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18th May 2023
IV paracetamol provides similar analgesic relief to other treatments used for acute pain in emergency care, but might not be the best first-line drug, a new study has found.
Use of intravenous (IV) paracetamol for patients presenting at an emergency department (ED) with acute pain, irrespective of the aetiology, provides a similar level of analgesia after 30 minutes as both IV NSAIDs or opiates. However, NSAIDs require less rescue analgesia than paracetamol, suggesting that in the absence of contra-indications, the former would be a better first-line choice. This is according to the findings of a meta-analysis by Qatarian researchers.
Pain is a common presenting complaint within an ED. For instance, a review of 1,665 visits to ED found that in 61.2% of cases, pain was documented somewhere on the chart. IV paracetamol is a commonly used analgesic, with some, albeit limited evidence of efficacy according to a review of 14 studies. Nevertheless, many of the studies included in the review had several methodological flaws, hence lowering the certainty of the findings.
Given these flaws, the researchers undertook the current study to update the earlier review, particularly as over 20 studies had been published since the original review in 2016. The team examined the comparative analgesia provided by IV paracetamol, NSAIDs (intravenous or intramuscular) or IV opioids all used alone, in adults attending an ED with acute pain due to various causes.
The primary outcome was the mean difference (MD) in pain reduction for each group (i.e. IV paracetamol, NSAIDs or opiates), 30 minutes (T30) post-dose. Secondary outcomes were the MD in pain reduction after 60 (T60), 90 (T90) and 120 (T120) minutes. The team also considered the need for rescue medication at the different time points for the three treatment interventions.
The review identified 27 trials with 5,427 patients and of which, 25 trials had data for use in the meta-analysis.
There was no significant difference in the mean pain reduction at T30 between IV paracetamol and opiates (MD = −0.13, 95% CI −1.49 to 1.22). Similarly, the difference between paracetamol and NSAIDs was also non-significant (MD = −0.27, 95% CI −1.0 to 1.54). However, while there were no important analgesic differences between the treatments, the researchers did identify significant heterogeneity across trials for all comparisons (p < 0.001 in all cases).
Despite the similar analgesic effects, the need for rescue analgesia at T30 was higher in the paracetamol compared to NSAID group (risk ratio, RR = 1.50, 95% CI 1.23 – 1.83) but not for paracetamol and opiates (RR = 1.07, 95% CI 0.67 – 1.70). Furthermore, adverse effects were 50% lower with paracetamol in comparison to opiates (RR = 0.50, 95% CI 0.40 – 0.62) but not different compared to NSAIDs (RR = 1.30, 95% CI 0.78 – 2.15).
At T60, T90 and T120, there was no difference between paracetamol and opiates though paracetamol was inferior to NSAIDs at T60.
These findings led the authors to conclude that while reductions in pain from IV paracetamol after 30 minutes were similar to the other two drug classes, since NSAID use was associated with a lower need for rescue analgesia, these drugs should be considered as a first-line treatment option unless there are contra-indications.
10th May 2023
A study of nearly 27,000 hypertensive patients identified how roughly a third (32.5%) of patients had uncontrolled disease. Therapy guidelines invariably recommend monotherapy as a first-line approach and combination treatment only if this fails to control blood pressure (BP). Despite this, a meta-analysis of 354 RCTs in 2003, found that a low-dose combination of BP lowering drugs increases efficacy and reduces adverse effects. More recently, another analysis revealed how use of three drugs gave better blood pressure control than increasing dual therapy doses. Whether a low-dose combination (LDC) of three to four drug classes as an initial therapy provides better blood pressure control than monotherapy or usual care is uncertain.
In a recent systematic review and meta-analysis, researchers set out to determine the efficacy and safety of a LDC initial approach to hypertension management. They looked for RCTs that compared LDC to either monotherapy, usual care, or placebo. The primary outcome was the decrease in systolic hypertension using either LDC, monotherapy, usual care or placebo. Other measures assessed were the proportion achieving a BP <140/90 mm Hg, rates of adverse effects and treatment withdrawal.
Low-dose combination and systolic hypertension
A total of 7 trials with 918 patients with a mean age of 59 years (38% female) met the inclusion criteria.
Mean systolic BP was significantly lower with LDC than either monotherapy or usual care (mean difference, MD = 7.4 mmHg). LDC also increased the proportion of participants achieving BP < 140/90 mm Hg at 4 to 12 weeks (Risk Ratio, RR = 1.40, 95% CI 1.27-1.52). These findings were maintained at 6 to 12 months.
Although LDC led to more dizziness (RR = 1.28, 95% CI 1.00-1.63) no other adverse effects or treatment withdrawal occurred.
These findings suggest that LDCs with 3 or 4 antihypertensives is effective and well-tolerated as an initial treatment of 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.
27th April 2023
Prostate cancer (PC) is the second most common cancer in men with over 1.4 million new cases in 2020. Findings from 2003, suggest that 5-alpha reductase inhibitors (5-ARIs) such as finasteride, prevent or delay the appearance of prostate cancer. Other work with another agent, dutasteride, also noted a lower risk of incident prostate cancer. However, in 2011, the FDA warned that 5-ARIs may increase the risk of a more serious form of prostate cancer. Despite this the available data is conflicting. For example, in one study, use of 5-ARIs led to a delay in cancer diagnosis and worsened cancer-specific outcomes in men with PC. In contrast, another could not detect an association between 5-ARI use and prostate cancer death.
In the present study, researchers undertook a meta-analysis on the association of 5-ARI use and death from prostate cancer. The primary outcome was the incidence of PC mortality among 5-alpha reductase inhibitor users and non-users.
5-alpha reductase inhibitor use and prostate cancer
There were 11 studies meeting the inclusion criteria, only one of which was an RCT and the remainder cohort studies. A total of 3,243,575 men were identified, 138,477 of whom were using a 5-ARI drug.
There was no significant association between 5-ARI use and prostate cancer death (hazard ratio, HR = 1.04, 95% CI 0.80 – 1.35, p = 0.79). In addition, there was also no association when restricting the analysis to exclude patients with a PC diagnosis at baseline (HR = 1.0, 95% CI 0.60 – 1.67, p = 0.99). When adjusting for prostate specific antigen level, there was a lower risk of prostate cancer mortality but this was non-significant (HR = 0.76, 95% CI 0.57 – 1.03, p = 0.08).
6th April 2023
In a systemic review and meta-analysis, Canadian researchers found that the performance of an artificial intelligence (AI) model for the diagnosis of hip fractures was comparable with that of expert radiologists and surgeons.
Artificial intelligence (AI) models being increasing used for a range of healthcare applications, although the evidence for a beneficial effect on clinician diagnostic performance is spare. In contrast, models based on deep learning algorithms offer some promise for diagnostic purposes with findings to date suggesting that the diagnostic performance of such systems are equivalent to that of health-care professionals. With hip fractures associated with a huge morbidity and mortality, how useful is an AI model (AIM) for the automatic identification and classification of hip fractures and how does this compare with clinicians were the questions addressed by researchers in the current study.
The team performed a systematic review of the literature and included studies that involved the development of machine learning models for the diagnosis of hip fractures from hip or pelvic radiographs or to predict any postoperative patient outcome following hip fracture surgery. The team examined the diagnostic accuracy of an AIM in comparison to expert clinicians and used the areas under the curve (AUC) for postoperative outcome prediction such as mortality between traditional statistical models and that developed by the machine learning models.
AI model and hip fracture diagnosis
A total of 39 studies were included, of which 46.2% used an AIM to diagnose hip fractures on plain radiographs and 53.8% used an AIM to predict patient outcomes following hip fracture surgery.
When compared with clinicians, the odds ratio for diagnostic error of the AI models was 0.79 (95% CI, 0.48 – 1.31 p = 0.36) for hip fracture radiographs. In other words, although the analysis favoured an AIM, statistically, models were no better than clinicians. In addition, the mean sensitivity for the model was 89.3% and the specificity 87.5% and the F1 score (which that assesses the model’s accuracy) was 0.90 (range 0 to 1.0).
For post-operative predictions, e.g., such as mortality, the mean AUC was 0.84 with AI models and 0.79 for alternative controls and therefore not significantly different (p = 0.09).
The authors concluded that while promising for the diagnosis of hip fractures, the performance of AI models was comparable with that of expert radiologists and surgeons, adding that AI outcome prediction appears to provide no substantial benefit over traditional multivariable predictive statistics.
Citation
Lex JR et al. Artificial Intelligence for Hip Fracture Detection and Outcome Prediction: A Systematic Review and Meta-analysis. JAMA Netw Open 2023
3rd March 2023
Ethnic patients and those from different geographical regions benefit from lipid-lowering therapy despite being under-represented in clinical trials, according to a systematic review by UK and Australian researchers
The benefits of LDL cholesterol-lowering treatment as a preventative strategy against atherosclerotic cardiovascular disease is now well established. Despite this recognition, some evidence points to differences in response between Caucasian and other ethnic patients. For example, one comparative study revealed how the dose of statins and the extent to which LDL-cholesterol is reduced, varied between White and Asian patients. Other work has shown that plasma levels of rosuvastatin and its metabolites are significantly higher in Chinese, Malay, and Asian-Indians compared to White patients. However, while there are apparent ethnic differences in response to lipid lowering therapy, what is less clear, is if this impacts on the incidence of adverse cardiovascular outcomes.
In the current study, researchers undertook a systemic review and meta-analysis of randomised clinical trials, to assess the reductions in cardiovascular events associated with lipid-lowering therapy in not only ethnic patients but different geographic regions. They included statins, ezetimibe and PCSK 9 inhibitors and set the outcome of interest as major adverse cardiovascular events (MACE) which was a composite of cardiovascular mortality, myocardial infarction, stroke and revascularisation.
Ethnic patients and MACE
A total of 53 trials including 329,897 participants with a mean age of 61.8 years (73% male) were included in the analysis. In the trials which reported ethnicities, 60.3% were White, 20.2% Japanese, 9.4% Asian, 5.5% Black and 4.7% Latin American.
When looking across regions, there were reductions in statistically significant reductions in MACE in Australasia (Risk Ratio, RR = 0.75), North America (RR = 0.75), Europe (RR = 0.78) and Japan (RR = 0.73).
When considering ethnicities, there were significant reductions among Black patients (RR = 0.55, 95% CI 0.37 – 0.82) and Japanese (RR = 0.73, 95% CI 0.63 – 0.85) but a non-significant reduction among Asians (RR = 0.76, 95% CI 0.54 – 1.08). In head to head comparisons between regions and different ethnicities, there were no significant differences in the extent of MACE reduction.
The authors concluded that while there was under-representation in clinical trials, ethnic patients and those from different regions appeared to derive at least as much cardiovascular benefit from lipid-lowering therapy as majority groups.
Citation
Sawant S, Wang N. Underrepresentation of ethnic and regional minorities in lipid-lowering randomized clinical trials: a systematic review and meta-analysis. Eur J Prevent Cardiol 2023
28th February 2023
Researchers from Washington university in the US, performed a systematic review and meta-analysis finding that the protection afforded by a prior COVID-19 infection was high against re-infection from most pre-omicron variants and remained high against severe disease for all variants and was comparable to the protection from a two-dose vaccination with mRNA vaccines.
To date, several studies have suggested that a previous infection with COVID-19 offers some degree of protection against re-infection. However, studies have included different time periods as well as COVID-19 variants yet there are no analyses that have provided an overview of how the level of protection against re-infection varies over time and in relation to the different variants.
In the current analysis, the US researchers extracted data from studies through to September 2022 that examined the reduction in risk of developing COVID-19 in those with a prior COVID-19 infection compared to those without a previous infection. The data were then analysed to show the effectiveness of a prior infection against several outcomes including the risk of re-infection, symptomatic disease and severe disease based on the variant and time since infection.
Prior COVID-19 infection and re-infection outcomes
A total of 65 studies were included in the analysis from 19 different countries.
The pooled protection against re-infection varied depending on the variant ranging from 82% against delta to 90% against alpha. In contrast, the pooled protection against re-infection with omicron BA.1 was 45.3%. The protection against symptomatic disease was broadly similar, e.g. 85% for delta and 87.2% against alpha and only 44% against omicron BA.1.
The protection against severe infection (i.e., hospitalisation or death) was high for delta (97.2%), slightly lower against alpha (79.6%) but actually also high against omicron BA.1 (81.9%).
The pooled protection against ancestral, alpha and delta variants was initially high at 85.2% after 4 weeks but reduced to 78.6% at 40 weeks. In contrast, protection against re-infection from omicron BA.1 rapidly declined to 36.1% at 40 weeks.
The authors concluded that protection against re-infection was high against most variants pre omicron BA.1 adding that this level of protection was at least equivalent, if not greater than that provided by two-dose mRNA vaccines, which has also been observed in a previous study.
Citation
COVID-19 Forecasting team. Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis. Lancet 2023
15th February 2023
According to the findings of a systematic review in the Lancet, COVID-19 vaccine effectiveness wanes over time, even following booster doses, indicating that in the longer-term, it may be necessary to continue with preventative measures such as face-mask wearing and physical distancing to help manage the pandemic.
While the introduction of COVID-19 vaccines had an enormous impact on hospitalisations and mortality due to infection with the virus, it has been recognised that induced antibody levels reduce over time. A previous systematic review in 2022 observed that while vaccine efficacy against severe disease only dropped by 10% from one to six months, it reduced by approximately 21% against infection after 6 months and by nearly 25% against symptomatic illness. However, the analysis did not consider the impact of COVID-19 booster doses. As a result, in the current study, researchers examined the effectiveness of vaccination against infection, hospitalisation and death among those who had received a booster dose.
The team examined studies that provided data on vaccine effectiveness for at least 112 days after the primary series of vaccinations or at least 84 days after receipt of a booster dose. They set the primary outcomes of interest as effectiveness against COVID-19 infection, hospitalisation and mortality.
Vaccine effectiveness against COVID-19 outcomes
A total of 68 studies were included in the final analysis.
Overall effectiveness against any strain of COVID-19 reduced from 83% after a primary series of vaccinations to 62% by 112 to 139 days. Similarly, baseline effectiveness against hospitalisation was initially high at 92% but dropped to 79% after 168 – 195 days, as did effectiveness against mortality (91% to 86%) over the same period of time.
Among those who had received booster doses and for which most studies included the omicron variant, vaccine effectiveness against infection was initially 70% but reduced to 43% after 112 days. Similarly, boosted doses against hospitalisation reduced from a baseline of 89% to 71% over the same period of time. The authors reported that there was insufficient data to assess the impact on mortality.
Commenting on their findings, the authors suggested that maintaining COVID-19 prevention behaviours including the wearing of face-masks and physical distancing as well as vaccination may be necessary to reduce transmission of the virus, given how immunity wanes over time. They called for future studies to investigate the effectiveness of simultaneously using multiple approaches such as vaccination and face-masks as transmission preventative strategies.
Citation
Wu N et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir Med 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
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
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