Colchicine for Secondary Prevention of Cardiovascular Disease

  • Stefan M. Nidorf
  • John W. Eikelboom
  • Peter L. Thompson
Coronary Heart Disease (JA Farmer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Coronary Heart Disease

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.

Keywords

Colchicine Secondary prevention of cardiovascular disease 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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.PubMedCrossRefGoogle Scholar
  2. 2.
    Stone GW, Maehara A, Lansky AJ, et al. Prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med. 2005;352:1685–95.PubMedCrossRefGoogle Scholar
  4. 4.••
    Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012;110:875–88. This article summarizes the multiple roles of neutrophils in atherosclerosis.PubMedCrossRefGoogle Scholar
  5. 5.
    Baetta R, Corsini A. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis. 2010;210:1–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368:2004–13.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Fuchs CS, Chan AT, Manson JE, et al. Anti-inflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113:1578–87.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Bolten WW. Problem of the atherothrombotic potential of non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2006;65:7–13.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;3:165–70.CrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.
  16. 16.•
    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.PubMedCrossRefGoogle Scholar
  17. 17.••
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.••
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.•
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    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.
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Cocco G, Chu DC, Pandol S. Colchicine in clinical medicine. A guide for internists. J Intern Med. 2010;21:503–8.Google Scholar
  24. 24.
    Hartung EF. History of the use of colchicum and related medicaments in gout. Ann Rheum Dis. 1954;13(3):190–200.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    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.PubMedCentralPubMedGoogle Scholar
  31. 31.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.•
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    Bauriedel G. Growth-inhibiting effect of colchicine on cultured vascular wall myocytes from arteriosclerotic lesions. Z Kardiol. 1992;81:92–8.PubMedGoogle Scholar
  39. 39.
    Molad Y. Update on colchicine and its mechanism of action. Curr Rheumatol Rep. 2002;4:252–6.PubMedCrossRefGoogle Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Denko CW, Petricevic M. Modification of cholesterol crystal-induced inflammation. Agents Actions. 1980;10:353–7.PubMedCrossRefGoogle Scholar
  43. 43.
    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.Google Scholar
  44. 44.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Frink RJ. Parallel cholesterol crystals: a sign of impending plaque rupture? Invasive Cardiol. 2010;22:406–11.Google Scholar
  46. 46.
    Michel JB, Virmani R, Arbustini E, et al. Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur Heart J. 2011;32:1977–85.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    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.Google Scholar
  49. 49.
    Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–71.PubMedCrossRefGoogle Scholar
  50. 50.••
    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.PubMedCrossRefGoogle Scholar
  51. 51.
    Lagunoff D, Chi EY. Effect of colchicine on rat mast cells. J Cell Biol. 1976;71:182–95.PubMedCrossRefGoogle Scholar
  52. 52.
    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.Google Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedGoogle Scholar
  55. 55.
    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.CrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    Schlesinger N, Thiele RG. The pathogenesis of bone erosions in gouty arthritis. Ann Rheum Dis. 2010;69:1907–12.PubMedCrossRefGoogle Scholar
  58. 58.
    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.CrossRefGoogle Scholar
  59. 59.
    Yang LP. Oral colchicine (Colcrys) in the treatment and prophylaxis of gout. Drugs. 2010;70:1603–13.PubMedCrossRefGoogle Scholar
  60. 60.
    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.Google Scholar
  61. 61.
    Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr. 2012;6:1142–6.CrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Diav-Citrin O et al. Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol. 2010;203:144. e1-6.PubMedCrossRefGoogle Scholar
  64. 64.
    Choi SSL, Chan KF, Ng HK, Mak WP. Colchicine-induced myopathy and neuropathy. Hong Kong Med J. 1999;5:204–7.PubMedGoogle Scholar
  65. 65.
    Malkinson FD, Lynfield YL. Colchicine alopecia. J Invest Dermatol. 1959;33:371–84.PubMedCrossRefGoogle Scholar
  66. 66.
    Ben-Chetrit E. Azoospermia in familial Mediterranean fever patients: the role of colchicine and amyloidosis. Ann Rheum Dis. 1998;57:259–60.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    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.Google Scholar
  68. 68.
    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.PubMedGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Imazio M, Brucato A, Trinchero R, et al. Colchicine for pericarditis: hype or hope? Eur Heart J. 2009;30:532–9.PubMedCrossRefGoogle Scholar
  71. 71.
    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).
  72. 72.
    Bismuth C, Gaultier M, Conso F. Medullary aplasia after acute colchicine poisoning. 20 cases. Nouv Presse Med. 1977;6:1625–9.Google Scholar
  73. 73.
    Center for Drug Evaluation and Research. Application number 22-352. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022352s000_MedR.pdf. (2008).
  74. 74.
    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.PubMedCrossRefGoogle Scholar
  75. 75.
    US National Library of Medicine. Colchicine. http://livertox.nih.gov/Colchicine.htm. (2013).
  76. 76.
    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.CrossRefGoogle Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    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.CrossRefGoogle Scholar
  80. 80.
    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.CrossRefGoogle Scholar
  81. 81.
    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.PubMedCrossRefGoogle Scholar
  82. 82.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Schlesinger N. Canakinumab in gout. Expert Opin Biol Ther. 2012;9:1265–75.CrossRefGoogle Scholar
  84. 84.
    Hacihamdioglu DO, Ozen S. Canakinumab induces remission in a patient with resistant familial Mediterranean fever. Rheumatology. 2012;51:1041.PubMedCrossRefGoogle Scholar
  85. 85.
    Lowry F. FDA panel says no to canakinumab for gout attacks. http://www.medscape.com/viewarticle/745076. (2011).
  86. 86.
    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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Stefan M. Nidorf
    • 1
  • John W. Eikelboom
    • 2
  • Peter L. Thompson
    • 3
  1. 1.Heart Care Western AustraliaPerthAustralia
  2. 2.McMaster UniversityHamiltonCanada
  3. 3.Heart Research Institute of Western Australia, Sir Charles Gairdner HospitalUniversity of Western AustraliaPerthAustralia

Personalised recommendations