A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV.
Journal
AIDS (London, England)
ISSN: 1473-5571
Titre abrégé: AIDS
Pays: England
ID NLM: 8710219
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
pubmed:
16
2
2021
medline:
20
5
2021
entrez:
15
2
2021
Statut:
ppublish
Résumé
People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH. This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks. Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks. Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo. In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis.
Identifiants
pubmed: 33587443
doi: 10.1097/QAD.0000000000002845
pii: 00002030-202106010-00005
pmc: PMC8916096
mid: NIHMS1680103
doi:
Substances chimiques
Colchicine
SML2Y3J35T
Banques de données
ClinicalTrials.gov
['NCT02624180']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1041-1050Subventions
Organisme : NIH HHS
ID : S10 OD020091
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125059
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL133358
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL125059
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL146201
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147660
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003098
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI094189
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Références
Boccara F, Lang S, Meuleman C, Ederhy S, Mary-Krause M, Costagliola D, et al. HIV and coronary heart disease: time for a better understanding . J Am Coll Cardiol 2013; 61:511–523.
Nou E, Lo J, Grinspoon SK. Inflammation, immune activation, and cardiovascular disease in HIV . AIDS 2016; 30:1495–1509.
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med 2017; 377:1119–1131.
Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease . Circulation 2000; 101:1899–1906.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance . Circulation 2007; 115:1285–1295.
Hsue PY, Ribaudo HJ, Deeks SG, Bell T, Ridker PM, Fichtenbaum C, et al. Safety and impact of low-dose methotrexate on endothelial function and inflammation in individuals with treated human immunodeficiency virus: AIDS Clinical Trials Group Study A5314 . Clin Infect Dis 2019; 68:1877–1886.
Nidorf M, Thompson PL. Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease . Am J Cardiol 2007; 99:805–807.
Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease . J Am Coll Cardiol 2013; 61:404–410.
Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries . N Engl J Med 1986; 315:1046–1051.
Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, Stuber M. Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease . J Am Coll Cardiol 2010; 56:1657–1665.
Hays AG, Iantorno M, Soleimanifard S, Steinberg A, Schar M, Gerstenblith G, et al. Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function . Am J Physiol Heart Circ Physiol 2015; 308:H1343–H1350.
Leucker TM, Gerstenblith G, Schar M, Brown TT, Jones SR, Afework Y, et al. Evolocumab, a PCSK9-monoclonal antibody, rapidly reverses coronary artery endothelial dysfunction in people living with HIV and people with dyslipidemia . J Am Heart Assoc 2020; 9:e016263doi: 10.1161/jaha.120.016263.
doi: 10.1161/jaha.120.016263
Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dubé MP, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: the ACTG (AIDS Clinical Trials Group) Study 5152s . J Am Coll Cardiol 2008; 52:569–576.
Hürlimann D, Chenevard R, Ruschitzka F, Flepp M, Enseleit F, Béchir M, et al. Effects of statins on endothelial function and lipid profile in HIV infected persons receiving protease inhibitor-containing antiretroviral combination therapy: a randomised double blind crossover trial . Heart 2006; 92:110–112.
Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease . N Engl J Med 1995; 332:481–487.
Mukerjee R, Wu CFJ. A modern theory of factorial design . New York: Springer-Verlag; 2006.
Iantorno M, Soleimanifard S, Schar M, Brown TT, Bonanno G, Barditch-Crovo P, et al. Regional coronary endothelial dysfunction is related to the degree of local epicardial fat in people with HIV . Atherosclerosis 2018; 278:7–14.
Iantorno M, Hays AG, Schar M, Krishnaswamy R, Soleimanifard S, Steinberg A, et al. Simultaneous noninvasive assessment of systemic and coronary endothelial function . Circ Cardiovasc Imaging 2016; 9:e003954doi: 10.1161/circimaging.115.003954.
doi: 10.1161/circimaging.115.003954
Wassmann S, Faul A, Hennen B, Scheller B, Bohm M, Nickenig G. Rapid effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function . Circ Res 2003; 93:e98–e103.
Schar M, Soleimanifard S, Bonanno G, Yerly J, Hays AG, Weiss RG. Precision and accuracy of cross-sectional area measurements used to measure coronary endothelial function with spiral MRI . Magn Reson Med 2019; 81:291–302.
Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-dose methotrexate for the prevention of atherosclerotic events . N Engl J Med 2019; 380:752–762.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events . N Engl J Med 2002; 347:1557–1565.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes . N Engl J Med 2004; 350:1495–1504.
Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CP, Braunwald E. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial . J Am Coll Cardiol 2005; 45:1644–1648.
Crittenden DB, Lehmann RA, Schneck L, Keenan RT, Shah B, Greenberg JD, et al. Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout . J Rheumatol 2012; 39:1458–1464.
Hennessy T, Soh L, Bowman M, Kurup R, Schultz C, Patel S, et al. The low dose colchicine after myocardial infarction (LoDoCo-MI) study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction . Am Heart J 2019; 215:62–69.
Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction . N Engl J Med 2019; 381:2497–2505.
Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in patients with chronic coronary disease . N Engl J Med 2020; 383:1838–1847.
Hays AG, Iantorno M, Schar M, Mukherjee M, Stuber M, Gerstenblith G, et al. Local coronary wall eccentricity and endothelial function are closely related in patients with atherosclerotic coronary artery disease . J Cardiovasc Magn Reson 2017; 19:51doi: 10.1186/s12968-017-0358-2.
doi: 10.1186/s12968-017-0358-2
Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial . Lancet HIV 2015; 2:e52–e63.
O’Brien M, Montenont E, Hu L, Nardi MA, Valdes V, Merolla M, et al. Aspirin attenuates platelet activation and immune activation in HIV-1-infected subjects on antiretroviral therapy: a pilot study . J Acquir Immune Defic Syndr 2013; 63:280–288.
Baker JV, Wolfson J, Peterson T, Mooberry M, Gissel M, Mystakelis H, et al. Factor Xa inhibition reduces coagulation activity but not inflammation among people with HIV: a randomized clinical trial . Open Forum Infect Dis 2020; 7:ofaa026doi: 10.1093/ofid/ofaa026.
doi: 10.1093/ofid/ofaa026
Reikvam DH, Meyer-Myklestad MH, Troseid M, Stiksrud B. Probiotics to manage inflammation in HIV infection . Curr Opin Infect Dis 2020; 33:34–43.