Ascend hf-101115080858-phpapp01

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Ascend hf-101115080858-phpapp01

  1. 1. 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
  2. 2. Disclosure InformationAdrian F. Hernandez, MDASCEND-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
  3. 3. Study organization Sponsor Executive Committee Independent DSMB Scios Inc. Chair: Rob Califf Chair: Sidney Goldstein Chris O’Connor (Co-PI), Randy Starling (Co-PI) Salim Yusuf, Paul Armstrong, Kenneth Dickstein, David DeMets, Michel Komajda, Barry Massie, John McMurray, Milton Packer, Markku Nieminen, Jean Rouleau, John Kjekshus Karl Swedberg, Vic Hasselblad Clinical Event International Steering Committee Committee Chair: John McMurray ROW: Coordinating center: North America Johnson & Johnson DCRI Academic Consortium: Global Clinical Adrian Hernandez, (DCRI, C5, Jefferson, Operations Craig Reist, Henry Ford, Canadian Gretchen Heizer VIGOUR Centre) >800 Investigators and Study Coordinators at 398 Sites
  4. 4. 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
  5. 5. 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 “Real world” treatment
  6. 6. Co-Primary objectivesTo assess whether nesiritide vs placebo,in addition to standard care provides:• Reduction in rate of HF rehospitalization 60 Markedly Better Moderately Better or all-cause mortality 40 Minimally Better through Day 30 % Subjects 20 No Change• Significant improvement Minimally Worse 0 Moderately Worse in self-assessed dyspnea 20 Markedly Worse at 6 or 24 hrs 40 Placebo Nesiritide using 7-point Likert scale
  7. 7. 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
  8. 8. Study design and drug procedures NesiritideAcute HF < 24 hrs 24–168 hrs Rxfrom IV RX Placebo Co-primary Co-primary All-cause endpoint: endpoint: mortality Dyspnea relief 30-day death or at 180 at 6 and 24 hrs HF rehosp 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
  9. 9. 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  Acute coronary syndrome • Rales >1/3 bases  Severe anemia or active bleeding 1 objective measure:  Treatment with levosimendan or • CXR with pulmonary edema milrinone • BNP ≥400 pg/mL or  Unstable doses of IV vasoactive NT-proBNP≥1000 pg/mL medication within 3 hours • Prior EF <40% within 12 months • PCWP > 20 mmHg
  10. 10. 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%
  11. 11. Enrollment 7141 patients 30 Countries & 398 Sites Western Europe = 7% 35 sites North America = 45% Central Europe = 14% 214 sites 48 sites Asia-Pacific = 25% 62 sites Latin America = 9% 39 sites >800 Investigators and Study Coordinators
  12. 12. Study population Randomized (n=7141)Placebo (n=3577) Nesiritide (n=3564)• Did not receive study drug (n=66) • Did not receive study drug (n=68) Hypotension (n=28) Hypotension (n=26) Exclusion criteria (n=8) Exclusion criteria identified (n=9) Physician decision (n=6) Physician decision (n=6) Participant withdrew consent (n=14) Participant withdrew consent (n=16) Other reason (n=10) Other reason (n=11) Placebo MITT=3511 Nesiritide MITT=3496
  13. 13. Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) Age (yrs) 67 (56, 76) 67 (56, 76) Female (%) 34.9 33.4 Black or African American 15.0 14.7 Systolic Blood Pressure (mmHg) 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) Medical History (%) 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 Continuous variables as median (IQR 25th, 75th); MITT population
  14. 14. Baseline characteristics Placebo Nesiritide (n=3496) (n=3511) Labs/Studies LVEF <40% within 12 mths (%) 79.5 80.8 BNP (pg/mL) 989 994 (543, 1782) (544, 1925) NT pro-BNP (pg/mL) 4461 4508 (2123, 9217) (2076, 9174) Creatinine (mg/dL) 1.2 1.2 (1.0, 1.6) (1.0, 1.5) Pre-randomization treatment (%) Loop diuretics 95.3 94.9 Inotropes 4.4 4.3 Vasodilators 14.1 15.7 Continuous variables as median (IQR 25th, 75th); MITT population
  15. 15. 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 6.0 % 6 4.0 4 3.6 2 0 30-day Death/HF 30-day Death HF Rehospitalization RehospitalizationRisk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)
  16. 16. 30 day death/HF readmission subgroupsAll Subjects N=6836 < 123 N=3346Baseline SBP (mmHg) ≥ 123 N=3490Baseline Ejection Fraction <40 N=4362(%) ≥ 40 N=1187Renal function- MDRD GFR <60 N=3395(mL/min/m2) ≥ 60 N=3093 No N=3092History of CAD Yes N=3742 No N=3923History of Diabetes Mellitus Yes N=2913 -10 -5 0 5 10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval
  17. 17. 30 day death/HF readmission subgroupsAll Subjects N=6836Inotrope Use at No N=6556Randomization Yes N=280 None N=5889 Any IV Vasodilators N=942Vasodilators No IV Nitroglycerin N=5943 IV Nitroglycerin N=892Diuretic Use from No N=691Hospitalization toRand Yes N=6145 No N=2609Study Drug Bolus Yes N=4227Time from Hosp to <15.5 N=3426Rand (hrs) ≥15.5 N=3410 -10 -5 0 5 10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval
  18. 18. Co-Primary Endpoint: 6 and 24 hour dyspnea 6 Hours 24 Hours 70 70 66.1% P=0.007 68.2% 60 P=0.030 60 50 42.1% 44.5% 50 27.5 30.4 40 40 13.4 15.0% Subjects % Subjects 30 30 20 20 38.6 37.8 28.7 29.5 10 10 0 0 10 10 32.8 22.1 21.2 34.1 20 20 9.5 8.6 30 30 40 20.3 40 3398 3371 21.7 50 Placebo Nesiritide 60 3444 3416 Placebo Nesiritide Markedly Better Moderately Better Minimally Better No Change Minimally Worse Moderately Worse Markedly Worse
  19. 19. Dyspnea at 6 and 24 HoursOdds for Marked-Moderate Improvement 6 hours 24 hoursAll Subjects N=6860 N=6769 <123 N=3369 N=3314SBP ≥123 N=3491 N=3455 <60 N=3494 N=3349GFR ≥60 N=3121 N=3075Ejection <40 N=4385 N=4335Fraction ≥40 N=1186 N=1171 No N=3115 N=3082CAD Yes N=3743 N=3685 No N=3930 N=3887Diabetes Yes N=2930 N=2882 0 1 20 1 2 OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other
  20. 20. Dyspnea at 6 and 24 HoursOdds for Marked-Moderate Improvement 6 hours 24 hoursAll Subjects N=6860 N=6769 No N=6574 N=6481Inotropes Yes N=286 N=288 None N=5912 N=5835 Any IV Vaso N=943 N=929Vasodilators No IV Nitro N=5965 N=5886 IV Nitro N=894 N=882 No N=691 N=679Diuretics Yes N=6169 N=6090StudyMedication No N=2612 N=2564Bolus Yes N=4248 N=4205Time from <15.5 N=3428 N=3369Hosp to ≥15.5 N=3432 N=3400Rand 0 1 2 0 1 2 OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other
  21. 21. Secondary endpoints Placebo Nesiritide Difference P- (n=3511) (n=3496) (95% CI) value Persistent or worsening HF or 4.8% 4.2% -0.5 all-cause mortality through 0.30 (165) (147) (-1.5 to 0.5) discharge Days alive and outside of 0.2 20.7 20.9 0.16 hospital through Day 30 (-0.13 to 0.53) CV death or CV rehosp 11.8% 10.9% -0.9 0.24 through Day 30 (402) (372) (-2.4 to 0.6) Placebo Nesiritide P-value (n=3511) (n=3496) Well Being at 6 hours* 40.3% 41.4% 0.32 Well Being at 24 hours* 63.7% 65.7% 0.02 *Combined response for moderately/markedly better
  22. 22. Renal Safety Placebo Nesiritide Anytime Through Day 30 P-value Placebo Nesiritide (n=3509) (n=3498) >25% decrease eGFR 29.5% 31.4% 0.11 End of Treatment Creatinine Discharge or 10 day Creatinine 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 Cum DistCum Dist 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 0 2 4 6 8 Creatinine (mg/dL) Creatinine (mg/dL)
  23. 23. Hypotension Risk Placebo Nesiritide P- Difference (n=3509) (n=3498) value (95% CI)Any hypotension 15.3% 26.6% 11.3 <.001(Through Day 10/discharge) (538) (930) (9.4 to 13.1) 12.4% 21.4% 9.0Asymptomatic Hypotension <.001 (436) (748) (7.2 to 10.7) 4.0% 7.1% 3.1Symptomatic Hypotension <.001 (141) (250) (2.1 to 4.2)
  24. 24. 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
  25. 25. 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 pre- specified 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.
  26. 26. 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
  27. 27. Steering CommitteeNorth America: Kirkwood F. Adams Jr MD; Javed Butler, MD;Maria RosaCostanzo, MD; Mark E. Dunlap, MD; Justin A. Ezekowitz, MBBCh, MSc; DavidFeldman, MD, PhD; Gregg C. Fonarow, MD; Stephen S. Gottlieb, MD, MHS; JamesA. Hill, MD, MS; Judd E. Hollander, MD; Jonathan G. Howlett, MD; MichaelHudson, MD; Mariell L. Jessup, MD; Serge Lepage, MD; Wayne C. Levy, MD;Naveen Pereira, MD; W.H. Wilson Tang, MD; John R. Teerlink, MD; Clyde W.Yancy, MDEurope: Stefan D. Anker, MD, PhD; Dan Atar, MD; Alexander Battler, MD; UlfDahlstrom, MD, PhD; Aleksandras Laucevicius, MD; Marco Metra, MD; AlexanderParkhomenko, MD; Piotr Ponikowski, MD, PhD; Jindrich Spinar, MD; SvetlaTorbova, MD; Filippos Triposkiadis, MD;Vyacheslav Mareev, MD; Adriaan A.Voors, MD, PhD;David J. Whellan, MD, MHS; Clyde W. Yancy, MD; Faiez Zannad,MD, PhDLatin America: Rodrigo Botero, MD; Nadine Clausell, MD; Ramón Corbalán, MD;Rafael Diaz, MD; Gustavo Méndez MachedoAsia 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;

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