Abstract
Preliminary evidence demonstrating that adding 0.5 mg of colchicine per day to statin and antiplatelet therapy reduced the risk of acute coronary events in patients with stable coronary artery disease has raised the hope that it may prove effective for the long-term secondary prevention of cardiovascular disease. The ability of colchicine to suppress blood levels of inflammatory mediators and prevent cholesterol-crystal-induced neutrophil-mediated inflammation implicated in the progression and instability of atherosclerosis adds plausibility to this clinical observation. Early intestinal intolerance in some patients is well recognized, but clinical experience gained over more than half a century with the continuous use of colchicine for the prevention of neutrophil-mediated inflammation in patients with familial Mediterranean fever and gout indicates that low-dose long-term therapy is safe. Nonetheless, before colchicine can be recommended for the secondary prevention of cardiovascular disease, further studies are required to confirm its safety and efficacy in a broad range of patients with coronary disease, and to determine whether doses of colchicine less than 0.5 mg/day might be effective and even better tolerated. Trials exploring the role of colchicine in the treatment of patients with acute coronary syndromes would also be of special interest but may require the use of doses higher than those used for long-term secondary prevention.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Bhatt DL, Eagle KA, Ohman EM, et al. REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–7.
Stone GW, Maehara A, Lansky AJ, et al. Prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–35.
Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med. 2005;352:1685–95.
Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012;110:875–88. This article summarizes the multiple roles of neutrophils in atherosclerosis.
Baetta R, Corsini A. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis. 2010;210:1–13.
Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368:2004–13.
Varas-Lorenzo C, Garcia Rodriguez LA, Maguire A, et al. Use of oral corticosteroids and the risk of acute myocardial infarction. Atherosclerosis. 2007;192:376–83.
Fuchs CS, Chan AT, Manson JE, et al. Anti-inflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113:1578–87.
Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071–80.
Bolten WW. Problem of the atherothrombotic potential of non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2006;65:7–13.
Antman EM, Bennett JS, Daugherty A. AHA scientific statements. Use of nonsteroidal antiinflammatory drugs. An update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115:1634–42.
Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;3:165–70.
Morris T, Stables M, Hobbs A, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183:2089–96.
Abela G, Vedre A, Janoudi A, et al. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol. 2011;107:1710–7.
Abela GS, Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events—a novel insight into plaque rupture by scanning electron microscopy. Scanning. 2006:1-10.
Abela GS, Aziz K, Vedre A, et al. Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes. Am J Cardiol. 2009;103:959–68.
Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61. This article demonstrates that cholesterol crystals can activate the NLRP3 inflammasome in animal models of atherosclerosis.
Rajamaki K, Lappalainen J, Öörni K, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5:e11765. This article demonstrates that cholesterol crystals can activate the NLRP3 inflammasome in human macrophages.
Grebe A, Latz E. Cholesterol crystals and inflammation. Curr Rheumatol Rep. 2013;15:313–20. This article discusses the inflammatory potential of cholesterol crystals in cardiovascular disease.
Nidorf SM, Eikelboom JW, Thompson PL. Targeting cholesterol crystal induced inflammation for the secondary prevention of cardiovascular disease. J Cardiovasc Pharmacol Ther. 2013. doi:10.1177/1074248413499972.
Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, et al. Controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med. 1974;291:932–4.
Cerquaglia C, Diaco M, Nucera G, et al. Pharmacological and clinical basis of treatment of familial Mediterranean fever (FMF) with colchicine or analogues: an update. Curr Drug Targets Inflamm Allergy. 2005;4:117–24.
Cocco G, Chu DC, Pandol S. Colchicine in clinical medicine. A guide for internists. J Intern Med. 2010;21:503–8.
Hartung EF. History of the use of colchicum and related medicaments in gout. Ann Rheum Dis. 1954;13(3):190–200.
Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis. Results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2005;112:2012–6.
Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med. 2005;165:1987–91.
Ferron GM, Rochdi M, Jusko WJ, et al. Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses. J Clin Pharmacol. 1996;10:874–83.
Chappey ON, Niel E, Wautier JL, et al. Colchicine disposition in human leukocytes after single and multiple oral administration. Clin Pharmacol Ther. 1993;54:360–7.
Langevitz P, Livneh A, Neumann L, et al. Prevalence of ischemic heart disease in patients with familial Mediterranean fever. Isr Med Assoc J. 2001;3:9–12.
Yüksel S, Ayvazyan L, Gasparyan AY. Familial Mediterranean fever as an emerging clinical model of atherogenesis associated with low-grade inflammation. Open Cardiovasc Med J. 2010;4:51–6.
Crittenden DB, Lehmann RA, Schneck L, et al. Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout. J Rheumatol. 2012;39:1458–64.
Nidorf SM, 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;99:805–7.
Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.
Nidorf SM, Eikelboom JW, Budgeon CA, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404–10. This article provides the first clinical evidence that colchicine may reduce the risk of cardiovascular events is patients with stable coronary disease when added to statin and antiplatelet therapy.
Cavallero C, Turolla E, Ricevuti G. Cell proliferation in the atherosclerotic plaques of cholesterol-fed rabbits: Part 1. Colchicine and [3H]thymidine studies. Atherosclerosis. 1871;13:9–20.
Wójcicki J, Hinek A, Jaworska M, et al. The effect of colchicine on the development of experimental atherosclerosis in rabbits. Pol J Pharmacol Pharm. 1986;38:343–8.
Spagnoli LG, Orlandi A, Santeusanio G. Foam cells of the rabbit atherosclerotic plaque arrested in metaphase by colchicine show a macrophage phenotype. Atherosclerosis. 1991;1:87–92.
Bauriedel G. Growth-inhibiting effect of colchicine on cultured vascular wall myocytes from arteriosclerotic lesions. Z Kardiol. 1992;81:92–8.
Molad Y. Update on colchicine and its mechanism of action. Curr Rheumatol Rep. 2002;4:252–6.
Ben-Chetrit E, Bergmann S, Sood R. Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. Rheumatology. 2006;45:274–82.
Malawista SE, Seegmiller JE. The effect of pretreatment with colchicine on the inflammatory response to microcrystalline urate: a model for gouty inflammation. Ann Intern Med. 1965;62:648–57.
Denko CW, Petricevic M. Modification of cholesterol crystal-induced inflammation. Agents Actions. 1980;10:353–7.
Netsky MG, Clarkson TB, Stokes D. The experimental production of arteriosclerosis response of the avian artery to intramural cholesterol and other insoluble substances. Am J Pathol. 1959;5:1081–9.
Suhalim JL, Chung CY, Lilledahl MB, et al. Characterization of cholesterol crystals in atherosclerotic plaques using stimulated Raman scattering and second-harmonic generation microscopy. Biophys J. 2012;102:1988–95.
Frink RJ. Parallel cholesterol crystals: a sign of impending plaque rupture? Invasive Cardiol. 2010;22:406–11.
Michel JB, Virmani R, Arbustini E, et al. Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur Heart J. 2011;32:1977–85.
Malawista SE, Duff GW, Atkins E, et al. Crystal induced endogenous pyrogen production. A further look at gouty inflammation. Arthritis Rheum. 1985;28:1039–46.
Seegmiller JE, Howell RR, Malawista SE. The inflammatory reaction to sodium urate. Its possible relationship to the genesis of acute gouty arthritis. JAMA. 1962;180:128–30.
Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–71.
Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation. 2002;106:2894–900.
Lagunoff D, Chi EY. Effect of colchicine on rat mast cells. J Cell Biol. 1976;71:182–95.
Perico N, Ostermann D, Bontempeill M, Morigi M, Amuchastegui CS, Zoja C, et al. Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation. J Am Soc Nephrol. 1996;4:594–601.
Ercolani L, Schulte WE. Metabolic and morphologic effects of colchicine on human T-lymphocyte expression of Fc mu and Fc gamma receptors. Cell Immunol. 1983;77:222–32.
Bauriedel G, Heimerl J, Beinert T, Welsch U, Höfling B. Colchicine antagonizes the activity of human smooth muscle cells cultivated from arteriosclerotic lesions after atherectomy. Coron Artery Dis. 1994;5:531–9.
Salai M, Segal E, Cohen I, Dudkiewicz I, Farzame N, Pitaru S. The inhibitory effects of colchicine on cell proliferation and mineralisation in culture. J Bone Joint Surg Br. 2001;83-B:912–5.
Simsek B, Islek I, Simsek T, Kucukoduk S, Cengiz K. Regression of nephrotic syndrome due to amyloidosis secondary to familial Mediterranean fever following colchicine treatment. Nephrol Dial Transplant. 2000;15:281–2.
Schlesinger N, Thiele RG. The pathogenesis of bone erosions in gouty arthritis. Ann Rheum Dis. 2010;69:1907–12.
Sari I, Yuksel A, Kozaci D, Selcuk S, Gokce G, Yildiz Y, et al. The effect of regular colchicine treatment on biomarkers related with vascular injury in newly diagnosed patients with familial Mediterranean fever. Inflammation. 2012;35:31191–7.
Yang LP. Oral colchicine (Colcrys) in the treatment and prophylaxis of gout. Drugs. 2010;70:1603–13.
Peters R, Lehman TJA, Schwabe AD. Colchicine use for familial Mediterranean fever—observations associated with long-term treatment. West J Med. 1983;1:43–6.
Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr. 2012;6:1142–6.
Wason S, Faulkner RD, Davis MW. Are dosing adjustments required for colchicine in the elderly compared with younger patients? Adv Ther. 2012;29:551–61.
Diav-Citrin O et al. Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol. 2010;203:144. e1-6.
Choi SSL, Chan KF, Ng HK, Mak WP. Colchicine-induced myopathy and neuropathy. Hong Kong Med J. 1999;5:204–7.
Malkinson FD, Lynfield YL. Colchicine alopecia. J Invest Dermatol. 1959;33:371–84.
Ben-Chetrit E. Azoospermia in familial Mediterranean fever patients: the role of colchicine and amyloidosis. Ann Rheum Dis. 1998;57:259–60.
Yilmaz R, Ozer S, Ozyurt H, et al. Serum vitamin B12 status in children with familial Mediterranean fever receiving colchicine treatment. HK J Paediatr. 2011;16:3–8.
Ben-Chetrit E, Navon P. Colchicine-induced leukopenia in a patient with familial Mediterranean fever: the cause and a possible approach. Clin Exp Rheumatol. 2003;21 Suppl 30:S38–40.
Alayli G, Cengiz K, Cantürk F, et al. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother. 2005;39:1358–61.
Imazio M, Brucato A, Trinchero R, et al. Colchicine for pericarditis: hype or hope? Eur Heart J. 2009;30:532–9.
US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm (2011).
Bismuth C, Gaultier M, Conso F. Medullary aplasia after acute colchicine poisoning. 20 cases. Nouv Presse Med. 1977;6:1625–9.
Center for Drug Evaluation and Research. Application number 22-352. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022352s000_MedR.pdf. (2008).
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63:3136–41.
US National Library of Medicine. Colchicine. http://livertox.nih.gov/Colchicine.htm. (2013).
Tawhida Y, Ghaffar A, Solaf M, et al. Colchicine resistant FMF is not always true resistance. Egypt J Med Hum Genet. 2011;12:99–101.
O’Keefe JH, McCallister BD, Bateman TM, et al. Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty. J Am Coll Cardiol. 1992;19:1597–600.
Deftereos S, Giannopoulos G, Raisakis K, et al. Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients. J Am Coll Cardiol. 2013;61(16):1679–85.
Khanna D, Khanna PP, Fitzgerald JD, et al. American College of Rheumatology guidelines for management of gout. Part 2: therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res. 2012;64:1447–61.
Raju NC, Yi Q, Nidorf M, et al. Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary syndrome or acute stroke: a pilot randomized controlled trial. J Thromb Thrombolysis. 2012;1:88–94.
Freigang S, Ampenberger F, Spohn G, et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol. 2011;41:2040–51.
Chia EW, Grainger R, Harper JL. Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low-dose colchicine. Br J Pharmacol. 2008;153:1288–95.
Schlesinger N. Canakinumab in gout. Expert Opin Biol Ther. 2012;9:1265–75.
Hacihamdioglu DO, Ozen S. Canakinumab induces remission in a patient with resistant familial Mediterranean fever. Rheumatology. 2012;51:1041.
Lowry F. FDA panel says no to canakinumab for gout attacks. http://www.medscape.com/viewarticle/745076. (2011).
Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;4:597–605.
Compliance with Ethics Guidelines
Conflict of Interest
Stefan M. Nidorf and Peter L. Thompson declare that they have no conflict of interest.
John W. Eikelboom is a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Jansen, and Sanofi-Aventis.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Coronary Heart Disease
Rights and permissions
About this article
Cite this article
Nidorf, S.M., Eikelboom, J.W. & Thompson, P.L. Colchicine for Secondary Prevention of Cardiovascular Disease. Curr Atheroscler Rep 16, 391 (2014). https://doi.org/10.1007/s11883-013-0391-z
Published:
DOI: https://doi.org/10.1007/s11883-013-0391-z