Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial

David Corcoran; Aleksandra  Radjenovic; Ify R. Mordi; Sheraz A Nazir; Simon J. Wilson; Markus Hinder; Denise P. Yates; Surendra Machineni; Jose Alcantara; Margaret F. Prescott; Barbara Gugliotta; Yinuo Pang; Niko Tzemos; Scott I Semple; David E Newby; Gerry P McCann; Iain Squire; Colin Berry

doi:10.1093/cvr/cvz345

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial

David Corcoran, Aleksandra Radjenovic , Ify R. Mordi, Sheraz A Nazir, Simon J. Wilson, Markus Hinder, Denise P. Yates, Surendra Machineni, Jose Alcantara, Margaret F. Prescott, Barbara Gugliotta, Yinuo Pang, Niko Tzemos, Scott I Semple, David E Newby, Gerry P McCann, Iain Squire, Colin Berry

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Aims
The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).
Methods and results
In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.
Conclusion
In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Original language	English
Pages (from-to)	320–329
Journal	Cardiovascular Research
Volume	117
Issue number	1
Early online date	17 Feb 2020
DOIs	https://doi.org/10.1093/cvr/cvz345
Publication status	Published - 1 Jan 2021

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10.1093/cvr/cvz345

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Corcoran, D., Radjenovic , A., Mordi, I. R., Nazir, S. A., Wilson, S. J., Hinder, M., Yates, D. P., Machineni, S., Alcantara, J., Prescott, M. F., Gugliotta, B., Pang, Y., Tzemos, N., Semple, S. I., Newby, D. E., McCann, G. P., Squire, I., & Berry, C. (2021). Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial. Cardiovascular Research, 117(1), 320–329. https://doi.org/10.1093/cvr/cvz345

@article{23be8735bae944fdbf41204eb41de275,

title = "Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial",

abstract = "AimsThe effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).Methods and resultsIn this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.ConclusionIn patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.",

author = "David Corcoran and Aleksandra Radjenovic and Mordi, {Ify R.} and Nazir, {Sheraz A} and Wilson, {Simon J.} and Markus Hinder and Yates, {Denise P.} and Surendra Machineni and Jose Alcantara and Prescott, {Margaret F.} and Barbara Gugliotta and Yinuo Pang and Niko Tzemos and Semple, {Scott I} and Newby, {David E} and McCann, {Gerry P} and Iain Squire and Colin Berry",

year = "2021",

month = jan,

day = "1",

doi = "10.1093/cvr/cvz345",

language = "English",

volume = "117",

pages = "320–329",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Elsevier",

number = "1",

}

Corcoran, D, Radjenovic , A, Mordi, IR, Nazir, SA, Wilson, SJ, Hinder, M, Yates, DP, Machineni, S, Alcantara, J, Prescott, MF, Gugliotta, B, Pang, Y, Tzemos, N, Semple, SI , Newby, DE, McCann, GP, Squire, I & Berry, C 2021, 'Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial', Cardiovascular Research, vol. 117, no. 1, pp. 320–329. https://doi.org/10.1093/cvr/cvz345

TY - JOUR

T1 - Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial

AU - Corcoran, David

AU - Radjenovic , Aleksandra

AU - Mordi, Ify R.

AU - Nazir, Sheraz A

AU - Wilson, Simon J.

AU - Hinder, Markus

AU - Yates, Denise P.

AU - Machineni, Surendra

AU - Alcantara, Jose

AU - Prescott, Margaret F.

AU - Gugliotta, Barbara

AU - Pang, Yinuo

AU - Tzemos, Niko

AU - Semple, Scott I

AU - Newby, David E

AU - McCann, Gerry P

AU - Squire, Iain

AU - Berry, Colin

PY - 2021/1/1

Y1 - 2021/1/1

N2 - AimsThe effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).Methods and resultsIn this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.ConclusionIn patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

AB - AimsThe effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).Methods and resultsIn this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.ConclusionIn patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

U2 - 10.1093/cvr/cvz345

DO - 10.1093/cvr/cvz345

M3 - Article

SN - 0008-6363

VL - 117

SP - 320

EP - 329

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomised placebo-controlled trial

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