Colchicine for the primary prevention of cardiovascular events

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the clinical benefit and harms of colchicine as primary prevention of cardiovascular outcomes in the general population.

Background

Description of the condition

Cardiovascular diseases (CVDs) include coronary heart disease (CHD), sudden cardiac death/sudden cardiac arrest, cerebrovascular disease, stroke/transient ischaemic attack, rheumatic heart disease, congenital heart disease, deep venous thrombosis, pulmonary embolism, and peripheral arterial disease.  From 1990 to 2019, the prevalence of cases of total CVDs has been nearly doubled from 271 million (95% uncertainty interval (UI): 257 to 285 million) to 523 million (95% UI: 497 to 550 million), respectively (Roth 2020). In addition, it has been estimated that CVDs caused 18.6 million (95% uncertainty interval: 17.1 to 19.7 million) deaths in 2019 (Roth 2020). Doubtlessly,  CVDs yield a high socio‐economic burden in the general population (Flora 2019).

The main cause of CVDs is atherosclerosis, which is the result of cellular‐molecular interactions in the artery wall (Gotlieb  1991); therefore, it is a chronic inflammatory disease with autoimmune foundations (Anyfanti 2021; Barrett 2020; Cochain 2017; Eshghjoo 2021;  Fazeli 2021; Frostegård 2013; Geovanini 2018; Gisterå 2017; Hansson 2006; Hussain 2020;  Kobiyama 2018; Libby 2019; Liu 2019;  Martinez 2018; Mizuno 2011; Oikonomou 2020; Ozen 2021; Patel 2021; Pant 2014; Rahman 2017; Shi 2010; Veronese 2018; Wolf 2019; Zhu 2018). Patients with autoimmune disorders, rheumatic arthritis, systemic lupus erythematosus, and osteoarthritis have a higher frequency of cardiovascular events as compared to the healthy population (Croca 2017;  Hannawi 2021; Li 2021; Liu 2018; Semb 2017; Vicente 2021; Yalcinkaya 2021). The incidence of myocardial infarction in people with rheumatoid arthritis seems to be comparable or higher than in people with diabetes mellitus (Ali 2021; Wang 2021). Therefore, rheumatoid arthritis should be considered as a prominent risk factor for CVDs events (Ferraz‐Amaro 2021), and a multidisciplinary team should be cardiologists ( (Ali 2021).

Recently, it has been pointed out a potential relationship between a pro‐protein convertase subtilisin/kexin type 9 (PCSK9) and an autoimmune disease (Ministrini 2021).

The interrelationship between immunity, inflammation, and atherosclerosis could explain the cardiovascular construct termed residual inflammatory risk (RIR) (Ridker 2018). The RIR is defined by the level of high‐sensitivity C‐reactive protein (hs‐CRP) higher than 2 mg/L (Ridker 2018), a well‐known biomarker of cardiovascular disease (Liuzzo 1994). The RIR should not be confused with the residual cholesterol risk (low‐density lipoprotein cholesterol ‐LDL‐C‐ higher to 100 mg/dL), residual triglyceride risk  (triglycerides higher to 200 mg/dL and high‐density lipoprotein cholesterol ‐HDL‐ lower to 40 mg/dL), residual lipoprotein a risk (Lp(a)) higher to 50 mg/dL), and residual thrombotic risk without a predefined biomarker (Ridker 2018). It has been suggested that, in primary prevention, the evaluation of hs‐CRP is a useful prognostic factor as much as other conventional measurements of cardiovascular risk, i.e.  ‐LDL‐Crotein cholesterol or high‐density lipoprotein cholesterol (HDL‐C) (Ridker 2018). Subclinical inflammation can be better monitored with hs‐CRP (Ridker 2018). Therefore, a decrease in inflammatory burden should decrease the risk of future cardiovascular disease (Whayne 2021).

Similarly, the concept of residual cardiovascular risk (RCR) has been proposed (Vanuzzo 2011). Hermans and colleagues 2010, defined it as the "residual risk of incident vascular events or progression of established vascular damage persisting in patients treated with current evidence‐based recommended care. This risk includes established risk factors, such as dyslipidaemia, high blood pressure, hyperglycaemia, inflammation,  unhealthy lifestyles, and the risk related to emerging or newer risk factors" (Hermans 2010).  Both RIR and  RCR are unique. The link between inflammation and atherosclerosis has been supported by the use of anti‐inflammatory therapies, biological agents, or anti‐inflammatory drugs used to treat non‐atherosclerotic inflammatory diseases and hence, reduce cardiovascular events (Arbel 2018; Bäck 2015; Kottoor 2018; Moriya 2019; Roman 2020). Colchicine belongs to the second group of medications (Chistiakov 2018; Dasgeb 2018; Imazio 2016; Thompson 2019; Whayne 2021). Colchicine's prescription in cardiovascular medicine is a new use for an ancient drug (Chen 2017; Tong 2016).

Colchicine has been used in  gout, familial Mediterranean fever disorders, osteoarthritis (Akman 2018; Alarcón 1981; Aran 2011; Cronstein 2013; Das 2002;  Halabe‐Cherem 2009; Kiraz 1998;  Lazaros 2018; Liantinioti 2018; Meneses 2015; Nuki 2008; Plotz 2021;  Richette 2010; Vilardell 1978), dermatological disorders (Kaur 2020; Fujii 2021; Micheletti 2020; Zhao 2021), urological disorders (Sinanoglu 2018; Akman 2011; Ibrahim 2019), hepatology (Gong 2004; Rambaldi 2001), respiratory medicine (Gomer 2010), gastroenterology (Verne 2003; Rajapakse 2001; Verne 1997), and from secondary prevention of cardiovascular outcomes (Fiolet 2020; Imazio 2005; Imazio 2005a; Imazio 2011; Imazio 2014; Imazio 2014; Imazio 2014a; Maisch 2004; Nidorf 2013; Nidorf 2014; Roubille 2020; Siak 2021; Tardif 2019; Xia 2021). The effect of colchicine is unique since it binds to unpolymerized tubulin heterodimers, forming a stable complex that effectively inhibits microtubule dynamics, not affecting the glucocorticoid signalling pathway as well arachidonic acid metabolites production and signal transduction (Deftereos 2013 ). Reglero‐Real 2021 and colleagues have reported the importance of leukocyte trafficking and organ damage and have shown that endothelial cell autophagy remodels endothelial cell architecture, restraining neutrophils diapedesis in inflamed tissue.  It follows then that colchicine could protect against damage in peripheral organs by a similar mechanism.

The Cochrane Review's scope will be the colchicine use for primary prevention of cardiovascular outcomes in the general population. 

Description of the intervention

Colchicine is a tricyclic alkaloid extracted from Colchicum autumnale and Gloriosa superba (Finkelstein 2010; Imazio 2021; Karamanou 2018).

This drug is administered in either solid or liquid oral dosage form (FDA 2021; FDA 2021a). It is rapidly absorbed from the gastrointestinal tract (Finkelstein 2010), and is mainly metabolized in the liver. Cytochrome P3A4 and P‐glycoprotein metabolize colchicine; thus, any drug that binds these proteins influences the colchicine's pharmacokinetics (Borron 1996; Nuki 2008; Slobodnick  2015). The leukocytes (white blood cells) are the main targets of colchicine (Chappey 1993). The drug's half‐life is between 41 and 46 hours for leukocytes and 49 hours for plasma (Chappey 1993).  Colchicine binds to albumin in ~40% (Sabouraud 1994), and it is excreted in unchanged form. As metabolites in the faeces (about 80%) and 10% to 20% are excreted in the urine, the levels increase with liver disease. In patients with kidney impairment, colchicine's clearance is also reduced (Liantinioti 2018). 

Colchicine has a narrow therapeutic index (Essame 2020; Finkelstein 2010; Ghawanmeh 2020), and its toxicity is associated with a poor prognosis (Essame 2020; Finkelstein 2010). Several drugs inhibit colchicine metabolism; either cytochrome P450 or P‐glycoprotein: macrolides (mainly clarithromycin), antiretroviral therapy, broad‐spectrum oral antifungal agent (ketoconazole, etc.), grapefruit juice, histamine H2‐antagonists (cimetidine), steroids (hydrocortisone, dexamethasone), selective serotonin reuptake inhibitors (fluoxetine, paroxetine), calcium‐channel blocker (verapamil, diltiazem), and immunosuppressors (cyclosporine A and tacrolimus are potent inhibitors). Colchicine's dosage must be reduced and closely monitored in patients with relevant hepatic and/or renal dysfunction (Cocco 2010; Curiel 2012; Hung 2005; Imai 2020). Thus, the patients receiving colchicine must be monitored closely, especially in elderly patients with kidney failure (Anonymous 2008; Ho 2019). Colchicine prescribers must know the drug interaction between colchicine and several drugs to reduce the likelihood of fatal and non‐fatal colchicine‐related side effects (Amanova 2014; Borron 1996; Dahan 2009; Davis 2013; Imai 2020; Magro 2021; Rollot 2004; Slobodnick  2015; Stewart 2020;​ Villa Zapata 2020). Colchicine increases the rate of diarrhoea and gastrointestinal adverse events that precedes liver, sensory, muscle, infectious, haematological adverse events, or death (Stewart 2020).  Recently, Dubé and colleagues described two genomic regions associated with gastrointestinal events in patients treated with colchicine. It may benefit some patients with genetic predispositions to lower tolerability of treatment with colchicine (Dubé 2021).

As mentioned above, the colchicine effect, despite its narrow therapeutic window, is to protect the damage of organs by impeding the recruitment of neutrophils and hence decrease the inflammatory burden.

How the intervention might work

Colchicine binds to the following three proteins: tubulin, cytochrome P450, and P‐glycoprotein (Slobodnick  2015). The first protein, tubulin, is the main one to explain the drug's clinical benefits and harms. The other two are essential to explain colchicine's pharmacokinetic properties as described. 

Colchicine acts by blocking the microtubules' functions (Wilson 1976). Microtubules are the main component of the eukaryotic cytoskeleton (Bershadsky 1988), which possess essential roles in cell division, shaping, motility, and intracellular transport (Forkosh 2020; Janke 2020; Morton 1999; Roll‐Mecak 2020, Taylor 1965). The colchicine target is tubulin; a protein made up of two subunits called alpha and beta (Janke 2020; Roll‐Mecak 2020). The union colchicine‐tubulin yields a microtubule‐disassembling (Chaldakov 2018) which explains the anti‐inflammatory benefits of colchicine (Forkosh 2020; Terkeltaub 2009). The inhibitory action may explain the benefits due to the colchicine effects over macrophages, platelets, endothelial cells, and leukocytes, especially neutrophils (Cerquaglia 2005; Cronstein 1995; Imazio 2016; Hu 2021; Leung 2015; Paschke 2013; Perico 1996; Pircher 2019; Liang 2019; Rudolph 1977).  Leung and colleagues have reported diverse molecular mechanisms induced by the inhibitory action of colchicine (Leung 2015). These cells play a central role in the inflammatory process by several pathways and, thus, in the previous steps of the atheroma plaque (d'Alessandro 2020;  Ma 2019; Nording 2020; Schrottmaier 2020). Therefore, colchicine could prevent cardiovascular events in a primary prevention setting (Tsivgoulis 2018).

Why it is important to do this review

This review is critical for the following reasons. First, according to a Cochrane Review, there is uncertainty about the benefits and risks of colchicine in the general population (Hemkens 2016). Of the 39 randomised controlled trials (RCTs) included in Hemkens 2016, 82% (32/39) come from populations with chronic liver diseases, renal and primary amyloidosis, gout, Behçet's syndrome, or idiopathic pulmonary fibrosis. Furthermore, several trials reported no cardiovascular risk profile. Therefore, this Cochrane Review is required to assess the clinical benefits and risks of colchicine in the primary prevention of cardiovascular events, either in people with or without cardiovascular risk factors.

Second, numerous non‐Cochrane systematic reviews emphasize the prevention of atrial fibrillation (AF) after a post‐cardiac procedure. Some included both levels of prevention (Lennerz 2017; Papageorgiou 2017; Salih 2017; Trivedi 2014; Verma 2015; Wang 2016). However, these meta‐analyses show inconsistencies: in the measure of evaluation of the effect of the intervention, i.e. odds ratio or risk ratio; reported funnel‐plots with less than 10 RCTs, lack of assessment of the risk of bias in the included trials or that used out‐of‐date assessment scales, and without information about the certainty of the evidence. Therefore, it is mandatory to specify the role of colchicine in the primary prevention of cardiovascular events with Cochrane's methodology. 

Third, it is necessary to conduct a critical appraisal of trials in the primary prevention of post‐pericardiotomy syndrome (Finkelstein 2002; Imazio 2010), and early postoperative pericardial and pleural effusions (Imazio 2011a; Meurin 2015). According to the information reported in the clinical practice guidelines of international scientific societies, there is uncertainty about the role of colchicine in the primary prevention of AF post‐cardiac surgery (Calkins 2017; January 2014; Kirchhof 2016). Fourth, there is uncertainty about the role of colchicine in the scope of the primary prevention of cardiovascular events in rheumatological diseases, which have inflammatory nature with a strong link with atherogenesis. Therefore, critical appraisal of the RCTs will be necessary to determine the certainty of the evidence. All this will allow us to get firm conclusions to facilitate better decision‐making in clinical and epidemiological practice.

Objectives

To assess the clinical benefit and harms of colchicine as primary prevention of cardiovascular outcomes in the general population.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs) irrespective of publication status. We will only include RCTs with a parallel design and a minimum follow‐up of  one year. The one‐year minimum follow‐up is based on the premise that cardiovascular events require enough time to develop. The exception will be for studies including people with post‐cardiac procedure atrial fibrillation, in which case there will not be a minimum follow‐up requirement.

We will exclude non‐randomized clinical trials. Furthermore, we will not apply any limitation by language, and country. We will include studies reported as full text, those published as abstract only, and unpublished data. Cross‐over and cluster‐randomized trials are not suitable due to the nature of the clinical conditions where colchicine is prescribed and its intervention's pharmacodynamic properties, especially the very long elimination half‐life of the colchicine.  

We will analyze carefully whether trials were published in predatory journals (https://beallslist.net/). A predatory journal is an exploitive for‐profit publication model that promises a quick and easy publishing process with supposedly high editorial and publishing standards; however, it lacks quality control, transparency, and impact factor, threatening the foundation of evidence‐based research (Van Nuland 2017).

 We will not exclude any trial published in a predatory journal; however, we will conduct a sensitivity analysis. 

Types of participants

We will only include adults (aged 18 years or more), regardless of gender, without a known history of cardiovascular outcomes (myocardial infarction, unstable angina, heart failure, stroke, pericardial effusion, atrial fibrillation, and peripheral arterial disease). We will include participants with any risk factor of cardiovascular outcomes (i.e. blood hypertension, obesity, dyslipidaemia, diabetes mellitus, and chronic kidney diseases).  

We will also include pregnant women. However, we will not report pregnancy or childbirth outcomes. It means that we will only report cardiovascular outcomes and harms if available.

If we identify an RCT including participants with or without a history of cardiovascular outcomes, we plan to check whether there was information by subgroup. If there is no report, the trial will be excluded. However, before making a final decision, we will contact the lead author.

Types of interventions

We will only include the intervention as monotherapy, given at any dosage. We will not pool all eligible comparators, but each will be a different comparison. For the purposes of the review, and in the absence of a standard definition of usual care, we will accept the following: quote: "it can include the routine care received by patients for prevention or treatment of diseases" (Gellman 2013).

1. Intervention

Colchicine is only administered orally. We will only consider colchicine given alone (monotherapy), regardless of colchicine dosage. 

2. Control

• Placebo

• Non‐steroidal anti‐inflammatory drugs:  indomethacin, celecoxib, mefenamic acid, naproxen, etoricoxib, ibuprofen, diclofenac, and high‐dose aspirin.

• Corticosteroids: dexamethasone, prednisone, deflazacort, prednisolone, and any other drug if it meets the criteria of this class of drugs.

• Immunomodulating drugs: cyclophosphamide, methotrexate, D‐penicillamine, and any other drug if it meets the criteria of this class of drugs.

• Usual care.

We plan to conduct the following comparisons.

• Colchicine versus placebo

• Colchicine versus non‐steroidal anti‐inflammatory drugs

• Colchicine versus corticosteroids

• Colchicine versus immunomodulating drugs

• Colchicine versus usual care

We will accept co‐interventions, including treatment of complications if they were administered equally to all intervention arms.

Types of outcome measures

Reporting one or more of the outcomes listed here in the trial is not an inclusion criterion for the review. We will try to access the trial protocol or contact the trial authors to ascertain all measured outcomes, even if not reported. Relevant trials that measured these outcomes but did not report their results, or these are not reported in a usable format, will be included in the narrative. We will not exclude an RCT solely based on the reporting of the outcome data.

For all outcomes that could happen more than once in a trial participant, we will report the number of people with at least one event.

All outcomes will be assessed at maximum follow‐up.

Primary outcomes

1. All‐cause mortality

2. Non‐fatal myocardial infarction

3. Stroke. We will include either acute ischaemic stroke or acute cerebral haemorrhage. However, the clinical diagnosis with imaging will be an eligibility criterion.

4. Adverse events: we will prioritize on: 

   1.  gastrointestinal (diarrhoea);

   2. liver (jaundice);

   3. kidney (acute renal failure);

   4. neurological (seizure, confusion);

   5. multiorgan failure.

Secondary outcomes

1. Cardiovascular mortality

2. Post‐cardiac procedure atrial fibrillation

3. Pericardial effusion

4. Symptoms or intervention related to peripheral artery disease

5. Heart failure

6. Unstable angina

We will exclude economic costs as an outcome of this Cochrane Review. However, we will state that economic costs will be discussed in the discussion section in a narrative form if data are available.

Search methods for identification of studies

Electronic searches

We will identify relevant trials through systematic searches of the following bibliographic databases.

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library

• MEDLINE (Ovid, from 1946 onwards)

• Embase (Ovid, from 1980 onwards)

• LILACS (Latin American and Caribbean Health Sciences Literature) (Bireme, from 1982 onwards).

The preliminary search strategy for MEDLINE (Ovid) will be adapted for use in the other databases (Appendix 1). The Cochrane sensitivity and precision‐maximizing RCT filter (Lefebvre 2019) will be applied to MEDLINE (Ovid) and adaptations of it to the other databases, except CENTRAL.

We will search all databases from their inception to the present, and we will impose no restriction on the language of publication or publication status.

We will not perform a separate search for adverse events of colchicine used for the treatment of any disease. We will consider the adverse events described in included studies only.

Searching other resources

We will also search in Web of Science CPCI‐S (Conference Proceedings citation index‐science to include conference abstracts. 

We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/) for ongoing or unpublished trials.

We will search the following regulatory data websites.

• European Medicines Agency (EMA) (www.ema.europa.eu/en)

• Food and Drugs Administration (FDA) (www.fda.gov/Drugs)

Three review authors (AMC, EAB, RR) will check reference lists of all primary studies and review articles for additional references. 

We will also examine any relevant retraction statements and errata for included studies. We will exclude the retraction RCTs.

Data collection and analysis

We will follow the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019).

Selection of studies

Two review authors (AMC, ACP) will independently screen titles and abstracts for the inclusion of all the potential studies. We will identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. If there are any disagreements, a third review author will be asked to arbitrate (RH). We will retrieve the full‐text study reports/publications and three review authors (DM, CMA, RR) will independently screen the full text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult to third‐person (JBS). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Liberati 2009).

Data extraction and management

We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. Three review authors (AMC, RR, DM) will extract study characteristics from included studies. AC and CMA will check all this information. We will extract the following study characteristics.

1. Methods: study design, the total duration of the study, follow‐up period, details of any 'run in' period, number of study centres and location, and study setting.

2. Participants: number (N) randomized, N lost to follow‐up/withdrawn, N analyzed, age (as reported by trialist), sex, body mass index (BMI) (it is relevant to determine obesity diagnosis), high‐sensitivity C‐reactive protein level, relevant details for co‐morbidities, inclusion criteria, and exclusion criteria.

3. Interventions: intervention, comparison, concomitant medications, and excluded medications. Appendix 2 shows details of the intervention description (Hoffmann 2014; Hoffmann 2017). We will collect adverse events information according to Li 2019. Appendix 3 shows details to recollect adverse events information with an Excel spreadsheet (Li 2019).

4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

5. Notes: number registration trial, trial conduction dates, a priori sample estimation, financial disclosures, other disclosures, and funding/support. Published in a predatory journal.

Two review authors (AMC, RR) will independently extract outcome data from included studies. We will resolve disagreements by consensus or by involving two review authors (RH, EA). One review author (AMC) will transfer data into the Review Manager (RevMan Web 2019). One review author (RR) will double‐check that data are entered correctly by comparing the data presented in the systematic review with the data extraction form. A second review author (DM) will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Three review authors (AMC, DM, and RR) will independently assess the risk of bias for each study using version two of the Cochrane risk of bias tool (RoB 2), outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Boutron 2019; Higgins 2019a). We will resolve any disagreements by discussion or by involving another review author (CMA). We will assess the risk of bias for the outcomes of the included trials that will be included in our summary of findings table (Schünemann 2019). 

We will perform analysis based on the intention‐to‐treat principle which includes all randomized participants, irrespective of the interventions that participants actually received. We will use the following domains to assess the risk of bias in the individually randomized trials:

• bias arising from the randomization process;

• bias due to deviations from intended interventions;

• bias due to missing outcome data;

• bias in the measurement of the outcome;

• and bias in the selection of the reported result (Higgins 2019a; Higgins 2019b).

We will use the signalling questions in the RoB 2 tool and rate each domain as 'low risk of bias', 'some concerns', or 'high risk of bias'.  The following response options will answers the signalling questions for these domains.

• Yes

• Probably yes

• Probably no

• No

• No information

 We will use algorithms to map our answers to the signalling questions per outcome and will propose a risk of bias for each domain (Higgins 2019b). 

When we judge a result to be at a particular level of risk of bias for an individual domain, it implies that the overall result has a risk of bias that is at least this severe. Therefore, a judgment of high risk of bias within any domain will have a similar implication for the result as a whole, irrespective of which domain is being assessed. ‘Some concerns’ in multiple domains may lead the review authors to decide on an overall judgment of high risk of bias for that outcome or group of outcomes (Higgins 2019a).

The overall risk of bias for the result is the least favourable assessment across the domains of bias.

1. Low risk of bias will denote that the study will be judged to be at low risk of bias for all domains for this result.

2. Some concerns will denote that the study will be judged to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain.

3. High risk of bias will denote that study will be judged to be at high risk of bias in at least one domain for this result or the study is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result (Higgins 2019a; Higgins 2019b).

We will store the data in an Excel tool to implement RoB 2 to show it to the readers (Higgins 2019b). 

Measures of treatment effect

Due to all outcomes of this Cochrane Review being dichotomous data, we will analyses them with the risk ratio (RR) with 95% confidence intervals (CIs).

Unit of analysis issues

The unit of analysis in this Cochrane Review will be the participant. The time of the analysis will be the longest established in each trial. In the case of multiple‐armed trials, we plan to combine the groups to yield a single pairwise comparison (Higgins 2019c ).

Dealing with missing data

We will assess the percentage of dropouts for each included trial, and for each intervention group, and will evaluate whether an intention‐to‐treat (ITT) analysis had been performed, or could have been performed from the available published information. We will try to contact the study authors to resolve any questions arising from this issue.

In order to undertake an ITT analysis, we will seek data from the trial authors about the number of participants in treatment groups, irrespective of their compliance and whether or not they were later thought to be ineligible, otherwise excluded from treatment, or lost to follow‐up.

We will include participants with incomplete or missing data in sensitivity analyses by imputing them according to the following scenarios.

• Extreme‐case analysis favouring the experimental intervention ('best‐worse' case scenario): none of the dropouts/participants lost from the experimental arm, but all of the dropouts/participants lost from the control arm experienced the outcome, including all randomized participants in the denominator (Hollis 1999).

• Extreme‐case analysis favouring the control ('worst‐best' case scenario): all dropouts/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomized participants in the denominator (Hollis 1999).

We will use Stata software to assess the impact of the missing data. 

Assessment of heterogeneity

The presence of heterogeneity will initially be detected from the visual assessment of the forest plots.

We will quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins 2003). We will assume a range of 50% to 90% may represent substantial heterogeneity (Deeks 2019). For a proper interpretation of the I², we will follow the relevant Cochrane Handbook's recommendations: "The importance of the observed value of I² depends on (1) magnitude and direction of effects, and (2) strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a confidence interval for I²: uncertainty in the value of I² is substantial when the number of studies is small)." (Deeks 2019). However, we will consider statistical heterogeneity to be present if I² is greater than 70% (Deeks 2019). 

Assessment of reporting biases

If there are 10 or more randomized clinical trials by the outcome, we will use the contour‐enhanced funnel plot to differentiate asymmetry that is due to publication bias from that due to other factors (Sterne 2011). We will assess the likelihood of publication bias with Harbord's test (Sterne 2011). We will use Stata statistical software to produce conventional and contour funnel plots.

Data synthesis

We will follow the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions to summarize study characteristics and prepare for synthesis (McKenzie 2019). If data pooling is not feasible, we will show the information as a narrative summary of the evidence presented in either text or tabular form. However, if there is evidence that an effect exists in at least one study,  we plan to use an albatross plot with combines P values (Harrison 2017; McKenzie 2019). Albatross plot requires a two‐sided P value, sample size, and direction of effect (or equivalently, a one‐sided P value and sample size) for each result (Harrison 2017; McKenzie 2019).

We will perform meta‐analyses with 95% CIs using random‐effects. In the case of statistical heterogeneity (I² > 70%), we will report the prediction interval (Deeks 2019; IntHout 2016; Riley 2011). If there were simultaneously statistical heterogeneity and three or more trials, we will determine the 95% prediction interval, which takes into account the whole distribution of the effects (Riley 2011). Prediction intervals in meta‐analysis show the expected range of true effects in similar studies (Borenstein 2017; IntHout 2016). The prediction interval will show the distribution of the true effect sizes, which does not mean precision of the mean of the effect sizes (Borenstein 2009, Borenstein 2017). We will estimate the 95% prediction interval with Stata statistical software (STATA) (Kontopantelis 2010). 

Regardless of the overall risk of bias, all RCTs will contribute to the primary analyses. We will conduct the meta‐analyses with Review Manager Web (RevMan Web 2019). 

Subgroup analysis and investigation of heterogeneity

 If there are 10 or more RCTs for the outcome and an I² is greater than 70%, we will conduct a meta‐regression with Stata statistical software.  We hypothesize that the following covariates could explain the potential statistical heterogeneity:  rheumatological disorders (rheumatoid arthritis or gout), cardiovascular risk factor, high‐sensitivity C‐reactive protein level, and rheumatoid arthritis (Deeks 2019).   

We plan to carry out the following subgroup analyses.

1. Participants with rheumatological disorders (rheumatoid arthritis or gout) compared to participants without rheumatological disorders. (Hypothesis: rheumatological disorders people could suppose a higher risk).

2. Participants with cardiovascular risk factors (diabetes mellitus, blood hypertension, chronic kidney disease) compared to participants without cardiovascular risk factors. (Hypothesis: participants with cardiovascular risk factors have a higher risk of cardiovascular outcomes).

3. Participants with high‐sensitivity C‐reactive protein levels higher than 2 mg/L versus participants with high‐sensitivity C‐reactive levels protein ≤ 2 mg/L. (Hypothesis: higher high‐sensitivity C‐reactive protein could suppose a higher risk).

We will conduct the subgroup analysis for all outcomes. We will use the formal test for subgroup differences in Review Manager (RevMan Web 2019) and base our interpretation on this.

Sensitivity analysis

We plan to carry out the following sensitivity analyses. 

1. Trials with a low risk of bias compared to trials with some concerns or a high risk of bias.

2. A fixed‐effect meta‐analysis compared to random‐effects model meta‐analysis.

3. Trials without support from a drug company compared to trials with support from the drug company. Trials with support tend to report positive effects.

4. Trials non‐published in predatory journals compared to trials published in predatory journals. Trials published in predatory journals tend to report positive effects.

We plan only to conduct these analyses for the primary outcomes. 

We will use the overall risk of bias for a study result, rather than specific domains. We will judge whether or not there is a difference between the primary analysis and sensitivity analysis by comparing changes in P values.

Summary of findings and assessment of the certainty of the evidence

We will create summary of the findings tables using the predefined outcomes in this Cochrane Review (all‐cause mortality, non‐fatal myocardial infarction, stroke, adverse events, cardiovascular mortality, post‐cardiac procedure atrial fibrillation, and symptoms or intervention‐related to peripheral artery disease). We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence as it relates to the RCTs which contribute data to the meta‐analyses for the predefined outcomes (Atkins 2004; Guyatt 2008). We will use methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2019) using GRADEpro software (GRADEpro GDT 2020). As listed in Types of interventions, each comparison will get a separate summary of findings table. We will justify all decisions to downgrade the quality of RCTs using footnotes and we will make comments to aid the reader's understanding of the review where necessary.

Judgment about the certainty of evidence will be made by two review authors (AMC, RR) working independently, with disagreements resolved by discussion or involving a third review author (DM). Judgments will be justified, documented, and incorporated into reporting of results for each outcome.

We will use the GRADE Working Group's statements to communicate findings combining size and certainty of an effect acceptable ( Santesso 2020).

Appendices

Appendix 1. Preliminary MEDLINE (Ovid) search strategy

1     Colchicine/ (14348)

2     Colchicine.tw. (15915)

3     1 or 2 (20953)

4     randomized controlled trial.pt. (536578)

5     controlled clinical trial.pt. (94267)

6     randomized.ab. (525623)

7     placebo.ab. (219437)

8     clinical trials as topic.sh. (196544)

9     randomly.ab. (360830)

10     trial.ti. (243020)

11     4 or 5 or 6 or 7 or 8 or 9 or 10 (1377865)

12     exp animals/ not humans.sh. (4855957)

13     11 not 12 (1268087)

14     3 and 13 (695)

Appendix 2. Intervention description and replication

1. Brief name: Provide the name or a phrase that describes the intervention

2. Why: describe any rationale, theory, or goal of the elements essential to the intervention

3. What (materials): Describe any physical or informational materials used in the intervention, including those provided to participants or used in intervention delivery or in the training of intervention providers. Provide information on where the materials can be accessed (for example, online appendix, URL)

4. What (procedures): Describe each of the procedures, activities, and/or processes used in the intervention, including any enabling or support activities

5. Who provided: For each category of intervention provider (for example, psychologist, nursing assistant), describe their expertise, background, and any specific training given

6. How: Describe the modes of delivery (such as face to face or by some other mechanism, such as internet or telephone) of the intervention and whether it was provided individually or in a group.

7. Where: Describe the type(s) of location(s) where the intervention occurred, including any necessary infrastructure or relevant features.

8. When and how much: Describe the number of times the intervention was delivered and over what period of time including the number of sessions, their schedule, and their duration, intensity or dose.

9. Tailoring: If the intervention was planned to be personalized, titrated, or adapted, then describe what, why, when, and how.

10. Modifications: If the intervention was modified during the course of the study, describe the changes (what, why, when, and how).

11. How well (planned): If intervention adherence or fidelity was assessed, describe how and by whom, and if any strategies were used to maintain or improve fidelity, describe them.

12. How well (actual): If intervention adherence or fidelity was assessed, describe the extent to which the intervention was delivered as planned.

Source: Hoffmann 2014.

Appendix 3. Adverse events information domains

1. Name of the adverse events (e.g. dizziness).

2. The reported intensity of the adverse event (e.g. mild, moderate, severe).

3. Whether the trial investigators categorized the adverse event as ‘serious’.

4. Whether the trial investigators identified the adverse event as being related to the intervention.

5. Time point (most commonly measured as a count over the duration of the study).

6. Any reported methods for how adverse events were selected for inclusion in the publication (e.g. ‘We reported all adverse events that occurred in at least 5% of participants’).

Source: Li 2019.

Contributions of authors

Arturo Martí‐Carvajal wrote the draft with inputs from all authors. 

Sources of support

Internal sources

• Universidad UTE and Cochrane Ecuador, Ecuador

  Academic and financial.

• Universidad Francisco de Vitoria, Centro Cochrane asociado de Madrid, Spain

  Academic and financial.

• Cátedra Rectoral de Medicina Basada en al Evidencia, Universidad de Carabobo, Venezuela

  Academic and financial.

External sources

• NIHR, UK

  This project was supported by the NIHR via Cochrane Infrastructure funding to the Heart Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health and Social Care.

• Iberoamerican Cochrane Center, Barcelona, Spain

  Academic.

Declarations of interest

Review authors declared having no conflicts of interest.

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