new study by medical researchers from the University of Virginia-USA has found that the common and cheap drug that is used to treat gout- Colchicine, also helps improve the survival rates of heart failure patients.
The study findings were published in the peer reviewed journal: Clinical Cardiology.
In this retrospective cohort study, we evaluated the use of colchicine for an acute gout flare during hospitalization for acute decompensated HF. We found that colchicine use during acute HF exacerbation was associated with decreased in-hospital all-cause mortality and in-hospital CV mortality, as well as increased hospital LOS.
The incidence of acute gout in this study population was 22.7% of all patient encounters. Although the rate of acute gout while receiving IV diuretics during hospitalization for acute HF is not extensively characterized in the literature, a 2017 study of patients treated with IV bumetanide during hospitalization for acute HF found the incidence of acute gout to be 13.6% over the course of the study.12 Our findings highlight the relative high prevalence of acute gout during treatment with IV diuretics for HF exacerbation.
Colchicine is a potent anti-inflammatory and antiproliferative drug that has been used for both acute gout treatment as well as prevention.10 Several studies have reported the safety and beneficial outcomes of colchicine in other cardiac conditions. A recent meta-analysis of patients with a range of CV disease states evaluated the impact of colchicine on a composite CV outcome, which consisted of the primary outcome of each individual trial and included mortality, acute coronary syndrome, MI, cerebrovascular accident, cardiac arrest, or revascularization.
The meta-analysis found that colchicine use was associated with a 56% decrease in the composite CV outcome (p = .0004), as well as a nonsignificant trend toward reduction in all-cause mortality (relative risk 0.50, p = .08).11 Several additional retrospective studies have also demonstrated favorable CV outcomes with the use of colchicine.13, 14
Recently, prospective, randomized, and placebo-controlled trials have also examined the potential benefit of colchicine in CV patients. The Colchicine Cardiovascular Outcomes Trial (COLCOT) evaluated the use of colchicine within 30 days after MI, and the Low Dose Colchicine 2 Trial (LoDoCo2) evaluated colchicine in patients with stable CAD. In COLCOT and LoDoCo2, colchicine resulted in a significant reduction in the primary outcomes, which were a composite of CV death and other clinical outcomes in both trials.25, 26
Additionally, a recent systematic review and meta-analysis assessed the impact of colchicine in patients with CAD in 13 randomized trials, which included a total of 13 125 patients.15 The study found that treatment with colchicine significantly reduced the risk of MI as well as stroke or transient ischemic attack when compared to placebo or standard care. However, colchicine was not associated with a significant reduction in all-cause or CV mortality.
While many of the existing studies have evaluated colchicine use in patients with CAD or prior MI, to our knowledge, only one trial to date has evaluated colchicine’s effects in stable HF.16 Investigators randomized stable symptomatic HF patients to receive either colchicine 0.5 mg twice daily or placebo for 6 months. The primary end point, which was the proportion of patients achieving at least one-grade improvement in New York Heart Association (NYHA) functional status classification, was not significantly different between the two groups (p = .365).
Colchicine use was associated with a significant decrease in measured inflammatory biomarkers including high sensitivity C-reactive protein and interleukin-6. There are some key differences notable in the aforementioned study compared with ours. First, investigators excluded patients hospitalized within the previous 3 months, whereas our population was comprised exclusively of patients admitted for an acute HF exacerbation.
Second, patients were given colchicine regardless of gout status, whereas in our study, patients who were given colchicine received it due to an acute gout flare. Third, investigators only included patients with left ventricular ejection fraction ≤40%, in contrast to our study which included HF patients regardless of ejection fraction.
Prior studies have also explored the impact of other gout therapies on HF outcomes. Hyperuricemia has been associated with an increased incidence of HF as well as increased mortality among those with HF. Therefore, uric acid lowering therapies have been considered potential medication candidates for improving HF outcomes. Initial studies demonstrated that allopurinol, a xanthine oxidase inhibitor, was associated with improved endothelial function in HF patients.17 Subsequently, the Effects of Xanthine Oxidase Inhibition on Hyperuricemic Heart Failure Patients (EXACT-HF) study randomized patients (with primarily NYHA Class II and III HFrEF and hyperuricemia) to allopurinol (target dose 600 mg daily) versus placebo for 24 weeks.18
The primary outcome, a composite clinical end point based on several factors including survival, worsening HF, and patient global assessment, was not significantly different between the allopurinol and placebo groups. While this prior study failed to demonstrate the efficacy of uric acid lowering with allopurinol on HF outcomes, colchicine has an important distinction related to its anti-inflammatory properties. This anti-inflammatory effect is what we believe may underlie the positive findings in our study. Additionally, the EXACT-HF study enrolled patients in the outpatient setting, while this study focused specifically on patients hospitalized with acute decompensated HF.
The mechanistic underpinnings of the potential beneficial effects of colchicine on CV events may involve its anti-inflammatory properties on the CV system.19 It has been postulated that activated neutrophils are present in atherosclerotic plaques and play a key role in the transformation of a stable to an unstable plaque.19 Colchicine’s anti-inflammatory effects and inhibition of neutrophil chemotaxis and activation may play a role in stabilizing plaques and preventing MI or ischemic strokes. Hitherto, the potential utility of colchicine in acute decompensated HF has not been considered.
Thus, the underlying mechanistic pathways that could explain the potential benefits of colchicine in the HF population are largely unknown but may be multifactorial. It has been well established that an acute HF admission is associated with increased short term mortality as well as other adverse CV events following an index admission.20 Accordingly, a worsening HF event has increasingly been recognized as an end point for enrollment in clinical trials.21-23
In this sense, acutely decompensated HF represents a distinct vulnerable phenotypic state characterized by multiple neurohormonal perturbations and a heightened proinflammatory milieu.24 It is tempting to surmise that our findings demonstrating the favorable effects of colchicine on HF mortality could potentially be explained by the modulating influence of the anti-inflammatory effects of colchicine on this distinct vulnerable phenotypic phase in the HF trajectory. If indeed our findings are validated, then consideration could be made for designing clinical trials that incorporate anti-inflammatory agents such as colchicine targeting this vulnerable phase of worsening HF.
Although colchicine first received approval from the US Food and Drug Administration in 2009, its modern use dates back two centuries. Indeed, papyri dating from 1500 BC describe the use of colchicine’s source plant – Colchicum autumnale – for pain and inflammation, making colchicine one of the world’s oldest anti-inflammatory therapeutics.35
Currently, colchicine is approved for treating and preventing acute gout and familial Mediterranean fever, and is used off label in Behçet’s disease, pericarditis and other inflammatory conditions.36
Colchicine and microtubules: inhibition of neutrophil activity
Microtubules are dynamic proteins that form via polymerisation of α-/β-tubulin dimers. Colchicine irreversibly intercalates into free α/β dimers that incorporate into and block microtubule extension.37 During inflammation, microtubules facilitate the movement of adhesion molecules onto cell surfaces. Colchicine concentrations are much higher in neutrophils than other leukocytes due to diminished activity of the P-glycoprotein membrane efflux pump that serves as an energy-dependent colchicine efflux transporter.38
Thus, neutrophils appear to be more sensitive than other cells to lower serum concentrations of colchicine. Cronstein et al demonstrated that colchicine causes a quantitative decrease in leucocyte (L)-selectin expression and diminishes qualitative expression of endothelial (E)-selectin, two proteins involved in rolling and adhesion of neutrophils on endothelium.39
Disruption of microtubules also inhibits neutrophil rheologic capacity, inhibiting their transmigration out of blood vessels.40
Additional studies show that colchicine directly inhibits intracellular neutrophil signalling and lysosomal enzyme release during phagocytosis. Colchicine-mediated inhibition of chemoattractant release (eg, leukotriene B4) suppresses neutrophil adhesion to inflamed endothelium.41
Colchicine also inhibits calcium influx, which raises intracellular cyclic adenosine monophosphate (cAMP) levels and dampens neutrophil responses.42 In lipopolysachharide-stimulated neutrophils, we observed that colchicine can dampen stimulated neutrophil metabolism as measured by extracellular acidification (unpublished, figure 4).
Colchicine and the inflammasome: inhibition of IL-1β and prevention of the cytokine storm
More recently, colchicine has been shown to decrease cytokine production by inhibiting activation of the NLRP3 inflammasome (figure 5). The mechanism(s) of colchicine’s action on the inflammasome remain an area of ongoing investigation.43 44
Colchicine’s interruption of inflammasome activation reduces IL-1β production, which in turn prevents the induction of IL-6 and TNF and the recruitment of additional neutrophils and macrophages.45 46 Whereas the effect of specific anti-IL-6 inhibition for COVID-19 treatment is somewhat controversial (online supplemental text 1), the ability of colchicine to affect multiple cytokines may offer unique advantages.
Colchicine and the Inflammation/thrombosis interface
Murine models show that colchicine inhibits neutrophil release of α-defensin, thereby potentially preventing large thrombus burdens.29 47 At supratherapeutic concentrations, colchicine, through its microtubule effects, converts normal discoid platelets to rounded, irregular structures and inhibits platelet activation by decreasing calcium entry.48
These mechanisms diminish in vitro platelet-to-platelet aggregation. In contrast, we demonstrated that standard clinical doses of colchicine do not decrease platelet-to-platelet aggregation but do diminish neutrophil-to-platelet aggregation,49 suggesting that colchicine at physiological doses may provide an inhibitory role at the inflammation/thrombosis interface without comprising homeostatic platelet-to-platelet function. Indeed, in vivo colchicine has not been shown to inhibit non-inflammatory-related thrombosis.
Adverse effects of colchicine
Colchicine metabolism occurs primarily inside hepatocytes via the cytochrome P450 3A4 (CYP3A4). Medications that strongly inhibit CYP3A4 metabolism (eg, ritonavir, ketoconazole, clarithromycin, cyclosporine, diltiazem, verapamil) pose a risk of drug-drug interactions. A small number of publications report cases of death after coadministration of clarithromycin and colchicine in patients with severe chronic renal disease.50 51 Similar cases have been rarely reported in patients receiving atorvastatin, a statin that is also processed by CYP-3A4, but not with statins that are not metabolised through CYP3A4.
In a recent placebo-controlled randomised trial of 4745 patient with a recent myocardial infarction, patients receiving daily colchicine experienced no adverse effects related to the coadministration of statins, including atorvastatin.52 In another recent placebo-controlled randomised trial of 5522 patients with stable coronary artery disease, daily colchicine resulted in numerically higher rates of myalgia (HR 1.15, 95% CI 1.01 to 1.31) and one case of rhabdomyolysis (the patient made a full recovery).53 However, a non-significant trend towards increased non-cardiovascular death was observed that requires further investigation. Overall, reports of severe colchicine toxicity tend to occur in the setting of errors in colchicine prescribing.
Approximately 10%–20% of colchicine is excreted renally.36 However, dose reductions may only be necessary in patients with severe renal impairment.54 As a lipophilic molecule, colchicine is usually protein-bound in plasma, with P-glycoprotein in the intestinal lining serving as the primary protein for gut excretion of colchicine. Cyclosporine and ranolazine compete for the ligand site on P-glycoprotein and can therefore lead to delayed elimination. At higher concentrations for longer durations, particularly in the setting of kidney disease, colchicine has been reported to occasionally induce a reversible neuromyopathy. Acute overdose may cause multiorgan system failure and death. Furthermore, increased adverse events may be noted in the simultaneous presence of moderate renal insufficiency with use of multiple CYP3A4 inhibitors.
A meta-analysis of 35 randomised trials of colchicine versus placebo found that the most common and significant adverse effect was diarrhoea.55 56 The only other adverse effect that occurred at a greater frequency than placebo was a set of pooled gastrointestinal symptoms including nausea, vomiting, diarrhoea, abdominal pain, loss of appetite, and bloating. A striking finding in this meta-analysis was the absence of increased infection rates in the colchicine compared with the placebo arm. However, in contrast to most available data, one retrospective and one prospective study did report increased pneumonia risk with colchicine (online supplemental table 1).
Colchicine and COVID-19: the clinical case
Several of the biological therapies that have been studied and/or used in the setting of severe SARS-CoV-2 infection target some of the same pathways as colchicine, including IL-1β (ie, anakinra) and IL-6 (ie, tocilizumab and sarilumab).57 Colchicine differs from these agents in having pleotropic mechanisms of action, being less potent on any single target, and being an oral agent. In contrast to the biological agents used in the midst of cytokine storm, colchicine is not immunosuppressive, is not known to increase risk of infection, and is inexpensive.
A review of the mechanisms of SARS-CoV-2 and colchicine in parallel reveals a potential intervention point that may prevent the progression from inflammatory activation (phase 2) to a hyperinflammatory state (phase 3). Taken together with the clinical data described herein, the potential benefits of colchicine are suggested to be maximised when used early in the disease process (ideally prior to phase 2, but certainly prior to phase 3), such as in non-hospitalised patients within a few days of diagnosis regardless of symptoms and/or within a few days of hospitalisation if not already critically ill. However, the optimal timing continues to require further investigation.
referencelink : https://ard.bmj.com/content/80/5/550