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Low-dose colchicine reduced cardiovascular events in people with stable ischemic heart disease in the , but cardiologists expressed concern that the clinical picture needs clarification before routine use.

A 0.5-mg dose daily yielded a 31% relative reduction in the composite of cardiovascular death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization compared with placebo (6.8% vs 9.6% after a median 28.6 months of follow-up, P<0.001).

Colchicine also reduced the composite of cardiovascular death, spontaneous MI, or ischemic stroke by a relative 28% (4.2% vs 5.7%, P=0.007), Stefan Nidorf, MD, of GenesisCare Western Australia in Perth, Australia, reported at the and simultaneously .

"I think the next time we interface with patients in our rooms we have to ask, 'Are we doing enough for this patient?' Beyond aspirin and statins, should we be considering treating the inflammatory axis? And now we have an opportunity to do that," Nidorf said.

It's now the second largest cardiovascular outcome trial showing benefits of this anti-inflammatory drug at a low dose, noted coauthor Arend Mosterd, MD, of University Medical Center Utrecht, the Netherlands, at a press briefing for the ESC hot line session. "It's a drug we already prescribe as cardiologists in the treatment of acute pericarditis."

Colchicine, also used at a higher dose for gout management, is "renowned for anti-inflammatory properties," Silvia Priori, MD, PhD, of the University of Pavia, Italy, said at a press briefing previewing the conference. "The repurposing of old drugs for new indications is a way of providing innovation at an affordable cost for the health system."

The had raised hopes for the anti-inflammatory hypothesis by showing the monoclonal antibody canakinumab (Ilaris), an interleukin-1β inhibitor, cut nonfatal MI or stroke and CV death by 15% in stable coronary disease patients, although with high cost and the FDA ultimately refusing a CV prevention indication.

A more broadly acting immunosuppressant, methotrexate, flopped in the CIRT trial in a stable but high-risk atherosclerosis population.

COLCOT with low-dose colchicine given early after MI had also shown a 27% relative reduction in CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization.

"We think that we have made our point in combination with our colleagues from the COLCOT trial," Mosterd argued.

Richard Kovacs, MD, immediate past president of the American College of Cardiology, agreed that "it's further evidence that we can intervene on inflammation in people with ischemic heart disease and make a difference."

However, "it's a piece of a puzzle, but I don't know that the picture is complete yet," he argued. "I'm still not clear in whom and when are we supposed to start this drug if we're going to make an impact."

The had suggested benefit in the same setting but with much lower statistical power and single-blind randomization.

LoDoCo2 included 5,522 patients ages 35 to 82 with evidence of coronary disease on invasive or CT angiography or a coronary-artery calcium score of at least 400 Agatston units. They had to be clinically stable for at least 6 months prior to enrollment. Advanced renal disease, heart failure, and severe valvular heart disease were excluded. After a 30-day open-label run-in for tolerability, they were randomized double-blind to colchicine or placebo.

While "much more impressive" than the original, LoDoCo2 still wasn't enough for Robert Eckel, MD, of the University of Colorado in Aurora and past president of the American Heart Association.

"It's a trial that needs to be validated in another population," he concluded.

He called it a concern that the death rate was numerically higher with colchicine (2.6% vs 2.2%) and just missed statistical significance for a higher number of noncardiovascular deaths (HR 1.51, 95% CI 0.99-2.31).

Another key question was generalizability, given that the trial was carried out in predominantly white countries (Australia and the Netherlands) and with a "surprising lack of women," said Kovacs. Pointing to different prevalence between the sexes in inflammatory disorders that carry cardiovascular risk, such as lupus and rheumatoid arthritis, he said, "I'm not ready yet to extrapolate from an 85% male population to a more diverse population."

Eckel also questioned the lack of data on inflammatory biomarkers like C-reactive protein (CRP) and interleukin 6 and the low prevalence of diabetes in the cohort (18%).

Nidorf noted that prior studies have shown colchicine lowers CRP. "Just the same way as we don't decide to treat a patient with coronary disease with a statin based on his cholesterol, we rather just max out his statin dose, I think we can now say we should be offering a safe and well tolerated therapy over the long term, such as colchicine, to patients particularly as the drug is widely available, it's inexpensive and the risk of starting and trialing therapy is very low. Making a decision based on CRP is going to be of little importance going forward."

While the drug appears well tolerated, about 10% of patients have GI side effects (those didn't pass the run-in phase in LoDoCo2), he pointed out. The key for them is to try a half-dose and then move back to a full dose if tolerated, he suggested. No infection risk was seen in the trial, but Nidorf cautioned that the drug does interact with clarithromycin.

in ST-segment elevation MI with primary PCI, and in stroke survivors are underway with low-dose colchicine and expected to reach completion by the end of 2021 to show whether the benefits can be replicated in those populations.

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