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2nd December 2022
Consumption of honey appears to improve cardiometabolic risk factors through favourable changes in glycaemic control and lipid levels according to a systematic review and meta-analysis by Canadian researchers.
Honey is a natural product formed from the nectar of flowers by honeybees and has a long history of use for both nutritional needs and its medicinal properties. Nevertheless, honey contains free sugars, and the World Health Organisation has called for adults and children to reduce their daily intake of free sugars to less than 10% of their total energy intake and have included honey as a source of free sugars. Despite the presence of free sugars, honey also contains flavonoids and phenolic acids which have a positive impact on health, through antioxidant and anti-inflammatory properties. These effects had led to the widespread use for the treatment of eye diseases, bronchial asthma, throat infections, tuberculosis, thirst, hiccups, fatigue, dizziness, hepatitis, and wounds, as well as being taken as a supplement.
Although excessive intake of free sugars is linked to higher rates of obesity, the cardiometabolic effects of honey intake have not been systematically explored and was the subject of the present study by the Canadian researchers. The team searched for both randomised and non-randomised controlled feeding studies that examined the effect of oral honey intake on adiposity, glycaemic control and lipid levels. The researchers measured the mean differences (MD) between participants assigned to honey and control arms.
Honey intake and cardiometabolic risk
A total of 18 controlled feeding trials in 1105 participants with a median age of 41.2 years (54% female) and which considered 33 different comparisons were identified and included in the analysis.
The researchers identified a significant reduction in total cholesterol (MD = -0.18 mmol/L, p = 0.011), LDL cholesterol (MD = -0.30 mmol/L, p = 0.0024) and an increase in HDL cholesterol (MD = 0.07 mmol/L, p < 0.001).
In addition, oral honey reduced fasting glucose (MD = -0.20 mmol/L, p = 0.017). However, there was also an increase of interleukin-6 (IL-6) levels (MD = 0.37 pg/ml, p = 0.046) and tumour necrosis factor alpha (MD = 1.44 pg/ml, p = 0.019). The reasons for an increase in IL-6 levels is unclear but some data points to how release of the cytokine from the contracting skeletal muscle is perhaps one of the molecular signals promoting the beneficial effects of exercise.
There were also differences based on the floral source and by processing, with robinia, clover and raw honey more beneficial than the processed form.
Summarising the benefits, the authors state that a median intake of 40 g of honey for 8 weeks appears to be sufficient to deliver the cardiometabolic benefits. Nevertheless, despite these positive findings, the authors did identify that much of the evidence was of low certainty and called for more studies focusing on the floral source and the processing of honey to increase the certainty of this evidence.
Citation
Ahmed A et al. Effect of honey on cardiometabolic risk factors: a systematic review and meta-analysis. Nutr Rev 2022
HDL cholesterol is generally considered to be protective against coronary heart disease (CHD) but a recent analysis that included both Black and White patients suggests that higher levels offer no protection in either race with an elevated CHD risk due to low levels only relevant for White individuals.
Globally, coronary heart diseases were estimated to kill 17.9 million people in 2019, which represents 32% of all global deaths, with 85% of deaths due to heart attack and stroke. Since the early 1970’s, there has been a well-established and inverse relationship between plasma high-density lipoprotein (HDL) cholesterol and CHD risk. However, whether this relationship remains for different ethnicities is uncertain. It is known for example, that after accounting for social determinants of health and other risk factors, Black patients have a similar risk of a fatal CHD to White patients, but that the risk for a nonfatal CHD is consistently lower for Black people. The underlying reasons behind this difference are unclear and have been further confounded by the somewhat paradoxical observation that low levels of HDL cholesterol are associated with a reduced risk of incident CHD in black participants.
In trying to better understand the relationship between HDL cholesterol and incident CHD, a team of US researchers turned to data collected in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, designed to examine underlying racial and regional differences in stroke and mortality. The researchers selected a cohort without baseline CHD and for whom a wide range of clinical and demographic factors were collected. The cohort was followed over time and the number of incident CHD (i.e., definite or probable nonfatal myocardial infarction or CHD death) were recorded.
HDL cholesterol and CHD events in Black and White patients
A total of 23,901 participants with a mean age of 64.1 years (58.3% female) and of whom, 57.7% self-identified as White were included in the analysis and followed for a median of 10.7 years. During the follow-up there were 1,615 CHD events of which 41.1% occurred in Black participants and 45.5% in women.
When analysing the relationship between CHD events and plasma LDL cholesterol in fully adjusted models, for every 1 standard deviation increase in LDL levels, there was a modest increase in CHD risk (Hazard ratio, HR = 1.10, 95% CI 1.05 – 1.17). Similarly, for triglyceride levels, there was also a modest increase in CHD risk (HR = 1.05, 95% CI 1.01 – 1.10). However, in fully adjusted models, there was a non-significant association between HDL cholesterol (HDL-C) levels and CHD risk (HR = 0.95, 95% CI 0.89 – 1.02).
But when researchers examined the relationship between HDL-C and CHD risk stratified by race, they found something unusual. As might be expected based on the currently known relationship, a low HDL-C level was associated with an increased risk of CHD, but this was only significant for White patients (HR = 1.22, 95% CI 1.05 – 1.43). Among Black patients the relationship was not significant (HR = 0.94, 95% CI 0.78 – 1.14). Furthermore, a high HDL-C level was not protective in either White (HR = 0.96, 95% CI 0.79 – 1.16) or Black (HR = 0.91, 95% CI 0.74 – 1.12) patients.
Based on these findings, the authors concluded that current high-density lipoprotein cholesterol–based risk calculations could lead to inaccurate risk assessment in Black adults.
Citation
Zakai NA et al. Race-Dependent Association of High-Density Lipoprotein Cholesterol Levels With Incident Coronary Artery Disease. J Am Coll Cardiol 2022
1st December 2022
A fentanyl vaccine administered to male and female rats produced significant levels of anti-fentanyl antibodies that were highly effective at neutralising the effects of the drug and reduced brain levels after administration according to the results of a study by researchers based at the University of Houston, US.
Opioid use disorder (OUD) can be defined as the chronic use of opioids that causes clinically significant distress or impairment. Deaths due to drug overdose are on the rise with data from the US showing that 96,779 drug overdose deaths were reported between March 2020 and March 2021 and that in January 2021, drug overdose deaths exceeded homicides by 306.7%. One particular opiate, fentanyl, has seen an increase in illicit use in recent years. In fact, since 2013, illicitly manufactured fentanyl and its analogues appeared on the streets and because the drug is so potent, only small amounts are needed to produce a pharmacological effect but there is a narrow margin between the safe and toxic doses. Although OUD can be managed with methadone, buprenorphine and naltrexone, relapse is both common with one study of 109 patients admitted to a residential addiction treatment service for detoxification, finding that an initial relapse occurred within one week in 59% of cases.
The use of immunopharmacotherapy, i.e., the use highly specific antibodies, raised passively or actively, to sequester drugs of interest in the bloodstream, has attracted much interest in recent years as a means of treating OUD. The principle is simple: a conjugate vaccine is designed to elicit an immune response to the abused opioid (e.g., heroin), producing antibodies that bind with heroin in the periphery and prevent it from crossing the blood brain barrier and activating reward circuit signalling. Previous work has shown that it is possible for a fentanyl vaccine to provide a robust blockade of fentanyl-induced analgesia and central nervous system penetration, and which strongly correlates with anti-Fentanyl immunoglobulin A. In the present study, the US researchers expanded upon earlier work to examine the effectiveness of a fentanyl vaccine.
Fentanyl vaccine effectiveness
Using both male and female rats, researchers found that the antibodies generated by vaccination increased over time. When fentanyl was administered 8 to 12 weeks after being vaccinated, the rats showed no response to fentanyl-induced analgesia compared to unvaccinated controls. Furthermore, significantly higher levels of the drug were detected in unvaccinated compared to vaccinated animals.
In other parts of their study, researchers found that vaccination prevented the decrease in physiological measures (e.g., oxygen saturation, heart rate) and a reduction in overall activity following administration of fentanyl. A further and valuable aspect of the study was how the fentanyl vaccine generated antibodies, were highly specific and only cross-reacted to fentanyl and sufentanil but not to morphine, methadone, buprenorphine or oxycodone. In other words, a vaccinated individual could still achieve pain relief if given other opioids.
Although these findings are preliminary, the authors concluded that their data support further clinical development of this vaccine to address OUD in humans.
Citation
Haile CN et al. An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats. Pharmaceutics 2022.
29th November 2022
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the approval of Dupixent (dupilumab) in the EU to treat adults with moderate-to-severe prurigo nodularis who are candidates for systemic therapy.
Prurigo nodularis (PN) is a skin disease that causes hard, pruritic nodules to form on the skin. The pruritus can be intense, causing people to scratch themselves to the point of bleeding or pain. It is categorised as a rare disease and one UK-based study estimated a prevalence of 3·27 patients per 10 000 population and the condition has a negative effect on patients’ quality of life.
Dupixent is a fully human monoclonal antibody that inhibits the signalling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways. The drug currently has several indications including the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years, as add-on maintenance treatment for severe asthma and as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyposis.
Dupixent clinical data
The efficacy data for Dupixent which led to the CHMP approval came from two randomised trials, PRIME and PRIME 2. In both PRIME and PRIME 2 the primary objective was to demonstrate the efficacy of dupilumab on itch response in patients with prurigo nodularis and which was inadequately controlled on topical prescription therapy or when those therapies are not advisable.
The PRIME trial included adults with PN and at least 20 nodules and severe itch who were randomly assigned to 300 mg dupilumab subcutaneously after a 600-mg loading dose or to matching placebo, every two weeks for 24 weeks. The primary endpoint was the number of patients who experienced at least a 4-point reduction in the Worst-Itch Numerical Rating Scale (WI-NRS) score from baseline to week 24.
Overall, 60% of dupixent patients achieved the primary endpoint, compared to placebo patients (18%, p < 0.0001). In the second trial, PRIME 2, the primary endpoint was the proportion who experienced a clinically meaningful reduction in itch from baseline at week 12. This occurred for 37% of Dupixent patients compared to 22% of placebo patients (p = 0.0216).
Sanofi and Regeneron (a partnering biotechnology company) are studying the use of dupilumab in a broad range of diseases including paediatric eosinophilic oesophagitis, hand and foot atopic dermatitis, chronic inducible urticaria-cold, chronic spontaneous urticaria and chronic obstructive pulmonary disease with evidence of type 2 inflammation.
Patients aged 45 years and older prescribed anti-diabetic medication have an increased risk of developing multiple sclerosis compared to younger patients, but in the younger age group, the risk is actually significantly reduced according to the findings of a study by US researchers based at the university of Arizona.
Globally, an estimated 2.8 million people live with multiple sclerosis (MS) and the prevalence has increased in every world region since 2013, with a pooled incidence across 75 countries of 2.1 per 100,000 persons/year. Moreover, there is a good deal of data to suggest that axonal degeneration is the major determinant of irreversible neurological disability in patients with MS.
Although the precise underlying cause for MS remains to be determined, observational research suggests both genetic and environment influences and which are widely believed to be autoimmune in nature. Nevertheless, one prospective study following people for 9 years, demonstrated a moderate but significant association of type 2 diabetes with MS incidence. In addition, it has also been found that patients with type 1 diabetes have a more than 3-fold increased risk of developing MS.
Given the association with diabetes, the US researchers wondered if the use of anti-diabetic medication might positively impact on the risk of developing MS. The team turned to a US insurance claims database and identified those with type 2 diabetes and set the index data as the first recorded entry of their type 2 diabetes (T2D) diagnosis and the start date of the study, as 12 months after this index date.
For their analysis, researchers categorised participants with T2D as either under or over 45 years of age and propensity matched both cohorts, based on several factors including age, gender and co-morbidities.
Multiple sclerosis risk and use of anti-diabetic medication
A total of 143,613 individuals prescribed anti-diabetic medication (mean age of 30.16 years) and 638,625 (mean age of 61.85) were identified and both groups propensity matched.
Among the younger diabetic cohort, there was a significantly reduced risk of developing multiple sclerosis (relative risk, RR = 0.22, 95% CI 0.17 – 0.29, p < 0.001). In contrast, among the older cohort, the risk of developing MS was actually significantly higher (RR = 1.36, 95% CI 1.25 – 1.47, p < 0.001). The increased or decreased risk was also apparent for both sexes although among older men the risk was only slightly elevated (RR = 1.17, 95% CI 1.01 – 1.37, p = 0.04).
Interestingly, when researchers considered the individual anti-diabetic medicines, the risk was higher (or lower for younger patients) for all classes e.g., insulin, metformin, sulfonylureas, glitazones, DPP4 inhibitors and the combination of metformin and sulfonylureas.
The authors concluded that exposure to anti-diabetic medication in those with type 2 diabetes either increased or decreased the subsequent risk of developing multiple sclerosis and that this elevated or reduced risk was age-dependent.
Citation
Branigan GL et al. Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics. Heliyon 2022.
28th November 2022
Use of radiotherapy for 30 years in patients following breast conserving surgery in conjunction with chemotherapy or tamoxifen, reduces the risk of ipsilateral breast tumour recurrence but does not affect overall survival, according to the findings of follow-up study presented at the European Breast Cancer Conference in November 2022.
For a lot of women with early-stage breast cancer, breast-conserving surgery removes macroscopic disease although the presence of any remaining microscopic tumour tissue, if left untreated, could lead to loco-regional recurrence or life-threatening distant metastases. As a result, adjuvant radiotherapy, is often used and the evidence from over 10,000 women, suggests that radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. In 1976, researchers began a randomised trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. Results after 6 years showed that the relapse rate in the ipsilateral breast was 24.5% in the non-irradiated group compared to 5.8% following breast irradiation. But the researchers continued to monitor patients and the results showed that after 20 years of follow-up, there were no significant differences in overall survival among women who underwent mastectomy and those who underwent lumpectomy with or without postoperative breast irradiation. However, the study did show that the cumulative incidence of recurrent tumour in the ipsilateral breast was 14.3% in the women who underwent breast irradiation, compared with 39.2% in the women without irradiation. In the present Now, researchers are able to present 30-year survival data.
Radiotherapy and overall survival following breast cancer surgery
A total of 585 patients aged ≤70 years with early breast cancer, underwent local excision with a 1 cm margin, axillary node sampling or axillary node clearance.
Overall, researchers observed that ipsilateral breast tumour recurrence was found to be significantly lower in the radiotherapy group (Hazard ratio, HR = 0.39, 95% CI 0.27 – 0.55). For example, local recurrence (LR) after 10 years was 8.8% vs 31% (radiotherapy vs non-irradiated) but this difference reduced after 30 years and was 27.8% (95% CI 19 – 36.5) in the irradiated group and 42.7% (95% CI 35.8 – 49.6) in the non-irradiated group.
Furthermore, there was no difference in overall survival after 30 years (HR = 1.08, 95% CI 0.89 – 1.30, p = 0.43) and the proportion of survivors was broadly similar over time. For instance, overall survival at 10 years was 72.5% vs 70.8% (irradiated vs non-irradiated) and this difference was broadly similar after 30 years (23.7% vs 27.5%).
In a press release from the conference, lead researcher, Professor Ian Kunkler said, ‘We found that there is no long-term improvement in overall survival for those women having radiotherapy‘. He added that ‘The benefits of having radiotherapy in terms of fewer local recurrences are only accrued over the first ten years after radiotherapy; thereafter, the rate of local recurrence is similar whether or not patients had radiotherapy.’
Citation
Williams L et al. Randomised controlled trial of breast conserving therapy: 30 year analysis of the Scottish breast conservation trial. Abstract No 2. 13th European Breast Cancer Conference.
Trastuzumab deruxtecan (brand name Enhertu) been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen according to a press release from the manufacturer, AstraZeneca.
Gastric cancer is the 5th most common cancer worldwide and there were more than 1 million new cases in 2020 and 719,523 deaths. If a gastric cancer is diagnosed and treated when localised, the 5-year survival rate is 70%. However, if the cancer has spread to surrounding areas and/or the regional lymph nodes, the 5-year survival rate is 32% and this rate reduces to 6% if the cancer undergoes metastases. Given this poor prognosis it is important to have gastric biomarkers one of which is the Human epidermal growth factor receptor 2 (HER2) protein. While over expression is increasingly recognised as a molecular abnormality in breast cancer, there is mounting evidence of the role of HER2 over expression in patients with gastric cancer, and it has been correlated to poor outcomes and a more aggressive disease. The frequency of HER2 over expression in gastric and gastro oesophageal cancer ranges from 4.4% to 53.4%, with a mean of 17.9%. Trastuzumab is a recombinant humanised monoclonal antibody that targets the HER2 protein. In fact, trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Data obtained from two clinical trials, suggests treatment with trastuzumab deruxtecan, improves both the response and overall survival in patients with metastatic gastric cancer.
Trastuzumab deruxtecan and gastric cancer outcomes
In an open label, dose-escalation and dose-expansion phase 1 trial, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, who received Trastuzumab deruxtecan (T-Dx-T) had a manageable safety profile and showed preliminary activity in heavily pre-treated patients with HER2-positive patients. These findings prompted the authors to suggest that T-Dx-T should be further investigated for HER2-positive gastric or gastro-oesophageal junction cancer patients. In a second phase 2 trial with HER2-positive advanced gastric cancer patients, researchers compared T-Dx-T with a physician’s choice of chemotherapy. The results showed that an objective response was seen in 51% of T-Dx-T compared with 14% of those in the physician’s choice group. In addition, the median overall survival was also longer with T-Dx-T than with chemotherapy (12.5 vs. 8.4 months).
The most recent data on T-Dx-T comes from a study reported at the ESMO Congress 2022 and provided an update from a second trial, DESTINY-GASTRIC-02, a T-Dx-T monotherapy open-label, single-arm trial in HER2-positive, unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma patients. The results demonstrated after a median duration of follow up of 10.2 months, a confirmed objective response rate of 41.8% was seen in T-Dx-T patients with a median duration of response of 8.1 months a progression-free survival of 5.6 months.
These two trials provided the necessary data to enable CHMP to give a positive opinion for the drug and it follows on from FDA approval of the drug in 2021.
25th November 2022
A digitised tumour-infiltrating lymphocyte scoring in non-small cell lung cancer helps to predict response to immune checkpoint inhibitors.
Tumour infiltrating lymphocyte (TIL) scoring based on a machine-learning model has superior classification accuracy for an immune checkpoint inhibitor (ICI) response in patients with advanced non-small cell lung cancer (NSCLC) according to a retrospective analysis by an international research group.
Immunotherapy with immune-checkpoint inhibitors (ICI) has revolutionised the field of oncology for many patients. Nevertheless, not all patients with non-small cell lung cancer benefit from these agents with studies suggesting that in advanced disease, at one year, the overall survival rate with, for example, nivolumab, was only 51%.
A more favourable response to ICI therapy occurs in those with high programmed cell death ligand-1 expression and a high tumour mutation burden (TMB).
A further prognostic factor associated with an improved prognosis in NSCLC patients is high tumour-infiltrating lymphocyte (TIL) levels, which are visually assessed on routine haematoxylin and eosin-stained slides. However, with the increasing use of machine-based learning algorithms in healthcare, some preliminary data highlights the potential for such assessment of haematoxylin and eosin-stained slide sections.
Given the prognostic value of TIL levels, for the present study, researchers developed a machine-learning TIL scoring model to evaluate its association with clinical outcomes in patients with advanced NSCLC. The researchers undertook a retrospective analysis of patient cohorts prescribed PD-(L)1 inhibitors initially for a discovery cohort within a French hospital, followed by an independent validation cohort from hospitals in the UK and the Netherlands.
The machine learning model counted tumour, stroma and tumour infiltrating lymphocyte cells whereas values for TMB and PD-L1 expression were determined separately.
A total of 685 patients with advanced-stage NSCLCL treated with first or second-line ICI monotherapy were included within the two independent cohorts. The median age in both groups was 66.
Among patients in the discovery cohort, those with a higher TIL cell count had a significantly longer median progression-free survival (Hazard ratio, HR = 0.74, 95% CI 0.61 – 0.90, p = 0.003) and a significantly longer overall survival (HR = 0.76, p = 0.02).
Moreover, similar findings of an association between higher tumour infiltrating lymphocyte cell count and both progression-free and overall survival were also observed in the validation cohort.
When using PD-L1 levels as a biomarker, the area under the curve (AUC) was 0.68 and for tumour infiltrating lymphocyte cell levels, only 0.55 and 0.59 for TMB. But when combined, both the PD-L1/TIL and TMB/PD-L1 had higher AUC values (0.68 and 0.70 respectively).
The authors concluded that TIL levels were robustly and independently associated with the response to ICI treatment and could be easily incorporated into the workflow of pathology laboratories at minimal additional cost and might even enhance precision therapy.
Citation
Rakaee M et al. Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC. JAMA Oncol 2022.
Pembrolizumab and radiotherapy failed to improve tumour control and survival compared to a standard of care regime with cetuximab and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck according to a phase II randomised study by French researchers.
Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma. Head and neck cancer is the seventh most common cancer worldwide and accounts for over 800,000 new cases annually.
Pembrolizumab is a monoclonal antibody directed against programmed cell death protein 1 (PD-1) and it has been shown that in combination with platinum and 5-fluorouracil, the drug is an appropriate first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). In addition, pembrolizumab monotherapy is also an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. However, while effective as monotherapy, the drug has also been found to significantly increase both the response and outcome in patients with metastatic non-small-cell lung cancer, when combined with radiotherapy. Many patients with HNSCC have locally advanced disease and are commonly managed with cetuximab plus radiotherapy which significantly improves overall survival at 5 years compared with radiotherapy alone, hence confirming the regime as an important treatment option in this group of patients. Nevertheless, the regime is associated with acute and late toxicities, including myelosuppression, severe nausea/vomiting, irreversible renal failure, hearing loss, and neurotoxicity, prompting the need for effective alternatives.
Based on the effectiveness of pembrolizumab and radiation therapy in patients with non-small cell lung cancer, in the present study, the French team tested this combination against cetuximab-radiotherapy in patients with non-operated stage III-IVa-b SCC of oral cavity, oropharynx, hypopharynx and larynx. Patients received once-daily radiotherapy with weekly cetuximab or 200mg Q3W pembrolizumab during RT and the primary endpoint was the loco-regional control (LRC) rate 15 months after radiotherapy.
Pembrolizumab and head and neck squamous cell carcinoma outcomes
A total of 133 patients with a median age was 65 years, 92% of whom were smokers, were randomised to either arm (67 to pembrolizumab) and followed for a median of 25 months.
The 15-month LRC rate was 59% with cetuximab and 60% with pembrolizumab, representing a non-significant difference (Odds ratio, OR = 1.05, 95% CI 0.43 – 2.59, p = 0.91). In addition, there were no significant difference between arms for progression-free survival (Hazard ratio, HR = 0.85, 95% CI 0.55 – 1.32, p = 0.47) or for overall survival (HR = 0.83, 95% CI 0.49 – 1.40, p = 0.49).
Despite the lack of difference in cancer outcomes, toxicity was lower with pembrolizumab than with cetuximab, with 74% vs 92% patients having at least one grade ≥ 3 adverse event (p=0.006) and which were mainly mucositis, radio-dermatitis and rash.
The authors concluded that compared to cetuximab with radiotherapy, pembrolizumab and concomitant radiotherapy, did not improve the tumour control and survival but appeared less toxic in unfit patients with locally, advanced, squamous cell carcinoma of the head and neck.
Citation
Toa Y et al. Pembrolizumab versus cetuximab, concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase 2 trial. Ann Oncol 2022
Anticoagulant reversal agents use following an intracranial haemorrhage, all appear to have a similar level of efficacy and safety according to the findings of a meta-analysis by US researchers.
The direct oral anticoagulants (DOACs) are increasingly preferred over warfarin in DOAC-eligible patients with atrial fibrillation and patients with venous thromboembolism. In fact, the more widespread introduction of these agents has been generally well received by patients who report a high level of treatment satisfaction.
Nevertheless, anticoagulant agents are associated with an increased risk of bleeding and the annual rate of intracranial haemorrhage in those taking DOACs is 0.1% to 0.2%. Several anticoagulant reversal agents are currently available and approved. For example, andexanet alfa (AA) has been approved where reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding with apixaban or rivaroxaban.
Similarly, idarucizumab is approved for the specific reversal of dabigatran. Prothrombin complex concentrates have been developed to contain highly concentrated coagulation factors and one particular agent, 4-factor prothrombin complex concentrate (4F-PCC), has been found to be a good treatment option in patients requiring DOAC reversal.
However, the newer and traditional agents have not been directly compared. As a result, in the present study, the US researchers undertook a systematic review of the safety and efficacy of these non-specific (i.e., 4F-PCC) and targeted anticoagulant reversal agents in patients with DOAC-related intracranial haemorrhage (ICH).
Included studies were those in which patients with an intracranial haemorrhage had been treated with a DOAC, there was reversal of the DOAC and anticoagulant reversal outcomes such as thromboembolism and mortality were reported. The primary outcome was the successful reversal of anticoagulation.
Anticoagulant reversal of DOAC therapy
A total of 36 studies including 1832 patients with an ICH and a mean age of 76 years (57% male) met the inclusion criteria.
For patients treated with 4F-PCC, anticoagulant reversal occurred in 77% of patients, compared to 75% for AA and 82% for idarucizumab when reversing dabigatran.
In terms of safety, all-cause mortality was also broadly similar for 4F-PCC and AA (26% vs 24%) and lower for idarucizumab (11%). Thromboembolic events were similar for 4F-PCC and idarucizumab (8% vs 5%) and slightly higher for AA (14%).
The authors concluded that while there were no direct head-to-head comparisons available, their findings suggested that the overall anticoagulation reversal, mortality, and thromboembolic event rates appeared similar among available DOAC reversal agents for managing ICH.
Citation
Chaudary R et al. Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis. JAMA Netw Open 2022.
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