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Take a look at a selection of our recent media coverage:
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.
Treatment with fluvoxamine (FA) in high-risk COVID-19 patients reduces the need for hospitalisation. This action likely arises because of an anti-inflammatory and anti-viral effect of the drug. In addition, inhaled budesonide improves the time to recovery and possibly hospital admissions or death in patients with COVID-19. As both drugs appear to be effective, whether fluvoxamine and inhaled budesonide together might offer additional benefit is unclear.
In the current trial, researchers randomised high-risk, ambulatory patients 1:1 to oral FA plus inhaled budesonide or matching placebos. Fluvoxamine 100 mg twice daily and budesonide 800 mcg twice daily were given for 10 days. The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalisation, and or suspected complications due to progression of COVID-19 within 28 days of randomisation.
Fluvoxamine and Inhaled budesonide and COVID-19 outcomes
The study had 1476 participants with 738 given FA and inhaled budesonide. Symptoms were present for a median of three days before randomisation. The median age was 51 years with women accounting for 60.8% of the total. Overall, 42% of participants had received 3 doses of a COVID-19 vaccine.
The proportion of patients in an emergency setting for more than 6 hours or hospitalised due to COVID-19 was lower in the treatment group than the placebo group (relative risk, RR = 0.50, 95% CI 0.25 – 0.92). These results gave a number needed to treat of 53.
The findings suggest that oral fluvoxamine plus inhaled budesonide in high-risk outpatients with early COVID-19 reduces the incidence of severe disease requiring advanced care.
Citation
Reis G et al. Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial. Ann Intern Med 2023
21st April 2023
Patients with biliary tract cancers often present at a late stage when curative surgery is not possible. Current treatment for advanced biliary cancer involves chemotherapy with cisplatin plus gemcitabine and which improves survival. Other work suggests that cisplatin treatment together with PD-1/PD-L1 blockade could increase the clinical response, particularly in lung cancer. In addition, treating advanced biliary cancer with pembrolizumab alone provides a small, but durable anti-tumour activity. However, one study with the PD-L1 inhibitor, durvalumab in advanced biliary tract cancer with cisplatin chemotherapy, showed good efficacy and an acceptable safety profile.
Researchers in the current study, sought to assess whether pembrolizumab plus cisplatin and gemcitabine chemotherapy might improve overall survival in advanced biliary tract cancer. Their randomised, placebo-controlled trial involved adult patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer. Adults were randomised 1:1 to pembrolizumab plus chemotherapy or placebo and chemotherapy. The primary outcome was overall survival whereas the secondary outcome explored safety.
Pembrolizumab plus chemotherapy and overall survival
There were 1069 participants of whom, 533 had pembrolizumab followed for 25.6 months. Median overall survival was 12·7 months with pembrolizumab plus chemotherapy and 10·9 months in the placebo group (hazard ratio, HR = 0·83, 95% CI 0·72 – 0·95, p = 0.0034).
A similar proportion of pembrolizumab and placebo patients had treatment-related adverse events with a maximum grade of 3 to 4 (70% vs 69%). However, death due to adverse events was slightly less with pembrolizumab (6% vs 9%).
Citation
Kelly KR et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023
Gepotidacin is a novel antibiotic and found to be non-inferior to nitrofurantoin in women with uncomplicated urinary tract infections.
Urinary tract infections (UTIs) have a lifetime incidence of 50-60% in adult women. While commonly treated with antibiotics, UTIs often recur in 16% of women. An uncomplicated UTI is mainly due to Escherichia coli but recent data indicates antimicrobial resistance is on the increase.
GSK’s novel and investigational, first-in-class, antibiotic, gepotidacin (GD) was non-inferior to nitrofurantoin in two phase III trials in women with an uncomplicated UTI (uUTI).
The drug inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Consequently, mutations in both enzymes would be needed for resistance to occur. While GD appears effective in uncomplicated UTI’s according to a phase 2 trial, there is an absence of phase 3 studies.
GSK describes the findings from two near identical, randomised, double-blind studies, EAGLE-2 and EAGLE-3. Both involved women and adolescents with an uUTI and had nitrofurantoin (100mg twice daily) as an active comparator. The primary efficacy endpoint was therapeutic success (TS) which was a combination of clinical and microbiological success. GD was given at a dose of 1,500 mg twice daily for 5 days. Participant assessment took place 10-13 days after initiation of treatment.
In EAGLE-2 the TC was 50.6% with gepotidacin and 47% with nitrofurantoin. In EAGLE-3, a higher proportion of participants receiving gepotidacin achieved a TS (58.5% vs 43.6%). Furthermore, across both trials, 94% of gepotidacin patients did not receive an additional antibiotic for their uUTI through to the follow-up visit on day 28.
The clinical cure rates were similar for gepotidacin and nitrofurantoin in both trials. However, the microbiological cure rate was higher with gepotidacin in EAGLE-3 (72.2% vs 57.2%).
The safety and tolerability profile of gepotidacin in the EAGLE-2 and EAGLE-3 phase III trials was consistent with previous trials of gepotidacin.
GSK expects to submit data to the FDA in the second quarter of 2023.
20th April 2023
Nivolumab plus ipilimumab as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (SCC), offers no clinical benefit over nivolumab alone.
Head and neck squamous cell carcinomas (HNSCC) occur in the mouth, pharynx and larynx. Moreover, HNSCC is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths reported in 2018. Prognosis in recurrent or metastatic HNSCC is generally poor with a median survival of 6 to 15 months. Nivolumab and ipilimumab are immune checkpoint inhibitors and nivolumab plus ipilimumab benefits those with advanced melanoma and renal cell carcinoma. Nevertheless, in combination, there was no benefit compared to EXTREME in those with HNSCC.
How each treatment compares alone and in combination for HNSCC is uncertain and was the subject of the current trial. Researchers randomised patients to nivolumab plus ipilimumab compared to nivolumab monotherapy as a first-line treatment for patients with platinum-refractory (PR) or platinum-eligible recurrent (PER) or metastatic HNSCC. The aim was to assess whether combination therapy improved the objective response rate (ORR) compared to nivolumab alone. The trial included adult patients with histologically confirmed recurrent or metastatic HNSCC not amenable to curative therapy. The trial randomised individuals 2:1 (combination vs monotherapy) and the primary endpoint was the ORR.
Nivolumab plus ipilimumab outcomes in HNSCC
The study recruited 425 patients, 241 who were PR and the remainder PER. Among the PR group, the ORR was 13.2% with the combination and 18.3% with nivolumab alone. For PER patients, the ORR was 20.3% with nivolumab plus ipilimumab vs 29.5% with nivolumab monotherapy.
Rates of grade 3 or 4 treatment-related adverse events were similar in both the PR and PER groups.
In their conclusion, the authors commented that the trial did not meet its primary end point of an ORR benefit with first-line nivolumab and ipilimumab vs nivolumab alone.
Citation
Harrington KJ et al. Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and NeckThe Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 2023
19th April 2023
Major depressive disorder affects around 14.3% of patients with cancer. Advances in psycho-oncology show that psychotropic drugs are effective for cancer patients. There is some data suggesting that psilocybin therapy for cancer patients improves depressed mood and anxiety. Whether this effect occurs in cancer patients with a diagnosis of major depressive disorder (MDD) is not clear.
In the current study, researchers gave adult cancer patients and a diagnosis of MDD, a single 25 mg dose of psilocybin. Individuals were divided into cohorts and had a single group preparation session and two group integration sessions. Therapeutic care was provided throughout the study using the 1:1 model of psychological support. Researchers assessed the safety of psilocybin therapy and the effect on depression with the Montgomery Asberg Depression Rating Scale (MADRS).
Psilocybin therapy outcomes
The study had 30 patients, all with MDD and assessments carried out after 8 weeks. The study observed a robust and significant decrease in MADRS score (p < 0.0001) at week 8 with a ≥ 50% decrease in the MADRS score in 24 patients at week 8. Half of the group had complete remission of depression symptoms (a MADRS score < 10) after 7 days which was still present at week 8.
Self-reported depressive symptom scores were 48% lower at week 8. The Maudsley visual analogue scale was 53% lower at week 8. There were no treated-related serious adverse effects reported.
Citation
Agrawal M et al. Assessment of Psilocybin Therapy for Patients With Cancer and Major Depression Disorder. JAMA Oncol 2023
ChatGPT shows some promise as an AI-assisted decision-support tool, particularly for questions that are relatively straightforward. However, it performed less well when providing answers to more complicated case vignettes.
Chat Generative Pre-trained Transformer (ChatGPT) is an interactive AI model. The system follows instructions and provides a detailed response. Furthermore, the system has the potential to assist with medical education and even clinical decision-making. In the current study, researchers set out to assess ChatGPT’s performance at answering cardiovascular questions and in providing suggestions in case vignettes. For the questions, the reference standard was the medical expert who developed the questions. As for the 20 vignettes, the standard was the attending physician or consulted expert and the advice provided was checked with reference to clinical guidelines. The straightforward cardiovascular questions, related to several topics including acute coronary syndrome, atrial fibrillation and cardiovascular risk management. Vignettes involved symptoms that were potentially due to a cardiac problem (e.g., chest pain, dyspnoea) or required a diagnostic/treatment plan.
ChatGPT performance
Using 50 multiple choice cardiovascular questions, ChatGPT was correct in 74% (37/50) of cases. Scoring varied from 80% (for coronary artery disease) to 60% (cardiovascular risk management). For the vignettes, when seeking primary care advice, ChatGPT correctly answered questions in 90% of cases. When asked more complicated questions, the system was correct in only 50% of cases.
The authors felt that ChatGPT performed well with straightforward, low complexity questions. However, they felt more work was needed to fully evaluate the system’s potential.
Citation
Harskamp RE et al. Performance of ChatGPT as an AI-assisted decision support tool in medicine: a proof-of-concept study for interpreting symptoms and management of common cardiac conditions (AMSTELHEART-2). MedRxiv 2023
18th April 2023
GD2-CART01 has been found in a phase 1-2 clinical trial to be both safe and effective for children with heavily pretreated neuroblastoma.
GD2-CART01 is a safe and feasible therapy for children with relapsed or refractory (R/R) high-risk neuroblastoma according to a phase 1 – 2 trial by Italian researchers.
Neuroblastoma is responsible for 11% of paediatric cancer deaths and these cancer cells express high levels of disialoganglioside GD2.
Moreover, targeting this protein, while a valid and safe strategy, requires further modification to promote CAR-T cell longevity.
In the current trial, researchers used a third-generation CAR-T cell therapy in patients with R/R high-risk neuroblastoma. The therapy included the inducible caspase 9 suicide gene, designed to kill cells in the presence of dangerous toxic effects.
The trial enrolled 27 children with heavily pretreated neuroblastoma.
The overall response rate was 63%; 9 children had a complete response and 8 a partial response. The three-year overall survival and event-free survival were 60% and 36%, respectively.
Overall, after infusion 33% of patients (eight patients) had a complete response or maintained a complete response (one patient).
Cytokine release syndrome occurred in 74% of patients but was of mild severity in the majority (95%). The suicide gene activation occurred in only one patient. GD2-targeted CAR T cells were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion.
The authors concluded that GD2-CART01 may induce sustained eradication of disease in a proportion of patients with R/R neuroblastoma.
Citation
Del Bufalo F et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Eng J Med 2023.
14th April 2023
German researchers have observed significant reduction in blood pressure (BP) following a moderate dietary reduction of salt intake in patients with primary aldosteronism.
The link between intake of sodium (in the form of salt) and hypertension is widely recognised such that reducing dietary intake not only lowers BP but is also associated with a reduction in morbidity and mortality from cardiovascular diseases. The presence of primary aldosteronism (PA) is a common cause of secondary hypertension and associated with excess cardiovascular morbidities. In fact, having PA is associated with more end-organ damage and an excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation compared to primary hypertension. An unfortunate consequence for patients with PA is a decreased taste sensitivity for salt, favouring high sodium consumption. Given this relationship, the German researchers wondered if a moderate dietary reduction in salt in patients with PA could reduce blood pressure.
Researchers identified a group of PA patients already under treatment with anti-hypertensives from a national registry. Individuals were recruited for a dietary salt restriction over 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion.
Moderate dietary salt reduction and blood pressure
A total of 41 participants with a mean age of 50 years (52.2% female) were included in the analysis.
At the end of the study, dietary salt intake which was originally estimated from urinary excretion to be 9.1 g/day, fell to 5.2 g/day (p < 0.001). In addition, systolic blood pressure reduced from 130 at baseline to to 121 mm Hg (p < 0.001) and diastolic blood pressure from 84 to 81 mm Hg (p = 0.003).
In addition, participants noted a significant weight loss of 1.4 kg (p < 0.001), largely due to water loss and an improvement in pulse pressure, an indicator of arterial stiffness (p < 0.001). Interestingly, there were also improvements in depression scores (p = 0.008).
The authors concluded that moderate dietary salt restriction intake in patients with PA substantially reduces BP and depressive symptoms.
Citation
Schneider H et al. Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial. J Intern Med 2023
Measuring serum endocan levels could be a useful way to determine the extent of ulcerative colitis in patients according to a study by Turkish researchers.
Ulcerative colitis (UC) is an inflammatory bowel disease in which there is mucosal inflammation. The British Society of Gastroenterology have provided guidance on the classification of the extent of disease. Where inflammation starts in the rectum and extends to involve the whole colon it is termed pancolitis. If the inflammation extends from the distal to the splenic flexure, it is known as left-distal UC. Endocan (EC) is a circulating proteoglycan, that has involvement in immunity, inflammation, and endothelial function. It could serve as a biomarker for inflammation but its potential for evaluation and monitoring in UC remains uncertain and was the aim of the current study.
The researchers recruited UC patients diagnosed clinically and endoscopically. In addition, none of those in the UC group were using any treatments. The team also included a control group, without systemic disease or use anti-inflammatory drugs. All patients had blood samples taken for measurement of CRP (C-reactive protein) and EC.
Endocan measurement and extent of ulcerative colitis
The study had 65 patients in total, 35 of whom had UC. There was a significant difference in CPR and EC levels between the UC and control patients (both p < 0.001). Significant differences were also present with endocan and CPR for the pancolitis and left-distal UC groups (p < 0.001). Furthermore, CPR and endocan levels showed a significant correlation (r2 = 0.54) in those with pancolitis. A cut-off value of endocan of 95.2 pg/ml could be used for the detection of diffuse colitis (p < 0.001).
Citation
Albayrak B et al. A novel inflammatory marker for extensive ulcerative colitis; Endocan. BMC Gastroenterol 2023
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