Here's a set of Natrecor abstracts just presented at the Heart Failure conference. Nothing revolutionary, but a steady accumulation of evidence that Natrecor is safe, easy to use and effective in varied settings, including at-home infusions.
[059] Effects of Intravenous Nesiritide on Coronary Vasomotor Regulation and Myocardial Oxygen Consumption
Andrew D. Michaels, Andrew Klein, Magge V. Lakshmi, Kanu Chatterjee Medicine, University of California, San Francisco, San Francisco, CA
Background: Nesiritide is a recombinant human B-type, or brain, natriuretic peptide which has been shown to be beneficial for patients with decompensated congestive heart failure. This study evaluated the effects of intravenous nesiritide on coronary blood flow and myocardial oxygen consumption. Methods: Patients referred for cardiac catheterization were enrolled in this study. Patients who were hypotensive, on vasopressors, and those who had received nitroglycerin or calcium blockers within 24 hours were excluded. After diagnostic catheterization and full heparinization, a 0.014-inch Doppler flow wire was positioned in the proximal portion of an unobstructed coronary artery to measure average peak velocity (APV). Right heart catheterization and simultaneous blood gas sampling from the coronary sinus and aorta were performed at baseline and after a 30-min intravenous infusion of nesiritide (2mcg/kg bolus and 0.01mcg/kg/min). Quantitative coronary angiography (QCA) was performed at baseline, 15-min, and 30-min. Coronary blood flow (CBF) was calculated as (coronary artery area)(APV)(0.3). Coronary resistance = MAP/CBF. Two-tailed p values are listed. Results: Five patients have been enrolled. Five additional patients will be enrolled into this study. The mean age is 56±14 years (range 45-80) and two are female. Mean left ventricular ejection fraction was 52±20% (range 20-65%). During the nesiritide infusion, pulmonary capillary wedge pressure decreased 37% (p=0.04), cardiac output increased 3% (p=0.78), and systemic vascular resistance decreased 10% (p=0.29). Coronary artery APV increased from 20±7 cm/s at baseline to 25±7 cm/s at 5 min (p=0.002), then returning back to baseline at 15 and 30 minutes. Coronary artery diameter at the Doppler wire tip increased 23±32% at 15 min (p=0.14) and 14±19% at 30 min (p=0.18) compared to baseline. CBF increased 56±99% at 15 min (p=0.19) and 30±41% at 30 min (p=0.43). Coronary resistance decreased 32±22% at 15 min (p=0.07) and 25±16% at 30 min (p=0.11). Myocardial oxygen extraction decreased 3.5±4.7% at 30 min (p=0.18). Conclusions: Nesiritide exerts coronary vasodilator effects, in both the epicardial conductance and resistance arteries. There is a trend toward decreased myocardial oxygen consumption during nesiritide infusion.
[176] The Effects of Nesiritide on Serum Levels of B-Type Natriuretic Peptide (BNP) in Patients Admitted for Decompensated
Congestive Heart Failure
Alan S. Maisel, Rosemary Cremo, Nancy Gardetto, Cherie Jaynes, Albert Chiu Veterans Affairs Medical Center, University of California, San Diego, San Diego, CA
Introduction: Patients with decompensated congestive heart failure are characterized by high levels of circulating BNP. The cardiac hormone, nesiritide, effectively lowers filling pressures and improves symptoms in these patients. However its effects on subsequent serum BNP levels are unknown.
Methods: We studied 20 patients admitted to the hospital with decompensated CHF and baseline BNP levels greater than 400 pg/ml (median = 1040, max = 4140). Patients were treated with a regimen including intravenous diuretics and nesiritide (2 mg/kg bolus followed by 0.01 mg/kg/min) for 24-48 hours. Serum BNP levels were measured at 12 different time points up to 24 hours after cessation of the infusion. Global well-being and dyspnea indexes were performed at 12 and 24 hours.
Results: BNP levels reached a peak of approximately 3000 pg/ml following the bolus and approximately 2x baseline throughout the infusion. There was a slight decline of BNP levels during treatment, likely representing a decrease in endogenous BNP production. Patients were back to baseline BNP levels between 1-2 hours post-treatment, after which there was a steady decrease in endogenous BNP levels, with a maximum effect at 6 hours after treatment cessation of 20%, which persisted through the 24 hour post-infusion measuring period. 17 of 20 patients (80%) felt improved following therapy.
Conclusion: A treatment regimen for patients with CHF that includes nesiritide will effectively lower endogenous BNP levels, suggesting a resetting of the neurohormonal axis and improvement in ventricular wall tension. Endogenous BNP measurements should be taken no sooner than 2 hours after completion of infusion. A maximum decrease will be seen 6 hours post-infusion.[figure1]
[177] A Pilot Study of the Safety and Efficacy of Nesiritide in the Management of Acute Decompensated Congestive Heart Failure
Complicated by an Acute Coronary Syndrome
W. Frank Peacock, Charles L. Emerman, Geraldine Smoluk, Mei Cheng, James Young Emergency Medicine, The Cleveland Clinic, Cleveland, OH; Scios Inc., Sunnyvale, CA; Cardiology, The Cleveland Clinic, Cleveland, OH
Purpose: To evaluate the safety and efficacy of nesiritide (NST) in patients with decompensated heart failure (HF) complicated by a concurrent acute coronary syndrome (ACS).
Methods: This is a retrospective study of patients with decompensated HF complicated by an ACS. Eligible patients were entered in the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial. In VMAC, investigators determined pulmonary artery catheter (PAC) requirement, then randomized patients to either nitroglycerin (NTG) and standard HF therapy or nesiritide and standard HF therapy. ACS was defined as unstable angina; ECG or serum evidence of MI; PTCA, CABG, or death; within 7 days of VMAC entry.
Results: The entry criteria were met by 61 patients, who had a mean age of 63.6 years. 54% were male, with an average ejection fraction of 34%; 43% were white, 34% Hispanic, and 15% were African American. NST was used in 34; NTG in 27. Overall presentation, medical history, physical exam findings, vital signs, cardiac rhythm, and Pulmonary Artery Catheterization (PAC) data was similar between the two groups (p>0.05). Mortality was similar through 6 months of follow up; NST 7.6% (2), NTG 15.3% (5), (p>0.05). Hypotension occurred in 22% (6) of NST and 15% (5) of NTG (p>0.05). In the overall group, changes in dyspnea and global clinical scores (GCS) were similar (p> 0.05). However, there were significant differences in response to pharmacologic treatment in patients not receiving a PAC. In non-PAC patients, 24-hour dyspnea scores were markedly or moderately (Mark-Mod) improved in 75% of the NST cohort, vs. 55% of the NTG treated patients (p=0.031). In patients receiving NST, 100% were at least minimally better, compared to 71% of patients receiving NTG. In the non-PAC group, 6 hour global clinical scores were mod-mark better in 75% of NST patients, contrasted to only 32% with a similar improvent from NTG (p=0.031). In non-PAC patients, there were no 30-day readmissions with NST, vs. 17% (4) with NTG. (p=0.276).
Conclusions: Nesiritide is safe and effective in decompensated HF complicated by an ACS.
[187] Management of Patients with Congestive Heart Failure after Hospitalization – Follow Up Serial Infusions of Nesiritide
(FUSION): Clinical Trial Design
Marc A. Silver, Mei L. Cheng, Sue Congdon, Bim P. Strausser Division of Cardiology, Advocate Christ Medical Center, Oak Lawn, IL; Scios, Inc., Sunnyvale, CA
Background. Decompensated heart failure (DHF) is a leading cause of hospital admission. It is estimated that in 2002 acute care costs (including hospitalization) for DHF will be over 15 billion dollars. There is an unmet need for therapies, which can reduce hospitalization and improve quality of life. The FUSION trial is designed to evaluate the safety and tolerability of serial doses of nesiritide (Natrecor®) administered to DHF patients at high risk for hospitalization.
Methods. FUSION is a multi-center, randomized, open label pilot study of 210 patients (70 per group). Key inclusion criteria include NYHA class III or IV adults who have received at least 2 treatments for acutely DHF in the last 12 months, and whose 6-minute walk test is 400 m. All patients are evaluated weekly and continue to receive their usual cardiac medications. They are randomized to one of three groups. In the first group no additional treatment is administered but may include IV inotropes. The other two groups exclude IV inotropes and are randomized to 1 of 2 serial infusion regimens of nesiritide: a low dose (on average 1 mg/kg bolus plus 0.005 mg/kg/min 4-6 hour infusion) or a higher dose (on average 2 mg/kg bolus plus 0.01 mg/kg/min infusion). The nesiritide dose may be increased or decreased within prescribed limits during the study. Patients will receive nesiritide infusions 1 to 3 times a week.
Patient enrollment is stratified into 2 groups using 7 prognostic factors to ensure balance between low and high risk for hospitalization. Patients will be treated for 12 weeks with a 4-week follow up. All patients are required to come in weekly for evaluation even if no infusion is given. B-type natriuretic peptide levels (BNP) will be drawn weekly pre-infusion, and endolthelin-1 and aldosterone levels will be drawn at baseline and weeks 4, 8, and 12. The Minnesota Living with Heart Failure questionnaire, Patient and Investigator Global Assessment questionnaires will be completed at weeks 4, 8, and 12. The 6-minute walk test will be repeated at weeks 6 and 12. Echocardiograms will be collected at screening and following week 12.
Conclusion. FUSION will provide valuable information on the safety and tolerability of nesiritide serial administration in the outpatient management of high-risk DHF patients.
[235] Early Adoption and Use of Nesiritide in the Treatment of Hospitalized Heart Failure Patients
Benjamin Gutierrez, Vanessa Hatch, Angela Blount Pharmaceutical Research Services, Premier, Inc, Charlotte, NC
Objective: Nesiritide (B-type natriuretic peptide, Natrecor®) was approved for the treatment of acute decompensated heart failure patients in August 2001. We present data on the early adoption and use of nesiritide for the treatment of heart failure (HF) patients from a large administrative inpatient database.
Methods: Using the Premier Perspective Database for a 6 month period, 9/01/01 - 3/31/02, drug utilization and cost measures for HF patients will be analyzed. HF patients include patients with ICD-9 code of 428.0, 428.1, and 428.9. Currently, we have 20 patients from September 2001 but patients are continuously being added to the database and we expect to present findings based on more than 200 patients. The HF patients treated with nesiritide will be compared to non-nesiritide treated HF patients from the same cohort of hospitals.
Results: From the initial patient sample (N=20), forty-five percent of all nesiritide-treated HF patients were admitted to the hospital from the emergency room. All nesiritide patients were admitted to the intensive care unit (ICU) but none expired during their hospitalization. Among these patients, there was less use of inotropic drugs, milrinone and dobutamine, and vasoactive drugs than for the typical hospitalized HF patient. Conclusions: The early adoption and use of nesiritide in the treatment of hospitalized HF patients appears to have decreased the use of inotropic agents and vasoactive drugs.
[153] Serum Levels of B-Type Naturetic Peptide after Cardiectomy and Implantation of a Total Artificial Heart
Reynolds M. Delgado III, O.H. Frazier, Timothy J. Myers, Toni Pool, Nanci Scroggins, Igor Gregoric, Tehreen Khan, Biswajit Kar, Branislav Radovancevic Cardiopulmonary Transplantation, Texas Heart Institute/St. Luke's Epsicopal Hospital, Houston, TX
Background: B-type Naturetic Peptide (BNP) is produced in the ventricular myocardium in response to stretch of the myocytes. There is thought to be no significant amounts produced by other tissues.
Methods: We performed serial serum BNP measurements in a patient after implantation of the AbioCor total artificial heart. A small amount of atrial tissue was left in place after implantation.
Results: One week prior to implantation, BNP level was 666 indicating severe heart failure. Nesiritide, (exogenous BNP) was administered post op days (POD) 1-12. It has a half life of 3 hours. On POD 32 the serum level was 443, on POD 49 it was 93, on POD 55 it was 67, and on POD 57 it was 106. During this time, the patient had no heart failure symptoms and had normal hemodynamics except for an elevated pulmonary artery pressure.
Conclusion: BNP levels remained at normal levels after cardiectomy for 45 days after withdrawl of exogenous BNP, indicating production of the hormone in sites other than ventricular myocardium.
[204] Safety of Nesiritide during Infusion for Decompensated Heart Failure
W. Frank Peacock, Charles L. Emerman, Geraldine Smoluk, Mei Cheng, James Young Emergency Medicine, The Cleveland Clinic, Cleveland, OH; Scios Inc., Sunnyvale, CA; Cardiology, The Cleveland Clinic, Cleveland, OH
Background: Nesiritide is approved for acutely decompensated congestive heart failure (HF). Preclinical trials have evaluated it in >1000 patients versus various controls. Our purpose was to evaluate nesiritide safety at various dosages against other HF agents.
Methods: Retrospective review of adverse events in 3 Phase III trials (Comparative, PRECEDENT, and VMAC) evaluating nesiritide (N=639) against control agents (N=401), including nitroglycerin and dobutamine. Statistical analyses utilized the Chi Square test and SASS statistical package.
Results: The mean age was 62 ± 13.7 years. 68% of patients were male, 37% were NYHA class IV at baseline, and 87% had systolic dysfunction. The most common side effect was dose related hypotension. At recommended dosing, there was no difference in hypotension rates between nesiritide and comparators (p> 0.05). Side effects more common in the comparators included ventricular tachycardia (dobutamine 11%, nesiritide 5%, p = 0.015) and headache (all controls 15%, nesiritide 8%; p = 0.001). Infusion site pain (p<0.05), and dizziness (p<0.05), during the first 24 hours were more frequent in the comparators. Bradycardia occurred more often with nesiritide (<1% control, 3% nesiritide; p = 0.002), but only 3 of 21 (14%) required treatment. Serum creatinine increases were reported with nesiritide (mean 0.1 mg/dL, max 3.8mg/dL; p >0.05), but only reached significance in the cohort exceeding recommended dosing (p <0.05). There were no differences in 30-day dialysis rates between nesiritide and comparators (p>0.05).
Conclusion: Nesiritide is safe and generally well tolerated in acutely decompensated congestive HF.
[205] Nesiritide in an Outpatient Infusion Clinic Setting – Case Studies of 17 Patients
Larry Altschul, Michael Masciello, Gina Massaro South Bay Cardiovascular Associates, West Islip, NY
Objective: To evaluate the clinical response of 17 congestive heart failure (CHF) patients treated with nesiritide (Natrecor), 1 to 3 times a week, in an outpatient setting.
Background: Nesiritide (human B-type natriuretic peptide or BNP) has been approved for the treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity. There has been little reported on outpatient serial use of nesiritide.
Methods: This is a retrospective evaluation of 17 NYHA Class III or IV CHF patients with a poor quality of life on maximally tolerated medical therapy, who have been treated with nesiritide for >12 weeks. In addition to standard care, patients received nesiritide 1-3 times a week as a 2-mg/kg bolus followed by a 4-hour infusion at 0.01-mg/kg/min. Dosing frequency was based on symptomology, supported by endogenous BNP levels.
Results: 17 patients were treated with nesiritide an average of 18+/-5 weeks. Mean decrease in endogenous BNP levels was >41% (range – 1 to 95%) or 529 pg/mL (12 patients had starting BNP levels >1300 pg/mL). 15/17 patients showed improvement in NYHA functional class. Mean weight change was -7 pounds. Most patients reduced or eliminated intravenous diuretic use, and 5 /17 reduced their oral diuretic dose. Only 2 patients have been hospitalized since starting nesiritide. 15/17 experienced significant improvements in their quality of life.
Conclusions: Serial treatment with nesiritide has resulted in significant improvements in clinical symptoms and quality of life for 15/17 patients summarized here. Results from these 17 case studies will be presented.
[221] Cost-Effectiveness of Nesiritide in Acute Decompensated Heart Failure
Claire B. Hunter, Daniel E. Hilleman, Mark A. Malesker, Christopher J. Holewinski School of Pharmacy and Allied Health Professions, Creighton University, Omaha, NE
Objectives: To evaluate the cost-effectiveness of nesiritide (N) in patients (pts) with acute decompensated heart failure (HF).
Methods: This study was a case-control health care resource utilization analysis of HF pts receiving N (cases) and not receiving N (controls) at a 400-bed University teaching hospital. 40 pts with acute decompensated HF (DRG127) admitted to the coronary care unit (CCU) comprised this study group. 20 pts serving as controls did not receive N were matched with 20 pts serving as controls receiving N within 36 hrs of hospital admission. Cases had to receive a minimum of 24 hrs of N.
Results: Costs of health care resources were based on cost-to-charge ratios. Pts receiving N had significantly shorter lengths of stay (LOS) in both the CCU (-9.25 hrs) and for total hospital LOS (-20.0 hrs). Pts receiving N had fewer diuretic (-2.5) and potassium doses (-2.7) and less blood draws for electrolytes/renal function (-2.3). Pts receiving N also received less dobutamine, dopamine, IV nitroglycerin, and milrinone. Utilization of other tests/diagnostic procedures was not significantly different between cases and controls. The difference in health care resource costs which included the cost of N ($625) for cases, was $500 less for cases than controls.
Implications: When N is added to therapy within the first 36 hrs of hospital admission to pts with acute decompensated HF, health care resources are reduced and a cost savings is realized.
[224] Decreased Filling Pressures by Nesiritide Infusions in Non-Decompensated Congestive Heart Failure Patients
Tom Bennett, Barbro Kjellstrom, George Schreiner, Frieder Braunschweig Heart Failure Management, Medtronic, Inc., Minneapolis, MN; Scios, Inc., Sunnyvale, CA; Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
Introduction. Nesiritide is a synthetic human B-type natriuretic peptide (Natrecor®, Scios, Inc) for intravenous therapy and is currently used to lower filling pressures in decompensated congestive heart failure (CHF). However, its effects in stable heart failure are unknown.
Methods. Four stable CHF patients (56-73 yr; NYHA Class II-III; LVEF 20-30%) with an Implantable Hemodynamic Monitor (IHM*) were included in a pilot study to document the acute and long term effects of nesiritide. The IHM continuously records heart rate (HR), right ventricular systolic (RVSP) and diastolic (RVDP) pressure and an estimate of pulmonary artery pressure (ePAD). Infusions of nesiritide (bolus + 0.01 ug/kg/min) or placebo were administered over 6 hours, one week apart in a randomized crossover protocol with patients and investigators blinded. IHM data were continuously recorded throughout the study. Clinical status, quality of life (QoL, Minnesota Living with Heart Failure), exercise tolerance (six-minute walk tests) and serum BNP were assessed before (1 day), during (2, 6 hours) and after (1, 3, 7 days) infusions.
Results. Nesiritide infusion was well tolerated in all patients. There were no significant differences in QoL scores, clinical status, 6-minute walk distance or post infusion BNP levels. However, in all patients there was a demonstrable hemodynamic response during nesiritide vs placebo: the mean pressure differences averaged over the 6-hr infusions for all patients were -7.2±3.0, -2.3±1.7 and -3.5±2.0 mmHg for RVSP, RVDP and ePAD, respectively, with no change in HR. Baseline and peak RV pressures during 6-minute hall walk were lower with nesiritide vs placebo while the pressure increase during the walk was not different. No responses were preserved long-term (1 week).
Conclusion. In patients with stable heart failure, nesiritide decreased cardiac filling pressures by a similar magnitude as previously reported in decompensated patients. This indicates that nesiritide infusion may have merit in non-decompensated CHF patients. However, the optimal dose, frequency and duration needed to produce long-term pressure lowering remains to be established. *The IHM used in this study is an investigational device.
[335] Intermittent Out-Patient Nesiritide Infusion Is an Effective Alternative to Hospital Admission for the Treatment of
Decompensated Heart Failure
John S. Golden, Catherine C. Fallick, Pamela P. Barnett, Susan J. Morikawa, Sharon R. Josephson, Mary C. Langford, Suzanne J. Wingate, Elizabeth A. Monson, Catherine A. Carlton Department of Cardiology, Kaiser Permanente of the Mid-Atlantic States, Fairfax, VA
Background: Recent trials have shown that 24-48 hour infusions of the B-type natriuretic peptide Nesiritide improve hemodynamics and symptoms in patients hospitalized with decompensated heart failure. To date, however, there has been no reported experience with use of this agent on an outpatient basis. We sought to evaluate the safety and efficacy of intermittent outpatient Nesiritide infusion in patients with decompensated heart failure refractory to standard therapy, including intravenous diuretics.
Methods: 7 patients (4 men, 3 women) with decompensated New York Heart Association class IV heart failure were treated with Nesiritide on an outpatient basis in our Heart Failure Treatment Program. All had dyspnea at rest despite treatment with intravenous diuretics within the previous week and were judged to require intravenous vasoactive drug therapy. Average age was 71.9 years. All were diabetic. 6 had severe left ventricular systolic dysfunction (average LVEF 23±8.1%). One had predominantly diastolic dysfunction. Baseline serum creatinine was 1.6±0.4 mg/dl. Background therapy included diuretics and ACE-inhibitors in all patients. 5 were on beta-blockers, 5 on Digoxin, and 4 on Spironolactone. Average baseline systolic blood pressure was 122.7±11.4 mm Hg. Nesiritide was administered by bolus (2mcg/kg) and 6-hour infusion (0.01 mcg/kg/min). Blood pressure and continuous telemetry monitoring were performed. Symptoms and urine output were assessed.
Results: All patients reported a marked improvement in baseline dyspnea. The average drop in systolic blood pressure at 3 hours was 9.6±7.1 mm Hg. One patient developed symptomatic hypotension after being given an initial beta-blocker dose during the infusion. Nesiritide was discontinued. Her symptoms resolved and blood pressure returned to baseline after 2 hours. Average urine output was 543±232 ml. There were no ventricular dysrhythmias. 3 patients have received multiple outpatient infusions since initial treatment. No patient has required hospital admission for decompensated heart failure (minimum follow-up 1 week, range: 2-12 weeks).
Conclusions: Intermittent outpatient Nesiritide infusion appears to be a safe, effective alternative to hospital admission for the treatment of decompensated heart failure. The role of intermittent outpatient therapy with this agent will be more fully defined by the results of ongoing prospective randomized clinical trials.
[351] Efficacy and Safety of Combined Nesiritide and Milrinone in the Treatment of Acutely Decompensated Heart Failure
Nandkishore R. Gurram, Dan Lewis, Sumant Lamba, Vaqar Ali, Pranab Das, Julia Osborne, Shelly Selby, Peggy Hardesty, Robin J. Trupp, William T. Abraham Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY
BACKGROUND
Nesiritide, a synthetic form of human B-type natruretic peptide, is a useful pharmacological agent for the treatment of acutely decompensated heart failure. Randomized controlled trials have evaluated its efficacy and safety when given along with other usual heart failure therapies with the notable exeption of intravenous Milrinone. Theoritically, the combination of nesiritide and milrinone could produce an additive risk of hypotension.
METHODS
To date, 26 patients participating in an ongoing observational clinical experience have recieved the combination of intravenous milrinone and nesiritide. Patients were begun on either milrinone (n = 18) or nesiritide (n = 8) and assessed over a period of 12 to 24 hours. Those patients with an inadequate hemodynamic or clinical response according to prespecified criteria (e.g. PCWP > 18 mm Hg, CI < 2.0, increasing serum creatinine, or poor diuresis), then underwent the addition of other agent. Combined effect on hemodynamics/clinical parameters and safety were recorded.
RESULTS
The following baseline charecteristics were noted :
Mean age, 57 +/- 3 years; 84 % men; ischemic etiology, 64 %; serum creatinine, 1.86 +/- 0.11 mg/dl; systolic blood pressure, 110 +/-3 mmHg (range 90-166 mmHg). The combination of nesiritide and milrinone significantly improved hemodynamics (CI 1.86 +/- 0.11 to 2.67 +/- 0.14 ml/min/m2, p < 0.000) and diuresis ( average weight loss 4.6 +/- 0.9 kg, p < 0.0001) over 24 to 48 hours. Renal function was preserved. There was one episode of symptomatic hypotension.
CONCLUSION
The combination of nesiritide and milrinone significantly improved hemodynamics and clinical status in true heart failure patients. The approximate history of incidence of symptomatic hypotension is comparable to that reposed with either agent alone. Thus the combination of milrinone and nesiritide appears to be both effective and safe for the treatment of decompensated heart failure. |
