Colchicine for prevention of cardiovascular events

Lars G Hemkens; Hannah Ewald; Viktoria L Gloy; Armon Arpagaus; Kelechi K Olu; Mark Nidorf; Dominik Glinz; Alain J Nordmann; Matthias Briel

doi:10.1002/14651858.CD011047.pub2

Cochrane Database of Systematic Reviews

Colchicina para la prevención de eventos cardiovasculares

Información

DOI:

https://doi.org/10.1002/14651858.CD011047.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

27 enero 2016see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Corazón

Copyright:

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Lars G Hemkens

Correspondencia a: Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University of Basel, Basel, Germany

[email protected]
Hannah Ewald

University Medical Library, University of Basel, Basel, Switzerland
Viktoria L Gloy

Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
Armon Arpagaus

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University of Basel, Basel, Switzerland
Kelechi K Olu

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University of Basel, Basel, Belgium
Mark Nidorf

Heart Care Western Australia, Perth, Australia
Dominik Glinz

Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
Alain J Nordmann

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University of Basel, Basel, Switzerland
Matthias Briel

Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland

Contributions of authors

Design of the study: LGH, MB
Data extraction: LGH, HE, VLG, AA, KKO, DG, AJN, MB
Data analysis: LGH, HE
Interpreation of results:LGH, HE, AJN, MN, MB
Writing the first draft: LGH, HE
Critical revision of the manuscript: All authors
Reading and approval of the final version of the paper: All Authors
Guarantor: LGH

Sources of support

Internal sources

No sources of support supplied

External sources

This project was supported by the National Institute for Health Research, 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, UK

Declarations of interest

All authors declare no financial relationships with any organisation that might have an interest in the submitted work in the previous three years.
Mark Nidorf was involved in one of the included studies, which was investigator‐initiated and conducted without external financial support.
All other authors declare no other relationships or activities that could appear to have influenced the submitted work.

Acknowledgements

The authors thank Mark A. Berendsen and Nicole Martin for conducting the literature searches, Kübra Özoglu for her excellent administrative support and assistance with literature management, Tiago V. Pereira, Benjamin Kasenda, Cemile Bathelt‐Cicek for assessing studies reported in Portuguese, Chinese, and Turkish. We thank the Cochrane Heart Group for their support in publishing this review. We thank all study investigators for providing helpful information on their studies.

Version history

Published

Title

Stage

Authors

Version

2016 Jan 27

Colchicine for prevention of cardiovascular events

Review

Lars G Hemkens, Hannah Ewald, Viktoria L Gloy, Armon Arpagaus, Kelechi K Olu, Mark Nidorf, Dominik Glinz, Alain J Nordmann, Matthias Briel

https://doi.org/10.1002/14651858.CD011047.pub2

2014 Mar 26

Colchicine for prevention of cardiovascular events

Protocol

Lars G Hemkens, Viktoria L Gloy, Kelechi K. Olu, Alain J Nordmann, Matthias Briel

https://doi.org/10.1002/14651858.CD011047

Differences between protocol and review

There were no relevant study protocol deviations.

We prespecified all analyses, with the exception of sensitivity analyses using alternative meta‐analytical models, which we deemed useful when we observed event rates close to 1% (Bradburn 2007). In addition, we analysed the risk of bias in more detail.

Since there were no data specifically for populations without a history of cardiovascular disease events or without established coronary heart disease, but data specifically for participants at high risk for cardiovascular events (secondary prevention of cardiovascular disease events or established coronary heart disease), we focused more specifically on this clinically very relevant population and described the findings for this population in more detail. To be consistent, we also report the subgroup analyses on colchicine dose for all outcomes. The prespecified approach and the analyses remained unchanged.

To reduce the overall number of subanalyses, we dropped the analysis on the type of condition (other than CVD) for which colchicine was given and the analysis including only studies reporting on both a primary outcome indicating potential benefit and adverse events, and we did not evaluate the impact of funding of the primary studies. We conducted sensitivity analyses only when there were at least three studies to be combined.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study Flow

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot: Mortality (all‐cause)

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Figure 5

Funnel plot: Adverse event (total)

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Figure 6

Funnel plot: Adverse event (gastrointestinal)

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Figure 7

Overview of results of meta‐analyses for colchicine treatment vs. control

ES: Effect Estimate; OR: Peto Odds Ratio; RR: risk ratio. * including one study without events ** including two studies without events.

Effects for some outcomes were estimated using Peto Odds Ratios because this is a more appropriate method when event rates are very low.

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Analysis 1.1

Comparison 1: Colchicine vs control, Outcome 1: Mortality (all‐cause)

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Analysis 1.2

Comparison 1: Colchicine vs control, Outcome 2: Myocardial infarction (total)

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Analysis 1.3

Comparison 1: Colchicine vs control, Outcome 3: Myocardial infarction (non‐fatal)

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Analysis 1.4

Comparison 1: Colchicine vs control, Outcome 4: Myocardial Infarction (fatal)

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Analysis 1.5

Comparison 1: Colchicine vs control, Outcome 5: Adverse event (serious)

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Analysis 1.6

Comparison 1: Colchicine vs control, Outcome 6: Adverse event (total)

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Analysis 1.7

Comparison 1: Colchicine vs control, Outcome 7: Adverse event (gastrointestinal)

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Analysis 1.8

Comparison 1: Colchicine vs control, Outcome 8: Mortality (cardiovascular)

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Analysis 1.9

Comparison 1: Colchicine vs control, Outcome 9: Stroke (total)

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Analysis 1.10

Comparison 1: Colchicine vs control, Outcome 10: Stroke (fatal)

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Analysis 1.11

Comparison 1: Colchicine vs control, Outcome 11: Stroke (non‐fatal)

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Analysis 1.12

Comparison 1: Colchicine vs control, Outcome 12: Heart failure (total)

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Analysis 1.13

Comparison 1: Colchicine vs control, Outcome 13: Heart failure (fatal)

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Analysis 1.14

Comparison 1: Colchicine vs control, Outcome 14: Heart failure (non‐fatal)

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Analysis 1.15

Comparison 1: Colchicine vs control, Outcome 15: Non‐scheduled hospitalisation (total)

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Analysis 1.16

Comparison 1: Colchicine vs control, Outcome 16: Non‐scheduled cardiovascular interventions

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Analysis 2.1

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 1: Mortality (all‐cause)

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Analysis 2.2

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 2: Mortality (cardiovascular)

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Analysis 2.3

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 3: Myocardial infarction (total)

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Analysis 2.4

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 4: Myocardial infarction (fatal)

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Analysis 2.5

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 5: Myocardial infarction (non‐fatal)

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Analysis 2.6

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 6: Adverse event (total)

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Analysis 2.7

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 7: Adverse event (gastrointestinal)

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Analysis 2.8

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 8: Adverse event (serious)

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Analysis 2.9

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 9: Stroke (total)

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Analysis 2.10

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 10: Stroke (fatal)

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Analysis 2.11

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 11: Stroke (non‐fatal)

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Analysis 2.12

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 12: Heart failure (total)

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Analysis 2.13

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 13: Heart failure (fatal)

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Analysis 2.14

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 14: Heart failure (non‐fatal)

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Analysis 2.15

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 15: Non‐scheduled hospitalisation (total)

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Analysis 2.16

Comparison 2: Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d, Outcome 16: Non‐scheduled cardiovascular interventions

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Analysis 3.1

Comparison 3: Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control, Outcome 1: Mortality (all‐cause)

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Analysis 3.2

Comparison 3: Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control, Outcome 2: Mortality (cardiovascular)

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Analysis 3.3

Comparison 3: Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control, Outcome 3: Myocardial infarction (fatal)

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Analysis 3.4

Comparison 3: Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control, Outcome 4: Adverse event (total)

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Analysis 3.5

Comparison 3: Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control, Outcome 5: Adverse event (gastrointestinal)

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Analysis 4.1

Comparison 4: Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment), Outcome 1: Mortality (all‐cause)

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Analysis 4.2

Comparison 4: Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment), Outcome 2: Mortality (cardiovascular)

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Analysis 4.3

Comparison 4: Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment), Outcome 3: Myocardial infarction (fatal)

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Analysis 4.4

Comparison 4: Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment), Outcome 4: Adverse event (total)

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Analysis 4.5

Comparison 4: Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment), Outcome 5: Adverse event (gastrointestinal)

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Analysis 5.1

Comparison 5: Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies), Outcome 1: Mortality (all‐cause)

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Analysis 5.2

Comparison 5: Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies), Outcome 2: Mortality (cardiovascular)

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Analysis 5.3

Comparison 5: Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies), Outcome 3: Myocardial infarction (fatal)

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Analysis 5.4

Comparison 5: Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies), Outcome 4: Adverse event (total)

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Analysis 5.5

Comparison 5: Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies), Outcome 5: Adverse event (gastrointestinal)

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Analysis 6.1

Comparison 6: Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment), Outcome 1: Mortality (all‐cause)

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Analysis 6.2

Comparison 6: Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment), Outcome 2: Mortality (cardiovascular)

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Analysis 6.3

Comparison 6: Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment), Outcome 3: Myocardial infarction (fatal)

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Analysis 6.4

Comparison 6: Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment), Outcome 4: Adverse event (total)

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Analysis 6.5

Comparison 6: Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment), Outcome 5: Adverse event (gastrointestinal)

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Analysis 7.1

Comparison 7: Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data), Outcome 1: Mortality (all‐cause)

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Analysis 7.2

Comparison 7: Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data), Outcome 2: Mortality (cardiovascular)

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Analysis 7.3

Comparison 7: Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data), Outcome 3: Myocardial infarction (fatal)

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Analysis 7.4

Comparison 7: Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data), Outcome 4: Adverse event (total)

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Analysis 7.5

Comparison 7: Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data), Outcome 5: Adverse event (gastrointestinal)

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Analysis 8.1

Comparison 8: Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only), Outcome 1: Mortality (all‐cause)

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Analysis 8.2

Comparison 8: Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only), Outcome 2: Mortality (cardiovascular)

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Analysis 8.3

Comparison 8: Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only), Outcome 3: Myocardial infarction (fatal)

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Analysis 8.4

Comparison 8: Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only), Outcome 4: Adverse event (total)

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Analysis 8.5

Comparison 8: Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only), Outcome 5: Adverse event (gastrointestinal)

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Summary of findings 1. Colchicine compared to any control treatment for prevention of cardiovascular events

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Colchicine compared to any control treatment for prevention of cardiovascular events
Patient or population: any patient population and people with high cardiovascular risk Settings: any Intervention: Colchicine Comparison: Any control treatment
	Assumed risk	Corresponding risk
	Any control treatment	Colchicine
Mortality (all‐cause) Follow‐up: 0.5 ‐ 14 years	193 per 1000	182 per 1000 (157 to 211)	RR 0.94 (0.82 to 1.09)	4174 (30 studies)	⊕⊕⊕⊝ moderate¹
	Patients with high cardiovascular risk
	32 per 1000	17 per 1000 (8 to 36)	RR 0.54 (0.26 to 1.14)	1230 (4 studies)	⊕⊕⊕⊝ moderate¹	Follow‐up: 0.5 ‐ 3 years
Mortality (cardiovascular) Follow‐up: 0.5‐14 years	27 per 1000	9 per 1000 (2 to 32)	RR 0.34 (0.09 to 1.21)	1132 (7 studies)	⊕⊕⊕⊝ moderate¹
	Patients with high cardiovascular risk
	31 per 1000	8 per 1000 (1 to 81)	RR 0.25 (0.02 to 2.66)	754 (2 studies)	⊕⊕⊝⊝ low^2,3	Follow‐up: 0.5 ‐ 3 years
Myocardial Infarction (total) Follow‐up: mean 3 years	58 per 1000	12 per 1000 (4 to 33)	RR 0.20 (0.07 to 0.57)	652 (2 studies⁴)	⊕⊕⊕⊝ moderate⁵	Most evidence provided by a single study
	Patients with high cardiovascular risk
	Study population		RR 0.20 (0.07 to 0.57)	532 (1 study)	⊕⊕⊕⊝ moderate⁵	Evidence provided by a single study. Follow‐up: mean 3 years Please see footnote⁶
	72 per 1000	18 per 1000 (5 to 41)
	Assumed 1‐year risk
	25 per 1000	6 per 1000 (2 to 14)
Adverse event (total) Follow‐up: 0.5 ‐ 14 years	Study population		RR 1.52 (0.93 to 2.46)	1313 (11 studies)	⊕⊝⊝⊝ very low^1,7,8	No study in participants with high cardiovascular risk reported on total adverse events.⁹
	89 per 1000	135 per 1000 (83 to 219)
	Assumed 1‐year risk
	89 per 1000	135 per 1000 (83 to 219)
Adverse event (gastrointestinal) Follow‐up: 0.5 ‐ 14 years	Study population		RR 1.83 (1.03 to 3.26)	1258 (11 studies)	⊕⊕⊝⊝ low^8,12	Please see footnote⁹
	132 per 1000	242 per 1000 (136 to 431)
	Assumed 1‐year risk
	132 per 1000	242 per 1000 (136 to 430)
Adverse event (serious) Follow‐up: mean 824 patient‐years	See comment	See comment	Not estimable	472 (4 studies)	⊕⊕⊝⊝ low^10,11	No illustration of comparative risks due to very uncertain assumed risks^10,11
Heart failure (total) Follow‐up: 0.5 ‐ 3 years	See comment	See comment	RR 0.62 (0.10 to 3.88)	426 (3 studies)	⊕⊕⊝⊝ low^3,4,5	No illustration of comparative risks due to very uncertain assumed risks
Stroke (total) Follow‐up: 0.5 ‐ 3 years	See comment	See comment	OR 0.38 (0.09 to 1.70)	874 (3 studies)	⊕⊕⊝⊝ low^3,4,5	No illustration of comparative risks due to very uncertain assumed risks
The basis for the assumed risk* is the mean control group risk across studies if not otherwise stated in comments/footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Peto Odds ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Confidence interval is compatible with participant‐relevant benefit and harm. ²Small number of events therefore downgraded for imprecision. ³Substantial imprecision because confidence interval compatible with major harm and major benefit. ⁴One study without events. ⁵Effect based on small number of events. ⁶For balancing benefits and harms using absolute risk measures (1‐year risk), we extrapolated the 1‐year risk of myocardial events assuming that the risk is constant over the entire follow‐up. ⁷High risk for attrition bias in 5 of 10 studies. ⁸Visual inspection of funnel plot shows asymmetry; lack of small studies reporting lower adverse event rates with colchicine than with comparator (the rate of adverse events with colchicine may appear too high due to bias). ⁹For balancing benefits and harms using absolute risk measures (1‐year risk), we assumed that all adverse events observed over the entire follow‐up accumulate within the first year of treatment. ¹⁰Only four studies reported on serious adverse events (zero events in approximately 800 patient‐years). In many other studies events occurred (e.g. deaths) that could be regarded as serious adverse events. ¹¹No indication for publication bias, but reporting quality very limited. ¹²Substantial between‐study heterogeneity (I² = 74%) without plausible explanation.

Summary of findings 1. Colchicine compared to any control treatment for prevention of cardiovascular events

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Table 1. Characteristics of included studies: Summary

Follow‐up¹
	All Studies	Studies in participants with high cardiovascular risk
Total number of studies	39 (100%)	4 (100%)
No. of participants in all studies	4992	1230
Publication year, median (range)	1996 (1974 ‐ 2014)	2013 (1992 ‐ 2014)
Publication year < 2000	24 (62%)	1 (25%)
Multicentre studies	9 (23%)	0 (0%)
Study size, median (IQR)	84 (54 ‐ 129)	251 (210 ‐ 406)
Participant age, median (IQR)	54 (51 ‐ 61)	66 (63 ‐ 67)
Men, median (IQR)	62 (25 ‐ 87)	77 (66 ‐ 88)
0.5 to 1 year	6 (15%)	3 (75%)
1 to 3 years	17 (44%)	0 (0%)
> 3 years	15 (38%)	1 (25%)
*Colchicine treatment*
≤ 1 mg/d	27 (69%)	3 (75%)
> 1 mg/d	12 (31%)	1 (25%)
Control treatment, n (%)
Active treatment	8 (21%)	0 (0%)
Inactive, placebo	31 (79%)	4 (100%)
*Clinical setting*
CVD, arteriosclerotic	3 (8%)	3 (75%)
CVD, other	1 (3%)	1 (25%)
Hepatobiliary disease	25 (64%)	0 (0%)
Other	10 (26%)	0 (0%)
*Cardiovascular risk profile*
Primary prevention	0 (0%)	0 (0%)
Secondary prevention	4 (10%)	4 (100%)
Not specified	34 (87%)	0 (0%)
Number of studies (% of column total) if not stated otherwise. IQR: Interquartile range ¹Longest follow‐up period for an outcome that was used in this systematic review.

Table 1. Characteristics of included studies: Summary

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Table 2. Characteristics of included studies: Overview

Study (Reference)	Participants (n)	Centres	Clinical setting	Age* (y)	Men (%)	Colchicine dose (mg/d)	Control	Follow‐up (yrs)ₑ
Studies in patients with high cardiovascular risk
Deftereos 2013	222	Single	PCI/CVD	64	65	2 x 0.5	Placebo	0.5
Deftereos 2014a	279	Single	Heart failure	67	67	1 ‐ 2 x 0.5²	Placebo	0.5
Nidorf 2013	532	Single	PCI/CVD	67	89	0.5	Usual care³	3
O'Keefe 1992	197	Single	PCI/CVD	61	86	2 x 0.6	Placebo	0.5
Other studies
Adhami 1998	52	Single	Liver disease	54	87	1⁴	Placebo	11
Almasio 2000	90	Multi	PBC	55	10	1	Placebo⁵	3
Antoniou 2006	50	Multi	Other	68	84	1	IFN‐gamma⁶	2.1
Bodenheimer 1988	57	N/R	PBC	52	9	2 x 0.6	Placebo	2.2
Buligescu 1989	180	N/R.	Liver disease	N/R	N/R	1	“Conventional therapy”	3
Colman 1998	129	N/R	Liver disease	N/R	N/R	1	Placebo	3.8
Copilot	555	N/R	Liver disease	51	70	2 x 0.6	Peg‐IFN‐alpha	2
CORE	84	Single	Other	54	35	1 ‐ 2 x 0.5²	Usual care³^,⁷	1.7
CORP	120	Multi	Other	48	46	0.5 ‐ 1²	Placebo⁸	2
CORP‐2	240	Multi	Other	49	50	1 ‐ 2 x 0.5²	Placebo	1.7
Cortez‐Pinto 2002	62	Single	Liver disease	54	89	1⁴	Placebo	3.4
Douglas 1998	26	Single	Other	68	77	0.6 ‐ 1.2⁹	Prednisone	2.5
Ikeda 1996	22	Single	PBC	61	14	1	Usual care ³^,⁵	2
Kaplan 1986	60	Single	PBC	N/Rₑ⁰	5	2 x 0.6	Placebo	2
Kaplan 1999	87	Single	PBC	51	6	2 x 0.6	Methotrexateₑₑ	10
Kershenobich 1976	28	N/R	Liver disease	N/R	N/R	1⁴	Placebo	2
Kershenobich 1988	100	Single	Liver disease	51	50	1⁴	Placebo	14
Kyle 1985	101	Single	Other	63	58	2 x 0.6ₑ²	Melphalan/prednisone	5
Kyle 1997	148	N/R	Other	64	N/R	2 x 0.6	Usual care ³^,ₑ³	9
Lin 1996	66	Single	Liver disease	40	88	1⁴	Usual care³	4
Lukina 1995	54	N/R	Other	N/R	N/R	1 ‐ 2	Dimethyl sulfoxide	2 or 7ₑ⁴
Morgan 2005	549	Multi	Liver disease	56	98	2 x 0.6	Placebo	6
Muntoni 2010	74	Single	Liver disease	53	62	1	"usual treatment for cirrhosis"	4
Nikolaidis 2006	38	Single	Liver disease	51	61	1^d	Usual care³	1
Olsson 1995	84	Multi	PSC	42	67	1	Placebo	3
Parise 1995	41	Single	Liver disease	49	88	1	Placebo	1
Paulus 1974	52	Multi	Other	53	100	3 x 0.5	Placeboₑ⁵	0.5
Poupon 1996	74	Multi	PBC	54	15	1⁴	Placebo⁵	2
Raedsch 1992	28	Single	PBC	54	0	1	Placebo⁵	2
Reinhardt 1986	74	Single	Liver disease	N/R	N/R	4 x 0.25^d	Placebo	3
Trinchet 1989	67	Single	Liver disease	52	57	1	Placebo	0.5
Vuoristo 1995	90	Multi	Liver disease	57	14	2x 0.5	Placebo	2
Wang 1994	100	Single	Liver disease	60	94	1	Placebo	2.2
Warnes 1987	64	Single	PBC	N/R	N/R	2x 0.5	Placebo	1.5
Yurdakul 2001	116	Single	Other	27	53	2 ‐ 4 x 0.5²	Placebo	2
*Age is reported as mean in all studies but three: Antoniou 2006; Kyle 1985; Nikolaidis 2006 reported median age. ¹Longest mean follow‐up‐period for a review‐relevant outcome. ²Weight adjusted maintenance dose. ³We assume usual care, but this was not explicitly reported. ⁴Five days per week. ⁵Ursodeoxycholic acid in both groups. ⁶Prednisolone in both groups. ⁷Aspirin in both groups. ⁸Aspirin or Ibuprofen in both groups. ⁹As tolerated. ¹⁰80% > 50 years. ¹¹Ursodeoxycholic acid in both groups after 2 years. ¹²Increased in 0.6 mg steps (as tolerated). Median dose 1.5 mg/d. ¹³Melphalan and prednisone in both groups. ¹⁴Two years in colchicine group, 7 years in control group. ¹⁵Probenecid in both groups.

Table 2. Characteristics of included studies: Overview

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Table 3. Results of subgroup and sensitivity analyses

Outcome	Studies (n)	Events (n)	Participants (n)	Summary effect (95% CI)	Heterogeneity (I²), %	Subgroup effect (P value)
Participants with high cardiovascular risk
All‐cause mortality	4	29	1230	RR 0.54 (0.26 to 1.14)	0%	0.13
Cardiovascular mortality	2	13	754	RR 0.25 (0.02 to 2.66)	49%	N/C
Myocardial infarction
fatal or non‐fatal	1	22	532	RR 0.20 (0.07 to 0.57)	‐	N/C
fatal	1	1	532	RR 0.30 (0.01 to 7.22)	‐	N/C
non‐fatal	1	21	532	RR 0.21 (0.07 to 0.61)	‐	N/C
Stroke
fatal or non‐fatal	2	7	754	OR 0.38 (0.09 to 1.70)	0%	N/C
fatal	2	1	754	OR 7.26 (0.14 to 365.85)	‐	N/C
non‐fatal	2	6	754	OR 0.23 (0.05 to 1.17)	0%	N/C
Heart failure
fatal or non‐fatal	1	3	222	RR 0.14 (0.01 to 2.69)	‐	N/C
fatal	1	1	222	RR 0.33 (0.01 to 7.95)	‐	N/C
non‐fatal	1	2	222	RR 0.20 (0.01 to 4.05)	‐	N/C
Hospitalisation	0	‐	‐	‐	‐	‐
Cardiovascular intervention	1	9	222	RR 0.79 (0.22 to 2.85)	‐	N/C
Adverse event, any	0	‐	‐	‐	‐	N/C
Adverse event, gastrointestinal	2	62	501	RR 2.41 (1.43 to 4.06)	0%	N/C
Colchicine dose
All‐cause mortality	‐	‐	‐	‐	‐	‐
≤ 1mg/d	21	268	2420	RR 0.82 (0.67 to 0.99)	0%	0.03
> 1mg/d	9	505	1754	RR 1.08 (0.93 to 1.25)	31%	‐
Adverse event, any
≤ 1mg/d	7	60	687	RR 1.75 (0.74 to 4.14)	40%	0.75
> 1mg/d	3	87	626	RR 1.47 (0.72 to 2.97)	73%	‐
Peto odds ratio for outcomes with event rates between 1% and 5%
All‐cause mortality in participants with high cardiovascular risk	4	29	1230	OR 0.53 (0.25 to 1.11)	0%	‐
Cardiovascular mortality	7	17	1132	OR 0.24 (0.09 to 0.64)	15%	‐
Mantel‐Haenszel risk ratio without zero correction for outcomes with event rates between 1% and 5%
All‐cause mortality in participants with high cardiovascular risk	4	29	1230	RR 0.54 (0.26 to 1.12)	0%	‐
Cardiovascular mortality	7	17	1132	RR 0.20 (0.06 to 0.68)	0%	‐
N/C: not calculated OR: Peto odds ratio RR: risk ratio

Table 3. Results of subgroup and sensitivity analyses

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Comparison 1. Colchicine vs control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

1.1.1 Participants with high cardiovascular risk	4	1230	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.26, 1.14]
1.1.2 Other	26	2944	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.84, 1.12]
1.2 Myocardial infarction (total) Show forest plot	2	652	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.07, 0.57]

1.2.1 Participants with high cardiovascular risk	1	532	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.07, 0.57]
1.2.2 Other	1	120	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.3 Myocardial infarction (non‐fatal) Show forest plot	2	652	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.61]

1.3.1 Participants with high cardiovascular risk	1	532	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.61]
1.3.2 Other	1	120	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.4 Myocardial Infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

1.4.1 Participants with high cardiovascular risk	1	532	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.00, 6.04]
1.4.2 Other	5	378	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.05, 2.47]
1.5 Adverse event (serious) Show forest plot	4	472	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable

1.5.1 Participants with high cardiovascular risk	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.5.2 Other	4	472	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.6 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

1.6.1 Participants with high cardiovascular risk	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.6.2 Other	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]
1.7 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

1.7.1 Participants with high cardiovascular risk	2	501	Risk Ratio (M‐H, Random, 95% CI)	2.41 [1.43, 4.06]
1.7.2 Other	9	757	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.82, 3.02]
1.8 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

1.8.1 Participants with high cardiovascular risk	2	754	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.02, 2.66]
1.8.2 Other	5	378	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.09, 3.32]
1.9 Stroke (total) Show forest plot	3	874	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.38 [0.09, 1.70]

1.9.1 Participants with high cardiovascular risk	2	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.38 [0.09, 1.70]
1.9.2 Other	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.10 Stroke (fatal) Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.10.1 Participants with high cardiovascular risk	2	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.26 [0.14, 365.85]
1.10.2 Other	2	161	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.11 Stroke (non‐fatal) Show forest plot	3	874	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.05, 1.17]

1.11.1 Participants with high cardiovascular risk	2	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.05, 1.17]
1.11.2 Other	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.12 Heart failure (total) Show forest plot	3	426	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.10, 3.88]

1.12.1 Participants with high cardiovascular risk	1	222	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.69]
1.12.2 Other	2	204	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.46, 2.51]
1.13 Heart failure (fatal) Show forest plot	3		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.13.1 Participants with high cardiovascular risk	1	222	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.00, 6.70]
1.13.2 Other	2	161	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.14 Heart failure (non‐fatal) Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.14.1 Participants with high cardiovascular risk	1	222	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.12]
1.14.2 Other	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
1.15 Non‐scheduled hospitalisation (total) Show forest plot	2	599	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]

1.15.1 Participants with high cardiovascular risk	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.15.2 Other	2	599	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]
1.16 Non‐scheduled cardiovascular interventions Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.16.1 Participants with high cardiovascular risk	1	222	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.22, 2.85]
1.16.2 Other	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 1. Colchicine vs control

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Comparison 2. Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

2.1.1 ≤ 1 mg/d	21	2420	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.67, 0.99]
2.1.2 > 1 mg/d	9	1754	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.93, 1.25]
2.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

2.2.1 ≤ 1 mg/d	5	955	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.06, 0.82]
2.2.2 > 1 mg/d	2	177	Risk Ratio (M‐H, Random, 95% CI)	3.10 [0.13, 73.12]
2.3 Myocardial infarction (total) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.3.1 ≤ 1 mg/d	1	532	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.07, 0.57]
2.3.2 > 1 mg/d	1	120	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.4 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

2.4.1 ≤ 1 mg/d	4	733	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.02, 0.87]
2.4.2 > 1 mg/d	2	177	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.66 [0.15, 386.16]
2.5 Myocardial infarction (non‐fatal) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.5.1 ≤ 1 mg/d	1	532	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.61]
2.5.2 > 1 mg/d	1	120	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.6 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

2.6.1 ≤ 1 mg/d	8	687	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.74, 4.14]
2.6.2 > 1 mg/d	3	626	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.72, 2.97]
2.7 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

2.7.1 ≤ 1 mg/d	9	1104	Risk Ratio (M‐H, Random, 95% CI)	2.15 [1.26, 3.66]
2.7.2 > 1 mg/d	2	154	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.61, 2.19]
2.8 Adverse event (serious) Show forest plot	4	472	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable

2.8.1 ≤ 1 mg/d	4	472	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.8.2 > 1 mg/d	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.9 Stroke (total) Show forest plot	3	874	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.38 [0.09, 1.70]

2.9.1 ≤ 1 mg/d	2	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.38 [0.09, 1.70]
2.9.2 > 1 mg/d	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.10 Stroke (fatal) Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

2.10.1 ≤ 1 mg/d	3	795	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.26 [0.14, 365.85]
2.10.2 > 1 mg/d	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.11 Stroke (non‐fatal) Show forest plot	3	874	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.05, 1.17]

2.11.1 ≤ 1 mg/d	2	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.05, 1.17]
2.11.2 > 1 mg/d	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.12 Heart failure (total) Show forest plot	3	426	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.10, 3.88]

2.12.1 ≤ 1 mg/d	1	222	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.69]
2.12.2 > 1 mg/d	2	204	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.46, 2.51]
2.13 Heart failure (fatal) Show forest plot	3		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

2.13.1 ≤ 1 mg/d	2	263	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.00, 6.70]
2.13.2 > 1 mg/d	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.14 Heart failure (non‐fatal) Show forest plot	2	342	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.12]

2.14.1 ≤ 1 mg/d	1	222	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.12]
2.14.2 > 1 mg/d	1	120	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
2.15 Non‐scheduled hospitalisation (total) Show forest plot	2	599	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]

2.15.1 ≤ 1 mg/d	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.31, 2.55]
2.15.2 > 1 mg/d	1	549	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]
2.16 Non‐scheduled cardiovascular interventions Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.16.1 ≤ 1 mg/d	1	222	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.22, 2.85]
2.16.2 > 1 mg/d	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 2. Colchicine vs control: subgroup analysis ‐ colchicine dose fixed ≤ 1 mg/d

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Comparison 3. Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

3.1.1 Placebo, inactive control	26	3479	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.84, 1.11]
3.1.2 Active control	4	695	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.41, 1.95]
3.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

3.2.1 Placebo, inactive control	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]
3.2.2 Active control	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

3.3.1 Placebo, inactive control	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]
3.3.2 Active control	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
3.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

3.4.1 Placebo, inactive control	9	725	Risk Ratio (M‐H, Random, 95% CI)	1.60 [0.90, 2.84]
3.4.2 Active control	2	588	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.41, 4.74]
3.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

3.5.1 Placebo, inactive control	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]
3.5.2 Active control	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 3. Colchicine vs control: sensitivity analysis ‐ placebo or other inactive control

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Comparison 4. Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

4.1.1 Low risk	6	1411	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.87, 1.22]
4.1.2 High or unclear risk	24	2763	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.74, 1.11]
4.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

4.2.1 Low risk	2	652	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.01, 0.69]
4.2.2 High or unclear risk	5	480	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.95]
4.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

4.3.1 Low risk	2	652	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.00, 6.04]
4.3.2 High or unclear risk	4	258	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.05, 2.47]
4.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

4.4.1 Low risk	3	415	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.61, 4.04]
4.4.2 High or unclear risk	8	898	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.81, 2.91]
4.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

4.5.1 Low risk	4	531	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.59, 2.04]
4.5.2 High or unclear risk	7	727	Risk Ratio (M‐H, Random, 95% CI)	2.17 [1.49, 3.17]

Comparison 4. Colchicine vs control: sensitivity analysis ‐ selection bias (random sequence generation and allocation concealment)

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Comparison 5. Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

5.1.1 Double‐blind	22	2538	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.07]
5.1.2 Not clearly double‐blind	8	1636	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.82, 1.32]
5.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

5.2.1 Double‐blind	6	600	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.95]
5.2.2 Not clearly double‐blind	1	532	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.01, 0.69]
5.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

5.3.1 Double‐blind	5	378	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.05, 2.47]
5.3.2 Not clearly double‐blind	1	532	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.00, 6.04]
5.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

5.4.1 Double‐blind	6	581	Risk Ratio (M‐H, Random, 95% CI)	1.77 [1.01, 3.12]
5.4.2 Not clearly double‐blind	5	732	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.49, 3.11]
5.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

5.5.1 Double‐blind	9	1198	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.98, 3.14]
5.5.2 Not clearly double‐blind	2	60	Risk Ratio (M‐H, Random, 95% CI)	5.91 [0.32, 110.47]

Comparison 5. Colchicine vs control: sensitivity analysis ‐ performance bias (double‐blinded studies)

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Comparison 6. Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

6.1.1 Outcome assessment blinded	4	1582	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.88, 1.25]
6.1.2 Not clearly blinded	26	2592	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.75, 1.09]
6.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

6.2.1 Outcome assessment blinded	3	874	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.02, 2.66]
6.2.2 Not clearly blinded	4	258	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.09, 3.32]
6.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

6.3.1 Outcome assessment blinded	2	652	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.00, 6.04]
6.3.2 Not clearly blinded	4	258	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.05, 2.47]
6.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

6.4.1 Outcome assessment blinded	3	444	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.58, 1.93]
6.4.2 Not clearly blinded	8	869	Risk Ratio (M‐H, Random, 95% CI)	2.07 [1.03, 4.16]
6.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

6.5.1 Outcome assessment blinded	5	977	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.77, 2.68]
6.5.2 Not clearly blinded	6	281	Risk Ratio (M‐H, Random, 95% CI)	5.06 [0.92, 27.72]

Comparison 6. Colchicine vs control: sensitivity analysis ‐ detection bias (blinding of outcome assessment)

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Comparison 7. Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

7.1.1 Low risk	6	1548	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.89, 1.25]
7.1.2 High or unclear risk	24	2626	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.73, 1.09]
7.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

7.2.1 Low risk	3	630	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.01, 13.68]
7.2.2 High or unclear risk	4	502	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.07, 2.30]
7.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

7.3.1 Low risk	3	630	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.96 [0.06, 15.36]
7.3.2 High or unclear risk	3	280	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.01, 1.18]
7.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

7.4.1 Low risk	2	360	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.66, 2.51]
7.4.2 High or unclear risk	9	953	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.89, 3.33]
7.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

7.5.1 Low risk	3	639	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.87, 3.16]
7.5.2 High or unclear risk	8	619	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.94, 5.04]

Comparison 7. Colchicine vs control: sensitivity analysis ‐ attrition bias (incomplete outcome data)

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Comparison 8. Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Mortality (all‐cause) Show forest plot	30	4174	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.09]

8.1.1 Full journal publication	26	3303	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.80, 1.09]
8.1.2 Abstract only	4	871	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.58, 1.57]
8.2 Mortality (cardiovascular) Show forest plot	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]

8.2.1 Full journal publication	7	1132	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.09, 1.21]
8.2.2 Abstract only	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
8.3 Myocardial infarction (fatal) Show forest plot	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]

8.3.1 Full journal publication	6	910	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.05, 1.62]
8.3.2 Abstract only	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	Not estimable
8.4 Adverse event (total) Show forest plot	11	1313	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.93, 2.46]

8.4.1 Full journal publication	9	725	Risk Ratio (M‐H, Random, 95% CI)	1.60 [0.90, 2.84]
8.4.2 Abstract only	2	588	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.41, 4.74]
8.5 Adverse event (gastrointestinal) Show forest plot	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]

8.5.1 Full journal publication	11	1258	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.03, 3.26]
8.5.2 Abstract only	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 8. Colchicine vs control: sensitivity analysis ‐ reporting bias (selective reporting, i.e. abstract publication only)

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