colchicine benefits post-MI

Another study presented at the Am Heart Assn meetings found that low-dose colchicine given within 30 days of myocardial infarction led to significantly lower subsequent ischemic cardiovascular events, the  COLCOT trial (see cad colchicine postMI nejm2019 in dropbox, or  DOI: 10.1056/NEJMoa191238)

Details:
-- 4745 patients who had had an MI in the prior 30 days were randomized to colchicine 0.5 mg daily vs placebo, in a Canadian government sponsored study
-- mean age 61, 20% female, 73% white, BMI 28, current smokers 30%, hypertension 51%, diabetes 20%, medications: aspirin 99%, other antiplatelet agents 98%, statin 99%, beta blocker 89%
-- enrollment was done a mean of 13.5 days post MI; 93% underwent PCI at the time of their MI
-- exclusions included patients with severe heart failure or LVEF <35%, stroke within the prior 3 months, inflammatory bowel disease or chronic diarrhea, clinically significant hematologic abnormalities or severe renal disease, severe hepatic disease, long-term steroid therapy.
-- primary efficacy endpoint was a composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization
-- follow-up was 22.6 months

Results:
-- primary endpoint occurred in 5.5% in those on colchicine vs 7.1% on placebo, a 23% reduction HR 0.77 (0.61-0.96), p=0.02
    -- death from cardiovascular causes decreased 16%, HR 0.84 (0.46-1.52)
    -- resuscitated cardiac arrest decreased 17%, HR 0.83 (0.25-2.73)
    -- myocardial infarction decreased 9%, HR 0.91 (0.68-1.21)
    -- stroke decreased 74%, HR 0.26 (0.10-0.70)
    -- urgent hospitalization for angina leading to coronary revascularization decreased 50%, HR 0.50 (0.31-0.81)
-- primary endpoints happened at a rate of 0.29 per 100 patient-months on colchicine vs 0.42 per 100 patient-months on placebo, rate ratio 0.66 (0.51-0.86)
-- review of their graph showed that there was a decrease in clinical events within 3 months after starting colchicine, which increased until about 14 months and then continued with parallel lines, suggesting persistent benefit
-- in the per-protocol analysis: primary endpoint was in 5.1% of the patients on colchicine vs 7.1% on placebo, a 29% decrease HR 0.71 (0.56-0.90)
-- secondary efficacy endpoint (cardiovascular death, cardiac arrest, MI, or stroke) occured in 4.7% on colchicine vs 5.5% on placebo, a 15% decrease HR 0.85 (0.66-1.10)
-- biomarkers:
    -- C-reactive protein and WBC levels: baselines of 4.28 mg/L and 8.6x10³/mL, respectively: 207 patients (nonrandomized sample) found that both of them decreased significantly after 6 months, but no significant difference if on colchicine vs placebo.
-- adverse effects:
    -- diarrhea in 9.7% of patients on colchicine vs 8.9% on placebo, nonsignificant difference
    -- pneumonia was found in 0.9% on colchicine vs 0.4% on placebo, p=0.03

Commentary:
--this was a well-done study with patients on state-of-the art background medications (statins, platelet inhibitors, etc), high levels (93%) getting percutaneous coronary intervention at the time of their MI, and finding benefit of colchicine in prevention of an array of adverse cardiovascular outcomes over the next 2 years.
-- as has been well-documented over decades, inflammation plays an important role in atherosclerosis, confirmed by the CANTOS trial where a specific monoclonal antibody targeting interleukin 1-b lowered the cardiovascular risk by 15% (though a recent study with methotrexate did not find benefit)
-- colchicine is an inexpensive potent anti-inflammatory medication that has been used for centuries for several inflammatory conditions including gout, familial Mediterranean fever, pericarditis. It specific mechanism of action is not totally clear: it seems to inhibit microtubule polymerization, and may have some direct anti-inflammatory effects on cytokines and cellular adhesion molecules
--one comment by the authors is that the colchicine did not seem to exert its positive effect by treating pericarditis (one known benefit), since pericarditis usually happens within a few days of MI, and in this study colchicine was started on average was 13.5 days out
--it is a bit surprising that there was no difference in the effect of colchicine on CRP levels. Was it because they measured it at the beginning then not again til 6 months (and the acute phase reactant had subsided equally in those both on colchicine and placebo by that time)?? an article on higher dose colchicine (1 mg/d) in those with acute coronary syndrome or stroke found no difference in hs-CRP at 30 days (though CRP values can change pretty quickly…): see https://www.ncbi.nlm.nih.gov/pubmed/21918905 .  Was it because CRP is not an unequivocal marker of inflammation (eg, it can be normal in lupus despite significant tissue damage and inflammation: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653962/ ). or could it be (as the authors suggest) just an unexpected finding because of testing a small group of nonrandomized patients in the context of this large study???

--in terms of the increase in pneumonia, one might speculate that the effects of colchicine on the immune system might predispose to infections. For example, in the CANTOS study with canakinumab, there were more cases of infections and sepsis, as well as more neutropenia and thrombocytopenia, in those on this specific interleukin 1-b inhibitor, and there were significantly more deaths attributed to infection or sepsis (incidence rate of 0.31 vs 0.18 events per 100 person-years)

--a prior blog found that colchicine was associated with lower cardiovascular risks when used to treat gout:

 see http://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html

--limitations of the study: mostly that it would be better to have a larger/longer study to confirm colchicine’s efficacy and assess the longterm adverse effects (though colchicine has been around forever and has been used longterm in many conditions, such as prophylaxis against recurrent gout, without evident serious problems), and get more insight into the benefits in different subgroups of patients; and this study was done largely in a white male population, perhaps limiting its generalizability

so, pretty interesting. adds to our current conceptual model that inflammation is a primary instigator of atherosclerotic disease (as well as a multitude of other problems, like diabetes, depression, cognitive decline, osteoporosis, COPD........), since treating the inflammatory response seems to help. I would add that there are other ways to decrease inflammation, eg exercise, Mediterranean diet, and decreasing smoking and central obesity, and these should be central to our decreasing these inflammatory conditions (though the pill also seems to help).

bottom line: colchicine is well-tolerated and i would consider it strongly in those with very high risk of a recurrent ischemic event (eg smokers), though it really would be great to have another, larger study with a more diverse population to confirm its benefits

geoff​

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

to get access to all of the blogs:

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

3. or you can just click on the magnifying glass on top right, then  type in a name in the search box and get all the blogs with that name in them

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list