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6th July 2023
Colchicine is a drug traditionally used for an acute attack of gout, but its most recent FDA approval has seen it repurposed for the management of atherosclerotic cardiovascular disease. Clinical writer Rod Tucker considers the evidence and what this means for CVD management.
Most clinicians will be familiar with the use of the anti-inflammatory agent colchicine as a treatment for acute attacks of gout, which is surprising given the lack of good quality evidence for the drug. But, recent events have put the drug on the map for a different purpose.
In late June 2023, the US Food and Drug Administration approved colchicine 0.5 mg for use in patients with cardiovascular disease to reduce adverse cardiac events. But how did a relatively inexpensive and widely used drug suddenly assume an important role in the management of atherosclerotic cardiovascular disease?
The prevailing wisdom is that atherosclerosis is due to the accumulation of cholesterol within the intimal of arteries and necessitates lipid-lowering therapy. An alternative cause, first mooted in 1999, has, until recently, been largely ignored. However, emerging evidence now implies that inflammation, rather than hypercholesterolaemia, is a more important driver of atherosclerosis, hence the rationale for the use of anti-inflammatory agents such as colchicine.
The fact that inflammation has a significant role in the development of atherosclerosis arose following the publication of the CANTOS study with canakinumab, which targets the pro-inflammatory agent interleukin-1β. In the trial, the use of canakinumab significantly reduced the primary efficacy endpoint of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death compared to the placebo.
While CANTOS clearly showed how reducing a single inflammatory marker lowered the risk of adverse cardiac events, earlier research had strongly implicated that neutrophils played a part in atherosclerosis.
The possible role of neutrophils in heart disease has been recognised for some time. In 1989, researchers identified an enhanced neutrophil function in patients with ischaemic heart disease although just where neutrophils sat in the pathophysiology of atherosclerosis remained unclear.
It was evident from a study in 1994, that inflammation was present at the immediate site of an atherosclerotic plaque rupture or erosion, leading to speculation that inflammatory changes had a pivotal role in destabilising the fibrous cap of an atherosclerotic plaque, enhancing the risk of coronary thrombosis.
The link between inflammation and neutrophils finally became much more intelligible in 2002, when it was discovered that neutrophil infiltration was actively associated with acute coronary events. Acknowledging the importance of neutrophils in cardiovascular disease, researchers then wondered if a drug that could inhibit the function of neutrophils might be advantageous to patients with cardiovascular disease.
Colchicine works by blocking the assembly and polymerisation of microtubules. These microtubules have numerous roles within cells including maintenance of cell shape, intracellular trafficking, cytokine and chemokine secretion, cell migration and the regulation of ion channels and cell division. But one important consequence of preventing the formation of microtubules is interference with neutrophil adhesion and recruitment to inflamed tissue.
It therefore seemed possible that a drug such as colchicine, might prove invaluable in patients with atherosclerotic cardiovascular disease. Whether this theoretical effect would benefit patients in practice remained to be seen.
The road to the current approval of colchicine in cardiovascular disease was a long one, and the earliest attempts were disappointing.
In a 1992 study, scientists explored the value of the drug at preventing restenosis in patients following angioplasty, although colchicine proved to be no more effective than placebo. Fast forward to 2013, a study among patients who had recently experienced a myocardial infarction found that a daily dose of colchicine 0.5 mg combined with statin therapy appeared to be effective for the secondary prevention of cardiovascular events in patients with stable coronary disease.
Over the next seven years, more positive findings rolled in. For example, the secondary preventative value of colchicine was replicated in a 2019 study. Additionally, colchicine reduced adverse outcomes, in patients with any evidence of coronary disease and in those following either a recent (six to 24 months) or a prior (two to longer than seven years) acute coronary syndrome.
Assimilating the results from available studies, a 2021 meta-analysis of randomised trials with low-dose colchicine (0.5 mg), concluded that the drug lowered the risk of MACE, myocardial infarction, stroke and the need for coronary revascularisation in a broad spectrum of patients with coronary disease.
Given that atherosclerotic cardiovascular disease is largely assumed to be a direct consequence of elevated cholesterol, how important is the presence of inflammation?
A recent analysis, published in The Lancet, directly addressed this question. Researchers turned to three major statins trials in patients with, or at high-risk of, atherosclerotic disease to analyse the relative importance of inflammation and hypercholesterolaemia. The findings were very clear: inflammation rather than elevated levels of LDL cholesterol was the stronger predictor of future risk for both cardiovascular events and death.
While the mainstay of cardiovascular disease management over the past 20 years has been predicated on the notion that hypercholesterolaemia is a major cause, recent data does indeed suggest that inflammation is actually a more relevant prognostic marker.
With cardiovascular diseases still the leading cause of global deaths, the approval of colchicine is recognition of the need for a paradigm shift in the care of patients with the disease, and this will hopefully make a greater impact on overall mortality.
22nd June 2023
Colchicine has become the first anti-inflammatory agent to be approved by the US Food and Drug Administration (FDA) for the treatment of cardiovascular disease (CVD).
According to the Europe-based manufacturer, Agepha Pharma, the FDA has approved colchicine 0.5 mg as the first anti-inflammatory athero-protective cardiovascular treatment, for patients either with established CVD or with multiple risk factors for the disease.
While both inflammation and hypercholesterolaemia jointly contribute to atherothrombotic disease, an analysis published in The Lancet in 2023, found that in patients receiving statins, inflammation was a stronger predictor for risk of future cardiovascular events and death than cholesterol. Colchicine achieves a beneficial effect in CVD at the cellular level through several mechanisms that include inhibition of endothelial cell dysfunction and inflammation, smooth muscle cell proliferation and migration, macrophage chemotaxis, migration, adhesion and platelet activation.
Evidence that colchicine is effective in CVD comes from a large study published in the New England Journal of Medicine. Over 5,000 patients with chronic coronary disease were randomised to colchicine 0.5 mg daily or matching placebo. The primary endpoint for the trial was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischaemic stroke or ischaemia-driven coronary revascularisation.
After a median of 28.6 months, significantly fewer patients assigned to colchicine experienced a primary endpoint event (hazard ratio, HR = 0.69, 95% CI 0.57 – 0.83, p < 0.001). Other work has also revealed how colchicine is effective in patients with chronic coronary disease both prior to and following an acute coronary syndrome.
Commenting on the approval, Paul Ridker, a consultant for Agepha Pharma as well as professor of medicine at Harvard Medical School and director of the Centre for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, said: ‘Approval by the FDA of the first drug to target cardiovascular inflammation is an important step forward for the care of our patients.
‘To treat coronary disease effectively, cardiologists must aggressively reduce inflammation and cholesterol. For appropriate patients already taking a statin, adding the anti-inflammatory drug colchicine at a dose of 0.5 mg daily has been proven to significantly lower risks of recurrent heart attack and stroke.‘
Colchicine is formulated as a once-daily, continuous-use oral treatment for adults that can be used safely either alone or in combination with standard-of-care lipid-lowering medications to effectively reduce the risk of heart attack and stroke.
The manufacturer anticipates that it will be available for prescription in the US in the second half of 2023. Potential plans for gaining approval in the UK or EU are currently unknown.
8th June 2023
In an exploratory analysis of low-dose colchicine use to reduce the occurrence of cardiovascular events, researchers have found that the drug lowers the incidence of hip and knee replacements for osteoarthritis (OA).
Published in the Annals of Internal Medicine, researchers examined the effect of colchicine on the incidence of hip and knee replacements in participants within the LoDoCo2 trial. This randomised, double-blind, placebo-controlled trial was designed to explore the effects of colchicine on the risk of cardiovascular events in patients with a recent myocardial infarction. Patients with coronary artery disease received either colchicine 0.5 mg daily or matching placebo.
In the exploratory analysis of data from LoDoCo2, the primary outcome of interest was the time to the first knee or hip replacement.
A total of 5,478 participants with a mean age of 66 years (15.3% female), were randomised to either colchicine (2,762) or placebo and followed for a median of 28.6 months.
Overall, the use of colchicine reduce the risk of knee or hip replacements by 31% (hazard ratio, HR = 0.69, 95% CI 0.51 – 0.95).
During a sensitivity analysis, this finding remained significant when excluding patients with gout (HR = 0.68, 95% CI 0.49 – 0.94) and those with a knee or hip replacement within the first three (HR = 0.61) or six (HR = 0.58) months after randomisation.
Whilst the trial did not specifically collect data on the incidence of OA, or any information on joint pain or physical functioning, it clearly had some effect on the course of the disease. The authors called for further studies to investigate colchicine therapy in slowing disease progression in OA.
OA is a condition associated with cartilage destruction, subchondral bone remodelling and inflammation of the synovial membrane which is thought to be due to an increased release of pro-inflammatory cytokines. In fact, use of canakinumab, an anti-interleukin-1β inhibitor and which is a pro-inflammatory cytokine, has been shown to reduce the incidence of both knee and hip replacement in patients with OA.
Colchicine works through tubulin disruption and this action down regulates multiple inflammatory pathways, suggesting that the drug may be of value as an anti-inflammatory agent.
10th February 2023
A study by Chinese researchers has shown that using colchicine for two days before and five days after, non-post-coronary artery bypass grafting (non-CABG) cardiac surgery, significantly lowers markers of myocardial injury and inflammation.
It has become recognised for many years that in cardiac surgery involving cardiopulmonary bypass, there is a systemic inflammatory response that leads to both organ injury and post-operative morbidity. While colchicine is often been used in the management of gout, the drug also has anti-inflammatory effects and can have a positive impact on several rheumatic diseases with a potential benefit in cardiac disease. Cardiac surgery is known to elevate markers of myocardial injury such as troponin levels and one study suggested that if post-operative values exceed ≥ 0.8 μg/L on the first post-operative day, a further 10% increase is significantly associated with all-cause, 12-month mortality and other adverse events. With some data showing that a perioperative course of colchicine, in patients undergoing standard coronary artery bypass grafting, reduced post-operative surgery-related myocardial damage, in the current study, the Chinese team wondered if this myocardial protective effect would extend to non-CAGB cardiac procedures.
Turning to patients undergoing other types of cardiac surgery such as mitral and aortic valve replacement, atrial septal defect repair and atrial myxoma resection, the researchers randomised patients, 1:1 to receive colchicine 0.5mg daily or placebo for three days before and five days after their cardiac surgery. The primary outcome was the level of cardiac troponin T (cTnT) 48 hours after surgery whereas secondary outcomes included biomarkers of myocardial injury including creatine kinase-MB (CK-MB) and procalcitonin (PCT).
Colchicine and myocardial injury
A total of 121 patients with a mean age of 59.4 years (57.8% male) were included and of whom, 59 were given colchicine.
At the 48-hour post-operative timepoint, patients assigned to colchicine had significantly lower cTnT (p < 0.001), CK-MB (p = 0.01) and PCT (p < 0.01) levels compared to placebo. In fact, cTnT levels remained significantly lower in those assigned to colchicine, 5 days after surgery (0.14 vs 0.23 μg/L, p = 0.001).
This findings led the authors to concluded that a short perioperative course of colchicine lowered post-operative biomarkers of myocardial injury and inflammation.
Citation
Pan T et al. The low-dose colchicine in patients after non-CABG cardiac surgery: a randomized controlled trial. Crit Care 2023
25th January 2022
Colchicine use in patients with coronary artery disease undergoing a percutaneous intervention, significantly reduced the incidence of major adverse cardiovascular events (MACE) according to a meta-analysis by a team from the University of Oxford, UK.
Coronary artery disease is characterised by atherosclerotic plaque accumulation in the epicardial arteries and can be managed with various interventions including lifestyle modification, pharmacological therapies and invasive interventions, all of which are designed to achieve disease stabilisation or regression.
One particular intervention is percutaneous coronary intervention (PCI) and defined as a non-surgical, invasive procedure which seeks to relieve the narrowing or occlusion of the coronary artery and improve blood supply to the ischaemic tissue.
The importance of inflammation in the pathogenesis of coronary artery disease was established many years ago and during PCI, damage to the endothelial layer after stent implantation can also lead to a further inflammatory response. Moreover, the presence of residual inflammation can increase the risk of subsequent complications such as a myocardial infarction therefore highlighting the importance of minimising inflammation to improve patient outcomes.
Colchicine use represents a low cost anti-inflammatory agent and there is evidence that they drug has beneficial effects as a secondary preventative measure, especially after a myocardial infarction. Nevertheless, the value of colchicine use as an adjunctive intervention to PCI to prevent cardiovascular events remains unclear and was the objective of the current analysis.
The team undertook a systematic review and meta-analysis for studies that compared the efficacy of colchicine use to either no use or placebo in patients undergoing PCI and which reported on MACE. The primary outcome measures were the MACE and which included outcomes including in-stent restenosis (ISR), repeat vessel revascularisation, stent thrombosis, stroke and all cause mortality.
Findings
A total of 7 trials including 6660 participants with a mean age of 60.9 years (3347 assigned to colchicine use) and a follow-up time ranging from 3 days to 22.6 months were analysed.
The incidence of MACE was 7.08% in those assigned to colchicine use and 9.15% in the control arm, leading to a significant reduction in MACE (risk ratio, RR = 0.73, 95% CI 0.61 – 0.87, p = 0.0003) and with little evidence of heterogeneity across the analysis.
Use of colchicine was associated with a significant reduction in stent thrombosis (RR = 0.50), repeat vessel revascularisation (RR = 0.47) and stroke (RR = 0.50). However, there was no significant difference in all-cause mortality (RR = 1.12, 95% CI 0.49 – 2.58, p = 0.79).
The authors calculated the number needed to treat with colchicine to prevent one episode of MACE to be 41. They concluded that colchicine use significantly reduced the risk of MACE in patients with coronary artery disease undergoing PCI and called for future trials to further evaluate the value of colchicine with different types of stents and alternative dosing regimes.
Citation
Aw KL et al. Colchicine for symptomatic coronary artery disease after percutaneous coronary intervention Open Heart 2022
28th May 2021
Infection with COVID-19 has been found to be associated with raised levels of systemic inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6) and other cytokines. In addition, data have revealed how engagement of protein platforms (inflammasomes) and in particular, the nucleotide binding domain-like pyrin domain 3 (NLRP3) inflammasome, is strongly associated with disease severity.
The anti-inflammatory gout drug, colchicine, is known to inhibit the NLRP3 inflammasome and may therefore be of value in the treatment of patients hospitalised with COVID-19. The randomised evaluation of COVID-19 therapy (RECOVERY) trial aims to evaluate a number of therapeutic options for the management of hospitalised patients infected with COVID-19. The RECOVERY group have investigated several different treatments and recently examined the use of colchicine. For the present trial, patients were randomised 1:1 to usual care or usual care plus colchicine at a dose of 1mg after randomisation, followed by 500mcg 12 hours later and then 500mcg twice daily (orally or via nasogastric tube) for 10 days or until discharged from hospital. However, although patients were randomised, this was an open label trial, hence both treating clinicians and patients were not masked to treatment allocation although the study steering group and investigated were masked to outcome data during the trial. The primary outcome was all-cause mortality and assessed at 28 days post-randomisation. Secondary outcomes included time to hospital discharge and the need for invasive mechanical ventilation.
Findings
A total of 5610 patients with a mean age of 63.4 years (31% female) and of predominately (77%) White ethnicity, were randomised to colchicine and 5730 to usual care. The median duration of treatment with colchicine was 6 days and use of all other treatments was similar between the two groups. The proportion of patients allocated to colchicine who achieved the primary outcome was not different to placebo (21%) and the median time to hospital discharge was 10 days and again, similar between the two groups. Moreover, an equal number of patients progressed to invasive mechanical ventilation (70%).
In discussing these findings, the authors commented on how the use of colchicine had no impact on mortality, duration of hospitalisation or the need for mechanical ventilation. Additionally, this effect was evidence across all ages, ethnic groups and irrespective of symptom duration prior to randomisation. They also speculated that the anti-inflammatory properties of colchicine were either inadequate or did not sufficiently target the pathways induced by COVID-19 and concluded that the drug was of no benefit to those hospitalised with COVID-19.
Citation
RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv 2021
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