SNOWMASS, COLO. – Evidence from three observational studies suggests colchicine has a strong protective effect against cardiovascular events in gout patients.
These data add to mounting evidence that the venerable 2,400-year-old medication also reduces the incidence of cardiac events in patients at elevated risk who don’t have gout, Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Michael H. Pillinger
He was a coinvestigator in the three observational studies, two of which are ongoing with only interim results available.
The first of these observational studies was a retrospective, cross-sectional pilot study of 1,288 gout patients in the New York Harbor Healthcare System Veterans Affairs database. The demographics, baseline comorbidities, and cardiovascular risk factors in the 576 colchicine users and 712 nonusers were closely similar. The key finding in this snapshot study: the prevalence of a history of acute MI was 1.2% in the colchicine users, compared with 2.6% in the non-users with gout, for a significant 54% relative risk reduction (J. Rheumatol. 2012;39:1458-64).
"That degree of risk reduction seems too good to be believed, and it probably is," according to Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.
But the next observational study showed a similar-size benefit. This was a retrospective cohort study of New York VA gout patients. It included only gout patients who met American College of Rheumatology diagnostic criteria as confirmed by manual chart review. There were 410 colchicine users with a collective 1,184 years of active use and another 682 years of lapse time, along with 234 colchicine nonusers with 1,041 years of follow-up time. Again, baseline demographics and comorbidities were remarkably similar for the two groups.
In an interim analysis, the incidence of acute MI was 0.7% among active users of colchicine, 2.0% in lapsed former users, and 3.1% in the nonuser controls. This translated to an incidence rate of 0.003 MIs per person-year in the colchicine users, 0.007 per person-year in the controls, and 0.009 MIs per person-year during a combined 1,723 person-years in the combined control group plus lapsed former users, for relative risk reductions of 57% and 67%, respectively. Still, the final results aren’t in yet, and this study is limited by a small number of events to date, its retrospective design, and the potential for confounding by indication, Dr. Pillinger noted.
Gout patients on colchicine in these two VA studies were on 0.6-1.2 mg/day rather than the now-standard 0.5 mg.
The latest observational study is a retrospective cohort study being conducted in collaboration with Dr. Peter Berger, chair of cardiology at the Geisinger Health System in Danville, Pa. To date, it includes 3,064 gout patients. The MI incidence thus far is 6.3/100 person-years in the colchicine users and 11.2/100 person-years among lapsed users. After controlling for potential confounders such as age, hypertension, and diabetes in a logistic regression analysis, however, the trend for reduced MI risk in the colchicine users hasn’t yet reached significance. Stay tuned, Dr. Pillinger said.
The mechanistic rationale by which colchicine might reduce cardiovascular events in gout patients lies in the fact that it is an anti-inflammatory drug and atherosclerosis is a powerfully inflammatory process. Colchicine is known to suppress production of TNF-alpha, interleukin-1beta, and other inflammatory cytokines by neutrophils, macrophages, and endothelial cells. These cell types are present in atherosclerotic plaque, the rheumatologist explained.
By the same rationale, colchicine might well be cardioprotective in individuals without gout. One strong piece of supporting evidence comes from a 3-year, randomized, observer-blinded clinical trial in which 532 Australian patients with stable coronary artery disease on background statin and antiplatelet therapy received 0.5 mg/day of colchicine or not. The composite primary endpoint comprised acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke occurred in 5.3% of the colchicine group, compared with 16.0% of controls. That’s a 67% relative risk reduction, with a highly favorable number-needed-to-treat of 11 (J. Am. Coll. Cardiol. 2013;61:404-10).
Dr. Pillinger reported being the recipient of research grants from Takeda, which markets colchicine (Colcrys), and Savient, which markets the gout drug pegloticase (Krystexxa).