Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Adrian F. Hernandez, MD On behalf of the ASCEND-HF Committees, Investigators and Study Coordinators Disclosure Information Adrian F. Hernandez, MD ASCEND-HF Trial FINANCIAL DISCLOSURE: Trial Sponsor: Scios Inc Research funding from Johnson & Johnson Honorarium from Amgen, Corthera Full listing of disclosures at dcri.org UNLABELED or UNAPPROVED USE: None Study organization Sponsor Scios Inc. Executive Committee Independent DSMB Chair: Rob Califf Chris O’Connor (Co-PI), Randy Starling (Co-PI) Paul Armstrong, Kenneth Dickstein, Michel Komajda, Barry Massie, John McMurray, Markku Nieminen, Jean Rouleau, Karl Swedberg, Vic Hasselblad Chair: Sidney Goldstein Salim Yusuf, David DeMets, Milton Packer, John Kjekshus International Steering Committee Clinical Event Committee Chair: John McMurray ROW: Coordinating center: Johnson & Johnson Global Clinical Operations DCRI Adrian Hernandez, Craig Reist, Gretchen Heizer North America Academic Consortium: (DCRI, C5, Jefferson, Henry Ford, Canadian VIGOUR Centre) >800 Investigators and Study Coordinators at 398 Sites Background Acute heart failure is a major health problem responsible for several million hospitalizations worldwide each year. Standard therapy has not changed since 1970s and includes diuretics and variable use of vasodilators or inotropes. In 2001, nesiritide was approved by the FDA to reduce PCWP and improve dyspnea, based on efficacy at 3 hrs. However, in 2005 two meta-analyses raised concerns regarding the risks of mortality and renal injury. Subsequently, an independent panel* was convened by Scios Inc and recommended that a clinical trial be conducted to definitively answer the question of nesiritide’s safety and efficacy. *chaired by Eugene Braunwald Design of ASCEND-HF: Guiding principles Independent framework Pragmatic trial model • Focused • Efficient study design • Streamlined procedures • Simple follow-up Permissive enrollment criteria for broad population Meaningful outcomes Standard of care per local practice (“real world”) Co-Primary objectives To assess whether nesiritide vs placebo, in addition to standard care provides: • Significant improvement in self-assessed dyspnea at 6 or 24 hrs using 7-point Likert scale 60 Markedly Better Moderately Better 40 % Subjects • Reduction in rate of HF rehospitalization or all-cause mortality through Day 30 20 0 Minimally Better No Change Minimally Worse Moderately Worse 20 40 Markedly Worse Secondary and safety objectives Secondary endpoints: • Overall well-being at 6 and 24 hours • Persistent or worsening HF and all-cause mortality from randomization through discharge • Number of days alive and outside of the hospital • Cardiovascular rehospitalization and cardiovascular mortality Safety endpoints: • All cause mortality • Renal: 25% decrease in eGFR at any time from study drug initiation through Day 30 • Hypotension: As reported by investigator as symptomatic or asymptomatic Study design and drug procedures Nesiritide Acute HF < 24 hrs from IV RX 24–168 hrs Rx Placebo Co-primary endpoint: Dyspnea relief at 6 and 24 hrs Co-primary endpoint: 30-day death or HF rehosp All-cause mortality at 180 days Double – blind placebo controlled IV bolus (loading dose) of 2 µg/kg nesiritide or placebo • Investigator’s discretion for bolus • Followed by continuous IV infusion of nesiritide 0.01 µg/kg/min or placebo for up to 7 days Usual care per investigators including diuretics and/or other therapies as needed Duration of treatment per investigator based on clinical improvement Inclusion and exclusion criteria Key inclusion criteria Key exclusion criteria Hospitalized for ADHF <24 hrs from Hypotension at baseline IV treatment (SBP <100 mm Hg or SBP<110 mm Hg with IV vasodilator) Dyspnea at rest or with minimal activity Significant lung disease that could interfere with interpretation of 1 clinical sign: dyspnea • Respiratory rate ≥ 20 breaths per min • Rales >1/3 bases 1 objective measure: • CXR with pulmonary edema • BNP ≥400 pg/mL or NT-proBNP≥1000 pg/mL • Prior EF <40% within 12 months • PCWP > 20 mmHg Acute coronary syndrome Severe anemia or active bleeding Treatment with levosimendan or milrinone Unstable doses of IV vasoactive medication within 3 hours Statistical methods Study population: modified intention-to-treat based on receiving study drug Primary analysis: • Co-primary endpoints tested using Bonferroni approach • Composite of HF rehospitalization and all-cause mortality tested at 0.045 significance level • Dyspnea tested at 0.005 level using Hochberg method: Significant if both 6- and 24-hr assessment P values ≤0.005; or If either 6- or 24-hr assessment P values ≤0.0025 Sample size determination: • Based on composite endpoint: 89% power with 7000 patients using chi-square test, assuming a placebo event rate of 14% and a relative risk reduction of 18.6% Enrollment 7141 patients 30 Countries & 398 Sites Western Europe = 7% 35 sites North America = 45% 214 sites Latin America = 9% 39 sites Central Europe = 14% 48 sites Asia-Pacific = 25% 62 sites >800 Investigators and Study Coordinators Study population Randomized (n=7141) Placebo (n=3577) • Did not receive study drug (n=66) Hypotension (n=28) Exclusion criteria (n=8) Physician decision (n=6) Participant withdrew consent (n=14) Other reason (n=10) Placebo MITT=3511 Nesiritide (n=3564) • Did not receive study drug (n=68) Hypotension (n=26) Exclusion criteria identified (n=9) Physician decision (n=6) Participant withdrew consent (n=16) Other reason (n=11) Nesiritide MITT=3496 Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) 67 (56, 76) 67 (56, 76) Female (%) 34.9 33.4 Black or African American 15.0 14.7 124 (110, 140) 123 (110, 140) Heart rate (beats/min) 82 (72, 95) 82 (72, 95) Respiratory rate (breaths/min) 24 (21,26) 23 (21, 26) Ischemic heart disease 60.8 59.5 Hypertension 72.6 71.8 Atrial fibrillation 37.7 37.4 Chronic respiratory disease 16.6 16.3 Diabetes 42.9 42.3 Age (yrs) Systolic Blood Pressure (mmHg) Medical History (%) Continuous variables as median (IQR 25th, 75th); MITT population Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) LVEF <40% within 12 mths (%) 79.5 80.8 BNP (pg/mL) 989 Labs/Studies NT pro-BNP (pg/mL) Creatinine (mg/dL) 994 (543, 1782) (544, 1925) 4461 4508 (2123, 9217) 1.2 (2076, 9174) 1.2 (1.0, 1.6) (1.0, 1.5) Loop diuretics 95.3 94.9 Inotropes 4.4 4.3 Vasodilators 14.1 15.7 Pre-randomization treatment (%) Continuous variables as median (IQR 25th, 75th); MITT population Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) 12 10.1 10 9.4 Placebo Nesiritide 8 % 6.1 6 4.0 4 6.0 3.6 2 0 30-day Death/HF Rehospitalization Risk Diff (95 % CI) -0.7 (-2.1; 0.7) 30-day Death -0.4 (-1.3; 0.5) HF Rehospitalization -0.1 (-1.2; 1.0) 30 day death/HF readmission subgroups N=6836 All Subjects Baseline SBP (mmHg) < 123 ≥ 123 N=3346 N=3490 Baseline Ejection Fraction (%) <40 ≥ 40 N=4362 N=1187 Renal function- MDRD GFR (mL/min/m2) <60 ≥ 60 N=3395 N=3093 History of CAD No Yes N=3092 N=3742 History of Diabetes Mellitus No Yes N=3923 N=2913 -10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo -5 0 5 Difference (%) and 95% Confidence Interval 10 30 day death/HF readmission subgroups N=6836 All Subjects Inotrope Use at Randomization No Yes N=6556 N=280 Vasodilators None Any IV Vasodilators No IV Nitroglycerin IV Nitroglycerin N=5889 N=942 N=5943 N=892 Diuretics No Yes N=691 N=6145 Study Drug Bolus No Yes N=2609 N=4227 Time from Hosp to Rand (hrs) <15.5 ≥15.5 N=3426 N=3410 -10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo -5 0 5 Difference (%) and 95% Confidence Interval 10 Co-Primary Endpoint: 6 and 24 hour dyspnea 6 Hours 24 Hours 70 70 P=0.030 60 42.1% 44.5% 50 13.4 15.0 40 40 % Subjects 60 30 20 10 28.7 29.5 0 34.1 32.8 38.6 37.8 22.1 21.2 9.5 8.6 3398 Placebo 3371 Nesiritide 30 20 10 10 30 21.7 20.3 3444 Placebo 3416 Nesiritide 40 50 60 30.4 20 30 40 27.5 0 10 20 % Subjects 50 66.1% P=0.007 68.2% Markedly Better Moderately Better Minimally Better Minimally Worse Moderately Worse Markedly Worse No Change Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement 6 hours All Subjects 24 hours N=6860 N=6769 SBP <123 ≥123 N=3369 N=3491 N=3314 N=3455 GFR <60 ≥60 N=3494 N=3121 N=3349 N=3075 Ejection Fraction <40 ≥40 N=4385 N=1186 N=4335 N=1171 CAD No Yes N=3115 N=3743 N=3082 N=3685 Diabetes No Yes N=3930 N=2930 N=3887 N=2882 0 1 20 1 OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other 2 Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement 6 hours 24 hours All Subjects Inotropes N=6860 N=6769 N=6574 N=286 N=6481 N=288 N=5912 N=943 N=5965 N=894 N=5835 N=929 N=5886 N=882 No Yes N=691 N=6169 N=679 N=6090 No Yes N=2612 N=4248 N=2564 N=4205 <15.5 ≥15.5 N=3428 N=3432 N=3369 N=3400 No Yes None Any IV Vaso Vasodilators No IV Nitro IV Nitro Diuretics Study Medication Bolus Time from Hosp to Rand 0 1 2 0 OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other 1 2 Secondary endpoints Placebo (n=3511) Nesiritide (n=3496) Difference (95% CI) Pvalue Persistent or worsening HF or all-cause mortality through discharge 4.8% (165) 4.2% (147) -0.5 (-1.5 to 0.5) 0.30 Days alive and outside of hospital through Day 30 20.7 20.9 0.2 (-0.13 to 0.53) 0.16 11.8% (402) 10.9% (372) -0.9 (-2.4 to 0.6) 0.24 CV death or CV rehosp through Day 30 Well Being at 6 hours* Well Being at 24 hours* Placebo (n=3511) Nesiritide (n=3496) P-value 40.3% 41.4% 0.32 63.7% 65.7% 0.02 *Combined response for moderately/markedly better Renal Safety Anytime Through Day 30 >25% decrease eGFR Placebo (n=3509) Nesiritide (n=3498) P-value 29.5% 31.4% 0.11 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.5 0.4 0.6 0.5 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 2 4 6 Creatinine (mg/dL) Nesiritide Discharge or 10 day Creatinine Cum Dist Cum Dist End of Treatment Creatinine Placebo 8 0 0 2 4 6 Creatinine (mg/dL) 8 Hypotension Risk Difference (95% CI) Placebo (n=3509) Nesiritide (n=3498) Any hypotension (Through Day 10/discharge) 15.3% (538) 26.6% (930) (9.4 to 13.1) Asymptomatic Hypotension 12.4% (436) 21.4% (748) 9.0 (7.2 to 10.7) <.001 Symptomatic Hypotension 4.0% (141) 7.1% (250) 3.1 (2.1 to 4.2) <.001 11.3 Pvalue <.001 30-day mortality meta-analysis Odds Ratio (95% CI) Mills (N=163) 0.38 (0.05, 2.74) Efficacy (N=127) 1.24 (0.23, 6.59) Comparative (N=175) 1.43 (0.50, 4.09) PRECEDENT (N=147) 0.59 (0.18, 2.01) VMAC (N=498) 1.63 (0.77, 3.44) PROACTION (N=237) 6.93 (0.89, 53.91) COMBINED 30 day w/out ASCEND 1.28 (0.73, 2.25) ASCEND-HF (N=7007) 0.89 (0.69, 1.14) COMBINED with ASCEND 1.00 (0.76, 1.30) 0.1 1 10 Conclusions Nesiritide did not reduce the rate of recurrent heart failure hospitalization or death at 30 days. Nesiritide reduced dyspnea to a modest degree, consistent with previous findings but did not meet prespecified protocol criteria for statistical significance at 6 and 24 hours. Nesiritide did not affect 30-day all cause mortality nor did it worsen renal function as had been suggested by prior meta-analyses of smaller studies. Implications Nesiritide can now be considered a safe therapy in patients with acute heart failure. Further analysis of ASCEND-HF is likely to permit better understanding of acute heart failure and patient profiles that may potentially benefit from nesiritide. Our results from this large randomized trial emphasize both the challenges of making therapeutic decisions on inadequate evidence as well as the urgent need for large, well-conducted trials capable of informing clinical practice Steering Committee North America: Kirkwood F. Adams Jr MD; Javed Butler, MD;Maria Rosa Costanzo, MD; Mark E. Dunlap, MD; Justin A. Ezekowitz, MBBCh, MSc; David Feldman, MD, PhD; Gregg C. Fonarow, MD; Stephen S. Gottlieb, MD, MHS; James A. Hill, MD, MS; Judd E. Hollander, MD; Jonathan G. Howlett, MD; Michael Hudson, MD; Mariell L. Jessup, MD; Serge Lepage, MD; Wayne C. Levy, MD; Naveen Pereira, MD; W.H. Wilson Tang, MD; John R. Teerlink, MD; David J. Whellan, MD; Clyde W. Yancy, MD Europe: Stefan D. Anker, MD, PhD; Dan Atar, MD; Alexander Battler, MD; Ulf Dahlstrom, MD, PhD; Aleksandras Laucevicius, MD; Marco Metra, MD; Alexander Parkhomenko, MD; Piotr Ponikowski, MD, PhD; Jindrich Spinar, MD; Svetla Torbova, MD; Filippos Triposkiadis, MD;Vyacheslav Mareev, MD; Adriaan A. Voors, MD, PhD; Faiez Zannad, MD, PhD Latin America: Rodrigo Botero, MD; Nadine Clausell, MD; Ramón Corbalán, MD; Rafael Diaz, MD; Gustavo Méndez Machedo Asia Pacific: Ping Chai, MD; Wen-Jone Chen, MD; Henry Krum, MBBS, PhD; Sanjay Mittal, MD; Byung Hee Oh, MD; Supachai Tanomsup, MD; Richard W. Troughton, MD, PhD; YueJin Yang, MD;