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1.
PLoS One ; 17(4): e0266245, 2022.
Article in English | MEDLINE | ID: covidwho-1775456

ABSTRACT

BACKGROUND: Colchicine has been used an effective anti-inflammatory drug to treat gout diseases. Owing to its pharmacodynamic of inhibiting interleukins, it has been repurposed to target the cytokine storm post-SARS-CoV-2 invasion. The goal of this meta-analysis was to evaluate the safety profile of colchicine in COVID-19 patients using the gold-standard randomised-control trials. METHODS: Electronic databases (Pubmed, Google Scholar, and Cochrane) were systematically searched until June 2021 and RCTs were extracted. Outcomes of interest included all-cause mortality, COVID-19 severity, mechanical ventilation, C-reactive protein and D-dimer levels. Using a random-effects model, dichotomous outcomes were pooled using odds ratios (OR) through the generic inverse variance formula while weighted mean differences were calculated using the Wan's method. P-values < 0.05 were considered statistically significant for all outcomes. RESULTS: A total population of 16,048 from five RCTs were included in the analysis. Of this, 7957 were randomized to colchicine, and 8091 received standard care, with an average age of 60.67 years. Colchicine was observed to significantly reduce COVID-19 severity (OR: 0.41, 95% CI [0.22, 0.76]; p = 0.005), and CRP levels (WMD: -19.99, 95% CI [-32.09, -7.89]; p = 0.001). However, there was no significant difference in D-dimer levels (WMD: 0.31, 95% CI [-0.61, 1.23]; p = 0.51), mechanical ventilation (OR: 0.42, 95% CI [0.17, 1.03]; p = 0.06; I2 = 74%) and all-cause mortality (OR: 0.98, 95% CI [0.83, 1.16]; p = 0.84) among patients receiving colchicine or standard care. CONCLUSION: Colchicine treatment decreased CRP levels and COVID-19 severity, with dimer levels, all-cause mortality and mechanical ventilation remaining seemingly unaffected. Thus, clinical trials need to be carried out that allow effective evaluation of colchicine in COVID-19 patients.


Subject(s)
COVID-19 , Colchicine , C-Reactive Protein , COVID-19/drug therapy , Colchicine/therapeutic use , Humans , Middle Aged , Odds Ratio , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2
2.
Expert Opin Pharmacother ; 23(6): 681-691, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1769033

ABSTRACT

INTRODUCTION: Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are first-line treatments for acute and recurrent pericarditis. Drugs blocking the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1ß (IL-1ß) axis are beneficial in patients with multiple recurrences. AREAS COVERED: In this review, the role of the NLRP3 inflammasome/IL-1ß axis in the pathophysiology of pericarditis is discussed. Updates about novel therapies targeting IL-1 for recurrent pericarditis (RP) and practical considerations for their use are provided. EXPERT OPINION: IL-1 inhibitors have been increasingly studied for RP in recent years. NLRP3 inflammasome is a key mediator in the pathophysiology of RP. IL-1ß, its main product, can sustain its own production and feeds local and systemic inflammation. Randomized clinical trials testing anakinra (a recombinant form of the IL-1 receptor antagonist blocking IL-1α and IL-1ß) and rilonacept (an IL-1α and IL-1ß trap) have shown that IL-1 blockade reduces recurrences. These trials also helped in phenotyping patients with RP. Patients with multiple recurrences and signs of pericardial and/or systemic inflammation might benefit from IL-1 blockers in order to interrupt cyclic flares of auto-inflammation. Given this evidence, guidelines should consider incorporating IL-1 blockers.


Subject(s)
Pericarditis , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Colchicine/therapeutic use , Humans , Inflammasomes/metabolism , Inflammasomes/therapeutic use , Inflammation/drug therapy , Pericarditis/diagnosis , Pericarditis/drug therapy
4.
Ann Med ; 54(1): 775-789, 2022 12.
Article in English | MEDLINE | ID: covidwho-1730419

ABSTRACT

INTRODUCTION: Colchicine, because of its anti-inflammatory and possible anti-viral properties, has been proposed as potential therapeutic option for COVID-19. The role of colchicine to mitigate "cytokine storm" and to decrease the severity and mortality associated with COVID-19 has been evaluated in many studies. OBJECTIVE: To evaluate the role of colchicine on morbidity and mortality in COVID-19 patients. METHODS: This systematic review was conducted in accordance with the PRISMA recommendations. The literature search was conducted in 6 medical databases from inception to February 17, 2021 to identify studies evaluating colchicine as a therapeutic agent in COVID-19. All included studies were evaluated for risk of bias (ROB) using the Revised Cochrane ROB tool for randomised controlled trials (RCTs) and Newcastle-Ottawa Scale (NOS) for case-control and cohort studies. RESULTS: Four RCTs and four observational studies were included in the final analysis. One study evaluated colchicine in outpatients, while all others evaluated inpatient use of colchicine. There was significant variability in treatment protocols for colchicine and standard of care in all studies. A statistically significant decrease in all-cause mortality was observed in three observational studies. The risk of mechanical ventilation was significantly reduced only in one observational study. Length of hospitalisation was significantly reduced in two RCTs. Risk for hospitalisation was not significantly decreased in the study evaluating colchicine in outpatients. Very few studies had low risk of bias. CONCLUSION: Based on the available data, colchicine shall not be recommended to treat COVID-19. Further high-quality and multi-center RCTs are required to assess the meaningful impact of this drug in COVID-19.KEY MESSAGESColchicine, an anti-inflammatory agent has demonstrated anti-viral properties in in-vitro studies by degrading the microtubules, as well as by inhibiting the production of pro-inflammatory cytokines.Colchicine has been studied as a potential therapeutic option for COVID-19, with variable results.Until further research can establish the efficacy of colchicine in COVID-19, the use of colchicine in COVID-19 shall be restricted to clinical trials.


Subject(s)
COVID-19 , COVID-19/drug therapy , Colchicine/therapeutic use , Humans , Morbidity , Observational Studies as Topic , Respiration, Artificial , SARS-CoV-2
5.
Inflamm Res ; 71(3): 293-307, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1729272

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is capable of inducing the activation of NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a macromolecular structure sensing the danger and amplifying the inflammatory response. The main product processed by NLRP3 inflammasome is interleukin (IL)-1ß, responsible for the downstream production of IL-6, which has been recognized as an important mediator in coronavirus disease 2019 (COVID-19). Since colchicine is an anti-inflammatory drug with the ability to block NLRP3 inflammasome oligomerization, this may prevent the release of active IL-1ß and block the detrimental effects of downstream cytokines, i.e. IL-6. To date, few randomized clinical trials and many observational studies with colchicine have been conducted, showing interesting signals. As colchicine is a nonspecific inhibitor of the NLRP3 inflammasome, compounds specifically blocking this molecule might provide increased advantages in reducing the inflammatory burden and its related clinical manifestations. This may occur through a selective blockade of different steps preceding NLRP3 inflammasome oligomerization as well as through a reduced release of the main cytokines (IL-1ß and IL-18). Since most evidence is based on observational studies, definitive conclusion cannot be drawn and additional studies are needed to confirm preliminary results and further dissect how colchicine and other NLRP3 inhibitors reduce the inflammatory burden and evaluate the timing and duration of treatment.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Colchicine/therapeutic use , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2 , Animals , COVID-19/immunology , Humans
6.
J Infect Dev Ctries ; 16(1): 57-62, 2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-1705131

ABSTRACT

INTRODUCTION: Colchicine is an ancient agent with well-known anti-inflammatory effects and commonly used in treatment of hyperinflammatory conditions. It has been argued that colchicine could be an appropriate treatment option in COVID-19 to control hyperinflammatory response. Here in this study, we aimed to investigate the impact of colchicine on outcomes of COVID-19 in our inpatient cohort. METHODOLOGY: In this retrospective cohort study, hospitalized COVID-19 patients were investigated. Demographics, comorbidities, COVID-19 symptoms, laboratory findings on admission and discharge, baseline and seventh day oxygenation status, rates of mortality, intensive care unit admission, administration of other anti-inflammatory treatments and length of hospital stay were compared between patients who received standard of care medications and who received colchicine additionally. RESULTS: Three hundred and thirty-six patients were included in the study (171 standard of care, 165 standard of care plus colchicine). The median length of hospital stay in colchicine group was significantly shorter. Rates of admission to intensive care unit, anti-inflammatory treatment administration and mortality did not differentiate between standard of care and colchicine groups. However, reduced rates of mortality and ICU admission were observed in patients who received colchicine with a dose of 1 mg/day when compared to patients who received 0.5 mg/day. CONCLUSIONS: Our study demonstrated that COVID-19 patients who received colchicine in addition to standard of care had shorter hospital stay. Our results further support the use of colchicine in treatment of COVID-19, particularly with a dose of 1 mg/day.


Subject(s)
COVID-19 , Colchicine , Colchicine/therapeutic use , Hospitalization , Humans , Intensive Care Units , Length of Stay , Retrospective Studies , SARS-CoV-2
7.
Eur J Intern Med ; 96: 34-41, 2022 02.
Article in English | MEDLINE | ID: covidwho-1670444

ABSTRACT

Colchicine is an old, inexpensive, and relatively safe anti-inflammatory drug traditionally used in gout and over the last 50 years in familial Mediterranean fever. A search of all high-hierarchy studies (randomized controlled trials [RCTs], systematic reviews and meta-analysis of RCTs) over the last 20 years revealed myriad other evidence-based applications. Colchicine seems efficacious in the treatment of acute pericarditis and prevention of recurrences and in the prevention of postcardiac injury syndrome and atrial fibrillation following cardiac surgery or percutaneous interventions. In patients already fully treated with statins and antiplatelet agents following acute coronary syndromes or stable coronary disease, adding low-dose colchicine achieved secondary prevention of major cardiovascular events (myocardial infarction, stroke, or cardiovascular death) with pooled risk reduction 0.75. Colchicine may also be useful in Behcet's syndrome and most recently, in improving outcomes of COVID-19 infection. Colchicine in the low doses used in most trials (≤ 1 mg/d) was generally safe and well-tolerated, excepting diarrhea (approximately 10%) which sometimes led to drug discontinuation. Further RCTs are required to confirm these results, and will likely lead to expanding indications for low-dose colchicine. Increasing numbers of patients will be treated with colchicine in the near future, with improved health outcomes, as long as basic caveats are heeded.


Subject(s)
Acute Coronary Syndrome , COVID-19 , Pharmaceutical Preparations , Colchicine/therapeutic use , Humans , SARS-CoV-2
8.
BMJ Case Rep ; 15(1)2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1642829

ABSTRACT

COVID 19, caused by SARS-CoV-2, is a highly infectious disease, mainly affects the respiratory system. In this article, we have presented a case of COVID-19, who presented solely with pericarditis without myocarditis, without any respiratory symptoms. The diagnosis was made based on clinical, electrocardiographic, radiological and biological findings. He was treated successfully with aspirin and colchicine. Our case highlights an atypical presentation of COVID-19, which should be kept in mind in the present pandemic and to diagnose and isolate early to limit the spread of infection.


Subject(s)
COVID-19 , Pericarditis , Colchicine/therapeutic use , Humans , Male , Pandemics , Pericarditis/diagnosis , Pericarditis/drug therapy , SARS-CoV-2
10.
PLoS One ; 16(12): e0261358, 2021.
Article in English | MEDLINE | ID: covidwho-1623654

ABSTRACT

INTRODUCTION: Colchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage. METHODS: The literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design (RCT vs observational) and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately. RESULTS: Eight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality-HR of 0.25 (95% CI: 0.09, 0.66) and OR of 0.22 (95% CI: 0.09, 0.57). There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not-OR of 0.26 (95% CI: 0.06, 1.09). CONCLUSION: Colchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Colchicine/therapeutic use , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , COVID-19/mortality , Female , Humans , Intensive Care Units , Male , Middle Aged , Patient Admission/statistics & numerical data , Polymerase Chain Reaction , Respiration, Artificial , Risk , Treatment Outcome
11.
Int J Infect Dis ; 116: 387-390, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1620729

ABSTRACT

OBJECTIVE: A predictive model for hospitalization due to COVID-19 or death was developed in the placebo group (N=2,084) from a large clinical trial of colchicine in COVID-19 patients (N = 4,159). RESULTS: The 7 variables retained in the predictive model were age, gender, body-mass index, history of respiratory disease, use of diabetes drugs, use of anticoagulants, and use of oral steroids at the time of randomization. An optimal threshold value identified from the predictive model was used to classify high-risk patients (those with a predicted probability above the optimal threshold) and low-risk patients (those with a predicted probability below the optimal threshold). The number needed to treat to prevent 1 hospitalization or death with colchicine treatment decreased from 71 in the whole study population (N = 4,159) to 29 in the high-risk subgroup (N=1,692). CONCLUSION: This model could serve to identify high-risk subjects who will particularly benefit from early colchicine therapy.


Subject(s)
COVID-19 , COVID-19/drug therapy , Colchicine/adverse effects , Colchicine/therapeutic use , Hospitalization , Humans , Risk Factors , SARS-CoV-2 , Treatment Outcome
12.
JAMA Netw Open ; 4(12): e2141328, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1592856

ABSTRACT

Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Colchicine/therapeutic use , Hospitalization , Intubation, Intratracheal , Respiration, Artificial , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/adverse effects , COVID-19/mortality , COVID-19/pathology , Colchicine/adverse effects , Female , Humans , Inflammation/drug therapy , Inflammation/etiology , Male , Middle Aged , SARS-CoV-2 , Standard of Care
13.
Immun Inflamm Dis ; 10(2): 255-264, 2022 02.
Article in English | MEDLINE | ID: covidwho-1589100

ABSTRACT

BACKGROUND: Overactivation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome can lead to severe illness in patients with coronavirus disease-2019 (COVID-19). The NLRP3 inhibitor, colchicine, therefore, appears to be promising for the treatment of COVID-19. AIMS: We aimed to perform a meta-analysis of randomized trials investigating the effect of colchicine in patients with COVID-19. MATERIALS & METHODS: We systematically searched electronic databases and clinical trial registries (up to October 17, 2021) for eligible studies. The outcomes of interest were all-cause mortality and duration of hospital stay. Meta-analysis with the random-effects model was used to estimate the pooled odds ratio (OR) of mortality and 95% confidence interval (CI). The pooled standardized mean difference of duration of hospital stay with 95% CI between colchicine users and non-colchicine users was estimated using Cohen's d index. RESULTS: The meta-analyses revealed no significant difference in the odds of mortality (pooled OR = 0.76; 95% CI: 0.53-1.07), but a significant reduction in the duration of hospital stay with the use of colchicine (pooled standardized mean difference = -0.59; 95% CI: -1.06 to -0.13). DISCUSSION AND CONCLUSION: The ability of colchicine to reduce the length of stay in hospitalized patients with COVID-19 is consistent with its potential to prevent clinical deterioration via inhibition of NLRP3 inflammasome. Nevertheless, such beneficial effects of colchicine did not translate into mortality benefits in patients with COVID-19.


Subject(s)
COVID-19 , Colchicine/therapeutic use , Humans , Length of Stay , Randomized Controlled Trials as Topic , SARS-CoV-2
14.
Medicina (Kaunas) ; 58(1)2021 Dec 23.
Article in English | MEDLINE | ID: covidwho-1580585

ABSTRACT

Despite the advance in the management of Coronavirus disease 2019 (COVID-19), the global pandemic is still ongoing with a massive health crisis. COVID-19 manifestations may range from mild symptoms to severe life threatening ones. The hallmark of the disease severity is related to the overproduction of pro-inflammatory cytokines manifested as a cytokine storm. Based on its anti-inflammatory activity through interfering with several pro and anti-inflammatory pathways, colchicine had been proposed to reduce the cytokine storm and subsequently improve clinical outcomes. Molecular docking analysis of colchicine against RNA-dependent RNA polymerase (RdRp) and protease enzymes of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) revealed that colchicine provided a grid-based molecular docking method, C-DOCKER interaction energy 64.26 and 47.53 (Kcal/mol) with protease and RdRp, respectively. This finding indicated higher binding stability for colchicine-protease complexes than the colchicine-RdRp complex with the involvement of seven hydrogen bonds, six hydrogen acceptors with Asn142, Gly143, Ser144, and Glu166 and one hydrogen-bond donors with Cys145 of the protease enzyme. This is in addition to three hydrophobic interactions with His172, Glu166, and Arg188. A good alignment with the reference compound, Boceprevir, indicated high probability of binding to the protease enzyme of SARS-CoV-2. In conclusion, colchicine can ameliorate the destructive effect of the COVID-19 cytokine storm with a strong evidence of antiviral activity by inhibiting the protease enzyme of SARS-CoV-2.


Subject(s)
COVID-19 , Colchicine/therapeutic use , Coronavirus 3C Proteases/antagonists & inhibitors , Cytokine Release Syndrome/drug therapy , COVID-19/drug therapy , Cytokine Release Syndrome/virology , Humans , Molecular Docking Simulation , SARS-CoV-2/drug effects
15.
Mod Rheumatol ; 32(2): 467-472, 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1569714

ABSTRACT

OBJECTIVE: To evaluate the course of coronavirus-19 (COVID-19) infection in paediatric familial Mediterranean fever (FMF) patients and to investigate the risk factors for COVID-19 infection. METHODS: Medical records of 100 consecutive paediatric FMF patients and their COVID-19 infection status were evaluated. Age- and gender-matched control group consisted of 51 patients with positive results for severe acute respiratory syndrome coronavirus 2. RESULTS: Twenty-five of 100 paediatric FMF patients were detected to have COVID-19 infection. A history of contact with a COVID-19 case was present in ∼95% of patients in both the FMF and control groups with COVID-19 infection. Asymptomatic infection was detected in two patients in the paediatric FMF group (8.0%) and 17 patients in the control group (33.3%) (P = .017). Mild disease was observed in 23 paediatric FMF patients (92.0%) and 28 control patients (54.9%) (P = .001), whereas moderate disease was present in only 6 control patients (11.7%) (0 vs 11.7%, P = .074). Severe or critical disease was not observed in any patients. CONCLUSION: Paediatric FMF patients receiving colchicine had no moderate COVID-19 disease compared to the control group. We suggest that colchicine use may tune down the severity of the disease even if it does not prevent COVID-19 infection.


Subject(s)
COVID-19 , Familial Mediterranean Fever , COVID-19/complications , Child , Colchicine/therapeutic use , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/drug therapy , Humans , SARS-CoV-2
16.
Lancet Respir Med ; 9(12): 1419-1426, 2021 12.
Article in English | MEDLINE | ID: covidwho-1555461

ABSTRACT

BACKGROUND: Colchicine has been proposed as a treatment for COVID-19 based on its anti-inflammatory actions. We aimed to evaluate the efficacy and safety of colchicine in patients admitted to hospital with COVID-19. METHODS: In this streamlined, randomised, controlled, open-label trial, underway at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Patients were eligible for inclusion in the study if they were admitted to hospital with clinically suspected or laboratory confirmed SARS-CoV-2 infection and had no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Eligible and consenting adults were randomly assigned (1:1) to receive either usual standard of care alone (usual care group) or usual standard of care plus colchicine (colchicine group) using web-based simple (unstratified) randomisation with allocation concealment. Participants received colchicine 1 mg after randomisation followed by 500 µg 12 h later and then 500 µg twice a day by mouth or nasogastric tube for 10 days in total or until discharge. Dose frequency was halved for patients receiving a moderate CYP3A4 inhibitor (eg, diltiazem), patients with an estimated glomerular filtration rate of less than 30 mL/min per 1·73m2, and those with an estimated bodyweight of less than 70 kg. The primary outcome was 28-day mortality, secondary endpoints included time to discharge, the proportion of patients discharged from hospital within 28 days, and, in patients not on invasive mechanical ventilation at randomisation, a composite endpoint of invasive mechanical ventilation or death. All analyses were by intention-to-treat. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. FINDINGS: Between Nov 27, 2020, and March 4, 2021, 11 340 (58%) of 19 423 patients enrolled into the RECOVERY trial were eligible to receive colchicine; 5610 (49%) patients were randomly assigned to the colchicine group and 5730 (51%) to the usual care group. Overall, 1173 (21%) patients in the colchicine group and 1190 (21%) patients in the usual care group died within 28 days (rate ratio 1·01 [95% CI 0·93 to 1·10]; p=0·77). Consistent results were seen in all prespecified subgroups of patients. Median time to discharge alive (10 days [IQR 5 to >28]) was the same in both groups, and there was no significant difference in the proportion of patients discharged from hospital alive within 28 days (3901 [70%] patients in the colchicine group and 4032 [70%] usual care group; rate ratio 0·98 [95% CI 0·94 to 1·03]; p=0·44). In those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (1344 [25%] in the colchicine group vs 1343 [25%] patients in the usual care group; risk ratio 1·02 [95% CI 0·96 to 1·09]; p=0·47). INTERPRETATION: In adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. FUNDING: UK Research and Innovation (Medical Research Council), National Institute of Health Research, and Wellcome Trust.


Subject(s)
COVID-19 , Colchicine/therapeutic use , Adult , COVID-19/drug therapy , COVID-19/mortality , Hospitalization , Humans , Indonesia , Length of Stay , Nepal , Respiration, Artificial , SARS-CoV-2 , United Kingdom
17.
Eur Rev Med Pharmacol Sci ; 25(22): 7151-7161, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1552082

ABSTRACT

OBJECTIVE: To assess the effectiveness of colchicine, compared with standard of care, for reducing mortality, admission to intensive care, and use of mechanical ventilation. MATERIALS AND METHODS: We performed a systematic review, meta-analysis, and sequential trial analysis. The terms (SARS-CoV-2 OR COVID-19 OR coronavirus) AND (colchicine) were searched in MEDLINE, Scopus, Embase, Cochrane Central Register of Controlled Trials, and preprint repositories (February 2020 to April 2021, extended to June 2021). Risk of bias for randomised controlled trials and observational studies were assessed using the tools RoB 2.0 and ROBINS-I, respectively. We performed subgroup analyses based on study design and sensitivity analyses based on time of colchicine administration. RESULTS: We included six observational studies (1329 patients) and five clinical trials (16,048 patients). All studies but one were conducted in the hospital setting. Colchicine treatment was not associated with a significant decrease in mortality (RR 0.93, 95% CI 0.87 to 1; p=0.06, I2=72%) with a significant subgroup effect (p<0.001) depending on the design of the studies. The drug was effective in observational studies (RR 0.57, 95% CI 0.46 to 0.70, p<0.001, I2=50%) but not in clinical trials (RR 0.99, 95% CI 0.92 to 1.07, p=0.89, I2=21%). The effect of colchicine on intensive care admissions and the need for mechanical ventilation could not be confirmed. Trial sequential boundaries for cumulative meta-analyses of randomised controlled trials suggested no significant effect on mortality (p=0.182) beyond the optimal information size (13,107 patients). CONCLUSIONS: Our results suggest that colchicine treatment has no effect on mortality in hospitalised patients with SARS-CoV-2 infection, and that no further confirmatory clinical trials are needed owing to futility.


Subject(s)
COVID-19/drug therapy , COVID-19/mortality , Colchicine/therapeutic use , Tubulin Modulators/therapeutic use , Adult , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Clinical Trials as Topic , Colchicine/administration & dosage , Critical Care/statistics & numerical data , Hospitalization/statistics & numerical data , Humans , Middle Aged , Mortality/trends , Observational Studies as Topic , Outcome Assessment, Health Care , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Sensitivity and Specificity , Treatment Outcome , Tubulin Modulators/administration & dosage
19.
Eur J Intern Med ; 97: 106-107, 2022 03.
Article in English | MEDLINE | ID: covidwho-1509756
20.
Br J Haematol ; 196(4): 923-927, 2022 02.
Article in English | MEDLINE | ID: covidwho-1488181

ABSTRACT

Patients who are severely affected by coronavirus disease 2019 (COVID-19) may develop a delayed onset 'cytokine storm', which includes an increase in interleukin-6 (IL-6). This may be followed by a pro-thrombotic state and increased D-dimers. It was anticipated that tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, would mitigate inflammation and coagulation in patients with COVID-19. However, clinical trials with TCZ have recorded an increase in D-dimer levels. In contrast to TCZ, colchicine reduced D-dimer levels in patients with COVID-19. To understand how the two anti-inflammatory agents have diverse effects on D-dimer levels, we present data from two clinical trials that we performed. In the first trial, TCZ was administered (8 mg/kg) to patients who had a positive polymerase chain reaction test for COVID-19. In the second trial, colchicine was given (0·5 mg twice a day). We found that TCZ significantly increased IL-6, α-Defensin (α-Def), a pro-thrombotic peptide, and D-dimers. In contrast, treatment with colchicine reduced α-Def and Di-dimer levels. In vitro studies show that IL-6 stimulated the release of α-Def from human neutrophils but in contrast to colchicine, TCZ did not inhibit the stimulatory effect of IL-6; raising the possibility that the increase in IL-6 in patients with COVID-19 treated with TCZ triggers the release of α-Def, which promotes pro-thrombotic events reflected in an increase in D-dimer levels.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Colchicine/therapeutic use , Fibrin Fibrinogen Degradation Products/analysis , alpha-Defensins/immunology , Aged , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Female , Fibrin Fibrinogen Degradation Products/immunology , Humans , Interleukin-6/blood , Interleukin-6/immunology , Male , Middle Aged , Neutrophils/drug effects , Neutrophils/immunology
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