6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`Colchicine in Acute Coronary Syndrome:
`When to Commence?
`
`Expert Analysis
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`1/9
`
`Quick Takes
`The insights emanating from recent large clinical trials studying the role of
`colchicine as anti-inflammatory treatment in patients with coronary disease
`come with new questions for regular clinical practice, such as when to
`commence treatment.
`Current data suggest initiating treatment early after myocardial infarction
`(MI) or in patients without cardio-renal failure treated in the outpatient
`clinic.
`The effect of colchicine persists throughout prolonged treatment,
`irrespective of timing of a prior acute coronary syndrome (ACS).
`Patients with coronary disease have a life-long increased risk of developing new
`major adverse cardiovascular events. Depending on co-morbidities and
`atherosclerotic burden, patients have a 5-year risk of up to 20% for MI, ischemic
`stroke, or death.
`1,2
` A proportion of this risk is attributable to the inflammatory
`drivers in atherosclerosis, often referred to as the residual inflammatory risk.
`3
`Sep 15, 2021     |   
`aernoud fiolet;
`Tjerk Simon Jacob Opstal, MD; Peter Thompson, MD; Jan
`Hein Cornel
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`2/9
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`‑
`
`CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) confirmed
`that modulating the inflammatory response by selective cytokine inhibition using
`the molecular antibody canakinumab can translate to clinical benefit.
`4
` Shortly
`after CANTOS, two major clinical trials reported on the efficacy of the broad-acting
`anti-inflammatory drug colchicine in both acute and chronic coronary disease.
`COLCOT (Colchicine Cardiovascular Outcomes Trial) recruited patients within 30
`days of MI. A total of 4,745 patients was randomized to colchicine 0.5 mg or
`placebo once daily. The trial showed a 23% relative risk reduction for the
`occurrence of the primary endpoint (the composite of death from cardiovascular
`causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina
`leading to coronary revascularization).
`5
` The LoDoCo2 (Low Dose Colchicine for
`Secondary Prevention of Cardiovascular Disease 2) trial recruited patients with
`chronic coronary disease. The trial randomized 5,522 patients to 0.5 mg colchicine
`or placebo once daily and demonstrated a 31% relative risk reduction for its
`primary endpoint (the composite of cardiovascular death, MI, ischemic stroke, or
`ischemia-driven revascularization) compared to placebo.
`6
`When pooled, the results of the low-dose colchicine studies show a relative risk
`reduction of 25% (relative risk 0.75; 95% confidence interval [CI], 0.61-0.91) for
`major adverse cardiovascular events, with consistent effects on the individual
`components and in various clinical subgroups.
`7
`Colchicine, originally extracted from the autumn crocus (Colchicum autumnale), is a
`widely available drug that is commonly used to treat gout, familial Mediterranean
`fever, and pericarditis. The mechanisms of action of the drug are broad and relate
`strongly to the inhibition of microtubule self-assembly. Microtubules are structural
`components that form the cytoskeleton, contribute to the shape and movement of
`cells, and facilitate trafficking of components within the cell. Relevant effects in
`the pathogenesis of atherosclerosis are the ability of colchicine to diminish
`neutrophil recruitment and adhesion and to inhibit nucleotide-binding
`oligomerisation domain-, leucine-rich repeat-, and pyrin domain-containing protein
`3 inflammasome activity.
`8,9
` Concentration of colchicine in leucocytes reaches its
`maximum within 48 hours of a single dose, and chemokine inhibitory effects occur
`within 6-24 hours after administration in patients with ACS.
`10,11
` Colchicine inhibits
`neutrophil degranulation proteins and is associated with a 30-40% reduction in
`high-sensitivity C-Reactive protein levels and a 16% reduction in interleukin
`6
`levels in patients with chronic coronary disease.
`12,13
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`3/9
`
`Colchicine has a clear dose-response effect for side effects.
`8
` High-dose colchicine
`(0.5 mg bi-daily or more) is used in gout, pericarditis, and in familial
`Mediterranean fever. It is also investigated in clinical studies of coronary
`interventions, post-thoracotomy syndromes, and ablation in atrial fibrillation. The
`incidence of any adverse side effect is at least twofold higher in studies using
`high-dose colchicine than the incidence that was observed in the low-dose
`colchicine studies in coronary disease.
`14
` However, these adverse effects are often
`benign and most often concern gastrointestinal upset. Whether the 20%
`difference in dosage commonly used in the United States (0.6 mg once daily)
`versus the dosage used in studies so far (0.5 mg once daily) will translate to a
`clinically relevant increase in adverse events in patients with coronary disease is
`not known but seems unlikely.
`Data on colchicine 0.6 mg and adverse events in coronary disease are scarce.
`Indirectly inferring a dose effect from current or future studies using 0.6 mg once
`daily will be challenging because variation in patient populations and run-in
`schemes also contribute to differences in incidence of side effects. Data on
`bioavailability of the two dose regimes are also limited. Determining a difference
`in side effects between 0.5 mg and 0.6 mg once daily would necessitate
`extrapolating bioavailability data, designing head-to-head comparisons of the two
`regimes, or using phase IV observational studies comparing the two dosages. The
`latter two methods need large study sizes to detect the probably subtle
`difference, if present.
`In translating the findings of benefit in coronary disease to regular clinical care of
`patients post-MI, one of the most relevant questions is when to commence
`therapy. Recent ancillary analyses have provided more guidance in this regard.
`15,16
`All patients in COLCOT had a prior MI. In 40% of patients, study medication was
`initiated within the first week after MI. Patients who received treatment early were
`generally younger, more often smokers, and more often taking beta-blockers.
`Time to treatment as effect modifier for the primary and secondary endpoint was
`investigated using a stratified post hoc Cox regression analysis. Effect size was
`most marked in patients who had treatment initiated within 3 days after MI
`(hazard ratio [HR] 0.52; 95% CI, 0.32-0.84).
`15
` The subgroup of patients in which
`therapy was initiated 8 days or more after MI was twice as large. The effect
`estimate in this subgroup was directionally consistent, albeit smaller and not
`statically significant (HR 0.82; 95% CI, 0.61-1.11). The authors did not report
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`4/9
`
`whether the differences in observed effect size between strata were statistically
`significant.
`The authors made a notable effort to quantify the relation of treatment effect size
`and time to treatment initiation by analyzing the latter as continuous factor
`(Figure 1). This analysis confirmed an early benefit of the treatment initiation but
`also came with imprecision to detect any signal in patients who started treatment
`more than 8 days after MI. Interestingly, relative risk reduction was greater in
`patients who commenced treatment more than 21 days after their index
`infarction. An important caveat in the interpretation of this finding is that not all
`unequally distributed characteristics were used in adjustment of these estimators.
`Second, whether this parabolic relation of treatment initiation and effect size—
`with greater effect size seen in both very early (<3 days) and very late (>21 days)
`treatment initiation—reflects separate biologic mechanisms of the drug or is a
`play of chance cannot be distinguished from these data. Early benefits could be
`based on the potential of colchicine to lower ischemia-reperfusion injury. A 5-day
`regimen of colchicine 0.5 mg twice daily in patients with ST-segment elevation MI
`led to smaller infarct sizes measured with magnetic resonance imaging and
`troponin-T and creatine kinase-MB levels compared to placebo.
`17
`Figure 1: Associations Between Time to Treatment Initiation and the Risk of
`Occurrence of the Primary Composite Endpoint
`The HR for the primary end point of composite of cardiovascular death, resuscitated cardiac
`arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization for
`colchicine 0.5 mg once daily or placebo expressed as function of time-to-treatment initiation. The
`adjusted HR and 95% CI come from a quadratic multivariable Cox regression model. Adapted with
`permission from Bouabdallaoui N, Tardif JC, Waters DD, 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;41:4092-9.
`15
`These data suggest that early initiation of low-dose colchicine is justified in
`patients with MI. However, less than 25% of the COLCOT cohort had follow-up for
`more than 28 months. When evaluating treatment effect late after a coronary
`event, data from the LoDoCo2 trial becomes complementary. In contrast to
`COLCOT, patients from the LoDoCo2 trial were recruited from outpatient clinics,
`irrespective of a prior coronary event. A fifth of patients in the LoDoCo2 trial had
`over 4 years of follow-up. In 50% of patients with a history of prior ACS, the most
`recent event occurred more than 4 years prior to randomization (median time
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`5/9
`
`since last ACS = 4 years; interquartile range = 2-10 years). Benefit of treatment in
`the LoDoCo2 trial was consistently seen in all subgroups of prior ACS (Figure 2):
`For patients with an ACS 6-24 months prior to randomization (HR 0.75; 95% CI,
`0.51-1.10)
`For patients with an ACS 2-7 years prior to randomization (HR 0.55; 95% CI,
`0.37-0.82)
`For patients with an ACS >7 years prior to randomization (HR 0.70; 95% CI,
`0.51-0.96)
`Figure 2: Cumulative Incidence of the Primary Composite Endpoint Stratified
`per Time Since Last ACS
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`6/9
`
`The primary composite endpoint was cardiovascular death, MI, or ischemic stroke or ischemia-
`driven coronary revascularization. The HR with 95% CI were estimated from Cox proportional
`hazard models. Adapted with permission from Opstal TSJ, Fiolet ATL, van Broekhoven A, et al.
`Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome. J
`Am Coll Cardiol 2021;78:859-66.
`16
`Although the relative risk reduction varied from 45% to 25% for these strata,
`differences were not statistically significant (p for interaction of treatment effect
`and prior ACS status = 0.590).
`16
` Trial data on colchicine were collected in a wide
`range of patients, with and without prior ACS. These data and tabular meta-
`analyses show consistent effects of treatment, regardless of prior events.
`5-7
`Whether a high atherothrombotic risk is associated with greater treatment benefit
`of colchicine has not yet been confirmed. Although it seems likely that there are
`atherothrombotic and inflammatory phenotypes that would benefit more from
`treatment with colchicine, exploratory subgroup analyses from the trials did not
`yet reveal any clinical effect modifiers. These data come with the caveat that such
`subgroup analyses are almost always underpowered.
`Post hoc sub-analyses from CANTOS did, however, show greatest benefit in those
`with greatest anti-inflammatory effect.
`18
` These data are in accordance with the
`observation that clinical benefit of statins is proportional to their anti-
`inflammatory effects.
`19
` Whether such associations also exist for colchicine is not
`yet known. A large clinical outcomes trial (COLCARDIO-ACS [Colchicine
`Cardiovascular Outcomes in Acute Coronary Syndrome]) will investigate the effect
`of the drug in patients with elevated high-sensitivity C-reactive protein. These data
`will contribute to the identification of high-responder populations. As for now, the
`available evidence suggests that colchicine can be used in the complete range of
`coronary syndromes irrespective of (recurrent) coronary events.
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
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`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`7/9
`
`When generalizing the findings from the colchicine trials, it should be noted that
`patients with heart failure and renal impairment were excluded from participation,
`and only a very low number of octogenarians was included in the studies.
`However, comorbidities were typical of patients with chronic coronary disease, as
`was concomitant drug use, with almost all patients using intensive lipid-lowering
`therapy, beta-blockers, and antiplatelet or anticoagulant agents.
`The insights emanating from recent large clinical outcome trials on the role of
`colchicine as anti-inflammatory treatment in patients with coronary disease come
`with new questions for regular clinical practice. Treatment with colchicine is now
`incorporated as a recommendation in the 2021 European Society of Cardiology
`guidelines on cardiovascular disease prevention in clinical practice.
`20
` When
`considering timing of treatment, the aforementioned subgroup analyses and
`clinical considerations contribute. Commencing treatment early after MI appears
`valid, as is starting therapy for patients without cardio-renal failure treated in the
`outpatient clinic. Current data suggest a consistent effect throughout prolonged
`treatment, irrespective of timing of a prior ACS.
`References
`1. Murchie P, Campbell NC, Ritchie LD, Simpson JA, Thain J. Secondary prevention
`clinics for coronary heart disease: four year follow up of a randomised
`controlled trial in primary care. BMJ 2003;326:84.
`2. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular
`Outcomes after Acute Coronary Syndrome. N Engl J Med 2018;379:2097-107.
`3. Ridker PM. How Common Is Residual Inflammatory Risk? Circ Res 2017;120:617-
`9.
`4. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with
`Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31.
`5. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine
`after Myocardial Infarction. N Engl J Med 2019;381:2497-505.
`6. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic
`Coronary Disease. N Engl J Med 2020;383:1838-47.
`7. Fiolet ATL, Opstal TSJ, Mosterd A, et al. Efficacy and safety of low-dose
`colchicine in patients with coronary disease: a systematic review and meta-
`analysis of randomized trials. Eur Heart J 2021;42:2765-75.
`8. Leung YY, Hui LLY, Kraus VB. Colchicine--Update on mechanisms of action and
`therapeutic uses. Semin Arthritis Rheum 2015;45:341-50.
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`6/13/23, 11:05 PM
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`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
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`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`8/9
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`9. Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the
`emerging role of colchicine to inhibit atherosclerosis-associated inflammation.
`Atherosclerosis 2018;269:262-71.
`10. 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.
`11. Robertson S, Payet C, Martinez GJ, et al. Abstract 13715: Colchicine Acutely
`Suppresses the NLRP3 Inflammasome in Acute Coronary Syndrome Patients
`Monocytes. Circulation 2015;132:A13715.
`12. Opstal TSJ, Hoogeveen RM, Fiolet ATL, et al. Colchicine Attenuates
`Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease: A
`LoDoCo2 Proteomic Substudy. Circulation 2020;142:1996-8.
`13. Fiolet ATL, Silvis MJM, Opstal TSJ, et al. Short-term effect of low-dose colchicine
`on inflammatory biomarkers, lipids, blood count and renal function in chronic
`coronary artery disease and elevated high-sensitivity C-reactive protein. PLoS
`One 2020;15:e0237665.
`14. Verma S, Eikelboom JW, Nidorf SM, et al. Colchicine in cardiac disease: a
`systematic review and meta-analysis of randomized controlled trials. BMC
`Cardiovasc Disord 2015;15:96.
`15. Bouabdallaoui N, Tardif JC, Waters DD, 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;41:4092-9.
`16. Opstal TSJ, Fiolet ATL, van Broekhoven A, et al. Colchicine in Patients With
`Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome. J Am
`Coll Cardiol 2021;78:859-66.
`17. Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-Inflammatory Treatment
`With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation
`2015;132:1395-403.
`18. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6
`signalling pathway and incidence rates of atherosclerotic events and all-cause
`mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis
`Outcomes Study (CANTOS). Eur Heart J 2018;39:3499-507
`19. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes
`after statin therapy. N Engl J Med 2005;352:20-8.
`20. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on
`cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-
`337.
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`6/13/23, 11:05 PM
`
`Colchicine in Acute Coronary Syndrome: When to Commence? - American College of Cardiology
`
`© 2023 American College of Cardiology Foundation. All rights reserved.
`
`https://www.acc.org/latest-in-cardiology/articles/2021/09/15/13/23/colchicine-in-acute-coronary-syndrome
`
`9/9
`
`Clinical Topics:
`Acute Coronary Syndromes , Arrhythm ias and C l in ica l EP ,
`Card iovascu lar Care Team , Non invas ive Imag ing , Per icard ia l D isease ,
`Prevent ion , ACS and Card iac B iomarkers , Imp lantab le Dev ices , SCD /Ventr icu lar
`Arrhythm ias , Atr ia l F ibr i l lat ion /Supraventr icu lar Arrhythm ias , Magnet ic
`Resonance Imag ing
`Keywords:
`Co lch icum , T ropon in T , In te r leuk in -6 , In f lammasomes , C -Reac t ive P ro te in ,
`Leuc ine , Co lch ic ine , Seconda ry P reven t ion , Ca rd iovascu la r D iseases , Acu te Co rona ry
`Synd rome , A t r ia l F ib r i l la t ion , Fam i l ia l Med i te r ranean Feve r , Cy tok ines , Pha rmaceu t ica l
`P repa ra t ions , Neu t roph i l In f i l t ra t ion , B io log ica l Ava i lab i l i ty , R isk , Py r in Doma in , Con f idence
`In te rva ls , Tho raco tomy , B ra in Ischem ia , Neu t roph i ls , T ime , S t roke , Myoca rd ia l In fa rc t ion ,
`An t i - In f lamma to ry Agen ts , A the rosc le ros is , Co rona ry D isease , Th rombos is , Magne t ic
`Resonance Imag ing , Ischem ia , Pe r ica rd i t is , Cy toske le ton , M ic ro tubu les , In fa rc t ion , Repe r fus ion
`In ju ry , Reg ress ion Ana lys is , Hosp i ta l iza t ion , Rena l Insu f f ic iency , Ambu la to ry Ca re Fac i l i t ies ,
`Ischem ic S t roke , Ischem ic S t roke , C rea t ine K inase , Hea r t A r res t , Nuc leo t ides , B io log ica l
`P roduc ts
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