Effect of Low Dose of Colchicine on Platelet Reactivity

Overview

Inflammation plays an important role in atherosclerosis and the occurrence of ischemic events. Statins, in addition to their lipid-lowering effect, have also documented anti-inflammatory effect that may partly explain their clinical benefit in reducing cardiovascular ischemic events. Colchicine is an orally administered anti-inflammatory drug that has been used for centuries in several anti-inflammatory or autoimmune diseases. Its mechanism of action occurs by the inhibition of tubulin polymerization and the generation of microtubules and by effects on cell adhesion molecules and inflammatory chemokines. However, there are no studies evaluating the in vivo "antiplatelet action" of colchicine in patients with established cardiovascular disease. We will evaluate the effect of low-dose 0.5 mg QD colchicine for 30 ± 3 days on platelet reactivity by MultiplateTRAP. Patients with proven chronic coronary artery disease, that is, documented previous myocardial infarction, will be randomized to receive colchicine 0.5 mg QD or placebo for a period of 30 ± 3 days.

Inflammation plays an important role in atherosclerosis and the occurrence of ischemic events. Statins, in addition to their lipid-lowering effect, have also documented an anti-inflammatory effect that may partly explain their clinical benefit in reducing cardiovascular ischemic events. More recently, canaquinumab, a monoclonal anti-interleukin 1β antibody, significantly reduced vascular events in patients after acute myocardial infarction with residual inflammation, but failed to demonstrate progression to diabetes, including in patients with pre-diabetes. On the other hand, methotrexate has not been shown to be effective in reducing events in a similar population. In addition to inflammation, thrombosis is directly involved in the pathogenesis of unstable ischemic syndromes. In this context, the association between greater platelet aggregability and clinical events is well established in the literature. The POPULAR study evaluated that after a 1-year follow-up, the primary outcome of death, non-fatal acute myocardial infarction, stent thrombosis or ischemic stroke occurred more frequently in patients with high platelet reactivity undergoing treatment with antiaggregants when evaluated by optical aggregometry and other point of care tests. Another study that evaluated the importance of the platelet response to medications was the ADAPT-DES, in which post-angioplasty patients on dual antiplatelet therapy were at higher risk of complications, especially stent thrombosis, when they presented with high platelet reactivity to clopidogrel. Both studies show the importance of the interaction between platelet changes and the medications that interact in this way and cardiovascular outcomes. Colchicine is an orally administered anti-inflammatory drug that was initially extracted from autumn saffron and has been used for centuries in various diseases of an anti-inflammatory / autoimmune nature. Its bioavailability after oral administration takes place via uptake in the jejunum and ileum, its lipophilic nature allows it to be absorbed quickly by various types of cells. Its mechanism of action occurs through the inhibition of tubulin polymerization and the generation of microtubules and, possibly, effects on cell adhesion molecules and inflammatory chemokines. Another route related to colchicine is the suppression of interleukin 1. It is able to prevent the intracellular assembly of the cytosolic protein complex NACHT-LRRPYD 3, responsible for the proteolytic cleavage of caspase-1, which breaks down and activates interleukin 1, blocking its maturation and secretion. In addition to the action on inflammation, colchicine may be involved in reducing platelet aggregation, as suggested in a mechanistic study that evaluated the in vitro action of colchicine on platelet aggregation in healthy individuals. In this study, in addition to demonstrating the lower aggregability by electrical impedance in the sample subjected to colchicine action, it was found that the drug also exerted effects via inhibition of key proteins involved in the rearrangement of the platelet cytoskeleton. To the best of our knowledge, however, there are no studies evaluating the in vivo "antiplatelet action" of colchicine in patients with established cardiovascular disease. In the population with coronary heart disease, two important randomized clinical studies have demonstrated the benefit of colchicine: 1) LoDoCo, which demonstrated a reduction in cardiovascular events (composed of infarction, unstable angina, cardiorespiratory arrest or stroke) with a low dose of colchicine in patients with stable coronary disease. ; 2) COLCOT showed a reduction in events, the composite of cardiovascular death, infarction, unstable angina, resuscitated cardiopulmonary arrest or stroke, in patients treated with colchicine after AMI. Despite the cardiovascular benefit demonstrated in high-risk patients, little is known about the pathophysiological mechanisms involved, being the subject of debates about whether the observed results would be related to the reduction of the progression of atheroscletotic disease, to an antiplatelet effect, or both. Primary objective: To evaluate the effect of colchicine in low dose for 30 ± 3 days on platelet aggregation by MultiplateTRAP. Secondary objectives Evaluate the primary objective of the study using Multiplate ADP, ASPI and Collagen. Exploratory Analysis Comparison between the colchicine and placebo groups at the end of the 30 ± 3-day follow-up of the following parameters: * Ultra-sensitive reactive C protein (hs-CRP); * Interleukin 6 (IL-6); * Interleukin 1 (IL-1); * Serum Tromboxane B2; * Count and fraction of reticulated platelets; * Mean platelet volume (MPV); * Total cholesterol / HDL / LDL / triglycerides, apolipoprotein A1, apolipoprotein B; * Analysis of vascular reactivity; * Transfer of lipids to HDL. Analyze the primary outcome of the study in the following subgroups: * Female versus male; * Age group ( equal or major to 65 years); * Presence or not of diabetes mellitus (characterized by use of hypoglycemic drugs previously and / or exam prior to randomization with HbA1c equal or minor to 6.5%); * LVEF equal or major 40%; * Obese versus non-obese (BMI equal or major 30) * Smoker versus non-smoker * median LDL * PCRus equal or major 2mg / dl Study design: Prospective, randomized, double-blind, placebo-controlled study. Patients with proven chronic coronary artery disease, documented by previous history of AMI, will be randomized to receive colchicine 0.5 mg once daily (intervention group) or placebo (control group) for a period of 30 ± 3 days. Randomization will be performed in 2 blocks of 40 patients at a rate of 1: 1. Blood samples will be obtained at the baseline visit and at the end-of-follow-up visit (30 ± 3days after the baseline visit). Inclusion criteria: Agreement to sign a free and informed consent form; age ≥ 18 years; patients with previous acute myocardial infarction (or more than 1 year according to the criteria of the 4th universal definition using ASA 100mg / day. Exclusion criteria: Use of any antithrombotic therapy other than AAS for less than 1 week; Stroke in the last 3 months; active infection or current use of systemic antimicrobial therapy; neoplasia in the last 3 years; inflammatory bowel disease or chronic diarrhea; hematological abnormality (Hb ≤ 11g / dL or\> 17g / dL, leukocytes ≤ 4,500 / mm3 or\> 11,000 / mm3, platelet count \<150,000 / mm3 or\> 450,000 / mm3); chronic kidney disease (estimated glomerular filtration rate \<30 ml / min / 1.73 m2) using the MDRD formula; liver disease defined by CHILD B or C; drug or alcohol abuse; dementia, psychiatric or any condition that, in the researcher's opinion, prevents participation and follow-up in the protocol; history of allergy to colchicine; current treatment with systemic corticosteroids or immunosuppressants. Sample calculation: In a prior study, published in 2020, it was found an average platelet aggregability by Multiplate-TRAP in patients with chronic coronary disease of 102 AUC +/- 26. Another study analyzing platelet aggregation in vitro in healthy volunteers, found a reduction in aggregability by ADP by 40%. In the present study, for a hypothesis of superiority with a 20% reduction in the mean platelet aggregation in favor of colchicine over placebo, considering an alpha = 0.05 (two-tailed) and a power = 90%, the calculated sample size is 70 patients (35 per group), with a total of 80 being included to compensate for possible losses.