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Effect of Bosentan on Claudication Distance and Endothelium-Dependent Vasodilation in Hispanic Patients With Peripheral Arterial Disease

Published:November 05, 2015DOI:https://doi.org/10.1016/j.amjcard.2015.10.032
      Endothelin (ET) is involved in the etiopathogenesis of peripheral arterial disease (PAD). We hypothesized that ET antagonism might improve the endothelial function, inflammatory status, and symptoms in PAD. This pilot randomized clinical trial was designed to determine the clinical efficacy, pleiotropic effects, and safety of dual ET-receptor antagonist bosentan in Hispanic patients with PAD presenting intermittent claudication. The Bosentan Population-Based Randomized Trial for Clinical and Endothelial Function Assessment on Endothelin Antagonism Therapy was a 12-month, randomized, controlled, parallel-group, double-blind, proof-of-concept pilot study evaluating the effect of bosentan on absolute claudication distance (primary efficacy end point), flow-mediated arterial dilation, and C-reactive protein levels (primary pleiotropic end points) in patients with PAD with Rutherford category 1 to 2 of recent diagnosis. Secondary end points included ankle-brachial index, subjective claudication distance, and safety. Of the 629 screened subjects, 56 patients were randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29). Six months after the initiation, a significant treatment effect in flow-mediated arterial dilation of 2.43 ± 0.3% (95% CI 1.75 to 3.12; p = 0.001), absolute claudication distance of 283 ± 23 m (95% CI 202 to 366; p = 0.01), ankle-brachial index of 0.16 ± 0.03 (95% CI 0.09 to 0.23; p = 0.001), and a decrease in C-reactive protein levels of −2.0 ± 0.5 mg/L (95% CI −2.8 to −1.1; p = 0.02) were observed in the bosentan-treated group compared to the control group. No severe adverse effects were found in the bosentan group. In conclusion, in Hispanic patients with intermittent claudication, bosentan was well tolerated and improved endothelial function and claudication distance as well as inflammatory and hemodynamic states.
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      References

        • Tsui J.C.
        • Dashwood M.R.
        A role for endothelin-1 in peripheral vascular disease.
        Curr Vasc Pharmacol. 2005; 3: 325-332
        • Lerman A.
        • Edwards B.S.
        • Hallett J.W.
        • Heublein D.M.
        • Sandberg S.M.
        • Burnett Jr., J.C.
        Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis.
        N Engl J Med. 1991; 325: 997-1001
        • De Haro Miralles J.
        • Florez Gónzalez A.
        • Varela Casariego C.
        • Acin García F.
        Onset of peripheral arterial disease: role of endothelin in endothelial dysfunction.
        Interact Cardiovasc Thorac Surg. 2010; 10: 760-765
        • Jagroop I.A.
        • Berwanger C.S.
        • Stansby G.
        • Mikhailidis D.P.
        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: 77-79
        • Shi-Wen X.
        • Denton C.P.
        • Dashwood M.R.
        • Holmes A.M.
        • Bou-Gharios G.
        • Pearson J.D.
        • Black C.M.
        • Abraham D.J.
        Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1.
        J Invest Dermatol. 2001; 116: 417-425
        • Boffa J.J.
        • Tharaux P.L.
        • Dussaule J.C.
        • Chatziantoniou C.
        Regression of renal vascular fibrosis by endothelin receptor antagonism.
        Hypertension. 2001; 37: 490-496
        • Park S.H.
        • Saleh D.
        • Giaid A.
        • Michel R.P.
        Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist.
        Am J Respir Crit Care Med. 1997; 156: 600-608
        • Shi-Wen X.
        • Chen Y.
        • Denton C.P.
        • Eastwood M.
        • Renzoni E.A.
        • Bou-Gharios G.
        • Pearson J.D.
        • Dashwood M.
        • du Bois R.M.
        • Black C.M.
        • Leask A.
        • Abraham D.J.
        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: 2707-2719
        • Finsnes F.
        • Skjonsberg O.H.
        • 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: 1404-1412
        • Rondelet B.
        • Kerbaul F.
        • Motte S.
        • van Beneden R.
        • Remmelink M.
        • Brimioulle S.
        • McEntee K.
        • Wauthy P.
        • Salmon I.
        • Ketelslegers J.M.
        • Naeije R.
        Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension.
        Circulation. 2003; 107: 1329-1335
        • Dumont A.S.
        • Lovren F.
        • McNeill J.H.
        • Sutherland G.R.
        • Triggle C.R.
        • Anderson T.J.
        • Verma S.
        Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits.
        J Neurosurg. 2001; 94: 281-286
        • Chen S.J.
        • Chen Y.F.
        • Meng Q.C.
        • Durand J.
        • Dicarlo V.S.
        • Oparil S.
        Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats.
        J Appl Physiol. 1995; 79: 2122-2131
        • Pearl J.M.
        • Wellmann S.A.
        • McNamara J.L.
        • Lombardi J.P.
        • Wagner C.J.
        • Raake J.L.
        • Nelson D.P.
        Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function.
        Ann Thorac Surg. 1999; 68: 1714-1721
        • Mulder A.L.
        • Golde J.M.
        • Goor A.A.
        • Giussani D.A.
        • Blanco C.E.
        Developmental changes in plasma catecholamine concentrations during normoxia and acute hypoxia in the chick embryo.
        J Physiol. 2000; 527: 593-599
        • De Haro J.
        • Acin F.
        • Bleda S.
        • Varela C.
        • Esparza L.
        Treatment of thromboangiitis obliterans (Buerger's disease) with bosentan.
        BMC Cardiovasc Disord. 2012; 12: 1-5
        • Taylor L.M.
        • Porter J.M.
        Proposed design for a double blinded trial to evaluate medications for treatment of intermittent claudication.
        J Vasc Surg. 1992; 15: 882-884
        • 2011 WRITING GROUP MEMBERS; 2005 WRITING COMMITTEE MEMBERS; ACCF/AHA TASK FORCE MEMBERS
        2011 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: 2020-2045
        • Norgren L.
        • Hiatt W.R.
        • Dormandy J.A.
        • Nehler M.R.
        • Harris K.A.
        • Fowkes F.G.
        • TASC II Working Group
        Inter-society consensus for the management of peripheral arterial disease (TASC II).
        J Vasc Surg. 2007; 45: S5-S67
        • Corretti M.C.
        • Anderson T.J.
        • Benjamin E.J.
        • Celermajer D.
        • Charbonneau F.
        • Creager M.A.
        • Deanfield J.
        • Drexler H.
        • Gerhard-Herman M.
        • Herrington D.
        • Vallance P.
        • Vita J.
        • Vogel R.
        • International Brachial Artery Reactivity Task Force
        Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
        J Am Coll Cardiol. 2002; 39: 257-265
        • De Haro J.
        • Acin F.
        • Lopez-Quintana A.
        • Medina F.J.
        • Martinez-Aguilar E.
        • Florez A.
        • March J.R.
        Direct association between C-reactive protein serum levels and endothelial dysfunction in patients with claudication.
        Eur J Vasc Endovasc Surg. 2008; 35: 480-486
        • Mangiafico R.A.
        • Malatino L.S.
        • Santonocito M.
        • Sarnataro F.
        • Dell'Arte S.
        • Messina R.
        • Santangelo B.
        Plasma endothelin-1 levels in patients with peripheral arterial occlusive disease at different Fontaine's stages.
        Panminerva Med. 1999; 41: 22-26
        • Dashwood M.R.
        • Jagroop I.A.
        • Gorog D.A.
        • Bagger J.P.
        A potential role for endothelin-1 in peripheral vascular disease.
        J Cardiovasc Pharmacol. 2000; 36: S93-S94
        • Clozel M.
        Endothelin receptor antagonists: current status and perspectives.
        J Cardiovasc Pharmacol. 2000; 35: S65-S68
        • Rubin L.J.
        • Roux S.
        Bosentan: a dual endothelin receptor antagonist.
        Expert Opin Investig Drugs. 2002; 11: 991-1002
        • Hernández-Perera O.
        • Pérez-Sala D.
        • Navarro-Antolín J.
        • Sánchez-Pascuala R.
        • Hernández G.
        • Díaz C.
        • Lamas S.
        Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.
        J Clin Invest. 1998; 101: 2711-2719
        • Moens A.L.
        • Goovaerts I.
        • Claeys M.J.
        • Vrints C.J.
        Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool?.
        Chest. 2005; 127: 2254-2263
        • Thijssen D.H.
        • Black M.A.
        • Pyke K.E.
        • Padilla J.
        • Atkinson G.
        • Harris R.A.
        • Parker B.
        • Widlansky M.E.
        • Tschakovsky M.E.
        • Green D.J.
        Assessment of flow-mediated dilation in humans: a methodological and physiological guideline.
        Am J Physiol Heart Circ Physiol. 2011; 300: H2-H12