Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationships relevant to this field of study.
Synopsis: Colchicine, in addition to statins and other standard secondary prevention therapies, appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.
Source: Nidorf SM, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-410.
It is well documented that coronary atheroma can be either stable or unstable and that the unstable, vulnerable plaque has all of the key histological features of inflammation. These features include a higher temperature and roughly four times more macrophages than exist in stable plaques. Also, most vulnerable plaques are characterized by a thin fibrous cover that is only one-third as thick as is found in stable atheroma.1-4 Despite routine and aggressive use of antiplatelet and statin therapies, patients with coronary artery disease — known or unknown — continue to be at risk for the development of cardiovascular events, possibly because the routine therapeutic approaches fail to target some of the inflammatory pathways that are frequently responsible for acute coronary syndromes (ACS). The atherosclerotic wall is subject to injurious forces that promote plaque instability, and the response to injury within the diseased vessel is frequently dependent on the architecture and content of the atherosclerotic lipid-rich plaques with neovascular bases,5,6 which are particularly susceptible to the effects of injury which may leave them vulnerable to neutrophil infiltration.7 Neutrophils may become activated upon exposure to the plaque contents, inciting an aggressive inflammatory response, which in turn accelerates plaque instability and increases the risk of plaque enlargement and rupture leading to acute coronary events.7
Nidorf and colleagues conducted a prospective, randomized, observer-blinded endpoint trial (PROBE) to determine whether adding colchicine in a dose of 0.5 mg/day to standard secondary prevention therapies, including aspirin and high-dose statins, reduces the risk of cardiovascular events in patients with clinically stable coronary disease.8 The trial cohort consisted of 532 patients with stable coronary disease who were receiving aspirin and/or clopidogrel and statins. Participants were randomly assigned to either receive the anti-inflammatory drug colchicine 0.5 mg/day or no colchicine and were followed for a median of 3 years. The primary outcome was the composite incidence of ACS, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke. The primary outcome occurred in 4.5% of the patients receiving colchicine vs 16% of the patients who did not receive colchicine. These results suggest that colchicine administered along with statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.
Commentary
The beneficial effects of colchicine on cardiovascular disease have been suggested by retrospective observations that the continuous use of the drug in patients with inflammatory disorders was associated with a lower than expected risk of acute myocardial infarctions9,10 and reduced levels of high sensitivity C-reactive protein levels in those patients with stable coronary artery disease.11 Although most physicians are familiar with the short-term use of colchicine because of its widespread use in patients with gout and pericarditis,12 few physicians prescribe it for continuous use in their patients. The long-term use of colchicine at doses of 1-2 mg/day has been documented to be safe and well tolerated.13 However, it should be noted that 11% of the patients in the present study8 had to withdraw from therapy early due to intestinal intolerance and another 5% ceased therapy later due to a range of side effects, indicating that the widespread use of the drug may be limited because of its side effects. In fact, it has been reported that combining colchicine with statin therapy may increase the risk of myalgia and even acute rhabdomyolysis in patients with renal impairment.14 As a result of these events in patients on colchicine therapy, any patients who are receiving regular colchicine therapy should receive close clinical supervision.
In summary, colchicine therapy may be an attractive remedy for the secondary prevention of cardiovascular events because it was proved to be extremely effective with a 67% coronary event reduction (i.e., about twice that obtained with aggressive statin therapy alone), is simple to use, is inexpensive, and long-term use rarely results in any major long-term toxicity. In fact, this study has the potential of being a breakthrough study demonstrating the positive effects of anti-inflammatory therapy in patients with coronary artery disease.8 However, because problems and complications do occur with its use, the results of the Nidorf study need to be confirmed in a larger, double-blind study in patients with coronary atherosclerosis. If the anti-inflammatory effects of colchicine are confirmed in larger trials, the Nidorf trial may stand as the seminal trial in the use of anti-inflammatory therapy to cool off hot hearts and thereby reduce cardiovascular events.
References
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14. Alayli G, et al. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother 2005;39:1358-1361.
Colchicine, in addition to statins and other standard secondary prevention therapies, appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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