Colchicine and cardiovascular prevention

•The approval of colchicine revolutionised the therapeutic algorithm for cardiovascular prevention bringing to the forefront the long-term direct targeting of inflammation.•Anti-inflammatory treatment with colchicine is a therapeutic tool to be added on top of the most advantageous standard of care in patients still at high risk of recurrent cardiovascular events.•The low cost of colchicine and the reassuring data on long-term safety strenghten the rationale to use this drug for cardiovascular prevention. "Scientia semper incerta est, expedit ut iudicium suspendat"Attributable to Marcus Tullius Cicer (106 b.C. – 43 b.C.) Over the last two decades, mounting evidence suggested that inflammation is a leading actor in the development and progression of cardiovascular diseases and that an interplay between inflammatory pathways and cardiovascular risk factors exists [[1]Libby P. The changing landscape of atherosclerosis.Nature. 2021; 592: 524-533Crossref PubMed Scopus (795) Google Scholar]. On this basis, direct anti-inflammatory agents on top of conventional treatment for the management of cardiovascular risk factors have been increasingly tested in randomised trials. In secondary prevention, canakinumab, a fully human monoclonal antibody directed against interleukin (IL)-1β, significantly reduced concentrations of IL-6 and high sensitivity C reactive protein (hsCRP) and was also associated with a significant reduction of major cardiovascular events (MACE) and death [[2]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 Sep 21; 377: 1119-1131Crossref PubMed Scopus (5698) Google Scholar]. However, despite an observed reduction in cancer mortality, high costs and safety concerns, particularly related to fatal infections and the lacked reduction in all-cause mortality, prevented further studies with this drug. At present, other IL pathways are under investigation in cardiovascular prevention and an ongoing trial with the IL-6 antagonist ziltivekimab, claimed to be safer than canakinumab, will be published in the next few years [[3]Ridker PM. From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction?.Cardiovasc Res. 2021 Sep 28; 117: e138-e140Crossref PubMed Scopus (35) Google Scholar]. Methotrexate failed to show any benefit on cardiovascular disease and was burdened by adverse events such as increased liver enzymes and reduced leukocytes [[4]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 Feb 21; 380: 752-762Crossref PubMed Scopus (852) Google Scholar]. Finally, colchicine a cheap, broad-spectrum anti-inflammatory agent historically used in gout and autoinflammatory diseases and with an acceptable safety profile was seen as the light at the end of the tunnel [[5]Deftereos SG Beerkens FJ Shah B Giannopoulos G Vrachatis DA Giotaki SG et al.Colchicine in Cardiovascular Disease: In-Depth Review.Circulation. 2022 Jan 4; 145: 61-78PubMed Google Scholar] (Fig. 1). Two pivotal trials, the Low-Dose Colchicine (LoDoCo) and LoDoCo-2 [[6]Nidorf SM Eikelboom JW Budgeon CA Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease.J Am Coll Cardiol. 2013 Jan 29; 61: 404-410Crossref PubMed Scopus (691) Google Scholar,[7]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 Nov 5; 383: 1838-1847Crossref PubMed Scopus (935) Google Scholar] demonstrated that adding colchicine to the standard of care in patients with stable coronary disease was able to reduce the occurrence of MACE and cardiovascular death over a median follow up of 28.6 months (LoDoCo-2) (hazard ratio (HR) and 95% confidence interval (CI) LoDoCo: 0.33, 0.18-0.59; LoDoCo-2: 0.69, 0.57-0.83) (Table 1).Table 1Summary of primary endpoints and data on mortality from key randomised trials. The colour code indicates if the primary endpoint and its components were met (green) not met (red) or not met with an alert on negative effects of colchicine /yellow). Open table in a new tab A recent metanalysis of randomised controlled trials derived a pooled HR of 0.68 (95% CI, 0.54-0.81) and highlighted that the reduction in cardiovascular events among patients randomized to colchicine was driven by statistically significant reductions in myocardial infarctions (MI), ischemic strokes, and urgent coronary revascularizations [[8]Samuel M Tardif JC Bouabdallaoui N Khairy P Dubé MP Blondeau L et al.Colchicine for Secondary Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.Can J Cardiol. 2021; 37: 776-785Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. On this basis, in June 2023 the Food and Drug Administration (FDA) approved the use of colchicine at the dosage of 0.5 mg once daily in patients with established atherosclerotic disease or with multiple risk factors for cardiovascular diseases [[9]Colchicine full prescribing information [Internet]. [cited 2023 Jun 29]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215727s000lbl.pdf.Google Scholar]. The European Society of Cardiology Guidelines on cardiovascular prevention also stated that low-dose colchicine (0.5 mg once daily) may be considered in secondary prevention of cardiovascular diseases, particularly if other risk factors are insufficiently controlled or if recurrent cardiovascular events occur under optimal therapy [[10]Visseren FLJ Mach F Smulders YM Carballo D Koskinas KC Bäck M et al.2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.Eur Heart J. 2021 Sep 7; 42: 3227-3337Crossref PubMed Scopus (2223) Google Scholar]. This revolutionised the therapeutic algorithm for cardiovascular prevention bringing to the forefront the long-term direct targeting of inflammation alongside the management of traditional cardiovascular risk factors. Following the FDA approval, expectations were so elevated that the old colchicine was commercialized in United States of America (USA) with the novel brand name of "Lodoco" with the indication "to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease". Despite the above, colchicine remains underused or not used at all in secondary cardiovascular prevention and the question remains on how to best fit this drug in the real-life clinical scenario. Furthermore, apart from the very recent approval in the USA and the less recent one in Canada, in other countries colchicine does not have this indication and therefore its use would remain off label. Additional promising data suggest that colchicine may be approved also for cardiovascular prevention in other conditions in the future [[11]Nidorf SM. Seeing Colchicine in a New Light: Repurposing Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease.Clin Ther. 2023 Jul 27; (S0149-2918(23)00257-6)Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Therefore, clinical implications of colchicine use for cardiovascular prevention in patients with stable atherosclerotic disease and potentially other indications deserve to be discussed. In the early 2000s the demonstration that statins could reduce circulating levels of hsCRP opened a new scenario demonstrating a link between inflammation and lipid metabolism [12Ridker PM Rifai N Pfeffer MA Sacks F Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators.Circulation. 1999 Jul 20; 100: 230-235Crossref PubMed Scopus (1435) Google Scholar, 13Albert MA Danielson E Rifai N Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study.JAMA. 2001 Jul 4; 286: 64-70Crossref PubMed Scopus (1566) Google Scholar, 14Ridker PM Rifai N Clearfield M Downs JR Weis SE Miles JS et al.Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.N Engl J Med. 2001 Jun 28; 344: 1959-1965Crossref PubMed Scopus (1521) Google Scholar]. The marketing of novel non-statin lipid-lowering drug class, namely pro-protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, revealed that the dramatic reduction of Low Density Lipoprotein cholesterol LDL-c came with a price since these drugs had no significant effect on hsCRP despite profound LDL-c reduction [15Sahebkar A Di Giosia P Stamerra CA Grassi D Pedone C Ferretti G et al.Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms.Br J Clin Pharmacol. 2016; 81: 1175-1190Crossref PubMed Scopus (94) Google Scholar, 16Sabatine MS Giugliano RP Keech AC Honarpour N Wiviott SD Murphy SA et al.Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.N Engl J Med. 2017 May 4; 376: 1713-1722Crossref PubMed Scopus (3858) Google Scholar, 17Schwartz GG Steg PG Szarek M Bhatt DL Bittner VA Diaz R et al.Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.N Engl J Med. 2018 Nov 29; 379: 2097-2107Crossref PubMed Scopus (2059) Google Scholar]. Furthermore, post-hoc data from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) and Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) trials in patients at high risk on statin treatment consistently documented that inflammation still plays an important prognostic role, even in subjects with very low LDL-c concentrations (<20 mg/dl), in whom hsCRP was able to independently modify cardiovascular risk [[18]Bohula EA Giugliano RP Leiter LA Verma S Park JG Sever PS et al.Inflammatory and Cholesterol Risk in the FOURIER Trial.Circulation. 2018 Jul 10; 138: 131-140Crossref PubMed Scopus (192) Google Scholar,[19]Pradhan AD Aday AW Rose LM Ridker PM. Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy.Circulation. 2018 Jul 10; 138: 141-149Crossref PubMed Scopus (150) Google Scholar]. In addition, the analysis of over 30'000 patients from the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) (n=9988), Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) (n=8179), and the Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) (n=13078) trials demonstrated that residual inflammatory risk was significantly associated with incident MACE and cardiovascular mortality whereas the relationship of residual cholesterol risk was neutral for MACE and of low magnitude for cardiovascular death [[20]Ridker PM Bhatt DL Pradhan AD Glynn RJ MacFadyen JG Nissen SE. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials.Lancet. 2023 Apr 15; 401: 1293-1301Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. This evidence supports the notion that additional anti-inflammatory treatment might provide benefit beyond aggressive lipid lowering in patients still at high risk of recurrent cardiovascular events. Therefore, colchicine should be regarded as a therapeutic tool to be added on top of the most advantageous standard of care, obviously including appropriate lifestyle modifications. The optimal management of traditional risk factors according to latest recommendations should remain the cornerstone of cardiovascular prevention and a second/third lipid-lowering drug as well as anti-diabetic drugs or other compounds should be used as needed before turning to colchicine [[10]Visseren FLJ Mach F Smulders YM Carballo D Koskinas KC Bäck M et al.2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.Eur Heart J. 2021 Sep 7; 42: 3227-3337Crossref PubMed Scopus (2223) Google Scholar]. In this regard, colchicine should be considered as one of the various choices that clinicians have in their armamentarium to treat residual cardiovascular risk and it cannot and should not replace anchor drugs for the management of other CV risk factors. This consideration is mainly related to the evident reduction in cardiovascular death observed in patients receiving colchicine, that was fully counterbalanced by the almost equally evident increment in all cause death in the LoDoCo-2 trial [[6]Nidorf SM Eikelboom JW Budgeon CA Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease.J Am Coll Cardiol. 2013 Jan 29; 61: 404-410Crossref PubMed Scopus (691) Google Scholar]. Nonetheless, it is important to acknowledge that these trials were not powered to assess mortality and since the number of deaths was small further data is required to draw definitive conclusions. One possible explanation for the number of patients enrolled, too low to assess mortality, may be the fact that the LoDoCo2 was a spontaneous study not funded by companies. However, it is reassuring that although the number of non-cardiovascular deaths was higher in patients assigned to colchicine, the incidence of specific causes of death, including cancer and infections was comparable to that of the placebo group [[21]Opstal TSJ Nidorf SM Fiolet ATL Eikelboom JW Mosterd A Bax WA et al.Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial.Int J Cardiol. 2023 Feb 1; 372: 1-5Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. The availability of a variety of therapeutic approaches targeting different pathways implies that clinicians fully understand the drivers of the residual risk for each patient in order to prioritise and choose the best drug(s) at the right time. In this regard, it is plausible that circulating levels of hsCRP may drive the therapeutic choice in favour or against a more intensive approach to cardiovascular prevention [[22]Ridker PM Koenig W Kastelein JJ Mach F Lüscher TF. Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention?.Eur Heart J. 2018 Dec 7; 39: 4109-4111Crossref PubMed Scopus (40) Google Scholar]. Nonetheless, hsCRP was not measured in the LoDoCo and LoDoCo-2 trials [[6]Nidorf SM Eikelboom JW Budgeon CA Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease.J Am Coll Cardiol. 2013 Jan 29; 61: 404-410Crossref PubMed Scopus (691) Google Scholar,[7]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 Nov 5; 383: 1838-1847Crossref PubMed Scopus (935) Google Scholar]. Therefore, the question remains as to whether measurement of this biomarker is really necessary to select patients for colchicine treatment. However, the dosing of hsCRP might be appropriate in patients already receiving multiple drugs and manifesting with recurrent cardiovascular events in order to maximize the benefit deriving from adding colchicine to the other drugs. All this keeping in mind that all of the trials with colchicine cannot be transposed to real life, particularly due to their relatively short duration. In this context, colchicine has been used for gout and pericarditis and, at least in gout, at relatively high doses for a short period of time. Thus, since the long-term low-dose treatment is envisaged, this adds a layer of complexity to the matter of safety in cardiovascular prevention. However, in Familiar Mediterranean Fever (FMF) and Behçet disease colchicine is often a lifelong therapy, administrated not only orally but even intravenously if needed without causing serious safety problems [[23]Grossman C Farberov I Feld O Livneh A Ben-Zvi I. Efficacy and safety of long-term treatment with intravenous colchicine for familial Mediterranean fever (FMF) refractory to oral colchicine.Rheumatol Int. 2019; 39: 517-523Crossref PubMed Scopus (12) Google Scholar]. Nonetheless, it is important to mention that although the survival of FMF patients in the colchicine era is comparable to that of the general population, when the adherence to colchicine treatment is adequate, renal involvement still predicts mortality [[24]Akar S Yuksel F Tunca M Soysal O Solmaz D Gerdan V et al.Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era.Medicine (Baltimore). 2012; 91: 131-136Crossref PubMed Scopus (39) Google Scholar]. In addition, the long-term therapy approach puts colchicine on the same level of other therapeutic strategies such as statins, anti-diabetic, anti-hypertensive and/or antiplatelet drugs based on the rationale of treating stable atherosclerosis. Therefore, a careful assessment of its safety profile in the target patient population is required. Most adverse events related to colchicine therapy are dose dependent, mild, and usually recede overtime or following dose-reduction. Gastrointestinal adverse events (e.g., diarrhoea) are the most frequent (10-20% of patients) and may lead to treatment discontinuation. At high dosage during prolonged periods of time, colchicine may lead to myelosuppression, neuromuscular toxicity and liver damage. Moreover, dose-adjustment is required in patients with chronic kidney disease to avoid accumulation to toxic levels [[5]Deftereos SG Beerkens FJ Shah B Giannopoulos G Vrachatis DA Giotaki SG et al.Colchicine in Cardiovascular Disease: In-Depth Review.Circulation. 2022 Jan 4; 145: 61-78PubMed Google Scholar]. In 2020 a meta-analysis including 8559 patients from 35 randomised controlled trials of colchicine versus placebo or active comparators across a number of different cardiovascular and non-cardiovascular indications demonstrated a significant pooled risk ratio (95% confidence interval) of 1.46 (1.20-1.77) for any adverse event and of 1.74 (1.32-2.30) for any gastrointestinal adverse event, but no higher risk of neuropathy-related, muscular, hepatic, infectious or haematological adverse events or death [[25]Stewart S Yang KCK Atkins K Dalbeth N Robinson PC. Adverse events during oral colchicine use: a systematic review and meta-analysis of randomised controlled trials.Arthritis Res Ther. 2020 Feb 13; 22: 28Crossref PubMed Scopus (96) Google Scholar]. Although these data are certainly encouraging, the authors of the meta-analysis pointed out that, since inclusion criteria of clinical trials are rather stringent, the results should be interpreted with caution as these are not necessarily generalizable to the general population. This is particularly relevant for chronic kidney disease since patients with severe forms are excluded from most clinical trials [[26]Pisaniello HL Fisher MC Farquhar H Vargas-Santos AB Hill CL Stamp LK et al.Efficacy and safety of gout flare prophylaxis and therapy use in people with chronic kidney disease: a Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-initiated literature review.Arthritis Res Ther. 2021 Apr 28; 23: 130Crossref PubMed Scopus (17) Google Scholar]. Therefore, real-life data may help shed some light on the matter and possibly identify dose specific or indication specific peculiarities. Another facet of the colchicine safety profile pertains to drug-drug interaction which is influenced by dose and duration of therapy [[27]Hansten PD Tan MS Horn JR Gomez-Lumbreras A Villa-Zapata L Boyce RD et al.Colchicine Drug Interaction Errors and Misunderstandings: Recommendations for Improved Evidence-Based Management.Drug Saf. 2023; 46: 223-242Crossref PubMed Scopus (8) Google Scholar]. Therefore, since these pharmacokinetic interactions may be of greater clinical significance with chronic administration of colchicine as in the setting of cardiovascular prevention, the use of low colchicine doses might further increase the possible safety risks. Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4) and it is also a substrate for the P-glycoprotein transporter. Therefore, when planning long term treatment, particularly in individuals with impaired liver and/or kidney function, a thorough assessment of concomitant drugs should be performed to identify CYP3A4/P-glycoprotein inhibitors and compounds that share colchicine's degradation pathway. To note, statins are a substrate for the P-glycoprotein transporter but generally well tolerated when used in colchicine-treated patients and despite their own risk of adverse musculoskeletal effects. Concordantly, the rare cases of rhabdomyolysis described with combination therapy usually occurred in individuals receiving higher doses of colchicine (>1 mg/day) [[28]Tufan A Dede DS Cavus S Altintas ND Iskit AB Topeli A. Rhabdomyolysis in a patient treated with colchicine and atorvastatin.Ann Pharmacother. 2006; 40: 1466-1469Crossref PubMed Scopus (53) Google Scholar]. Of interest, in the largest studies assessing colchicine for CV prevention, over 90% of enrolled patients were on statins without safety concerns being raised. Therefore, this interaction does not seem very relevant when 0.5mg colchicine is used. Taken together, the available evidence on colchicine safety is somehow reassuring in view of long-term use at low doses in multimorbid individuals already receiving multiple drugs. However, it is advisable to be alert particularly in the initial post-approval phase. It is worth mentioning that in addition to cardiovascular prevention in patients with established atherosclerotic disease, colchicine has been investigated in a variety of acute and chronic settings giving rise to hopes but also disappointments [[5]Deftereos SG Beerkens FJ Shah B Giannopoulos G Vrachatis DA Giotaki SG et al.Colchicine in Cardiovascular Disease: In-Depth Review.Circulation. 2022 Jan 4; 145: 61-78PubMed Google Scholar] (Table 2).Table 2Randomised controlled trials evaluating colchicine in the cardiovascular setting.INDICATIONN OF STUDIESDOSEDURATIONFOLLOW UP TIMEREFStable coronary disease30.5mg/day7 days-44 months28 days-44 months[[6]Nidorf SM Eikelboom JW Budgeon CA Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease.J Am Coll Cardiol. 2013 Jan 29; 61: 404-410Crossref PubMed Scopus (691) Google Scholar,[7]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 Nov 5; 383: 1838-1847Crossref PubMed Scopus (935) Google Scholar,[42]Kajikawa M Higashi Y Tomiyama H Maruhashi T Kurisu S Kihara Y et al.Effect of short-term colchicine treatment on endothelial function in patients with coronary artery disease.Int J Cardiol. 2019 Apr 15; 281: 35-39Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]Stable chronic heart failure10.5mg/day6 months6 months[43]Deftereos S Giannopoulos G Panagopoulou V Bouras G Raisakis K Kossyvakis C et al.Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.JACC Heart Fail. 2014; 2: 131-137Crossref PubMed Scopus (112) Google ScholarAcute coronary syndromes130.5-2mg*Short-term studies dose within hours before and after percutaneous coronary intervention or surgical procedure.1 day-22 months5 days-22 months[[29]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 Dec 26; 381: 2497-2505Crossref PubMed Scopus (1557) Google Scholar,[31]Tong DC Quinn S Nasis A Hiew C Roberts-Thomson P Adams H et al.Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial.Circulation. 2020 Nov 17; 142: 1890-1900Crossref PubMed Scopus (186) Google Scholar,44Akodad M Lattuca B Nagot N Georgescu V Buisson M Cristol JP et al.COLIN trial: Value of colchicine in the treatment of patients with acute myocardial infarction and inflammatory response.Arch Cardiovasc Dis. 2017; 110: 395-402Crossref PubMed Scopus (81) Google Scholar, 45Akrami M Izadpanah P Bazrafshan M Hatamipour U Nouraein N Drissi HB et al.Effects of colchicine on major adverse cardiac events in next 6-month period after acute coronary syndrome occurrence; a randomized placebo-control trial.BMC Cardiovasc Disord. 2021 Dec 7; 21: 583Crossref PubMed Scopus (24) Google Scholar, 46Aslanabadi N Khiali S Joudi S Mamdouhi M Entezari-Maleki T. Colchicine for the Prevention of Myocardial Injury Following Elective PCI: A Randomized Clinical Trial.Pharm Sci. 2022; 28: 596-602Google Scholar, 47Deftereos S Giannopoulos G Raisakis K Kossyvakis C Kaoukis A Panagopoulou V et al.Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients.J Am Coll Cardiol. 2013 Apr 23; 61: 1679-1685Crossref PubMed Scopus (149) Google Scholar, 48Deftereos S Giannopoulos G Angelidis C Alexopoulos N Filippatos G Papoutsidakis N et al.Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study.Circulation. 2015 Oct 13; 132: 1395-1403Crossref PubMed Scopus (204) Google Scholar, 49Hennessy 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: 62-69Crossref PubMed Scopus (91) Google Scholar, 50Hosseini SH Talasaz AH Alidoosti M Tajdini M Van Tassell BW Etesamifard N et al.Preprocedural Colchicine in Patients With Acute ST-elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention: A Randomized Controlled Trial (PodCAST-PCI).J Cardiovasc Pharmacol. 2022 Oct 1; 80: 592-599Crossref PubMed Scopus (5) Google Scholar, 51Mewton N Roubille F Bresson D Prieur C Bouleti C Bochaton T et al.Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction.Circulation. 2021 Sep 14; 144: 859-869Crossref PubMed Scopus (72) Google Scholar, 52O'Keefe JHJ McCallister BD Bateman TM Kuhnlein DL Ligon RW Hartzler GO. Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty.J Am Coll Cardiol. 1992; 19: 1597-1600Crossref PubMed Scopus (150) Google Scholar, 53Shah B Pillinger M Zhong H Cronstein B Xia Y Lorin JD et al.Effects of Acute Colchicine Administration Prior to Percutaneous Coronary Intervention: COLCHICINE-PCI Randomized Trial.Circ Cardiovasc Interv. 2020; 13e008717Crossref Scopus (111) Google Scholar, 54Cole J Htun N Lew R Freilich M Quinn S Layland J. Colchicine to Prevent Periprocedural Myocardial Injury in Percutaneous Coronary Intervention: The COPE-PCI Pilot Trial.Circ Cardiovasc Interv. 2021; 14e009992Crossref Scopus (24) Google Scholar]Cardiac surgery100.5-2mg*Short-term studies dose within hours before and after percutaneous coronary intervention or surgical procedure.5 days-1 month14 days-12 months[33Imazio M Brucato A Ferrazzi P Rovere ME Gandino A Cemin R et al.Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy.Circulation. 2011 Nov 22; 124: 2290-2295Crossref PubMed Scopus (222) Google Scholar, 34Imazio M Brucato A Ferrazzi P Pullara A Adler Y Barosi A et al.Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial.JAMA. 2014 Sep 10; 312: 1016-1023Crossref PubMed Scopus (257) Google Scholar, 35Imazio M Trinchero R Brucato A Rovere ME Gandino A Cemin R et al.COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial.Eur Heart J. 2010; 31: 2749-2754Crossref PubMed Scopus (208) Google Scholar, 36Imazio M Brucato A Rovere ME Gandino A Cemin R Ferrua S et al.Colchicine prevents early postoperative pericardial and pleural effusions.Am Heart J. 2011; 162 (e1): 527-532Crossref PubMed Scopus (43) Google Scholar, 37Tabbalat RA Hamad NM Alhaddad IA Hammoudeh A Akasheh BF Khader Y. Effect of ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Trial.Am Heart J. 2016; 178: 102-107Crossref PubMed Scopus (46) Google Scholar, 38Tabbalat RA Alhaddad I Hammoudeh A Khader YS Khalaf HA Obaidat M et al.Effect of Low-dose ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Low Dose Trial.J Int Med Res. 2020; 48300060520939832Crossref PubMed Scopus (16) Google Scholar, 39Shvartz V Le T Enginoev S Sokolskaya M Ispiryan A Shvartz E et al.Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.J Cardiovasc Dev Dis. 2022 Oct 20; 9PubMed Google Scholar, 40Finkelstein Y Shemesh J Mahlab K Abramov D Bar-El Y Sagie A et al.Colchicine for the prevention of postpericardiotomy syndrome.Herz. 2002; 27: 791-794Crossref PubMed Scopus (111) Google Scholar,[55]Meurin P Lelay-Kubas S Pierre B Pereira H Pavy B Iliou MC et al.Colchicine for Post-Operative Pericardial Effusion: Preliminary Results of the POPE-2 Study.J Am Coll Cardiol. 2015 Sep 8; 66: 1198-1199Crossref PubMed Scopus (15) Google Scholar,[56]Pan T Jiang CY Zhang H Han XK Zhang HT Jiang XY et al.The low-dose colchicine in patients after non-CABG cardiac surgery: a randomized controlled trial.Crit Care. 2023 Feb 7; 27: 49Crossref PubMed Scopus (2) Google Scholar]Atrial fibrillation21mg/day3 months3-15 months[[57]Deftereos S Giannopoulos G Kossyvakis C Efremidis M Panagopoulou V Kaoukis A et al.Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study.J Am Coll Cardiol. 2012 Oct 30; 60: 1790-1796Crossref PubMed Scopus (204) Google Scholar,[58]Deftereos S Giannopoulos G Efremidis M Kossyvakis C Katsivas A Panagopoulou V et al.Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life.Heart Rhythm. 2014; 11: 620-628Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar] Short-term studies dose within hours before and after percutaneous coronary intervention or surgical procedure. Open table in a new tab Thirteen studies explored the use of colchicine in patients with acute coronary syndromes with enrolment being performed within hours or up to 30 days after the event and focusing on different outcomes. It interesting to note that among these studies only the Colchicine Cardiovascular Outcomes Trial (COLCOT) [[29]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 Dec 26; 381: 2497-2505Crossref PubMed Scopus (1557) Google Scholar] stands out showing a clear efficacy of colchicine in preventing cardiovascular events and cardiovascular death over 22.6 months of follow up (HR, 95% CI: 0.77, 0.61 to 0.96). Of interest, when exploring how time-to-treatment initiation influenced the beneficial impact of colchicine, the primary endpoint was significantly lower in patients starting colchicine on day 8 (HR, 95% CI: 0.82 (0.61-1.11) [[30]Bouabdallaoui N Tardif JC Waters DD Pinto FJ Maggioni AP Diaz R et al.Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).Eur Heart J. 2020 Nov 7; 41: 4092-4099Crossref PubMed Scopus (169) Google Scholar]. The other studies on acute coronary syndromes outlined that adding periprocedural colchicine in patients undergoing percutaneous coronary intervention provides a minimal, if any, advantage in the short term. However, it is worth mentioning that although in COLCOT the cumulative primary end point was significantly reduced, some fundamental components such as myocardial infarction and CV mortality were not. In this regard, one possible explanation for the number of patients enrolled, too low to assess mortality, may be the fact that the LoDoCo2 was a spontaneous study not funded by Companies. On the contrary, in the Colchicine in Patients With Acute Coronary Syndromes (COPS) trial the composite primary end point was not significantly reduced even if a favourable trend was observed [[31]Tong DC Quinn S Nasis A Hiew C Roberts-Thomson P Adams H et al.Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial.Circulation. 2020 Nov 17; 142: 1890-1900Crossref PubMed Scopus (186) Google Scholar]. These observations highlight that a controversy in this area still exists and it needs to be addressed. Nonetheless, these findings fit well with the concept that colchicine may be more useful in a sub-acute/chronic stable setting to achieve long-term effects rather than in the acute phase where targeting inflammation may be not so relevant on top of the restoration of blood flow, at least in some patients. A recent study expanded the findings of the COLCOT trial by changing the rationale of post-acute coronary syndromes colchicine application. The Mono Antiplatelet and Colchicine Therapy (MACT) pilot study recruited patients with non–ST and ST-segment elevation acute coronary syndrome undergoing percutaneous angioplasty with drug-eluting stents and treated them with a P2Y12 inhibitor (ticagrelor or prasugrel) and colchicine instead of the usual dual antiplatelet therapy consisting of aspirin plus a P2Y12 inhibitor [[32]Lee SY Jeong YH Yun KH Cho JY Gorog DA Angiolillo DJ et al.P2Y(12) Inhibitor Monotherapy Combined With Colchicine Following PCI in ACS Patients: The MACT Pilot Study.JACC Cardiovasc Interv. 2023 Aug 14; 16: 1845-1855Crossref PubMed Scopus (7) Google Scholar]. Although this study displays some limitations such as the lack of a control group and the selective use of drug eluting stent, the results are encouraging and showed a reduction of hsCRP and platelet reactivity at one month and very low rates of stent thrombosis at 3 months. Finally, some studies focused on patients undergoing cardiac surgery with post-operative atrial fibrillation or post-pericardiotomy syndrome as primary outcomes [33Imazio M Brucato A Ferrazzi P Rovere ME Gandino A Cemin R et al.Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy.Circulation. 2011 Nov 22; 124: 2290-2295Crossref PubMed Scopus (222) Google Scholar, 34Imazio M Brucato A Ferrazzi P Pullara A Adler Y Barosi A et al.Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial.JAMA. 2014 Sep 10; 312: 1016-1023Crossref PubMed Scopus (257) Google Scholar, 35Imazio M Trinchero R Brucato A Rovere ME Gandino A Cemin R et al.COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial.Eur Heart J. 2010; 31: 2749-2754Crossref PubMed Scopus (208) Google Scholar, 36Imazio M Brucato A Rovere ME Gandino A Cemin R Ferrua S et al.Colchicine prevents early postoperative pericardial and pleural effusions.Am Heart J. 2011; 162 (e1): 527-532Crossref PubMed Scopus (43) Google Scholar, 37Tabbalat RA Hamad NM Alhaddad IA Hammoudeh A Akasheh BF Khader Y. Effect of ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Trial.Am Heart J. 2016; 178: 102-107Crossref PubMed Scopus (46) Google Scholar, 38Tabbalat RA Alhaddad I Hammoudeh A Khader YS Khalaf HA Obaidat M et al.Effect of Low-dose ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Low Dose Trial.J Int Med Res. 2020; 48300060520939832Crossref PubMed Scopus (16) Google Scholar, 39Shvartz V Le T Enginoev S Sokolskaya M Ispiryan A Shvartz E et al.Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.J Cardiovasc Dev Dis. 2022 Oct 20; 9PubMed Google Scholar, 40Finkelstein Y Shemesh J Mahlab K Abramov D Bar-El Y Sagie A et al.Colchicine for the prevention of postpericardiotomy syndrome.Herz. 2002; 27: 791-794Crossref PubMed Scopus (111) Google Scholar]. Although, the overall bulk of evidence is small, and sometimes conflicting current guidelines on pericardial diseases of the European Society of Cardiology recommend that colchicine should be considered after cardiac surgery using weight-adjusted doses and without a loading dose for the prevention of post-pericardiotomy syndrome if there are no contraindications and it is tolerated. Preventive administration of colchicine is also recommended for 1 month (Class IIa, Level A) [[41]Adler Y Charron P Imazio M Badano L Barón-Esquivias G Bogaert J et al.2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2015 Nov 7; 36: 2921-2964Crossref PubMed Scopus (1307) Google Scholar]. In conclusion, as we build real-life experience on the new cardiovascular mission of colchicine, we urge clinicians to share their experience with the scientific community and ultimately contribute to the most accurate definition of the target patient who can benefit the most from colchicine in cardiovascular prevention. Waiting to clear our mind and continuing with the use of colchicine in gout and pericarditis–despite of FDA approval and different guidelines – let's cautiously suspend the judgment on colchicine in cardiovascular prevention. The authors declare they have no conflict of interest.