Colchicine for prevention of cardiovascular events

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate potential benefits and harms of a continuous long-term treatment with colchicine to prevent cardiovascular events in people with and without previous cardiovascular events.

Background

Description of the condition

Cardiovascular disease (CVD) is the leading cause of death worldwide (WHO 2011). CVD is a class of diseases that affect the heart and blood vessels. CVD includes coronary heart disease and cerebrovascular disease, both diseases of the blood vessels supplying the heart or brain with oxygenated blood. One important pathophysiologic mechanism of CVD is the development of atherosclerotic lesions, so called 'plaques' (Libby 2013; Shah 2003; Shah 2009). These lesions may cause chronic ischemia and subsequent organ damage leading, for example, to heart failure. However, such plaques may also rupture and cause acute thrombotic events such as myocardial infarctions or strokes (Libby 2013; Shah 2003; Shah 2009). The mechanisms leading to destabilization of atherosclerotic plaques and subsequent rupture are not completely understood, but inflammatory processes seem to play an important role (Libby 2013; Shah 2009). This is based on observations that inflammatory cells concentrate at ruptured plaques (Carr 1997; Libby 2013), and there is strong evidence that raised blood levels of inflammatory markers (C-reactive protein) are associated with increased risk of coronary events (Emerging Risk Factors Collaboration 2010).

Description of the intervention

Colchicine is a very old, inexpensive drug with strong anti-inflammatory effects (Niel 2006; Terkeltaub 2009). Extracts from autumn crocus (Colchicum autumnale) have been used for centuries to treat acute gout (Cocco 2010; Rodnan 1970; Terkeltaub 2009). In the 18th century, an alkaloid was identified as the active pharmaceutical ingredient of this plant, which became known as colchicine and which since then has been widely used for treatment of gout (Rodnan 1970; Schlesinger 2004).

In addition to gout, colchicine is also used for treatment of several other diseases, including familial Mediterranean fever (FMF), Behçet's disease, primary biliary cirrhosis, and pericarditis (Cocco 2010; Terkeltaub 2009). The complex molecular and cellular mechanisms of action of colchicine and its pharmacological properties have recently been systematically reviewed by Terkeltaub 2009. While the mechanism of action against diverse diseases is not completely understood, over recent years the understanding of how and under what circumstances colchicine can be used to treat diverse clinical conditions has continuously evolved (Terkeltaub 2009). Colchicine's anti-inflammatory action is strongly related to its effects on leukocytes by modifying their adhesion, migration, cytokine production and secretion (Cronstein 2006; Niel 2006; Terkeltaub 2009).

Colchicine has a relatively narrow therapeutic window and high interindividual pharmacokinetic variability (Niel 2006; Terkeltaub 2009; Yang 2010). Despite its widespread use in treatment of gout, evidence is limited allowing assessment of the optimal dosage of colchicine for this condition. A Cochrane review published in 2006 identified only a single randomized controlled trial (RCT) comparing colchicine to placebo (with 42 participants) and no trial comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or to other treatments (Schlesinger 2006). In this trial, acute gout was treated with a regimen of 1 mg of oral colchicine followed by 0.5 mg every two hours until symptoms were relieved or adverse effects occurred. The participants received a mean dose of 6.7 mg colchicine and all those in the active treatment group had gastrointestinal side effects (diarrhea or vomiting), while five control participants developed nausea but without diarrhea or vomiting (Ahern 1987). A recent RCT including 185 participants explored the comparative effectiveness of such a high-dose treatment for acute gout (here 4.8 mg over six hours, i.e. 1.2 mg initially and 0.6 mg every hour) with a low-dose regimen (1.8 mg over one hour, i.e. 1.2 mg initially and 0.6 mg one hour later) and with placebo (Terkeltaub 2010). The gout-related benefits of treatment (pain reduction) were similar in both active treatment regimens. However, while with the high-dose regimen 77% of participants had diarrhea (19% severe), 77% nausea, and 17% vomiting, with low-dose treatment 23% of participants had diarrhea (none severe), 4% nausea and none had vomiting (placebo: 14%, 5%, 0% respectively). Serious adverse events did not occur in this study.

Low-dose colchicine for the treatment and prevention of pericarditis has been shown to be effective in several RCTs without providing indications of severe adverse effects occurring in the first six months of treatment (Imazio 2012). The daily dose used in five trials was 0.5 to 1.0 mg and 1.5 mg/day in one trial. Among 684 participants with a maximum follow-up of six months, gastrointestinal intolerance was the most frequent side effect and no severe adverse events were reported (Imazio 2012).

In people at increased risk for cardiovascular events, low-dose colchicine treatment is a novel and non-standard treatment approach. It has been evaluated as continuous treatment over six months in doses of 0.5 mg/day (Nidorf 2013), and 1 mg/day (Deftereos 2013). An earlier trial used colchicine after coronary angioplasty at a dose of 1.2 mg/day over six months (O'Keefe 1992). Side effects in these studies were predominantly gastrointestinal, with other reported adverse effects including myalgia, myositis, and muscle cramps, and a small number of cases of increased creatine kinase levels, rash, accelerated hair loss, alopecia, itch, peripheral neuritis, and death (Deftereos 2013; Nidorf 2013; O'Keefe 1992).

How the intervention might work

Colchicine might inhibit the inflammatory mechanisms leading to the development or destabilization of atherosclerotic plaques. Colchicine treatment was associated with a decrease of high-sensitivity C-reactive protein in people with stable coronary artery disease (Nidorf 2007), but this was not observed in a randomized trial of participants with acute coronary syndrome or acute stroke (Raju 2012).

However, recently published results from RCTs on prevention of cardiovascular events suggest a considerable benefit of low-dose colchicine treatment in people at increased risk for cardiovascular events (Deftereos 2013; Nidorf 2013). Nidorf 2013 analyzed in a RCT with blinded outcome assessment 532 participants with stable coronary disease who were treated with colchicine 0.5 mg/day or no colchicine. Median follow-up was three years. The primary outcome (a combined endpoint of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke) was significantly reduced with colchicine treatment (hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.18 to 0.59; P < 0.001; number needed to treat for an additional beneficial outcome (NNTB): 11). Deftereos 2013 analyzed in a placebo-controlled, double-blinded study 222 participants with diabetes undergoing a percutaneous coronary intervention (PCI) with a bare-metal stent (BMS). Colchicine treatment (1 mg/day) over six months significantly reduced the risk for in-stent restenoses (odds ratio (OR) 0.38, 95% CI 0.18 to 0.79, P = 0.007, NNTB: 6).

Why it is important to do this review

While recent studies (Deftereos 2013; Nidorf 2013) suggest a considerable benefit of low-dose colchicine treatment, their results are inconsistent with previous findings where no benefit for prevention of restenosis after coronary angioplasty was demonstrated (O'Keefe 1992).

There is thus far no systematic review of the available evidence on the effects of colchicine treatment on cardiovascular events that would allow a valid assessment of the potential long-term benefits and harms of this intervention for primary or secondary prevention of cardiovascular events.

Objectives

To evaluate potential benefits and harms of a continuous long-term treatment with colchicine to prevent cardiovascular events in people with and without previous cardiovascular events.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs) and pseudo-randomized controlled trials. We will include studies reported as full-text, those published as abstract only, and unpublished data. We will consider data from the first phase only of randomized cross-over trials for inclusion. We will exclude 'N of 1' trials and non-randomized (observational) research.

Types of participants

We will include trials in adults (aged 18 years and over) with any condition or disease.

Types of interventions

We will include trials comparing treatment with colchicine for any condition or any disease on a continuous basis (treatment over at least six months at any dose and with any type of application) with any treatment (including usual care or placebo) not containing colchicine. We will accept any co-interventions, provided they are identical in the compared study groups and not part of the randomized treatment.

Types of outcome measures

For all outcomes we will use the number of participants, not the number of events.

Primary outcomes
  1. All-cause mortality

  2. Myocardial infarction (fatal and non-fatal)

  3. Adverse events, any (total, gastrointestinal, serious).

The intervention to be investigated in this systematic review is typically intended to be used as lifelong treatment of a chronic condition. Thus we require a sufficient treatment duration to allow valid assessment of the long-term benefits and harms. We will therefore include only trials reporting on any of these outcomes at least six months after randomization.

Following the US Food and Drug Administration (FDA) definition, we will consider an adverse event or suspected adverse reaction "serious" if:

"it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse" ( FDA 2013).

If adverse events are reported as "serious" but the definition is unclear, and if this could not be clarified with the authors, or the definition does not agree with the FDA version, we will consider these outcomes "serious" for the main analysis but will exclude such studies in a sensitivity analysis.

We will not consider composites of the listed outcomes.

Secondary outcomes
  1. Cardiovascular mortality (total)

  2. Stroke (fatal and non-fatal)

  3. Heart failure (fatal and non-fatal)

  4. Non-scheduled hospitalizations (all-cause and due to cardiovascular reasons)

  5. Non-scheduled cardiovascular interventions (PCI/angioplasty or coronary artery bypass graft (CABG)).

We will not include studies reporting only on secondary outcomes and not on any of the primary outcomes.

Should data on quality of life or economic costs be available in any eligible study, we will comment on these outcomes in the Discussion section in a narrative form.

Search methods for identification of studies

Electronic searches

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

  • Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library

  • MEDLINE (Ovid)

  • EMBASE (Ovid)

The preliminary search strategy for MEDLINE (Ovid) (see Appendix 1) will be adapted for use in the other databases. We will slightly modify the Cochrane precision-maximizing RCT filter (Lefebvre 2011) to increase sensitivity, and will apply it to MEDLINE (Ovid) and adaptations of it to the other databases, except for CENTRAL.

We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/).

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

We will conduct the searches with the support of an experienced professional librarian.

Searching other resources

We will check reference lists of all eligible primary studies for additional references. We will contact authors of included studies for information on unreported outcomes, missing outcome data in their studies, and for further unpublished studies.

We will use the citation search in Web of Science (Thomson Reuters) to identify potentially relevant articles citing key papers in this area of research: Deftereos 2013, Nidorf 2013, and O'Keefe 1992.

Data collection and analysis

Selection of studies

Two authors (two from LGH, VG, KO, AJN, MB) will independently screen titles and abstracts of all the potential studies for inclusion, and will code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. If there are any disagreements, a third author will arbitrate (LGH or MB). We will retrieve the full-text study reports/publication, and two authors (two from LGH, VG, KO, AJN, MB) will independently screen the full-texts and identify studies for inclusion, and will identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (LGH or MB). 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 a 'Characteristics of excluded studies' table.

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. One of the authors (LGH, VG, KO, AJN, MB) will extract study characteristics from included studies, and a second author will verify the extractions. We will extract the following study characteristics.

  1. Methods: study design, total duration of study, details of any 'run in' period, number of study centers and location, study setting, withdrawals, and date of study.

  2. Participants: N, mean age, age range, gender, condition or disease, inclusion criteria, and exclusion criteria.

  3. Interventions: intervention, comparison, concomitant medications, and excluded medications.

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

  5. Notes: funding for trial, and notable conflicts of interest of trial authors.

Two authors (from LGH, VG, KO,AJN,MB) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third author (LGH or MB). One author (LGH) will transfer data into the Review Manager 5 (RevMan 2012) file. We will double-check that data is entered correctly by comparing the data presented in the systematic review with the study reports. A second author (LGH) will spot-check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two authors (from LGH, VG, KO, AJN, MB) will independently assess the risks of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (LGH, VG, KO, AJN, or MB). We will assess the risks of bias according to the following domains.

  1. Random sequence generation

  2. Allocation concealment

  3. Blinding of participants and personnel

  4. Blinding of outcome assessment

  5. Incomplete outcome data

  6. Selective outcome reporting

  7. Other bias.

We will grade each potential source of bias as being at high, low or unclear risk and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarize the risk of bias judgments across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and will report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyze dichotomous data as odds ratios, risk ratios, or absolute risk differences with 95% confidence intervals.

We will undertake meta-analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical questions are similar enough for pooling to make sense.

Unit of analysis issues

We will include RCTs with parallel group design (unit of randomization will typically be the individual participant) and we do not anticipate any major unit of analysis issues. From cross-over trials, we will consider the first phase only for inclusion. We will not exclude cluster randomized trials, but we do not anticipate such designs. If we should identify such studies, we will decide at the individual study level whether or not to include the data into the quantitative evidence synthesis. If a study includes multiple intervention groups, we will not include the same intervention group more than once in the meta-analyses. We will decide at the individual study level whether to combine study groups before using data in the meta-analysis or selecting study groups.

Dealing with missing data

We will contact investigators or study sponsors where possible in order to verify key study characteristics and obtain missing numerical outcome data (e.g. when a study is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will use a sensitivity analysis to explore the impact of including such studies in the overall assessment of results

Assessment of heterogeneity

We will use the I² (Higgins 2003) and tau statistics to describe heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will report it and explore possible causes by prespecified subgroup analysis. Given the wide perspective of the review with broad inclusion criteria and the highly diverse fields of application of the intervention in various settings, we do not expect the true effects of the intervention to be homogeneous.

Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases for the primary outcomes.

Data synthesis

We will use a random-effects model to synthesize the identified treatment effects, because we anticipate that the true effects of colchicine treatment will be very variable across included studies, especially in the context of the broad inclusion criteria.

Summary of findings table

We will create a 'Summary of findings' table using the following outcomes:

  1. All-cause mortality

  2. Cardiovascular mortality (total)

  3. Myocardial infarction (fatal and non-fatal)

  4. Stroke (fatal and non-fatal)

  5. Heart failure (fatal and non-fatal)

  6. Adverse events, any (total, serious).

We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using GRADEpro software. We will justify all decisions to down- or up-grade the quality of studies using footnotes and we will make comments to aid the reader's understanding of the review where necessary.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses according to:

  1. Colchicine dose

  2. Type of condition for which colchicine was given

  3. Type of comparator

  4. Primary/secondary prevention of CVD.

We will use the following outcomes in subgroup analyses:

  1. All-cause mortality

  2. Cardiovascular mortality (total)

  3. Myocardial infarction (fatal and non-fatal)

  4. Stroke (fatal and non-fatal)

  5. Heart failure (fatal and non-fatal)

  6. Adverse events, any (total, serious).

We will use the formal test for subgroup interactions in Review Manager 5 (RevMan 2012).

Sensitivity analysis

We plan to carry out the following sensitivity analyses:

  1. Including only studies with an overall low risk of bias (all outcomes)

  2. Including only studies reporting on both a primary outcome indicating potential benefit and the secondary outcome adverse events (all outcomes)

  3. Including only studies with a definition of serious adverse events that clearly agrees with the FDA definition (FDA 2013) (for serious adverse events only).

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice, and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

Appendices

Appendix 1. MEDLINE search strategy

1306 draft search strategy for protocol

With modified Cochrane precision-maximising RCT filter

Database: Ovid MEDLINE(R) <1946 to June Week 2 2013>

Search Strategy:

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1 exp Colchicine/ (13484)

2 colcemid*.tw. (1379)

3 demecolcine.tw. (203)

4 colchamine.tw. (41)

5 lumicolchicine*.tw. (244)

6 gamma-lumicolchicine*.tw. (18)

7 beta-lumicolchicine.tw. (48)

8 colchicin*.tw. (12264)

9 colchichine.tw. (10)

10 aqua colchin.tw. (0)

11 colchicum.tw. (151)

12 colchily.tw. (0)

13 colchimedio.tw. (0)

14 colchiquim.tw. (0)

15 colchisol.tw. (0)

16 colchysat.tw. (2)

17 colcine.tw. (0)

18 colcrys.tw. (4)

19 colgout.tw. (0)

20 goutichine.tw. (0)

21 goutnil.tw. (0)

22 kolkicin.tw. (0)

23 nsc 757.tw. (0)

24 tolchicine.tw. (0)

25 or/1-24 (18450)

26 randomized controlled trial.pt. (366634)

27 controlled clinical trial.pt. (87662)

28 randomized.ab. (266125)

29 placebo.ab. (144826)

30 clinical trials as topic.sh. (169887)

31 randomly.ab. (187502)

32 trial.ti. (114819)

33 26 or 27 or 28 or 29 or 30 or 31 or 32 (841780)

34 exp animals/ not humans.sh. (3908355)

35 33 not 34 (775181)

36 25 and 35 (389)

37 (trial* or random*).tw. (970398)

38 33 or 37 (1214949)

39 38 not 34 (1093431)

40 25 and 39 (611)

Contributions of authors

LGH and MB designed the protocol.
LGH wrote the first draft.
VG, KO, AJN, and MB commented on the draft.
All authors approved the final version of the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Santesuisse, Switzerland.

    LGH, VG, AJN, and MB are supported by Santesuisse.

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