A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure

Acute Decompensated Heart Failure (ADHF) is the inability of the heart to pump efficiently, which can result in symptoms like shortness of breath at rest or with minimal activity. ADHF is a condition in which the heart cannot perform the necessary circulation of blood through the body. This is a randomized (study medication is assigned by chance), double-blind (neither the patient or the doctor knows whether the patient is assigned to receive study drug or placebo \[does not contain study drug\]), placebo-controlled, parallel group, multicenter study of the effectiveness of nesiritide administered continuously through a vein for a minimum of 24 hours up to a maximum of 7 days. The study hypothesis is that nesiritide given in addition to standard care is superior to placebo given in addition to standard care as measured by relief of breathing difficulties (by patient evaluation utilizing a breathlessness scale) at 6 hours or 24 hours after nesiritide administration, and reduction in rehospitalization due to heart failure and death from study drug administration through Day 30. The study drug (nesiritide) or placebo dose being studied is 0.010 mcg/kg/min with or without a 2 mcg/kg initial bolus (one time injection) of nesiritide. Patient safety will be monitored throughout the study through physical exams, vital signs (heart rate, blood pressure, respiratory rate, and temperature), blood tests, and side effects. The patients assigned to the nesiritide group will receive a continuous intravenous (into a vein) infusion at 0.010 mcg/kg/min of nesiritide with or without a 2 mcg/kg bolus (one time injection). The patients assigned to the placebo group will receive matching placebo bolus and infusion. The bolus is given over one minute and the continuous infusion is given for at least 24 hours and up to 7 days.

• Nesiritide (Drug): 0.01 mcg/kg/min IV infusion (with or without 2 mcg/kg bolus) for 24 to 168 hrs
• Placebo (Drug): matching placebo infusion:0.01 mcg/kg/min IV infusion (with or without 2 mcg/kg bolus) for 24 to 168 hrs

Primary outcomes

• Composite of Rehospitalization Due to Heart Failure and All-Cause Mortality [Randomization to Day 30]
• Dyspnea Self-Assessment at 6 Hours After Initiation of Study Drug [6 hours after initiation of study drug]: Dyspnea symptoms were measured by patient self-assessed Likert scale at 6 hours after study drug initiation.The Likert scale is a 7-point ordinal categorical scale (the 7 categories are markedly better, moderately better, minimally better, unchanged, minimally worse, moderately worse, and markedly worse.)
• Dyspnea Self-Assessment at 24 Hours After Initiation of Study Drug [24 hours after study drug initiation]: Dyspnea symptoms were measured by patient self-assessed Likert scale at 24 hours after study drug initiation. The Likert scale is a 7-point ordinal categorical scale (the 7 categories are markedly better, moderately better, minimally better, unchanged, minimally worse, moderately worse, and markedly worse.)

Secondary outcomes

• Overall Well-Being Self-Assessment at 6 Hours After Initiation of Study Drug [6 hours after study drug initiation]: Overall well-being was measured by patient self-assessed Likert scale at 6 hours after study drug initiation. The Likert scale is a 7-point ordinal categorical scale (the 7 categories are markedly better, moderately better, minimally better, unchanged, minimally worse, moderately worse, and markedly worse.)
• Overall Well-Being Self-Assessment at 24 Hours After Initiation of Study Drug [24 hours after study drug initiation]: Overall well-being was measured by patient self-assessed Likert scale at 24 hours after study drug initiation. The Likert scale is a 7-point ordinal categorical scale (the 7 categories are markedly better, moderately better, minimally better, unchanged, minimally worse, moderately worse, and markedly worse.)
• Composite of Persistent or Worsening Heart Failure and All-Cause Mortality [Randomization to hospital discharge (up to Day 30)]: Clinical manifestations of worsening or persistent decompensated heart failure were defined by at least one of the following: new, persistent or worsening: dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, pulmonary basilar rales/crackles, jugular venous distension, renal hypoperfusion with no other apparent cause, or radiologic evidence of worsening heart failure. And was also defined by a new therapy specifically for the treatment of worsening or persistent decompensated heart failure.
• Number of Days Alive and Outside the Hospital [Randomization to Day 30]
• Composite of Cardiovascular Rehospitalization and Cardiovascular Mortality [Randomization to Day 30]

Other outcomes

• All-Cause Mortality Through Day 30 [Randomization to Day 30]: All deaths were adjudicated by an independent Clinical Events Committee.
• All-Cause Mortality Through Day 180 [Randomization to Day 180]: All deaths were adjudicated by an independent Clinical Events Committee.
• Cardiovascular Mortality Through Day 30 [Randomization to Day 30]: All deaths were adjudicated by an independent Clinical Events Committee (CEC) and the cardiovascular deaths were classified by the CEC based on the primary causes.
• Number of Patients With Renal Impairment [Study drug initiation to Day 30]: Renal impairment was defined as a greater than 25% decrease from baseline in the Modification of Diet in Renal Disease calculated glomerular filtration rate.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Hospitalized for the management of acute decompensated heart failure (ADHF) or diagnosed with ADHF within 48 hours after being hospitalized for another reason; Diagnosis of ADHF is defined as dyspnea (difficulty breathing) at rest or dyspnea with minimal activity.

Exclusion Criteria:

At high risk for hypotension (low blood pressure); Acute coronary syndrome as primary diagnosis; History of cardiac valvular stenosis, restrictive cardiomyopathy, hypertrophic cardiomyopathy, or pericardial tamponade; Previous enrollment in a nesiritide study; Persistent, uncontrolled hypertension (SBP \[systolic blood pressure\] >180 mmHg).

Participant flow

Outcome results

• Composite of Rehospitalization Due to Heart Failure and All-Cause Mortality (Primary), Number, Participants: Nesiritide 321; Placebo 345 (p 0.313)
• Dyspnea Self-Assessment at 6 Hours After Initiation of Study Drug (Primary), Number, Participants: Nesiritide 513; Placebo 460 (p 0.030)
• Dyspnea Self-Assessment at 24 Hours After Initiation of Study Drug (Primary), Number, Participants: Nesiritide 1025; Placebo 935 (p 0.007)
• Overall Well-Being Self-Assessment at 6 Hours After Initiation of Study Drug (Secondary), Number, Participants: Nesiritide 449; Placebo 418 (p 0.318)
• Overall Well-Being Self-Assessment at 24 Hours After Initiation of Study Drug (Secondary), Number, Participants: Nesiritide 913; Placebo 843 (p 0.018)
• Composite of Persistent or Worsening Heart Failure and All-Cause Mortality (Secondary), Number, Participants: Nesiritide 147; Placebo 165 (p 0.295)
• Number of Days Alive and Outside the Hospital (Secondary), Mean, Days: Nesiritide 20.9 +/- 6.88; Placebo 20.7 +/- 7.05 (p 0.160)
• Composite of Cardiovascular Rehospitalization and Cardiovascular Mortality (Secondary), Number, Participants: Nesiritide 372; Placebo 402 (p 0.238)
• All-Cause Mortality Through Day 30 (Other pre specified), Number, Participants: Nesiritide 126; Placebo 141
• All-Cause Mortality Through Day 180 (Other pre specified), Number, Participants: Nesiritide 429; Placebo 447
• Cardiovascular Mortality Through Day 30 (Other pre specified), Number, Participants: Nesiritide 112; Placebo 124
• Number of Patients With Renal Impairment (Other pre specified), Number, Participants: Nesiritide 1032; Placebo 968 (p 0.109)

Adverse events

Serious adverse events by term

Other adverse events by term

217 more terms not shown.

Limitations and caveats: Only summary counts of deaths by group are provided for other pre-specified endpoints "All-cause mortality through Day 30" and "All-cause mortality through Day 180." Formal statistical comparisons were not planned.

228 more sites not listed.

• Results publication: Gui H, Tang WHW, Francke S, Li J, She R, Bazeley P, Pereira NL, Adams K, Luzum JA, Connolly TM, Hernandez AF, McNaughton CD, Williams LK, Lanfear DE. Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial. Circ Heart Fail. 2023 Sep;16(9):e010438. doi: 10.1161/CIRCHEARTFAILURE.122.010438. Epub 2023 Jul 26. PMID 37725680
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• Results publication: Blumer V, Mentz RJ, Sun JL, Butler J, Metra M, Voors AA, Hernandez AF, O'Connor CM, Greene SJ. Prognostic Role of Prior Heart Failure Hospitalization Among Patients Hospitalized for Worsening Chronic Heart Failure. Circ Heart Fail. 2021 Apr;14(4):e007871. doi: 10.1161/CIRCHEARTFAILURE.120.007871. Epub 2021 Mar 29. PMID 33775110
• Results publication: Greene SJ, DeVore AD, Sheng S, Fonarow GC, Butler J, Califf RM, Hernandez AF, Matsouaka RA, Samman Tahhan A, Thomas KL, Vaduganathan M, Yancy CW, Peterson ED, O'Connor CM, Mentz RJ. Representativeness of a Heart Failure Trial by Race and Sex: Results From ASCEND-HF and GWTG-HF. JACC Heart Fail. 2019 Nov;7(11):980-992. doi: 10.1016/j.jchf.2019.07.011. Epub 2019 Oct 9. PMID 31606362
• Results publication: Greene SJ, Hernandez AF, Sun JL, Butler J, Armstrong PW, Ezekowitz JA, Zannad F, Ferreira JP, Coles A, Metra M, Voors AA, Califf RM, O'Connor CM, Mentz RJ. Relationship Between Enrolling Country Income Level and Patient Profile, Protocol Completion, and Trial End Points. Circ Cardiovasc Qual Outcomes. 2018 Oct;11(10):e004783. doi: 10.1161/CIRCOUTCOMES.118.004783. PMID 30354576
• Results publication: Verma AK, Sun JL, Hernandez A, Teerlink JR, Schulte PJ, Ezekowitz J, Voors A, Starling R, Armstrong P, O'Conner CM, Mentz RJ. Rate pressure product and the components of heart rate and systolic blood pressure in hospitalized heart failure patients with preserved ejection fraction: Insights from ASCEND-HF. Clin Cardiol. 2018 Jul;41(7):945-952. doi: 10.1002/clc.22981. Epub 2018 Jul 17. PMID 29781109
• Results publication: Bhatt AS, Cooper LB, Ambrosy AP, Clare RM, Coles A, Joyce E, Krishnamoorthy A, Butler J, Felker GM, Ezekowitz JA, Armstrong PW, Hernandez AF, O'Connor CM, Mentz RJ. Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). J Am Heart Assoc. 2018 Feb 3;7(3):e006740. doi: 10.1161/JAHA.117.006740. PMID 29431103
• Results publication: Greene SJ, Hernandez AF, Dunning A, Ambrosy AP, Armstrong PW, Butler J, Cerbin LP, Coles A, Ezekowitz JA, Metra M, Starling RC, Teerlink JR, Voors AA, O'Connor CM, Mentz RJ. Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure: From the ASCEND-HF Trial. J Am Coll Cardiol. 2017 Jun 27;69(25):3029-3039. doi: 10.1016/j.jacc.2017.04.043. PMID 28641792
• Results publication: Greene SJ, Hernandez AF, Sun JL, Metra M, Butler J, Ambrosy AP, Ezekowitz JA, Starling RC, Teerlink JR, Schulte PJ, Voors AA, Armstrong PW, O'Connor CM, Mentz RJ. Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Circ Heart Fail. 2016 Sep;9(9):e002986. doi: 10.1161/CIRCHEARTFAILURE.116.002986. PMID 27623769
• Results publication: Ezekowitz JA, Podder M, Hernandez AF, Armstrong PW, Starling RC, O'Connor CM, Califf RM. Arrival by ambulance in acute heart failure: insights into the mode of presentation from Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF). BMJ Open. 2016 Mar 17;6(3):e010201. doi: 10.1136/bmjopen-2015-010201. PMID 26988350
• Results publication: Abualnaja S, Podder M, Hernandez AF, McMurray JJ, Starling RC, O'Connor CM, Califf RM, Armstrong PW, Ezekowitz JA. Acute Heart Failure and Atrial Fibrillation: Insights From the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) Trial. J Am Heart Assoc. 2015 Aug 24;4(8):e002092. doi: 10.1161/JAHA.115.002092. PMID 26304935
• Results publication: Patel PA, Heizer G, O'Connor CM, Schulte PJ, Dickstein K, Ezekowitz JA, Armstrong PW, Hasselblad V, Mills RM, McMurray JJ, Starling RC, Tang WH, Califf RM, Hernandez AF. Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF. Circ Heart Fail. 2014 Nov;7(6):918-25. doi: 10.1161/CIRCHEARTFAILURE.113.000872. Epub 2014 Oct 3. PMID 25281655
• Results publication: van Deursen VM, Hernandez AF, Stebbins A, Hasselblad V, Ezekowitz JA, Califf RM, Gottlieb SS, O'Connor CM, Starling RC, Tang WH, McMurray JJ, Dickstein K, Voors AA. Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF). Circulation. 2014 Sep 16;130(12):958-65. doi: 10.1161/CIRCULATIONAHA.113.003046. Epub 2014 Jul 29. PMID 25074507
• Results publication: Kaul P, Reed SD, Hernandez AF, Howlett JG, Ezekowitz JA, Li Y, Zheng Y, Rouleau JL, Starling RC, O'Connor CM, Califf RM, Armstrong PW. Differences in treatment, outcomes, and quality of life among patients with heart failure in Canada and the United States. JACC Heart Fail. 2013 Dec;1(6):523-30. doi: 10.1016/j.jchf.2013.07.004. Epub 2013 Oct 23. PMID 24622005
• Results publication: Toma M, Ezekowitz JA, Bakal JA, O'Connor CM, Hernandez AF, Sardar MR, Zolty R, Massie BM, Swedberg K, Armstrong PW, Starling RC. The relationship between left ventricular ejection fraction and mortality in patients with acute heart failure: insights from the ASCEND-HF Trial. Eur J Heart Fail. 2014 Mar;16(3):334-41. doi: 10.1002/ejhf.19. Epub 2013 Dec 14. PMID 24464687
• Results publication: Reed SD, Kaul P, Li Y, Eapen ZJ, Davidson-Ray L, Schulman KA, Massie BM, Armstrong PW, Starling RC, O'Connor CM, Hernandez AF, Califf RM. Medical resource use, costs, and quality of life in patients with acute decompensated heart failure: findings from ASCEND-HF. J Card Fail. 2013 Sep;19(9):611-20. doi: 10.1016/j.cardfail.2013.07.003. PMID 24054337
• Results publication: Howlett JG, Ezekowitz JA, Podder M, Hernandez AF, Diaz R, Dickstein K, Dunlap ME, Corbalan R, Armstrong PW, Starling RC, O'Connor CM, Califf RM, Fonarow GC; ASCEND-HF Investigators. Global variation in quality of care among patients hospitalized with acute heart failure in an international trial: findings from the acute study clinical effectiveness of nesiritide in decompensated heart failure trial (ASCEND-HF). Circ Cardiovasc Qual Outcomes. 2013 Sep 1;6(5):534-42. doi: 10.1161/CIRCOUTCOMES.113.000119. Epub 2013 Jul 30. PMID 23899930
• Results publication: Eapen ZJ, Reed SD, Li Y, Kociol RD, Armstrong PW, Starling RC, McMurray JJ, Massie BM, Swedberg K, Ezekowitz JA, Fonarow GC, Teerlink JR, Metra M, Whellan DJ, O'Connor CM, Califf RM, Hernandez AF. Do countries or hospitals with longer hospital stays for acute heart failure have lower readmission rates?: Findings from ASCEND-HF. Circ Heart Fail. 2013 Jul;6(4):727-32. doi: 10.1161/CIRCHEARTFAILURE.112.000265. Epub 2013 Jun 14. PMID 23770519
• Results publication: Ezekowitz JA, Hu J, Delgado D, Hernandez AF, Kaul P, Leader R, Proulx G, Virani S, White M, Zieroth S, O'Connor C, Westerhout CM, Armstrong PW. Acute heart failure: perspectives from a randomized trial and a simultaneous registry. Circ Heart Fail. 2012 Nov;5(6):735-41. doi: 10.1161/CIRCHEARTFAILURE.112.968974. Epub 2012 Oct 2. PMID 23032196
• Results publication: Ezekowitz JA, Hernandez AF, O'Connor CM, Starling RC, Proulx G, Weiss MH, Bakal JA, Califf RM, McMurray JJ, Armstrong PW. Assessment of dyspnea in acute decompensated heart failure: insights from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the contributions of peak expiratory flow. J Am Coll Cardiol. 2012 Apr 17;59(16):1441-8. doi: 10.1016/j.jacc.2011.11.061. PMID 22497823
• Results publication: O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, Heizer GM, Komajda M, Massie BM, McMurray JJ, Nieminen MS, Reist CJ, Rouleau JL, Swedberg K, Adams KF Jr, Anker SD, Atar D, Battler A, Botero R, Bohidar NR, Butler J, Clausell N, Corbalan R, Costanzo MR, Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, Ezekowitz JA, Feldman D, Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, Hollander JE, Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC, Mendez GF, Metra M, Mittal S, Oh BH, Pereira NL, Ponikowski P, Tang WH, Tanomsup S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA, Whellan DJ, Zannad F, Califf RM. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011 Jul 7;365(1):32-43. doi: 10.1056/NEJMoa1100171. PMID 21732835

• Scios, Inc. Clinical Trial, Study director, Scios, Inc.