Background
Colchicine is an available, safe, and effective anti-inflammatory drug and has been suggested as a COVID-19 treatment, but its usefulness in hospitalized severe COVID-19 patients has not ...been thoroughly demonstrated.
Objective
To address the safety and efficacy of colchicine in hospitalized patients with severe COVID-19.
Design
We conducted a triple-blind parallel non-stratified placebo-controlled clinical trial.
Participants
We recruited 116 hospitalized patients with severe COVID-19 in Mexico.
Interventions
Patients were randomized to receive 1.5 mg of colchicine or placebo at the time of the recruitment in the study (baseline) and 0.5 mg BID PO to complete 10 days of treatment.
Main Measures
The primary composite outcome was the progression to critical disease or death. Besides, we evaluated immunological features at baseline and after recovery or disease progression in 20 patients.
Key Results
Fifty-six patients were allocated to colchicine and 60 patients received placebo. The study was suspended after the second interim analysis demonstrated colchicine had no effect on the primary outcome (OR 0.83, 95%CI 0.35–1.93,
P
= 0.67), nor in the days of ICU and hospital stays. Adverse events were similar between groups (OR 1.63, 95% CI 0.66–3.88,
P
= 0.37). After colchicine treatment, patients had higher BUN and lower serum levels of IL-8, IL-12p70, and IL-17A.
Conclusions
Colchicine is safe but not effective in the treatment of severe COVID-19.
Trial Registration
ClinicalTrials.gov Identifier: NCT04367168.
To assess the proportion of myeloid-derived suppressor cells (MDSCs), their expression of arginase-1 and programmed cell death ligand 1 (PD-L1) and their relationship with the clinical phenotype of ...patients with idiopathic inflammatory myopathies (IIMs).
We recruited 37 IIM adult patients and 10 healthy donors in Mexico City. We evaluated their clinical features, the proportion of MDSCs and their expression of PD-L1 and arginase-1 by flow cytometry. Polymorphonuclear (PMN)-MDSCs were defined as CD33dim, CD11b+ and CD66b+ while monocytic (M)-MDSCs were CD33+, CD11b+, HLA-DR- and CD14+. Serum cytokines were analysed with a multiplex assay. We compared the quantitative variables with the Kruskal-Wallis and Mann-Whitney U tests and assessed correlations with Spearman's ρ.
Most patients had dermatomyositis n = 30 (81.0%). IIM patients had a peripheral expansion of PMN-MDSCs and M-MDSCs with an enhanced expression of arginase-1 and PD-L1. Patients with active disease had a decreased percentage {median 1.75% interquartile range (IQR) 0.31-5.50 vs 10.71 3.16-15.58, P = 0.011} of M-MDSCs and a higher absolute number of PD-L1+ M-MDSCs median 23.21 cells/mm3 (IQR 11.16-148.9) vs 5.95 (4.66-102.7), P = 0.046 with increased expression of PD-L1 median 3136 arbitrary units (IQR 2258-4992) vs 1961 (1885-2335), P = 0.038. PD-L1 expression in PMN-MDSCs correlated with the visual analogue scale of pulmonary disease activity (r = 0.34, P = 0.040) and damage (r = 0.36, P = 0.031), serum IL-5 (r = 0.55, P = 0.003), IL-6 (r = 0.46, P = 0.003), IL-8 (r = 0.53, P = 0.018), IL-10 (r = 0.48, P = 0.005) and GM-CSF (r = 0.48, P = 0.012). M-MDSCs negatively correlated with the skeletal Myositis Intention to Treat Index (r = -0.34, P = 0.038) and positively with IL-6 (r = 0.40, P = 0.045).
MDSCs expressing arginase-1 and PD-L1 are expanded in IIM and correlate with disease activity, damage accrual and serum cytokines.
Background and Aims Childhood acute lymphoblastic leukemia (ALL) is the leading cause of childhood cancer-related deaths worldwide. Multiples studies have shown that ALL seems to be originated by an ...interaction between environmental and genetic susceptibility factors. The ARID5B polymorphisms are among the most reproducible ALL associated-risk alleles in different populations. The aim of the present study was to examine the contribution of ARID5B, CEBPE, and PIP4K2 risk alleles for the development of ALL in children from Mexico City and Yucatan, Mexico. Methods A study was conducted with a total of 761 unrelated subjects. Two hundred eighty five ALL cases (111 from Yucatan and 174 from Mexico City) and 476 healthy subjects. Genotyping included the rs7088318 ( PIP4K2A ), rs10821936 ( ARID5B ), rs7089424 ( ARID5B ) and rs2239633 ( CEBPE ) polymorphisms. Results Associations between ALL and rs10821936 and rs7089424 ARID5B SNPs were found (OR = 1.9, 95% CI (1.5–2.4) and OR = 2.0, 95% CI (1.6–2.5), respectively). Moreover, a higher risk was observed in the homozygous risk genotypes of carriers from Mexico City (OR = 3.1, 95% CI (2.0–4.9) and OR 3.1, CI 95% (2.0–4.8), respectively). Otherwise, the rs7088318 ( PIP4K2A ) and rs2239633 ( CEBPE ) polymorphisms were not associated with ALL risk. Conclusions Our analysis suggests that ARID5B confers risk for childhood ALL in a Mexican population.
Background and Aims It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase ( TPMT ) mutant allele carriers are at high risk to develop severe and potentially fatal ...hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico. Methods We included 849 unrelated subjects, of which 368 ALL children and 342 non-ALL subjects were from Mexico City, and 60 ALL cases and 79 non-ALL individuals were from Yucatan. Genotyping of the rs1800462, rs1800460 and rs1142345 SNPs was performed by 5′exonuclease technique using TaqMan probes (Life Technologies Foster City, CA). Results The mutant TPMT alleles were present in 4.8% (81/1698 chromosomes) and only 0.2% were homozygote TPMT*3A/TPMT*3A . We did not find statistically significant differences in the distribution of the mutant alleles between patients from Mexico City and Yucatan in either ALL cases or non-ALL. Nonetheless, the TPMT*3C frequency in ALL patients was higher than non-ALL subjects ( p = 0.03). To note, the null homozygous TPMT*3A/TPMT*3A genotype was found in 2.5% of the non-ALL subjects. Conclusions TPMT mutant alleles did not exhibit differential distribution between both evaluated populations; however, TPMT*3C is overrepresented in ALL cases in comparison with non-ALL group. Assessing the TPMT mutant alleles could benefit the ALL children and those undergoing 6-MP and MX treatment.
Real-world data from different regions are needed to support the external validity of controlled trials and assess the impact of new oral anticoagulants (NOAC) in clinical practice.
“GLORIA-AF” is a ...large, ongoing, multicenter, global, prospective registry program in patients with newly diagnosed non-valvular atrial fibrillation (NVAF) at risk of stroke. Newly diagnosed patients with NVAF (within 4.5 months) and a CHA2DS2-VASc score ≥ 1 were consecutively enrolled. The study objective was to estimate the incidence rate of stroke and major bleeding after a two year follow up of patients on dabigatran that participated in the “GLORIA-AF” study (Phase II) in Latin America.
Latin America included 378 eligible patients that received dabigatran in eight countries (Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Perú, and Venezuela): 56.3% were male; mean age was 70.3 ± 10.8 years; 43.4% had paroxysmal AF; 36.0% persistent AF and 20.6% permanent AF. Mean CHA2DS2-VASc score was 3.2 ± 1.4; mean HAS-BLED score was 1.2 ± 0.8. Incidence rates for clinical events after 2-years of follow-up per 100 patient-years were as follows: stroke 0.33 (95% CI: 0.04–1.17), major bleeding 0.49 (95% CI: 0.10–1.42) and all-cause death 4.06 (95% CI: 2.63–6.00). Persistence with dabigatran at 6, 12 and 24 months was 91%, 86%, and 80%, respectively.
These regional data shows the sustained safety and effectiveness of dabigatran over two years of follow-up, consistent with already available evidence. An increase in accessibility and incorporation of NOAC to anticoagulant treatment strategies could potentially have a positive impact on AF stroke prevention in Latin America.
Among patients who had had an acute coronary syndrome, the risk of death from coronary heart disease, nonfatal myocardial infarction, stroke, or unstable angina requiring hospitalization at 2.8 years ...was lower among those randomly assigned to alirocumab than among those assigned to placebo.
Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein ...cholesterol (LDL-C).
A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).
One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.
Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range IQR: 6.7 to 59.6 mg/dl) and LDL-C corrected for cholesterol content in lipoprotein(a) predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio HR: 0.85; 95% confidence interval CI: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).
Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)
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GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in ...patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non-vitamin K antagonist oral anticoagulant (NOAC), became available.
This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1.
During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients' baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics.
Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA
DS
-VASc Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category score ≥2; 86.1%); 13.9% had moderate risk (CHA
DS
-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment.
The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation GLORIA-AF; NCT01468701).
Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by ...proprotein convertase subtilisin-kexin type 9 inhibition in such patients is undetermined.
This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval CI: 0.6% to 2.3%), 1.9% (95% CI: -2.4% to 6.2%), and 13.0% (95% CI: -2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: -0.1% to 1.0%), 1.3% (95% CI: -1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).
In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab ODYSSEY OUTCOMES: NCT01663402).
The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or ...maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.
This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.
Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.
With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
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