LoDoCo2: Added Steam for Colchicine as Secondary Prevention

Patrice Wendling

August 31, 2020

The anti-inflammatory drug colchicine picked up new support as secondary prevention in chronic coronary disease, cutting the risk of cardiovascular events by one third when added to standard prevention therapies in the double-blind LoDoCo2 study.

Across a median follow up of 29 months in more than 5000 patients, almost 1 in 10 patients assigned to placebo experienced the primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization. That risk was 31% lower and resulted in 77 fewer events in those assigned to colchicine (hazard ratio [HR], 0.69; 95% CI, 0.57 - 0.83).

The beneficial effect of low-dose colchicine 0.5 mg daily was seen early on and accrued over time, extending to 5 of the 8 secondary end points, including a near 30% reduction in the composite of major adverse cardiac events, as well as reductions in the individual endpoints of MI and ischemia-driven revascularization.

Dr Mark Nidorf

"It did that with broadly consistent effects across a range of clinical subgroups, which together speak to the strength of the effect of colchicine on cardiovascular outcomes in the sort of patients we routinely see in our clinics," primary investigator Mark Nidorf, MD, MBBS, GenesisCare Western Australia, Perth, said at the digital European College of Cardiology (ESC) Congress 2020.

The results were published simultaneously in the New England Journal of Medicine.

"The totality of evidence from the big three double-blind placebo controlled trials — CANTOS, COLCOT, and LoDoCo2 — are highly consistent and should be practice changing," Paul Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston, Massachusetts, told theheart.org | Medscape Cardiology.

Massimo Imazio, MD, the formal discussant for the study and professor of cardiology at the University of Turin, Italy, also called for repurposing the inexpensive gout medication for cardiovascular patients.

"I would like to congratulate the authors for a well-designed, large randomized trial that in my view provides convincing evidence that colchicine is safe and efficacious for secondary prevention in chronic coronary syndrome, of course if tolerated," he said.

Imazio noted that colchicine demonstrated similar benefits in the smaller, open-label LoDoCo trial but that 1 in 10 patients couldn't tolerate the drug, largely due to gastrointestinal issues. The LoCoDo2 investigators very wisely opted for a 30-day run-in period for tolerance without a loading dose, and 90% of patients in each arm continued study medication while 3.4% stopped due to perceived effects.

Clinicians should bear in mind the potential for side effects and interactions with other medications, particularly statins, observed Imazio. "So monitoring of repeat blood tests is indicated, especially blood cell count, transaminase, and [creatine kinase] CK."

Colchicine can be problematic in patients with chronic kidney disease, as it is renally excreted, particularly if patients also take some common antibiotics such as clarithromycin, said Ridker, who led the landmark CANTOS trial. "So while these data are exciting and confirm the importance of inflammation inhibition in stable coronary disease, colchicine is not for all patients."

During the discussion of the results, Nidorf said: "We were very concerned at the outset that there would be an interaction because there is certainly literature there, particularly in renal patients. But as the data showed, the incidence of myotoxicity was decidedly rare."

Further, myotoxic episodes were independently assessed by a blinded reviewer and, although there was one case of mild rhabdomyolysis in the treatment group, it was considered not primarily due to colchicine, he said. "So we're fairly comfortable that you can use colchicine at low dose quite comfortably with full-dose statins."

Notably, 94% of patients in both groups were taking statins, and two thirds were on moderate or high-dose statins. About one quarter were on dual-antiplatelet therapy and 12% on an anticoagulant.

In all, 5522 patients aged 35 to 82 years (mean 66 years) were randomly assigned to colchicine 0.5 mg once daily or placebo on top of proven secondary prevention therapies, and all but one was available for analysis.

Most were male (85%), one half had hypertension, 18% had diabetes, and 84% had a history of acute coronary syndrome, with an equal number having undergone revascularization. Patients with advanced renal disease, severe heart failure, or severe valvular heart disease were excluded.

Colchicine, when compared with placebo, was associated with significant lower incidence rates of the top five ranked secondary endpoints:

  • CV death, MI, or ischemic stroke (4.2% vs 5.7%; HR, 0.72)

  • MI or ischemia-driven revascularization (5.6% vs 8.1%; HR, 0.67)

  • CV death or MI (3.6% vs 5.0%; HR, 0.71)

  • Ischemia-driven revascularization (4.9% vs 6.4%; HR, 0.75)

  • MI (3.0 vs 4.2%; HR, 0.70)

The incidence rates were similar for the remaining three secondary outcomes: ischemic stroke (0.6% vs 0.9%), all-cause death (2.6% vs 2.2%), and CV death (0.7% vs 0.9%), Nidorf reported.

The effect of colchicine was consistent in 13 subgroups, including those with and without hypertension, diabetes, or prior acute coronary syndrome. Patients in Australia appeared to do better with colchicine than those in the Netherlands, which was a bit unexpected but likely due to the play of chance, Nidorf said.

"Importantly, the effect when we looked at the predictors of outcome of our patients in this trial, they related to factors such as age and diabetes, which were included in both populations. So we believe the effect of therapy to be universal," he added.

Session moderator Stephan Achenbach, MD, chair of cardiology at the University of Erlangen, Germany, however, noted that event rates were about 3% per year and many patients had undergone coronary revascularizations for acute coronary syndromes, suggesting this may be a preselected, somewhat higher-risk cohort. "Do you think we can transfer these findings to the just average patient who comes in with chest pain and gets an elective PCI?" he asked.

Nidorf replied that unlike the patients in COLCOT, who were randomized to colchicine within 30 days of an MI, acute events occurred more than 24 months before randomization in most (68.2%) patients. As such, patients were quite stable, and major adverse cardiac event and CV death rates were also exceedingly low.

"We did not see them as a particularly high-risk group, which I think is one of the beauties of this study," Nidorf said. "It looks at people that are very similar to those who come and meet us in our clinics for regular review and follow-up."

"And in that regard, I think the next time we're faced with patients in our rooms, we have to ask the question: 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," he said.

Serious adverse effects were similar in the colchicine and placebo groups, including hospitalizations for infection (5.0% vs 5.2%), pneumonia (1.7% vs 2.0%) or gastrointestinal reasons (1.9% vs 1.8%). Myotoxicity occurred in 4 and 3 patients, respectively.

Although the signal for increased risk of infection observed in CANTOS and COLCOT was not borne out, Nidorf observed that chest infections can occur frequently in these patients and echoed cautions about a potential unfavorable interaction between clarithromycin and colchicine.

"If we are to use this drug widely, clinicians will need to learn how to use this drug and what drugs to avoid, and that's an important teaching point," he said.

Limitations of the study are the small number of women and lack of routine measurement of C-reactive protein or other inflammatory markers at baseline.

The study was supported by the National Health Medical Research Council of Australia, a grant from the Sir Charles Gairdner Research Advisory Committee, the Withering Foundation the Netherlands, the Netherlands Heart Foundation, the Netherlands Organization for Health Research and Development, and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The authors' disclosures are listed in the article .

N Engl J Med. Published August 31, 2020. Abstract

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