Presenters for Journal Club: James Cooper Eugenie Shieh Aaron Schueneman Tim Niessen

Introduction Nesitiride developed as a novel IV vasodilator in decompensated heart failure Recombinant brain natriuretic peptide Alternative to inotropic therapy 1 st randomized double blind trial of Nesitiride in decompensated heart failure

Study Outline Hypothesis: Niseritide improves dyspnea and PCWP (vs IV NG or placebo) Study Design: Randomized Controlled Trial Setting: 55 community and academic hospitals in U.S. Participants: 489 pt w/ dyspnea at rest from decompensated HF Data Collection: dyspnea scale, followed by measurement of PCWP at 3 hours Primary Outcomes: – Change in PCWP – dyspnea at 3 hrs Secondary Outcomes: – Safety – 30-day re-hospitalization rate, 7-day and 6-month mortality

Methods Inclusion Criteria Dyspnea at rest due to dCHF (class IV) severe enough to require hospitalization and IV tx Cardiac etiology of dyspnea = PCWP ≥ of the following – JVD – PND or 2-pillow orthopnea – Abdominal discomfort due to mesenteric ischemia – CXR c/w dCHF Acute decompensation of chronic HF, gradual worsening of chronic HF, new acutely dCHF Allowed prior and current use of dobutamine and dopamine Exclusion Criteria SBP < 90 mmHg Cardiogenic shock or volume depletion Contraindication to IV vasodilator Acutely unstable clinical status that would not permit a 3 hr placebo period Use of IV NTG that could not be withheld Mechanical ventilation Anticipated survival <30-35 days

Methods RHC No RHC NTG nesiritide placebo 3hr NTG nesiritide 3-48 hr Crossover to double blind treatment same Same as left Investigator’s clinical decision Randomization

Results: Patient Characteristics 84% had class III/IV HF prior to presentation Vast majority had evidence of fluid overload ACS accounted for 12% of presentations 85% had EF < 40%; mean EF 27% 21% had creatinine > 2.0 mg/dl 47% had diabetes mellitus Mean SBP 121mmHg; 18% 140mmHg Mean PCWP 28mmHg; Mean cardiac index 2.2 L/min/m2 Groups well matched

Results: Between Group Differences More men in the nesiritide vs. NTG group (73% vs. 60%) More in the nesiritde group vs. NTG group: – Were on class III anti-arrhythmics at baseline (19% vs. 12%) – Were given a vasoactive IV drug within 24 hours prior to the study (29% vs. 25%) – Had a study drug added to ongoing therapy with either dopamine or dobutamine (18% vs. 10%)

Primary Endpoint #1: Change in PCWP

Primary Outcome #2: Change in Dyspnea

Results: Secondary Endpoints More headache in NTG group (20% vs. 8%) No difference in number of ischemic events, hypotensive episodes or arrhythmias in first 24h Duration of hypotension > in nesiritide (2.2 vs. 0.7 hours) 30-day re-admit rate nesiritide vs. NTG: – 23% vs. 20% for all causes – 7% vs. 13% for CHF specifically 7-day mortality: 0.5% NTG vs. 1.5% nesiritide 6-month all cause mortality: – NTG 20.8% (95% CI 15.5% %) – Nesiritide 25.1% (95% CI 20.0% – 30.5%)

Author Conclusions Nesiritide rapidly improves hemodynamics as measured by RHC better than placebo and better than nitroglycerin. Nesiritide subjectively improves dyspnea, compared to placebo and is no different when compared to nitroglycerin.

Strengths Large, multicenter, with heterogeneous patient population Randomized. Placebo then crossover to active controls Double-dummy blinded.

FDA Approval JAMA 2006;296:1877

Dissent “Nesiritide was approved on the basis of a single trial in which surrogate end points were assessed three hours after administration… In my view nesiritide has not yet met the minimal criteria for safety and efficacy” Topol, NEJM :114

Lies, Damned Lies, and Statistics Endpoint selection: – Surrogate outcome measures. – “hard” vs subjective outcomes / blinding – Clinical vs statistical significance Placebo vs head-to-head comparisons & “standard therapy”:

NEJM 2011;365:32-43