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10th February 2023
The anti-diabetic drug, dapagliflozin (brand name Forxiga) has been approved in the EU for patients with heart failure across the full spectrum of ejection fractions its manufacturer AstraZeneca has announced.
It has been estimated that globally, 64.3 million people are living with heart failure and chronic heart failure represents a leading cause of hospitalisation among those 65 years and older. Although dapagliflozin, which is a sodium-glucose cotransporter-2 inhibitor, used in the management of type 2 diabetes, it also appears to reduce adverse outcomes in patients with heart failure. In fact, studies have shown how the drug is effective in type 2 diabetics and heart failure, with an ejection fraction of less than 40%. Furthermore, in pursuing the value of the drug in heart failure, more recent data show that dapagliflozin at a dose of 10 mg daily, was able to reduce the combined risk of worsening heart failure and cardiovascular death in patients with either a mildly reduced or preserved ejection fraction.
Dapagliflozin use across heart failure ejection fractions
In a patient-level pooled analysis of the only two trials which tested dapagliflozin in heart failure with ejection fractions either ≤40% or >40%, there was no evidence that the effect of the drug varied by ejection fraction. In fact, the combined analysis revealed how dapagliflozin reduced both the risk of cardiovascular death and hospitalisations for heart failure.
Predicting frequent emergency care use by patients with chronic health conditions with machine learning models does not offer any additional benefit to existing modelling approaches according to the findings of a retrospective analysis by Canadian researchers.
While, not universally accepted, those with at least three or more visits per year have been used to describe a frequent emergency care user. Such individuals often have complex health needs which are not met through primary care provision and consequently their condition deteriorates, leading to an emergency department (ED) visit. Although frequent emergency care users (FECU) represent only a small proportion of the overall population seen in an ED, they do account for a disproportionately large number of visits. Currently, logistic regression models have been used for analysing frequent users in emergency departments. However, the development of machine learning models that can incorporate large amounts of both clinical and non-clinical data, have the potential to help identify FECU individuals. Such models have already been used, for example, in predicting the need for hospitalisation at the time of triage for children with an asthma exacerbation. Nevertheless, no studies have explored the use of machine learning models – and how these compare with logistic regression – to predict frequent emergency care use in adults with chronic conditions.
In the present study the Canadian team retrospectively examined the performance of four machine learning models in comparison to a logistic regression model, for the prediction of frequent ED use in adults with a range of chronic conditions. They identified two cohorts: those who had at least 3 and 5 visits per year. The models used a number of predictor variables including age, gender and residential area and focused on chronic diseases such as coronary artery disease, mental disorders, epilepsy and chronic non-cancer pain. The models were used to predict frequent ED use as a binary outcome, i.e., frequent user or not and the outcomes were compared in terms of the area under the curve (AUC), sensitivity and specificity.
Frequent emergency care user model predictions
The analysis identified 451,775 ED users and of whom, 9.5% had at least three visits per year and 3% five visits.
The AUC for the logistic regression model for frequent users with 3 visits/year was 0.748, giving a sensitivity of 60% and a specificity of 78%. Two of the machine learning models gave a similar AUC (0.749 and 0.744) whereas the random forest model was much worse (AUC = 0.538). For prediction of frequent users with 5 visits/year, the model performance was broadly similar, i.e., machine learning-based models were no better.
Overall, the authors commented on how none of the machine learning models outperformed the logistic regression model and the most important predictor variable was the number of visits in the previous year. The authors did feel that access to more variables could have helped in refining the predictive accuracy of the machine learning models. Nevertheless, they emphasised the need for future work to consider complex non-linear interactions, since in such cases, machine learning models were likely to be superior to existing ones.
Citation
Chiu YM et al. Machine learning to improve frequent emergency department use prediction: a retrospective cohort study. Sci Rep 2023
A study by Chinese researchers has shown that using colchicine for two days before and five days after, non-post-coronary artery bypass grafting (non-CABG) cardiac surgery, significantly lowers markers of myocardial injury and inflammation.
It has become recognised for many years that in cardiac surgery involving cardiopulmonary bypass, there is a systemic inflammatory response that leads to both organ injury and post-operative morbidity. While colchicine is often been used in the management of gout, the drug also has anti-inflammatory effects and can have a positive impact on several rheumatic diseases with a potential benefit in cardiac disease. Cardiac surgery is known to elevate markers of myocardial injury such as troponin levels and one study suggested that if post-operative values exceed ≥ 0.8 μg/L on the first post-operative day, a further 10% increase is significantly associated with all-cause, 12-month mortality and other adverse events. With some data showing that a perioperative course of colchicine, in patients undergoing standard coronary artery bypass grafting, reduced post-operative surgery-related myocardial damage, in the current study, the Chinese team wondered if this myocardial protective effect would extend to non-CAGB cardiac procedures.
Turning to patients undergoing other types of cardiac surgery such as mitral and aortic valve replacement, atrial septal defect repair and atrial myxoma resection, the researchers randomised patients, 1:1 to receive colchicine 0.5mg daily or placebo for three days before and five days after their cardiac surgery. The primary outcome was the level of cardiac troponin T (cTnT) 48 hours after surgery whereas secondary outcomes included biomarkers of myocardial injury including creatine kinase-MB (CK-MB) and procalcitonin (PCT).
Colchicine and myocardial injury
A total of 121 patients with a mean age of 59.4 years (57.8% male) were included and of whom, 59 were given colchicine.
At the 48-hour post-operative timepoint, patients assigned to colchicine had significantly lower cTnT (p < 0.001), CK-MB (p = 0.01) and PCT (p < 0.01) levels compared to placebo. In fact, cTnT levels remained significantly lower in those assigned to colchicine, 5 days after surgery (0.14 vs 0.23 μg/L, p = 0.001).
This findings led the authors to concluded that a short perioperative course of colchicine lowered post-operative biomarkers of myocardial injury and inflammation.
Citation
Pan T et al. The low-dose colchicine in patients after non-CABG cardiac surgery: a randomized controlled trial. Crit Care 2023
A pilot study undertaken within a Chicago hospital emergency department could pave the way for the widespread development of diabetic screening programs.
It has been estimated that globally, approximately 415 million are living with diabetes yet an estimated 46% of those with the condition are undiagnosed. Although an emergency department is designed to provide critical access to healthcare, it also provides an opportunity to identify and subsequently link patients to other services. For example, screening services within an emergency department (ED) have previously been established for HIV as well as for substance use disorders. In addition, one 2016 Australian study that involved routine ED testing of HbA1c in an area with a known high prevalence of diabetes, concluded that such an initiative was a feasible way to identify those with undiagnosed disease and provided an opportunity to improve patient care. Moreover, it has become recognised, particularly in the US, that ethnic minorities and low-income adults are disproportionately affected by diabetes with a resultant increased risk of both diabetic complications and mortality. As a result, in the current study, researchers examined whether a pilot diabetic screening program performed within an ED, might enable the identification of the condition, especially among those of ethnic minorities.
The researchers made use of a best practice alert built into the electronic medical record which flagged ED patients who were at risk of diabetes, i.e., patients aged 45 years and older or 18 to 44 year olds with a recorded body mass index of 25 or greater, without a recorded history of diabetes or a HbA1c measurement within the last 3 years. The team then attempted to contact all potentially eligible patients.
Diabetic screening program and diabetes detection
A total of 352 eligible individuals with a mean age of 52.2 years (54.5% female) were identified. Among the cohort, 264 were diagnosed with prediabetes (a HbA1c level of 5.7 to 6.4%) and 88 diabetes (HbA1c > 6.5%). Among those with diabetes, 62 had severe disease (HbA1c > 10%) and nearly two-thirds of patients (64.8%) were non-Hispanic Black or of unknown ethnicity and 19.6% were Hispanic. Interestingly, among the entire cohort, 74.7% had no prior diagnosis of either prediabetes or diabetes.
While the researchers were able to successfully identify patients with undiagnosed diabetes, particularly among ethnic minorities, questions remained as to the value of undertaking diabetic screening within an ED in other areas and whether such an initiative would prove to be cost-effective.
Citation
Danielson KK et al. Prevalence of Undiagnosed Diabetes Identified by a Novel Electronic Medical Record Diabetes Screening Program in an Urban Emergency Department in the US. JAMA Netw Open 2023.
9th February 2023
The use of contrast enhanced (CE) ultrasound for patients with abdominal trauma prior to computed tomography imaging has a higher diagnostic accuracy in comparison to conventional ultrasound according to the results of a systematic review and meta-analysis by researchers from the Brookdale University Hospital and Medical Center, New York, US.
Undertaking an extended Focused Assessment with Sonography in Trauma (eFAST) is commonly performed as part of the initial assessment of patients who have experienced trauma. Moreover, a systematic review has shown how eFAST serves as a useful bedside tool which is able to rule-in pneumothorax, pericardial effusion as well as intra-abdominal free fluid within a trauma setting but is less useful as a rule-out tool. The diagnostic capability of ultrasound can be improved with the use of a contrast media. In fact, contrast enhanced ultrasound in children has been found to have a comparable performance to both CT and MRI with a very high degree of specificity and hence has the potential to reduce irradiation exposure in paediatric patients. It has also been shown that contrast enhanced ultrasound seems to be both safe and accurate for the identification of abdominal solid organ injuries in children who have experienced a blunt abdominal trauma. Nevertheless, the comparative accuracy of CE ultrasound has not been directly compared to eFAST during the initial trauma assessment and was the subject of the review by the US researchers. The team focused on the use of both ultrasound methods for the initial assessment of patients with abdominal trauma before CT imaging. Paired pooled sensitivity and specificity were used to assess the relative merits of both approaches.
Contrast enhanced ultrasound diagnostic value in abdominal trauma
Following a literature search, a total of 10 eligible studies with 1,359 patients and 30 pairwise comparisons were included in the analysis.
Overall, the paired, pooled sensitivity for CE ultrasound was 0.933 (95% CI 0.917 – 0.948) compared to 0.559 (95% CI 0.527 – 0.591) for conventional ultrasound (p < 0.001). The pooled specificity was also significantly higher (0.995 vs 0.975, p < 0.001). In fact, in sub-group analysis, CE ultrasound was superior to conventional ultrasound for all other areas including the liver, kidneys and adrenals, spleen and for the presence of active bleeding.
Based on these findings, the authors concluded that CE ultrasound was a superior method for differentiating abdominal trauma injuries when used as an initial means of assessment in emergency departments.
Citation
Sutarjono B et al. Is it time to re-think FAST? A systematic review and meta-analysis of Contrast-Enhanced Ultrasound (CEUS) and conventional ultrasound for initial assessment of abdominal trauma. BMC Emerg Med 2023
8th February 2023
A randomised trial of a patient-centred deprescribing intervention in older adults led to a significant reduction in medicine use compared to a control group who did not receive the intervention according to a study by US researchers based in Tennessee.
Polypharmacy is defined by the use of five or more medicines and one US study found that in 2010, among elderly patients (65 years and older), polypharmacy was present in 39% of cases. Polypharmacy increases the risk of adverse drug reactions and somewhat alarmingly in one analysis of 2,105 older adults discharged from hospital, 74% were prescribed a polypharmacy regimen.
Consequently, deprescribing interventions to reduce medication burden are likely to decrease the risk subsequent adverse events associated with the use of multiple treatments. In the current study, the US team examined the effectiveness of a deprescribing framework at reducing medication burden. The intervention had been previously piloted in one centre and was found to be effective, leading to US to undertake randomised, controlled trial of the intervention.
The intervention itself involved nurses or pharmacists reviewing the medicines of older adults prior to hospital discharge to a post-acute care (PAC) facility and the outcomes compared with the usual hospital discharge care.
The primary outcome was the total medication count at hospital and PAC discharge and participants were followed-up for assessment, 90 days after being discharged from the PAC facility. Secondary outcomes included the total number of potentially inappropriate medications (PIMs) as well as the drug burden index (DBI) which measured sedative and anticholinergic burden.
Deprescribing intervention and total medication burden
A total of 284 participants (142 per group) with a mean age of 76.2 years (62% female) were included in the final analysis and the median length of PAC facility stay was 22 days. Overall, the median number of prehospital medications per patient was 16.
As a result of the intervention, participants were taking a mean of 14% fewer medications upon discharge from the PAC facility (mean ratio, MR = 0.86, 95% CI 0.80 – 0.93, p < 0.001). In addition, at the 90-day assessment, those previously assigned to the intervention were taking 15% fewer medicines (MR = 0.85, 95% CI 0.78 – 0.92, p < 0.001) compared to the control group.
The intervention group were also prescribed fewer PIMs and had a lower DBI after 90 days yet the incidence of adverse drug events was similar between the intervention and control groups (hazard ratio, HR = 0.83, 95% CI 0.52 – 1.30).
The authors concluded that their deprescribing intervention was both safe and effective at reducing overall medication burden and called for future studies to examine the impact of the intervention on both patient-reported and long-term clinical outcomes.
Citation
Vasilevskis EE et al. Deprescribing Medications Among Older Adults From End of Hospitalization Through Postacute CareA Shed-MEDS Randomized Clinical Trial. JAMA Intern Med 2023.
An overview of systematic reviews by researchers from Australia and the UK which examined the use of an antidepressant for the management of a range of chronic pain conditions, has concluded that the evidence of efficacy for all classes of drugs was moderate to low.
The presence of chronic pain is a common condition with one US survey finding that 50.2 million adults reported experiencing pain on most days or every day. Although both opioids and non-steroidal anti-inflammatory agents can be used to treat chronic pain, guidance from NICE in the UK, advises that the pharmacological management of such pain should involve the use of an antidepressant and which should be either amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline. But exactly how effective are antidepressant drugs for the management of chronic pain was the subject of the recent review by the Australian and UK researchers. The team undertook an overview of all available systematic reviews describing the use of an antidepressant (compared to placebo) for the management of any chronic painful condition in adults. The researchers set their primary outcome as pain and which could be measured with any instrument. The pain outcomes were then converted to a 0 to 100 scale and for which 0 represented no pain and 100, worst pain.
Antidepressant use and pain outcomes
A total of 26 studies with over 25,000 participants were included in the final analysis and which covered 22 distinct pain conditions and 42 antidepressants (8 different classes) versus placebo comparisons.
Overall, none of the reviews provided high certainty evidence on the efficacy of an antidepressant for pain in the management of any of the conditions examined. There were 11 comparisons of 9 different conditions where antidepressants were effective, largely serotonin-norepinephrine (noradrenaline) re-uptake inhibitors. This latter class was effective (mainly duloxetine) for back pain, postoperative pain, neuropathic pain and fibromyalgia. In the other cases, the antidepressants were deemed to be either ineffective or the evidence was inconclusive.
Interestingly, the researchers found that 74% of tricyclic antidepressant prescriptions were for a pain condition yet of 14 pain problems examined, this class of drugs were only effective for three conditions (irritable bowel syndrome, neuropathic pain and chronic tension-type headache). However, the certainty of the evidence was low in each case.
The authors concluded that overall, the efficacy of antidepressants was found in only 11 of the 42 comparisons and suggested that a more nuanced approach was needed when using these drugs for a painful condition.
Citation
Ferreira GE et al. Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews. BMJ 2023
7th February 2023
US researchers have identified a plasma proteomic signature that is able to distinguish between patients with osteoarthritis whose disease is progressive or non-progressive and which is superior to currently used methods.
In a global analysis from 2017, it was found that the annual incidence rate of osteoarthritis was 181.2 per 100,000 patients and the authors noted that the burden of disease is increasing in most countries. Currently, there is a need to develop OA prognostic markers and in 2016, researchers identified a method for diagnosing radiographic OA based on a series of serum biomarkers. More recently, a number of systemic biomarkers were identified and deemed to have promise as predictors of both pain and structural worsening of OA. To date, measurement of urinary carboxyl-terminal cross-linked telopeptide of type II collagen (uCTXII) appears to be the strongest predictor of clinically relevant osteoarthritis progression. In the current study, the US team used uCTXII as the ‘best-in-class’ biomarker to evaluate the performance of the proteomic signature they had identified back in 2016, for predicting clinically relevant knee OA progression, defined in terms of both joint structure and pain worsening, over a period of 48 months.
Using a cohort of 596 individuals with OA, the US team set out to measure the effectiveness of their proteomic signature (based on the area under the receiver operating curve, AUC) at distinguishing between progressors and non-progressors.
Osteoarthritis proteomic signature and identification of disease progressors
Data were available for 596 individuals with knee OA with a mean age of 61.6 years (58.7% female) and who at baseline, had moderate to severe radiographic knee OA.
Based on the proteomic signature, containing 13 distinct proteins, the AUC was 73% for differentiating between progressors (based on a measure of both radiographic joint space loss and pain scores). In contrast, the uCTXII model only had an AUC of 58% which was comparable to a model based only on baseline structural OA and the severity of pain (59%).
The researchers went a step further and assessed their proteomic model (but with only 11 proteins) in a second OA cohort and determined an AUC of 70% for distinguishing progressors from non-progressors.
They concluded that their plasma biomarker signature was able to effectively identify clinically relevant knee OA progressors from non-progressors, adding that the proteomic signature may be of value during clinical trials to identify those with the greatest need for treatment.
Citation
Zhou K et al. A “best-in-class” systemic biomarker predictor of clinically relevant knee osteoarthritis structural and pain progression. Sci Adv 2023
6th February 2023
Sanofi, has described how its novel, investigative agent efanesoctocog alfa is effective in the management of patients with haemophilia A.
In those with severe haemophilia A, levels of endogenous plasma factor VIII are below 1% and such individuals can experience recurrent bleeds and which are treated using replacement therapy with clotting factor concentrates as prophylaxis or on-demand therapy for bleeding.
Within the plasma, the majority of Factor VIII circulates attached to von Willebrand factor and this modulates its half-life and provides protection from degradation. However, coupling of both proteins imposes constraints on the half-life of factor VIII. Efanesoctocog alfa represents a novel form of factor VIII replacement that is physically decoupled from endogenous endogenous von Willebrand factor, thereby extending the half-life of factor VIII.
Although not yet approved, the available data for efanesoctocog alfa, which was published in the New England Journal of Medicine, concluded that it provided superior bleeding prevention compared to pre-study prophylaxis, as well as the achievement of near to near-normal factor VIII activity and improvements in physical health.
In the trial (XTEND-1), efanesoctocog alfa was able to deliver normal or near-normal (> 40%) factor VIII activity for the majority of the week with a single, once weekly dosing. In fact, the mean annualised bleeding rate (ABR) was 0.71 (95% CI 0.52 – 0.97) yielding a 77% reduction compared to prophylaxis with factor VIII (P < 0.001) based on an intra-subject comparison.
Other data showed that efanesoctocog alfa led to significant (compared to baseline) improvements in physical health, pain intensity and joint health after 52 weeks. Additionally, the product was well tolerated and inhibitor development to factor VIII was not detected and treatment-emergent adverse effects, in greater than 5% of participants were headache, arthralgia, fall and back pain.
Efanesoctocog alfa is currently under FDA review and regulatory submission in the EU is anticipated in the second half of 2023.
According to the manufacturer, Pilant Therapeutics, results from a phase 2a placebo-controlled trial, showed that bexotegrast at a daily dose of 320 mg, achieved a statistically significant mean increase in forced vital capacity (FVC) from baseline up to week 12 in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterised by scarring of unknown cause, giving rise to dyspnoea and a non-productive cough. The data comes from the INTEGRIS-IPF trial, a multi-national, randomised, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability and pharmacokinetics of once daily bexotegrast in people with idiopathic pulmonary fibrosis. The study included four doses (40, 80, 160 and 320 mg) and patients were randomised 3:1 (active vs placebo). Although the primary outcomes for INTEGRIS-IPF were not related to efficacy, exploratory efficacy analyses included changes in FVC and biomarkers such as PRO-C3, which is raised in patients with IPF and associated with disease progression.
Bexotegrast and IPF outcomes
A total of 21 patients were assigned to the 320 mg dose and there was a mean FVC increase of 29.5ml compared to baseline at 12 weeks compared to a decrease of 110.7ml for those assigned to placebo (p < 0.05). Moreover, the mean increase was statistically superior to placebo at all timepoints. In addition, patients receiving 320 mg saw a significant reduction in PRO-C3 levels at both week 4 and 12 (p <0.01) compared to placebo.
The 24-week data for patients treated with bexotegrast should be available in the second quarter of 2023.
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