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Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients

  • Arrigo Francesco Giuseppe CiceroEmail author
  • Eugenio Roberto Cosentino
  • Masanari Kuwabara
  • Daniela Degli Esposti
  • Claudio Borghi
IM - ORIGINAL
  • 63 Downloads

Abstract

Hyperuricemia is an emerging risk factor for the development of heart failure (HF) and is associated with a worsen prognosis of the disease. The effect of urate lowering drugs (ULT) and, in particular, the xanthine oxidase inhibitor in patients with HF is controversial. The aim of the study is to compare the effects of treatment with two different xanthine oxidase inhibitors (allopurinol or febuxostat) on cardiovascular mortality in elderly patients with chronic HF in a setting of clinical practice. In this observational trial, 255 elderly patients affected by chronic HF and treated with ULT on top of optimal medical treatment for HF. The sample included only outpatients with mild-to-moderate HF mainly secondary to chronic arterial hypertension or coronary artery disease and not previously hospitalized for HF. Patient treated with febuxostat (N. 120) and allopurinol (N. 135) were balanced for most of the baseline variables. In particular age, NYHA class distribution, drug treatment and renal function were comparable at the baseline and during the observation in both groups (p > 0.05). After a mean follow-up period of 5.1 years, the cumulative cardiovascular survival was 0.96 (95% CI 0.93–0.99) in febuxostat-treated patients and 0.89 (95% CI 0.84–0.93) in those treated with allopurinol. The between group difference, adjusted for the main confounding risk factors, was statistically significant (p = 0.04). Our study results suggest that possibility that febuxostat, a selective XO inhibitor, may favorably affect cardiovascular mortality in comparison with allopurinol in elderly patients with mild-to-moderate HF. This preliminary observation deserves further evaluation in the next future.

Keywords

Allopurinol Febuxostat Heart failure Hyperuricemia Mortality 

Notes

Funding

This research was funded by institutional funding of the University of Bologna.

Compliance with ethical standards

Conflict of interest

Prof. Claudio Borghi is scientific consultant for Menarini International, no one of the other authors have direct nor indirect conflict of interest in the publication of this paper.

Statements of human and animal rights

The study was carried out in the setting of current clinical practice and has been carried out in agreement with the Declaration of Helsinki.

Informed consent

The study was approved by the local ethical board and each subject signed an informed consent.

References

  1. 1.
    Huang H, Huang B, Li Y, Huang Y, Li J, Yao H, Jing X, Chen J, Wang J (2014) Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 16(1):15–24.  https://doi.org/10.1093/eurjhf/hft132 CrossRefGoogle Scholar
  2. 2.
    Mantovani A, Targher G, Temporelli PL, Lucci D, Gonzini L, Nicolosi GL, Marchioli R, Tognoni G, Latini R, Cosmi F, Tavazzi L, Maggioni AP, Investigators GISSI-HF (2018) Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: a post hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. Metabolism 83:205–215.  https://doi.org/10.1016/j.metabol.2018.02.007 CrossRefGoogle Scholar
  3. 3.
    Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, Colucci WS, Mann DL, Liu P, Givertz MM, Schwarz RP, Investigators OPT-CHF (2008) Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 51:2301–2309.  https://doi.org/10.1016/j.jacc.2008.01.068 CrossRefGoogle Scholar
  4. 4.
    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, NHLBI Heart Failure Clinical Research Network (2015) Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study. Circulation 131(20):1763–1771.  https://doi.org/10.1161/circulationaha.114.014536 CrossRefGoogle Scholar
  5. 5.
    Cicero AF, Pirro M, Watts GF, Mikhailidis DP, Banach M, Sahebkar A (2018) Effects of allopurinol on endothelial function: a systematic review and meta-analysis of randomized placebo-controlled trials. Drugs 78(1):99–109.  https://doi.org/10.1007/s40265-017-0839-5 CrossRefGoogle Scholar
  6. 6.
    Cicero AF, Rosticci M, Fogacci F, Grandi E, D’Addato S, Borghi C, Brisighella Heart Study Group (2017) Serum uric acid level is associated to poorly controlled blood pressure and arterial stiffness in hypertensive subjects: data from the Brisighella Heart Study. Eur J Intern Med 37:38–42.  https://doi.org/10.1016/j.ejim.2016.07.026 CrossRefGoogle Scholar
  7. 7.
    Borghi C, Cosentino ER, Rinaldi ER, Cicero AF (2014) Uricemia and Ejection Fraction in elderly heart failure outpatients. Eur J Clin Invest 44:573–578.  https://doi.org/10.1111/eci.12273 CrossRefGoogle Scholar
  8. 8.
    Tamariz L, Hernandez F, Bush A, Palacio A, Hare JM (2014) Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 11(7):1102–1108.  https://doi.org/10.1016/j.hrthm.2014.04.003 CrossRefGoogle Scholar
  9. 9.
    Nodera M, Suzuki H, Matsumoto Y, Kamioka M, Kaneshiro T, Yoshihisa A, Ohira T, Takeishi Y (2018) Association between serum uric acid level and ventricular tachyarrhythmia in heart failure patients with implantable cardioverter-defibrillator. Cardiology 140(1):47–51.  https://doi.org/10.1159/000488851 CrossRefGoogle Scholar
  10. 10.
    Filippatos GS, Ahmed MI, Gladden JD, Mujib M, Aban IB, Love TE, Sanders PW, Pitt B, Anker SD, Ahmed A (2011) Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J 32:712–720.  https://doi.org/10.1093/eurheartj/ehq473 CrossRefGoogle Scholar
  11. 11.
    Vaduganathan M, Greene SJ, Ambrosy AP, Mentz RJ, Subacius HP, Chioncel O, Maggioni AP, Swedberg K, Zannad F, Konstam MA, Senni M, Givertz MM, Butler J, Gheorghiade M, EVEREST trial investigators (2014) Relation of serum uric acid levels and outcomes among patients hospitalized for worsening heart failure with reduced ejection fraction (from the efficacy of vasopressin antagonism in heart failure outcome study with Tolvaptan trial). Am J Cardiol 114(11):1713–1721.  https://doi.org/10.1016/j.amjcard.2014.09.008 CrossRefGoogle Scholar
  12. 12.
    Otaki Y, Watanabe T, Kinoshita D, Yokoyama M, Takahashi T, Toshima T, Sugai T, Murase T, Nakamura T, Nishiyama S, Takahashi H, Arimoto T, Shishido T, Miyamoto T, Kubota I (2017) Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int J Cardiol 228:151–157.  https://doi.org/10.1016/j.ijcard.2016.11.077 CrossRefGoogle Scholar
  13. 13.
    Borghi C, Cicero AF (2017) Serum uric acid and cardiometabolic disease. Another brick in the wall? Hypertension 69:1011–1013.  https://doi.org/10.1161/HYPERTENSIONAHA.117.09081 CrossRefGoogle Scholar
  14. 14.
    Sugihara S, Yamamoto K, Hisatome I (2016) Can xanthine oxidase inhibitors improve cardiac function in patients with chronic heart failure? Int Heart J 57:661–662.  https://doi.org/10.1536/ihj.16-480 CrossRefGoogle Scholar
  15. 15.
    Bove M, Cicero AF, Veronesi M, Borghi C (2016) An evidence-based review on urate lowering treatments: implications for optimal treatment of chronic hyperuricaemia. Vasc Health Risk Manag 13:23–28.  https://doi.org/10.2147/VHRM.S115080 CrossRefGoogle Scholar
  16. 16.
    Cicero AF, Morbini M, Urso R, Rosticci M, Parini A, Grandi E, D’Addato S, Borghi C, Brisighella Heart Study Group (2016) Association between self-reported snoring and arterial stiffness: data from the Brisighella Heart Study. Intern Emerg Med 11(1):77–83.  https://doi.org/10.1007/s11739-015-1310-9 CrossRefGoogle Scholar
  17. 17.
    Cicero AF, Desideri G, Grossi G, Urso R, Rosticci M, D’Addato S, Borghi C, Brisighella Heart Study Group (2015) Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: data from the Brisighella Study. Intern Emerg Med 10(1):25–31.  https://doi.org/10.1007/s11739-014-1098-z CrossRefGoogle Scholar
  18. 18.
    Valente MA, Hillege HL, Navis G, Voors AA, Dunselman PH, van Veldhuisen DJ, Damman K (2014) The chronic kidney disease epidemiology collaboration equation outperforms the modification of diet in renal disease equation for estimating glomerular filtration rate in chronic systolic heart failure. Eur J Heart Fail 16(1):86–94.  https://doi.org/10.1093/eurjhf/hft128 CrossRefGoogle Scholar
  19. 19.
    Cheitlin MD, Armstrong WF, Aurigemma GP, ACC, AHA, ASE et al (2003) ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (ACC/AHA/ASE committee to update the 1997 guidelines for the clinical application of echocardiography). J Am Soc Echocardiogr 16:1091–1110Google Scholar
  20. 20.
    Lang RM, Bierig M, Devereux RB et al (2005) Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18:1440–1463CrossRefGoogle Scholar
  21. 21.
    Simera I, Moher D, Hoey J, Schulz KF, Altman DG (2010) A catalogue of reporting guidelines for health research. Eur J Clin Invest 40:35–53CrossRefGoogle Scholar
  22. 22.
    Belfiore A, Palmieri VO, Di Gennaro C, Settimo E, De Sario MG, Lattanzio S, Fanelli M, Portincasa P (2019) Long-term management of chronic heart failure patients in internal medicine. Intern Emerg Med.  https://doi.org/10.1007/s11739-019-02024-4 (Epub ahead of print) Google Scholar
  23. 23.
    Bove M, Cicero AF, Borghi C (2017) The effect of xanthine oxidase inhibitors on blood pressure and renal function. Curr Hypertens Rep 19:95.  https://doi.org/10.1007/s11906-017-0793-3 CrossRefGoogle Scholar
  24. 24.
    Hare JM, Johnson RJ (2003) Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 107:1951–1953CrossRefGoogle Scholar
  25. 25.
    Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, Harrison DG, Hornig B, Drexler H (2002) Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106:3073–3078CrossRefGoogle Scholar
  26. 26.
    Pacher P, Nivorozhkin A, Szabó C (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58:87–114CrossRefGoogle Scholar
  27. 27.
    Duan X, Ling F (2008) Is uric acid itself a player or a bystander in the pathophysiology of chronic heart failure? Med Hypotheses 70:578–581CrossRefGoogle Scholar
  28. 28.
    Cicero AF, Kuwabara M, Johnson R, Bove M, Fogacci F, Rosticci M, Giovannini M, D’Addato S, Borghi C, Brisighella Heart Study group (2018) LDL-oxidation, serum uric acid, kidney function and pulse-wave velocity: data from the Brisighella Heart Study cohort. Int J Cardiol 261:204–208.  https://doi.org/10.1016/j.ijcard.2018.03.077 CrossRefGoogle Scholar
  29. 29.
    White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L, CARES Investigators (2018) Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 378(13):1200–1210.  https://doi.org/10.1056/NEJMoa1710895 CrossRefGoogle Scholar
  30. 30.
    Foody J, Turpin RS, Tidwell BA, Lawrence D, Schulman KL (2017) Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor. Am Health Drug Benefits 10:393–401Google Scholar
  31. 31.
    Xue L, Liu Y, Xue H, Xue J, Sun K, Wu L, Hou P (2017) Low uric acid is a risk factor in mild cognitive impairment. Neuropsychiatr Dis Treat 13:2363–2367.  https://doi.org/10.2147/NDT.S145812 CrossRefGoogle Scholar
  32. 32.
    Molino-Lova R, Sofi F, Pasquini G, Vannetti F, Del Ry S, Vassalle C, Clerici M, Sorbi S, Macchi C (2017) Higher uric acid serum levels are associated with better muscle function in the oldest old: results from the Mugello Study. Eur J Intern Med 41:39–43.  https://doi.org/10.1016/j.ejim.2017.03.014 CrossRefGoogle Scholar
  33. 33.
    Desideri G, Castaldo G, Lombardi A, Mussap M, Testa A, Pontremoli R, Punzi L, Borghi C (2014) Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci. 18(9):1295–1306Google Scholar
  34. 34.
    Bredemeier M, Lopes LM, Eisenreich MA, Hickmann S, Bongiorno GK, d’Avila R, Morsch ALB, da Silva SF, Campos GGD (2018) Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 18(1):24.  https://doi.org/10.1186/s12872-018-0757-9 CrossRefGoogle Scholar
  35. 35.
    Borghi C, Cicero AF (2017) Uric acid: beyond the interpretation of serum levels. Brit Med J 357:j2376Google Scholar

Copyright information

© Società Italiana di Medicina Interna (SIMI) 2019

Authors and Affiliations

  1. 1.Internal Medicine UnitS. Orsola-Malpighi University HospitalBolognaItaly
  2. 2.Cardiology DepartmentToranomon HospitalTokyoJapan

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