Weekly Journal Scan: colchicine after an acute ischaemic stroke shows no <i>CHANCE</i> of preventing recurrent events

Comment on the article ‘Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo-controlled trial’ published in the BMJ, https://doi.org/10.1136/bmj-2023-079061. The Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) was an investigator-initiated, randomized, double blind, placebo-controlled trial conducted at 244 centres in China. The trial enrolled patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or high-risk transient ischaemic attack (TIA) who had a high-sensitivity C-reactive protein level ≥ 2 mg/L. The aim was to evaluate the efficacy and safety of low-dose colchicine vs. placebo, started within 24 h of symptom onset, in reducing subsequent stroke within 90 days.1 Between August 2022 and April 2023, 8343 patients were enrolled (median age 66 years; 38% women; 89% with ischaemic stroke, and 11% with TIA; median level of high-sensitivity C-reactive protein, 4.8 mg/L). Patients were enrolled if they had a National Institutes of Health Stroke Scale score of ≤5: median 2, interquartile range 1–4 (range 0–42, with higher scores indicating more severe stroke). Patients with qualifying high-risk TIA were enrolled if they had an ABCD2 stroke risk score ≥ 4: median 5, interquartile range 4–5 (range 0–7, with higher scores indicating higher risk of stroke).2 Patients were randomly assigned 1:1 to receive colchicine (0.5 mg twice daily on Days 1–3, followed by 0.5 mg daily) or placebo for 90 days on a background of standard medical therapy, including antiplatelet drugs (95%), statins (96%), hypoglycaemic (76%), and anti-hypertensive drugs (73%). The primary efficacy outcome was any new stroke (ischaemic or haemorrhagic) within 90 days after randomization. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. The primary outcome of any new stroke at 90 days occurred in 264 patients (6.3%; 8 haemorrhagic strokes) in the colchicine group and in 270 patients (6.5%; 7 haemorrhagic strokes) in the placebo group (hazard ratio, 0.98; 95% confidence interval, 0.83–1.16; P = .79). All secondary outcomes were also neutral, with no differences between the two treatment groups. These results were consistent across multiple subgroups, except that there was an apparent trend for colchicine reducing risk at ages < 65 years and increasing risk in older patients. No excess in adverse events was observed in patients treated with colchicine. Serious adverse events occurred in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P = .83). Fifteen patients (0.4%) in the colchicine group and 18 patients (0.4%) in the placebo group died from non-cardiovascular causes. Similar rates of study drug discontinuation owing to serious adverse events were observed in the two groups (1.6% vs. 1.5%). Abnormal hepatic function (0.3% vs. 0.1%; P = .03) and diarrhoea (1.7% vs. 0.7%; P < .001) were more frequent in the colchicine group than in the placebo group. After an ischaemic stroke or TIA, patients are at high risk of stroke recurrence, coronary events, and cardiovascular mortality.2 Most stroke recurrences occur during the first 3 months and especially within 7 days of symptom onset.2 This risk is still high, despite substantial improvements in diagnostic and treatment strategies.3 Inflammation plays a critical role in the pathogenesis and prognosis of ischaemic stroke.4 Increasing levels of high-sensitivity C-reactive protein are associated with higher risks of stroke recurrence and functional impairment in stroke survivors.5–8 Therefore, inflammation could be one of the potential therapeutic targets to reduce the residual risk of recurrent stroke.4,9 However, ischaemic stroke is a heterogeneous condition caused by several mechanisms, including atherosclerosis of the large arteries, small artery disease, and cryptogenic causes (including subclinical atrial fibrillation and foramen ovale patency). The relative contribution of inflammation to these different stroke subtypes is not clear.10 Colchicine has several anti-inflammatory properties. It prevents microtubule development by inhibiting leukocyte function and blocks the assembly of the inflammasome, preventing the release of pro-inflammatory cytokines, some of which may play a role in stroke.11 Over the past 3 decades, observational studies and randomized controlled trials (RCTs) have shown that colchicine reduces the risk of major cardiovascular events in patients with known coronary artery disease (CAD), although concerns persist regarding non-cardiovascular death. The most pronounced effect is on incident stroke rather than myocardial infarction (MI) or coronary revascularization,12 generating growing interest in testing its effects in secondary stroke prevention. The CHANCE-3 is the largest multi-centric randomized trial that evaluated the efficacy and safety of acute use of colchicine for the prevention of early recurrent stroke in more than 8000 Chinese patients, recruited over an extraordinarily short period of 8 months. Despite the expectations, the study did not support the hypothesis that low-dose colchicine may reduce the risk of stroke. Several issues may explain the largely negative findings of this trial. Firstly, the CHANCE trial was sized to detect a 25% reduction in the risk of any new stroke, perhaps an unrealistic expectation given the full concomitant use of other preventive therapies. Secondly, RCTs of low-dose colchicine in patients with known CAD have focused on the long-term risk of cardiovascular events.12 Colchicine use resulted in lower rates of cardiovascular events over a median of 23 months in the COLCOT trial, which included patients after an acute MI. In the LoDoCo2 trial, which enrolled patients with chronic CAD, the benefits of low-dose colchicine emerged early and continued to accumulate throughout the duration of the study, with no attenuation during up to 5 years of treatment.12 In the present trial, the authors focused on the highest risk period after ischaemic stroke and tested the effect of colchicine on the prevention of early recurrent events. Therefore, the duration of treatment and follow-up were short potentially limiting the likelihood of detecting a longer-term benefit. Thirdly, approximately one-third of the patients were excluded because they had high-sensitivity C-reactive protein < 2 mg/L. Although this may be the correct approach to select patients for anti-inflammatory treatments in the chronic phase, relying on biomarker measurements might be misleading during the acute phase. However, previous studies showed that the risk of stroke recurrence increased by increasing the high-sensitivity C-reactive protein concentration or using the cut-off of 2 mg/L at baseline. Furthermore, the significance of high-sensitivity C-reactive protein disappeared after the acute phase, between 72 h and 8 days.6 In the current study, the pharmacological effects of low-dose colchicine were not evaluated, since high-sensitivity C-reactive protein levels were not measured at 90-day follow-up, impairing the interpretation of results. The apparent discrepancy between the encouraging epidemiological evidence and the negative results of the CHANCE trial is a reminder that association does not necessarily imply causation. Other constraints hinder definitive conclusions, such as the enrolment of an exclusively Chinese population, the under-representation of women, the lack of data on intracranial and extracranial atherosclerosis features, and the absence of information on the effects of the main secondary stroke prevention treatments, such as blood pressure control, that might have influenced the outcome. In addition, the tight 24-hour window for study enrolment limited the routine evaluation of cardio-embolism and other alternative causes of stroke prior to randomization. These data, which could have provided useful information to better understand the lack of effect of colchicine, were also lacking during the study period. Finally, important pathophysiological differences exist in early recurrent events between CAD and ischaemic stroke.13 Therefore, low-dose colchicine may not be the appropriate drug for the short-term secondary preventive treatment in this population. More recently, the open-label CONVINCE (colchicine for prevention of vascular inflammation in non-cardioembolic stroke) trial was published, which compared long-term colchicine therapy added to usual care, initiated between 72 h and 28 days after ischaemic stroke or TIA, vs. usual care. CONVINCE included ∼3000 patients recruited in Canada and Europe over a 6-year period. In the intention-to-treat analysis, the incidence of the primary efficacy outcome (a composite of first fatal or non-fatal recurrent ischaemic stroke, MI, cardiac arrest, or hospitalization for unstable angina) was comparable between groups over a median follow-up of 34 months.14 In conclusion, the results of CHANCE-3 and CONVINCE do not support an appreciable role of colchicine-sensitive inflammatory pathway(s) in stroke recurrence. Ischaemic stroke is a heterogeneous disease, and the relative contribution of inflammation in disease mechanisms is not well understood. The optimal design of future RCTs of anti-inflammatory therapies to prevent recurrence after stroke must be based on a clear understanding of the potential pathophysiologic role of inflammation according to stroke subtype and individual patient factors. G.L. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis and reports grant support (to the institution) for investigator-initiated research from the American Heart Association, the Italian Ministry of University and Research, and the Italian Ministry of Health (grant: ‘Ricerca Corrente’). D.P. received speaker’s fees from Daiichi Sankyo, outside the submitted work. D.P. is supported by a research grant from Italian Ministry of Health (grant: ‘Ricerca Corrente’).

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.