Inflammation appears to play a role in atherosclerosis, raising the possibility that treatments that reduce inflammation could prevent cardiovascular events. In a randomized, placebo-controlled trial ...involving 4745 patients with recent myocardial infarction, low-dose colchicine (0.5 mg once daily) prevented ischemic cardiovascular events.
Abstract
Aims
The COLchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated the benefits of targeting inflammation after myocardial infarction (MI). We aimed to determine whether ...time-to-treatment initiation (TTI) influences the beneficial impact of colchicine.
Methods and results
In COLCOT, patients were randomly assigned to receive colchicine or placebo within 30 days post-MI. Time-to-treatment initiation was defined as the length of time between the index MI and the initiation of study medication. The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. The relationship between endpoints and various TTI (<3, 4–7 and >8 days) was examined using multivariable Cox regression models. Amongst the 4661 patients included in this analysis, there were 1193, 720, and 2748 patients, respectively, in the three TTI strata. After a median follow-up of 22.7 months, there was a significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < Day 3 compared with placebo hazard ratios (HR) = 0.52, 95% confidence intervals (CI) 0.32–0.84, in contrast to patients in whom colchicine was initiated between Days 4 and 7 (HR = 0.96, 95% CI 0.53–1.75) or > Day 8 (HR = 0.82, 95% CI 0.61–1.11). The beneficial effects of early initiation of colchicine were also demonstrated for urgent hospitalization for angina requiring revascularization (HR = 0.35), all coronary revascularization (HR = 0.63), and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all P < 0.05).
Conclusion
Patients benefit from early, in-hospital initiation of colchicine after MI.
Trial Registration
COLCOT ClinicalTrials.gov number, NCT02551094.
Graphical Abstract
Summary
Graft‐versus‐host disease (GVHD) is a major cause of transplant‐related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in ...haploidentical HSCT. GVHD may be prevented by ex vivo graft T‐cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose‐finding study, 19 adults (median age: 54 years) with high‐risk haematological malignancies were treated with T‐cell‐depleted human leucocyte antigen‐haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104–5 × 106 CD3+ cells/kg (median 31 days post‐transplant). No patient received post‐transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long‐term follow ‐up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3–2 × 106 CD3+ cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse‐related mortality was 33% and overall survival was 67% in these patients.
Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to ...investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.
The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.
Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0–61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio OR 0·79, 95·1% CI 0·61–1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57–0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).
In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.
The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.
Vascular inflammation is increased in patients with psoriasis. This randomized, double-blind, multicenter study evaluated the effects of tumor necrosis factor-α antagonist adalimumab on vascular ...inflammation in patients with psoriasis. A total of 107 patients were randomized (1:1) to receive adalimumab for 52 weeks or placebo for 16 weeks followed by adalimumab for 52 weeks. Vascular inflammation was assessed with positron emission tomography-computed tomography. There were no differences in the change from baseline in vessel wall target-to-background ratio (TBR) from the ascending aorta (primary endpoint) (adalimumab: TBR = 0.002, 95% confidence interval CI = –0.048 to 0.053; placebo: TBR = –0.002, 95% CI = –0.053 to 0.049; P = 0.916) and the carotids (adalimumab: TBR = 0.031, 95% CI = –0.005 to 0.066; placebo: TBR = 0.018, 95% CI = –0.019 to 0.055; P = 0.629) at week 16 between adalimumab and placebo. After 52 weeks of treatment with adalimumab there was no significant change from start of treatment in TBR from the ascending aorta (TBR = –0.006, 95% CI = –0.049 to 0.038; P = 0.796), but there was an increase in TBR in carotids (TBR = 0.027, 95% CI = 0.000 to 0.054; P = 0.046). This study showed no difference over 16 weeks in vascular inflammation in patients treated with a tumor necrosis factor-α antagonist or placebo and a modest increase in vascular inflammation in carotids after 52 weeks of treatment with adalimumab.
Persistent postoperative pain continues to be an underrecognized complication. We examined the prevalence of and risk factors for this type of pain after cardiac surgery.
We enrolled patients ...scheduled for coronary artery bypass grafting or valve replacement, or both, from Feb. 8, 2005, to Sept. 1, 2009. Validated measures were used to assess (a) preoperative anxiety and depression, tendency to catastrophize in the face of pain, health-related quality of life and presence of persistent pain; (b) pain intensity and interference in the first postoperative week; and (c) presence and intensity of persistent postoperative pain at 3, 6, 12 and 24 months after surgery. The primary outcome was the presence of persistent postoperative pain during 24 months of follow-up.
A total of 1247 patients completed the preoperative assessment. Follow-up retention rates at 3 and 24 months were 84% and 78%, respectively. The prevalence of persistent postoperative pain decreased significantly over time, from 40.1% at 3 months to 22.1% at 6 months, 16.5% at 12 months and 9.5% at 24 months; the pain was rated as moderate to severe in 3.6% at 24 months. Acute postoperative pain predicted both the presence and severity of persistent postoperative pain. The more intense the pain during the first week after surgery and the more it interfered with functioning, the more likely the patients were to report persistent postoperative pain. Pre-existing persistent pain and increased preoperative anxiety also predicted the presence of persistent postoperative pain.
Persistent postoperative pain of nonanginal origin after cardiac surgery affected a substantial proportion of the study population. Future research is needed to determine whether interventions to modify certain risk factors, such as preoperative anxiety and the severity of pain before and immediately after surgery, may help to minimize or prevent persistent postoperative pain.
Abstract
We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical ...trial. We found a significant association at 5p13.3 (rs1173773;
P
= 4.94 × 10
–8
) near the natriuretic peptide receptor 3 gene (
NPR3
). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331;
P
= 2.95 × 10
–8
) in interaction with colchicine (
P
= 1.19 × 10
–5
) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.
Reduction of inflammation with colchicine has emerged as a therapeutic option for secondary prevention of cardiovascular disease (CVD) in patients with coronary artery disease (CAD). Our objective ...was to consolidate evidence from randomized controlled trials (RCTs) evaluating the efficacy and safety of low-dose colchicine for secondary prevention of CVD among patients with CAD on standard medical therapy.
RCTs comparing the incidence of cardiovascular (CV) events between patients with clinically manifest CAD randomized to colchicine vs placebo (or no colchicine) were included. The primary composite efficacy endpoint included CV mortality, myocardial infarction (MI), ischemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random-effects model was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).
Four RCTs, with a pooled sample size of 11,594 patients, were included (colchicine n = 5774; placebo/no colchicine n = 5820). Included RCTs studied populations with stable CAD (N = 2) and acute coronary syndrome (N = 2). Compared with placebo or no colchicine, colchicine was associated with a statistically significant reduction in the incidence of the primary composite endpoint (pooled HR, 0.68; 95% CI, 0.54-0.81; I2 = 37.7%). The reduction in CV events among patients randomized to colchicine was driven by statistically significant reductions in MIs, ischemic strokes, and urgent coronary revascularizations (P < 0.05 for all) and was relatively consistent among subgroups. The incidence of safety outcomes did not differ between groups (P > 0.05).
In secondary prevention of CV events, the addition of low-dose colchicine to standard medical therapy reduces the incidence of major CV events—except CV mortality—when compared with standard medical therapy alone.
L’emploi de la colchicine pour réduire l’inflammation s’est révélé être une option thérapeutique dans le cadre de la prévention secondaire des maladies cardiovasculaires (MCV) chez les patients atteints d’une coronaropathie. Notre objectif était de rassembler les données probantes issues d’essais contrôlés avec répartition aléatoire évaluant l’efficacité et l’innocuité de l’administration de colchicine à faible dose pour la prévention secondaire des MCV chez les patients atteints d’une coronaropathie recevant un traitement standard.
Notre étude comprenait les essais contrôlés avec répartition aléatoire comparant l’incidence des événements cardiovasculaires (CV) chez des patients atteints d’une coronaropathie cliniquement observable et répartis aléatoirement pour recevoir de la colchicine ou un placebo (ou un traitement sans colchicine). Le critère d’évaluation principal de l’efficacité regroupait la mortalité d’origine CV, l’infarctus du myocarde (IM), l’accident vasculaire cérébral (AVC) ischémique et la revascularisation coronaire d’urgence. Le modèle à effets aléatoires DerSimonian-Laird a été utilisé pour calculer les rapports des risques instantanés (RRI) groupés et les intervalles de confiance (IC) à 95 %.
Quatre essais contrôlés avec répartition aléatoire, réunissant au total 11 594 patients, ont été inclus (colchicine : n = 5774; placebo/traitement sans colchicine : n = 5820). Deux de ces essais incluaient des patients atteints de coronaropathie stable (n = 2), et les deux autres, des patients présentant un syndrome coronarien aigu (n = 2). Comparativement au placebo ou au traitement sans colchicine, la colchicine a entraîné une réduction statistiquement significative de l’incidence des événements du critère d’évaluation principal composé (RRI groupés : 0,68; IC à 95 % : de 0,54 à 0,81; I2 : 37,7 %). La réduction des événements CV chez les patients répartis aléatoirement pour recevoir de la colchicine était due à des réductions statistiquement significatives des IM, des AVC ischémiques et des revascularisations coronaires d’urgence (p < 0,05 dans tous les cas) et était relativement constante dans tous les sous-groupes. L’incidence des problèmes d’innocuité était la même dans les deux groupes (p > 0,05).
Chez les patients en prévention secondaire des événements CV, l’ajout de colchicine à faible dose au traitement standard réduit l’incidence des événements CV majeurs – sauf la mortalité d’origine CV – comparativement au traitement standard seul.
Clinical evidence has suggested that the oat-soluble fiber β-glucan might have lipid-lowering effects.
The present clinical trial was conducted to evaluate the efficacy and safety of high-medium ...molecular weight β-glucan on serum low-density lipoprotein (LDL) cholesterol and other lipid subfractions in subjects with hyperlipidemia.
A randomized double-blinded trial was performed to assess the efficacy and safety of β-glucan supplementation in reducing lipid levels. Subjects with LDL cholesterol levels of >3.37 mmol/L when treated or not with a statin were randomly assigned to receive 1 of 3 daily doses of a tableted formulation of β-glucan (1.5, 3, or 6 g) or placebo. The primary efficacy end point was the change from baseline to 12 wk in LDL cholesterol. Secondary end points of lipid subfractions and safety were also assessed.
A total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 β-glucan groups, and 65 subjects were assigned to the placebo group. The mean change from baseline to 12 wk in serum LDL cholesterol level was 0.08, 0.11, and −0.04 mmol/L in the 3 β-glucan groups (P = 0.23, 0.18, and 0.72 compared with the placebo group, respectively) and −0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL cholesterol subclass particle concentration, non–high-density lipoprotein cholesterol, apolipoprotein B, very low–density lipoprotein cholesterol, and high-sensitivity C-reactive protein were also not significant in the β-glucan groups when compared with the placebo group. Gastrointestinal adverse events were reported in 23.4%, 34.8%, and 66.7% of patients in the β-glucan groups and in 36.9% of patients in the placebo group (P < 0.0001 for the overall comparison across the 4 groups).
In subjects with LDL cholesterol levels of >3.37 mmol/L, a tablet formulation of β-glucan was not effective in reducing LDL cholesterol concentration or other lipid subfractions when compared with a placebo.
This trial was registered at clinicaltrials.gov as NCT03857256.
Background
The Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non‐ST‐Segment Elevation Myocardial Infarction (SELECT‐ACS) trial ...suggested beneficial effects of inclacumab, a monoclonal antibody directed against P‐selectin, on periprocedural myocardial damage. This study evaluated the effect of inclacumab on myocardial damage according to varying time intervals between study drug infusion and percutaneous coronary intervention (PCI).
Methods and Results
Patients (n=544) enrolled in the SELECT‐ACS trial and randomized to receive 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 hours before PCI) were divided according to the time interval between study drug infusion and PCI. The primary end point was the change in troponin I from baseline at 16 and 24 hours after PCI. In patients receiving inclacumab 20 mg/kg with a short (less than median) time interval between infusion and PCI, placebo‐adjusted geometric mean percent changes in troponin I, creatine kinase–myocardial band, and peak troponin I at 24 hours were −45.6% (P=0.005), −30.7% (P=0.01), and −37.3% (P=0.02), respectively. No significant changes were observed in patients with a long (greater than median) time interval between infusion and PCI. Placebo‐adjusted geometric mean percent changes in troponin I and creatine kinase–myocardial band were −43.5% (P=0.02) and −26.0% (P=0.07), respectively, when inclacumab 20 mg/kg was administered between 1 and 3 hours before PCI, whereas the drug had no effect with longer intervals.
Conclusions
Inclacumab 20 mg/kg significantly reduces myocardial damage after PCI in patients with non–ST‐segment elevation myocardial infarction, and benefits are larger when the infusion is administered <3 hours before PCI.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01327183.
PDF
