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9th May 2023
Undiagnosed hypertension appears to be present in a large number of young men and who seem to be otherwise healthy. Rod Tucker explores the evidence and discusses how screening young adults for the condition could have a big impact on patient care.
Globally, hypertension is the main cause of cardiovascular disease and leading cause of early death. Moreover, there are several recognised risk factors for the disease and modification of these can reduce the risk of developing hypertension. But to what extent does the condition remain undiagnosed and what specific factors contribute to this under-diagnosis?
This was a question posed in a recent report by the UK’s Office for National statistics (ONS). The team used data from a sample of 21,476 adults and examined both the prevalence of the condition and the degree to which it was undiagnosed. The report estimated that hypertension (defined as blood pressure greater than 140/90mmHg) affected approximately 32% of adults living in private households in England. An additional finding was the condition remained undetected in 29% of cases, which equates to some 4.2 million adults across England.
But perhaps of greater concern, was that hypertension was less likely to be diagnosed among younger adults, largely because, as a group, such individuals are generally perceived as having better health. The ONS analysis suggested that undiagnosed hypertension was present in 66% of men and 26% of women, aged 16-24.
To put this into perspective, the ONS estimated that only 17% of men and 21% of women aged 75 years and over – where hypertension is much more common – had undiagnosed disease. Although younger men were were proportionately more likely to be undiagnosed than older adults, the highest total estimated number of cases of unrecognised hypertension was seen in males aged 55-64 years (500,000 cases) and females aged 65-74 years (460,000 cases).
But were there any specific factors or reasons to account for undiagnosed disease? In a further analysis, the ONS identified, for instance, hypertension was more prevalent when an individual self-reported their general health as ‘very good or good’ (males 41%, females 28%) compared with ‘bad or very bad’ (males 18%, females 14%). Interestingly, while being overweight or obese are recognised risk factors for the condition, undetected disease was actually more likely in men who were not overweight or obese (44%) compared with obese individuals (30%). Additional factors included those who had never smoked (36%) and if they lived in a rural (42%) as opposed to an urban location (32%).
The authors of the report propose that their data provides valuable insight for health services to help improve outcomes. Yet, this immediately raises a problem for healthcare providers in that the current risk stratification process for hypertension screening is predicated on the fact that the disease has a lower prevalence in younger adults. For example, one US study of 21,581 individuals found that a normal blood pressure was observed in 57.8% of those aged 18-44.
In other work by the CDC in the US, hypertension was identified in just over a fifth (22.4%) of those aged 18-39. Consequently, younger adults are likely to be excluded from hypertension services. In fact, the recently introduced NHS community pharmacy blood pressure check service in the UK is designed to ‘identify people over the age of 40 who have previously not been diagnosed with hypertension’.
Is it right to exclude younger people from hypertension screening? While levels of hypertension are generally lower in the younger age group, this is confounded to some extent by the current obesity epidemic. For instance, it has been suggested that approximately 30% of obese adolescents have hypertension. Furthermore, other estimates are that one in eight adults aged between 20 and 40 years have hypertension and that it is associated with abnormalities on heart and brain imaging, increasing the likelihood of cardiovascular events by middle age. Nevertheless, despite these risks, there is currently a paucity of randomised trial data demonstrating a health benefit from blood pressure lowering in this patient group.
But if there is one important take-home message from the ONS report, it is that the current risk stratification for hypertension screening requires modification and should not be age-restricted. Screening young people, especially if they are either overweight or obese, would enable an assessment of end-organ damage in those with even mildly elevated blood pressure. This revised strategy would allow clinicians to provide relevant lifestyle advice and to instigate therapy where this fails. Such an approach would inevitably help to identify and improve outcomes for those with undiagnosed hypertension.
4th May 2023
Nausea and vomiting were responsible for 1.6 million US emergency department (ED) visits in 2007. Antiemetic drugs such as ondansetron and metoclopramide are effective. Despite this, there is a lack of evidence to support the efficacy of one drug over any other. There is some evidence that inhaled isopropyl alcohol (IPA) appears effective for post-operative nausea and vomiting (PONV). For example, 70% inhaled IPA is more effective than promethazine in PONV. How well inhaled IPA compares to other anti-emetics is currently unknown.
The present meta-analysis searched for trials using IPA to treat adult ED patients with nausea and vomiting. The primary outcome was set as a change in nausea severity, measured by a validated scale.
Inhaled isopropyl alcohol and nausea reduction
Only two trials with a total of 195 patients met the inclusion criteria. The pooled decrease in nausea severity was 2.18 on a 0-10 scale, favouring inhaled IPA over placebo. A further trial comparing inhaled IPA and oral ondansetron did not meet the inclusion criteria but was useful for a secondary analysis. This analysis found a similar decrease in nausea (2.16).
There were no differences between inhaled IPA and placebo for the number of vomiting episodes.
The authors report that the available evidence suggests that inhaled IPA significantly reduces self-reported nausea in patients presenting to the ED with the condition. However, they note that only 275 participants have evaluated the intervention, adding the need for larger trials of the intervention.
Upper gastrointestinal (GI) bleeding mortality is 5-10% largely due to peptic ulcers and portal hypertensive gastropathy. A common scoring system to evaluate patients with upper GI bleeding is the Glasgow-Blatchford Score (GBS). In fact, the European Society of Gastrointestinal Endoscopy suggests that a GBS score of <1 prior to endoscopy, indicates a low risk of re-bleeding. Both GBS and a modified version appear to be moderately accurate for decision-making in those with an upper GI bleed. CANUKA has a similar performance to the GBS and more accurately identifies those with a low risk for adverse outcomes. Nevertheless, currently, there is a lack of comparative data on these three systems.
Recently, researchers sought to compare the effectiveness of each system for identifying patients at low risk of death or the need for a subsequent intervention. Using a retrospective approach, the team considered emergency department patients with an upper GI bleed. They explored the need for blood transfusion, endoscopic haemostasis or re-bleeding within seven days. The scoring system sensitivity, specificity, positive and negative predictive values were used as outcome measures. Cut-off thresholds for low risk of the GBS, the modified version (mGBS) and CANUKA were set at <1, 0 and <2 respectively.
GBS and CANUKA identification of low-risk upper GI bleeding patients
There were 386 patients with a median age of 60 years (65.3% male) with sufficient data to calculate the three scores.
Using the threshold levels for GBS, mGBS and CANUKA, 24.9%, 18.2% and 18.9% of patients respectively, were at low risk. Furthermore, with these cut-off levels, only 2.2%, 4.6% and 0% respectively, required a further intervention. Sensitivity values with these cut-offs were broadly similar (98.2% to 100% for CANUKA). The negative predictive values ranged from 97.8% (GBS) to 100% for CANUKA. In addition, no deaths occurred for patients identified as being at low risk.
These findings led the authors to conclude that a Glasgow-Blatchford score of <1 and a CANUKA score of <2 appears to be safe for identifying patients at low risk of death or the need for an intervention following an upper GI bleed.
Low back pain (LBP) is responsible for nearly 5% of all emergency department visits. Opioids and NSAIDs are useful emergency department (ED) treatments for acute LBP. Moreover, skeletal muscle relaxants, including diazepam (DP) and methocarbamol (MC) can serve as viable alternatives. Despite this, there is insufficient evidence to identify whether any one class of medication has a net advantage.
This lack of evidence led to researchers to undertake the current study. This double-blind RCT set out to compare intravenous DP with MC in acute non-traumatic musculoskeletal LBP. Both groups of patients also received morphine. Pain assessment was performed using a simple numeric rating scale, NRS, ranging from 0 (no pain) to 10 (worst possible pain). The primary outcome was the difference in pain relief post-intervention after 60 minutes.
Diazepam and post-intervention pain relief
There were 101 patients with 51 who received diazepam. Pain scores were lower with both treatments in comparison to baseline levels (p < 0.001). After 60 minutes, pain score reductions were slightly greater with DP (p = 0.048). The length of stay in the ED was similar between the two groups (MC = 5.9 hours vs DP = 4.8 hours, p=0.365). However, patients receiving diazepam were more likely to report drowsiness (4% vs 15% , p = 0.001).
These findings led the authors to concluded that DP and MC gave rise to similar pain relief after 60 minutes. Nevertheless, DP use may be associated with more drowsiness.
Raised cardiac troponin in acute dyspnoea could be a useful prognostic marker in those without an acute myocardial infarction (MI).
Acute dyspnoea is a common complaint within an emergency department (ED). Dyspnoea is also a common symptom of an acute myocardial infarction (MI), affecting nearly two-thirds of patients. This consequently necessitates prompt patient assessment.
High-sensitivity cardiac troponin T (CTT) can quickly assess patients with chest pain to rule out an MI. Nevertheless, elevated cardiac troponin T levels can also occur in those experiencing chest pain without an MI.
In the current study, researchers set out to determine role of CTT in ED patients presenting with acute dyspnoea not due to an acute MI. Adult patients with acute dyspnoea were included and CTT levels measured together with their clinical history. CTT levels were divided into three levels: <15, 15-100 and >100 µg/l. An analysis provided the three-month relative risk of mortality with adjustment to models for a patient’s clinical history.
Cardiac troponin and three-month mortality risk
A sample of 1001 patients had usable data. With CTT levels < 15 set as the reference point, a CTT level between 15 and 100 gave rise to a more than three-fold higher mortality risk (Hazard ratio, HR = 3.68 (95% CI 1.72-7.84). The mortality risk was even higher with levels above 100 µg/l (HR = 10.523, 95% CI 4.46-24.80).
Patients with higher cardiac troponin levels were generally older, had a higher number of co-morbidities and more severe symptoms. The researchers felt that the data highlighted the value of CTT as an important risk factor in acute dyspnoea without a cardiac cause.
3rd May 2023
Janus kinase inhibitor (JAK inhibitors) use is common for a range of rheumatic conditions. However, prior data suggests an elevated malignancy risk with the Janus kinase inhibitor tofacitinib than with a tumour necrosis factor inhibitor (TNFi). In contrast, a recent and real-world data analysis was unable to detect a higher cancer risk with JAK inhibitors.
At the British Society for Rheumatology Conference 2023, UK researchers undertook a meta-analysis of the malignancy risk with JAK inhibitors. The analysis examined the risk of all JAK inhibitors with other agents such as TNFi and methotrexate (MTX). Researchers sought phase 2/3/4 randomised trials and long-term extension (LTE) studies. The JAK inhibitors were tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib. Studies examining the drugs in rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, or atopic dermatitis were included. The researchers used the incidence of malignancy as their primary outcome. Secondary outcomes were either non-melanoma skin cancers (NMSCs) or malignancies excluding NMSCs.
Malignancy risk and JAK inhibitor use
Data from a total of 62 RCTs and 14 LTE studies were eligible for analysis. There were 71,767 person-years of exposure to JAK inhibitors, 2,680 to placebo, 7,827 to TNFi and 1,074 to MTX.
The incidence rate ratio (IRR) for malignancy risk in JAKis compared to placebo, including NMSCs was non-significant (IRR = 0.81, 95% CI 0.52 – 1.26, p = 0.36). Similarly, for JAKis and MTX (IIR = 0.73, 95% CI 0.33 – 1.61, p = 0.43).
In contrast, compared with TNFis, use of a JAKi was associated with a higher malignancy risk (IRR = 1.54, 95% CI 1.19 – 2.01, p = 0.001). These findings were consistent for the secondary analyses, i.e., when analysing NMSC only, excluding NMSC and when including LTE data.
Vitamin D can modulate both innate and adaptive immune responses. Moreover, recent work suggests that vitamin D exerts anti-proliferative effects on tumour cells. Some research also demonstrates how the vitamin up-regulates programmed death ligand 1 expression. This findings indicates a possible synergic effect in combination with immune-checkpoint inhibitor treatment. But whether this improves the objective response rate during advanced melanoma treatment remains unclear.
The current study looked at the effect of vitamin D levels during anti-PD-1 immunotherapy with nivolumab or pembrolizumab in advanced, inoperable or metastatic melanoma. Serum levels of vitamin D were either reduced (group 1) or normal (group 2). Researchers then compared the objective response rate, progression-free and overall survival between the two groups.
Objective response rate and vitamin D levels
Data were available for 200 patients. Among those in group 1, the objective response rate (ORR) was significantly lower than for group 2 (36.2% vs 56%, p = 0.011). Similarly, there was a shorter progression-free survival (5.75 vs 11.25 months, p = 0.037). In addition, a lower proportion of patients had a complete response (7.8% vs 10.3%). Finally, the overall survival was lower in group 1 but the difference with group 2 was non-significant (27 vs 31.5 months, p = 0.39).
The researchers suggest that vitamin D levels should be within the normal range during anti-PD-1 immunotherapy in advanced melanoma patients.
Multiple sclerosis (MS) affects more than two million people worldwide and is currently incurable. Some evidence shows that high levels of vitamin D reduce the risk of MS. In fact, among MS patients using interferon beta-1b, adding vitamin D reduces disease activity. Despite this, randomised trials of vitamin D in relapsing-remitting MS fail to show an improvement. Nevertheless, these trials only involve interferon beta. Glatiramer acetate reduces the relapse rate in MS and therefore affects disability. Whether addition of vitamin D to glatiramer could reduce the relapse rate in MS is uncertain.
The present study tested if adding vitamin D to glatiramer could reduce disease activity in those with active MS. In a phase 3 RCT, participants had either a high (5000 IU/day) or low (600 IU/day) dose of vitamin D in conjunction with glatiramer. Participants with relapsing-remitting (RR) MS aged 18–50 years and with recent disease activity were eligible to enrol. Participated had an Expanded Disability Status Scale score ≤4.0 and a minimum serum vitamin D level of 15 ng/ml. The primary outcome was the proportion experiencing a confirmed relapse.
Glatiramer acetate and vitamin D and relapses
A total of 172 individuals, 89 receiving high dose vitamin D were enrolled. Participants were followed for 96 weeks.
Confirmed relapse rates did not differ at week 96 (hazard ratio, HR = 1.17, 95% CI 0.67 – 2.05, p = 0.57).
The authors suggested that vitamin D and glatiramer does not reduce the risk of clinical relapse in people with RRMS.
2nd May 2023
Osteoarthritis (OA) is a common form of arthritis which globally affects 528 million people. Treatment focuses on drug therapy, self-management and exercise. In addition, there are currently no preventative therapies available. Metformin is an oral hypoglycaemic agent for the treatment of type 2 diabetes. The drug also appears to have other actions including the ability to suppress inflammation. In fact, there appears to be a beneficial effect on long-term knee joint outcomes in those with osteoarthritis and obesity. However, whether metformin can prevent the development OA is less clear.
In the current study, US researchers explored if metformin was able to lower the risk of developing OA as well as the need for joint replacement in type 2 diabetics. The team undertook a retrospective analysis using sulfonylureas as a comparator anti-diabetic therapy. Individuals with a prior diagnosis of OA were not included in their analysis. Researchers propensity-matched metformin and sulfonylurea patients 1:1. The primary outcome of interest was the time to an incident diagnosis of OA, 90 days after starting either medication.
Osteoarthritis development and anti-diabetic therapy
There were 41,874 individuals with a mean age of 62 years (41.8% female) with usable data for analysis. Among this total, 20,937 were receiving metformin.
The risk of developing osteoarthritis was 24% lower in those using metformin than a sulfonylurea (Hazard ratio, HR = 0.76, 95% CI 0.68 – 0.85, p < 0.001). However, there was no significant difference between the two groups in the risk for joint replacement (HR = 0.80, 95% CI 0.50 – 1.27, p = 0.34). Similar findings were obtained in a sensitivity analysis (HR = 0.77, 95% CI 0.65 – 0.90, p < 0.001) for OA.
These findings led the authors to suggest that metformin may have a protective effect against the development of OA.
Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) that presents with inflammation of the colonic mucosa. Estimates suggest that in 2017 there were 6·8 million global cases of IBS. To date, conventional IBD medical therapies currently only target the inflammatory component of the condition. However, evidence suggests microorganisms within the intestine have pro-inflammatory or anti-inflammatory activities which may modulate IBD. The concept of ‘dysbiosis‘, i.e., an alteration of the commensal microbial organisms relative to those in healthy individuals, may play a role in IBD. Faecal transplantation (FT) may play a role to correct dysbiosis in UC. In fact, there is evidence that the strategy is effective for Clostridium difficile infection.
Whether faecal transplantation is effective for ulcerative colitis was the subject of a recent Cochrane review. The researchers looked for randomised controlled trials that studied adults and children with UC or Crohn’s disease (CD). Eligible studies made use of FT, which is the delivery of healthy donor stool containing gut microbiota to a recipient’s gastrointestinal tract to treat UC or CD. The review examined both clinical and endoscopic disease remission.
Faecal transplantation and ulcerative colitis
A total of 12 studies with 550 participants were included. Studies lasted for 6 to 12 weeks.
Findings suggest that faecal transplantation may increase rates of induction of clinical remission in UC compared to control (risk ratio, RR = 1.79, 95% CI 1.13 – 2.84). Similarly, FT may increase rates of induction of endoscopic remission in UC (RR = 1.45, 95% CI 0.64 – 3.29). However, since the confidence intervals are wide, there is low certainty evidence for this effect. Two additional studies gave very uncertain evidence that FT could maintain clinical remission.
Taken together, it appears that FT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. But there was less evidence that FT was effective for maintenance of remission in people with the condition.
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