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Take a look at a selection of our recent media coverage:
4th September 2023
Individuals with a greater exercise capacity have a reduced risk of developing atrial fibrillation (AFib), ischaemic stroke and major adverse cardiovascular events (MACE), according to the findings of a large study presented at the European Society of Cardiology (ESC) Congress, 2023.
AFib is the most common cardiac arrhythmia and has a number of different causes including auto-immune diseases such as rheumatoid arthritis.
Whether being physically fit might reduce the risk of developing AFib is unclear, although some evidence reveals a graded, inverse relationship between cardiorespiratory fitness and incident AFib, especially among obese individuals.
The study included 15,450 individuals without AFib who had a mean age of 54.9 years (59% male). All participants were referred for a treadmill test between 2003 and 2012.
Fitness was assessed using the Bruce protocol, where participants are asked to walk faster and at a steeper grade in successive three-minute stages. It was then calculated according to the rate of energy expenditure the participants achieved, which was expressed in metabolic equivalents (METs).
Participants were then divided into three fitness levels according to the METs achieved during the treadmill test: low (less than 8.57 METs), medium (8.57 to 10.72) and high (more than 10.72).
The researchers looked for independent associations between exercise capacity on the treadmill and the risk of new-onset AFib, risk of ischaemic stroke and MACE. The results were adjusted for potential confounders including age, sex, cholesterol level, kidney function, prior stroke, hypertension and any medications.
During the period of follow-up, new-onset AFib occurred in 3.33% of participants.
In fully adjusted models, each one MET increase in exercise treadmill testing, there was an associated 8% lower risk of AFib incidence (hazard ratio, HR = 0.92, 95% CI 0.88 – 0.97).
In addition, this one MET increase was also associated with a lower risk of ischaemic stroke (HR = 0.88, 95% CI 0.83 – 0.94) and a 14% reduced risk of MACE (HR = 0.86, 95% CI 0.84 – 0.88).
In fact, the probability of remaining free from AFib over a five-year period was calculated to be 97.1%, 98.4% and 98.4% in the low, medium and high exercise capacity groups, respectively.
Study author Dr Shih-Hsien Sung of the National Yang Ming Chiao Tung University in Taipei, Taiwan, said: ‘This was a large study with an objective measurement of fitness and more than 11 years of follow up. The findings indicate that keeping fit may help prevent atrial fibrillation and stroke.‘
17th August 2023
JAK inhibitors are known to increase the risk of major adverse cardiovascular events when used in rheumatoid arthritis, but does this elevated risk also apply when this class of drugs is used in atopic eczema? Clinical writer Rod Tucker investigates.
Since the 1990s, the treatment of severe rheumatoid arthritis (RA) has centred on biologics such as tumour necrosis factor (TNF) inhibitors. However, a better understanding of cell signalling pathways and, in particular, intracellular signal transduction, led to the development of alternative therapies, one of which being oral Janus kinase (JAK) inhibitors. Several of these have been approved for use in RA since 2011.
What’s more, as JAK inhibitors disrupt intracellular signalling through a variety of cytokine and haematopoietic growth factor receptors, this mode of action suggests the drug class may have a much wider role in a number of immune-mediated inflammatory diseases. As such, approvals for JAK inhibitors in Crohn‘s disease, psoriasis and atopic eczema have been seen in recent years.
Despite their apparent effectiveness in RA, a recent post-marketing study has raised safety concerns over JAK inhibitors compared to TNF inhibitors. The Oral Rheumatoid Arthritis Trial (ORAL) was a randomised, post-authorisation, non-inferiority trial designed to evaluate the safety and efficacy of the JAK inhibitor tofacitinib compared to a TNF inhibitor such as etanercept or adalimumab. It focused on patients with RA who were aged 50 or older and had at least one additional cardiovascular risk factor.
The findings were somewhat disturbing. JAK inhibitor use led to a significantly higher incidence of both major adverse cardiovascular events (MACE) and cancers compared to a TNF inhibitor, even though the efficacies were broadly similar.
The ORAL trial served to highlight how JAK inhibitors may increase the risk of MACE when used in patients with RA who are already at an elevated risk due to their condition. Indeed, a meta-analysis of 24 studies with over 111,000 RA patients estimated a 50% higher risk of cardiovascular mortality.
So, with three JAK inhibitors (upadacitinib, baricitinib and abrocitinib) approved for atopic eczema, and representing an important and promising development for its treatment, should dermatologists be concerned over the risk of MACE when using this class of drugs?
Before considering whether JAK inhibitors might increase the risk of adverse cardiovascular sequelae in those with atopic eczema, its worth exploring whether atopic eczema, itself an inflammatory condition, is linked to a higher risk of MACE. After all, such a risk is theoretically possible, given the emerging evidence of the pivotal role of inflammation in the development and progression of both cardiac and vascular diseases.
The current evidence of an association between atopic eczema and MACE is equivocal. Some work, for instance, clearly demonstrates that atopic eczema is associated with increased risk of myocardial infarction compared to the general population. In contrast, another study found no such independent association in women.
Nevertheless, pooling data from several studies does suggest a positive relationship. For example, a 2018 meta-analysis of 15 studies, which included over 3.5 million participants, did show that atopic eczema was independently associated with an increased risk of stroke and myocardial infarction, especially in male subjects and those with more severe disease.
In addition, a recent Danish study, looked at what happened to patients over time following a diagnosis of atopic eczema. It included over 40,000 atopic eczema patients and an equal number of matched controls and found that adults were at a significantly higher risk of experiencing a subsequent cardiovascular disease.
Finally, a UK prospective study including 387,439 patients with atopic eczema followed for over five years, concluded that severe active atopic eczema was associated with an increased risk of cardiovascular outcomes.
While prospective studies are subject to confounding, Mendelian randomisation studies, are able to provide an estimate causality without the influence of confounders. One such study showed that asthma and atopic eczema were causal risk factors for heart failure and suggested that the underlying inflammatory nature of both diseases was a major contributory factor.
As ever, things are never that straightforward. In a recent bidirectional Mendelian randomisation study, it was found that there was no robust association between cardiovascular disease and atopic eczema.
In trying to establish if there was a higher risk of MACE in patients with atopic eczema prescribed a JAK inhibitor, researchers recently undertook a systematic review and meta-analysis. The findings were published in July 2023 in the British Journal of Dermatology and included phase 2b or 3 randomised controlled trials and controlled cohort studies.
The primary outcome was the occurrence of MACE, which the researchers defined as a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death.
A total of 23 studies were included in the analysis. Very few cases of MACE were found, leading the researchers to suggest that JAK inhibitors may have little-to-no effect on the occurrence of MACE in patients with atopic eczema compared to placebo. However, they did add the caveat that the evidence was uncertain.
In addition, MACE generally occurred in patients at a high cardiovascular risk and not in the younger, healthy patients typically seen in routine clinical practice.
Further and reassuring evidence of the absence of a possible association with MACE comes from real-world studies on the use of JAK inhibitors in atopic eczema. There have been at least four such studies, none of which have identified any cases of MACE, even though some have been conducted in patients with more severe disease.
Although patients with atopic eczema may have a higher risk of MACE, this is more likely to occur either in those with severe disease or for patients at a greater risk of cardiovascular disease. Over time, pharmacovigilance data will no doubt shed further light on the level of risk associated with JAK inhibitors.
For now, the European Medicines Agency (EMA) issued advice in January 2023 on the use of JAK inhibitors in all chronic inflammatory disorders, including atopic eczema. This recommended avoiding against the use of a JAK inhibitor in those aged 65 years or above, in patients at an increased risk of major cardiovascular problems, smokers and individuals at a higher risk of cancer, unless there are no suitable alternatives.
For most patients with atopic eczema, JAK inhibitors represent a potentially game-changing addition to a dermatologist’s armamentarium for their treatment. Provided that clinicians heed the current safety guidance, those prescribed a JAK inhibitor for atopic eczema have much to gain but without the attendant risk of MACE.
24th April 2023
Use of bempedoic acid among those who are statin-intolerant reduces the incidence of major adverse cardiovascular events compared to placebo.
Bempedoic acid (BA) modulates both ATP-citrate lyase and AMP-activated protein kinase activity reducing LDL cholesterol.
In addition, bempedoic acid is an alternative LDL lowering agent for statin-intolerant patients. Nevertheless, although the drug can reduce LDL cholesterol whether it could reduce adverse cardiovascular effects is uncertain. This was the purpose of the current CLEAR outcomes trial.
In a randomised, double-blind, placebo-controlled trial, researchers gave the drug to statin-intolerant patients. The participants were also at an increased risk of a cardiovascular event. This could be either due to a prior cardiac event (secondary prevention) or an elevated risk (primary prevention). Participants received oral bempedoic acid 180 mg daily or placebo. The primary endpoint was a four-component composite of major adverse cardiovascular events. These events were death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation.
Bempedoic acid outcomes
There were 13,970 patients in the trial with 6,992 receiving BA. Participants were followed for a median of 40.6 months.
The mean LDL cholesterol level after 6 months of treatment with BA was 2.77 mmol/L and 3.52 mmol/L in the placebo group. The incidence of a primary endpoint event was significantly lower with BA than with placebo (hazard ratio, HR = 0.87, 95% CI 0.79 – 0.96, p = 0.004). There were significantly better outcomes for BA on most other outcomes. But bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes and death from any cause.
Citation
Nissen SE et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Eng J Med 2023.
9th January 2023
Combining a patient’s coronary artery calcium score and their cystatin C level provides an incremental risk assessment of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death, in patients symptomatic with chest pain according to the findings of a study by Chinese researchers.
The World Health Organisation describes how cardiovascular diseases are the leading cause of global deaths, with an estimated 17.9 million lives lost each year. Consequently, risk stratification tools are required to inform on the subsequent management decisions for patients. One such measure to assist in cardiovascular disease risk stratification is the coronary artery calcium (CAC) score, which is a highly specific feature of coronary atherosclerosis. In fact, the extent of CAC has been shown to accurately predicts 15-year mortality in a large cohort of asymptomatic patients. Another potentially useful marker is Cystatin C (Cys-C) which is cysteine protease inhibitor produced at a constant rate by all nucleated cells and used as a sensitive marker of renal function. Moreover, Cys-C has been found to be a strong predictor of the risk of death and cardiovascular events in elderly patients.
Given the potential and independent value of these markers for predicting the risk of a cardiovascular event, the Chinese researchers wondered if there was an association between baseline CAC scores and Cys-C levels and both MACCEs and all-cause death in symptomatic, chest pain patients. They included all individuals presenting with symptomatic chest pain suggestive of CHD and who were referred for cardiac computed tomography (CT) by their cardiologists, which enabled assessment of the coronary artery calcium score. Based on the CT findings, patients were classified into two groups: those with CAC scores < 100 or CAC scores ≥ 100. Blood samples were taken to measure Cys-C levels and risk stratification of CAC score and Cys-C level were as follows: low risk (CAC score < 100 or Cys-C < 0.995 mg/L. and high risk (CAC score ≥ 100 or Cys-C ≥ 0.995 mg/L).
Coronary artery calcium and cysteine C levels and MACCEs
A total of 7140 participants with a median age of 63 years (64.9% male) were included and followed for a median of 1,106 days. During the period of follow-up, 305 MACCEs and 191 all-cause death events were observed.
A higher incidence of MACCEs were independently associated with CAC scores ≥ 100 (hazard ratio, HR = 1.46, 95% CI 1.15 – 1.85, p = 0.002) and where Cys-C levels were ≥ 0.995 mg/L (HR = 1.57, 95% CI 1.24 – 2.00, p < 0.001).
When categorised as high risk (i.e., CAC score ≥ 100 or Cys-C ≥ 0.995 mg/L), patients also had a significantly increased risk of MACCEs (HR = 2.33, 95% CI 1.64 – 3.29, p < 0.001). In addition, this high risk pattern was also associated with a significantly greater risk of all-cause mortality (HR = 2.85, 95% CI 1.79 – 4.55, p < 0.001). In fact, even in patients with CAC scores of < 100 but a Cys-C ≥ 0.995 mg/L, there was an increased risk of MACCEs (HR = 1.76, p = 0.003) and all-cause mortality (HR = 2.02, p = .007).
The authors concluded that the combined stratification of CAC score and Cys-C showed an incremental risk of MACCEs and all-cause death thus reflecting complementary prognostic value of these measures.
Citation
Luo F et al. Coronary artery calcium and cystatin C for risk stratification of MACCEs and all-cause death in symptomatic patients. Clin Cardiol 2022
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
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