Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage: A Placebo-Controlled Trial

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Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage: A Placebo-Controlled Trial

Aristeidis H. Katsanos, MD https://orcid.org/0000-0002-6359-0023 ar.katsanos@gmail.com, Kelvin K.H. Ng, MD https://orcid.org/0000-0002-1603-9634, Thalia S. Field, MD https://orcid.org/0000-0002-1176-0633, Aravind Ganesh, MD https://orcid.org/0000-0001-5520-2070, Joanna D. Schaafsma, MD https://orcid.org/0000-0003-4326-5597, Shirin Jalini, MD https://orcid.org/0009-0007-7548-6702, Ashfaq Shuaib, MD https://orcid.org/0000-0002-3380-7068, … Show All … , and Ashkan Shoamanesh, MD https://orcid.org/0000-0002-2802-1626Author Info & Affiliations

Stroke

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https://doi.org/10.1161/STROKEAHA.126.055934

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Abstract

BACKGROUND:

There is a need for novel treatments that lower the risk of major adverse cardiovascular events and secondary inflammatory brain injury after an intracerebral hemorrhage (ICH).

METHODS:

We performed a double-blind, placebo-controlled, pilot randomized clinical trial at 11 centers across Canada to determine the feasibility of testing colchicine after an acute ICH. We recruited adults presenting within 48 hours of ICH onset with vascular neuroimaging evidence or risk factors for atherosclerosis. Participants were randomized to oral colchicine 0.5 mg daily or placebo and followed to a common study termination date. The primary feasibility outcome was the recruitment rate (participants/center per year). Secondary feasibility outcomes included retention of participants at 6 months and medication adherence at 12 months. This trial is registered (ClinicalTrials.gov ID: REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219).

RESULTS:

Between August 2022 and March 2024, 52 participants were allocated to colchicine 0.5 mg daily and 48 participants to placebo daily. Participants were, on average, 68 years old, and 60% were male. The mean time from ICH onset to randomization was 35 hours. The average recruitment rate was 8.9 participants/site per year. Retention at 6 months was 92% (colchicine 91% versus placebo 93%). Following randomization, 14 participants (27%) in the colchicine group and 13 participants (27%) in the placebo group permanently discontinued the study drug. Excluding participants who died or permanently discontinued the study intervention, 12-month medication adherence was 97%, with similar rates between the colchicine and placebo groups (100% versus 93%). We detected no difference in predefined exploratory efficacy or safety end points between the 2 groups over the median follow-up time of 364 days.

CONCLUSIONS:

It is feasible to test low-dose colchicine after an acute ICH. Future randomized clinical trials should account for the high rates of early permanent study drug discontinuation in this patient population.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219.

Graphical Abstract

Thromboinflammation is believed to worsen neurological outcomes and contribute to ischemic vascular events in patients with small vessel disease, including intracerebral hemorrhage (ICH). The management of patients with ICH is challenging and requires balancing the benefit of ischemic vascular preventive treatments against any possible increase in bleeding risk.¹ ICH survivors have a constant risk of rebleeding, with the annual rate of ICH recurrence ranging from 1.3% to 7.4%.² Because of their preexisting vascular risk factors and comorbidities, ICH survivors are at considerably higher risk of major adverse cardiovascular events (MACE),^3–5 which is further aggravated by the cessation of antithrombotic medications for significant periods after ICH.⁶ These findings highlight the need for novel treatments that lower the high vascular risk over the long term in ICH survivors, particularly in the early post-ICH period when patients are not receiving antithrombotic medications.

Randomized-controlled clinical trials (RCTs) have established that colchicine reduces the risk of MACE (risk ratio, 0.73 [95% CI, 0.65–0.90]) and ischemic stroke (risk ratio, 0.73 [95% CI, 0.58–0.90]) in patients with a history of coronary artery disease, with no increase in ICH risk.⁷ Results from an observational study further suggest that patients with diabetes receiving colchicine treatment have lower risks of stroke, with the risk reduction for both ischemic and hemorrhagic stroke being proportionate to the duration of colchicine use.⁸ In an experimental murine collagenase-induced ICH model, we provided proof of concept for the safety of oral colchicine after ICH, detecting no increase in hematoma volume and less perihematomal brain inflammation at a scaled dose equivalent to the 0.5 mg daily that was used in trials testing colchicine in patients with coronary artery disease, when compared with placebo.⁹

We initiated the CoVasc-ICH trial (Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage) to determine the feasibility of testing colchicine for reducing the risk of MACE and secondary inflammatory brain injury following an acute spontaneous ICH.