Nesiritide in Patientswith Acute Decompensated Heart Failure By Sheelendra Shakya Cardiology Unit II, First Affiliated Hospital, Jiamusi University
Introduction Acute decompensated heart failure is a major health problem that is associated with several million hospitalizations worldwide each year, poor short- term outcomes, and high costs. Despite the magnitude of the problem, rates of early death and rehospitalization have not improved over the past several decades.
Acute Decompensated Heart Failure Majority of patients hospitalized with HF have evidence of systemic hypertension on admission and commonly have preserved left ventricular ejection fraction (LVEF). Most hospitalized patients have significant volume overload, and congestive symptoms predominate. Patients with severely impaired systolic function, reduced blood pressure and symptoms from poor end-organ perfusion are in the distinct minority. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Causes of DecompensationPrecipitating factors No. Percentage (%)Arrhythmia 7155 13.5Uncontrolled Hypertension 5220 10.7Ischemia/ACS 6552 14.7Worsening renal function 3304 6.8Pneumonia/Respiratory process 7426 15.3Nonadherence to medications 4309 8.9Nonadherence to diet 2504 12.7Other 6171 12.7 Optimize-HF; Arch Int Med 2008; 168:847-54
No. of precipitating factors No. Percentage (%) 0 18798 38.7 1 20504 42.2 2 6599 13.6 3 2050 4.2 >= 4 661 1.4Arrhythmias, worsening renal function might be secondary than primary. Optimize-HF; Arch Int Med 2008; 168:847-54
Diagnosis The diagnosis of ADHF should be based primarily on signs and symptoms. When the diagnosis is uncertain, determination of plasma B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration is recommended in patients evaluated for dyspnea who have signs and symptoms compatible with HF. The natriuretic peptide concentration should not be interpreted in isolation, but in the context of all available clinical data bearing on the diagnosis of HF, and with the knowledge of cardiac and non-cardiac factors that can raise or lower natriuretic peptide levels. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Treatment Goals Improve symptoms, especially congestion and low-output symptoms Restore normal oxygenation Optimize volume status Identify etiology Identify and address precipitating factors Optimize chronic oral therapy Minimize side effects Identify patients who might benefit from revascularization Identify patients who might benefit from device therapy Identify risk of thromboembolism and need for anticoagulant therapy Educate patients concerning medications and self management of HF Consider and, where possible, initiate a disease management program. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Treatment Strategy Fluid Overload: Sodium (2g/day) and fluid restriction (<2 L/day) Loop diuretics administered at doses needed to produce a rate of diuresis sufficient to achieve optimal volume status with relief of signs and symptoms of congestion, without inducing an excessively rapid reduction in intravascular volume or serum electrolytes. Addition of second type of diuretic (metolazone or spironolactone) orally or i.v. (cholorothiazide) Ultrafiltration Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Supplemental Oxygen Routine administration of supplemental Oxygen in presence of hypoxia only. Use of non-invasive positive pressure ventilation may be considered for severly dyspneic patientswith clinical evidence of pulmonary edema. Venous thromboembolism prophylaxis UFH or LMWH to prevent proximal DVT and PE is recommended for patients who are not already anticoagulated and have no contraindication to anticoagulation. If contraindicated, consider intermittent pneumatic compression devices or graded compression stockings. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
IV vasodilators In absence of symptomatic hypotension, intravenous nitroglycerin, nitroprusside or nesiritide may beNesiritide considered for rapid improvement of congestivecontroversy symptoms or severe hypertension and for patients who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies. Frequent blood monitoring is recommended upon use. Decreased in dosage or discontinued if symptomatic hypotension or worsening renal function develops. Can be reintroduced once symptoms resolved. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
IV inotropes Milrinone or dobutamine may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by LV dilation, reduced LVEF, and diminished peripheral perfusion or end-organ dysfunction (low output syndrome), particularly if SBP <90mmHg, symptomatic hypotension despite adequate filling pressure, or are unresponsive to, or intolerant of, intravenous vasodilators. In patients with evidence of fluid overload if they respond poorly to iv diuretics or manifest diminished or worsening renal function. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
ACE inhibitors ACE inhibitors are recommended for routine administration to symptomatic and asymptomatic patients with LVEF < 40%. Angiotensin Receptor Blockers (ARBs) In patients who cannot tolerate ACE inhibitors due to cough, ARBs are recommended. The combination of hydralazine and an oral nitrate may be considered in such patients not tolerating ARB therapy. Individual ARBs may be considered as initial therapy rather than ACE inhibitors for patients with the following conditions: HF post MI Chronic HF and reduced LVEF Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Beta blockers Beta blockers shown to be effective in clinical trials of patients with HF are recommended for patients with an LVEF <=40%. The combination of a beta blocker and an ACE inhibitor is recommended as routine therapy for asymptomatic patients with a LVEF <=40% in both post MI and non post MI. Patients with a recent decompensation of HF after optimization of volume status and successful discontinuation of intravenous diuretics and vasoactive agents, including inotropic support. Whenever possible, beta blocker therapy should be initiated in the hospital setting at a low dose prior to discharge in stable patients. Beta blocker therapy is recommended in the great majority of patients with HF and reduced LVEF, even if there is concomitant diabetes, chronic obstructive lung disease, or peripheral vascular disease. It is recommended that beta blocker therapy be continued in most patients experiencing a symptomatic exacerbation of HF during chronic maintenance treatment, unless they develop cardiogenic shock, refractory volume overload, or symptomatic bradycardia. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Anticoagulation and Antiplatelet drugs Treatment with warfarin (goal international normalized ratio [INR] 2.0-3.0) is recommended for all patients with HF and chronic or documented paroxysmal, persistent, or long-standing atrial fibrillation or a history of systemic or pulmonary emboli, including stroke or transient ischemic attack, unless contraindicated. It is recommended that patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documented LV thrombus be treated with warfarin (goal INR 2.0-3.0) for the initial 3 months post-MI unless contraindicated. Long-term treatment with an antiplatelet agent, generally aspirin in doses of 75 to 81 mg, is recommended for patients with HF due to ischemic cardiomyopathy, whether or not they are receiving ACE inhibitors. Warfarin (goal INR 2.0-3.0) and clopidogrel (75 mg) also have prevented vascular events in post-MI patients and may be considered as alternatives to aspirin. Routine use of aspirin is not recommended in patients with HF without atherosclerotic vascular disease. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Digoxin Digoxin may be considered to improve symptoms in patients with reduced LVEF (LVEF <=40%) who have signs or symptoms of HF while receiving standard therapy, including ACE inhibitors and beta blockers in NYHA grade II,III,IV. Digoxin should be considered for achieving adequate control of the ventricular response to atrial fibrillation in patients with HF. Amiodarone In patients with HF and an ICD, amiodarone may be considered to reduce the frequency of recurrent symptomatic arrhythmias causing ICD shocks. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Discharge Criteria Exacerbating factors addressed. Near optimal volume status observed. Transition from iv to oral diuretic successfully completed. Patient and family education completed, including clear discharge instructions. LVEF documented. Smoking cessation counseling initiated. Near optimal pharmacologic therapy achieved, including ACEI and beta blocker. Follow –up clinic visit scheduled usually for 7-10 days. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
Discharge criteria Oral medication regimen stable for 24 hours No intravenous vasodilator or inotropic agent for 24 hours Ambulation before discharge to assess functional capacity after therapy Plans for postdischarge management (scale present in home, visiting nurse or telephone follow up generally no longer than 3 days after discharge) Referral for disease management, if available. Journal of Cardiac Failure Vol. 16 No. 6 June 2010
The Nesiritide Timeline 1999: Coronary Vasodilatory effects of BNP documented 2001: Approved by FDA for use in ADHF 2005 Concerns of worsening renal function and increased death rate 2010 Concerns addressed by ASCEND-HF
Nesiritide Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory properties, was approved in 2001 for use in patients with acute heart failure on the basis of studies showing a reduction in pulmonary-capillary wedge pressure and improvement in dyspnea at 3 hours. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246-53. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531-40. Zellner C, Protter AA, Ko E, et al. Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries. Am J Physiol 1999;276:H1049-57.
Facilitates cardiovascular fluid homeostasis through counter-regulation of the renin-angiotensin-aldoesterone system, stimulating cyclic guanosine monophosphate, leading to smooth muscle cell relaxation.
VMAC trial Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) A Study Comparing Blood Flow and Clinical and Safety Effects of the Addition of Nesiritide, Placebo or Intravenous Nitroglycerin to Standard Care for the Treatment of Worsening Congestive Heart Failure. Multicenter, Randomized, Double-Blind, Placebo- Controlled Study Study Period from Oct 1999 to August 2000 N=498
Outcome measures Primary Outcome Secondary Outcome Change from baseline to 3 hours Effect on PCWP (pulmonary after the start of study drug in capillary wedge pressure) and PCWP (pulmonary capillary dyspnea (difficult breathing) 1 wedge pressure) in subjects who hour after the start of study have right heart catheters; drug; Change from baseline in Onset of effect on PCWP; dyspnea (difficult breathing) 3 hours after the start study drug Effect on PCWP 24 hours after the start of study drug; Overall safety profile
Inclusion criteria Patients with dyspnea (difficulty breathing and shortness of breath) at rest, while supine, or immediately upon minimal activity such as talking, eating, or bathing Having evidence of heart disease, rather than pulmonary disease, as the primary cause for the dyspnea (by demonstrating at least two of the following: jugular venous distension, paroxysmal nocturnal dyspnea or 2- pillow orthopnea within 72 hours before the start of study drug, abdominal discomfort due to hepato-splanchnic congestion, chest x-ray with findings indicative of heart failure) Having elevated cardiac filling pressures either by clinical estimate in non- catheterized patients, or a measured pulmonary capillary wedge pressure (PCWP) >= 20 mm Hg in catheterized patients Requiring hospitalization and intravenous therapy for at least 24 hours for the treatment of acutely decompensated heart failure.
Exclusion Criteria Patients having systolic blood pressure consistently less than 90 mm Hg Having cardiogenic shock (a sudden decrease in blood pressure that results in decreased perfusion of body tissues and organs), volume depletion, or any other clinical condition that would contraindicate the administration of an intravenous agent with potent vasodilating properties Having their most recent pulmonary capillary wedge pressure (PCWP) < 20 mm Hg within 24 hours before randomization Having a clinical status so acutely unstable that the potential subject could not tolerate placement of a right heart catheter or the 3-hour placebo period Unable to have intravenous nitroglycerin withheld (e.g., intravenous nitroglycerin for management of an acute coronary syndrome).
Study Drug Administration Nitroglycerin: 216 patients were taking a titrated dose of nitroglycerin, Nesiritide fixed-dose: 211 received 2 mcg/kg bolus and 0.01 mcg/min infusion of nesiritide and Nesiritide adjustable dose: 62 received 2 mcg/kg bolus and 0.01 mcg/min infusion nesiritide for the first 3 hours, followed by an adjustable dose that could be increased up to 0.03 mcg/kg/min. Placebo
Outcome BNP significantly reduced PCWP and all PA pressures, compared to NTG and PL, by 15 minutes and through the 3 hour period. At 3 hours, dyspnea was improved by BNP compared to PL (p=0.034); the change in dyspnea with NTG was not statistically significant (p=0.191). By 24 hours, symptomatic hypotension occurred in only 4% of BNP patients and 5% of NTG patients, whereas more headache occurred with NTG (20% vs. 8%, p<0.001). Fewer adverse events overall occurred in patients treated with BNP than with NTG (p<0.001).
Conclusion When added to standard care, fixed-dose administration of nesiritide produced a more rapid and greater improvement in hemodynamics than NTG titration or standard care alone (PL). Nesiritide, but not NTG, was associated with significant improvements in dyspnea, compared to standard care alone (PL).
Limitations Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renalHR function reflects hemodynamic effect or renal injury is1.5 unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-91. Compared with non inotrope-based control therapy, nesiritide may be associated with an increased risk of death afterHR treatment for acutely decompensated heart failure. The1.8 possibility of an increased risk of death should be investigated in a large-scale, adequately powered, controlled trial before routine use of nesiritide for acutely decompensated heart failure. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900-5.
ASCEND-HF Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial was designed to evaluate the effect of nesiritide, in addition to standard care, on rates of self reported dyspnea at 6 and 24 hours, rehospitalization for heart failure or death from any cause at 30 days, and renal dysfunction. Multicentered, Randomized, Double-blind, Placebo- controlled trial. conducted from May 2007 through August 2010 at 398 centers throughout the world.
Study Patients Hospitalized for heart failure occurring within 24 hours before they received their first intravenous treatment for heart failure. Diagnosed of acute decompensated heart failure less than 48 hours after hospitalization for another cause.
Additional Criteria Dyspnea at rest or with minimal activity One or more accompanying signs respiratory rate ≥20 breaths per minute pulmonary congestion or edema with rales one third of the way or more up the lung fields) One or more objective measures of heart failure evidence of congestion or edema on chest radiography, a BNP level ≥400 pg per milliliter an N-terminal pro-BNP level ≥1000 pg per milliliter pulmonary-capillary wedge pressure >20 mm Hg left ventricular ejection fraction <40% in the previous 12 months
Key exclusion criteria A high risk of hypotension Systolic pressure <100 mm Hg or 110 mm Hg with the use of intravenous nitroglycerin Acute coronary syndrome as primary diagnosis History of cardiac valvular stenosis, restrictive cardiomyopathy, hypertrophic cardiomyopathy, or pericardial tamponade Persistent, uncontrolled hypertension (SBP [systolic blood pressure] >180 mmHg) Previous enrollment in a nesiritide study Normal level of BNP or N-terminal pro-BNP Severe pulmonary disease End-stage renal disease during receipt of renal replacement therapy Clinically significant anemia
Study Drug administration Eligible Patients Management All participants received standard therapies, including diuretics, morphine, and other vasoactive medications. Study group: Nesiritide infusion at 0.010 μg per kilogram per minute (with or without a 2 μg per kilogram bolus) for 24 hours or more for up to 7 days.Nesiritide Placebo Placebo group: Matching placeboN = 3496 N = 3511 infusion at 0.010 μg per kilogram per minute for 24 hours or more for up to 7 days.
Outcome measures Primary Endpoint Likert Scale Composite of Rehospitalization 7-point ordinal categorical scale Due to Heart Failure and All- Cause Mortality Markedly better [ Time Frame: Randomization to Day 30 ] Moderately better Dyspnea Self-Assessment at 6 Minimally better Hours After Initiation of Study Unchanged Drug [ Time Frame: 6 hours after initiation of study drug ] Minimally worse Dyspnea Self-Assessment at 24 Moderately worse Hours After Initiation of Study Markedly worse Drug [ Time Frame: 24 hours after study drug initiation ]
Outcome measures Secondary Endpoints Persistent/Worsening HF Overall Well-Being Self-Assessment at 6 Clinical manifestations of worsening or Hours After Initiation of Study Drug persistent decompensated heart failure [ Time Frame: 6 hours after study drug initiation ] were defined by at least one of the following: Overall Well-Being Self-Assessment at 24 New, persistent or worsening: Hours After Initiation of Study Drug [ Time Frame: 24 hours after study drug initiation ] dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, Composite of Persistent or Worsening Heart pulmonary basilar rales/crackles, Failure and All-Cause Mortality jugular venous distension, renal [ Time Frame: Randomization to hospital discharge (up to Day 30) ] hypoperfusion with no other apparent cause, or Number of Days Alive and Outside the Radiologic evidence of worsening Hospital [ Time Frame: Randomization to Day 30 ] heart failure. A new therapy specifically for the Composite of Cardiovascular Rehospitalization and Cardiovascular treatment of worsening or persistent Mortality [ Time Frame: Randomization to Day 30 ] decompensated heart failure.
Results Primary Endpoint Although a small increase in the number of patients reporting improvement in dyspnea was observed at both the 6- and 24-hour time points, this finding did not meet the prespecified criteria for significance. Rehospitalization for heart failure or death from any cause at 30 days occurred in 321 patients in the nesiritide group (9.4%) as compared with 345 patients in the placebo group (10.1%) (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7;P = 0.31)
Conclusion The use of nesiritide in patients with acute decompensated heart failure neither increased nor decreased the incidence of death or rehospitalization for heart failure at 30 days. Self reported dyspnea at 6 and 24 hours was marginally improved when nesiritide was added to conventional therapy, but this finding did not meet prespecified criteria for statistical significance. Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial.
Addressing the concern There was no significant difference between the groups with respect to the rate of death from any cause at 30 days. There was no significant difference between the nesiritide group and the placebo group with respect to the proportion of patients with renal impairment at any time from randomization through day 30 regardless of the degree of baseline renal insufficiency.
The incidence of renal injury was not different between nesiritide- and nitroglycerin-treated patients with acute heart failure; however, nitroglycerin was associated with a decline in glomerular filtration rate and increase in blood urea nitrogen despite higher baseline and on treatment blood pressures. Ng, T. M.; Ackerbauer, K. A.; Hyderi, A. F., et al., Comparative effects of nesiritide and nitroglycerin on renal function, and incidence of renal injury by traditional and RIFLE criteria in acute heart failure. J Cardiovasc Pharmacol Ther 2012, 17 (1), 79-85.
Nesiritide can be administered safely without negatively impacting long-term renal function in patients admitted with Decompensated Heart Failure with preserved Ejection Fraction. Kelesidis, I.; Mazurek, J.; Khullar, P., et al., The effect of nesiritide on renal function and other clinical parameters in patients with decompensated heart failure and preserved ejection fraction. Congest Heart Fail 2012, 18 (3), 158-64.
Nesiritide resulted in improvements in dyspnea and edema, and similar adverse effects compared with conventional treatment. In spite of no reduction on short-term mortality and a reversible influence on renal function, nesiritide was still an important chioce for the elderly (>/=75 years) with AHF. Fu, S.; Yi, S.; Zhu, B., et al., Efficacy and safety of a modified dosage regimen of nesiritide in patients older than 75 years with acute heart failure. Aging Clin Exp Res 2012.
Summary Nesiritide neither increases nor decreases the rate of death and rehospitalization. The observed effect of nesiritide on dyspnea is small (and not significant) with the coadministration of other therapies that relieve congestion. Nesiritide is not associated with worsened renal function, but it is associated with an increase in the rate of hypotension.Thank you Nesiritide results in improvements in dyspnea and edema and can still benefit patients admitted with Decompensated Heart Failure with preserved Ejection Fraction or the elderly. Nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. The decision to use Nesiritide must be based on an individual patient basis.