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Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Adrian F. Hernandez, MD On behalf of the ASCEND-HF Committees, Investigators.

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Presentation on theme: "Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Adrian F. Hernandez, MD On behalf of the ASCEND-HF Committees, Investigators."— Presentation transcript:

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 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

3 International Steering Committee Executive Committee 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 Sponsor Scios Inc. Independent DSMB Chair: Sidney Goldstein Salim Yusuf, David DeMets, Milton Packer, John Kjekshus Study organization North America Academic Consortium: (DCRI, C5, Jefferson, Henry Ford, Canadian VIGOUR Centre) ROW: Johnson & Johnson Global Clinical Operations Coordinating center: DCRI Adrian Hernandez, Craig Reist, Gretchen Heizer >800 Investigators and Study Coordinators at 398 Sites Clinical Event Committee Chair: John McMurray

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  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”) Design of ASCEND-HF: Guiding principles

6 To assess whether nesiritide vs placebo, in addition to standard care provides: Reduction in rate of HF rehospitalization or all-cause mortality through Day 30 Significant improvement in self-assessed dyspnea at 6 or 24 hrs using 7-point Likert scale Co-Primary objectives % Subjects Markedly Better Minimally Worse Moderately Better Moderately Worse Minimally Better Markedly Worse No Change

7  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 Secondary and safety objectives

8  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 Study design and drug procedures Nesiritide Placebo 24–168 hrs Rx Acute HF < 24 hrs from IV RX 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

9  Hospitalized for ADHF <24 hrs from IV treatment  Dyspnea at rest or with minimal activity  1 clinical sign: 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  Hypotension at baseline (SBP <100 mm Hg or SBP<110 mm Hg with IV vasodilator)  Significant lung disease that could interfere with interpretation of dyspnea  Acute coronary syndrome  Severe anemia or active bleeding  Treatment with levosimendan or milrinone  Unstable doses of IV vasoactive medication within 3 hours Key inclusion criteriaKey exclusion criteria Inclusion and exclusion criteria

10  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 significance level Dyspnea tested at 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 ≤  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% Statistical methods

11 Enrollment North America = 45% 214 sites Latin America = 9% 39 sites Asia-Pacific = 25% 62 sites Central Europe = 14% 48 sites Western Europe = 7% 35 sites 7141 patients 30 Countries & 398 Sites >800 Investigators and Study Coordinators

12 Randomized (n=7141) Study population Placebo MITT=3511 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) Nesiritide MITT=3496 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)

13 Placebo (n=3511)Nesiritide (n=3496) Age (yrs)67 (56, 76) Female (%) Black or African American Systolic Blood Pressure (mmHg)124 (110, 140)123 (110, 140) Heart rate (beats/min)82 (72, 95) Respiratory rate (breaths/min)24 (21,26)23 (21, 26) Medical History (%) Ischemic heart disease Hypertension Atrial fibrillation Chronic respiratory disease Diabetes Baseline characteristics Continuous variables as median (IQR 25 th, 75 th ); MITT population

14 Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) Labs/Studies LVEF <40% within 12 mths (%) BNP (pg/mL) 989 (543, 1782) 994 (544, 1925) NT pro-BNP (pg/mL) 4461 (2123, 9217) 4508 (2076, 9174) Creatinine (mg/dL) 1.2 (1.0, 1.6) 1.2 (1.0, 1.5) Pre-randomization treatment (%) Loop diuretics Inotropes Vasodilators Continuous variables as median (IQR 25 th, 75 th ); MITT population

15 Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization Hazard Ratio 0.93 (95% CI: 0.8,1.08) Placebo Nesiritide HF Rehospitalization30-day Death/HF Rehospitalization 30-day Death Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0) % P=0.31

16 All Subjects N=6836 Baseline SBP (mmHg) < 123 ≥ 123 N=3346 N=3490 Baseline Ejection Fraction (%) <40 ≥ 40 N=4362 N=1187 Renal function- MDRD GFR (mL/min/m 2 ) <60 ≥ 60 N=3395 N=3093 History of CAD No Yes N=3092 N=3742 History of Diabetes Mellitus No Yes N=3923 N= day death/HF readmission subgroups Difference (%) and 95% Confidence Interval Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo

17 All Subjects N=6836 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= day death/HF readmission subgroups Difference (%) and 95% Confidence Interval Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo

18 % Subjects 24 Hours Markedly Better Minimally Worse Moderately Better Moderately Worse Minimally Better Markedly Worse No Change Co-Primary Endpoint: 6 and 24 hour dyspnea % Subjects Hours 3444 Placebo P= Nesiritide Placebo Nesiritide P= %44.5% 66.1% 68.2%

19 All SubjectsN=6860N=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= hours6 hours Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement OR 1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other

20 All SubjectsN=6860N=6769 Inotropes No Yes N=6574 N=286 N=6481 N=288 Vasodilators None Any IV Vaso No IV Nitro IV Nitro N=5912 N=943 N=5965 N=894 N=5835 N=929 N=5886 N=882 Diuretics No Yes N=691 N=6169 N=679 N=6090 Study Medication Bolus No Yes N=2612 N=4248 N=2564 N=4205 Time from Hosp to Rand <15.5 ≥15.5 N=3428 N=3432 N=3369 N= hours6 hours Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement OR 1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other

21 Placebo (n=3511) Nesiritide (n=3496) Difference (95% CI) P- value 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 (-0.13 to 0.53) 0.16 CV death or CV rehosp through Day % (402) 10.9% (372) -0.9 (-2.4 to 0.6) 0.24 Secondary endpoints Placebo (n=3511) Nesiritide (n=3496) P-value 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 Renal Safety Anytime Through Day 30 Placebo (n=3509) Nesiritide (n=3498) P-value >25% decrease eGFR29.5%31.4%0.11 End of Treatment Creatinine Creatinine (mg/dL) Cum Dist Discharge or 10 day Creatinine Creatinine (mg/dL) Cum Dist Nesiritide Placebo

23 (n=3509) Nesiritide (n=3498) Risk Difference (95% CI) P- value Any hypotension (Through Day 10/discharge) 15.3% (538) 26.6% (930) 11.3 (9.4 to 13.1) <.001 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 Hypotension

24 COMBINED 30 day w/out ASCEND1.28 (0.73, 2.25) 30-day mortality meta-analysis Odds Ratio (95% CI) PROACTION (N=237)6.93 (0.89, 53.91) 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) ASCEND-HF (N=7007) 0.89 (0.69, 1.14) COMBINED with ASCEND1.00 (0.76, 1.30)

25  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. Conclusions

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 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;

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