Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure

Transcription

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 Study organization Sponsor Scios Inc. 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 Independent DSMB Chair: Sidney Goldstein Salim Yusuf, David DeMets, Milton Packer, John Kjekshus International Steering Committee Clinical Event Committee Chair: John McMurray ROW: Johnson & Johnson Global Clinical Operations Coordinating center: 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

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 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 )

6 % Subjects Co-Primary objectives 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 Markedly Better Moderately Better Minimally Better No Change Minimally Worse Moderately Worse Markedly Worse

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 Study design and drug procedures Nesiritide Acute HF < 24 hrs from IV RX 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

9 Inclusion and exclusion criteria Key inclusion criteria 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 Key exclusion criteria 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

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 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%

11 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

12 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) 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) Placebo MITT=3511 Nesiritide MITT=3496

13 Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) Age (yrs) 67 (56, 76) 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) 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 Continuous variables as median (IQR 25 th, 75 th ); MITT population

14 Baseline characteristics Labs/Studies Placebo (n=3511) Nesiritide (n=3496) LVEF <40% within 12 mths (%) BNP (pg/ml) 989 (543, 1782) NT pro-bnp (pg/ml) 4461 (2123, 9217) Creatinine (mg/dl) 1.2 (1.0, 1.6) 994 (544, 1925) 4508 (2076, 9174) 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 12 P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) Placebo 8 Nesiritide % day Death/HF Rehospitalization 30-day Death HF Rehospitalization Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

16 30 day death/hf readmission subgroups All Subjects N=6836 Baseline SBP (mmhg) Baseline Ejection Fraction (%) Renal function- MDRD GFR (ml/min/m 2 ) History of CAD History of Diabetes Mellitus < <40 40 <60 60 No Yes No Yes N=3346 N=3490 N=4362 N=1187 N=3395 N=3093 N=3092 N=3742 N=3923 N= Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval

17 30 day death/hf readmission subgroups All Subjects N=6836 Inotrope Use at Randomization Vasodilators Diuretics Study Drug Bolus Time from Hosp to Rand (hrs) No Yes None Any IV Vasodilators No IV Nitroglycerin IV Nitroglycerin No Yes No Yes < N=6556 N=280 N=5889 N=942 N=5943 N=892 N=691 N=6145 N=2609 N=4227 N=3426 N= Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval

18 % Subjects % Subjects Co-Primary Endpoint: 6 and 24 hour dyspnea 6 Hours 24 Hours P= % 44.5% % P= % Placebo 3371 Nesiritide Placebo 3416 Nesiritide Markedly Better Moderately Better Minimally Better No Change Minimally Worse Moderately Worse Markedly Worse

19 Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement 6 hours 24 hours All Subjects N=6860 N=6769 SBP < 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= OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other

20 Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement 6 hours 24 hours All Subjects N=6860 N=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 Time from Hosp to Rand No Yes < N=2612 N=4248 N=3428 N=3432 OR <1: Favors Placebo; OR >1: Favors Nesiritide; Odds Ratio of Markedly/Moderately vs. Other N=2564 N=4205 N=3369 N=3400

21 Secondary endpoints 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 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 Cum Dist Cum Dist Renal Safety Anytime Through Day 30 Placebo (n=3509) Nesiritide (n=3498) P-value >25% decrease egfr 29.5% 31.4% 0.11 Placebo Nesiritide End of Treatment Creatinine Discharge or 10 day Creatinine Creatinine (mg/dl) Creatinine (mg/dl)

23 Hypotension Placebo (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

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)

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 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.

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;

28 BACKUP SLIDES

29 Subgroups: Bolus and IV NTG Odds for Marked/Moderate Improvement (95% CI) 6 Hours Without Bolus 1.06 (0.90, 1.23) With Bolus 1.14 (1.01, 1.28) Without IV NTG 1.12 (1.01, 1.24) With IV NTG 1.02 (0.78, 1.33) 24 Hours Without Bolus 1.07 (0.91, 1.26) With Bolus 1.12 (0.98, 1.27) Without IV NTG 1.12 (1.01, 1.25) With IV NTG 0.96 (0.71, 1.28)

30 Blood Pressure Over Time Systolic Blood Pressure

31 Dyspnea (higher is better) EFFECT OF NESIRITIDE IN NAÏVE PATIENTS P = P = Hr 24 Hr Dyspnea Measurement Placebo Nesiritide

32 Relative Odds for Better Status Dyspnea (Higher is Better) Baseline treatment and 6 hour dyspnea relief P=0.04 P= P= None Diuretic only Diuretic & Vasodilator N= Baseline Treatment Placebo Nesiritide

33 Power Post-hoc Power Calculation Relative Risk

34 Relative Odds for Better Status Dyspnea (Higher is Better) Overall effect of time from presentation to study drug on 6 hour dyspnea relief P=< to 4 4 to 8 8 to to to to to to 36 >36 N= Time to Drug (hours)

35 Relative Odds for Better Status Dyspnea (Higher is Better) Estimate of effect of nesiritide on 6 hour dyspnea relief based on time from presentation to study drug Time to Drug Placebo Nesiritide Placebo Nesiritide Mean (pts) Mean (pts) Chi-square for treatment = 9.66 for 2 d.o.f., p =

36 Blood Pressure Over Time Placebo Nesiritide Systolic Blood Pressure (mmhg) Baseline 3 hrs 24 hrs End Rx D/C