Browsing by Author "Ezekowitz, Justin A."

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    Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)
    (Oxford University Press, 2017-08-07) Pang, Peter S.; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Teerlink, John R.; Voors, Adriaan A.; Bharucha, David; Goin, Kathleen; Soergel, David G.; Felker, G. Michael; Emergency Medicine, School of Medicine
    Aims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.
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    Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study
    (Elsevier, 2021) Felker, G. Michael; McMurray, John J. V.; Cleland, John G.; O’Connor, Christopher M.; Teerlink, John R.; Voors, Adriaan A.; Belohlavek, Jan; Böhm, Michael; Borentain, Maria; Bueno, Hector; Cole, Robert T.; DeSouza, Mary M.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Lang, Ninian N.; Kessler, Paul D.; Martinez, Felipe A.; Mebazaa, Alex; Metra, Marco; Mosterd, Arend; Pang, Peter S.; Ponikowski, Piotr; Sato, Naoki; Seiffert, Dietmar; Ye, June; Emergency Medicine, School of Medicine
    Objectives: The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events. Background: Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF). Methods: This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic). Results: In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation. Conclusions: Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period.
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    Neutrophil-to-Lymphocyte Ratio and Outcomes in Patients Admitted for Acute Heart Failure (As Seen in the BLAST-AHF, Pre-RELAX-AHF, and RELAX-AHF Studies)
    (Elsevier, 2022) Davison, Beth A.; Takagi, Koji; Edwards, Christopher; Adams, Kirkwood F., Jr.; Butler, Javed; Collins, Sean P.; Dorobantu, Maria I.; Ezekowitz, Justin A.; Filippatos , Gerasimos; Greenberg , Barry H.; Levy , Phillip D.; Masip, Josep; Metra, Marco; Pang , Peter S.; Ponikowski , Piotr; Severin , Thomas M.; Teerlink, John R.; Teichman, Sam L.; Voors, Adriaan A.; Werdan, Karl; Cotter, Gad; Emergency Medicine, School of Medicine
    Previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) is a novel yet readily evaluable inflammatory biomarker that may be useful for determining cardiovascular prognosis during acute episodes. The study investigated the role of NLR in predicting cardiovascular (CV) outcomes in patients with acute heart failure (HF). Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. Dyspnea visual analog scale area under the curve through day 5, worsening HF through day 5, 30-day all-cause mortality, 60-day HF/renal failure rehospitalizations or CV death, 180-day all-cause mortality, and 180-day CV death were assessed. There were several differences in the baseline characteristics of the patients divided by NLR tertile, with patients in the higher NLR having worse clinical characteristics. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio [HR] per log2 NLR increment: 1.66 [1.22 to 2.25], p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 [1.12 to 1.57], p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 [1.08 to 1.50], p = 0.003), and 180-day CV death (adjusted HR 1.24 [1.04 to 1.49], p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides.