Time- o- ea men ini ia ion o colchicine and
ca dio ascula ou comes a e myoca dial
in a c ion in he Colchicine Ca dio ascula
Ou comes T ial (COLCOT)
Nadia Bouabdallaoui
1
, Jean-Claude Ta di
1
*, Da id D. Wa e s
2
,
Faus o J. Pin o
3
, Aldo P. Maggioni
4
, Ra ael Diaz
5
, Colin Be y
6
,
Wol gang Koenig
7,8,9
, Jose Lopez-Sendon
10
, Habib Gam a
11
, Ghassan S. Kiwan
12
,
Lucie Blondeau
13
, And eas O anos
13
, Reda Ib ahim
1
,JeanC.G e´goi e
1
,
Ma ie-Pie e Dube´
1
, Michelle Samuel
1
, Oli ie Mo el
14,15
, Pascal Lim
16
,
Oli ie F. Be and
17
, Simon Kouz
18
, Ma ie-Claude Gue in
13
, Philippe L. L’Allie
1
,
and F ancois Roubille
19
1
Mon eal Hea Ins i u e, 5000 Belange S ee , Mon eal, Quebec H1T 1C8, Canada and Uni e si e´ de Mon e´al, Mon eal, Quebec, Canada;
2
San F ancisco Gene al Hospi al,
Cali o nia;
3
San a Ma ia Uni e si y Hospi al (CHULN), CAML, CCUL, Faculdade de Medicina da Uni e sidade de Lisboa, Lisboa, Po ugal;
4
ANMCO Resea ch Cen e , Fi enze,
I aly;
5
Es udios Clinicos La inoame ica, Rosa io, A gen ina;
6
Uni e si y o Glasgow and NHS Glasgow Clinical Resea ch Facili y, Glasgow, UK;
7
Deu sches He zzen um
Mu¨nchen, Technische Uni e si a¨ Mu¨nchen, Munich, Ge many;
8
DZHK (Ge man Cen e o Ca dio ascula Resea ch), pa ne si e Munich Hea Alliance, Munich, Ge many;
9
Ins i u e o Epidemiology and Medical Biome y, Uni e si y o Ulm, Ge many;
10
H La Paz, IdiPaz, UAM, Cibe -CV Mad id, Spain;
11
Fa ouma Bou guiba Uni e si y Hospi al,
Monas i , Tunisia;
12
Belle ue Medical Cen e , Bei u , Lebanon;
13
The Mon eal Heal h Inno a ions Coo dina ing Cen e (MHICC), Mon eal, Canada;
14
Di ision o
Ca dio ascula Medicine, Nou el Hoˆpi al Ci il, S asbou g Uni e si y Hospi al, S asbou g, F ance;
15
INSERM (F ench Na ional Ins i u e o Heal h and Medical Resea ch), UMR
1260, Regene a i e Nanomedicine, FMTS, S asbou g, F ance;
16
Depa men o Ca diology, AP-HP, Hoˆpi al Uni e si ai e Hen i-Mondo and INSERM U955, Uni e si e´ Pa is-Es
C e´ eil, C e´ eil, F ance;
17
Ins i u de Ca diologie e Pneumologie de Que´bec, Quebec Ci y, Canada;
18
Cen e Hospi alie Re´gional de Lanaudie` e, Jolie e, Canada; and
19
Uni e si e´ de Mon pellie , INSERM, CNRS, CHU de Mon pellie , F ance;
Recei ed 1 July 2020; e ised 15 July 2020; edi o ial decision 27 July 2020; accep ed 28 July 2020
Aims The COLchicine Ca dio ascula Ou comes T ial (COLCOT) demons a ed he bene i s o a ge ing in lamma ion
a e myoca dial in a c ion (MI). We aimed o de e mine whe he ime- o- ea men ini ia ion (TTI) in luences he
bene icial impac o colchicine.
............................ ............. ............. .................. ............. ............. ............................... ............. ............. .................. ............. .........
Me hods
and esul s
In COLCOT, pa ien s we e andomly assigned o ecei e colchicine o placebo wi hin 30 days pos -MI. Time- o-
ea men ini ia ion was de ined as he leng h o ime be ween he index MI and he ini ia ion o s udy medica ion.
The p ima y e icacy endpoin was a composi e o ca dio ascula dea h, esusci a ed ca diac a es , MI, s oke, o
u gen hospi aliza ion o angina equi ing co ona y e ascula iza ion. The ela ionship be ween endpoin s and a i-
ous TTI (<3, 4–7 and >8 days) was examined using mul i a iable Cox eg ession models. Amongs he 4661
pa ien s included in his analysis, he e we e 1193, 720, and 2748 pa ien s, espec i ely, in he h ee TTI s a a.
A e a median ollow-up o 22.7 mon hs, he e was a signi ican educ ion in he incidence o he p ima y endpoin
o pa ien s in whom colchicine was ini ia ed < Day 3 compa ed wi h placebo [haza d a ios (HR) = 0.52, 95% con-
idence in e als (CI) 0.32–0.84], in con as o pa ien s in whom colchicine was ini ia ed be ween Days 4 and 7
(HR = 0.96, 95% CI 0.53–1.75) o > Day 8 (HR = 0.82, 95% CI 0.61–1.11). The bene icial e ec s o ea ly ini ia ion
o colchicine we e also demons a ed o u gen hospi aliza ion o angina equi ing e ascula iza ion (HR = 0.35),
* Co esponding au ho . Email: jean-claude. a di @icm-mhi.o g
V
CThe Au ho (s) 2020. Published by Ox o d Uni e si y P ess on behal o he Eu opean Socie y o Ca diology.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/licenses/by-nc/4.0/),
which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac
jou nals.pe [email protected]
Eu opean Hea Jou nal (2020) 00, 1–8 FAST TRACK CONGRESS
doi:10.1093/eu hea j/ehaa659 Ischemic Hea Disease
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all co ona y e ascula iza ion (HR = 0.63), and he composi e o ca dio ascula dea h, esusci a ed ca diac a es ,
MI, o s oke (HR = 0.55, all P< 0.05).
............................ ............. ............. .................. ............. ............. ............................... ............. ............. .................. ............. .........
Conclusion Pa ien s bene i om ea ly, in-hospi al ini ia ion o colchicine a e MI.
............................ ............. ............. .................. ............. ............. ............................... ............. ............. .................. ............. .........
T ial
Regis a ion
COLCOT ClinicalT ials.go numbe , NCT02551094.
䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏
Keywo ds Ca dio ascula in lamma ion •Time- o- ea men ini ia ion •Colchicine •COLCOT •In lammasome
In oduc ion
Myoca dial in a c ion (MI) is associa ed wi h an acu e exace ba ion
o ca dio ascula (CV) in lamma ion supe imposed on he ch onic
a he oscle osis- ela ed in lamma o y p ocess.
1
In ense in lamma-
ion obse ed a he ime o an acu e MI has been shown o be
in ol ed in he pa hogenesis o pos -in a c ion emodelling, wi h
NLRP3 in lammasome ac i a ion playing a pa icula ly impo an
and dele e ious ole in his se ing.
2–5
Colchicine is an inexpensi e,
o ally adminis e ed, po en an i-in lamma o y medica ion ha was
ini ially ex ac ed om he plan au umn c ocus. I s mechanism o
ac ion is h ough he inhibi ion o ubulin polyme iza ion leading
o e ec s on cellula adhesion molecules, in lamma o y chemo-
kines, and he in lammasome.
6–8
Colchicine a he low dose o
0.5 mg daily was shown o signi ican ly educe he isk o ischae-
mic CV e en s by 23% compa ed wi h placebo when ini ia ed
wi hin he i s 30 days a e MI in he COLchicine Ca dio ascula
Ou comes T ial (COLCOT).
9
Whe he he iming o in lamma ion educ ion a e MI has a clinic-
al impac is no known. Speci ically, he impo ance o ini ia ing colchi-
cine immedia ely du ing he hospi aliza ion o MI emains o be
de e mined. We hypo hesized ha ea ly ini ia ion o in lamma ion e-
duc ion wi h colchicine is associa ed wi h g ea e clinical bene i s
a e MI. The e o e, we aimed o de e mine whe he TTI o colchi-
cine in luenced i s bene icial impac on CV ou comes in COLCOT.
Me hods
S udy design and pa ien popula ion
COLCOT was an in e na ional mul icen e, andomized, double-blinded
ial ha andomly assigned pa ien s o ecei e ei he low-dose colchicine
G aphical Abs ac
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2N. Bouabdallaoui e al.
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(0.5 mg once daily) o placebo. The s udy p o ocol and main esul s ha e
been published.
9
Pa ien s we e conside ed eligible i hey had a ecen MI
(<30 days). Main exclusion c i e ia we e se e e hea ailu e, educed le
en icula ejec ion ac ion (<35%), ecen s oke (<3 mon hs), ype 2
MI, ecen (<3 yea s), o planned co ona y a e y bypass g a (CABG),
his o y o cance (<3 yea s), and in lamma o y bowel disease o ch onic
dia hoea. All pa ien s en olled in he ial bene i ed om pe cu aneous
co ona y in e en ion whene e indica ed and guidelines-di ec ed man-
agemen o CV disease p io o andomiza ion.
9
Clinical ollow-up con-
sis ed o e alua ions a 1 and 3mon hs a e andomiza ion and e e y
3 mon hs he ea e . An independen clinical endpoin commi ee,
blinded o ial-g oup assignmen , adjudica ed clinical endpoin s. The ial
was locally app o ed by he a ious ins i u ional e iew boa ds, and all
pa ien s signed a w i en in o med consen be o e en olmen .
9
E icacy endpoin s
The p ima y e icacy endpoin was a composi e o CV dea h, esusci a ed
ca diac a es , MI, s oke, o u gen hospi aliza ion o angina equi ing
co ona y e ascula iza ion. The seconda y endpoin s consis ed o he
componen s o he p ima y e icacy endpoin , all-cause dea h, and a com-
posi e o CV dea h, esusci a ed ca diac a es , MI, o s oke.
9
Explo a o y endpoin s included all co ona y e ascula iza ions, including
bo h elec i e and u gen co ona y e ascula iza ions.
9
Cu -o s o ime- o- ea men ini ia ion o
colchicine
Th ee di e en cu -o s o TTI we e used in o de o de e mine he as-
socia ion be ween ea ly ini ia ion o he apy and clinical ou comes. These
cu -o s we e de e mined based on he usual jou ney o pa ien s wi h
MI.
10,11
The i s 30-day pos -MI imeline was di ided in o h ee inde-
penden pe iods o ime and analysed as such: om Day 0 o 3, e e ing
o in-hospi al managemen ; om Day 4 o 7, e e ing o ea ly pos -
discha ge pe iod, and om Day 8 o 30, e e ing o la e pos -discha ge
pe iod.
S a is ical analysis
Da a we e cen ally analysed by an independen academic bios a is ics
cen e a he Mon eal Heal h Inno a ions Coo dina ing Cen e .
9
The
p esen analysis was conduc ed amongs pa ien s who ecei ed a leas
one dose o he s udy medica ion ( e e ed o as he sa e y popula ion in
he main p o ocol,
9
Figu e 1). Time- o- ea men ini ia ion was de ined as
he leng h o ime in days be ween he index MI and he ini ia ion o he
s udy medica ion, and h ee speci ic cu -o s we e analysed (<_Day3,
Days 4 o 7, and >_ Day 8). Ea ly ini ia ion o he apy was de ined as TTI
<_3 days. Baseline cha ac e is ics we e summa ized using coun s and pe -
cen ages o ca ego ical a iables and mean ± s anda d de ia ion (SD) o
con inuous a iables. Fo each baseline cha ac e is ic, compa isons we e
made using ANOVA o con inuous a iables and Chi-Squa e es o ca -
ego ical a iables acco ding o TTI s a a. Analyses o he e icacy end-
poin s, exp essed as ime o e en , we e conduc ed acco ding o TTI.
Adjus ed haza d a ios (HR) along wi h 95% con idence in e als (CI)
we e calcula ed om s epwise mul i a iable Cox eg ession models
adjus ed o he same co a ia es ha we e used in he main analysis o
he COLCOT ial.
9
All s a is ical es s we e wo-sided and conduc ed a
he 0.05 signi icance le el. S a is ical analyses we e pe o med wi h he
use o SAS so wa e, e sion 9.4 (SAS Ins i u e).
Resul s
Baseline cha ac e is ics
O he 4745 pa ien s andomized in COLCOT, 4661 we e included
in he p esen analysis (colchicine, N= 2322; placebo, N=2339)
(Figu e 1). O e all, pa ien s we e andomized a 13.5 ± 10.1 days ol-
lowing he index MI, 25.6% be ween Days 0 and 3, 15.4% be ween
Days4and7and59.0%a Day8o a e .Baselinecha ac e is ics
we e simila be ween he colchicine and placebo g oups (Table 1).
Pa ien s we e mos ly men (81.0%) wi h a mean age o 60.5 yea s,
20.2% had diabe es, 51.0% had a his o y o hype ension, 29.7% we e
ac i e smoke s, and 16.8% had had a p io pe cu aneous co ona y
in e en ion (PCI). Backg ound he apy included aspi in, a second
Randomized,
n=4745
Placebo,
n=2379
Colchicine,
n=2366
Medicaon ne e aken,
n=33
Sa e y
Populaon,
n=2346
Medicaon ne e aken,
n=36
Sa e y
Populaon,
n=2330
Excluded om he p esen analysis,
Paen s andomized > 30 days ae Index
MI, n=3
No Index MI, n= 3
Type 2 MI, n=1
Analyzed
wi hin he
Placebo
g oup,
n=2339
Excluded om he p esen analysis,
Paen s andomized > 30 days ae Index
MI, n=6
No Index MI, n=2
Type 2 MI, n=0
Analyzed
wi hin he
Colchicine
g oup,
n=2322
Figu e 1 Subjec disposi ion, low cha diag am.
Time- o- ea men ini ia ion o colchicine and ca dio ascula ou comes in COLCOT 3
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an i-pla ele agen and a s a in in 98.8%, 98.0%, and 99.0% o pa ien s,
espec i ely. The as majo i y o pa ien s (93.0%) unde wen PCI
du ing he index hospi aliza ion, wi h no di e ence in e ms o ime
o PCI be ween he wo g oups.
Baseline cha ac e is ics acco ding o TTI s a a a e shown in
Table 2. Pa ien s in whom he apy was ini ia ed be ween Days 0 and
3, when compa ed wi h hose a Days 8–30, we e younge
(59.1± 10.8 s. 61.3± 10.4 yea s) and mo e o en ac i e smoke s
(43.8% s. 20.2%), had less commonly hype ension (41.1% s.
56.2%), and diabe es (17.4% s. 22.0%) bu unde wen mo e o en
PCI associa ed wi h he index MI (95.8% s. 91.3%), all P<0.05.
E ec s o ime- o- ea men ini ia ion on
he p ima y e icacy endpoin
The e ec s o colchicine on he p ima y endpoin acco ding o TTI
a e shown in Table 3and Figu e 2. A p ima y endpoin e en occu ed
in 4.3% o pa ien s in he colchicine g oup, as compa ed wi h 8.3% o
hose in he placebo g oup when TTI was be ween Days 0 and 3
(N= 1193, HR = 0.52, 95% CI 0.32–0.84, P= 0.007, Figu e 3A).
Co esponding a es we e 6.0% and 5.9% when TTI was be ween
Days4and7(N= 720) and 5.7% and 7.1% when TTI was on Day 8
o a e (N= 2748), bu hese di e ences be ween g oups did no
each s a is ical signi icance. Table 3also shows he pe cen ages o
pa ien s wi h e en s and he haza d a ios o he componen s o he
p ima y endpoin , including CV dea h (HR = 1.04, 95% CI 0.15–7.37),
esusci a ed ca diac a es (HR = 0.33, 95% CI 0.03–3.20), MI
(HR = 0.58, 95% CI 0.32–1.05), s oke (HR = 0.21, 95% CI 0.02–
1.81), and u gen hospi aliza ion o angina equi ing co ona y e as-
cula iza ion (HR = 0.35, 95% CI 0.14–0.88).
E ec s o ime- o- ea men ini ia ion on
he seconda y and explo a o y e icacy
endpoin s
The e ec s o colchicine on he seconda y and explo a o y endpoin s
a e shown in Table 3. The seconda y e icacy endpoin consis ing o a
composi e o CV dea h, ca diac a es , MI, o s oke occu ed in
3.3% o he pa ien s in he colchicine g oup and in 6.1% o hose in
he placebo g oup when TTI was be ween Days 0 and 3 (HR = 0.55;
95% CI, 0.32–0.95, Figu e 3B). The explo a o y endpoin o all co on-
a y e ascula iza ions occu ed in 5.5% o pa ien s in he colchicine
.................................................. .............................................................. .................................................. ..................................................
Table 1 Baseline cha ac e is ics acco ding o ea men alloca ion
Cha ac e is ics All pa ien s Colchicine g oup Placebo g oup
(N54661) (N52322) (N52339)
Age (yea s), mean ± SD 60.5 ± 10.6 60.6 ± 10.6 60.5 ± 10.6
Male sex, no. (%) 3774 (81.0%) 1861 (80.1%) 1913 (81.8%)
BMI (kg/m
2
), mean ± SD 28.3 ± 4.7 28.2 ± 4.8 28.4 ± 4.7
Cu en smoking, no./ o al no. (%) 1382/4659 (29.7) 694/2322 (29.9%) 688/2337 (29.4%)
His o y o hype ension, no. (%) 2377 (51.0) 1160 (50.0) 1217 (52.0)
His o y o diabe es, no. (%) 942 (20.2) 451 (19.4) 491 (21.0)
P io MI, no. (%) 751 (16.1) 360 (15.5) 391 (16.7)
P io PCI, no. (%) 783 (16.8) 382 (16.5) 401 (17.1)
P io CABG, no. (%) 146 (3.1) 66 (2.8) 80 (3.4)
P io HF, no. (%) 90 (1.9) 48 (2.1) 42 (1.8)
P io s oke o TIA, no. (%) 119 (2.6) 53 (2.3) 66 (2.8)
PCI associa ed wi h he index e en , no. (%) 4336 (93.0) 2154 (92.8) 2182 (93.3)
Medica ion use, no. (%):
Aspi in 4605 (98.8) 2291 (98.7) 2314 (98.9)
O he an i-pla ele agen 4567 (98.0) 2267 (97.6) 2300 (98.3)
S a in 4615 (99.0) 2297 (98.9) 2318 (99.1)
Be a-blocke 4143 (88.9) 2077 (89.4) 2066 (88.3)
TTI 0–3 days, no. (%) 1193 (25.6) 604 (26.0) 589 (25.2)
TTI 4–7 days, no. (%) 720 (15.4) 364 (15.7) 356 (15.2)
TTT >_8 days, no. (%) 2748 (59.0) 1354 (58.3) 1394 (59.6)
Time om index MI o andomiza ion (days),
mean ± SD
13.5 ± 10.1 13.5 ± 10.1 13.5 ± 10.0
Time om Index MI o PCI (days), mean ± SD 1.4 ± 2.9 1.4 ± 2.9 1.4 ± 2.9
Time om PCI o andomiza ion (days), mean ±
SD
11.9 ± 9.9 11.9 ± 9.9 11.9 ± 9.9
Da a we e missing on he ollowing cha ac e is ics: age (assessed acco ding o da e o bi h; see below) o 431 pa ien s (213 in he colchicine g oup and 218 in he placebo
g oup) and body-mass index ( he weigh in kilog ams di ided by he squa e o he heigh in me e s) o 5 (1 and 4 pa ien s, espec i ely).
Da e o bi h was no equi ed ield because i was conside ed in some coun ies o be sensi i e da a ha could allow o he iden i ica ion o pa ien s.
Fo s a is ical epo ing, missing in o ma ion ega ding he day o bi h was eplaced by 15, and missing in o ma ion ega ding he mon h and day o bi h was eplaced by 1 July.
CABG, co ona y a e y bypass g a su ge y; HF, hea ailu e; PCI, pe cu aneous co ona y in e en ion; TIA, ansien ischaemic a ack.
4N. Bouabdallaoui e al.
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g oup, as compa ed wi h 8.7% o hose in he placebo g oup when
TTI was be ween Days 0 and 3 (HR = 0.63, 95% CI 0.40–0.97). The e
we e six dea hs in bo h s udy g oups when TTI was be ween Days 0
and 3 (HR = 1.03, 95% 0.33–3.19).
Discussion
This analysis o COLCOT shows ha ea ly ini ia ion o low-dose col-
chicine wi hin he i s 3days a e MI is associa ed wi h a educ ion
o 48% in he isk o he p ima y endpoin consis ing o a composi e
o CV dea h, esusci a ed ca diac a es , MI, s oke, o u gen hospi-
aliza ion o angina equi ing co ona y e ascula iza ion, in compa i-
son wi h placebo. This esul was due o a lowe incidence o MIs,
s okes, and u gen hospi aliza ions o angina leading o co ona y
e ascula iza ion. The seconda y e icacy endpoin consis ing o a
composi e o CV dea h, esusci a ed ca diac a es , MI, o s oke was
also signi ican ly educed by 45% wi h ea ly ini ia ion o low-dose col-
chicine. The bene i s we e mo e ma ked when ea men was ini i-
a ed wi hin he i s 3 days a e MI, as compa ed wi h be ween Days
4 and 30, suppo ing he s a egy o in-hospi al ini ia ion o colchicine
in o de o imp o e CV ou comes pos -MI.
Acu e in lamma o y esponse ollowing
myoca dial in a c ion
Con incing e idence con e ge owa ds in lamma ion as a key ac o
in CV disease p og ession and exace ba ion.
12
In he acu e phase o
MI, ca diomyocy e nec osis gene a es damage-associa ed molecula
pa e ns, which in u n ac i a e he complemen cascade and s imu-
la e oll-like ecep o and in e leukin-1 signalling.
13,14
These ac o s
igge an in ense in lamma o y esponse ha may lead o ad e se
myoca dial emodelling
4
and in which ac i a ed in lammasomes wi h-
in myoca dial ib oblas s play a c ucial ole.
2,3,5
Fu he mo e, an acu e
sys emic in lamma ion esponse has been demons a ed in pa ien s
wi h ecen MI
15,16
and associa ed wi h in a c size.
17
Colchicine binds
o ubulin and p e en s mic o ubule polyme iza ion, consequen ly
educing in lammasome ac i a ion and p o-in lamma o y cy okine e-
lease. Colchicine concen a es p e e en ially in whi e blood cells,
hus exe ing i s an i-in lamma o y e ec s e en a low doses.
18
The
impo ance o ea ly ini ia ion o colchicine on CV ou comes a e MI
in COLCOT is compa ible wi h an e ec on inna e immune cells.
17
Sho - e m an i-in lamma o y he apy wi h colchicine was also asso-
cia ed wi h smalle in a c size and educed in lamma o y esponse in
a pilo s udy o pa ien s wi h STEMI unde going p ima y PCI.
19
.................................................. .............................................................. .................................................. ..................................................
Table 2 Baseline cha ac e is ics acco ding o ime- o- ea men ini ia ion
Cha ac e is ics TTI 0–3 days TTI 4–7 days TTT 8days P
a
P
b
(N51193) (N5720) (N52748)
Age (yea s), mean ± SD 59.1 ± 10.8 60.1 ± 11.0 61.3 ± 10.4 <0.0001 <0.0001
Male sex, no. (%) 980 (82.2) 605 (84.0) 2189 (80.0) 0.014 0.071
BMI (kg/m
2
), mean ± SD 28.1 ± 4.6 27.7 ± 4.6 28.6 ± 4.8 <0.0001 0.004
Cu en smoking, no. (%) 522 (43.8) 306 (42.6) 554 (20.2) <0.0001 <0.0001
His o y o hype ension, no. (%) 490 (41.1) 343 (47.6) 1544 (56.2) <0.0001 <0.0001
His o y o diabe es, no. (%) 208 (17.4) 130 (18.1) 604 (22.0) 0.001 0.001
P io MI, no. (%) 170 (14.3) 111 (15.4) 470 (17.1) 0.070 —
P io PCI, no. (%) 182 (15.3) 107 (14.9) 494 (18.0) 0.035 0.037
P io CABG, no. (%) 34 (2.9) 30 (4.2) 82 (3.0) 0.218 —
P io HF, no. (%) 14 (1.2) 12 (1.7) 64 (2.3) 0.046 0.017
P io s oke o TIA, no. (%) 20 (1.7) 21 (2.9) 78 (2.8) 0.084 —
PCI associa ed wi h he index e en , no. (%) 1143 (95.8) 685 (95.1) 2508 (91.3) <0.0001 <0.0001
Medica ion use, no. (%)
Aspi in 1181 (99.0) 715 (99.3) 2709 (98.6) 0.219 —
O he an i-pla ele agen 1177 (98.7) 708 (98.3) 2682 (97.6) 0.072 —
S a in 1188 (99.6) 708 (98.3) 2719 (98.9) 0.024 0.047
Be a-blocke 1093 (91.6) 642 (89.2) 2408 (87.6) 0.001 0.0003
Time om index MI o andomiza ion (days),
mean ± SD
2.1 ± 0.8 5.1 ± 1.1 20.8 ± 6.6 —
Time om index MI o PCI (days), mean ± SD 0.4 ± 0.7 1.4 ± 1.8 1.8 ± 3.6 <0.0001 <0.0001
Time om PCI o andomiza ion (days), mean ±
SD
1.6 ± 0.9 3.7 ± 1.9 18.8 ± 7.3 <0.0001 <0.001
Da a we e missing on he ollowing cha ac e is ics: age (assessed acco ding o da e o bi h; see below) o 431 pa ien s (213 in he colchicine g oup and 218 in he placebo
g oup) and body-mass index ( he weigh in kilog ams di ided by he squa e o he heigh in me e s) o 5 (1 and 4 pa ien s, espec i ely).
Da e o bi h was no a equi ed ield because i was conside ed in some coun ies o be sensi i e da a ha could allow o he iden i ica ion o pa ien s. Fo s a is ical epo ing,
missing in o ma ion ega ding he day o bi h was eplaced by 15, and missing in o ma ion ega ding he mon h and day o bi h was eplaced by 1 July.
CABG, co ona y a e y bypass g a su ge y; HF, hea ailu e; PCI, pe cu aneous co ona y in e en ion; TIA, ansien ischaemic a ack.
a
G oup compa ison TTI 0–3 s. TTI 4–7 s. TTI >_ 8 days.
b
G oup compa ison TTI 0–3 s. TTI >_ 8 days.
Time- o- ea men ini ia ion o colchicine and ca dio ascula ou comes in COLCOT 5
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.The bene i o colchicine in educing he isk o s oke was la ge in
COLCOT, which suppo s he a ou able ascula e ec s o in lam-
ma ion educ ion wi h his medica ion. Whe he he e is a pa icula
e ec o colchicine on he ce eb al ascula bed is unknown. In con-
as , he e was no signi ican impac o colchicine on he incidence o
a ial ib illa ion in COLCOT.
Ta ge ing esidual ca dio ascula isk
wi h an i-in lamma o y he apy
In lamma ion con ibu es o all phases o a he oscle o ic disease, and
ecen da a om andomized ials ha e p o ided no els insigh s in o
he ole o in lamma ion modula ion o CV isk educ ion.
20
The
Canakinumab An i-In lamma o y Th ombosis Ou comes S udy
(CANTOS) o pa ien s wi h s able co ona y disease demons a ed
ha he selec i e IL-1 binhibi o canakinumab yielded a educ ion o
15% in he isk o a CV e en ,
21
which was co ela ed wi h he lowe -
ing o in lamma ion bioma ke le els.
22
The main COLCOT esul s
e ealed ha colchicine educed he isk o ischaemic CV e en s by
23% in he pos -MI se ing.
9
Resul s om he p esen COLCOT ana-
lysis sugges ha ea ly supp ession o in lamma ion a e MI p o ides
.................................................. .............................................................. .................................................. ..................................................
Table 3 E icacy endpoin s acco ding o ime- o- ea men ini ia ion (N54661, colchicine s. placebo)
Endpoin s TTI 0–3 days, N51193 TTI 4–7 days, N5720 TTI 8 days, N52748
Colchicine s. placebo, no. (%) Colchicine s. placebo, no. (%) Colchicine s. placebo, no. (%)
HR (95%CI); PHR (95%CI); PHR (95%CI); P
P ima y composi e endpoin 26 (4.3%) s. 49 (8.3%) 22 (6.0%) s. 21 (5.9%) 77 (5.7%) s. 99 (7.1%)
0.52 (0.32–0.84); P= 0.007 0.96 (0.53–1.75); P= 0.896 0.82 (0.61–1.11); P= 0.200
CV dea h 2 (0.3%) s. 2 (0.3%) 2 (0.5%) s. 4 (1.1%) 15 (1.1%) s. 18 (1.3%)
1.04 (0.15–7.37); P= 0.970 0.45 (0.08–2.46); P= 0.356 0.89 (0.45–1.76); P= 0.734
Resusci a ed ca diac a es 1 (0.2%) s. 3 (0.5%) 2 (0.5%) s. 1 (0.3%) 2 (0.1%) s. 2 (0.1%)
0.33 (0.03–3.20); P= 0.340 1.90 (0.17–20.95); P= 0.600 1.02 (0.14–7.22); P= 0.986
MI 17 (2.8%) s. 29 (4.9%) 16 (4.4%) s. 9 (2.5%) 52 (3.8%) s. 59 (4.2%)
0.58 (0.32–1.05); P= 0.071 1.67 (0.74–3.78); P= 0.218 0.93 (0.64–1.35); P= 0.710
S oke 1 (0.2%) s. 5 (0.8%) 1 (0.3%) s. 3 (0.8%) 2 (0.1%) s. 11 (0.8%)
0.21 (0.02–1.81); P= 0.156 0.28 (0.03–2.71); P= 0.272 0.19 (0.04–0.84); P= 0.029
U gen hospi aliza ion o angina
equi ing co ona y
e ascula iza ion
6 (1.0%) s. 17 (2.9%) 4 (1.1%) s. 6 (1.7%) 15 (1.1%) s. 26 (1.9%)
0.35 (0.14–0.88); P= 0.026 0.63 (0.18–2.24); P= 0.476 0.61 (0.32–1.16); P= 0.131
Seconda y composi e endpoin 20 (3.3%) s. 36 (6.1%) 18 (4.9%) s. 16 (4.5%) 67 (4.9%) s. 77 (5.5%)
0.55 (0.32–0.95); P= 0.031 1.04 (0.53–2.03); P= 0.919 0.92 (0.66–1.28); P= 0.629
All-cause dea h 6 (1.0%) s. 6 (1.0%) 8 (2.2%) s. 7 (2.0%) 26 (1.9%) s. 31 (2.2%)
1.03 (0.33–3.19); P= 0.962 1.03 (0.37–2.84); P= 0.957 0.90 (0.53–1.51); P= 0.684
All co ona y e ascula iza ions 33 (5.5%) s. 51 (8.7%) 25 (6.9%) s. 18 (5.1%) 72 (5.3%) s. 94 (6.7%)
0.63 (0.40–0.97); P= 0.037 1.41 (0.76–2.61); P= 0.275 0.81 (0.59–1.10); P= 0.172
The p ima y composi e endpoin included CV dea h, esusci a ed ca diac a es , MI, s oke, o u gen hospi aliza ion o angina equi ing co ona y e ascula iza ion. The sec-
onda y composi e endpoin included CV dea h, esusci a ed ca diac a es , MI, and s oke. Only he ini ial e en was coun ed in he analyses o ime o i s e en o he p i-
ma y composi e endpoin and o he seconda y composi e endpoin .
Co a ia es included in he s epwise mul i a iable Cox eg ession models a e: age; sex; BMI; smoking s a us; his o y o diabe es; his o y o hype ension; his o y o dyslipidaemia;
p io MI; p io co ona y e ascula iza ion (p io PCI o p io CABG); p io hea ailu e. All models also included TTI, g oup and he in e ac ion be ween g oup and TTI.
CI, con idence in e al; CV, ca dio ascula ; MI, myoca dial in a c ion; HR, haza d a io; PCI, pe cu aneous co ona y in e en ion; TTI, ime- o- ea men ini ia ion.
Figu e 2 Associa ions be ween ime- o- ea men ini ia ion and
he isk o occu ence o he p ima y composi e endpoin . The
adjus ed haza d a io and 95% con idence in e als come om a
quad a ic mul i a iable Cox eg ession model.
6N. Bouabdallaoui e al.
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e en g ea e bene i s, wi h a educ ion o 48% in he isk o he com-
posi e p ima y endpoin when colchicine was ini ia ed be ween Days
0 and 3. The demons a ed cos -e ec i eness o low-dose colchicine
also suppo s i s la ge-scale use a e MI.
23
Resul s o he LoDoCo2
24
s udy o pa ien s wi h s able co ona y a e y disease will complemen
hose o COLCOT in he pos -MI se ing.
Limi a ions
This analysis has limi a ions. Time- o- ea men ini ia ion was ana-
lysed using h ee s a a chosen acco ding o he usual jou ney o
pa ien s wi h uncomplica ed MI. A la ge ial migh ha e allowed a
be e assessmen o indi idual endpoin s and subg oups.
Conclusions
Ea ly ini ia ion o low-dose colchicine a e MI g ea ly educed he
isk o ischaemic CV e en s compa ed wi h placebo. These esul s
suppo in-hospi al ini ia ion o adjunc i e an i-in lamma o y he apy
wi h colchicine o pos -MI p e en ion.
Acknowledgemen s
The COLCOT ial was suppo ed by he Go e nmen o Quebec,
he Canadian Ins i u es o Heal h Resea ch, he Mon eal Hea
Ins i u e Founda ion and o he philan h opic ounda ions. We hank
he ial in es iga o s and co-o dina o s a all he cen es; ial moni-
o s and s a om he Mon eal Heal h Inno a ions Coo dina ing
Cen e , including Gab iela S ama escu, MD, O ilia Goga, MD, and
Ou ida Mehenni Hadje es, MD, o medical e iew; E
` e Roy-Cla el,
MSc, CMC, And e´e B unelle, BA, and Luc Dion, MSc, o da a man-
agemen and p og amming; Syl ie Le´ esque, MSc, Anna Nozza, MSc,
Ma ie` e Cosse e, MSc, Annik Fo ie , MSc, and Daniel Cou noye ,
MSc, o assis ance wi h bios a is ics; and Randa Zam ini, BSc,
Ma ianne Ru iange, PhD, And e´aAliciaDumon ,BSc,Myle`ne
P o enche , PhD, and Zoha Basse i ch, BSc, o clinical ope a ions;
and he pa icipa ing pa ien s o hei con ibu ion o he ial.
Funding
The COLCOT ial was suppo ed by he Go e nmen o Quebec, he
Canadian Ins i u es o Heal h Resea ch, he Mon eal Hea Ins i u e
Founda ion and o he philan h opic ounda ions. The unding sou ces had
no ole in s udy design, conduc , o analyses.
Con lic o in e es : N.B. epo s pe sonal ees om As aZeneca,
ou side he submi ed wo k; J.-C.T. epo s g an s om Go e nmen o
Quebec, Canadian Ins i u es o Heal h Resea ch, Mon eal Hea Ins i u e
Founda ion, du ing he conduc o he s udy; g an s om Ama in, g an s
and pe sonal ees om As a Zeneca, g an s, pe sonal ees and o he
om Dalco , g an s om Espe ion, Ionis, g an s and pe sonal ees om
Sano i, Se ie , g an s om RegenXBio, ou side he submi ed wo k; In
addi ion, J.-C.T. has a pa en Gene ic ma ke s o p edic ing esponsi e-
ness o he apy wi h HDL- aising o HDL mimicking agen pending, a pa-
en Me hods o using low-dose colchicine a e MI pending o In en ion
assigned o he Mon eal Hea Ins i u e, and a pa en Me hods o ea ing
a co ona i us in ec ion using Colchicine pending; D.D.W. epo s pe son-
al ees om Pha mascience, ou side he submi ed wo k; F.J.P. has no hing
o disclose; A.P.M. epo s pe sonal ees om Baye , F esenius, and
No a is, ou side he submi ed wo k; R.D. epo s g an s om MHIRC,
du ing he conduc o he s udy; g an s om DALCOR, ou side he sub-
mi ed wo k; C.B. has no hing o disclose; W.K. epo s pe sonal ees
om As aZeneca, No a is, P ize , The Medicines Company, DalCo ,
Kowa, Amgen, Co idia, Daiichi-Sankyo, Be lin-Chemie, Sano i, and
B is ol-Mye s Squibb, g an s and non- inancial suppo om Singulex,
Abbo , Roche Diagnos ics, and Beckmann, ou side he submi ed wo k;
J.L.-S. epo s g an s om Mon eal Hea Ins i u e, du ing he conduc o
he s udy; g an s om Baye , P ize , Sano i, and Bohe inge Ingleheim, ou -
side he submi ed wo k; H.G. has no hing o disclose; G.S.K. ecei ing
lec u e ees om Baye , Se ie , No a is, As aZeneca, B is ol-Mye s
Squibb, Roche, and P ize ; L.B., A.O., R.I., and J.C.G. ha e no hing o
Figu e 3 Kaplan–Meie e en cu es o he p ima y and seconda y e icacy composi e endpoin s in he colchicine g oup and he placebo g oup
acco ding o ime- o- ea men ini ia ion. The inse shows he same da a on an enla ged y-axis. (A) Cumula i e incidence o he p ima y composi e
endpoin in pa ien s wi h ime- o- ea men ini ia ion <_3days;(B) Cumula i e incidence o he seconda y composi e endpoin in pa ien s wi h ime-
o- ea men ini ia ion <_3days.
Time- o- ea men ini ia ion o colchicine and ca dio ascula ou comes in COLCOT 7
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disclose; M.-P.D. epo s g an s om Go e nmen o Quebec, du ing he
conduc o he s udy; pe sonal ees om Dalco , pe sonal ees and o he
om GlaxoSmi hKline, o he om As aZeneca, P ize , Se ie , and
Sano i, ou side he submi ed wo k; In addi ion, M.-P.D. has a pa en
Me hods o T ea ing o P e en ing Ca dio ascula Diso de s and
Lowe ing Risk o Ca dio ascula E en s issued o Dalco , no oyal ies
ecei ed, a pa en Gene ic Ma ke s o P edic ing Responsi eness o
The apy wi h HDL-Raising o HDL Mimicking Agen issued o Dalco , no
oyal ies ecei ed, and a pa en Me hods o using low-dose colchicine
a e MI wi h oyal ies paid o In en ion assigned o he Mon eal Hea
Ins i u e; M.S., O.M., P.L., and O.F.B. ha e no hing o disclose; S.K. epo s
pe sonal ees and o he om Med onic, g an s, pe sonal ees and o he
om Sano i, o he om Johnson & Johnson, pe sonal ees and o he
om Amgen, g an s, pe sonal ees and o he om As aZeneca and
No a is, o he om Celgene, Biogen, Gilead, Roche, and Bos on
Scien i ic, pe sonal ees and o he om Bausch Heal h, o he om GSK,
pe sonal ees and o he om BMS, o he om TG The apeu ics, Bec on
Dickinson, and Spec um Pha maceu icals, pe sonal ees om Me ck, Eli
Lilly, P ize , and Baye , g an s and pe sonal ees om Boeh inge -
Ingelheim, pe sonal ees om Se ie , g an s om Espe ion, Dalco , Eisai,
Ama in, and The acos, ou side he submi ed wo k; M.-C.G. and P.L.L.
ha e no hing o disclose; F.R. epo s g an s, pe sonal ees and non-
inancial suppo om AIR LIQUIDE, g an s and pe sonal ees om
ABBOTT, pe sonal ees om VIFOR, g an s and pe sonal ees om
NOVARTIS,pe sonal ees omSe ie ,Abiomed,andZoll,g an sand
pe sonal ees om ASTRA ZENECA, pe sonal ees om Med onic, pe -
sonal ees om Resmed, om LVL, Eole, pe sonal ees om P ize , ou -
side he submi ed wo k.
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