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy. New Intravenous inotropic drugs such as dopamine, dobutamine or milrinone might be reasonable for those patients presenting with documented severe systolic dysfunction, low blood pressure and evidence of low cardiac output, with or without congestion, to maintain systemic perfusion and preserve end-organ performance. New

The Hospitalized Patient Monitoring and Measuring Fluid Intake and Output Effect of HF treatment should be monitored with careful measurement of fluid intake and output; vital signs; body weight, determined at the same time each day; clinical signs (supine and standing) and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of intravenous diuretics or active titration of HF medications. New

Diuretic Strategies in Patients with Acute Decompensated Heart Failure A. Bolus dosing more effective B. Continuous infusion more effective C. Higher dose more effective than lower dose D. Both B and C are correct

Diuretic Strategies in Patients with Acute Decompensated Heart Failure In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2. 5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The co-primary end points were patients’ global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visualanalogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et. al. , N Engl J Med 2011; 364: 797 -805

Fluid and Sodium Restriction in Acute Decompensated Heart Failure Fluid and sodium restriction in ADHF patients improves weight loss and clinicaal stability in hospitalized ADHF patients – A. True – B. False

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial To compare the effects of a fluid-restricted (maximum fluid intake, 800 m. L/d) and sodium restricted (maximum dietary intake, 800 mg/d) diet (intervention group [IG]) vs. a diet with no such restrictions (control group [CG]) on weight loss and clinical stability during a 3 -day period in patients hospitalized with ADHF JAMA Intern Med. 2013; 173(12): 1058 -1064

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013; 173(12): 1058 -1064

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013; 173(12): 1058 -1064

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013; 173(12): 1058 -1064

The Hospitalized Patient In all patients hospitalized with HF, both with preserved and low ejection fraction, transition should be made from intravenous to oral diuretic therapy with careful attention to oral diuretic dosing and monitoring of electrolytes. With all medication changes, the patient should be monitored for supine and upright hypotension and worsening renal function and HF signs/symptoms. New

The Hospitalized Patient Preserving End-Organ Performance In patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures (e. g. , elevated jugular venous pressure; elevated pulmonary artery wedge pressure), intravenous inotropic or vasopressor drugs should be administered to maintain systemic perfusion and preserve end-organ performance while more definitive New therapy is considered. Invasive hemodynamic monitoring should be performed to guide therapy in patients who are in respiratory distress or with clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from New clinical assessment.

Intravenous Inotropic Agents Used in ADHF http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

Inotropic Support in Acute Heart Failure n n In the presence of significant hypotension, dopamine may enhance both blood pressure and peripheral organ perfusion. Dopamine, in pressor doses (greater than 5 mcg/kg/min), increases myocardial oxygen demand potentially limits augmentation of peripheral perfusion via peripheral vasoconstriction

Issues with Intravenous Inotropes Initial choice of therapy n Weaning n Patient related variables n Differences in efficacy n Adverse effect profile n Survival data n “Long-term” infusions n

The Hospitalized Patient I IIa IIb III Invasive Hemodynamic Monitoring Invasive hemodynamic monitoring can be useful for carefully selected patients with acute HF who have persistent symptoms despite empiric adjustment of standard therapies, and New a. whose fluid status, perfusion, or systemic or pulmonary vascular resistances are uncertain; b. whose systolic pressure remains low, pr is associated with symptoms, despite initial therapy; c. whose renal function is worsening with therapy; d. who require parenteral vasoactive agents; or e. who may need consideration for advanced device therapy or transplantation.

The Hospitalized Patient Parenteral Inotropes I IIa IIb III Use of parenteral inotropes in normotensive patients with acute decompensated HF without evidence of decreased organ New perfusion is not recommended. I IIa IIb III Routine use of invasive hemodynamic monitoring in normotensive patients with acute decompensated HF and congestion with symptomatic response to diuretics and vasodilators is not recommended. New

Vasodilator Support in Acute Heart Failure Nitroglycerin, nitroprusside, and nesiritide, have been demonstrated to improve symptoms and hemodynamics in acute heart failure.

Vasodilator Support in Acute Heart Failure Nitroprusside infusions (initial dose 0. 1 mcg/kg/min) improve symptoms of pulmonary congestion, and signs of peripheral perfusion. n Titration of infusion rate is initailly based on invasive hemodynamic monitoring. n

Vasodilator Support in Acute Heart Failure n Nitroprusside patient variables: – Chronic liver disease – Renal insufficiency – Blood pressure – Malnourished patients

Vasodilator Support in Acute Heart Failure n Nitroprusside toxicities: – Cyanide intoxication: metabolic acidosis – Thiocyanate toxicity: Hyper-reflexia, seizures, altered mental status. Serum concentration assay available

Vasodilator Support in Acute Heart Failure Nitroglycerin infusion may be preferred in patients an active or recent history of ischemia. n Nitroglycerin is a less potent arteriolar dilator than nitroprusside n

Vasodilator Support in Acute Heart Failure n n n Nesiritide is a brain naturetic peptide (BNP) which has significant vasodilator effects. Dosing regimen, 0. 2 mcg/kg bolus followed by 0. 01 mcg/kg/min continuous infusion Reduces LV filling pressure, variable effect on CO, urine output, sodium excretion Better than diuretics for dyspnea Longer t ½ than nitroglycerin or nitroprusside Adverse renal outcomes

History of New Treatments in ADHF 1988: Milrinone approved based on small hemodynamic studies n 2000: Levosimendan approved in Sweden then 40 countries n 2001: Nesiritide based on 489 patient VMAC trial n

Research on Drugs for Acute Heart Failure n n Pub. Med search for “heart failure” (19, 154)/”randomized controlled trials”(2176)/”acute disease”(61) for novel, intravenous treatments for acute heart failure Search results: Levosimendan, nesiritide, rolofylline, tezosentan

Levosimendan (REVIVE I and II) 700 patients, placebo controlled n Primary endpoint: Clinical composite based on patient global assessment during first 5 days of treatment (positive) n Increased ventricular/atrial arrhythmias, symptomatic hypotension, early mortality n JCHF. 2013; 1(2): 103 -111. doi: 10. 1016/j. jchf. 2012. 004

Levosimendan vs. Dobutamine (SURVIVE) 1327 patients n Primary endpoint: All cause mortality at 180 days not achieved n No secondary endpoints achieved n Decreased BNP n JAMA. 2007 May 2; 297(17): 1883 -91

Nesiritide (ASCEND-HF) Placebo controlled post approval trial n Prespecified primary endpoint (dyspnea relief) not met n No beneficial effect on hospital readmisiion, all-cause mortality, worsening renal function n N Engl J Med 2011; 365: 32 -43

Rolofylline (Protect) 2033 patients n Failed to meet primary clinical composite endpoint n No reduction in hospital readmissions n Complicated by seizures and stroke n N Engl J Med 2010; 363: 1419 -28

Tezosentan (VERITAS) 1448 patients n No improvement in dyspnea n No improvement in worsening heart failure or death at 7 days n No improvement in renal function, hospital readmission or mortality n JAMA 2007; 298: 2009 -19

The Hospitalized Patient Reconciling and Adjusting Medications should be reconciled in every patient and adjusted as appropriate on admission to and discharge from the hospital. New In patients with reduced ejection fraction experiencing a symptomatic exacerbation of HF requiring hospitalization during chronic maintenance treatment with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta-blocker therapy, it is recommended that these therapies be continued in most patients in the New absence of hemodynamic instability or contraindications.

Serelaxin n Recombinant human relaxin-2 (peptide that regulates maternal adaptations to pregnancy) Increased arterial compliance, cardiac output, renal blood flow. Suggested benefit on dyspnea and postdischarge clinical outcomes in patients admitted with evidence of congestion, normal to elevated blood pressure, mild to moderate renal dysfunction.

Serelaxin (RELAX-AHF) n n Prospective, randomized, double-blind, placebo-controlled, parallel group trial 1161 patients comparing serelaxin to placebo. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnea relief compared with patients treated with standard care and placebo Lancet 2013; 381: 29– 39

Serelaxin (RELAX-AHF) Inclusion Criteria n n n Acute heart failure within past 16 hours, Dyspnea at rest or minimal exertion Pulmonary congestion on CXR BNP > 350 ng/L, NT-pro. BNP > 1400 ng/L GFR 30 – 75 ml/min/1. 73 m 2 Systolic BP > 125 mm Hg Treated with > 40 mg iv furosemide Lancet 2013; 381: 29– 39

RELAX-AHF Trial

RELAX-AHF Trial Lancet 2013; 381: 29– 39

RELAX-AHF Trial Lancet 2013; 381: 29– 39

Serelaxin June 2013: FDA grants serelaxin “breakthroughtherapy” designation based on RELAX-HF Trial Breakthrough designation therapy reserved for the development or review of drugs seen as poteentiaal game changers for serious and life-threatening conditions that have preliminary evidence in at least one clinically significant endpoint over other available therapies

Other Investigational Drugs for AHF n TRV 027 – Β-arrestin-biased AT 1 R ligand, competitively inhibits G-protein signaling – Reduces MAP, increases cardiac contractility, maintains stroke volume, preserves GFR – Anti-apoptotic effect n Ularitide – Synthetic foem of urodilatin (naturetic peptide produced by kidneys) – Binds to specific naturetic peptide receptors, imcreasing intracellular cyclic GMP – Relaxes smooth muscle cells, vasodilation and increased renal blood flow – Ongoing TRUE-AHF study: Symptoms, HF improvement, and death

Other Investigational Drugs for AHF n Omecamtiv mecarbil – Selective cardiac myosin activator – ATOMIC-AHF was a randomized, double-blind, placebo-controlled Phase II clinical trial that enrolled 613 patients hospitalized with acute heart failure (AHF) treated for 48 hours with an intravenous formulation of omecamtiv mecarbil or placebo and designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and potential efficacy of omecamtiv mecarbil in patients with AHF – The primary efficacy endpoint of dyspnea symptom response was not met; favorable trends between the dose and plasma concentration of omecamtiv mecarbil and dyspnea response. The incidence of worsening heart failure within seven days of initiating treatment appeared lower in each of the cohorts on omecamtiv mecarbil. Rates of adverse events (AEs), serious AEs, adjudicated deaths and hospitalizations were similar between omecamtiv mecarbil and placebo groups. Omecamtiv mecarbil was not associated with an increased incidence of tachyarrhythmias nor were heart rate or blood pressure adversely affected.

Continuation of Outpatient ACE/ARB Therapy Blood pressure n Renal function n Volume dependency n Substitution of hydralazine/nitrates n

Beta Blocker Use in ADHF Foranow GC. J Am Coll Cardiol 2008; 52: 190 -9

Beta Blockers in Acute Decompensated Heart Failure Foranow GC. J Am Coll Cardiol 2008; 52: 190 -9

The Hospitalized Patient In patients hospitalized with HF with reduced ejection fraction not treated with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta-blocker therapy, initiation of these therapies is recommended in stable patients prior to hospital discharge. New Initiation of beta-blocker therapy is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. Beta-blocker therapy should be initiated at a low dose and only in stable patients. Particular caution should be used when initiating betablockers in patients who have required inotropes during their hospital course. New

The Hospitalized Patient Severe Symptomatic Fluid Overload I IIa IIb III In patients with evidence of severely symptomatic fluid overload in the absence of systemic hypotension, vasodilators such as intravenous nitroglycerin, nitroprusside or neseritide can be beneficial when added to diuretics and/or in those who do not respond to diuretics alone. New

The Hospitalized Patient Reconciling and Adjusting Medications Comprehensive written discharge instructions for all patients with a hospitalization for HF and their caregivers is strongly recommended, with special emphasis on the following 6 aspects of care: diet, discharge medications, with a special focus on adherence, persistence, and uptitration to recommended doses of ACE inhibitor/ARB and beta-blocker medication, activity level, follow-up appointments, weight monitoring, and what to do if HF symptoms worsen. New

Recommendations for Hospital Discharge http: //circ. ahajournals. org/content/early/2013/06/03/CIR. 0 b 013 e 31829 e 8776. citation

Improvement of Guideline Beta-Blocker Prescribing in Heart Failure: A Cluster-Randomized Pragmatic Trial of a Pharmacy Intervention We conducted a pragmatic cluster-randomized trial, where facilities (n 5 12) with patients (n 5 220) were the clusters. Eligible patients had a beta-blocker prescription that was not guideline concordant. Level 1 intervention included information to a pharmacist on facility guideline concordance. Level 2 also provided a list of patients not meeting guideline goals. Intervention and follow-up periods were each 6 months. Achievement of full concordance with recommendations was low (4%e 5%) in both groups, primarily due to lack of tolerability. However, compared with level 1, the level 2 intervention was associated with 1. 9 fold greater odds of improvement in prescribing (95% confidence interval [CI] 1. 1 e 3. 2). Level 2 patients also had greater odds of a higher dose (1. 9, 95% CI 1. 1 e 3. 3). The intervention was aided by the patient lists provided, the electronic medical record system, and staff support. Journal of Cardiac Failure Vol. 19 No. 8 2013

Acute Decompensated Heart Failure Few well controlled trials n Little data to demonstrate improved morbidity/mortality n Need for newer, more effective, lower ADR-inducing agents n