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Take a look at a selection of our recent media coverage:

Cocoa flavanol supplement fails to reduce cardiovascular events

5th July 2022

An RCT has found that a cocoa flavanol supplement failed to reduce the incidence of adverse cardiovascular events compared to placebo

The use of a cocoa flavanol supplement in older patients free of cardiovascular disease or cancer, failed to reduce the incidence of adverse cardiovascular events compared to placebo according the findings of a randomised, controlled trial by a the COSMOS research group.

Cocoa contains a number of flavan-3-ols and which have been reported to exhibit several health beneficial effects that occur via an antioxidant, anti-carcinogen, cardio-preventive, antimicrobial, anti-viral, and neuro-protective effects. In addition, the presence within cocoa of methylxanthines enhances the beneficial vascular effects commonly ascribed to cocoa flavanol intake. Much of the research on the cardiovascular benefits of cocoa has centred on the consumption of chocolate and a 2020 meta-analysis concluded that it could have a small inverse association with coronary heart disease and stroke but cautioned how this was based on low credibility evidence. Nevertheless, several, small scale studies have shown even among healthy individuals how regular intake of cocoa flavanols improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular. While small scale studies appear to show that there are benefits cocoa, there have been no large-scale trials assessing the benefits of a cocoa flavanol supplement in comparison to a placebo.

For the present study, the US team undertook a randomised, placebo-controlled trial, which they termed the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). The trial was designed to test whether a cocoa flavanol supplement and a multivitamin could prevent cardiovascular disease among older adults. Individuals were randomly assigned to one of four arms; active cocoa ((500 mg flavanols/day) and a multivitamin; active cocoa and placebo vitamin; active multivitamin and placebo or finally two placebos. The primary outcome was a composite of total cardiovascular outcomes which had several outcomes e.g., incident myocardial infarction, coronary revascularisation, cardiovascular mortality and hospitalisation for unstable angina. The secondary outcomes included a total of CVD and all-cause mortality and the individual components of the composite primary outcome.

Cocoa flavanol supplement and cardiovascular outcomes

A total of 21,442 individuals with a mean age of 72.1 years (59.1% female) were randomised and followed-up for a median of 3.6 years. During the follow-up, 410 participants taking the cocoa supplement and 456 taking placebo experienced a cardiovascular event and this difference was not statistically significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.02, p = 0.11).

For the secondary outcome of cardiovascular death, there was a significant reduction among those assigned to the cocoa flavanol supplement (HR = 0.73, 95% CI 0.54 – 0.98) but the difference for each of the other secondary outcomes was non-significant. In addition, while the number of deaths was slightly lower among those taking the cocoa supplement compared to placebo (353 vs 397), this difference was non-significant.

The authors concluded while there were no apparent differences in the primary outcome, additional research was needed to further clarify if a cocoa flavanol supplement could reduce cardiovascular events.

Citation
Sesso HD et al. Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial Am J Clin Nutr 2022

Liberation time from respiratory support similar for high-flow nasal cannula and CPAP in acutely ill children

24th June 2022

High-flow nasal cannula therapy is equivalent to continuous positive airway pressure for release time from respiratory support in children

The use of high-flow nasal cannula (HFNC) therapy as a first-line non-invasive respiratory support system appears to be non-inferior to continuous positive airway pressure (CPAP) for the time to liberation of respiratory support in critically ill children. This was the conclusion of a randomised trial by UK researchers.

Respiratory distress is common cause of paediatric intensive care unit admission and strategies to address oxygenation problems in critically ill patients with hypoxemic respiratory failure include use of simple oxygen equipment, use of non-invasive ventilation, or use of invasive ventilation. Non-invasive mechanical ventilation procedures include CPAP whereas HFNC is considered as a cross over therapy from basic oxygen therapy to non-invasive ventilation. In a systemic review, HFNC was shown to reduce the rate of intubation, mechanical ventilation and the escalation of respiratory support. However, whether or not HFNC is superior to other forms of non-invasive respiratory support such as CPAP with respect to the length of time required for such respiratory support in acutely ill children remains to be determined. In a feasibility study in 2018 designed to compare HFNC with CPAP, it was concluded that such a trial would be possible. Following on from this initial study, for the present trial, the UK team set out to determine if HFNC was comparable to CPAP in terms of to the time to liberation from respiratory support in acutely ill children admitted to a paediatric critical care unit.

In their pragmatic, unblinded trial, the researchers randomised children 1:1 to receive either HFNC or CPAP although physicians were permitted to switch from HFNC to CPAP (or visa versa) where they felt it would be clinically appropriate.

The primary outcome of interest was the time from randomisation to liberation from respiratory support, defined as the start of the 48-hour period during which the patient was free from all respiratory support. For their secondary outcomes, the authors focused on several outcomes including the duration of stay within the critical care unit, mortality and use of sedatives during non-invasive respiratory support.

HFNC therapy outcomes

A total of 573 children with a median age of 9 months (39% girls) were included and randomised to either HFNC (295) or CPAP. The most common reasons for intensive care admission were in the HFNC group were bronchiolitis (48.5%) or another respiratory condition (18.6%) and these proportions were similar in the CPAP group.

The median time to liberation of respiratory support in the HFNC group was 52.9 hours compared to 47.9 hours in the CPAP group and this difference was not statistically significant (hazard ratio, HR = 1.03, 95% CI 0.86 – 1.22).

For the secondary outcomes the use of sedatives during respiratory support were significantly less for children using HFNC (odds ratio, OR = 0.59, 95% CI 0,39 – 0.88), as was the mean duration of their critical care stay (mean difference = – 3 days) and the mean duration of hospital day (mean difference = -7.6 days).

The authors concluded that HFNC was non-inferior to CPAP with respect to the liberation of respiratory support.

Citation
Ramnarayan P et al. Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Therapy on Liberation From Respiratory Support in Acutely Ill Children Admitted to Pediatric Critical Care Units: A Randomized Clinical Trial JAMA 2022

Intravenous vitamin C associated with increased mortality risk in sepsis patients

Intravenous vitamin C given to sepsis patients receiving vasopressor therapy increased the risk of death and persistent organ dysfunction

The use of intravenous vitamin C for intensive care patients with sepsis who were also in receipt of vasopressor therapy, increased the risk of both death and persistent organ dysfunction according to the findings of LOVIT, a randomised, placebo-controlled trial.

Sepsis represents the body’s inflammatory response to infection and has been found to be the cause of one in every two to three hospital deaths, most of whom had sepsis upon admission to hospital. Moreover, sepsis represents a major cause of death, with an estimated 48·9 million global incident cases and 11·0 million sepsis-related deaths in 2017. Intravenous vitamin C may be an important adjunctive therapy for critically ill patients. In fact, evidence suggests that critically ill patients have low vitamin C concentrations and that those with septic shock have significantly depleted vitamin C levels probably due to the increased metabolism from the enhanced inflammatory response in these patients. In a 2017 retrospective study, researchers observed that the use of intravenous vitamin C in sepsis patients, together with corticosteroids and thiamine, was effective in preventing progressive organ dysfunction and in reducing the mortality of patients with severe sepsis and septic shock. However, subsequent studies were less consistent, with one network meta-analysis concluding that metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality. In contrast, another meta-analysis concluded that intravenous vitamin C administration appeared to be safe and may be associated with a trend toward reduction in overall mortality in critically ill patients. Nevertheless, in another study of167 patients with sepsis and acute respiratory distress syndrome, a 96-hour infusion of vitamin C compared did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury.

Given the potentially conflicting results to date on the value of vitamin C, for the present study, researchers undertook a randomised, placebo-controlled trial, Lessening Organ Dysfunction with Vitamin C (LOVIT). The trial was designed to test whether intravenous vitamin C would reduce both the risk of death or persistent organ dysfunction in adults with sepsis and who were receiving vasopressor therapy within an intensive care unit (ICU). The team recruited adult patients who had been within an ICU for no longer than 24 hours, with a proven or suspected infection as the main diagnosis and who were receiving a vasopressor. Participants were randomised 1:1 to receive intravenous vitamin C as a bolus dose of 50 mg/kg, administered over 30 to 60 minutes every 6 hours for a total of 96 hours. The control group received a matching infusion containing either 5% dextrose or normal saline. The primary outcome of the trial was a composite of death or persistent organ dysfunction, whereas one of the secondary outcomes was 28-day mortality.

Intravenous vitamin C and death or persistent organ dysfunction

A total of 863 patients with a mean age of 65.1 years (37.6% female) were randomised to either intravenous vitamin C or matching placebo. The median stay within the ICU was 6 days and with an overall hospital stay of 16 days.

The primary outcome occurred in 44.5% of those in the vitamin C group and 38.5% of placebo patients and this difference was significant (risk ratio, RR = 1.21, 95% CI 1.04 – 1.40, p = 0.01).

For the secondary outcome of 28-day mortality, death occurred in 35.4% of those using vitamin C and 31.6% of those receiving placebo (RR = 1.17, 95% CI 0.98 – 1.40). Similarly, the proportion of patients with persistent organ dysfunction was present in 9.1% of those given vitamin C and 6.9% of those taking placebo (RR = 1.30, 95% CI 0.83 – 2.05).

The authors concluded that in adults with sepsis who were receiving vasopressor therapy, use of intravenous vitamin C led to a higher risk of death or persistent organ dysfunction compared to placebo.

Citation
Lamontagne F et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit N Eng J Med 2022

IV fluid restriction no effect on 90-day mortality in septic shock

23rd June 2022

IV fluid restriction for ICU patients with septic shock has no detrimental effect on 90-day mortality compared to unrestricted fluid use

Intravenous (IV) fluid restriction in patients admitted to an intensive care (ICU) unit with septic shock resulted in a non-significant difference in 90-day mortality compared to standard intravenous fluid therapy. This was the conclusion of a large, randomised trial by researchers in the CLASSIC group.

Sepsis has been defined by the World Health Organisation as a syndromic response to infection and often a final, common pathway leading to death. Furthermore, sepsis is a major cause of mortality with a 2017 estimate indicating that 48·9 million incident cases of sepsis were recorded worldwide and 11·0 million sepsis-related deaths, representing 19·7% of all global deaths. The term ‘septic shock’ is described as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities occur and which are associated with a greater risk of mortality than with sepsis alone.

The use of large volume fluid resuscitation is viewed as the cornerstone of treatment for septic shock with the surviving sepsis campaign guidelines providing a strong recommendation to rapidly administer a minimum of 30 mL/kg crystalloid solution intravenously in all patients with elevated blood lactate levels. Nevertheless, the guidelines acknowledge that there is no credible evidence to support this recommendation. In fact, a 2020 systematic review comparing IV fluid restriction or higher fluid volumes, concluded that there was very little quality evidence supporting the decision on the volumes of IV fluid therapy in adults with sepsis.

Based on this uncertainty, for the present study, the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial was established to evaluate the effects of IV fluid restriction on mortality and other relevant outcomes in adult patients with septic shock admitted to an ICU. For the trial, patients with septic shock, defined as a suspected or confirmed infection and a plasma lactate level of 2 mmol/L or higher and who had already received at least one litre of IV fluids within the previous 24 hours were enrolled. Participants were randomised 1:1 to either restrictive IV fluids or standard IV therapy during their ICU stay. For the IV fluid restriction group, further fluids were only permitted under certain specified conditions e.g., if patient had severe hypo-perfusion, to replace documented losses e.g. gastrointestinal or drain losses, to correct dehydration or finally, to ensure a total fluid intake of 1 litre. In contrast, there were no restrictions on the amount of fluids that could be given to patients in the standard fluid group. The primary outcome of interest was death within 90-days of randomisation whereas secondary outcomes related to the number of patients with one or more serious adverse events.

IV fluid restriction and mortality

A total of 1,545 patients were randomised to either restrictive fluids (median age 71 years, 59.9% male) or standard fluid therapy and during the study period, patients in both groups remained in the ICU for a median of 5 days.

The median fluid cumulative volume was 1798 ml in the restricted fluid group compared to 3811 ml in the standard group.

After 90 days, death occurred in 42.3% of those in the IV fluid restriction group and in 42.1% of those in the standard fluid group ((adjusted absolute difference = 0.1%, p = 0.96).

In terms of safety, there were one or more adverse events in 29.4% of those in the restricted fluid group and 30.8% in the standard fluid group. In addition, at day 90, the number of patients alive and without life support, days alive and out of hospital were similar between the two groups.

The authors concluded that among adults with septic shock in an ICU, there were no mortality differences for those with IV fluid restriction compared to patients receiving standard IV fluid therapy.

Citation
Meyhoff TS et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock N Eng J Med 2022

Green tea extract decreases severity of radiation-induced dermatitis in breast cancer patients

22nd June 2022

A green tea extract containing epigallocatechin-3-gallate significantly reduced radiation-induced dermatitis in women with breast cancer

A solution a green tea extract has been found to reduce both the incidence and severity of radiation-induced dermatitis in women undergoing adjunctive radiotherapy after breast cancer surgery. This was the conclusion of a phase 2 randomised, placebo-controlled trial by a team of Chinese researchers.

Breast cancer affects a large number of women and according to the World Health Organisation, in 2020, there were 2.3 million women diagnosed with breast cancer and and which led to 685 000 deaths. For the treatment of women with breast cancer, the results from a 20-year follow-up study have shown that lumpectomy, i.e., where there is removal of enough normal breast tissue to ensure that the margins of the resected specimen were free of tumour, followed by irradiation, continues to be an appropriate therapy for women, provided an acceptable cosmetic result can be obtained. However, one troublesome adverse effect of radiotherapy is radiation-induced dermatitis (RID) and while the use of topical prophylactic corticosteroids (e.g., mometasone) is recommended to reduce discomfort and itching, there is no evidence to support the superiority for any specific intervention.

To date, there is some, limited data to show that a green tea extract containing epigallocatechin-3-gallate (EGCG) can help with restitution of skin integrity, possibly mediated via an anti-inflammatory effect. Furthermore, some evidence also shows that a green tea extract can reduce the acute skin-induced reactions after radiation which include pain, the burning-feeling, itching, pulling and tenderness. However, whether the use of this extract could actually prevent the development of radiation-induced dermatitis is unclear and was the subject of the present study.

The Chinese team recruited women with breast cancer undergoing postoperative radiotherapy and then randomised them (2:1), to either the green tea extract or placebo (which was a normal saline solution). Both solutions were sprayed to the whole of the radiation field from day one of therapy and continued until two weeks after completion of treatment. An assessment of RID was made weekly using a scale ranging from 0 (no change) to 4 (worse impairment), i.e., higher scores indicate more severe dermatitis. In addition, patient-reported symptoms including pain, itch and tenderness were also included. The primary outcome was the incidence of grade 2 or worse RID whereas secondary outcomes included patient symptoms.

Green tea extract and RID outcomes

A total of 165 women with a median age of 46 years were enrolled and randomised to EGCG or placebo.

During radiotherapy as the dose was increased, RID began to occur two to three weeks after the start of treatment and the mean appearance time was delayed in the EGCG group compared to placebo (3.27 weeks vs 2.89 weeks, p = 0.001).

The incidence of grade 2 or above RID was 50.5% in the green tea extract group and 72.2% in the placebo arm (p = 0.008). In addition, symptom scores were also lower among the women receiving EGCG.

The authors concluded that prophylactic use of a green tea extract significantly reduced both the incidence and severity of RID and that the extract has the potential to become a new choice for skin care in women receiving radiotherapy.

Citation
Zhao H et al. Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial JAMA Dermatol 2022

Weekly tirzepatide provides substantial reductions in body weight

21st June 2022

Weekly tirzepatide injections for obese patients over a period of 72 weeks has been shown to give rise to large reductions in body weight

Weekly tirzepatide injections to patients with a body mass index (BMI) greater than 30 over a period of 72 weeks have been found to produce significant reductions in body weight. This was the conclusion of the SURMOUNT-1 trial according to the study’s investigators.

According to the World Health Organization (WHO), the terms, overweight and obesity are defined by abnormal or excessive fat accumulation and that present a risk to health. The terms are assessed with respect to body mass index such that individuals with a BMI > 25 are considered to be overweight and obese, where the BMI exceeds 30. Obesity is a global problem and using data from 2016, WHO estimates that 1.9 billion adults were overweight and 650 million obese and there is good evidence that a higher BMI is associated with an increased risk of all-cause mortality.

Tirzepatide is a novel, dual glucose-like peptide-1 and a glucose-dependent insulinotropic polypeptide GLP-1 receptor agonist, which has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. In addition to glargine for example, weekly tirzepatide has been found to produce statistically significant improvements in glycaemic control in type 2 diabetic patients after 40 weeks as well as a reduction in body weight.

For the present trial, investigators undertook a double-blind, randomised, placebo-controlled trial in adults with a BMI of 30 or more, testing three doses (5, 10 and 15 mg) of weekly tirzepatide. In addition, to an elevated BMI, enrolled adults were also required to have at least one weight-related complication e.g., hypertension, dyslipidaemia or cardiovascular disease. Individuals were randomised 1:1:1:1 to weekly tirzepatide at a dose of 5, 10 or 15 mg or placebo and doses were administered for a period of 72 weeks as an adjunct to a lifestyle intervention, which included lifestyle counselling sessions and advice to undertake at least 150 minutes of physical exercise per week. The coprimary endpoints were the percentage change in body weight from baseline and a weigh reduction of 5% or more at week 72. Secondary endpoints included weight reductions or 10%, 15% and 20% or more at week 72.

Weekly tirzepatide and weight loss

A total of 2,539 individuals with a mean age of 44.9 years (67.5% female) were randomised to one of the four interventions. The mean baseline BMI for the whole cohort was 38 and 94.5% of participants had a BMI of 30 or higher.

The mean percentage change in body weight at week 72 was -15% for the 5mg dose, – 19.5% for 10mg and -20.9% with 15mg compared to -3.1% with placebo (p < 0.001 for all comparisons with placebo).

Overall, 57% of participants given 15mg tirzepatide had a 20% or more reduction in body weight.

The safety profile of the drug was excellent with adverse effects generally of mild to moderate severity and largely gastrointestinal in nature. Adverse effects leading to treatment discontinuation occurred in 6.2% of those given 15mg tirzepatide compared with 2.6% in the placebo group.

The authors concluded that once weekly tirzepatide resulted in substantial and sustained reductions in body weight.

Citation
Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity N Engl J Med 2022

Clinical benefits of molnupiravir may extend beyond hospitalisation and death

17th June 2022

A further analysis of trial data suggests additional clinical benefits of molnupiravir in the treatment of patients infected with COVID-19

The clinical benefits of molnupiravir may not just be restricted to a reduction in either hospitalisation or death, according to the results of a secondary analysis of data from the MOVe-OUT trial by an international group of researchers in collaboration with the manufacturer, Merck and Co.

Molnupiravir is a small-molecule ribonucleoside prodrug of N-hydroxycytidine (NHC) and was studied in MOVe-OUT a phase 3, double-blind, randomised, placebo-controlled trial. The aim of the trial was to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in non-hospitalised, unvaccinated adults with mild-to-moderate, COVID-19 and at least one risk factor for severe COVID-19 illness. The findings of the study indicated that the drug, given at a dose of 800 mg every 12 hours for 5 days, was able to reduce the risk of hospitalisation or death when given within 5 days of the onset of COVID-19 symptoms.

While molnupiravir was clearly effective, researchers wondered if there were any further clinical benefits attributable to the drug and therefore decided to perform a secondary analysis of data generated in the trial. In particular, the researchers focused on the need for respiratory interventions, COVID-19-related acute care visits and changes in the level of inflammatory markers such as C-reactive protein (CRP). The reported outcomes were assessed in terms of the relative risk reduction (RRR).

Additional clinical benefits of molnupiravir

The trial randomised 1433 participants to either molnupiravir or placebo. A reduction in CRP levels was noted as early as day 3 and this was greater than for the placebo group (-1.44 vs 1.92, molnupiravir vs placebo, p value not stated) and in fact, CRP levels in the placebo group did not reduce until day 10.

Fewer patients given molnupiravir required any respiratory interventions (RRR = 34.3%, 95% CI 4.3% – 54.9%), in particular noninvasive mechanical ventilation (RRR = 75.4%). In addition, among the subgroup of patients who became hospitalised, fewer treated with molnupiravir required any form of respiratory intervention (RRR = 21.3%).

There was also difference in the proportion of molnupiravir patients requiring either an acute care visit (RRR = 32.1%) or a COVID-19-related acute care visit (RRR = 33.8%) compared to those taking placebo.

While there were apparent improvements in numerical changes in CRP values, the authors did not report the associated statistics for the change and it is therefore unclear whether the observed differences between the outcomes examined were statistically significant. It is also unclear if these differences were clinically meaningful. A further limitation recognised by the authors was that the data were derived from patients who were unvaccinated against COVID-19 and so the generalisability of the findings to patients already vaccinated are not clear.

Despite these limitations, the authors concluded that their findings suggested added clinical benefits from the use of molnupiravir in the treatment of non-hospitalised adults with mild to moderate COVID-19.

Citation
Johnson MG et al. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19. A Randomized, Placebo-Controlled Trial Ann Intern Med 2022

Multiplex PCR point-of-care testing does not reduce antibiotic use in acutely ill children

14th June 2022

Multiplex PCR testing for respiratory pathogens does not reduce antibiotic prescribing among acutely ill children in comparison to usual care

The use of multiplex PCR for point-of-care testing for respiratory pathogens does not result in a significant reduction of antibiotic use among acutely ill children presenting at an emergency department compared to usual care. This was the conclusion of a randomised, controlled trial by Finnish researchers.

Acute respiratory tract infections are one of the leading causes of emergency department visits and are often due to viral pathogens. Moreover, children suffering from infectious diseases of either bacterial and viral origin, are often treated with empirical antibiotics due to a similarity in the presenting symptoms. For example, in a study of pharyngitis presentations in children, there was evidence of substantial antibiotic overuse and inappropriate antibiotic selection. Such over-prescribing highlights the need for strategies to guide prescribing decisions and one such approach is the use of multiplex PCR point-of-care testing. In fact, one randomised trial in children 3 to 36 months of age with febrile acute respiratory tract infections, found that among those assigned to rapid respiratory viral testing on admission, there was a significant reduction in antibiotic prescription after discharge from the emergency department. Based on these findings, in the present study, the Finnish team hypothesised that the use of a rapid multiplex PCR point-of-care testing panel for respiratory viral and bacterial pathogens would reduce the prescribing of antibiotics in acutely ill children.

Upon arrival at an emergency care department, children aged 0 to 17 years with a fever and or respiratory symptoms including tachycardia, shortness of breath, apnoea, were recruited and randomised 2:1 to either multiplex PCR point-of-care testing (which tested for 18 respiratory viruses and 3 bacteria) or usual care, where the patients were only tested using the multiplex system according to the clinical judgement of the treating physician. For the intervention group, the multiplex PCR test results were available within 70 minutes but not until the following day for the control group. The team set the primary outcome as the proportion of children with any antibiotic therapy that was started or on-going in the emergency department. For their secondary outcome, the team compared the number of diagnostic and radiographic imaging procedures undertaken in the two groups.

Multiplex PCR point-of-care testing and antibiotic use

A total of 1243 children were included of whom, 829 with a mean age of 3 years (55.9% male) were randomised to multiplex PCR testing. Among these children, 18.7% had only fever, where as 41.7% had both a fever and respiratory tract symptoms.

A prescription for antibiotics was given to 27.3% of children assigned to the multiplex PCR testing group and 28.5% of those in the control arm (risk ratio, RR = 0.96, 95% CI 0.79 – 1.16).

For the secondary outcome, there were no differences in either the number of diagnostic tests or imaging and overall emergency department costs were similar.

The authors concluded that systematic testing for respiratory pathogens in an emergency department had limited impacted on clinical decision-making over whether or not to prescribe antimicrobial therapy.

Citation
Mattila S et al. Effect of Point-of-Care Testing for Respiratory Pathogens on Antibiotic Use in Children: A Randomized Clinical Trial JAMA Netw Open 2022


Adjuvant metformin of no benefit in non-metastatic breast cancer

7th June 2022

Addition of metformin to standard chemotherapy for breast cancer did not produce a significant improvement of invasive disease-free survival

Adding metformin to standard breast cancer chemotherapy in women with non-metastatic, high-risk operable breast cancer, did not lead to a significant improvement of invasive disease-free survival. This was the conclusion of a randomised trial conducted by researchers in Canada, Switzerland and the UK.

Diabetic patients who develop cancer havea 40% higher mortality risk than non-diabetics. In addition, studies have suggested that type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer. The drug metformin is a biguanide that is used in the treatment of type 2 diabetes and works by decreasing gluconeogenesis and increases peripheral utilisation of glucose. In a 2015 meta-analysis of 11 studies, that compared the outcomes of breast cancer therapy in diabetes with and without metformin, the authors concluded that use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients. However, this is not a consistent finding in the literature. For instance, another study of over 2,300 women with breast cancer, the authors concluded that their study failed to show an association between improved survival and increased cumulative metformin use in breast cancer patients who had recent-onset diabetes. In contrast, a 2012 retrospective analysis, found that diabetic patients with breast cancer who received metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than those not receiving the drug.

However, the data in the above studies is derived from observational studies which are subject to several forms of bias. As a result, for the current study, the researchers focused specifically on metformin and undertook a randomised trial to determine whether the use of metformin in breast cancer patients without diabetes, positively impacted on treatment outcomes.

Adult women without diabetes who received standard therapy for a T1 to T3, No to N3, MO breast cancer were recruited and stratified as either oestrogen and/or progesterone receptor positive (ER/PgR +) or negative (ER/PgR -). Enrolled participants were then randomised 1:1, to 850 mg of metformin once daily or matching placebo for 4 weeks. The dose was then increased to twice daily for 5 years. Patients were followed-up at 6 and 12 months and then annually. The primary endpoint of the trial was invasive disease-free survival. Secondary outcomes included overall survival and the incidence rates for death.

Metformin and invasive disease-free survival

A total of 3649 women with a mean age of 52.4 years of whom, 2533 were ER/PgR + were recruited. However, futility was declared for the ER/PgR- group and so the analysis was restricted to the 2533 women who were ER/PgR +.

After a median follow-up of 96.2 months, 18.4% of women had invasive disease-free survival (234 in the metformin group vs 231 in the placebo arm), giving an incidence rate of 2.78 per 100 patient-years in the metformin group and 2.74 in the placebo group (hazard ratio, HR = 1.01, 95% CI 0.84 – 1.21, p = 0.93). Similarly, the risk of death was not significantly different (HR = 1.10, 95% CI 0.86 – 1.41, p = 0.47). Although futility was declared for those with ER/PgR-, among the patients who were followed up for a median of 94.1 months, there was also no difference in the level of invasive disease-free survival (HR = 1.01, 95% CI 0.79 – 1.30, p = .082). There were also no significant differences in any of the secondary outcomes.

The authors concluded that despite the evidence from observational studies, use of adjunctive metformin did not improve invasive disease-free survival in women with breast cancer.

Citation
Goodwin PJ et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial JAMA 2022

Eldecalcitol could reduce onset of diabetes in patients with impaired glucose tolerance

6th June 2022

Use of the vitamin D analogue eldecalcitol could potentially reduce the development of type 2 diabetes based on the findings of a recent RCT

Eldecalcitol, a vitamin D analogue, could prevent the development of overt type 2 diabetes in patients with impaired glucose tolerance although more data are required. This was the finding from a randomised, placebo-controlled trial by a team of Japanese researchers.

In 2017, it was estimated that globally, there were approximately 462 million individuals with type 2 diabetes ( 6.3% of the world’s population) and over 1 million deaths per year attributed to the disorder. Pre-diabetes is best described as an intermediate metabolic state between normoglycaemia and diabetes that is characterised by impaired glucose tolerance and impaired fasting glucose. Moreover, the presence of impaired glucose tolerance is associated with an increased risk of cardiovascular disease.

The potential role of vitamin D in diabetes has been suggested by the evidence that insulin secreting cells are able to not only produce but respond to the natural hormone 1-alpha, 25-Dihydroxyvitamin D3. In addition, low plasma 25-hydroxyvitamin D levels are associated with increased risk of type 2 diabetes in the general population. Furthermore, a systemic review and meta-analysis has revealed how in people with impaired glucose tolerance, vitamin D supplementation reduces the risk of type 2 diabetes and increases the reversion rate to normoglycaemia. Despite this, other studies have found that supplementation with vitamin D in patients who are not deficient in the vitamin is unlikely to prevent progression from pre-diabetes to diabetes.

With uncertainty over the value of vitamin D supplementation in those with impaired glucose tolerance, the present study undertook a randomised, placebo-controlled trial with eldecalcitol, a vitamin D analogue. The aim was to determine if eldecalcitol (which is used in Japan as a treatment for the prevention of osteoporosis) at a dose of 75mcg/day to patients with impaired glucose tolerance could prevent the development of type 2 diabetes.

Enrolled participants had a fasting glucose level < 126mg/dl and a glycated haemoglobin of < 6.5%. The primary outcome was the development of type 2 diabetes defined by either a glycated haemoglobin > 6.5% and a fasting glucose concentration > 200mg/dl. The main secondary outcome was regression to normoglycaemia.

Eldecalcitol and development of type 2 diabetes

A total of 1256 participants with a mean age of 61.3 years (44.5% female) were randomised to eldecalcitol (630) or placebo and followed for a median of 2.9 years. Among participants, the mean baseline 25-hydroxyvitamin D concentration was 20.9ng/ml.

During the follow-up period, 12.5% of those in the eldecalcitol group and 14.2% of those assigned to placebo developed type 2 diabetes (hazard ratio, HR = 0.87, 95% CI 0.67 – 1.17, p = 0.39), representing a non-significant difference. The proportion of patients regressing to normoglycaemia was also similar and not significantly different (HR = 1.15, 95% CI 0.93 – 1.41, P = 0.21).

Interestingly, when the researchers undertook a regression analysis that adjusted for 11 pre-specified covariates including age, sex, body mass index, glycated haemoglobin, they found that eldecalcitol was effective for the prevention of type 2 diabetes (HR = 0.69, 95% CI 0.51 – 0.95, p = 0.02).

They concluded that while eldecalcitol did not significantly reduce the incidence of type 2 diabetes or the level of regression to normoglycaemia, after adjustment for confounders, the drug was found to be effective at reducing the incidence of diabetes. As a result, it could be possible that eldecalcitol prevents the development of type 2 diabetes and they called for further work to examine their findings in more detail.

Citation
Kawahara T el al. Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population BMJ 2022