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CONVINCE

Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial

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Year of Publication: 2024

Authors: Peter Kelly, Robin Lemmens, Christian Weimar, ..., Christopher Price

Journal: The Lancet

Citation: Lancet 2024;404:125-133

Link: https://doi.org/10.1016/S0140-6736(24)00968-1

Clinical Question

Does long-term colchicine (0.5mg daily) added to guideline-based usual care reduce recurrent vascular events compared with usual care alone in patients with non-cardioembolic ischaemic stroke or high-risk TIA?

Bottom Line

Colchicine did not significantly reduce the primary composite endpoint in the ITT analysis (HR 0.84, p=0.12), though the direction of effect favored colchicine and the trial was likely underpowered due to COVID-19 pandemic impacts. On-treatment analysis showed borderline significance. Colchicine consistently reduced inflammatory markers (CRP) throughout follow-up, supporting the biological rationale for anti-inflammatory therapy in stroke secondary prevention.

Major Points

  • Primary endpoint occurred in 9.8% of colchicine group vs 11.7% of usual care group (HR 0.84, 95% CI 0.68-1.05, p=0.12)
  • Trial achieved only 92.1% of planned outcomes (338/367) due to COVID-19-related budget constraints and early termination
  • On-treatment analysis showed HR 0.796 (95% CI 0.63-0.9992) favoring colchicine
  • Per-protocol analysis consistent with on-treatment results (HR 0.794, 95% CI 0.63-0.998)
  • Colchicine significantly reduced CRP at 28 days (p=0.0007), 1 year (p=0.0005), 2 years (p=0.0002), and 3 years (p=0.02)
  • Subgroup with prior coronary artery disease showed greater benefit (HR 0.57, 95% CI 0.35-0.94) though interaction test not significant
  • 20.5% non-adherence rate in colchicine group, similar to other long-term colchicine trials without run-in
  • No excess serious adverse events; GI side effects (diarrhea, nausea) more common with colchicine as expected
  • First RCT of long-term colchicine for stroke secondary prevention; supports rationale for further trials

Design

Study Type: Randomised, parallel-group, open-label, blinded endpoint assessed (PROBE) controlled phase 3 trial

Randomization: 1

Blinding: Open-label treatment allocation; outcome adjudication by independent committee blinded to treatment assignment

Enrollment Period: December 19, 2016 to November 21, 2022

Follow-up Duration: Median 33.6 months (last follow-up January 31, 2024)

Centers: 144

Countries: Ireland, Germany, Belgium, UK, Poland, Portugal, Canada, Lithuania, Estonia, Denmark, Switzerland, Spain, France

Sample Size: 3144

Analysis: Intention-to-treat; Cox proportional hazards regression adjusting for minimisation variables; prespecified on-treatment and per-protocol sensitivity analyses; p-value threshold adjusted to 0.048 for two interim analyses

Inclusion Criteria

  • Age ≥40 years
  • Clinically stable
  • Non-severe ischaemic stroke (modified Rankin Scale score ≤3)
  • OR high-risk TIA: transient focal motor/speech symptoms with ABCD2 score ≥4, OR ≥50% large artery stenosis on imaging, OR DWI hyperintensity consistent with symptoms
  • Non-cardioembolic etiology: large artery atherosclerosis of ipsilateral carotid/vertebral/intracranial artery, lacunar disease, or cryptogenic embolism
  • Randomisation window 72 hours to 28 days post-qualifying event

Exclusion Criteria

  • Qualifying event likely caused by atrial fibrillation or other cardiac embolism
  • Qualifying event caused by arterial dissection or other defined causes
  • Pre-existing moderate-to-severe renal, liver, or blood disorders
  • Peripheral neuropathy
  • Myopathy
  • Inflammatory bowel disease or chronic diarrhoea
  • Regular immunosuppressant medications
  • Moderate-to-strong CYP3A4 inhibitors
  • P-glycoprotein inhibitors

Arms

FieldColchicine + Usual CareControl
InterventionColchicine 0.5mg orally once daily plus guideline-based usual care (antiplatelet therapy, statins, blood pressure management)Guideline-based usual care only (antiplatelet therapy, statins, blood pressure management)
DurationUntil trial end (median 33.6 months)Until trial end (median 33.6 months)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation for unstable angina (admission ≥24h or calendar date change)Primary185/1575 (11.7%); 3.92 per 100 person-years153/1569 (9.8%); 3.33 per 100 person-years0.840.12
Key secondary endpoint (ischaemic stroke, MI, cardiac arrest, or vascular death)Secondary177/1575 (11.2%); 3.77 per 100 person-years147/1569 (9.4%); 3.20 per 100 person-years0.85
All ischaemic stroke (fatal and non-fatal)Secondary136/1575 (8.6%); 2.96 per 100 person-years108/1569 (6.9%); 2.39 per 100 person-years0.8
Non-fatal ischaemic strokeSecondary131/1575 (8.3%); 2.77 per 100 person-years103/1569 (6.6%); 2.24 per 100 person-years0.8
Non-fatal myocardial infarctionSecondary29/1575 (1.8%); 0.61 per 100 person-years26/1569 (1.7%); 0.57 per 100 person-years0.93
Vascular deathSecondary17/1575 (1.1%); 0.38 per 100 person-years16/1569 (1.0%); 0.37 per 100 person-years0.97
On-treatment analysis - Primary endpointSecondary185/1575 (11.7%); 3.92 per 100 person-years124/1559 (8.0%); 3.2 per 100 person-years0.796
Per-protocol analysis - Primary endpointSecondaryPer-protocol populationPer-protocol population0.794
All serious adverse eventsAdverse1115 (70.8%)1096 (69.9%)0.99
Non-cardiovascular deathsAdverse41 (2.6%)45 (2.9%)1.1
Serious adverse events due to cancerAdverse86 (5.5%)81 (5.2%)0.95
Serious adverse events due to infectionAdverse325 (20.6%)313 (19.9%)0.97
All haemorrhage SAEsAdverse31 (2.0%)28 (1.8%)0.91
Intracranial haemorrhageAdverse14 (0.9%)12 (0.8%)0.86
Loose stools or diarrhoeaAdverse32 (2.0%)190 (12.1%)5.42
NauseaAdverse22 (1.4%)54 (3.4%)2.42
GoutAdverse18 (1.1%)6 (0.4%)0.34
Rash, itch, or alopeciaAdverse10 (0.6%)29 (1.8%)2.88

Subgroup Analysis

Results consistent across prespecified subgroups (age, sex, qualifying event type, time to randomisation, hypertension, diabetes, smoking, carotid stenosis). Patients with prior coronary artery disease showed numerically greater benefit (HR 0.57, 95% CI 0.35-0.94) compared to those without (HR 0.95, 95% CI 0.75-1.21), though interaction test not significant (p=0.4).

Criticisms

  • Open-label design without placebo control (budget constraints); though outcomes were adjudicated by blinded committee
  • Trial stopped early due to COVID-19 pandemic budget constraints, achieving only 92% of planned outcomes and likely underpowered
  • COVID-19 pandemic disrupted recruitment (2-month pause) and may have influenced event rates during follow-up
  • 20.5% non-adherence rate in colchicine group may have diluted treatment effect in ITT analysis
  • Predominantly White European population (95%) limits generalisability
  • Women under-represented (30.3%) despite efforts to improve recruitment
  • Heterogeneous stroke population including lacunar and cryptogenic subtypes where anti-inflammatory benefit may differ
  • Hospitalisation for unstable angina included in primary endpoint (though only 4% of outcomes)
  • No baseline selection for elevated inflammatory markers (unlike CHANCE3 which required CRP ≥2)

Funding

Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation 397530000), Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium

Based on: CONVINCE (The Lancet, 2024)

Authors: Peter Kelly, Robin Lemmens, Christian Weimar, ..., Christopher Price

Citation: Lancet 2024;404:125-133

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