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30th March 2023
An augmented, double wide-area circumferential catheter ablation (WACA) was no better than the standard single WACA for the prevention of atrial fibrillation (AF) recurrence in patients with paroxysmal AF, according to a randomised trial by Canadian researchers.
The proportion of patients affected by AF varies with age, is slightly more common in men and according to one European study, the prevalence ranged from 0.12 – 0.16% in those under 49 years of age to between 10 and 17% in those 80 years and older. While anti-arrhythmic drugs are effective, among patients with paroxysmal AF who have not tried such drugs, radio-frequency ablation results in a lower rate of recurrent atrial tachyarrhythmias after 2 years. Ectopic beats from the pulmonary veins (PV) often trigger AF and hence catheter ablation approaches have focused on PV isolation (PVI). However, PV electrical reconnection is frequently detected in subjects experiencing recurrent arrhythmia and relatively common, affecting affecting 58% of AF-free patients. Given this high level of AF recurrence, in the current study, the Canadian team wondered if an augmented double wide-area circumferential ablation, i.e., that included a wider area of atrial ablation, might be more effective than the standard, single WACA.
The researchers randomised patients 18 years and older with symptomatic paroxysmal AF, in a 1:1 fashion, to receive radio-frequency catheter ablation for pulmonary vein isolation with either a standard single WACA or an augmented double WACA. The primary outcome was atrial tachyarrhythmia (including atrial tachycardia, atrial flutter, or AF, lasting longer than 30 seconds) recurrence between 91 and 365 days post-ablation.
Augmented vs standard ablation outcomes
A total of 398 patients with a mean age of 61 years (32.9% female) were randomised to the single WACA or control arm (195) or the double WACA arm (203).
In total, 26.7% in the single WACA arm and 24.6% in the double WACA arm had recurrent AA at 1 year (relative risk, RR = 0.92 95% CI 0.66 – 1.29, p = 0.64). Furthermore, a similar proportion in both arms (10.3% vs 7.4%, single vs double WACA) underwent repeated catheter ablation (RR = 0.72, 95% CI 0.38 – 1.36).
There were also no differences in the level of serious adverse events (6.7% vs 6.9%, single vs double WACA).
The authors concluded that additional ablation by performing a double ablation lesion set did not result in improved freedom from recurrent AA compared with a standard single ablation set.
Citation
Nair GM et al. Standard vs Augmented Ablation of Paroxysmal Atrial Fibrillation for Reduction of Atrial Fibrillation Recurrence: The AWARE Randomized Clinical Trial. JAMA Cardiol 2023
Higher atmospheric ozone levels have been linked to a greater risk of a hospital admission for a range of adverse cardiovascular events according to the findings of a time-series analysis by Chinese researchers.
Although there are a number of clearly recognised risk factors for cardiovascular disease, recent studies generally support positive associations of exposure to chemical environmental stressors such as air pollution, with an increased risk for cardiovascular mortality and morbidity. Moreover, some evidence points to adverse effects associated with exposure to ozone and which appears to affect several pathways associated with cardiovascular disease. In addition, other work found a statistically significant association between short-term changes in ozone and mortality for 95 large US urban communities. However, while these data link ozone with mortality, much less is known about the association between the gas and cardiovascular morbidity and for which, hospital admissions, could serve as a useful proxy.
In the current study, Chinese researchers undertook a multi-city, time-series study to explore the associations of exposure to ambient ozone with daily hospital admissions for cardiovascular diseases over a two-year period. The city-specific daily concentrations of 8-hour maximum average ozone (O3) and 24-hour average of O3 were obtained, together with data on both fine particles (PM2.5), inhaled particles (PM10), and other gases such as sulphur and nitrogen dioxide and carbon monoxide.
Ozone pollution levels and risk of hospital admissions for cardiovascular disease
During the two-year period, there were 6,444,441 hospital admissions for adverse cardiovascular events in the 70 cities included in the study.
The results showed that a 10 μg/m3 increment in the two-day average daily, 8-hour maximum ozone concentrations, was associated with an increased risk for admission of 0.46% for coronary heart disease, 0.45% for angina pectoris, 0.75% for acute myocardial infarction and 0.41% for ischaemic stroke.
In fact, the researchers also calculated the excess risk attributable to higher ozone levels and different adverse cardiovascular events. For example, that there was a 6.52% excess risk of an acute myocardial infarction (AMI) for a high O3 concentrations (≥100 μg/m3) compared to lower levels of < 70 μg/m3, which is considered to be naturally occurring level that is not due to human activity. Furthermore, the AMI risks were also elevated by 3.28% when ozone levels were ≥ 70 μg/m3 and 2.35% for levels between 70 and 99 μg/m3.
The authors concluded that ambient ozone was associated with increased risk of hospital admission for cardiovascular events and which was higher as levels of the gas increased. They added that these data should prompt the need for greater control of high ozone pollution.
Citation
Jiang Y et al. Ozone pollution and hospital admissions for cardiovascular events. Eur Heart J 2023
29th March 2023
A prospective study by the Master@Heart Consortium has revealed that individuals who participate in lifelong endurance exercise, had a more unfavourable coronary plaque profile compared to healthy and active non-athletes.
It is generally accepted that undertaking regular physical activity such as walking, running, or swimming, induces favourable cardiovascular adaptations that prevent the development of coronary artery disease and reduces symptoms in patients with established cardiovascular disease. In fact, heavy physical exertion is known to trigger the onset of acute myocardial infarction, particularly in people who are habitually sedentary. Work with athletes however, has revealed how those with the highest exercise volumes more often have coronary artery calcification and atherosclerotic plaques, although these plaques are of a more benign composition.
In the current study, researchers set out to better understand the apparent paradox of greater coronary atherosclerosis among those undertaking endurance exercise yet fewer cardiovascular adverse events. They hypothesised that such individuals were likely to have a more favourable plaque composition, i.e., a reduced prevalence of non-calcified and mixed plaques, which could therefore explain the lower risk of cardiovascular events. The researchers studied lifelong endurance athletes, those who undertook endurance exercise but after the age of 30 and heathy, non-athletic individuals. The primary endpoint of the study was the prevalence of coronary plaques (calcified, mixed, and non-calcified) on computed tomography coronary angiography and these findings were adjusted for several cardiovascular risk factors.
Endurance exercise and coronary plaques
A total of 191 lifelong endurance athletes, 191 late-onset athletes and 176 healthy non-athletes, all male with a low cardiovascular risk profile, with a median age of 55 years were included.
Compared to healthy controls, lifelong endurance exercise was associated with the presence of ≥1 coronary plaque (odds ratio, OR = 1.86, 95% CI 1.17 – 2.94), ≥1 proximal plaque (OR = 1.96, 95% CI 1.24 – 3.11), ≥ 1 calcified plaques (OR = 1.58, 95% CI 1.01 – 2.49), ≥1 non-calcified proximal plaque (OR = 2.80, 95% CI 1.39 – 5.65) and ≥1 mixed plaque (OR =1.78, 95% CI 1.06 – 2.99).
Taken together, the authors concluded that participation in lifelong endurance exercise was not associated with a more favourable coronary plaque composition compared to those with a healthy lifestyle. They called for further research to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum.
Citation
De Bosscher R et al. Lifelong endurance exercise and its relation with coronary atherosclerosis. Eur Heart J 2023
28th March 2023
Two identical randomised, double-blind, placebo-controlled trials have shown that treatment with lebrikizumab alone in patients 12 years of age and older with moderate to severe atopic eczema led to a significant improvement in disease severity.
Although atopic eczema affects approximately 20% of children, the condition persists in around 7% of adults. Moreover, atopic eczema has a huge negative impact on the quality of life of sufferers and can even increase the risk of suicide ideation.
While it has been recognised in recent years that elevated levels of both interleukin-4 and interleukin-13 (IL-13) are implicated in the pathophysiology of the disease, it has been recently demonstrated that IL-13 is the primary up-regulated cytokine in skin biopsy samples from patients with atopic eczema. The monoclonal antibody, lebrikizumab exerts selective antagonism of IL-13 and which is sufficient to control atopic eczema and improve patient’s quality of life.
In fact, a recent, randomised, phase 3 trial demonstrated the benefit of lebrikizumab when combined with topical steroids in adolescents and adults with moderate to severe atopic eczema. However, whether lebrikizumab is effective alone is currently unclear and was the objective of the current study.
The current publication includes the findings from two identical phase 3 trials, ADvocate1 and ADvocate2, in which patients with moderate-to-severe atopic eczema, aged 12 years and older, were randomised 2:1 to either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks.
The primary outcome was based on an Investigator’s Global Assessment (IGA) score of 0 or 1 (indicating clear (0) or almost clear (1)), with a reduction of at least 2 points from baseline and was assessed after 16 weeks. The main secondary outcome was a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response), whereas other measures included assessments of itch and of itch interference with sleep.
Lebrikizumab and atopic eczema disease severity
In the first trial, 424 patients with a mean age of 35.5 years (51.8% female) were randomised to lebrikizumab (283) or placebo with similar demographics in the second trial.
In the first trial, the primary outcome occurred in 43.1% of those assigned to lebrikizumab group and in 12.7% placebo patients and this difference was statistically significant (p < 0.001). In addition, a significant difference was seen in the EASI-75 response (58.8% vs 16.2%, p < 0.001). Similar and significant findings were observed in the second trial.
In both trials, a significantly higher proportion of patients given lebrikizumab group also achieved reductions in pruritus and improvements in sleep loss scores.
The authors concluded that 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic eczema.
Citation
Silverberg JI et al. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis. N Eng J Med 2023.
24th March 2023
The use of neoadjuvant socazolimab with cisplatin chemotherapy appears to be a promising approach to the treatment of locally advanced oesophageal squamous cell carcinoma (OSCC) according to the findings of a phase 2, randomised trial by Chinese researchers.
Data from 2020 show that globally, there were 604,000 new cases of oesophageal cancer and which gave rise to 544,000 deaths. Survival from advanced oesophageal cancer is poor and following surgery, one study identified how 1-year survival was 29% and 5-year survival only 6%. Although programmed cell death protein 1 inhibitors such as pembrolizumab with chemotherapy significantly prolonged overall survival compared to placebo as a first-line treatment for advanced OSCC, much less is known about the value of programmed cell death ligand 1 (PD-L1) inhibitors for this cancer. Evidence to date, shows that one such PD-L1 inhibitor, socazolimab, demonstrated a durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer. But whether neoadjuvant socazolimab in combination with nab-paclitaxel and cisplatin chemotherapy is of benefit to patients with locally advanced OSCC is uncertain and was examined in the current randomised, phase 2 trial.
The Chinese team randomised participants 1:1 to socazolimab plus nab-paclitaxel and cisplatin or the same regimen without PD-L1 inhibitor and which formed the placebo arm. The primary endpoint was a major pathological response (MPR) whereas the secondary endpoints were a pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety.
Neoadjuvant socazolimab associated outcomes
A total of 64 patients with a median age of 62 years (79.7% male) were enrolled and equally randomised between the two groups.
There were 29 patients in each arm who subsequently underwent surgery. The MPR rate was 69% in the socazolimab group and 62.1% in the placebo arm although this difference was not significant (p = 0.509). Similarly, whilst the pCR rate was higher with socazolimab (41.4%) than in the placebo group (27.6%), again this was not significant (p = 0.311).
However, there was a significantly higher incidence rate of ypT0 for socazolimab (37.9%) compared to placebo (3.5%, p = 0.001) and the rate of T down-staging was also higher (65.5% vs 62.1%). At the time of publication, the EFS and OS outcomes were not mature.
The authors concluded that neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T down-staging in locally advanced OSCC and without increasing surgical complication rates.
Citation
Li Y et al. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC. BMC Med 2023
23rd March 2023
Increased plasma caffeine levels may help reduce body mass index as well as fat mass and the risk of developing type 2 diabetes.
A higher plasma caffeine (PC) concentration may produce a lower body mass index (BMI) as well as reducing body fat and the risk of type 2 diabetes, according to the findings of a genetic study by Swedish and UK researchers.
Caffeinated beverages such as coffee, tea and soda drinks are widely consumed across the world. Given that caffeine has a known thermogenic effect and which might help lower body weight, there is the potential that caffeine-containing beverages may have a role in lowering the risk of disease related to adiposity.
In fact, there is already some data to suggest that caffeine-containing drinks such as coffee are inversely associated with risk of type 2 diabetes.
It is recognised the caffeine metabolism occurs mainly in the liver by the cytochrome P450 isoform 1A2 (CYP1A2) and how genetic variations near two genes, CYP1A2 and AHR (which regulates the expression of CYP1A2) are linked to PC concentrations. In fact, individuals with genetic variants linked to slower caffeine metabolism, although generally consuming less caffeine-related beverages, do have higher plasma caffeine levels.
Using Mendelian randomisation, researchers sought to investigate the effects of long-term exposure to higher plasma caffeine concentrations on adiposity, type 2 diabetes and major cardiovascular diseases.
They used data from a genome-wide association meta-analysis of 9876 individuals of European ancestry from six population-based studies and which identified genome-wide significant associations of single nucleotide polymorphisms near CYP1A2 and AHR loci with plasma caffeine concentrations.
Researchers identified that genetically predicted higher PC concentrations in those carrying the two gene variants, were in fact, associated with a lower BMI, with one standard deviation (SD) increase in predicted PC equal to about 4.8 kg/m2 in BMI (p < 0.001).
Similarly, for whole-body fat mass, one SD increase in PC equated to a reduction of about 9.5 kg (p < 0.001), although interestingly, there was no association with fat-free body mass (p= 0.17).
Again among genetically predicted higher PC concentrations, there were also significant and lower associations with the risk of developing type 2 diabetes, with the combined odds ratio of type 2 diabetes per SD increase in PC concentration being 0.81 (95% CI 0.74 – 0.89, p < 0.001).
The authors concluded that while their study found evidence of a causal association between a higher plasma caffeine concentration and lower levels of adiposity and a reduced risk of type 2 diabetes, they called for randomised trials to further examine the role of caffeine in reducing the risk of obesity and diabetes.
Citation
Larrson SC et al. Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study. BMJ 2023.
Ide-cel therapy for with relapsed and refractory multiple myeloma who had received between two to four previous regimens, significantly prolonged progression-free survival compared to a standard-regimen group, according to a recent and international, open-label, phase 3 trial.
A 2020 study found that the global incidence of multiple myeloma was 160,000 and which led to l106,000 deaths. While autologous stem cell transplantation has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades, nearly all patients will eventually experience disease relapse. Although the introduction of CD38-targeting monoclonal antibodies (MCA), daratumumab and isatuximab, have significantly impacted the management of patients with multiple myeloma, patients who are refractory to CD38 MCA have a poor prognosis. In an earlier, phase 2 trial, ide-cel induced responses in the majority of heavily pre-reated patients with refractory and relapsed multiple myeloma.
In the current study, researchers undertook a phase 3 trial of ide-cel in adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab). Individuals were randomised 2:1 to ide-cel or one of five standard regimens. The primary end point was set as progression-free survival, whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) underwent randomisation, with 254 assigned to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease.
At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, compared to 4.4 months in the standard-regimen group (Hazard ratio, HR for disease progression or death = 0.49, 95% CI 0.38 – 0.65, p < 0.001). A response was seen in a significantly higher proportion of patients who received ide-cel compared to the standard regimen (71% vs 42%, p < 0.001) and a complete response occurred in 39% and 5% respectively. At the time of publication, overall survival data were immature.
Adverse events of grade 3 or 4 occurred more frequently in the ide-cel group (93% vs 75%) and cytokine release syndrome occurred in 88% of the ide-cel group although this was largely of grade 1 or 2 severity. Neurotoxic effects occurred in 15% of the ide-cel group, with 3% having an event of grade 3 or higher.
The authors concluded that ide-cel treatment gave rise to significantly prolonged progression-free survival and an improved response compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma.
Citation
Rodrigeuz-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Eng J Med 2023
More aggressive end-of-life care (EOL) has been found to be more prevalent among patients residing within nursing homes in comparison to their community dwelling counterparts according to an analysis by US researchers.
Aggressive or poor quality EOL cancer care measures have been defined to include starting new anticancer therapies or continuation of ongoing treatments very near death, a high number of emergency room visits, inpatient hospital admissions, or intensive care unit, in the days near the end of life. In contrast, better EOL measures include, early palliative care which places an emphasise on managing symptoms, strengthening coping, and cultivating illness understanding and prognostic awareness in a responsive and time-sensitive manner. In fact, it has been shown that early palliative care led to significant improvements in both quality of life and mood, less aggressive EOL care and longer survival.
In the current study, researchers wanted to compare the level of aggressive EOL care care experienced by nursing home residents in comparison to that received by those in community dwellings. The team used a national cancer surveillance database linked to Medicare (a US insurance database) to examine older patients with several forms of cancer. They used claims data to identify the above mentioned markers of aggressive EOL e.g., cancer-directed treatment (such as surgery, radiotherapy or chemotherapy), more than 1 emergency department visit etc.
Aggressive end-of-life care in nursing home residents with cancer
A total of 146,329 patients with a mean age of 78.2 years (51.9% male) were included in the analysis.
Overall, aggressive EOL care was more common among nursing home compared to community dwelling residents (63.6% vs 58.3%, adjusted odds ratio, aOR = 1.04, 95% CI 1.02 – 1.07). This included a higher odds of more than 1 hospital admission (aOR = 1.06) and a 61% higher odds of death in hospital (aOR = 1.61, 95% CI 1.57 – 1.65). In contrast, nursing home residents were less likely to receive cancer-directed treatment in the last 30 days of life (aOR = 0.57) and of enrolling in a hospice in the last 3 days of life (aOR = 0.89).
The authors concluded by calling for multilevel interventions to decrease aggressive EOL care that target the main factors associated with its prevalence, including hospital admissions in the last 30 days of life and in-hospital death.
Citation
Koroukian SM et al. Incidence of Aggressive End-of-Life Care Among Older Adults With Metastatic Cancer Living in Nursing Homes and Community Settings. JAMA Netw Open 2023
21st March 2023
UK researchers report that the findings of a 15-year follow-up trial of different interventions, showed that in men with an elevated prostate specific antigen test, prostate cancer mortality was low, irrespective of the assigned treatment intervention.
In 2020, there were more than 1.4 million new global cases of prostate cancer and and over 375,000 associated deaths, making it the second most common cancer in men. In the UK in 1999, the Prostate Testing for Cancer and Treatment (ProtecT) trial began in which men aged between 50 and 69 years of age received a prostate-specific antigen test. In cases where the test gave a value of 3·0 μg/L or higher, men were offered a biopsy and where localised prostate cancer was diagnosed, they were enrolled in a trial to evaluate the effectiveness of three different treatment interventions: active monitoring; prostatectomy or radiotherapy. In the current study, researchers have reported upon the findings after 15 years of follow-up, in which they were able to evaluate the effectiveness of the three different interventions. The primary outcome of the study was death from prostate cancer, as adjudicated by an independent cause-of-death committee
Prostate cancer mortality on follow-up
In total, 545 men were randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to radiotherapy. Follow-up data was available for 98% of the entire cohort.
In total, there were 45 deaths due to prostate cancer. However, prostate cancer mortality was broadly similar across the three groups: 3.1% in the active-monitoring group, 2.2% in the prostatectomy group and 2.9% in the radiotherapy group and this difference was not significant (p = 0.53 for group comparison). However, while the development of metastases was more common in the active monitoring group (9.4%), it was similar in the prostatectomy (4.7%) and radiotherapy groups (5.0%).
The authors concluded that given how prostate cancer-specific mortality was low regardless of the treatment assigned, the choice of therapy should involve weighing trade-offs between benefits and harms associated with different treatments options for men with localised prostate cancer.
Citation
Hamdy FC et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Eng J Med 2023
Levels of the inflammatory marker, high-sensitivity C-reactive protein (CRP) serve as a better predictor for the risk of future cardiovascular events and death in comparison to LDL cholesterol (LDLC), according to an analysis of data from three, large, cardiovascular trials by US researchers.
It has been recognised for many years that high-sensitivity CRP predicts the risk of future myocardial infarction and stroke in healthy men and this relationship also holds true for women. In addition, while hyperlipidaemia is a risk factor for cardiovascular disease, it is also known that addition of drugs with an anti-inflammatory effect, such as colchicine to statin therapy, also significantly reduces the risk of cardiovascular events in patients with chronic cardiac disease.
Given how both inflammation and elevated LDL cholesterol are important cardiovascular risk factors, because patients prescribed statins can still experience an adverse cardiovascular event, an important question is how to deal with this residual risk. In other words, should clinicians treat with additional lipid lowering therapy (to minimise the residual cholesterol risk) or use an anti-inflammatory agent (to lower the residual inflammatory risk)?
Using data from three large statin trials (PROMINENT, REDUCE-IT and STRENGTH) the US researchers compared the highest and lowest quartiles of high-sensitivity CRP and LDLC , to determine the best predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death.
High-sensitivity CRP and cardiovascular outcomes
A total of 31,245 patients were included and participants aged between 64 and 65 with the proportion of females ranging from 28 to 35%.
Combining data from the three trials showed that the presence of residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (adjusted Hazard Ratio, aHR = 1.31, 95% CI 1.20 – 1.43, p < 0.0001) for the highest vs the lowest high-sensitivity CRP quartiles. This relationship was also true for cardiovascular mortality (aHR = 2.68, p < 0.0001) and all-cause mortality (aHR = 2.42, p < 0.0001).
However, when comparing the highest to lowest quartiles of LDL cholesterol, the relationship was non-significant for major adverse cardiovascular events (aHR = 1.07, p = 0.11) but was significant, albeit smaller, compared to high-sensitivity CRP, for cardiovascular death (aHR = 1.27, p = 0.0086) and all-cause mortality (aHR = 1.16, p = 0.025).
The authors concluded that in those already prescribed a statin, high-sensitivity CRP proved to be a stronger marker for the prediction of future cardiovascular events and death compared to LDL cholesterol levels. They added that their findings suggested that both aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
Citation
Ridker PM et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023
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