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Erschienen in: Clinical Research in Cardiology 2/2018

06.10.2017 | Original Paper

Relationship between baseline systolic blood pressure and long-term outcomes in acute heart failure patients treated with TRV027: an exploratory subgroup analysis of BLAST-AHF

verfasst von: Gad Cotter, Beth A. Davison, Javed Butler, Sean P. Collins, Justin A. Ezekowitz, G. Michael Felker, Gerasimos Filippatos, Phillip D. Levy, Marco Metra, Piotr Ponikowski, John R. Teerlink, Adriaan A. Voors, Stefanie Senger, David Bharucha, Kathleen Goin, David G. Soergel, Peter S. Pang

Erschienen in: Clinical Research in Cardiology | Ausgabe 2/2018

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Abstract

Introduction

TRV027, a ‘biased’ ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF).

Methods

Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: < 127, ≥ 127 to < 140, and ≥ 140 mmHg.

Results

A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP ≥ 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14–1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28–1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile.

Conclusions

This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.
Literatur
1.
Zurück zum Zitat Rajagopal K, Whalen EJ, Violin JD et al (2006) Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci USA 103:16284–16289CrossRefPubMedPubMedCentral Rajagopal K, Whalen EJ, Violin JD et al (2006) Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci USA 103:16284–16289CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Soergel DG, Subach RA, Cowan CL, Violin JD, Lark MW (2013) First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol 53:892–899CrossRefPubMed Soergel DG, Subach RA, Cowan CL, Violin JD, Lark MW (2013) First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol 53:892–899CrossRefPubMed
3.
Zurück zum Zitat Felker GM, Butler J, Collins SP, Cotter G, Davison BA, Ezekowitz JA, Filippatos G, Levy PD, Metra M, Ponikowski P, Soergel DG, Teerlink JR, Violin JD, Voors AA, Pang PS (2015) Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (biased ligand of the angiotensin receptor study in acute heart failure). JACC Heart Fail 3:193–201CrossRefPubMed Felker GM, Butler J, Collins SP, Cotter G, Davison BA, Ezekowitz JA, Filippatos G, Levy PD, Metra M, Ponikowski P, Soergel DG, Teerlink JR, Violin JD, Voors AA, Pang PS (2015) Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (biased ligand of the angiotensin receptor study in acute heart failure). JACC Heart Fail 3:193–201CrossRefPubMed
4.
Zurück zum Zitat Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (biased ligand of the angiotensin receptor study in acute heart failure). JACC Heart Fail. 2015; 3: 193–201 Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (biased ligand of the angiotensin receptor study in acute heart failure). JACC Heart Fail. 2015; 3: 193–201
5.
Zurück zum Zitat Bonetti M, Gelber RD (2004) Patterns of treatment effects in subsets of patients in clinical trials. Biostatistics 5:465–481CrossRefPubMed Bonetti M, Gelber RD (2004) Patterns of treatment effects in subsets of patients in clinical trials. Biostatistics 5:465–481CrossRefPubMed
6.
Zurück zum Zitat Saville BR, Herring AH, Koch GG (2010) A robust method for comparing two treatments in a confirmatory clinical trial via multivariate time-to-event methods that jointly incorporate information from longitudinal and time-to-event data. Stat Med 29:75–85PubMedPubMedCentral Saville BR, Herring AH, Koch GG (2010) A robust method for comparing two treatments in a confirmatory clinical trial via multivariate time-to-event methods that jointly incorporate information from longitudinal and time-to-event data. Stat Med 29:75–85PubMedPubMedCentral
7.
Zurück zum Zitat Sun H, Davison BA, Cotter G, Pencina MJ, Koch GG (2012) Evaluating treatment efficacy by multiple end points in phase II acute heart failure clinical trials: analyzing data using a global method. Circ Heart Fail 5:742–749CrossRefPubMed Sun H, Davison BA, Cotter G, Pencina MJ, Koch GG (2012) Evaluating treatment efficacy by multiple end points in phase II acute heart failure clinical trials: analyzing data using a global method. Circ Heart Fail 5:742–749CrossRefPubMed
8.
Zurück zum Zitat Sackner-Bernstein JD1, Skopicki HA, Aaronson KD (2005) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111:1487–1491CrossRefPubMed Sackner-Bernstein JD1, Skopicki HA, Aaronson KD (2005) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111:1487–1491CrossRefPubMed
9.
Zurück zum Zitat Aaronson KD, Sackner-Bernstein J (2006) Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 296:1465–1466CrossRefPubMed Aaronson KD, Sackner-Bernstein J (2006) Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 296:1465–1466CrossRefPubMed
10.
Zurück zum Zitat Voors AA, Davison BA, Felker GM, Ponikowski P, Unemori E, Cotter G et al (2011) Early drop in systolic blood pressure and worsening renal function in acute heart failure: renal results of pre-RELAX-AHF. Eur J Heart Fail 13:961–967CrossRefPubMed Voors AA, Davison BA, Felker GM, Ponikowski P, Unemori E, Cotter G et al (2011) Early drop in systolic blood pressure and worsening renal function in acute heart failure: renal results of pre-RELAX-AHF. Eur J Heart Fail 13:961–967CrossRefPubMed
11.
Zurück zum Zitat Patel PA, Heizer G, O’Connor CM, Schulte PJ, Dickstein K, Ezekowitz JA et al (2014) Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF. Circ Heart Fail 7:918–925CrossRefPubMedPubMedCentral Patel PA, Heizer G, O’Connor CM, Schulte PJ, Dickstein K, Ezekowitz JA et al (2014) Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF. Circ Heart Fail 7:918–925CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Cotter G, Davison B (2014) Intravenous therapies in acute heart failure—lack of effect or lack of well powered studies? Eur J of Heart Fail 16:355–357CrossRef Cotter G, Davison B (2014) Intravenous therapies in acute heart failure—lack of effect or lack of well powered studies? Eur J of Heart Fail 16:355–357CrossRef
13.
Zurück zum Zitat Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J et al (2013) Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 1:103–111CrossRefPubMed Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J et al (2013) Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 1:103–111CrossRefPubMed
14.
Zurück zum Zitat Packer M, O’Connor C, McMurray JJ, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J, TRUE-AHF Investigators (2017) Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med 376:1956–1964CrossRefPubMed Packer M, O’Connor C, McMurray JJ, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J, TRUE-AHF Investigators (2017) Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med 376:1956–1964CrossRefPubMed
15.
Zurück zum Zitat Ishihara S, Gayat E, Sato N, Arrigo M, Laribi S, Legrand M, Placido R, Manivet P, Cohen-Solal A, Abraham WT, Jessup M, Mebazaa A (2016) Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure. Clin Res Cardiol 105:971–980CrossRefPubMed Ishihara S, Gayat E, Sato N, Arrigo M, Laribi S, Legrand M, Placido R, Manivet P, Cohen-Solal A, Abraham WT, Jessup M, Mebazaa A (2016) Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure. Clin Res Cardiol 105:971–980CrossRefPubMed
16.
Zurück zum Zitat Miró Ò, Gil V, Müller C, Mebazaa A, Bueno H, Martín-Sánchez FJ, Herrero P, Jacob J, Llorens P. How does a clinical trial fit into the real world? The RELAX-AHF study population into the EAHFE registry. Clin Res Cardiol 2015; 104: 850 – 60 Miró Ò, Gil V, Müller C, Mebazaa A, Bueno H, Martín-Sánchez FJ, Herrero P, Jacob J, Llorens P. How does a clinical trial fit into the real world? The RELAX-AHF study population into the EAHFE registry. Clin Res Cardiol 2015; 104: 850 – 60
17.
Zurück zum Zitat Kim KS, Abrham D, Williams B, Violin JD, Mao L, Rockman HA (2012) β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury. Am J Physiol Heart Circ Physiol 303:H1001–H1010CrossRefPubMedPubMedCentral Kim KS, Abrham D, Williams B, Violin JD, Mao L, Rockman HA (2012) β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury. Am J Physiol Heart Circ Physiol 303:H1001–H1010CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Ivanov M, Mihailović-Stanojević N, Grujić Milanović J, Jovović Đ, Marković-Lipkovski J, Ćirović S, Miloradović Z. Losartan improved antioxidant defense, renal function and structure of postischemic hypertensive kidney. PLoS One 9:e96353 Ivanov M, Mihailović-Stanojević N, Grujić Milanović J, Jovović Đ, Marković-Lipkovski J, Ćirović S, Miloradović Z. Losartan improved antioxidant defense, renal function and structure of postischemic hypertensive kidney. PLoS One 9:e96353
Metadaten
Titel
Relationship between baseline systolic blood pressure and long-term outcomes in acute heart failure patients treated with TRV027: an exploratory subgroup analysis of BLAST-AHF
verfasst von
Gad Cotter
Beth A. Davison
Javed Butler
Sean P. Collins
Justin A. Ezekowitz
G. Michael Felker
Gerasimos Filippatos
Phillip D. Levy
Marco Metra
Piotr Ponikowski
John R. Teerlink
Adriaan A. Voors
Stefanie Senger
David Bharucha
Kathleen Goin
David G. Soergel
Peter S. Pang
Publikationsdatum
06.10.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Clinical Research in Cardiology / Ausgabe 2/2018
Print ISSN: 1861-0684
Elektronische ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-017-1168-0

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