Gout: Colchicine Linked to Reduced CV Risk

Janis C. Kelly

January 22, 2016

Colchicine, long used to reduce inflammation in gout flares, might also protect patients with gout from cardiovascular (CV) events, according to a study published online November 18, 2015, in the Annals of the Rheumatic Diseases.

The study's key findings were that patients with gout who used colchicine had fewer CV events and lower all-cause mortality than similar patients with gout whose treatment did not include colchicine, said lead author Daniel H. Solomon, MD, MPH, from Brigham and Women's Hospital and chief of the Section of Clinical Sciences in Rheumatology at Harvard Medical School, Boston, Massachusetts.

Dr Solomon and colleagues used retrospective data from an electronic medical record database linked with Medicare claims for 2006 to 2011 to test the hypothesis that colchicine use would be associated with reduced CV risk in patients with gout, who are otherwise at increased risk for atherosclerosis because of their underlying rheumatoid disease. Colchicine had previously been studied for secondary prevention of CV events in other subgroups.

The study cohort included 501 patients with gout who had "new use" colchicine prescriptions and 501 similar patients who did not use colchicine. Participants were followed for a median of 16.5 months. The primary CV outcome was a composite of myocardial infarction, stroke, or transient ischemic attack. Secondary outcomes were primary CV events plus revascularization procedures and all-cause death.

The researchers reported 28 primary CV events among colchicine users and 82 among nonusers, for incidence rates of 35.6 vs 81.8 per 1000 person-years.

After adjustment, the primary CV event risk was 49% lower with colchicine (hazard ratio, 0.51; 95% confidence interval, 0.30 - 0.88; P = .016), and all-cause mortality was 73% lower (hazard ratio, 0.55; 95% confidence interval, 0.35 - 0.85; P = .007). Adjustment for covariates included age, sex, race, history of CV disease, diabetes, hypertension, statin use, aspirin use, antihypertensive use, smoking, body mass index, nonsteroidal anti-inflammatory drugs or selective COX-2 inhibitors, oral steroids, allopurinol and chronic kidney disease, or end-stage renal disease.

Dr Solomon told Medscape Medical News the researchers were surprised at how quickly the colchicine protective effect became apparent. Kaplan-Meier survival plots showed that the curves for primary CV and for all-cause mortality diverged within the first few months of use and remained separate for up to 4 years of follow-up.

The authors stress that the study is hypothesis generating and that the results require confirmation in a randomized controlled trial. Meanwhile, there are implications for clinicians treating patients with gout.

"If providers deem a patient at high risk of CVD (i.e., multiple risk factors), then careful CV risk factor management is critical. This would include controlling blood pressure, lipids, diabetes, and stressing the importance of exercise and weight control. Those are all evidence-based interventions that will lower the risk of future CV events," said Dr Solomon.

"Beyond this, it may be worth assessing whether the patient tolerates colchicine 0.6 mg per day. If so, then one might discuss with patients whether using colchicine as additional preventive therapy is worth considering. Colchicine should only be used very cautiously in patients with chronic kidney disease."

Cardiologist S. Mark Nidorf, MD, MBBS, from HeartCare Western Australia, Perth, who has studied colchicine for secondary prevention of cardiovascular disease in patients with stable coronary artery disease, told Medscape Medical News that this article adds to evidence favoring wider testing of colchicine for CVD prevention.

"The study by Solomon et al is the second retrospective study in patients hospitalized for gout and discharged on low-dose colchicine to demonstrate the potential cardiovascular benefits of therapy in these patients. The first was by Crittenden et al.... What makes these data interesting is the potential for them to be generalized to the wider population of patients with proven coronary disease," said Dr Nidorf, who was not involved in either study.

He also pointed out that data from the study by Dr Solomon and colleagues show that the CV benefit was not just a matter of using colchicine and avoiding the use of nonsteroidal anti-inflammatory drugs, as 40% of the patients receiving colchicine were also taking a nonsteroidal anti-inflammatory drug compared with 9% of colchicine nonusers.

"Furthermore, 41% of patients in this cohort had evidence of renal impairment and took therapy without problems, which is strongly reassuring that at low dose, colchicine therapy is safe in such patients," he added.

"Based upon the two retrospective studies in this population, it would be fair to say that continued use of low-dose colchicine for prophylaxis against gout is safe and preferred over [nonsteroidal anti-inflammatory drugs], especially in people with proven coronary disease; however, the primary reason for prescribing the drug in these patients should be for prevention of gout, rather than prevention of CV events. The real question is whether colchicine provides benefits over and above aspirin and statin therapy in patients with proven coronary disease," Dr Nidorf said.

Dr Solomon and Dr Nidorf both emphasized the need for a randomized controlled trial to confirm the colchicine protective effect, as well as the difficulties in conducting such a study.

"It would be very useful to randomize gout patients at high risk of future CV events to either receive active colchicine or placebo. The outcome of interest would be future CV events," said Dr Solomon. "The challenge with conducting this study is that it would likely require 6000 to 7000 subjects followed for 2 to 3 years. This would likely cost approximately $60 to $70 million. Who would fund such a study is not clear."

According to Dr Nidorf, interest in examining the potential effects of low-dose colchicine in patients with proven vascular disease is increasing, based on clinical observations, improved understanding of colchicine's mechanisms of action, and meta-analyses that point to the potential benefits of colchicine in patients with coronary disease. The results of larger prospective trials that are now ongoing are expected to provide more certainty about the beneficial effects.

He predicted that if low-dose colchicine is confirmed to be safe and effective for routine clinical use, it is likely to emerge as a cornerstone for secondary prevention of CV disease, in part because of the drug's low cost and ready availability. "This story still has a long way to run," Dr Nidorf said.

Dr Solomon receives salary support from unrelated grants to Brigham and Women's Hospital from Lilly, Pfizer, and Amgen. Dr Solomon and one coauthor receive research funding from Astra Zeneca on gout that is unrelated to the current paper. The coauthor also receives salary support from unrelated grants to Brigham and Women's Hospital from Lilly and Pfizer. The other authors and Dr Nidorf have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online November 18, 2015. Abstract

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