Colchicine in Acutely Decompensated HFREF

Description

Colchicine – a pleotropic anti-inflammatory drug Colchicine is a natural alcaloid extract from plants of the genus Colchium (autumn crocus). From a pharmacological point of view, colchicine binds in a poorly reversible manner to tubulin and prevents microtubule formation, therefore interfering with organelle trafficking, intercellular adhesion and cellular migration. Interestingly, colchicine at therapeutic concentration was shown to inhibit nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 inflammasome, hence inhibit the release of interleukin-1 (IL-1), to reduce the surface expression and downstream signaling of tumor necrosis factor (TNF) and alter leukocyte and endothelial expression of L-selectin and E-selecting respectively, potentially interfering with leukocytes homing and extravasation. The net effect is a potently anti-inflammatory, which lead to successful use of colchicine in the treatment of primarily inflammatory condition, in particular acute arthritis such as gout or pseudogout, and serositis.

Colchicine in cardiovascular disease The positive effects of colchicine in cardiovascular conditions have long been appreciated. In particular, colchicine has been successfully used to resolve pericardial inflammation, and eventually symptoms, in pericarditis, and to effectively prevent recurrences in those individuals who develop recurrent pericarditis. More recent data have shown a significant reduction of recurrent myocardial infarction (MI) and stroke with low dose colchicine among patient with recent MI, possibly due to resolution of “vulnerable” plaque phenotype or prevention of plaque activation in the setting of an acute inflammatory condition. Interestingly, a recent meta-analysis showed that low dose colchicine was in fact able to significantly abate systemic inflammation among patients with chronic coronary artery disease. Of note, the effect was most pronounced among patients with baseline high-sensitivity C-reactive protein (hs-CRP) ≥3.0 mg/l and for treatment duration over 7 days, and was higher for doses of 1.0 mg daily than lower colchicine doses.

Heart failure is an inflammatory condition Inflammation promotes and aggravates heart failure (HF). Of note, master inflammatory cytokines, in particular interleukin-1 (IL-1) was shown to cause direct cardio-depression and induce myocyte contractile dysfunction in both humans and pre-clinical models of cardiovascular diseases. Of note, elevated levels of inflammation and sustained subclinical inflammation over time is associated with worse HF outcomes. After a HF exacerbation, patients are at higher risk of further decompensation. Such time window lasts approximately 30 to 90 days and has been defined the vulnerable period of HF. Given that elevated inflammatory burden has been associated with early HF adverse events, it is possible, although yet unproven, that inflammation could play a role in the vulnerable period.

Targeted inhibition of inflammatory pathways was shown to abate systemic inflammation in HF patients, and to improve cardiovascular performance in terms of exercise capacity and peak VO2 on cardiopulmonary exercise tests. A single-center randomized controlled trial randomizing 267 patients with HF with reduced ejection fraction, who were clinically stable, to receive either placebo or colchicine showed a significant reduction of inflammatory biomarkers, namely high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6). No reduction in mortality or HF-related hospitalization was observed, but a trend towards improved subjective symptoms was observed. Of note, the study did not include patients with recently decompensated HF, which are the ones who show signs of greater systemic inflammation, are at increased risk for adverse outcomes and are most likely to significantly benefit from additional treatments. In the prior study, patients were indeed not selected according to baseline levels of inflammation. In particular, epidemiological studies have shown how higher baseline levels of inflammation are associated with worse HF prognosis, and our group has shown that HFrEF patients with high inflammatory burden at baseline are likely to benefit from modulation of inflammation. More recently, a retrospective, single-center study performed at University of Virginia showed that among 1047 patients admitted for acutely decompensated HF (ADHF) those (N=237) who were chronically on Colchicine for other, non-cardiac reasons, i.e. crystal arthropathy, had significantly better in-hospital outcomes when compared to HF patient who did not chronically receive colchicine (N=810). Of note, this appears to be the largest study to assess the effects of colchicine in this population and suggesting a promising therapeutic role for colchicine in ADHF.

Because elevated levels of clinical and subclinical inflammation are associated with worse outcomes and since patients are at higher risk of further decompensation within 30 to 90 days after an episode of HF, a 90 day dosing window was chosen. Unfortunately, no data on the effect of colchicine on the vulnerable period (first 90 days after the acute episode) was available in the prior study.

The investigators hypothesize that treatment with colchicine is safe to start in patients with acutely decompensated HF, and it will significantly inhibit systemic inflammation, as shown by a reduction of biomarkers of systemic inflammation, i.e. hsCRP, in patients with acutely decompensated HF with reduced left ventricular ejection fraction.