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American Journal of Cardiovascular Drugs

, Volume 19, Issue 2, pp 203–209 | Cite as

Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial

The CLAU Randomized Trial Long-Term Outcome
  • Joaquin De Haro
  • Silvia BledaEmail author
  • Carmen Gonzalez-Hidalgo
  • Ignacio Michel
  • Francisco Acin
Original Research Article
  • 51 Downloads

Abstract

Introduction

The Clinical and Endothelial Function Assessment after Endothelin Receptor Antagonist (CLAU) trial demonstrated the effect of bosentan on the endothelial function, inflammatory status and claudication distance in Hispanic patients with incipient peripheral arterial disease (PAD). Our aim was to assess the protective effect on cardiovascular events of bosentan versus conventional anti-atherosclerosis therapy.

Methods

CLAU included 56 patients with intermittent claudication, randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29), associating the best medical treatment. Log-rank and hazard ratio (HR) analyses were performed to estimate the relative efficacy of bosentan in preventing incidence of major adverse events (MAE) including target limb revascularization (TLR), amputation, myocardial infarction (MI), and all-cause death; major cardiovascular adverse events (MACE) including TLR, amputation, MI, stroke, and cardiovascular-cause death; and major adverse limb events (MALE), which combines TLR and amputation.

Results

During the follow-up period (34 ± 5 months), five MAE occurred in the control group only (17.2%), including two TLR, one amputation, one stroke, and an MI. The ratio of event-free survival for MAE to 3 years follow-up was higher in the group treated with bosentan (100% vs 66%, p = 0.01, HR = 76; 95% confidence interval 0.05–104,677, p = 0.24). A similar trend was observed in incidence of MACE (100% vs 66%, p = 0.01) and MALE (100% vs 80%, p = 0.15).

Conclusion

Treatment with bosentan in the early low-to-mild stages of PAD may prevent cardiovascular events and the need for lower limb revascularization in the Hispanic population.

Trial Registration ClinicalTrials.gov identifier NCT25102012.

Notes

Compliance with Ethical Standards

Conflict of interest

The authors, Joaquin De Haro, Silvia Bleda, Carmen Gonzalez Hidalgo, Ignacio Michel, and Francisco Acin, declare they have no conflicts of interest relevant to the content of this article.

Funding

This clinical trial was funded by a research Grant from the Foundation of the Spanish Society of Angiology and Vascular Surgery.

References

  1. 1.
    Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325(14):997–1001.CrossRefPubMedGoogle Scholar
  2. 2.
    De Miralles Haro J, Florez Gónzalez A, Varela Casariego C, García Acin F. Onset of peripheral arterial disease: role of endothelin in endothelial dysfunction. Interact Cardiovasc Thorac Surg. 2010;10(5):760–5.CrossRefGoogle Scholar
  3. 3.
    Jagroop IA, Berwanger CS, Stansby G, Mikhailidis DP. Plasma endothelin-1 concentrations in non-insulin-dependent diabetes mellitus and nondiabetic patients with chronic arterial obstructive disease of the lower limbs. Int Angiol. 1999;18(1):77–9.PubMedGoogle Scholar
  4. 4.
    Tsui JC, Dashwood MR. A role for endothelin-1 in peripheral vascular disease. Curr Vasc Pharmacol. 2005;3(4):325–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Shi-Wen X, Denton CP, Dashwood MR, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Investig Dermatol. 2001;116(3):417–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Boffa JJ, Tharaux PL, Dussaule JC, Chatziantoniou C. Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension. 2001;37(2 Part 2):490–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Amiri F, Virdis A, Neves MF, et al. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation. 2004;110(15):2233–40.CrossRefPubMedGoogle Scholar
  8. 8.
    Shi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell. 2004;15(6):2707–19.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Finsnes F, Skjonsberg OH, Tonnessen T, Naess O, Lyberg T, Christensen G. Endothelin production and effects of endothelin antagonism during experimental airway inflammation. Am J Respir Crit Care Med. 1997;155(4):1404–12.CrossRefPubMedGoogle Scholar
  10. 10.
    Rondelet B, Kerbaul F, Motte S, et al. Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation. 2003;107(9):1329–35.CrossRefPubMedGoogle Scholar
  11. 11.
    De Haro J, Bleda S, Varela C, Esparza L, Acin F, Bosentan Population-Based Randomized Trial for Clinical and Endothelial Function Assessment on Endothelin Antagonist Therapy in Patients With Intermittent Claudication (CLAU) Investigators. Effect of bosentan on claudication distance and endothelium-dependent vasodilation in Hispanic patients with peripheral arterial disease. Am J Cardiol. 2016;117(2):295–301.CrossRefPubMedGoogle Scholar
  12. 12.
    Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, et al. ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;124(18):2020–45.CrossRefGoogle Scholar
  13. 13.
    Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5–67.CrossRefPubMedGoogle Scholar
  14. 14.
    Clozel M. Endothelin receptor antagonists: current status and perspectives. J Cardiovasc Pharmacol. 2000;35(4 Suppl 2):S65–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Rubin LJ, Roux S. Bosentan: a dual endothelin receptor antagonist. Expert Opin Investig Drugs. 2002;11(7):991–1002.CrossRefPubMedGoogle Scholar
  16. 16.
    Iglarz M, Clozel M. Mechanisms of ET-1-induced endothelial dysfunction. J Cardiovasc Pharmacol. 2007;50(6):621–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Iglarz M, Silvestre JS, Duriez M, Henrion D, Lévy BI. Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor-no pathway. Arterioscler Thromb Vasc Biol. 2001;21(10):1598–603.CrossRefPubMedGoogle Scholar
  18. 18.
    Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2(3):221–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Angiology and Vascular Surgery Department, Getafe University HospitalMadridSpain

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