Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. 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 103:16284–16289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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 53:892–899

    Article  CAS  PubMed  Google Scholar 

  3. 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 3:193–201

    Article  PubMed  Google Scholar 

  4. 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. Bonetti M, Gelber RD (2004) Patterns of treatment effects in subsets of patients in clinical trials. Biostatistics 5:465–481

    Article  PubMed  Google Scholar 

  6. 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 29:75–85

    PubMed  PubMed Central  Google Scholar 

  7. 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 5:742–749

    Article  PubMed  Google Scholar 

  8. Sackner-Bernstein JD1, Skopicki HA, Aaronson KD (2005) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111:1487–1491

    Article  CAS  PubMed  Google Scholar 

  9. Aaronson KD, Sackner-Bernstein J (2006) Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 296:1465–1466

    Article  CAS  PubMed  Google Scholar 

  10. 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 13:961–967

    Article  PubMed  Google Scholar 

  11. 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 7:918–925

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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 16:355–357

    Article  CAS  Google Scholar 

  13. 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 1:103–111

    Article  PubMed  Google Scholar 

  14. 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 376:1956–1964

    Article  CAS  PubMed  Google Scholar 

  15. 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 105:971–980

    Article  PubMed  Google Scholar 

  16. 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. 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–H1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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

Download references

Author information

Authors and Affiliations

  1. Momentum Research Inc., Suite 801, 3100 Tower Blvd, Durham, NC, 27707, USA

    Gad Cotter, Beth A. Davison & Stefanie Senger

  2. SUNY Stony Brook School of Medicine, New York, NY, USA

    Javed Butler

  3. Vanderbilt University, Nashville, TN, USA

    Sean P. Collins

  4. University of Alberta, Edmonton, AB, Canada

    Justin A. Ezekowitz

  5. Duke University School of Medicine and the Duke Clinical Research Institute, Durham, NC, USA

    G. Michael Felker

  6. Department of Cardiology, School of Medicine, Heart Failure Unit, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece

    Gerasimos Filippatos

  7. Wayne State University School of Medicine and Cardiovascular Research Institute, Detroit, MI, USA

    Phillip D. Levy

  8. Cardiology, University of Brescia, Brescia, Italy

    Marco Metra

  9. Medical University, Clinical Military Hospital, Wroclaw, Poland

    Piotr Ponikowski

  10. Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, CA, USA

    John R. Teerlink

  11. University of Groningen, Groningen, The Netherlands

    Adriaan A. Voors

  12. Allergan plc (Forest Labs), Jersey City, NJ, USA

    David Bharucha

  13. Trevena Inc, King of Prussia, PA, USA

    Kathleen Goin & David G. Soergel

  14. Indiana University School of Medicine and Regenstrief Institute, Indianapolis, IN, USA

    Peter S. Pang

Authors
  1. Gad Cotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beth A. Davison
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javed Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sean P. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Justin A. Ezekowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Michael Felker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerasimos Filippatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Phillip D. Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marco Metra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Piotr Ponikowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John R. Teerlink
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Adriaan A. Voors
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefanie Senger
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Bharucha
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kathleen Goin
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David G. Soergel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter S. Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gad Cotter.

Ethics declarations

Conflict of interest

Drs. Cotter, Davison, and Senger are employees of Momentum Research, which has provided consulting services to NovaCardia, Merck, Corthera, Novartis, Singulex, ChanRx, Laguna Pharmaceuticals, Sorbent Therapeutics, Celyad SA, Trevena, Amgen and Anexon. Butler—Research—NIH, PCORI, and European Union, Consultant to Amgen, Bayer, Boehringer Ingelheim, Cardiocell, Merck, Novartis, Trevena, Relypsa, ZS Pharma. Collins—Research—NIH, PCORI, Novartis, Cardiorentis, Trinity; Consulting: Cardiorentis, Novartis, Trevena, Siemens. Ezekowitz has received grants or honoraria from Novartis, Servier, Bayer, Merck, Trevena, Amgen, Canadian Institutes of Health Research, National Institutes of Health, Heart and Stroke Foundation of Canada. Felker: Consulting for Trevena, Novartis, Amgen, BMS, Stealth Bio-therapeutics, GSK, Medtronic, Myokardia, Grant funding from NIH, AHA, Roche Diagnostics, Otsuka, Novartis, Amgen, Merck. Filippatos: committee fees from Bayer, Novartis, and Servier. Levy- Research- NIH, PCORI, Novartis, Cardiorentis, Trevena; Consulting: Novartis, Cardiorentis, Trevena, ZS Pharma. Metra: Consulting from: Amgen, Bayer, Novartis, Relypsa. Ponikowski: consulting from Bayer, Boehringer Ingelheim, Novartis. Teerlink: Consulting from: Amgen, Bayer, BMS, Cytokinetics, Gilead, Merck, Novartis, Relypsa, Stealth Bio-therapeutics, ZS Pharma; Research funding from: Amgen, Bayer, BMS, Cardio3Biosciences, Medtronic, Novartis, St. Jude, Trevena. Voors: received consultancy fees and/or research grants from: AstraZeneca, Bayer, BMS, Boehringer, Cardio3Biosciences, GSK, Merck/MSD, Novartis, Servier, Sphingotec, Stealth, Trevena, Vifor. Bharucha is an employee of Allergan plc (Forest Labs), a sponsor of this trial. Soergel and Goin are employees of Trevena, the primary sponsor of this trial. Peter S. Pang is or has been in the last one year a Consultant for: BMS, Janssen, Medtronic, the Medicines Company, Novartis, Trevena, scPharmaceuticals, Cardioxyl, Roche Diagnostics, Relypsa, Research Support: Roche, Novartis, PCORI, Indianapolis EMS.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cotter, G., Davison, B.A., Butler, J. et al. 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. Clin Res Cardiol 107, 170–181 (2018). https://doi.org/10.1007/s00392-017-1168-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-017-1168-0

Keywords

Search

Navigation