European Heart Journal (2021) 42, 2745–2760 STATE OF THE ART REVIEW

doi:10.1093/eurheartj/ehab221 Ischaemic heart disease

Colchicine and the heart

1 2
Massimo Imazio * and Mark Nidorf
1
Cardiology, Cardiothoracic Department, University Hospital “Santa Maria della Misericordia”, ASUFC, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy; and
2
GenesisCare, 3/140 Mounts Bay Rd, Perth, Western Australia, Australia

Received 28 December 2020; revised 11 February 2021; editorial decision 23 March 2021; accepted 28 March 2021; online publish-ahead-of-print 7 May 2021

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Colchicine is a unique, sophisticated anti-inflammatory agent that has been used for decades for the prevention of acute inflammatory
flares in gout and familial Mediterranean fever. In recent years, clinical trials have demonstrated its potential in a range of cardiovascu-
lar (CV) conditions. Colchicine is avidly taken up by leucocytes, and its ability to bind to tubulin and interfere with microtubular func-
tion affects the expression of cytokines and interleukins, and the ability of neutrophils to marginate, ingress, aggregate, express super-
oxide, release neutrophil extracellular traps, and interact with platelets. In patients with acute and recurrent pericarditis, clinical trials
in >1600 patients have consistently shown that colchicine halves the risk of recurrence [relative risk (RR) 0.50, 95% confidence inter-
val (CI) 0.42–0.60]. In patients with acute and chronic coronary syndromes, multicentre randomized controlled trials in >11 000
patients followed for up to 5 years demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic
stroke and ischaemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49–0.81). The use of colchicine at doses of 0.5–1.0 mg daily
in CV trials has proved safe. Early gastrointestinal intolerance limits its use in 10% of patients; however, 90% of patients tolerate it
well over the long term. Despite isolated case reports, clinically relevant drug interactions with moderate to strong CYP3A4 inhibi-
tors/competitors or P-glycoprotein inhibitors/competitors are rare if this dosage of colchicine is used in the absence of advanced renal
or liver disease. The aim of this review is to summarize the contemporary data supporting the efficacy and safety of colchicine in
patients with CV disease.
...................................................................................................................................................................................................
..

* Corresponding author. Email: [email protected]

C The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
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2746 M. Imazio and M. Nidorf

Graphical Abstract

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The central mechanism of the anti-inflammatory action of colchicine is the inhibition of microtubule function leading to the inhibition of granulocyte func-
tion, interference with selectin expression and neutrophil–platelet interactions, and non-specific inhibition of the assembly of the inflammasome in inflam-
matory cells. These actions could exert therapeutic effects in different cardiovascular diseases (e.g. pericarditis, acute and chronic coronary syndromes,
atrial fibrillation, and heart failure).

....................................................................................................................................................................................................
Keywords Colchicine • Pericarditis • Acute coronary syndrome • Chronic coronary syndrome • Coronary artery
disease • Atrial fibrillation • Heart failure • Inflammasome

..
Introduction ..
..
Despite its use over centuries, the exact mechanism of action of
colchicine is still under investigation. In the 1950s and 1960s, the
Colchicine is one of the oldest remedies still in use. It is derived from
..
.. microtubule was identified as the primary cellular target.
the bulb-like corms of the Colchicum autumnale plant, also known as .. Microtubules are key constituents of the cellular cytoskeleton and
..
autumn crocus. Its history as an herbal remedy for joint pain goes .. are essential to several cellular functions, including maintenance of
back to Egyptian times, and it was first mentioned in the medical lit- .. cell shape, intracellular trafficking, cytokine secretion, cell migration,
..
erature in the Ebers Papyrus, an Egyptian medical manuscript written .. and regulation of ion channels and cell division. Colchicine binds to
around 1500 BC (Figure 1).1,2,1w Colchicum extract was first described ... tubulin heterodimers and alters the tubulin conformation, preventing
..
as a treatment for acute gout by Pedanius Dioscorides in De Materia .. any further growth of microtubules at low doses, but promoting their
Medica (first century AD). Use of colchicine continued over centu- .. depolymerisation at high doses.3 Anti-inflammatory effects of colchi-
..
ries and Colchicum corms were used by Avicenna, the famous Persian .. cine are derived from a combination of actions (Figure 2). The effect
physician, and were recommended by Ambroise Paré in the 16th .. of colchicine on tubulin affects the assembly of inflammasome and
..
century. They were also mentioned in the London Pharmacopoeia in .. the expression of interleukin (IL)-1b, and other ILs, including IL-18 by
1618.1 The active ingredient, colchicine, was isolated in the early
.. macrophages; and impairs neutrophil chemotaxis, adhesion, mobiliza-
..
1800 s by the French chemists Pierre-Joseph Pelletier and Joseph .. tion, recruitment, production and release of superoxide, and the ex-
..
Bienaimé Caventou, and remains in use today as a purified natural .. pression of neutrophil extracellular traps (NETs). Moreover,
product.2w The name ‘colchicine’ is derived from the ancient and le- .. colchicine decreases neutrophil L-selectin expression, and modulates
..
gendary kingdom of Colchis from where Jason recovered the Golden .. E-selectin expression on the cell surface of endothelial cells, thereby
Fleece and where C. autumnale plants were widespread.1,2
.. impairing neutrophil recruitment. In addition, colchicine may interfere
Colchicine and the heart 2747

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Figure 1 Colchicine is the active principle derived from Colchicum autumnale plants. The drug has been cited as medical remedy for the first time in
the ancient Ebers papyrus (1500 BC). The name ‘colchicine’ is after the ancient and legendary kingdom of Colchis, where Colchicum autumnale plants
were widespread.

with neutrophil-platelet interactions, which play a role in athero-

.. neutrophils peak within 48 h in healthy subjects, which explains why
..
thrombosis.4–7,3w–5w .. its acute biological effects require 24–48 h to fully develop.
The aim of this article is to critically review the usefulness of colchi-
..
.. Colchicine has an elimination half-life of 27–31 h. Thus, after discon-
cine in the treatment of a range of cardiovascular (CV) conditions, .. tinuation, its biological effects on leucocytes decline within 48 h.8,5w
..
focusing on the most relevant clinical studies. A literature review was .. Between 10% and 30% of the drug is protein-bound. Colchicine is
performed including studies published up to January 2021. .. partially metabolized in the liver by de-acetylation with an elimination
..
Bibliographic databases were searched (MEDLINE/PubMed, BioMed .. half-life of 12–30 min and is excreted by the kidneys (20–40%) and in
Central, the Cochrane Collaboration Database of Randomized Trials,
.. the bile (60–80%). Decreased clearance through either of these two
..
Scopus, ClinicalTrials.gov, EMBASE, Google Scholar) using the search .. pathways may increase the risk of drug accumulation.6w Two major
..
terms ‘colchicine’ AND ‘cardiovascular disease’ OR ‘coronary artery .. interactions of colchicine with specific proteins modulate its pharma-
disease’ OR ‘pericarditis’ OR ‘atrial fibrillation’ OR ‘heart failure’. The .. cokinetics beyond tubulin: cytochrome P450 3A4 (CYP3A4) and P-
..
research was restricted to English language. The authors independent- .. gp. CYP3A4 metabolizes colchicine in the liver (Figure 3). P-gp is an
ly screened titles and abstracts of all studies, while potentially eligible .. ATP-dependent phospho-glycoprotein located in the cell membrane
..
studies were appraised as full text. The most relevant papers are ... and responsible for the excretion of the drug in the intestine, liver,
included in the reference list (Supplementary material online, Figure). .. kidney, and blood–brain barrier.6w
..
..
..
Pharmacology ..
.. Potential drug–drug interactions
..
Colchicine is absorbed by the jejunum and ileum. Bioavailability is .. with colchicine
variable (mean 45%); however, peak serum concentrations are usual-
..
..
ly reached within 0.5–3 h of oral administration and decline over the .. The risk of serious drug–drug interaction (DDIs) in patients taking
..
next 2 h but subsequently rise due to enterohepatic recycling.4 .. colchicine relates to the prescribed dose, the presence of advanced
Colchicine becomes highly concentrated in leucocytes, especially .. renal or liver disease, and the nature of adjunctive medication. Table 1
..
neutrophils, due to their limited expression of P-glycoprotein (P-gp). .. provides a list of commonly used medications metabolized via
After single 1 mg oral dose, intracellular concentrations within
.. CYP3A4 and P-gp grouped by potency,9,7w and lists the maximum
2748 M. Imazio and M. Nidorf

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Figure 2 Colchicine anti-inflammatory actions start with the interference with microtubule assembly and function and its capability to concentrate
in inflammatory cells with limited expression of P-glycoprotein (e.g. granulocytes). Anti-inflammatory effects of colchicine are derived from a combin-
ation of different actions: (i) inhibition of granulocytes, (ii) interference with qualitative and quantitative expression of selectins on endothelial and in-
flammatory cells and platelet aggregation stimulated by inflammation, and (iii) non-specific inhibition of the inflammasome by interference with the
assembly of its components when inflammation is stimulated.

..
doses of colchicine that have been reported as being safe in patients .. low incidence of myotoxicity (<1%) that was no different compared
with and without advanced renal or liver disease.10
.. to those taking placebo.15,16
..
Concomitant use of colchicine must be carefully considered in all .. The experience with DDIs associated with the use of colchicine in
patients prescribed with several specific drugs, including clarithromy-
.. patients with CV disease therefore mirrors the experience of its use
..
cin and anti-fungal agents, even in the absence of severe renal or liver .. in familial Mediterranean fever (FMF) and gout, and confirms that ser-
..
dysfunction.11 In patients without advanced renal or liver disease, .. ious DDIs are rare when therapy is administered at low doses, is not
long-term colchicine has been safely used at doses up to 1.0 mg daily .. prescribed concomitantly with a few selective drugs, and is used cau-
..
in combination with other medication without dose adjustments.8w .. tiously in patients with advanced liver (e.g. Child-Pugh score C) or
Colchicine has been used at doses up to 1.0 mg daily in the presence
.. renal disease (estimated glomerular filtration rate <30 mL/min).
..
of mild renal and liver disease; however, because the risk of DDIs is ..
..
enhanced with drugs that have effects on CYP3A4 and P-gp, it is pru- ..
dent to limit the dose to 0.5 mg daily. If colchicine is required in ..
..
Safety and long-term tolerance
patients with severe renal or liver disease, doses of 0.5 mg should be .. While a deliberate overdose of colchicine may be fatal in up to 10%
administered no more than on alternate days .12,9w ..
.. of cases,15w judicious use of colchicine at doses of 0.5–1.0 mg daily
..
.. has proven safe, as evidenced by a decade of observations in a wide
.. range of patients with FMF, gout, pericarditis, and more recently, cor-
Concomitant use with statins ..
.. onary disease.17–21 In a recent systematic review focused on adverse
Despite isolated case reports of myotoxicity after concomitant use
.. events in patients treated with colchicine in trials for CV indications,
..
of colchicine and statin therapy,13,14,10w–14w a recent review of DDIs .. the occurrence of any adverse event was reported in 15.3% of
..
associated with statin use by the American Heart Association (AHA) .. patients treated with colchicine vs. 13.9% of patients treated with pla-
did not raise concern about the co-administration of colchicine in .. cebo [relative risk (RR) 1.26, 95% confidence interval (CI) 0.96–1.64,
..
patients without advanced renal disease.15 This advice is consistent .. P = 0.09].16
with evidence from large placebo-controlled CV trials that included .. Nonetheless, lower gastrointestinal side effects are common and
..
patients on moderate and high-dose statin therapy, which showed a . result in early treatment discontinuation, limiting colchicine use in
Colchicine and the heart 2749

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Figure 3 Colchicine uptake occurs in the ileum and jejunum. The drug is metabolized by the liver through cytochrome P450 3A4 (CYP3A4) and
excreted into the bile and urine through P-glycoprotein. Colchicine can also cross the placenta and enters breast milk by P-glycoprotein.

Table 1 Safe use of colchicine with commonly used drugs that affect clearance of colchicine10

CYP3A4 inhibitors P-glycoprotein inhibitors Safe colchicine use

....................................................................................................................................................................................................................
Strong
Clarithromycin Clarithromycin Concomitant use of colchicine is generally avoided at any dose as an overlap of ther-
Telithromycin Itraconazole apy for short periods may be rarely toxic even in patients with normal renal
Ketoconazole Ketoconazole function.10,8w
Voriconazole Voriconazole
Fluconazole Fluconazole
Moderate
Cyclosporine HIV medications (ritonavir) Doses up to 0.5 mg daily are likely safe in patients with normal renal and liver function.
Ritonavir In patients with renal or liver failure avoid if possible or reduce colchicine dose to alter-
nate day.11,12,22,9w
Mild
Erythromycin Diltiazem Doses up to 1.0 mg daily.
Ciprofloxacin Verapamil No dose adjustment required in patients with normal renal or liver function.11–13,9w
Cobicistat Amiodarone
Imatinib Carvedilol
Atorvastatin Quinidine
Grapefruit Ranolazine
Erythromycin
Simvastatin
2750 M. Imazio and M. Nidorf

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Figure 4 Anti-inflammatory actions of colchicine have been studied for different cardiovascular indications: pericarditis (well-established and
recommended by guidelines), acute and chronic coronary syndromes (emerging indication), prevention of post-operative atrial fibrillation and atrial
fibrillation after ablation, and heart failure (still ongoing and to be well-defined).

..
10% of patients. These effects are dose-related, usually occur within .. loss in FMF. Despite entering breast milk, colchicine is considered
days of starting therapy, may settle spontaneously during ongoing .. safe during breast feeding.17,18
..
treatment, but invariably settle once colchicine is discontinued. .. Hence, when used at doses up to 1.0 mg daily in patients without
In contrast to early intolerance, over prolonged follow-up in the .. advanced renal or liver disease, colchicine is safe. In the 90% of
..
LoDoCo2 trial, late intolerance to colchicine was uncommon (3.4%) .. patients who do not develop early treatment intolerance, long-term
and equal to placebo.21 The incidence of self-reported myalgia was
.. use at this dosage proved to be safe and well tolerated.
..
higher in patients on colchicine (21% vs. 18.5%; RR 1.16, 95% CI 1.02– ..
1.32, P = 0.03), but this was not a common cause for treatment discon-
..
..
tinuation. As indicated above, the incidence of myotoxicity associated .. Cardiovascular indications for
..
with raised creatinine kinase was rare (<1%) and did not differ be- ..
..
colchicine
tween those assigned to colchicine or placebo. Other adverse effects
..
of colchicine use, including hepatotoxicity, neutropenia or agranulo- .. For over a century, treatment and prevention of acute gout was the
cytosis, rashes, infection, or death, have not featured in CV trials of col- .. most common clinically approved indication for short and long-term
..
chicine; however, all trials to date were not sufficiently powered to .. use of colchicine. Over 50 years ago, the safety and effectiveness of
detect differences in the incidence of these rare events.16 .. continuous life-long colchicine for the prevention of acute inflamma-
In a recent review of drug-induced agranulocytosis,22 over 120 drugs
... tory flares in patients with FMF led to its regulatory approval for this
..
including colchicine were listed as potentially causal. However, in the cur- .. purpose. Long-term colchicine has also been used off-label for the
rent literature only one case report is described in a patient taking low-
.. management of Behçet syndrome and pseudogout.17 Almost
..
dose therapy with no history of renal or liver disease .16w .. 35 years ago, colchicine was introduced in the field of cardiology for
.. the treatment and prevention of recurrent pericarditis,17w and in the
Prolonged use of colchicine has been associated with a transient ..
rise in liver enzymes in 2% of patients, but as with statin therapy .. last 15 years, its utility and safety have been assessed for secondary
..
this did not result in treatment discontinuation or severe liver dys- .. prevention of coronary atherosclerosis,19 for the prevention of atrial
function. Other reported possible side-effects, including alopecia and .. fibrillation (AF) in specific settings (post-operative and after ablation),
..
neuropathy, have rarely been reported (<1% of users), and appear to .. and for the prevention of heart failure (Figure 4).20 From a clinical per-
resolve rapidly after colchicine withdrawal.14,16 Although colchicine .. spective, the utility of low-dose colchicine in patients with CV disease
..
crosses the placenta, continuous use at doses of 0.5–1.0 mg daily dur- .. is enhanced by its lack of effect on bleeding risk, blood pressure, QT
ing pregnancy does not increase the risk of birth defects or pregnancy
.. interval, arrhythmias, and by the low risk of DDIs, when used
Colchicine and the heart 2751

..
concomitantly with commonly prescribed CV medications in patients .. inflammatory persistent effusion 7–30 days after cardiac surgery in the
without advanced renal or liver disease. .. absence of pericarditis.
..
.. A summary of the main studies in the setting of pericarditis is
.. reported in Table 2. Overall, in patients with pericarditis, colchicine
Colchicine for the treatment of ..
.. added on top of standard anti-inflammatory therapies halved the risk
..
acute and recurrent pericarditis .. of recurrence and, in patients undergoing cardiac surgery, it halved
.. the incidence of post-pericardiotomy syndrome (RR 0.50, 95% CI
The use of colchicine for the treatment of pericarditis was first pro- .. 0.42–0.60) (Figure 5).
..
posed in 1987 by Bayes de Luna et al.17w The rationale for its use in ..
this setting stems from the observation that colchicine was safe and ..
..
highly effective in preventing acute flares of polyserositis in patients .. Colchicine for secondary
with FMF. Following a series of case reports and almost 20 years after ..
.. prevention of chronic coronary

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Bayes de Luna’s letter, the first randomized, open-label trials of colchi- ..
cine for the treatment of acute (COPE trial)23 and recurrent pericardi-
.. disease
..
tis (CORE trial)24 were published (Table 2). In both trials, colchicine ..
was used on top of standard anti-inflammatory therapy. Participants
.. Investigations on the use of colchicine for secondary prevention in
.. patients with coronary disease stemmed from the well-known role
were randomized to colchicine at a loading dose of 1–2 mg, followed ..
by a maintenance dose of 0.5–1.0 mg daily (adjusted according to body
.. that inflammation plays in the chronic and acute phases of disease,
.. and the observation that long-term use of colchicine was safe and ef-
weight) for 3–6 months. These trials demonstrated the effectiveness ..
of colchicine and, aside from diarrhoea occurring in 8–10% of patients,
.. fective for secondary prevention of acute inflammatory flares in
.. patients with gout and FMF.34,35
colchicine therapy was safe and well tolerated. ..
.. The normal vascular endothelium is protective having antiplatelet,
The efficacy of colchicine therapy was then confirmed in subse- .. anticoagulant, vasodilator, and profibrinolytic actions.18w,19w The
quent double-blind randomized controlled trials in patients with ..
.. resting endothelium is also anti-inflammatory, as it acts to prevent
acute and recurrent pericarditis, including the CORP,25 ICAP,26 and ..
CORP-2 trials.27 In these trials, no loading dose was administered but .. leucocyte adhesion. Coronary risk factors including systemic arterial
.. hypertension, hyperlipidaemia, and diabetes mellitus may promote
daily dose was weight-adjusted (0.5 mg once daily for patients <70 kg ..
or 0.5 mg twice daily). Therapy was continued for 3 months in .. endothelial dysfunction and trigger activation of endothelial cells, acti-
.. vating a proinflammatory process that leads to the early steps and
patients with acute pericarditis, and for 6 months in patients with re- ..
current pericarditis. .. progression of atherosclerosis.20w,21w
.. Accumulation of free cholesterol within the vessel wall predis-
In contrast, one recent small open-label study reported neutral ..
effects of colchicine in patients with acute idiopathic pericarditis who .. poses to ongoing spontaneous self-assembly of free cholesterol into
.. its crystalline forms, which can induce inflammatory injury by activat-
had not received corticosteroids.28 However, in this study, the use of ..
colchicine was delayed, and the diagnostic criteria for pericarditis dif- .. ing the innate immune response. Appreciating the role that choles-
.. terol crystals play in the transformation of atheroma into the
fered from previous trials and those outlined in the European Society ..
of Cardiology guidelines.29 Nonetheless, as shown in Figure 5, when
.. atherosclerotic plaque, and how this may result in acute plaque dis-
.. ruption, added plausibility to the potential value of colchicine.36,37
taken together, these trials convincingly demonstrated that colchicine ..
halves the risk of recurrent pericarditis over 18 months.
.. This insight was further enhanced by the CANTOS trial, which con-
..
.. firmed that IL-1b plays a central role in the atherosclerotic process.38
.. Unlike canakinumab used in CANTOS to specifically inhibit IL-1b,
..
Colchicine for the prevention of .. colchicine has much broader anti-inflammatory effects beyond inhib-
.. ition of IL-1b. As indicated above, colchicine may accumulate within
postpericardiotomy syndrome ..
.. macrophages, inhibiting assembly of inflammasome and the expres-
..
In 2002, Finkelstein et al.30 evaluated the effect of colchicine in patients .. sion of IL-1b. It may also dampen the production of several other
undergoing cardiac surgery. Participants were randomized to either .. proinflammatory cytokines, including IL-18. As colchicine accumu-
.. lates in the endothelium, it reduces the expression of selectins that
colchicine 1.5 mg daily or placebo for 1 month. The incidence of post- ..
pericardiotomy syndrome was halved in patients taking colchicine .. promote ingress of circulating leucocytes, and accumulation of col-
.. chicine in neutrophils affects their ability to marginate, aggregate and
(11% vs. 22%), with a trend towards statistical significance. A few years ..
later, two large randomized controlled trials assessed the effect of col- .. express cytokines, express NETs and interact with platelets, leading
..
chicine 0.5–1.0 mg daily for 1 month in patients undergoing cardiac sur- .. to a reduction of platelet aggregation.22w–24w
gery.31,32 In the COPPS trial, colchicine reduced the incidence of post- .. In 2007, Nidorf et al. demonstrated that in patients with stable cor-
..
pericardiotomy syndrome at 12 months compared with placebo (9% .. onary disease and elevated high-sensitivity C-reactive protein (hs-
vs. 21%, P < 0.01)31; and in the COPPS-2 trial, colchicine also reduced .. CRP) despite statin and antiplatelet therapy, colchicine 0.5 mg twice
..
the incidence of post-pericardiotomy syndrome (19% vs. 29%, .. daily consistently decreased hs-CRP after 30 days of treatment, sug-
P < 0.01), but did not reduce the occurrence of pericardial or pleural .. gesting that colchicine had anti-inflammatory effects over statin and
..
effusion.32 More recently, in a randomized trial by Meurin et al.,33 col- .. antiplatelet therapy.39
chicine did not reduce effusion volume nor prevent late cardiac tam-
.. In 2013, Nidorf et al. conducted the first clinical trial of colchicine
..
ponade in a cohort of 197 patients with moderate to large-sized non- . in patients with coronary disease. The low-dose colchicine
2752 M. Imazio and M. Nidorf

Table 2 Studies on colchicine for the treatment of pericardial diseases

Study Study design Dosing Clinical setting Patients Main results

....................................................................................................................................................................................................................
COPE trial23 (2005) Randomized trial Colchicine, 1 mg on first Acute pericarditis 120 Reduction of recurrent
(open-label) day, followed by pericarditis (11% vs.
0.5 mg daily (if 32%, P < 0.01, NNT
<70 kg) or 1 mg 5) and symptoms
twice daily followed persistence at 72 h
by 0.5 mg twice daily (12% vs. 37%,
(if >_70 kg), for P < 0.01)
3 months

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CORE trial24 (2005) Randomized trial Colchicine, 1 mg on first First recurrence of 84 Reduction of recurrent
(open-label) day, followed by pericarditis pericarditis (24% vs.
0.5 mg daily (if 51%, P = 0.02, NNT
<70 kg) or 1 mg 4) and symptoms
twice daily followed persistence at 72 h
by 0.5 mg twice daily (10% vs. 31%,
(if >_70 kg), for P = 0.03)
6 months
CORP trial25 (2011) Double-blind RCT Colchicine, 1 mg on first First recurrence of 120 Reduction of recurrent
day followed by pericarditis pericarditis (24% vs.
0.5 mg daily (if 55%, P < 0.01) and
<70 kg) or 1 mg symptoms persist-
twice daily followed ence at 72 h (23%
by 0.5 mg twice daily vs. 53%, P < 0.01)
(if >_70 kg), for
6 months
ICAP trial26 (2013) Double-blind RCT Colchicine, 0.5 mg daily Acute pericarditis 240 Reduction of recurrent
(if <70 kg) or 0.5 mg or incessant pericar-
twice daily (if ditis (17% vs. 37%,
>_70 kg), for 3 months P < 0.01, NNT 4)
and symptoms per-
sistence at 72 h
(19% vs. 40%,
P < 0.01)
CORP-2 trial27 (2014) Double-blind RCT Colchicine, 0.5 mg daily Recurrent pericarditis 240 Reduction of recurrent
(if <70 kg) or 0.5 mg (second or subse- pericarditis (22% vs.
twice daily (if quent recurrence) 42%, P < 0.01, NNT
>_70 kg), for 6 months 5)
Sambola et al.28 (2019) Randomized trial (open Colchicine, 0.5 mg twice Acute pericarditis 110 Failure to reduce re-
label) daily (if <70 kg) or current pericarditis
1 mg twice daily (if (13% vs. 8%, P =
>_70 kg), for 3 months NS)
Finkelstein et al.30 (2002) Randomized trial Colchicine, 1.5 mg daily Post-pericardiotomy 163 Failure to reduce post-
(open-label) from the third post- syndrome following pericardiotomy syn-
operative day, for cardiac surgery drome (11% vs.
1 month 22%, P = 0.135)
COPPS trial31 (2010) Double-blind RCT Colchicine, 1 mg on the Post-pericardiotomy 360 Reduction of post-
third postoperative syndrome following pericardiotomy syn-
day followed by cardiac surgery drome (9% vs. 21%,
0.5 mg daily (if P < 0.01)
<70 kg) or 1 mg
twice daily followed
by 0.5 mg twice daily
Continued
Colchicine and the heart 2753

Table 2 Continued

Study Study design Dosing Clinical setting Patients Main results

....................................................................................................................................................................................................................
(if >_70 kg), for
1 month
COPPS-232 (2014) Double-blind RCT Colchicine from 48 to Post-pericardiotomy 360 Reduction of post-
72 h before surgery, syndrome following pericardiotomy syn-
0.5 mg daily (if cardiac surgery drome (19% vs.
<70 kg) or 0.5 mg 29%, P < 0.01) al-
twice daily (if though it did not re-
>_70 kg), for 1 month duce occurrence of

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postoperative AF
(34% vs. 42%, P =
NS) or pericardial/
pleural effusion
(57% vs. 59%, P =
NS)
Meurin et al.33 (2015) Double-blind RCT Colchicine, 1 mg daily Pericardial effusion fol- 197 Failure to reduce effu-
for 2 weeks lowing cardiac sion volume on a 0–
surgery 4 scale (-1.1 ± 1.3 vs.
-1.3 ± 1.3 grades) or
late cardiac tampon-
ade (7% vs. 6%, P =
NS)

AF, atrial fibrillation; NNT, number needed to treat; RCT, randomized controlled trial.

..
(LoDoCo) pilot study was a randomized open-label trial conducted .. Colchicine for the prevention of
with a PROBE design in 532 patients with stable coronary artery dis-
..
.. restenosis following coronary
ease, who were enrolled regardless of baseline hs-CRP.40 Patients ..
..
receiving long-term colchicine 0.5 mg daily had a significant reduction .. angioplasty and surgical
of composite CV events [acute coronary syndrome (ACS), out-of- ..
hospital cardiac arrest, non-cardioembolic ischaemic stroke] [5.3%
..
..
revascularization
vs. 16%; hazard ratio (HR) 0.33, 95% CI 0.18–0.59]. The benefit was .. Studies evaluating the use of colchicine for the prevention of coron-
..
mainly driven by a decreased occurrence of unstable angina. .. ary artery restenosis after percutaneous coronary intervention (PCI)
Subsequently, two observational studies in patients treated for ..
.. have provided mixed results (Table 3). Two studies in the pre-stent
gout demonstrated that those prescribed with colchicine had a signifi- .. era showed a neutral effect of colchicine in the prevention of resten-
cantly reduced risk of CV events, including myocardial infarction, ..
.. osis following plain old balloon angioplasty.25w,26w However, in a later
transient ischaemic attack and stroke (odds ratio 0.51, 95% CI 0.30– .. study on diabetic patients undergoing PCI with bare-metal stent, col-
0.88), and all-cause mortality (HR 0.27, 95% CI 0.17–0.43).41,42 ..
.. chicine was associated with a lower rate of in-stent restenosis (16%
In 2020, the LoDoCo2 trial was published.21 In this double-blind ..
.. vs. 33%, P < 0.01)43 and a similar trend was reported in a sub-analysis
placebo-controlled trial, a total of 5522 patients from Australia and .. of the COLCOT trial.27w
the Netherlands were randomized to either colchicine 0.5 mg daily ..
or placebo. The primary endpoint was a composite of CV death,
.. In a trial on patients undergoing on-pump coronary artery bypass
.. grafting, colchicine reduced perioperative myocardial damage
spontaneous myocardial infarction, ischaemic stroke, or ischaemia- ..
.. assessed with peak troponin T and creatine kinase-myocardial brain
driven coronary revascularization. Over 90% of patients enrolled .. fraction (CK-MB) concentrations within 48 h.28w
proved tolerant to colchicine and were randomized into the trial. At ..
..
a median follow-up of 29 months, colchicine significantly reduced the ..
primary endpoint compared with the placebo group (HR 0.69, 95% ..
.. Colchicine for secondary
CI 0.57–0.83; P < 0.001) without significant side effects. As in the ..
LoDoCo pilot study, the benefits of colchicine were seen soon after ..
..
prevention following acute
therapy was initiated and continued to accrue over the course of the .. coronary syndromes
trial. The treatment effect extended beyond the primary composite ..
..
to include major adverse CV events and the individual outcomes of .. Early trials of colchicine in the setting of an ACS designed to assess
myocardial infarction and unplanned coronary revascularization.21
.. the effect of colchicine on biomarkers of inflammation and
2754 M. Imazio and M. Nidorf

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Figure 5 Risk of pericarditis in patients treated with or without colchicine in different settings (acute, recurrent pericarditis, and prevention of the
post-pericardiotomy syndrome). CI, confidence interval; M-H, Mantel-Haenszel.

Table 3 Studies on colchicine for the prevention of chronic coronary syndromes

Study Study design Dosing Clinical setting Patients Main results

....................................................................................................................................................................................................................
Nidorf et al.39 (2007) Prospective study Colchicine 0.5 mg twice Stable coronary artery 64 Reduction of hs-CRP (from
daily for 1 month plus disease patients with 4.58 ± 2.05 mg/L to 1.78 ±
aspirin and high-dose elevated hs-CRP 1.38 mg/L, P < 0.01)
atorvastatin
LoDoCo trial40 (2013) Randomized trial (ob- Colchicine 0.5 mg daily Stable coronary artery 532 Reduction of cardiovascular
server blinded) for a median of disease events (ACS, out-of-hos-
36 months plus sta- pital cardiac arrest, non-
tins and standard sec- cardioembolic ischaemic
ondary prevention stroke): 5.3% vs. 16% (HR
drugs 0.33, 95% CI 0.18–0.59)
LoDoCo2 trial21 Double-blind RCT Colchicine 0.5 mg daily Stable coronary artery 5522 Reduction of CV death, myo-
(2020) vs. placebo disease cardial infarction, ischae-
mic stroke, or ischaemia-
driven coronary revascula-
rization: 6.8% vs. 9.6% (HR
0.69, 95% CI 0.57–0.83)
O’Keefe et al.25w Double-blind RCT Colchicine 0.6 mg twice Patients undergoing 197 Failure to reduce restenosis
(1992) daily for 6 months POBA (46% vs. 47%, P = NS)
Freed et al.26w (1995) Open-label pilot trial Colchicine 0.6 mg twice Patients undergoing 50 Failure to inhibit restenosis
daily for 6 months POBA (restenosis rate of 53%)
Deftereos et al.43 Double-blind RCT Colchicine 0.5 mg twice Diabetic patients under- 196 Reduction of in-stent resten-
(2013) daily for 6 months going PCI with bare- osis (16% vs. 33%,
metal stent P < 0.01)
Giannopoulos et al.28w Double-blind RCT Colchicine, 0.5 mg twice On-pump coronary ar- 59 Reduction of peak high-sensi-
(2015) daily (half dose if tery bypass grafting tivity troponin T concen-
<60 kg), for 10 days tration within 48 h
(616 pg/mL vs. 1613 pg/
mL, P < 0.01) and CK-MB
concentration (44.6 ng/mL
vs. 93 ng/mL, P < 0.01)

ACS, acute coronary syndrome; CI, confidence interval; CK-MB, creatine kinase-myocardial brain fraction; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; PCI,
percutaneous coronary intervention; POBA, plain old balloon angioplasty; RCT, randomized controlled trial.
Colchicine and the heart 2755

..
myocardial injury have provided mixed results. In a pilot randomized .. in the colchicine group (5 vs. 0; P = 0.024, log-rank). As in the
trial including patients with ACS or stroke, colchicine failed to reduce .. COLCOT trial, the incidence of other adverse effects including
..
30-day hs-CRP (median 1.0 mg/L vs. 1.5 mg/L, P = 0.22).29w In the ob- .. gastrointestinal effects did not differ between groups (colchicine
servational study by Akodad et al. on patients presenting with ST-ele- .. 23.0% vs. placebo 24.3%).
..
vation myocardial infarction (STEMI), colchicine also had a neutral ..
effect on hs-CRP peak values during the index hospitalization.30w On ..
..
the contrary, in the randomized trial by Deftereos et al. in patients .. Critique of the trials of colchicine
with STEMI, short-term colchicine reduced CK-MB (3144 vs. ..
.. in cardiovascular disease
6184 ng/mL, P < 0.01) and infarct size on magnetic resonance imaging ..
(18.3 vs. 23.2 mL/1.73 m2, P = 0.02).31w .. To date, four independent randomized controlled trials—LoDoCo,40
..
A remodelling effect of colchicine on atherosclerotic plaques was .. LoDoCo2,21 COLCOT,44 and COPS47—evaluating the effect of col-
shown in a study by Vaidya et al. in patients with a recent ACS. .. chicine in a broad spectrum of >11 000 patients with acute and chron-
..

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Patients receiving colchicine had a reduction of both hs-CRP and low .. ic coronary disease followed for up to 5 years, demonstrated that
attenuation plaque volume on coronary computed tomography
..
.. colchicine may reduce the risk of CV death, myocardial infarction, is-
angiography.32w .. chaemic stroke and ischaemia-driven revascularization by >30% (RR
The only trial sufficiently powered to assess the clinical effects of
..
.. 0.63, 95% CI 0.49–0.81) (Figure 6). Although each has employed a sim-
colchicine following an ACS was the COLCOT trial.44 In this trial, .. ple pragmatic design, each has limitations and all have raised important
patients with a recent (<1 month) myocardial infarction were
..
.. questions.
randomized to colchicine 0.5 mg daily or placebo and followed up for .. Specifically, none used clinical or biological markers of risk or in-
4 years. Patients assigned to colchicine had a lower incidence of the
..
.. flammation for the selection of participants. Each recruited predom-
composite of CV death, cardiac arrest, myocardial infarction, stroke, .. inantly men. None reported cholesterol levels or blood pressure at
..
or urgent hospitalizations for angina (5.5% vs. 7.1%; HR 0.77, 95% CI .. enrolment. The COLCOT trial did not report the rate of dropout
0.61–0.96). The outcome was mainly driven by a reduction in the inci- ..
.. due to early intolerance to colchicine, only the composite outcome
dence of stroke and urgent revascularization for angina. A sub-study .. was found to be significantly reduced, and there was a higher inci-
of COLCOT suggested that the treatment effect was more marked ..
.. dence of (non-fatal) respiratory infections. The COPS trial had a trun-
when colchicine was initiated within 3 days of the onset of myocardial .. cated follow-up, the primary outcome included all-cause mortality
infarction (HR 0.52, 95% CI 0.32–0.84); however, the major benefits ..
.. rather than CV mortality and, as noted, a higher incidence of non-CV
were accrued well after hospital discharge.45 In contrast to the ..
.. death was recorded in patients receiving colchicine. By design,
LoDoCo2 trial, colchicine use was associated with a low but .. LoDoCo2 excluded 10% of enrolled patients who proved intoler-
increased incidence of hospitalization for (non-fatal) pneumonia .. ant to colchicine, which may in part explain why the effect size
(0.9% vs. 0.4%, P = 0.03).21,44 ..
.. appeared greater than the other trials, and why it was able to demon-
Two additional studies of colchicine in ACS were published in ..
2020: the COLCHICINE-PCI trial46 and the COPS trial.47 .. strate an effect on individual outcomes including myocardial infarc-
.. tion and unplanned revascularization. Nonetheless, a regional
COLCHICINE-PCI investigated the effects of acute preprocedural ..
oral administration of 1.8 mg of colchicine on PCI-related myocardial
.. difference in the effect of colchicine was observed and, as in the
.. COPS trial, a low but disproportionate number of participants
injury.46 Among 400 subjects undergoing PCI, preprocedural admin- ..
istration of colchicine attenuated the increase in IL-6 and hs-CRP
.. randomized to colchicine were found to have died from non-CV
.. causes (incidence, 0.7 vs. 0.5 events per 100 person-years; HR 1.51;
after PCI when compared with placebo but had no effect on enzym- ..
atic measures of infarct size. The lack of treatment effect on myocar-
.. 95% CI 0.99–2.31).47
.. Despite the lack of data on cholesterol levels and blood pressure
dial injury was in contrast to that on infarct size in patients ..
undergoing elective surgical revascularization. This difference in out-
.. at randomization, most patients in these trials were receiving moder-
..
come likely reflects the clinical setting of each trial, as in .. ate or high-dose statin therapy, and an equal proportion in each
.. treatment group was taking lipid-lowering and anti-hypertensive
COLCHICINE-PCI colchicine therapy was started late in the course ..
of an evolving infarction, and did not control for the complexity of .. therapy. Although overall data do not appear sufficient to establish if
.. some patients may benefit more than others, subgroup analyses
coronary stenting, which may have resulted in a greater risk of myo- ..
cardial injury due to atheroembolism. .. showed consistent effects of colchicine in a broad range of patients.
.. The concern related to the imbalance in the number of non-CV
In the COPS trial, 795 patients with an ACS were randomized to ..
either colchicine (0.5 mg twice daily for the first month, then 0.5 mg .. deaths in LoDoCo2 and COPS has largely been addressed by meta-
.. analyses that have demonstrated that colchicine does not increase
daily for 11 months) or placebo.47 The primary outcome was a com- ..
posite of all-cause mortality, ACS, ischaemia-driven (unplanned) ur- .. the risk of all-cause mortality or non-CV death,33w–35w and the lack
..
gent revascularization, and non-cardioembolic ischaemic stroke. .. of association between colchicine and death from sepsis or cancer,
Although underpowered to assess the effect on clinical outcome, .. or between the duration of therapy and non-CV death (in the COPS
..
over the 12-month follow-up, there were 24 events in the colchicine .. trial 3/5 patients died late of a non-CV cause after <30 day exposure
group compared with 38 events in the placebo group (P = 0.09, log- .. to colchicine) makes it unlikely that a biological explanation will be
..
rank). However, in contrast to the LoDoCo and COLCOT trials, .. found for these observations. Despite the regional variance in treat-
there was a trend towards a higher rate of all-cause mortality (8 vs. 1;
.. ment effect noted in LoDoCo2, the effect of colchicine was direc-
..
P = 0.017, log-rank), mostly due to a higher number of non-CV deaths . tionally consistent between regions, and the consistent results of
2756 M. Imazio and M. Nidorf

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Figure 6 Forest plot of the primary clinical efficacy endpoint derived from main randomized controlled trials in acute and chronic coronary syn-
dromes (A for the primary composite endpoint and B for the single components of the primary composite endpoint). CI, confidence interval; M-H,
Mantel-Haenszel.
Colchicine and the heart 2757

Table 4 Studies on colchicine for the prevention of acute coronary syndromes

Study Study Dosing Clinical Patients Main results

design setting
....................................................................................................................................................................................................................
Raju et al.29w Double-blind Colchicine 1.0 mg ACS or stroke 82 Failure to reduce hs-CRP at 30 days (median 1.0 mg/l vs.
(2012) RCT daily for 1.5 mg/l, P = 0.22)
1 month
Deftereos et Double-blind Loading dose of STEMI 151 Reduction of CK-MB plasma concentration (3144 ng/mL vs.
al.31w (2015) RCT 2 mg followed 6184 ng/mL, P < 0.01) and infarct size by magnetic reson-
by 0.5 mg ance imaging (18.3 mL/1.73 m2 vs. 23.2 mL/1.73 m2,
twice daily for P = 0.02)

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5 days
Akodad et al.30w Prospective Colchicine 1 mg STEMI 44 Failure to reduce CRP peak value during the index hospital-
(2017) study once daily plus ization (29.03 mg/L vs. 21.86 mg/L, P = 0.36), even after ad-
OMT for justment for the culprit artery (27 mg/L vs. 25 mg/L,
1 month P = 0.79)
Vaidya et al.32w Prospective Colchicine 0.5 mg Recent ACS 80 Reduction of LAPV (15.9 mm3 vs. 6.6 mm3, P = 0.008) and
(2018) study daily plus OMT (<1 month) hs-CRP (1.10 mg/L vs. 0.38 mg/L, P < 0.01)
for 12 months
COLCOT trial44 Double- blind Colchicine 0.5 mg Recent myocar- 4745 Reduction of CV events (composite of CV death, cardiac ar-
(2019) RCT daily for a me- dial infarction rest, myocardial infarction, stroke, or urgent hospitaliza-
dian of (<1 month) tions for angina): 5.5% vs. 7.1% (HR 0.77, 95% CI 0.61–
20 months 0.96)
COLCHICINE- Double-blind Preprocedural 50% patients with 400 The primary outcome of PCI-related myocardial injury did
PCI46 (2020) RCT oral adminis- an ACS not differ between colchicine (n = 206) and placebo
tration of (n = 194) groups (57.3% vs. 64.2%, P = 0.19)
1.8 mg of
colchicine
COPS trial47 Double-blind Colchicine 0.5 mg ACS 795 The primary outcome of all-cause mortality, ACS, ischaemia-
(2020) RCT twice daily for driven (unplanned) urgent revascularization, and non-car-
the first dioembolic ischaemic stroke did not differ between colchi-
month, then cine (n = 396) and placebo (n = 399): 24 vs. 38 events
0.5 mg daily (P = 0.09)
The composite of CV death, ACS, stroke and unplanned
revascularization 0.54 (0.29–0.99)

ACS, acute coronary syndrome; CK-MB, creatine kinase-myocardial brain fraction; CV, cardiovascular; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; LAPV, low
attenuation plaque volume; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; STEMI, ST-elevation myocardial
infarction.

..
COLCOT and COPS clearly indicate that the effects of colchicine .. towards a reduction in CV death. Finally, these trials also indicate
are not region-dependent. .. that, when used judiciously, colchicine 0.5 mg daily does not in-
..
Impressively the results of these trials have been broadly con- .. crease the risk of sepsis, cancer, neutropenia, myotoxicity, or
sistent. The LoDoCo and COLCOT trials confirmed that colchi-
.. bleeding.
..
cine reduced the risk of the composite outcome of myocardial .. Thus, collectively the current trials of colchicine in patients with
infarction, ischaemic stroke, unplanned revascularization and CV
.. CV disease suggest that colchicine slows the progression of athero-
..
death, and when the primary outcome of the COPS trial is .. sclerosis by limiting plaque growth, reducing the risk of plaque in-
..
aligned with LoDoCo, LoDoCo2, and COLCOT (by excluding .. stability and the risk of in-stent restenosis,43,27w,33w–35w and indicate
non-CV death) the effect on the composite CV outcome was .. that when used judiciously, it is safe. As such, they lay the foundation
..
also significant (Table 4). Furthermore, combined data from these .. to support repurposing colchicine for secondary prevention in
trials confirm that colchicine reduces the risk of the individual out- .. patients with CV disease on top of statin and antiplatelet therapy.
..
comes of myocardial infarction, ischaemic stroke, and unplanned .. In the next 3–5 years, the CLEAR SYNERGY study, the
revascularization, and demonstrate a (non-significant) trend
.. CONVINCE trial (NCT02898610), and the COLCARDIO trial
2758 M. Imazio and M. Nidorf

Table 5 Studies on colchicine for the prevention of atrial fibrillation

Study Study design Dosing Clinical setting Patients Main results

....................................................................................................................................................................................................................
COPPS-POAF48 Double-blind RCT Colchicine, 1 mg on Atrial fibrillation follow- 336 Reduction of postop-
(2011) third postoperative ing cardiac surgery erative atrial fibrilla-
day followed by tion (12% vs. 22%,
0.5 mg daily (if P = 0.021)
<70 kg) or 1 mg
twice daily followed
by 0.5 mg twice daily
(if >_70 kg), for

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1 month
Deftereos et al.38w Double-blind RCT Colchicine 0.5 mg twice Atrial fibrillation recur- 161 Reduction of postop-
(2012) daily for 3 months rence following pul- erative atrial fibrilla-
monary vein isolation tion (16% vs. 34%,
P < 0.01), CRP at
day 4 (-1.18 mg/L vs.
-0.46 mg/L, P < 0.01)
and IL-6 at day 4
(-0.50 pg/mL vs.
-0.10 pg/mL,
P < 0.01)
Deftereos et al.50 Double-blind RCT Colchicine 0.5 mg twice Atrial fibrillation recur- 223 Reduction of postop-
(2014) daily for 3 months rence following pul- erative atrial fibrilla-
monary vein isolation tion (31% vs. 49%,
P = 0.01), improve-
ment of the physical
domain of quality of
life scores at
12 months
(63.6 ± 13.8 vs.
52.5 ± 18.1, P < 0.01)
END-AF trial36w Double-blind RCT Colchicine 0.5 mg twice Atrial fibrillation follow- 360 Failure to reduce the
(2016) daily plus 2 mg before ing cardiac surgery occurrence of post-
surgery (half dose if operative atrial fib-
<70 kg) for 8 days rillation (14% vs.
(mean) 20%, P = NS)
Zarpelon et al.37w Double-blind RCT Colchicine 1 mg twice Atrial fibrillation follow- 140 Failure to reduce the
(2016) daily before surgery, ing cardiac surgery occurrence of post-
then 0.5 mg twice operative atrial fib-
daily until discharge rillation (7% vs. 13%,
P = NS)

CRP, C-reactive protein; IL-6, interleukin-6; RCT, randomized controlled trial.

(ACTRN12616000400460) will collectively recruit >9000 patients

..
.. Following bypass surgery
and will undoubtedly provide further insights into the efficacy, long- .. Atrial fibrillation is the most common complication after cardiac sur-
..
term safety and tolerability of colchicine 0.5 mg daily in various sub- .. gery and is a common cause of prolonged and recurrent hospitaliza-
sets of patients with CV disease. ..
.. tion following surgery. Due to its efficacy in the prevention of the
.. post-pericardiotomy syndrome, several small trials have investigated
..
.. the use of colchicine for the prevention of postoperative AF. In a sub-
Colchicine for the prevention of .. study of the COPPS trial (the COPPS-POAF sub-study), colchicine
..
atrial fibrillation .. 1 mg daily started on the third postoperative day, followed by 0.5–
.. 1 mg daily, reduced the incidence of postoperative AF at 30 days
..
Table 5 provides a summary of the main studies in the setting of AF. . compared to placebo (12% vs. 22%, P = 0.021).48 Two more recent
Colchicine and the heart 2759

..
trials reported neutral results; however, both trials were limited by .. shown that long-term low-dose colchicine can be safely used on top
shorter periods of observation,36w,37w suggesting the need for add- .. of lipid-lowering and antiplatelet therapy in the absence of advanced
..
itional studies to assess the effect of preoperative colchicine for the .. renal or liver disease to improve disease-free survival. Over the next
prevention of postoperative AF. .. 3–5 years, ongoing trials will add information about the benefits of col-
..
.. chicine in CV disease in a further 9000 patients.
Following pulmonary vein ablation ..
..
Early AF recurrence following pulmonary vein isolation has been ..
associated with local inflammation triggered by ablation. The use col- .. Supplementary material
..
chicine to prevent AF relapses after ablation has been assessed in ..
two randomized trials by Deftereos et al.49,38w In the first trial con-
.. Supplementary material is available at European Heart Journal online.
..
ducted in 2012, colchicine 0.5 mg twice daily started on the day of ab- .. Conflict of interest: M.I. has been Advisory Board member for
lation and continued for 3 months, reduced the incidence of
.. ACARPIA (colchicine), KINIKSA (rilonacept), and SOBI (anakinra),
..

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postoperative AF (16% vs. 34%, P < 0.01), CRP at day 4 (-1.18 mg/L .. M.C. reported no disclosures.
..
vs. -0.46 mg/L, P < 0.01) and IL-6 at day 4 (-0.50 pg/mL vs. -0.10 pg/ ..
mL, P < 0.01).38w In the second trial, which included a larger cohort of .. References
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