Evaluation of high-sensitivity C-reactive protein and uric acid in vericiguat-treated patients with heart failure with reduced ejection fraction

Frank Kramer, Sebastian Voss, Lothar Roessig, Bernd-Wolfgang Igl, Javed Butler, Carolyn S P Lam, Aldo P Maggioni, Sanjiv J Shah, Burkert Pieske, Frank Kramer, Sebastian Voss, Lothar Roessig, Bernd-Wolfgang Igl, Javed Butler, Carolyn S P Lam, Aldo P Maggioni, Sanjiv J Shah, Burkert Pieske

Abstract

Aims: The effects of vericiguat vs. placebo on high-sensitivity C-reactive protein (hsCRP) and serum uric acid (SUA) were assessed in patients with heart failure with reduced ejection fraction (HFrEF) in the Phase 2 SOCRATES-REDUCED study (NCT01951625).

Methods and results: Changes from baseline hsCRP and SUA values at 12 weeks with placebo and vericiguat (1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg, respectively) were assessed. The probability of achieving an hsCRP value of ≤3.0 mg/L or SUA value of <7.0 mg/dL at week 12 was tested. Median baseline hsCRP and SUA levels were 3.68 mg/L [interquartile range (IQR) 1.41-8.41; n = 335] and 7.80 mg/dL (IQR 6.40-9.33; n = 348), respectively. Baseline-adjusted mean percentage changes in hsCRP were 0.2%, -19.5%, -24.3%, -25.7% and -31.9% in the placebo and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the vericiguat 10.0 mg group (P = 0.035). Baseline-adjusted mean percentage changes in SUA were 5.0%, -1.3%, -1.1%, -3.5% and -5.3% in the placebo, and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the 5.0 mg and 10.0 mg groups (P = 0.0202 and P = 0.004, respectively). Estimated probability for an end-of-treatment hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL was higher with vericiguat compared with placebo. The effect was dose-dependent, with the greatest effect observed in the 10.0 mg group.

Conclusions: Vericiguat treatment for 12 weeks was associated with reductions in hsCRP and SUA, and a higher likelihood of achieving an hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL.

Keywords: Biomarker; C-reactive protein; Heart failure; Uric acid; Ventricular ejection fraction; Vericiguat.

© 2020 Bayer AG Pharmaceuticals. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1
Figure 1
Baseline‐adjusted mean changes (%) in (A) high‐sensitivity C‐reactive protein (hsCRP) and (B) serum uric acid (SUA) from baseline to end of treatment. CI, confidence interval; geom.mean, geometric mean. *Statistical significance relative to placebo.
Figure 2
Figure 2
Estimated probabilities for (A) high‐sensitivity C‐reactive protein (hsCRP) and (B) serum uric acid (SUA) reduction to below risk level and (C, D) subgroup sizes per treatment arm at baseline and end of treatment (EoT). In (B), 1.25 mg and 2.5 mg vericiguat trend lines overlap SUA data. Numbers within the bar charts represent the numbers of patients with specified (C) hsCRP or (D) SUA values at baseline or EoT. The total numbers of patients per treatment arm for placebo and vericiguat 10.0 mg were 65 and 66, respectively, for hsCRP data, and 67 and 72, respectively, for SUA data.

References

    1. Williams ES, Shah SJ, Ali S, Ya Na B, Schiller NB, Whooley MA. C‐reactive protein, diastolic dysfunction, and risk of heart failure in patients with coronary disease: heart and soul study. Eur J Heart Fail 2008;10:63–69.
    1. Ayoub KF, Pothineni NVK, Rutland J, Ding Z, Mehta JL. Immunity, inflammation, and oxidative stress in heart failure: emerging molecular targets. Cardiovasc Drugs Ther 2017;31:593–608.
    1. Shah SJ, Marcus GM, Gerber IL, Mckeown BH, Vessey JC, Jordan MV, Huddleston M, Foster E, Chatterjee K, Michaels AD. High‐sensitivity C‐reactive protein and parameters of left ventricular dysfunction. J Card Fail 2006;12:61–65.
    1. Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res 2015;116:1254–1268.
    1. McMurray JJ, Kjekshus J, Gullestad L, Dunselman P, Hjalmarson A, Wedel H, Lindberg M, Waagstein F, Grande P, Hradec J, Kamensky G, Korewicki J, Kuusi T, Mach F, Ranjith N, Wikstrand J; CORONA Study Group . Effects of statin therapy according to plasma high‐sensitivity C‐reactive protein concentration in the controlled rosuvastatin multinational trial in heart failure (CORONA): a retrospective analysis. Circulation 2009;120:2188–2196.
    1. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R, Cohn JN; Val‐HeFT Investigators. C‐reactive protein in heart failure prognostic value and the effect of valsartan. Circulation 2005;112:1428–1434.
    1. Castro AR, Silva SO, Soares SC. The use of high sensitivity C‐reactive protein in cardiovascular disease detection. J Pharm Pharm Sci 2018;21:496–503.
    1. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJ. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107:1991–1997.
    1. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–1821.
    1. Mogensen UM, Kober L, Jhund PS, Desai AS, Senni M, Kristensen SL, Dukat A, Chen CH, Ramires F, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Solomon SD, Swedberg K, Packer M, McMurray JJV. Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM‐HF. Eur J Heart Fail 2018;20:514–522.
    1. Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J 2009;73:411–418.
    1. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO‐independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006;5:755–768.
    1. Armstrong PW, Roessig L, Patel MJ, Anstrom KJ, Butler J, Voors AA, Lam CSP, Ponikowski P, Temple T, Pieske B, Ezekowitz J, Hernandez AF, Koglin J, O'Connor CM. A multicenter, randomized, double‐blind, placebo‐controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: the VICTORIA trial. JACC Heart Fail 2018;6:96–104.
    1. Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, Ponikowski P, Shah SJ, Solomon SD, Kraigher‐Krainer E, Samano ET, Muller K, Roessig L, Pieske B; SOCRATES‐REDUCED Investigators and Coordinators. Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES‐REDUCED randomized trial. JAMA 2015;314:2251–2262.
    1. Pieske B, Butler J, Filippatos G, Lam C, Maggioni PA, Ponikowski P, Shah S, Solomon S, Kraigher‐Krainer E, Samano ET, Scalise AV, Müller K, Roessig L, Gheorghiade M; SOCRATES Investigators and Coordinators . Rationale and design of the SOluble guanylate cyclase stimulatoR in heArT failurE studies (SOCRATES). Eur J Heart Fail 2014;16:1026–1038.
    1. Rickham PP. Human experimentation. Code of ethics of the World Medical Association. Declaration of Helsinki. Br Med J 1964;2:177.
    1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. Circulation 2003;107:499–511.
    1. Ahluwalia A, Foster P, Scotland RS, McLean PG, Mathur A, Perretti M, Moncada S, Hobbs AJ. Antiinflammatory activity of soluble guanylate cyclase: cGMP‐dependent down‐regulation of P‐selectin expression and leukocyte recruitment. Proc Natl Acad Sci U S A 2004;101:1386–1391.
    1. Bahls M, Felix SB. Cachexia and right ventricular dysfunction in chronic heart failure: what is the chicken and what the egg? Eur Heart J 2016;37:1692–1694.
    1. Valentova M, von Haehling S, Bauditz J, Doehner W, Ebner N, Bekfani T, Elsner S, Sliziuk V, Scherbakov N, Murin J, Anker SD, Sandek A. Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure. Eur Heart J 2016;37:1684–1691.
    1. Pasini E, Aquilani R, Testa C, Baiardi P, Angioletti S, Boschi F, Verri M, Dioguardi F. Pathogenic gut flora in patients with chronic heart failure. JACC Heart Fail 2016;4:220–227.
    1. Zhang Y, Bauersachs J, Langer HF. Immune mechanisms in heart failure. Eur J Heart Fail 2017;19:1379–1389.
    1. Laurent S, Bruno RM. Gut microbiome composition, a third player in the inflammation–arterial stiffness relationship. Eur Heart J 2018;39:2398–2400.
    1. Alvarez AM, Mukherjee D. Liver abnormalities in cardiac diseases and heart failure. Int J Angiol 2011;20:135–142.
    1. Maleki M, Vakilian F, Amin A. Liver diseases in heart failure. Heart Asia 2011;3:143–149.
    1. Amin A, Chitsazan M, Shiukhi Ahmad Abad F, Taghavi S, Naderi N. On admission serum sodium and uric acid levels predict 30 day rehospitalization or death in patients with acute decompensated heart failure. ESC Heart Fail 2017;4:162–168.
    1. Palazzuoli A, Ruocco G, Pellegrini M, Beltrami M, Giordano N, Nuti R, McCullough PA. Prognostic significance of hyperuricemia in patients with acute heart failure. Am J Cardiol 2016;117:1616–1621.
    1. Okazaki H, Shirakabe A, Kobayashi N, Hata N, Shinada T, Matsushita M, Yamamoto Y, Shibuya J, Shiomura R, Nishigoori S, Asai K, Shimizu W. The prognostic impact of uric acid in patients with severely decompensated acute heart failure. J Cardiol 2016;68:384–391.
    1. Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tang WH, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Margulies KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Shah MR, Hernandez AF. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT‐HF) study. Circulation 2015;131:1763–1771.
    1. Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, Colucci WS, Mann DL, Liu P, Givertz MM, Schwarz RP. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT‐CHF study. J Am Coll Cardiol 2008;51:2301–2309.

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