colchicine may lower cardiac risk in patients with gout

There have been several articles suggesting that allopurinol is associated with decreased cardiovascular events (for example, see http://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html  ). This might be attributed to the cardiotoxic effects of hyperuricemia itself, or perhaps through its association with the metabolic syndrome (see the above allopurinol blog for more details, as well as http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html  for an evolutionary perspective).  However a recent study found that colchicine in patients with gout also seems to be associated with fewer cardiovascular events (see cad colchicine dec events annrheumdis2016 in dropbox, or Solomon DH. Ann Rheum Dis 2015; doi: 10.1136/annrheumdis-2015-207984). Details:

--all patients were identified with a diagnosis of gout in their electronic record in a large academic hospital (99% accurate diagnosis, on a sample of 100 records) and linked them with cardiovascular outcome data and medication claims from Medicare.

-- 501 colchicine users (defined as those with colchicine prescribed, but no previous colchicine prescriptions in the past 90 days ) and 501 nonusers. Mean follow-up 16.5 months

-- Mean age 73, 36% female, 72% white/18% black/4% Hispanic, 13% known CV disease, 10% prior heart failure, 38% diabetes, 40% on aspirin, 38% never smokers, BMI 30, 42% chronic kidney disease.

-- Primary outcome: MI, stroke, or TIA.

-- However, there were some significant differences between colchicine users and nonusers, including: hypertension in 77% of colchicine users and 28% of nonusers, statin use 50% vs. 16%, uric acid levels 8.4 mg/DL vs. 7.1 (but of note, only 278 of the 1002 patients actually had uric acid levels documented), 42% vs. 16% were on allopurinol, 42% vs. 9% were on NSAIDs, and 42% vs. 12% were on oral steroids.

Results:

-- 28 primary CV events were observed among colchicine users and 82 among nonusers, incidence rates per 1000 person-years were: 35.6 for users and 81.8 for nonusers.

-- With full adjustment (age, gender, race, history of CV disease and risk factors, as well as medications including NSAIDs, allopurinol, chronic kidney disease), colchicine was associated with:

-- 49% lower risk of all primary CV outcomes, HR 0.51 (0.30 – 0.88)

-- 73% reduction in all-cause mortality, HR 0.27 (0.17 – 0.43)

-- the curves for all of these outcomes were tending to splay apart over time. Of note, however, those who were on colchicine for the longest did have more cardiovascular events, with the group doing best being those who used colchicine less than three months.

--though only a quarter of the patients had uric acid levels checked, there was a similar trend by uric acid levels as with the primary analysis.

Commentary:

-- the putative mechanism by which colchicine might decrease cardiovascular events is through its down regulation of inflammatory cytokines and neutrophil chemotaxis, decreasing inflammation. And it does have clinical benefit in several inflammatory conditions including recurrent pericarditis, familial Mediterranean fever, …

-- As with all observational studies, there may be inherent biases. They did try to control for underlying diseases, but there still could be some bias to not using colchicine in those who were sicker. There might also have been a bias that those on colchicine may have been more willing to take medications, which could elicit a higher placebo effect. It would be really helpful to have a controlled trial of chronic allopurinol vs. chronic colchicine use in patients with recurrent gout attacks, both to compare the efficacy in preventing gout as well as differences in cardiovascular outcomes.

-- So, how did this study affect our clinical practice? Probably not a lot, without a study showing clearly that colchicine is as effective as allopurinol/hypouricemic agents in decreasing cardiovascular events. Since there are still more data supporting the cardioprotection of hypouricemic agents,  I will still continue with them primarily. However, in the remote past, I had many patients on chronic colchicine for recurrent gout with excellent effectiveness in gout attack prevention. At a dose of 0.6 mg per day (though some clinicians used 0.6 mg bid), colchicine was very well-tolerated and seemed to have fewer adverse effects than allopurinol. So, as a result of this current study, I am more inclined to use chronic colchicine again, especially  if someone is intolerant of thehypouricemia agents. (In this latter case, I had moved more to treating the recurrent gout attacks with intra-articular steroids.)