COLCOT Renews Hope for Anti-inflammatory in Secondary Prevention: Colchicine

PHILADELPHIA, PA—Colchicine, an anti-inflammatory indicated for gout and pericarditis, can lower the risk of ischemic cardiovascular events in patients who’ve recently had an MI, according to the randomized COLCOT trial.

Previously, the LoDoCo trial showed that, at the same low dose of 5 mg, colchicine reduced the risk of CV events in the setting of stable CAD. But, as the COLCOT researchers point out in their paper published online today in the New England Journal of Medicine, that study was small at only 532 patients and did not involve a placebo. By contrast, COLCOT enrolled more than 4,700 patients.

“There is ample evidence that supports the role of inflammation in atherosclerosis and its complications,” lead author Jean-Claude Tardif, MD (Montreal Heart Institute, Canada), said in a media briefing here at the American Heart Association (AHA) 2019 Scientific Sessions.

These latest data come 2 years after CANTOS garnered headlines at the European Society of Cardiology Congress by showing a modest reduction in major CV events with the human monoclonal antibody canakinumab (Ilaris) in stable CAD patients. Despite excitement over the trial’s validation of the inflammation hypothesis, hopes began to fade after the drug’s manufacturer, Novartis, decided not to pursue a CV indication. A year later, CIRT failed to show CV benefit with another anti-inflammatory, methotrexate.

Asked where this field lies today, Tardif pointed to colchicine as a path forward: used for centuries, the drug is taken orally and is widely available. “While the results in terms of magnitude are fairly similar to CANTOS, [our study] is probably more readily translatable to the clinic,” he said.

We have a safe drug that’s easily available. It’s going to be hard to kind of hold this one back.  Donald Lloyd-Jones

Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who moderated the press conference, predicted that guideline writers will now have to wrestle with the possibility that colchicine might join “our cocktail for post-MI patients.”

“We have now one trial, modestly sized but with a significant reduction in endpoints,” Lloyd-Jones commented. “I think this is going to start a very important conversation in understanding: should we be using this in everybody?” Future subgroup analyses will be helpful, he added, “but we have a safe drug that’s easily available. It’s going to be hard to kind of hold this one back.”

But Lloyd-Jones and others emphasized one key caveat for US consumers: cost. The regulatory history of colchicine involves belated branding, unexpected price hikes, and limited generic availability in the United States. Ensuring access to the drug is important if there is to be wider use, they asserted.

COLCOT

COLCOT investigators randomized 4,745 patients (mean age 60.6 years; 19.2% women) in 12 countries to colchicine (0.5 mg once daily) or placebo. Patients enrolled at a mean of 13.5 days after MI, and 93.0% had undergone PCI. Tardif pointed out that “the standard of care was very good in this study,” with 99% of individuals on aspirin, 98% on another antiplatelet, 99% on statin therapy, and approximately 89% on a beta-blocker.

The primary efficacy endpoint consisted of death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent rehospitalization for angina leading to coronary revascularization.

The main intention-to-treat analysis showed that over a median follow-up of 22.6 months the patients in the colchicine group were at significantly lower risk of experiencing a primary-endpoint event than were those who received placebo (5.5% vs 7.1%; HR 0.77; 95% CI 0.61-0.96). This reduction was also seen in adjusted and per-protocol analyses.

Colchicine was not associated with significant decreases in the individual components of CV death, resuscitated cardiac arrest, or MI. However, the drug did lower the risk of stroke (HR 0.26; 95% CI 0.10-0.70) and urgent hospitalization for angina leading to coronary revascularization (HR 0.50; 95% CI 0.31-0.81).

Drug discontinuations did not differ between colchicine and placebo users. Serious adverse events were equally common overall between the two study arms, though pneumonia was more common with colchicine than with placebo (0.9% vs 0.4%; P = 0.03). GI events as a whole were similar in the two groups. Patients in the colchicine group were more likely to experience nausea (1.8% vs 1.0%; P = 0.02).

“The COLCOT results apply to patients who have recently suffered a myocardial infarction. Further research is needed to assess the benefits of colchicine in other high-risk patients,” Tardif observed. To meet this knowledge gap, the researchers are launching the COLCOT-T2D trial of 10,000 type 2 diabetes patients without known CAD.

Aruna Pradhan, MD, MPH (Brigham and Women’s Hospital, Boston, MA), discussing the results in today’s press conference, praised the COLCOT trial: “It was a large, simple, and well-designed event-driven trial which aimed to answer one core question. This will be a landmark study. These results provide confirmation that inflammation management reduces cardiovascular risk and it [stands out] as an example of successful repurposing of a broadly available and relatively safe generic drug for a new application.”

But she emphasized the lack of effect on “more robust” hard outcomes like death and MI as well as the “weak” signal for stroke. Pradhan also cautioned that “complete ascertainment of adverse events was not performed in this trial,” so there could be unmeasured factors that would limit long-term use. For example, there could be issues in patients with chronic kidney disease, she suggested, seeing as how colchicine is renally cleared.

‘There’s Something Wrong With This System’

For Pradhan and others at the press conference, though, the availability of generic colchicine—or the lack thereof—is worrisome.

Lloyd-Jones shared a story about a patient of his who has stable CAD and has been taking generic colchicine for gout. “He told me that, just in the last month, his colchicine out-of-pocket costs went from $50 a month to $270 a month in Chicago,” he said. “That is very concerning to me. I really wonder if there’s some gaming going on here and I do not want to see that with this drug.

“Importantly,” Lloyd-Jones continued, COLCOT “was not an industry-sponsored trial, and I think that’s a really key point about this trial.”

An issue “very dear to my heart” as not only a researcher but also a clinician, Tardif said, is ensuring patients across the world have access to needed medications. In Montreal, a mere 90-minute flight from Philadelphia, colchicine costs 27 cents a day, he said. “So there’s something wrong with this system.”

“Amen,” Lloyd-Jones replied.

To TCTMD, Lloyd-Jones elaborated on the situation with colchicine generics in the United States. His patient, he said, no longer takes colchicine regularly and now primarily takes a uric acid-lowering agent and spot treats with colchicine. Lloyd-Jones cautioned that it’s possible these price changes arise from the patient’s insurance plan.

“I don’t want to get far down this road here,” he commented, “but we are seeing alarming increases in the costs of medications, both overall and out of pocket for patients, and I just think that’s something we have to keep hammering on—it is unacceptable, especially for very . . . inexpensively produced drugs to be seeing price escalations like this. There’s no reason for it other than the profit margin.”

Pradhan noted to TCTMD that colchicine is sold as a branded generic in the United States, sold by only a few manufacturers. “So the costs may stay elevated for that reason, that it’s not as broadly available as other generics.”

After the US Food and Drug Administration’s Unapproved Drugs Initiative enabled colchicine to be sold under the brand name of Colcrys starting in 2009, drug manufacturer URL Pharma soon upped its price from pennies to around $5 a pill. Takeda bought the company in 2012. Subsequently, in 2015, a generic version of the drug entered the US market.