CONVINCE
Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial
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
PDF: https://pure.amsterdamumc.nl/files/15665...ke-convince.pdf
PDF: 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?
Study Overview
Objective
To investigate whether long-term colchicine added to guideline-based usual care reduces recurrent vascular events compared with usual care alone in patients with non-cardioembolic ischaemic stroke or high-risk TIA
Study Summary
- Colchicine 0.5mg daily did not significantly reduce the primary composite endpoint vs usual care (HR 0.84, 95% CI 0.68-1.05, p=0.12)
- Direction of effect favored colchicine with 16% relative hazard reduction but trial was underpowered due to COVID-19 pandemic
- On-treatment analysis showed borderline significant benefit (HR 0.80, 95% CI 0.63-0.9992)
- Colchicine significantly reduced CRP levels at all follow-up timepoints
Intervention
Colchicine 0.5mg orally once daily plus guideline-based usual care vs usual care alone
Patients per Arm
1569 colchicine vs 1575 usual care (ITT population: 3144)
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
Baseline Characteristics
| Characteristic | Usual Care | Colchicine |
|---|---|---|
| Age - years | 66.2 (9.9) | 66.4 (10.0) |
| Sex - Female | 29.5% | 31.1% |
| Sex - Male | 70.5% | 68.9% |
| Race - White | 95.7% | 95.2% |
| Race - Black | 2.5% | 2.3% |
| Race - Asian | 1.2% | 1.7% |
| Race - Other | 0.6% | 0.8% |
| Onset to randomisation - days | 9 (5-18) | 9 (5-17) |
| Qualifying event - Stroke | 87.8% | 88.0% |
| Qualifying event - TIA | 12.2% | 12.0% |
| Modified Rankin Scale score | 1 (0-2) | 1 (0-2) |
| NIHSS score | 1 (0-3) | 1 (0-3) |
| ABCD2 score (TIA only) | 4 (3-5) | 5 (4-6) |
| Lacunar stroke | 30.8% | 29.8% |
| Carotid stenosis >50% | 21.9% | 22.2% |
| Carotid revascularisation at 28 days | 2.2% | 2.9% |
| Thrombolysis | 13.8% | 16.3% |
| Thrombectomy | 5.4% | 5.5% |
| Previous stroke | 11.0% | 10.0% |
| Hypertension | 65.5% | 65.4% |
| Diabetes | 21.8% | 22.8% |
| Smoker | 21.8% | 22.3% |
| Previous coronary artery disease | 9.7% | 8.0% |
| Peripheral artery disease | 4.1% | 4.0% |
| Gout | 4.1% | 3.3% |
| Baseline CRP - mg/L | 3 (1-6) | 3 (1.1-6) |
| Any antiplatelet at randomisation | 97.9% | 97.1% |
| Any statin at randomisation | 94.0% | 93.7% |
Arms
| Field | Colchicine + Usual Care | Control |
|---|---|---|
| Intervention | Colchicine 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) |
| Duration | Until trial end (median 33.6 months) | Until trial end (median 33.6 months) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, hospitalisation for unstable angina (admission ≥24h or calendar date change), or vascular death | Primary | 185/1575 (11.7%); 3.92 per 100 person-years | 153/1569 (9.8%); 3.33 per 100 person-years | 0.84 | 0.12 |
| Key secondary endpoint (non-fatal ischaemic stroke, MI, cardiac arrest, or vascular death) | Secondary | 177/1575 (11.2%); 3.77 per 100 person-years | 147/1569 (9.4%); 3.20 per 100 person-years | 0.85 | |
| All ischaemic stroke (fatal and non-fatal) | Secondary | 136/1575 (8.6%); 2.96 per 100 person-years | 108/1569 (6.9%); 2.39 per 100 person-years | 0.8 | |
| Non-fatal ischaemic stroke | Secondary | 131/1575 (8.3%); 2.77 per 100 person-years | 103/1569 (6.6%); 2.24 per 100 person-years | 0.8 | |
| Non-fatal myocardial infarction | Secondary | 29/1575 (1.8%); 0.61 per 100 person-years | 26/1569 (1.7%); 0.57 per 100 person-years | 0.93 | |
| Hospitalisation for unstable angina (non-fatal) | Secondary | 8/1575 (0.5%); 0.17 per 100 person-years | 6/1569 (0.4%); 0.13 per 100 person-years | 0.75 | |
| Non-fatal cardiac arrest | Secondary | 0/1575 (0%); 0 per 100 person-years | 2/1569 (0.1%); 0.04 per 100 person-years | NC | |
| Vascular death | Secondary | 17/1575 (1.1%); 0.38 per 100 person-years | 16/1569 (1.0%); 0.37 per 100 person-years | 0.97 | |
| Non-fatal MI and cardiac arrest | Secondary | 29/1575 (1.8%); 0.64 per 100 person-years | 28/1569 (1.8%); 0.64 per 100 person-years | 1 | |
| All cardiac events (fatal and non-fatal) | Secondary | 49/1575 (3.1%); 1.07 per 100 person-years | 45/1569 (2.9%); 1.01 per 100 person-years | 0.95 | |
| On-treatment analysis - Primary endpoint | Secondary | 185/1575 (11.7%); 3.92 per 100 person-years | 124/1559 (8.0%); 3.2 per 100 person-years | 0.796 | |
| Per-protocol analysis - Primary endpoint | Secondary | Per-protocol population (n=1572) | Per-protocol population (n=1565) | 0.794 | |
| _note | Adverse | Denominators: colchicine n=1569, usual care n=1575. Numbers refer to events, not patients, as some patients had more than one adverse event. Effect measures are relative risks (RR) per Table 3. | |||
| All serious adverse events | Adverse | 1115 (70.8%) | 1096 (69.9%) | 0.99 | |
| Non-cardiovascular deaths | Adverse | 41 (2.6%) | 45 (2.9%) | 1.1 | |
| Non-outcome deaths | Adverse | 49 (3.1%) | 55 (3.5%) | 1.13 | |
| Serious adverse events due to cancer | Adverse | 86 (5.5%) | 81 (5.2%) | 0.95 | |
| Fatal cancer | Adverse | 10 (0.6%) | 13 (0.8%) | 1.3 | |
| Serious adverse events due to infection | Adverse | 325 (20.6%) | 313 (19.9%) | 0.97 | |
| Fatal infections | Adverse | 14 (0.9%) | 7 (0.4%) | 0.5 | |
| All haemorrhage SAEs | Adverse | 31 (2.0%) | 28 (1.8%) | 0.91 | |
| Intracranial haemorrhage | Adverse | 14 (0.9%) | 12 (0.8%) | 0.86 | |
| Gastrointestinal haemorrhage | Adverse | 14 (0.9%) | 13 (0.8%) | 0.93 | |
| Other haemorrhage | Adverse | 3 (0.2%) | 3 (0.2%) | 1 | |
| Serious muscle symptoms (rhabdomyolysis, myopathy, or myalgia) | Adverse | 2 (0.1%) | 0 | NC | |
| Gout | Adverse | 18 (1.1%) | 6 (0.4%) | 0.34 | |
| Myelosuppression causing neutropenia | Adverse | 4 (0.3%) | 0 | NC | |
| Loose stools or diarrhoea | Adverse | 32 (2.0%) | 190 (12.1%) | 5.42 | |
| Nausea | Adverse | 22 (1.4%) | 54 (3.4%) | 2.42 | |
| Raised transaminases or hepatic enzymes | Adverse | 28 (1.8%) | 44 (2.8%) | 1.56 | |
| Renal impairment | Adverse | 79 (5.0%) | 63 (4.0%) | 0.81 | |
| Neuropathy | Adverse | 3 (0.2%) | 10 (0.6%) | 3.33 | |
| Rash, itch, or alopecia | Adverse | 10 (0.6%) | 29 (1.8%) | 2.88 | |
| Oligospermia or azoospermia | Adverse | 0 | 1 (0.1%) | NC | |
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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