Table of Contents
Summary
Background
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.
Methods
Findings
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).
Interpretation
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.
Funding
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.
Introduction
The steroid dexamethasone reduces mortality in patients admitted to hospital with COVID-19, but only if they receive mechanical ventilation or supplemental oxygen.
Dexamethasone in hospitalized patients with Covid-19 – Preliminary report.
In the open-label STOIC trial,
- Ramakrishnan S
- Nicolau Jr, DV
- Langford B
- et al.
the inhaled steroid budesonide decreased the requirement for urgent medical care in patients with early COVID-19. In addition, the anti-interleukin (IL)-6-receptor antibody tocilizumab was shown to reduce the likelihood of progression to mechanical ventilation in patients admitted and treated in hospital for COVID-19 pneumonia.
- Salama C
- Han J
- Yau L
- et al.
The IL-1 receptor antagonist anakinra might also be effective in some patients with COVID-19.
- Cavalli G
- De Luca G
- Campochiaro C
- et al.
- Nieto-Torres JL
- Verdiá-Báguena C
- Jimenez-Guardeno JM
- et al.
Activation of the NLRP3 inflammasome by SARS-CoV-2 has been shown in lung tissues of patients with COVID-19.
- Rodrigues TS
- de Sa KSG
- Ishimoto AY
- et al.
This intracellular complex activates several ILs, which then trigger an inflammatory cascade. Given that elevated concentrations of IL-1β and IL-6 are associated with adverse clinical outcomes in COVID-19,
,
- Thwaites RS
- Sevilla Uruchurtu AS
- Siggins M
- et al.
targeting the NLRP3 inflammasome (which is responsible for the maturation and secretion of IL-1β) might reduce related complications in patients at risk of cytokine activation.
Evidence before this study
We searched MEDLINE (PubMed), Embase, and Cochrane central to identify studies investigating the role of the host inflammatory response in COVID-19 complications and randomised controlled trials (RCTs) of anti-inflammatory agents aimed at preventing this response, from inception until April 12, 2021. To maximise sensitivity, we also searched for citations in Google Scholar, Scopus, and Web of Science. Search terms included “COVID-19”, “coronavirus”, “inflammation”, “inflammatory storm”, “cytokine”, “cytokine storm”, “anti-inflammatory agents”, and “colchicine”, either separately or in combination. The inhaled steroid budesonide was shown in the open-label STOIC trial to reduce the requirement for urgent medical care in patients with early COVID-19. Activation of the NLRP3 inflammasome by SARS-CoV-2 was observed in lung tissues of patients with COVID-19. Prevention of COVID-19 complications in an outpatient setting ideally requires a clinically approved, orally administered, and inexpensive medication targeting the inflammasome with a known favourable safety profile.
Added value of this study
Potential clinical benefits of colchicine have been reported in observational studies and two small RCTs (including GRECCO) of patients admitted to hospital with COVID-19. In our COLCORONA double-blinded, placebo-controlled, randomised trial of 4488 non-hospitalised patients, including the 327 (7%) without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among the 4159 (93%) of patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo.
Implications of all the available evidence
Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients, the burden on health-care systems caused by hospital admissions, and the benefit of colchicine in patients with PCR-proven COVID-19, we propose that colchicine is a safe and inexpensive anti-inflammatory agent that could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of patients who have positive PCR tests and have been treated in the community (such as the PRINCIPLE trial) is recommended. Additional trials such as the AGILE-ACCORD might enrich our therapeutic armamentarium to prevent COVID-19-related complications in ambulatory patients.
- Imazio M
- Bobbio M
- Cecchia E
- et al.
,
- Tardif JC
- Kouz S
- Waters DD
- et al.
,
- Nidorf SM
- Fiolet ATL
- Mosterd A
- et al.
,
- Cerquaglia C
- Diaco M
- Nucera G
- La Regina M
- Montalto M
- Manna R
Its mechanism of action is through the inhibition of tubulin polymerisation, with effects on the inflammasome, cellular adhesion molecules, and inflammatory chemokines.
- Ravelli RBG
- Gigant B
- Curmi PA
- et al.
,
,
- Perico N
- Ostermann D
- Bontempeill M
- et al.
In an experimental model of acute respiratory-distress syndrome, colchicine was shown to reduce inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment.
- Dupuis J
- Sirois MG
- Rhéaume E
- et al.
Substantial clinical benefits of colchicine have also been reported in observational studies and two randomised controlled trials of patients admitted to hospital with COVID-19.
- Deftereos SG
- Giannopoulos G
- Vrachatis DA
- et al.
,
- Lopes MA
- Bonjomo LP
- Giannini MC
- et al.
,
- Zavaleta MH
- Corzo CAC
- Silva FB
- et al.
,
- Scarsi M
- Piantoni S
- Colombo E
- et al.
We did the COLchicine CORONAvirus SARS-CoV-2 (COLCORONA) trial in community-treated patients with COVID-19 to establish the effects of colchicine on complications, including hospital admission and death, as well as its safety and tolerability.
Methods
Study design
Trial population
Case definition for coronavirus disease 2019 (COVID-19).
Women were either not of childbearing potential or practicing adequate contraception.
Written informed consent was obtained electronically or on paper from all patients before enrolment following a telemedicine or in-person visit.
Randomisation and masking
Masked randomisation was centralised and done electronically through an automated interactive web-response system (IWRS). Participants were randomly assigned (1:1) to either colchicine treatment or placebo, using an allocation sequence that was computer-generated using a blocking schema with block sizes of six. Allocation sequence was not stratified. Eligible patients were randomly assigned by research nurses through the IWRS system that provided the bottle number to send to patients. The randomisation list was computer-generated by an unmasked biostatistician and uploaded to an interactive web response system (Dacima). The database was a validated electronic-data-capture system (eCRF) using InForm 6.0 provided by Oracle. The eCRF was developed by the MHICC as per their internal standard-operating procedures. All eCRF users were trained as per completion guidelines and the data entry was done directly by the study staff during phone calls with the patients. The data cleaning activities were done as per the MHICC data-management plan. All staff involved, including study investigators, nurses, and patients were masked to the treatment received.
Procedures
All patients received either 0·5 mg colchicine orally administered twice per day for the first 3 days and then once per day for 27 days thereafter, or matching placebo. Study medication was delivered at the patient’s house within 4 h of enrolment. The study medication and matching placebo were provided by Pharmascience (Montreal, Canada), which had no role in the design or conduct of the trial or the preparation or review of this manuscript.
Clinical evaluations occurred by telephone at 15 days and 30 days following randomisation for evaluation of the occurrence of any trial endpoints or other adverse events.
Endpoints
The primary efficacy endpoint was a composite of death or hospital admission because of COVID-19 infection in the 30 days after randomisation. The secondary endpoints consisted of the components of the composite primary endpoint, and the need for mechanical ventilation in the 30 days after randomisation. Pneumonias, other serious adverse events, and non-serious adverse events were also collected.
Statistical analysis
Assuming a primary endpoint event rate of 7% in the placebo group, we estimated that a sample size of approximately 6000 patients randomly allocated to treatment with 3000 patients in each treatment group would be required to detect a target 25% relative-risk reduction with colchicine (corresponding to a primary endpoint event rate of 5·25% with colchicine, for an absolute difference of 1·75%) with a power of 80% and a two-sided test at the 0·05 significance level. Because the efficacy interim analyses were done with the conservative O’Brien-Fleming approach, their impact on final significance was deemed to be minimal and no sample-size adjustment was done for interim analyses.
Efficacy analyses were done according to the intention-to-treat principle. The primary endpoint was compared between the two treatment groups using a χ2 test, and the odds ratio (OR) along with the 95·1% CI was provided. Secondary endpoints were analysed similarly. Because of potential limitations to the specificity of COVID-19 diagnosis made on clinical or epidemiological criteria alone, a pre-specified subgroup analysis of the primary endpoint examined patients who were enrolled based on a positive PCR test. Pre-specified subgroup analyses of the primary endpoint were done using logistic-regression models including the treatment group, the subgroup factor, and the treatment x subgroup-factor interaction. Investigation of secondary endpoints in subgroups were done as post-hoc analyses. A pre-specified sensitivity analysis of the primary endpoint was done by imputing a primary event in event-free patients who did not complete the study (ie, discontinued before day 30 or for whom no information was available at end of study).
Three formal interim efficacy analyses on the primary endpoint were planned after 25%, 50%, and 75% of the primary endpoint events had occurred. The prespecified stopping rule for efficacy was based on the Lan-DeMets procedure with the O’Brien-Fleming α-spending function to determine the significance level. Futility was assessed by computing the conditional power under the original alternative and judged at 15%. Results of the interim analyses were generated by an unmasked biostatistician and were provided only to the data-safety monitoring board members. During the entire duration of the trial, the study team, including the biostatisticians who wrote the statistical analysis plan and generated the final results, remained masked to treatment allocation.
Role of the funding source
The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
Results
FigureTrial profile
Of a sample of 5536 patients screened in Canada, 775 (14%) patients were randomly assigned to treatment, because 2392 (43%) patients did not have at least one high-risk characteristic (which was an inclusion criterion) or met at least one exclusion criterion, and 2369 (43%) patients declined participation. Note that information on screened individuals is only available for those recruited in Canada.
Table 1Characteristics of the patients at randomisation in the intent-to-treat population
Data are n (%) unless otherwise specified. BMI=body-mass index. MI=myocardial infarction.
Table 2Rates and odds ratios for major clinical outcomes in the intent-to-treat population
In a prespecified sensitivity analysis of the primary endpoint to account for missing data where an event was imputed in all patients who were event free and who did not complete the study (32 patients in the colchicine group and 49 patients in the placebo group), the primary-endpoint event rate was 136 (6·1%) of 2235 patients in the colchicine group and 180 (8·0%) of 2253 patients in the placebo group (OR 0·75, 95% CI, 0·59–0·94; p=0·013).
Table 3Rates and odds ratios for major clinical outcomes in the subgroup of patients with PCR-confirmed COVID-19 in the intent-to-treat population
Data are n (%). Evaluation of the primary endpoint in the subgroup of patients with PCR-confirmed COVID-19 was prespecified and that of components of the primary endpoint and the secondary endpoints were done as post-hoc analyses.
Table 4Primary-efficacy composite endpoint in prespecified subgroups of the intent-to-treat population
Data are n (%) of N. ACEi=angiotensin-converting enzyme inhibitor. ARB=angiotensin-receptor blocker.
Table 5Proportions of patients with adverse events in the safety population
Data are n (%). The safety population refers to the patients who took at least one dose of trial medication. AE=adverse event. SAE=serious adverse event. NA=not applicable.
Discussion
In COLCORONA, the risk of the primary composite efficacy endpoint of death or hospital admission due to COVID-19 infection in the 30 days following randomisation was not statistically significantly lower among the patients who were randomly assigned to receive colchicine than in those who received placebo.
Because of the shortage of reagents for PCR tests and the restriction in the use of such testing early in the pandemic, diagnosis of probable COVID-19 through an epidemiological link or compatible symptoms was initially allowed in the study. These patients had a primary event rate that was half (3%) that observed in those with confirmed diagnosis by PCR testing (6%).
When the patients who had a confirmed diagnosis of COVID-19 are considered, the benefit of colchicine on the primary-efficacy endpoint was more marked and statistically significant. The relative-risk reduction that we observed was similar to the one planned in the sample-size calculation. Treatment with colchicine was associated with concordant effects on hospital admissions, use of mechanical ventilation, and deaths in patients with a diagnosis of COVID-19 confirmed by PCR testing.
- Takahashi T
- Ellingson MK
- Wong P
- et al.
These differences might at least in part explain the apparent difference in response to colchicine in COVID-19. Of note, the concomitant use of an inhibitor of the renin-angiotensin system did not appear to modify the clinical response to colchicine.
- Deftereos SG
- Giannopoulos G
- Vrachatis DA
- et al.
,
- Lopes MA
- Bonjomo LP
- Giannini MC
- et al.
Colchicine has previously been shown to reduce acute lung injury in an experimental model of acute respiratory-distress syndrome.
- Dupuis J
- Sirois MG
- Rhéaume E
- et al.
The risk of viral inflammatory pneumonitis therefore appears to be lowered by colchicine in patients with COVID-19. Reassuringly, there was no evidence of an increased risk of bacterial pneumonia in COLCORONA.
- Samuel M
- Tardif JC
- Bouabdallaoui N
- et al.
In addition, a significant reduction in the concentration of D dimer, a plasma biomarker used for the diagnostic investigation of pulmonary embolism, was observed with colchicine compared with the control in the GRECCO study.
- Deftereos SG
- Giannopoulos G
- Vrachatis DA
- et al.
Furthermore, colchicine has previously been shown in murine models to lower the release of α defensin associated with large thrombus burdens and in clinical studies to reduce the aggregation between neutrophils and platelets.
- Abu-Fanne R
- Stepanova V
- Litvinov RI
- et al.
,
,
- Shah B
- Allen N
- Harchandani B
- et al.
Thus, there is no known potential biological basis to suggest a causal link between colchicine therapy and thromboembolic disease. The incidence of pulmonary embolism is high in COVID-19, and occurs in up to 25% of patients with associated pneumonia.
- Bompard F
- Monnier H
- Saab I
- et al.
More than 57% of patients dying from COVID-19 have evidence of deep venous thrombosis or pulmonary embolus at autopsy.
- Wichmann D
- Sperhake JP
- Lutgehetmann M
- et al.
In COLCORONA, the incidence of pulmonary embolism in patients requiring hospital admission was 11 (10·9%) of 101 patients in the colchicine group and two (1·6%) of 128 in the placebo group. The totality of the evidence suggests that the low rate of pulmonary embolisms in the placebo group represents an anomaly. The more common presence and greater severity of COVID-19 pneumonia infiltrates in patients receiving placebo might have reduced the clinical suspicion for pulmonary embolism in symptomatic patients.
- Deftereos SG
- Giannopoulos G
- Vrachatis DA
- et al.
,
- Lopes MA
- Bonjomo LP
- Giannini MC
- et al.
Finally, our results apply to patients who have a proven diagnosis of COVID-19, are at risk of clinical complications, and are not admitted to hospital at the time of treatment initiation. The number needed to treat with colchicine to prevent one primary endpoint event was 70 (95% CI 36–1842) for patients with PCR-proven COVID-19, 29 (14 to not defined) for those with diabetes, 31 (11 to not defined) for patients aged 70 years and older, 39 (21–259) in men, 52 (21 to not defined) in patients with respiratory disease, and 25 (10 to not defined) in those with cardiovascular disease.
In conclusion, 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.
Contributors
J-CT and lead statistician M-CG had full access to the trial database, generated statistical analyses, made the decision to submit the manuscript for publication, and assume responsibility for the accuracy and completeness of the data and analyses and for the fidelity to the protocol. Concept and design was done by J-CT, NB, PLL’A, JD, AD, MP, PAT, and GB. Acquisition, analysis, or interpretation of data was done by J-CT, NB, PLL’A, DG, BS, MHP, JL-S, PdL, JD, SS, DF, J-DT, DB, EG, CL, AD, AYJ, DDW, PH, NEL, FL, NS, ER-C, ZB, AO, GS, JCG, LB, CL, P-OH, SL, MC, AN, MC-B, M-PD, M-CG, and GB. Drafting of the manuscript was done by J-CT and M-CG. Critical revision of the manuscript for important intellectual content was done by J-CT, NB, SGD, PLL’A, DG, BS, MHP, JL-S, PdL, LV, SA, JD, AD, MP, PAT, SS, DF, J-DT, DB, EG, CL, AD, AYJ, DDW, PH, NEL, FL, NS, ER-C, ZB, AO, GS, JCG, LB, CL, P-OH, J-SP, SL, MC, AN, M-CB, M-PD, M-CG, and GB. Statistical analysis was done by SL, MC, AN, M-CB, and M-CG. J-CT obtained funding. Administrative, technical, or material support was offered by J-CT, LV, SA, DB, EG, CL, AD, FL, NS, ER-C, ZB, AO, GS, LB, CL, and P-OH. Supervision was provided by J-CT, NB, PLL’A, BS, MHP, JL-S, PdL, LV, ZB, AO, and GB. SS, DF, and EG had the role of research nurses.
Declaration of interests
J-CT reports grants from Government of Quebec, the National Heart, Lung, and Blood Institute of the US National Institutes of Health (NIH), the Montreal Heart Institute Foundation, the Bill & Melinda Gates Foundation, Amarin, Esperion, Ionis, Servier, and RegenXBio, along with grants and personal fees from AstraZeneca, Sanofi, and Servier, and grants, personal fees, and minor equity interests from Dalcor. In addition, J-CT’s institution has submitted a pending patent for a method of treating a coronavirus infection using colchicine, and a pending patent on early administration of low-dose colchicine after myocardial infarction. J-CT has waived his rights in all patents related to colchicine and does not stand to benefit financially if colchicine becomes used as a treatment for COVID-19. M-PD and J-CT have a patent method for treating or preventing cardiovascular disorders and lowering risk of cardiovascular events issued to Dalcor, no royalties received, a patent genetic markers for predicting responsiveness to therapy with HDL-raising or HDL mimicking agent issued to Dalcor, no royalties received, and a patent method for using low-dose colchicine after myocardial infarction with royalties paid to invention assigned to the Montreal Heart Institute. NB reports personal fees from AstraZeneca. BS reports grants from NIH NHLBI; MHP reports grants from Hikma Pharmaceuticals and Horizon Therapeutics, and personal fees from Horizon Therapeutics. JL-S reports grants from Bayer, Pfizer, Amgen, and Boheringer Ingelheim, and personal fees from Menarini. AD reports personal fees from CAE Healthcare and Masimo and grants from Edwards. POH reports grants from NIH, Montreal Heart Institute, Gilead, and other types of support from Merck. AO reports grants from the COVID-19 Therapeutics Accelerator. J-SP reports personal fees from Université Laval. M-PD reports personal fees and other types of support from Dalcor and personal fees from GlaxoSmithKline, AstraZeneca, Pfizer, Servier, and Sanofi. All other authors declare no competing interests.
Data sharing
Acknowledgments
The authors acknowledge the expert secretarial assistance of Lucie Lefebvre in the preparation and submission of this manuscript.
Supplementary Material
References
- 1.
Cytokine storm.
N Engl J Med. 2020; 383: 2255-2273
- 2.
Treating the host response: an alternative way to manage Ebola in Africa and the next influenza pandemic.
J Glob Health. 2019; 9010322
- 3.
Dexamethasone in hospitalized patients with Covid-19 – Preliminary report.
N Engl J Med. 2021; 384: 693-704
- 4.
Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial.
Lancet Respir Med. 2021; ()
- 5.
Tocilizumab in patients hospitalized with Covid-19 pneumonia.
N Engl J Med. 2021; 384: 20-30
- 6.
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
Lancet Rheumatol. 2020; 2: e325-e331
- 7.
Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome.
Virology. 2015; 485: 330-339
- 8.
Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients.
J Exp Med. 2020; 218e20201707
- 9.
Interleukin-6 in Covid-19: A systematic review and meta-analysis.
Rev Med Virol. 2020; 30: 1-9
- 10.
Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19.
Sci Immunol. 2021; 69873
- 11.
Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial.
Circulation. 2005; 112: 2012-2016
- 12.
Efficacy and safety of low-dose colchicine after myocardial infarction.
N Engl J Med. 2019; 381: 2497-2505
- 13.
Colchicine in patients with chronic coronary disease.
N Engl J Med. 2020; 383: 1831-1847
- 14.
Pharmacological and clinical basis of treatment of familial Mediterranean fever (FMF) with colchicine or analogues: an update.
Curr Drug Targ Inflamm Allergy. 2005; 4: 117-124
- 15.
Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain.
Nature. 2004; 428: 198-202
- 16.
The role of interleukin-1 and the inflammasome in gout: implications for therapy.
Arthritis Rheumat. 2007; 56: 3183-3188
- 17.
Colchicine interferes with L-selectin and leukocyte function associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.
J Am Soc Nephrol. 1996; 7: 594-601
- 18.
Colchicine reduces lung injury in experimental acute respiratory distress syndrome.
PLoS One. 2020; 15e0242318
- 19.
Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial.
JAMA Network Open. 2020; 3e2013136
- 20.
Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
RMD Open. 2021; 7e001455
- 21.
Characteristics and risk factors for mortality in patients hospitalized by COVID-19 in a public hospital in Tacna.
SciFlo. 2021; ()
- 22.
Association between treatment with colchicine and improved survival in a single-center cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome.
Ann Rheum Dis. 2020; 79: 1286-1289
- 23.
Case definition for coronavirus disease 2019 (COVID-19).
- 24.
Sex differences in immune responses that underlie COVID-19 disease outcomes.
Nature. 2020; 588: 315-320
- 25.
Colchicine for secondary prevention of cardiovascular disease: A systematic review and meta-analysis of randomized controlled trials.
Can J Cardiol. 2020; ()
- 26.
Neutrophil defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability.
Blood. 2019; 133: 481-493
- 27.
Hadassah researchers pinpoint source of corona blood clots. ISRAEL21c (internet).
- 28.
Effect of colchicine on platelet-platelet and platelet-leukocyte interactions: a pilot study in healthy subjects.
Inflammation. 2016; 39: 182-189
- 29.
Pulmonary embolism in patients with COVID-19 pneumonia.
Eur Respir J. 2020; 562001365
- 30.
Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study.
Ann Intern Med. 2020; 173: 268-277
Article Info
Publication History
Identification
Copyright
© 2021 The Author(s). Published by Elsevier Ltd.
User License
ScienceDirect
Linked Articles
- Exploiting an early immunological window of opportunity in COVID-19
-
Substantial advances in COVID-19 therapeutics have been made over the past year. Highly effective vaccines now exist to reduce a vaccinated person’s risk of developing symptomatic disease and progressing to require hospital admission. For patients who are being treated in hospital and require supplemental oxygen, dexamethasone improves survival,1 with an additional benefit from tocilizumab if systemic inflammation is present.2 However, there remains an unmet need for therapeutic interventions that inhibit disease progression in symptomatic people in the community and prevent hospital admission.
- Full-Text
-
