Does colchicine work for CVD or doesn’t it? That’s the question the study authors hoped to answer, but there’s little consensus.
Depending on one’s perspective, the anti-inflammatory colchicine is either an unsung and underprescribed drug for patients with cardiovascular disease, or it’s an agent with limited clinical benefit and an unfavorable safety profile.
The publication of two new meta-analyses is unlikely to clear things up anytime soon, however.
In both, treatment with colchicine reduced the risk of vascular events in patients with established disease, but the magnitude of benefit differed. In one, there was a modest 12% reduction in the risk of major adverse cardiovascular events while in the other, the relative reduction in MACE risk was as large as 25%, with even bigger effects on MI, ischemic stroke, and coronary revascularization.
Unsurprisingly, the research teams behind the papers come to quite different conclusions, even though many of the trials making up the meta-analyses overlapped.
For the first group, which included senior researcher Jean-Claude Tardif, MD, PhD (Montreal Heart Institute/Université de Montréal, Canada), who previously led the COLCOT trial, the results provide “further robust evidence” that adding low-dose colchicine to standard-of-care therapy decreases the incidence of major cardiovascular events.
“The pooled efficacy of colchicine in vascular disease patients remains substantial, with a greater protective effect than intensive lipid-lowering therapies, such as [PCSK9] inhibitors,” they write in their paper published in the July 7, 2025, issue of the European Heart Journal.
The other investigators, some of whom conducted the CLEAR SYNERGY (OASIS 9) trial, are more skeptical in their report.
“At the end of the day, I still am not sure that that colchicine works and is effective,” senior researcher Sanjit Jolly, MD (Hamilton General Hospital, McMaster University, Canada), told TCTMD. “Meta-analyses are good in terms of putting the data together, but I still think that if there’s going to be a recommendation to treat everyone with colchicine, we actually need a trial of 20,000 patients, just like industry would do for a new drug, to really defend and prove the findings.”
For Jolly, if there is a benefit, it’s likely quite small.
“There may be a modest treatment effect, but it certainly causes [gastrointestinal] hospitalizations and diarrhea,” he said. “If I was a patient and my overall risk was low, I probably wouldn’t want to take it. If I’d been back to the hospital multiple times, and my [cardiovascular] risk is very high, and maybe there’s a chance colchicine will reduce it, then I’d take it.”
Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA), who wasn’t involved in either meta-analysis, pointed out that both are based on study-level data, which adversely affects how the results are interpreted. For the larger meta-analysis, which was led by Jolly’s group, the 12% relative reduction in MACE is underwhelming, he said. Moreover, the reduction was driven by a 16% reduction in MI, which had a P value of 0.02. That isn’t considered a robust result for these types of analyses, he said.
“Furthermore, there was substantial statistical and clinical heterogeneity across trials, which challenges the poolability of these trials,” Kaul told TCTMD. “So, from a methodological standpoint, these meta-analyses fall short of what I consider a top-tier meta-analysis. It is not clear to me what these pooled analyses offer that we didn’t know from the individual trials.”
The last three trials—two done in patients with prior stroke and CLEAR SYNERGY in post-MI patients—didn’t show any benefit with colchicine, he said.
On the other hand, Steven Nissen, MD (Cleveland Clinic, OH), considers the new analyses “reasonable,” saying they tend to confirm what “most of us would consider to be true, which is that there is a favorable effect of anti-inflammatory therapy in the absence of any modulation of lipids on cardiovascular outcomes.”
Nissen noted that the CANTOS trial showed there was a “modest, but definite” effect of treating prior MI patients with the anti-inflammatory canakinumab. That drug, however, never received an indication for cardiovascular event reduction, with Novartis opting instead to keep it for treating patients with rare inherited autoinflammatory disorders, such as systemic juvenile idiopathic arthritis, and gout flare-ups.
A 25% Reduction in MACE
Two years ago, the US Food and Drug Administration approved low-dose, 0.5-mg colchicine (Lodoco; Agepha Pharma) as the first anti-inflammatory agent indicated for reducing cardiovascular events among adults who have established atherosclerotic cardiovascular disease (ASCVD) or are at risk of developing it. It is also approved for the treatment of gout at the 0.6-mg dose.
In the American College of Cardiology/American Heart Association guidelines for the management of patients with chronic coronary disease, the addition of colchicine has a class 2b (level of evidence B) indication to reduce the risk of recurrent ASCVD events. The 2025 guidelines for the management of patients with ACS also state that low-dose colchicine may be reasonable to reduce the risk of recurrent major adverse cardiac events. In Europe, colchicine has a class IIa recommendation for use in patients with ASCVD.
Regulatory approval was based on the large LoDoCo2 trial of patients with stable chronic coronary disease, but there have been other studies that have shown a benefit with colchicine, including COLCOT. In 2024, however, the CLEAR SYNERGY trial, which was led by Jolly, failed to show colchicine was effective in patients treated with PCI after acute MI.
To help provide a clearer picture, two groups launched meta-analyses. The first, which was done by Michelle Samuel, PhD (University Medical Center Groningen, the Netherlands), Tardif, and colleagues, included six randomized, controlled trials with colchicine in 21,800 patients. The studies included LoDoCo, COLCOT, COPS, LoDoCo2, CONVINCE, and CLEAR SYNERGY. LoDoCo, like LoDoCo2, included patients with stable coronary artery disease, while COLCOT and CLEAR SYNERGY tested colchicine in post-MI patients. The CONVINCE study evaluated colchicine in the poststroke setting, and COPS included patients with ACS.
The mean age of patients randomized in the trials ranged from 60 to 67 years, and more than 90% were treated with statin therapy.
Treatment with colchicine was associated with a significant 25% lower risk of major adverse cardiovascular events, a composite of cardiovascular death, MI, ischemic stroke, and urgent revascularization, when compared with placebo. Colchicine was also associated with a 29% lower risk of MI, a 37% lower risk of ischemic stroke, and a 33% lower risk of urgent revascularization. There was no impact on cardiovascular mortality.
There was no difference in outcomes across subgroups stratified by age, sex, or diabetes status, but the researchers point out the analysis was underpowered to assess outcomes by subgroups, particularly in women.
Regarding adverse events, colchicine was not associated with an increased risk of infection, pneumonia, hospitalization for a GI event, or cancer diagnosis. There was also no impact on all-cause or noncardiovascular mortality.
From Six to Nine Studies
The second meta-analysis, conducted by Marc-André d’Entremont, MD (Hamilton General Hospital/McMaster University), Jolly, and colleagues, included nine trials and 30,659 patients with known coronary artery disease or stroke. In addition to the six trials that made up the prior analysis, researchers included COLOCT, a smaller imaging study in patients with ACS; CHANCE-3, a large trial of patients with a minor-to-moderate ischemic stroke or TIA and elevated high-sensitivity C-reactive protein (hs-CRP); and a 2013 study looking at colchicine for the prevention of in-stent restenosis after PCI in diabetic patients.
Patients ranged in age from 58 to 67 years, and women made up 11.1% to 37.6% of participants. More than 90% were treated with statins.
Overall, treatment with colchicine was associated with a significant 12% reduction in the risk of cardiovascular mortality, MI, or stroke compared with placebo. With coronary revascularization as part of the composite endpoint, the relative reduction in risk with colchicine was 19%. There was no significant reduction in the risk of cardiovascular death or stroke, but there was a significant 16% reduction in risk of MI.
Colchicine also was associated with a 35% increased risk of GI events, but there were no associated risks of pneumonia, newly diagnosed cancer, or noncardiovascular death.
To TCTMD, Jolly said that they had planned the meta-analysis before the results of CLEAR SYNERGY were known and that they included trials testing colchicine in patients with coronary artery disease and stroke. Regarding the different treatment effects, Jolly believes it comes down to including more studies.
“Their meta-analysis suggests that there’s a bigger treatment effect, but it’s really what you put in,” he said. “We put in more trials and they excluded some trials, and that exclusion will essentially increase your effect size.”
Tardif, for his part, has previously argued that the neutral CLEAR SYNERGY trial is an outlier, and that its results are discordant from COLCOT, LoDoCo2, and other published data. In their new paper, the researchers suggest that CLEAR SYNERGY was negatively impacted by the COVID-19 pandemic, noting that there was a benefit with colchicine in the period before the pandemic hit, but the benefit was lost during it.
To TCTMD, Jolly disputed the interpretation, noting there was no significant interaction when they looked at outcomes in the prepandemic and pandemic phases of the trial. “It doesn’t pan out,” he said. “The event rates aren’t any different. We extended the follow-up, and we extended the recruitment period, so we [continued] after COVID-19 and there’s still no treatment effect.”
‘Modest Absolute Benefits’
In June, JACC published a series of commentaries on the 2025 ACS guidelines, including one by Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), who led the CANTOS trial with canakinumab. He notes that prescriptions of low-dose colchicine for ASCVD prevention and treatment are rare, which is troubling for some in the preventive cardiology community given COLCOT and LoDoCo2, as well as the 2023 FDA approval of colchicine.
“After aspirin and statins, low-dose colchicine may well be the third most cost-effective treatment developed for chronic stable atherosclerosis,” writes Ridker.
In an editorial accompanying the meta-analyses, Stuart Pocock, PhD (London School of Hygiene & Tropical Medicine, England), and Guiomar Mendieta, MD, PhD (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain), note that the benefit of colchicine appears largely confined to patients with coronary artery disease.
Based on their calculations, they say the absolute risk difference in MI with colchicine versus placebo is around 0.67%. This translates into a number needed to treat of 149. With coronary revascularization, the absolute risk difference is around 1.0%, with 100 patients who need to be treated to prevent one event.
“While the reductions in risk of MI and coronary revascularization are statistically significant, they are modest absolute benefits and are not backed up by any corresponding evidence regarding mortality and stroke,” write Pocock and Mendieta.
Jolly, for his part, said that while CLEAR SYNERGY included acute MI patients, median follow-up was 3 years, with some patients followed for 5 years. In a landmark analysis from 1 to 5 years, they still observed no benefit with treatment. “Many people say, ‘Well, it works in chronic and doesn’t work in acute [disease],’ but I don’t think we can say that for sure because the acute trials were essentially chronic [disease] after the first year,” he said.
More Trials to Come
Clinically, Kaul said that he measures hs-CRP in patients but doesn’t escalate risk factor-modification therapies based on high levels. “I don’t recall ever prescribing it or seeing patients who have been prescribed colchicine for cardiovascular risk reduction,” he said.
Nissen noted that most physicians don’t use colchicine, but said he will in select cases after he has done all he can to treat other cardiovascular risk factors.
“If I have a patient where I’ve done everything else for them and they’re still at high risk, or maybe they’ve had another event and their CRP is elevated, I do give them colchicine,” he said. “I don’t give them the proprietary product that’s expensive, the 0.5-mg dose. I give them 0.6 mg, which is available generically.”
Colchicine is still being put to the test in randomized trials, with at least three actively recruiting patients. In COLCOT-T2D, Canadian investigators are randomizing roughly 10,000 high-risk, primary prevention patients with type 2 diabetes to treatment with colchicine or placebo. The Australian COLCARDIO-ACS study will test colchicine against placebo in 3,000 patients with recent ACS and high hs-CRP levels, while the Belgian COL BE PCI trial will include patients with chronic and acute coronary disease undergoing PCI.
Beyond colchicine, the inflammatory hypothesis continues to be put to the test. In ARTEMIS, investigators are investigating whether the IL-6 ligand inhibitor ziltivekimab (Novo Nordisk) reduces the risk of MACE in acute MI patients. The ZEUS trial with ziltivekimab is looking at effectiveness of treatment in people with ASCVD, chronic kidney disease, and inflammation.