LoDoCo: Cheap, Widely Available Colchicine Reduces Events in Secondary Prevention

November 05, 2012

LOS ANGELES — You can't teach an old dog new tricks, they say, but Australian researchers may have discovered that an old drug--one used to treat gout and familial Mediterranean fever--has a few useful tricks yet up its proverbial sleeve for the treatment of CVD.

In this prospective, randomized, open, blinded end-point study testing the effectiveness of colchicine in secondary prevention, investigators showed that the drug reduced the risk of the primary end point--defined as ACS, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke--by 67%, driven largely by a reduction in non–stent-related ACS.

"Over more than three years of follow-up, less than 2% of patients on colchicine had a myocardial infarction or a period of unstable angina, indicating that the effects of therapy were not only quite striking but also consistent across all clinical end points," said lead researcher Dr Stefan Nidorf (Heart Research Institute of Western Australia, Perth). "Regardless of the mechanism, the clinical implications are the same, and that is because colchicine is so well studied, readily available, simple to use, inexpensive, and without major irreversible, long-term toxicity when used over decades. Its role in the routine management of patients with proven coronary disease clearly requires further investigation."

Reducing clinical instability

The results of the study, known as the Low-Dose Colchicine (LoDoCo) study, were presented here today at the American Heart Association 2012 Scientific Sessions. During the presentation, Nidorf explained that activated neutrophils in the culprit lesions of patients presenting to the hospital with ACS had raised the possibility that inhibiting neutrophil function might reduce the risk of plaque instability and subsequently clinical instability in patients with CVD.

Low-dose colchicine has a wide range of anti-inflammatory effects and has been shown to be effective in preventing neutrophil-mediated inflammation, as documented by its efficacy in the treatment of gout. The drug is initially associated with some gastrointestinal distress, said Nidorf, but is safe to use long term. For patients with familial Mediterranean fever, colchicine is used lifelong.

In total, 532 patients with angiographic proof of stable CAD were randomized to low-dose colchicine treatment or placebo for a minimum of two years. During a median follow-up of three years, the primary outcome occurred in 40 of 250 patients randomized to placebo (16%) and 15 of 232 patients randomized to colchicine (5.3%). This translated into a significant relative risk reduction of 67%. The number needed to treat to prevent one primary clinical outcome was 11. The benefit was evident across multiple subgroups.

Discussing the results, Dr Shinya Goto (Tokai University School of Medicine, Kanagawa, Japan) praised the investigators but said the hypothesis-generating study would be unlikely to alter clinical practice just yet. That said, he believes larger studies should be performed given the benefit of treatment observed in LoDoCo, as well as biological studies showing that a huge amount of leukocytes are involved in MI-causing thrombus. Importantly, the benefit of colchicine was evident on top of a wide range of CV medications patients were being treated with.

Future studies will need to include other ethnicities to determine whether the results translate to other populations, and researchers will need to identify and exclude patients at high risk for gastrointestinal distress. In LoDoCo, approximately 11% of patients dropped out of the trial--most doing so early--because of GI-related issues.

Commenting on the study results to heartwire , Dr Seth Bilazarian (Pentucket Medical Associates, Haverhill, MA) said he was very excited to see such positive results for an old standby. "Our familiarity and longtime use of this drug in gout makes this a very attractive treatment option," he said.

"However, the speaker's comment that this is an inexpensive therapy is actually no longer true in the US." Last year a single company, URL Pharma, conducted safety and efficacy studies on the drug, ultimately obtaining FDA approval for a product that predates that agency itself. As a result, generic competition is no longer on the market.

"My patients, my father, all these people went from paying very little every month, to paying $170, $180 per month. In the US, it's almost as expensive as taking dual antiplatelet therapy."