Colchicine

Colchicine is an old, cheap gout drug that calms inflammation. Taken at a low daily dose, it has cut repeat heart attacks and strokes in people with coronary heart disease, which is the clearest evidence that calming inflammation itself can prevent disease. But its largest trial, started right after a heart attack, found no benefit, and it has never been tested in healthy people or as an anti-ageing drug.

Don't take colchicine for longevity or to bring down a C-reactive protein (CRP, a blood marker of inflammation) number. If you already have stable coronary heart disease, low-dose colchicine (0.5 mg a day) is a prescription option to discuss with your cardiologist, on top of standard treatment rather than instead of it. It interacts dangerously with some common antibiotics, antifungals and heart drugs, so every prescriber and pharmacist needs to know you take it.

What it is

Colchicine is a gout drug that calms inflammation. In heart disease it is used at a low dose of 0.5 mg once a day. In the US, low-dose colchicine is now approved to cut the risk of heart attack, stroke, cardiovascular death and the need for artery-opening procedures in adults with established atherosclerosis (furred-up arteries) or several cardiovascular risk factors.^[1] The trials summarised below all enrolled people who already had coronary heart disease.

The trial that first suggested inflammation could be a target

The idea was first tested with a different drug. In the CANTOS trial, about 10,000 people who had already had a heart attack and still had a raised CRP of 2 mg/L or more were given canakinumab, an antibody that blocks the inflammatory signal interleukin-1β. At the 150 mg dose, repeat heart attacks, strokes and cardiovascular deaths were about 15% lower, with no change in cholesterol. Fatal infections were more common, though, and overall deaths did not fall.^[2] Low-dose colchicine was then tested for the same job.

What the colchicine trials found

Two trials were positive:

Stable coronary disease. Among 5,522 people with long-standing coronary heart disease, colchicine cut heart attacks, strokes, cardiovascular deaths and artery-opening procedures prompted by poor blood flow from 9.6% to 6.8% over about two and a half years, about 31% fewer.^[3]
Started within a month of a heart attack. In 4,745 people, events fell from 7.1% to 5.5%.^[4]

The largest colchicine trial was not. CLEAR started the drug right after a heart attack in 7,062 people and found no benefit over three years (9.1% against 9.3%), even though CRP fell by about 1.3 mg/L.^[5]

Pooled across six trials and 21,774 patients, colchicine still cut major cardiovascular events by about a quarter, but it had no clear effect on deaths from heart disease.^[6] The fair reading is that it probably helps people with stable coronary disease, while the evidence for starting it straight after a heart attack is mixed.

Who it was tested in, and who it wasn't

Every one of these trials enrolled people who already had heart disease. None enrolled healthy people, and none tested whether the drug slows ageing, so they say nothing about taking colchicine to prevent a first heart attack or to "lower inflammaging".

CLEAR is a warning against treating CRP as the target on its own: the drug brought the number down, and heart attacks, strokes and related events did not fall. A high CRP is a warning about what is driving it; see hs-CRP and chronic inflammation.

Side effects seen in the trials

The trial reports flag a few safety signals:

Stomach upset. Diarrhoea was more common on colchicine in CLEAR (10.2% against 6.6%).^[7] In the trial started within a month of a heart attack it was about the same (9.7% against 8.9%).
Pneumonia. Serious pneumonia was more common on colchicine in that same trial (0.9% against 0.4%).^[8]
Deaths from other causes. In the stable-coronary-disease trial, deaths not caused by heart disease were more frequent on colchicine (0.7 against 0.5 per 100 people per year, about 50% higher in relative terms), a difference that just missed statistical significance.^[9]
Muscle aches. In the stable-coronary-disease trial, muscle pain was reported by 21.2% of people on colchicine against 18.5% on placebo.^[10]

Who must not take it, and what it interacts with

The US prescribing information is strict.^[11]

Ruled out: kidney failure (creatinine clearance below 15 mL per minute), severe liver disease, an existing blood disorder, and any strong blocker of the liver enzyme CYP3A4 or the drug pump P-glycoprotein, because life-threatening and fatal colchicine poisoning has been reported in that combination. Examples are the antibiotic clarithromycin, the antifungals itraconazole and ketoconazole, HIV protease inhibitors such as ritonavir, and the transplant drug ciclosporin (cyclosporine).
Needs monitoring: milder blockers, including the heart drugs diltiazem and verapamil, the antibiotic erythromycin and the antifungal fluconazole, raise colchicine levels; with kidney or liver problems on top, the combination should be avoided. Grapefruit and grapefruit juice raise levels too, so avoid them.
Muscle damage: adding colchicine to a long-term statin, or a statin to colchicine, has caused muscle breakdown (rhabdomyolysis), including deaths; fibrates such as gemfibrozil carry a similar warning, and muscle breakdown has also been reported with the heart drug digoxin. If you also take a statin, unexplained muscle pain or weakness needs checking.
Blood counts: colchicine can suppress the bone marrow, causing dangerously low blood counts. New stomach symptoms are often the first sign of colchicine poisoning and should prompt a check.

What to do

If you are healthy, don't take colchicine to prevent heart disease or slow ageing; no trial has tested that.
If you have stable coronary heart disease, ask your cardiologist whether low-dose colchicine fits on top of your statin and other treatment.
Don't use a falling CRP as proof it is working; the trials judged it on heart attacks and strokes, not on the marker.
Tell every prescriber and pharmacist you take it, especially before a course of antibiotics or antifungals, and avoid grapefruit.
Report new or persistent stomach upset, unexplained muscle pain or weakness, or signs of a chest infection to whoever prescribed it.