Summary
Background
Inflammation is involved during acute myocardial infarction, and could be an interesting target to prevent ischaemia-reperfusion injuries. Colchicine, known for its pleiotropic anti-inflammatory effects, could decrease systemic inflammation in this context.
Aims
To evaluate the impact of colchicine on inflammation in patients admitted for ST-segment elevation myocardial infarction (STEMI).
Methods
All patients admitted for STEMI with one of the main coronary arteries occluded, and successfully treated with percutaneous coronary intervention, were included consecutively. Patients were randomized to receive either 1 mg colchicine once daily for 1 month plus optimal medical treatment or optimal medical treatment only. C-reactive protein (CRP) was assessed at admission and daily until hospital discharge. The primary endpoint was CRP peak value during the index hospitalization.
Results
Forty-four patients were included: 23 were treated with colchicine; 21 received conventional treatment only. At baseline, both groups were well balanced regarding age, sex, risk factors, thrombolysis in myocardial infarction flow and reperfusion delay. The culprit artery was more often the left anterior descending artery in the colchicine group ( P = 0.07), reflecting a more severe group. There was no significant difference in mean CRP peak value between the colchicine and control groups (29.03 mg/L vs 21.86 mg/L, respectively; P = 0.36), even after adjustment for type of culprit artery (26.99 vs 24.99 mg/L, respectively; P = 0.79).
Conclusion
In our study, the effect of colchicine on inflammation in the context of STEMI could not be demonstrated. Further larger studies may clarify the impact of colchicine in acute myocardial infarction.
Résumé
Contexte
L’inflammation, impliquée au cours de l’infarctus du myocarde, pourrait représenter une cible thérapeutique intéressante et limiter les lésions d’ischémie-reperfusion. La colchicine, aux effets anti-inflammatoires pléiotropes, pourrait diminuer l’inflammation systémique au cours de l’infarctus du myocarde.
Objectif
Évaluer l’impact de la colchicine sur l’inflammation systémique, dans l’infarctus du myocarde avec sus-décalage du segment ST.
Méthodes
Tous les patients admis pour infarctus du myocarde avec occlusion de l’une des trois artères principales traités avec succès par angioplastie primaire étaient inclus de manière consécutive. Ils étaient randomisés pour recevoir 1 mg de colchicine par jour pendant 1 mois, en sus du traitement médical optimal, ou le traitement médical optimal seul. La C-réactive protéine était dosée à l’admission et quotidiennement jusqu’à la sortie. Le critère de jugement principal était le pic de CRP au cours de l’hospitalisation.
Résultats
Quarante-quatre patients ont été inclus, 23 ont reçu la colchicine et 21 le traitement conventionnel seul. Les caractéristiques de base étaient comparables entre les 2 groupes concernant l’âge, le sexe, les facteurs de risque cardiovasculaires, le flux TIMI et le délai de reperfusion. L’artère interventriculaire antérieure était le plus souvent l’artère coupable dans le groupe colchicine ( p = 0,07) reflétant un groupe plus sévère. Il n’y avait aucune différence significative entre les 2 groupes concernant la valeur du pic de CRP (29,03 mg/L dans le groupe colchicine vs 21,86 mg/L dans le groupe témoin ; p = 0,36), même après ajustement sur le type d’artère coupable (26,99 vs 24,99 mg/L ; p = 0,79).
Conclusion
Aucun effet de la colchicine sur l’inflammation systémique dans l’infarctus du myocarde n’a pu être démontré. Des études complémentaires de plus grande envergure apparaissent nécessaires pour clarifier l’impact de la colchicine dans l’infarctus du myocarde.
Background
After an acute myocardial infarction (AMI), inflammation is deeply involved in the pathophysiology of ischaemia-reperfusion lesions, as well as in the remodelling phenomenon . In patients admitted for AMI, systemic biological inflammation is usually observed, and is reflected in a biological peak of C-reactive protein (CRP) around day 3 ; this peak is recognized as a prognostic marker, with a well-known correlation with infarct size . During ischaemia, inflammatory factors and cytotoxic substances are released by inflammatory cells in myocardial tissue, leading to the systemic response (and CRP production). During reperfusion, oxygenated blood worsens the injury via the release of free oxygen radicals, and aggravates the inflammatory reactions. Endothelial permeability is then increased, leading to myocardial cell injury, apoptosis and necrosis, with myocardial destruction.
Many biological, immunomodulatory and antioxidative strategies have been proposed for cardioprotection . However, no anti-inflammatory drugs have been shown to be clinically efficient, and none is presently used, except the pleiotropic effect of statins . New biotherapies (especially targeting the interleukin-1 pathway) are currently under development in this clinical setting.
Colchicine has been used for centuries for the treatment and prevention of gouty attacks and rheumatic complaints, and is one of the oldest drugs still currently available . Colchicine may exert pleiotropic anti-inflammatory effects, especially through the inhibition of neutrophil migration , and may also have direct anti-inflammatory effects , by inhibiting key inflammatory signalling networks, known as the inflammasome and proinflammatory cytokines . Furthermore, colchicine has been shown to exert antiatherosclerotic actions , and was proposed to reduce inflammation in patients with stable coronary disease .
Recently, colchicine has been shown to decrease infarct size, with a reduction in the concentration of creatine kinase muscle-brain (CK-MB) fraction and infarct size on cardiac magnetic resonance imaging (MRI) in patients with AMI .
Taking all these considerations together, CRP could be considered as an acceptable surrogate endpoint representing the involvement of inflammation in post-AMI outcome. Our aim was to evaluate the impact of colchicine on inflammation, on the basis of CRP peak, in patients admitted for AMI.
Methods
This interventional, open-label, controlled, prospective study was conducted in the university hospital of Montpellier, France. All participants provided written informed consent, and the protocol was performed according to the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of Montpellier. The study was registered in the clinical trials database ( NCT02363725 ).
Population
All patients admitted consecutively to our institution between December 2014 and May 2015 for ST-elevation myocardial infarction (STEMI), with occlusion of one of the main coronary arteries (thrombolysis in myocardial infarction [TIMI] grade 0 or 1 flow), and successfully treated with primary percutaneous coronary intervention (PCI), were considered for inclusion in the study ( Fig. 1 ). The diagnosis of AMI was based on typical chest pain lasting for > 30 minutes and < 12 hours. Emergency PCI was performed because of signs of ongoing ischaemia (persistent pain or/and ST-segment elevation). The culprit lesion was defined as the occluded artery consistent with the electric territory.
The main exclusion criteria were cardiogenic shock, severe chronic kidney failure (clearance < 30 mL/kg/min), colchicine intolerance or contraindication.
Medical treatment
All patients received the recommended medical treatment, including aspirin, a P2Y 12 inhibitor and unfractionated heparin. Before the primary PCI procedure, all patients received, following the emergency protocol: 250–500 mg of aspirin intravenously, 4000–5000 IU of heparin intravenously and a loading dose of clopidogrel (600 mg) or prasugrel (60 mg) or ticagrelor (180 mg). Additional treatment with glycoprotein IIb/IIIa inhibitors or intracoronary treatments, such as vasodilators, were left to the discretion of the interventional cardiologist. All patients were monitored initially in the intensive care unit, and were then transferred to the conventional cardiology ward; they were treated with optimal medical treatment, including angiotensin-converting enzyme inhibitors, beta-blockers, dual antiplatelet therapy, including aspirin with clopidogrel or prasugrel or ticagrelor, and lipid-lowering drugs (atorvastatin 80 mg or rosuvastatin 20 mg), following the current guidelines .
Procedure characteristics
The first coronary angiography injection determined coronary perfusion according to the TIMI criteria . Primary PCI was performed in accordance with guidelines , and the number and types of stents were left to the discretion of the interventional cardiologist. PCI success was determined by a TIMI grade 3 flow at the end of the procedure, which has been linked with morbidity and mortality after pharmacological and mechanical reperfusion in clinical trials of STEMI .
Treatment allocation
Eligible patients were automatically randomized with a 1:1 ratio to either colchicine and optimal medical treatment or optimal medical treatment alone. Randomization was centralized, available online, performed by minimization and stratified on age and sex. The study drug (oral colchicine, 1 mg once daily) was administered on the first day of the AMI and for 1 month, without a loading dose.
Blood sampling
Venous blood samples were collected at admission and then daily until hospital discharge. Biochemistry variables were performed on a cobas ® 8000 analyser using reagents from Roche Diagnostics (Meylan, France) with the c701© module and the e602© module for immunoassay. Evaluations of high-sensitivity CRP by the immunoturbidimetric method, of creatinine by the enzymatic method, and of creatine kinase according to the International Federation of Clinical Chemistry-approved method (creatine kinase-N-acetylcysteine kinetic measurement; 37 °C) were carried out at inclusion and every day until the end of hospitalization. The high-sensitivity cardiac troponin T (hs-cTnT) assay was performed on the cobas ® 8000/e602 analyser. The lowest concentration measurable at the 10% assay imprecision (CV) level is 13 ng/L, and the 99th percentile among healthy individuals is 14 ng/L (confidence interval: 12.7–24.9) , according to the manufacturer. The estimated glomerular filtration rate was computed using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation . Procalcitonin was measured by a commercial chemiluminescence assay on a Kryptor ® immunoanalyser (ThermoFisher, Agnières, France), following the manufacturer’s instructions.
Primary and secondary endpoints
The primary endpoint was the CRP peak value during the index hospitalization. The secondary endpoints were troponin peak, tolerance of colchicine, hospitalization duration, major adverse cardiac events (death, resuscitated cardiac arrest, ventricular arrhythmias, stent thrombosis, myocardial infarction, urgent coronary revascularization and acute heart failure) at 1-month follow-up, cardiac remodelling on echocardiography (left ventricular end-systolic and end-diastolic volumes) and MRI data.
Statistical analyses
The initial hypothesis was a reduction in median CRP concentration of at least 15%. A 0.72-standard deviation associated with the “group-effect” was estimated based on a preliminary study conducted in the unit. To obtain an estimation of this “group-effect” with ± 10% precision for a 5% alpha and allowing for 10% of patients being lost to follow-up, it was necessary to include 44 patients.
The preliminary descriptive analysis included either means ± standard deviations or medians and first and third quartiles for continuous variables (depending on the normality of the data, checked with the Shapiro-Wilk test), and frequencies for categorical variables. Continuous variables were compared between the two study groups using Student’s t test if the data were normal or the Wilcoxon-Mann-Whitney test otherwise. Categorical variables were compared using the χ 2 test or Fisher’s exact test when χ 2 validity conditions were not met.
The evolution of the biological variables (CRP, creatinine phosphokinase, procalcitonin) was compared between the two study groups using the maximum value for each patient and the area under curve. As the type of culprit artery differed between groups at baseline, the analysis of the primary endpoint (CRP peak value) was adjusted for this variable with a two-factor analysis of variance, considering the effect of group (colchicine or control) and type of culprit artery (left anterior descending [LAD] or others). For each biological variable (CRP, creatinine phosphokinase, procalcitonin), a graphical representation of the evolution of the mean and standard error from days 1 to 5 since inclusion was produced for the two study groups. As the time span between two successive measurements varied for each patient, cubic smoothing splines were fitted to the data to obtain predictions every 24 hours since inclusion, from 1 to 5 days (using a smoothing parameter of 0.35 for all variables). Statistical analyses were carried out with SAS 9 (SAS Institute, Cary, NC, USA) for descriptive statistics and analysis of variance (PROC GLM), and with R version 3.0.2 (package stats, function “smooth.spline”; package pracma, function “trapz”) for calculating area under the curve.
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