Colchicine and the Failing Heart: A “FINER” Anti-Inflammatory Agent?

Abstract

Since the original description of proinflammatory cytokines in patients with heart failure in 1990 (1), there has been enormous interest in the role that these molecules play in regulating cardiac structure and function, particularly with regard to their potential role in disease progression in heart failure. The recognition of the important pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. Unfortunately, these targeted approaches were negative with respect to the primary end points of the trial, and in some patients resulted in worsening heart failure and/or death (2, 3). Collectively, these two clinical trials have had a chilling effect on further attempts to target inflammation in heart failure, and have raised a number of nagging questions about what role, if any, that proinflammatory cytokines play in the pathogenesis of heart failure, Germane to the present discussion, in the current issue of the Journal Deftereos and colleagues report their findings on a six month course of treatment with colchicine in patients with heart failure with a depressed ejection fraction ≤ 40% (4). The rationale for this study was that colchicine has been known to exert anti-inflammatory effects in various cardiovascular settings (reviewed in reference 5), and might therefore also be useful in treating heart failure patients. Patients with stable heart failure on appropriate medical therapy were randomized to receive colchicine (0.5mg twice daily) or placebo for six months. The primary end point of the study, for which the trial was powered adequately, was the proportion of patients achieving at least a one grade improvement in the New York Heart Association functional class. Secondary end points, for which the trial was not adequately powered for, included a composite of death and hospitalization for heart failure, the change in left ventricular and end diastolic-diameter (2-D echocardiography), change in left ventricular ejection fraction and change in treadmill exercise time. In comparison to patients who were treated with conventional heart failure therapy, the authors observed that 11% of the control subjects had an improvement in New York Heart Association class whereas 14% of patients in the colchicine group experienced an improvement in New York Heart Association classification (p=0.36). Moreover, the composite of death or hospitalization for heart failure was 9.4% in the control group compared with 10.1% in the colchicine group (p=0.84). The changes in treadmill exercise time were insignificant in the control and treatment arms. Importantly the magnitude of the decrease in circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6) were both significantly reduced in the colchicine treated group when compared to placebo. There was ~ a two-fold (p = 0.007) increase in gastrointestinal symptoms in the treatment group, whereas there were no serious complications in terms of renal and/or hepatic function. The authors conclude that anti-inflammatory treatment with colchicine in patients with stable heart failure, although effective in reducing inflammation biomarker levels, did not significantly affect functional class or the likelihood of death or hospitalization. Given the negative outcome of previous trials using anti-inflammatory agents in heart failure, the current study raises further questions about targeting of inflammation in this patient population.