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21st December 2022
Cannabidiol (CBD) oil given to patients with advanced cancer receiving palliative care provided no additional benefit to that care according to the findings of a randomised trial by Australian researchers.
Although there have been several advances in medical care, a proportion of patients with advanced cancer still experience substantial symptom distress. The use of palliative care seeks to improve both symptom control and quality of life but despite this, some symptoms can be difficult to control, necessitating more effective medications. Both cannabis and cannabinoid drugs containing cannabidiol, are widely used to treat disease or alleviate symptoms. However, a 2015 meta-analysis concluded that whilst there was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity, there was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy. In a feasibility study, Australian researchers examined the use of global symptom burden measures to assess the response to medicinal cannabis with both cannabidiol and tetrahydrocannabinol. They concluded that doses of both cannabidiol and tetrahydrocannabinol were generally well tolerated and that the outcome measure of total symptom distress was promising as a measure of overall symptom benefit.
Based on the these early and promising findings, the same group undertook a randomised trial to determine whether cannabidiol oil could improve symptom distress in patients with advanced cancer receiving palliative care. They included adult participants with advanced cancer and symptom distress which was measured using the Edmonton Symptom Assessment Scale [ESAS]. Participants received titrated CBD oil 100 mg/mL, 0.5 mL once daily to 2 mL three times a day, or matched placebo for 28 days. The ESAS scale is designed to rate the intensity of nine common symptoms experienced by cancer patients, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being and shortness of breath. For the trial participants, the inclusion criterion was an ESAS score greater than or equal to 10/90. The primary outcome was set as the total ESAS symptom distress score (TSDS) at day 14, with a response defined as a decrease greater than or equal to, 6 at day 14.
Cannabidiol oil and symptom distress
A total of 58 patients receiving CBD and 63 placebo, reached the primary analysis point (i.e., day 14) and the median dose of participant-selected CBD was 400 mg per day.
The unadjusted change in TSDS from baseline -6.2 for the placebo group and -3.0 for those receiving CBD and this difference was non-significant (p = 0.24). Equally, there was no significant difference in proportion of responders (placebo = 58.7% and CBD = 44.8% p = 0.13).
In fact, during the study, all components of the ESAS improved (that is, reduced) over time with no difference between the placebo and CBD arms. In addition, there was no detectable effect of CBD on quality of life, depression, or anxiety. Overall, most participants reported feeling better (53% CBD vs 65% placebo) or much better (70% CBD and 64% placebo) by day 14.
The authors concluded that CBD oil did not add value to the reduction in symptom distress provided by specialist palliative care alone.
Citation
Hardy J et al. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol 2022
In a head-to-head trial, zanubrutinib provided superior progression-free survival compared to ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, according the the results to a study by team of international researchers.
Chronic lymphocytic leukaemia (CLL) is an adult leukaemia characterised by abnormal accumulation of immunologically incompetent lymphocytes in blood, bone marrow, lymph nodes, and spleen and accounts for 25–30% of all leukaemias in Western Countries, leading to over 100,000 incident cases with more than 40,000 global deaths reported in 2019. In contrast, small lymphocytic lymphoma (SLL) comprises approximately 7% of newly-diagnosed cases of non-Hodgkin’s lymphomas although often at the time of diagnosis, most patients present with advanced-stage disease including generalised lymphadenopathy, hepatosplenomegaly and bone marrow involvement.
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signalling and which is critical for proliferation and survival of leukaemia cells in many B cell malignancies. Moreover, oral irreversible BTK inhibitors such as ibrutinib, have been shown to provide a high response rates in patients with relapsed/refractory CLL and mantle-cell lymphoma. Zanubrutinib is a highly selective Bruton tyrosine kinase inhibitor that is well tolerated and demonstrated activity in patients with relapsed/refractory mantle cell lymphoma. In a multinational, phase 3, randomised trial, the same international research group, performed a head-to-head comparison of zanubrutinib with ibrutinib as treatment for relapsed or refractory CLL or small lymphocytic lymphoma (SLL). At a pre-specified interim analysis, the results showed that zanubrutinib provided a significantly higher overall response rate, lower atrial fibrillation rate and improved progression-free survival compared to ibrutinib after 15 months. In the current study, researchers provided an update on progression-free survival after nearly 30 months. In the trial, participants with relapsed or refractory CLL or SLL and who had received at least one previous course of therapy, were randomised 1:1 receive zanubrutinib at a dose of 160 mg twice daily or ibrutinib at a dose of 420 mg daily until the occurrence of disease progression or unacceptable toxic effects.
Zanubrutinib and progression-free survival
A total of 652 patients with a median age of 67 years (68.3% male) were included and randomised to zanubrutinib (327) or ibrutinib and followed for a median of 29.6 months.
In terms of progression-free survival, zanubrutinib was superior for disease progression or death with 87 vs. 118 occurrences of disease progression or death (hazard ratio, HR = 0.65, 95% CI 0.49 – 0.86, p = 0.002). At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group.
Furthermore, the safety profile of zanubrutinib was better than ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.
The authors concluded that among those with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib and that the drug was associated with fewer cardiac adverse events.
Citation
Brown JR et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2022
According the findings of a systematic review and meta-analysis undertaken by Korean researchers and presented at the American Society of Haematology conference, 2022, tafasitamab showed a trend for best efficacy among failed autologous stem cell transplantation (ASCT) or ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients.
Diffuse large B cell lymphoma is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas and which presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extra-nodal site. Non-Hodgkin lymphomas account for about 80% of all lymphomas and while there are more than 30 subtypes, the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Although 5-year survival rates range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Moreover, outcomes for refractory or relapsed patients are poor, with one study of 861 patients, 636 of whom had refractory disease, finding that the median overall survival was 6.3 months and that only 20% of patients were alive at 2 years. For patients with relapsed/refractory disease, there are several combination chemotherapy regimens available including tafasitamab-cxix, polatuzumab vedotin-piiq, bendamustine as well as CAR T cell therapies. Nevertheless, the most effective treatment remains to be determined.
In the present study, the Korean researchers performed a systematic review and meta‐analysis to identify prospective phase II or III clinical studies evaluating the efficacy of treatments for ASCT-failed or ineligible relapse/refractory DLBCL patients. They used random effects models to estimate one-year progression-free survival rate, complete remission rate, and subgroup differences. In addition, meta-regression models were performed with adjustment for relevant covariates, particularly the median number of previous lines of systemic therapy and CAR T cell therapy was used as a reference treatment in the meta-regression analysis.
Tafasitamab and one-year progression-free survival
The researchers identified 56 cohorts in 50 studies with 3,544 relapsed/refractory DLBCL patients. For the analysis, treatment regimens were divided into nine groups: CAR T cell therapy, chemotherapy, lenalidomide-based therapy, ibrutinib-based therapy, tafasitamab-based therapy, polatuzumab plus bendamustine and rituximab (pola-BR), loncastuximab, selinexor, and others.
The pooled one-year progression-free survival rate was 0.40 (95% CI 0.35 – 0.46) for CAR T cell therapy, 0.23 (95% CI 0.16 – 0.30) for chemotherapy, 0.28 (95% CI 0.19 – 0.37) for lenalidomide and 0.46 (95% CI 0.37 – 0.56) for tafasitamab.
Although CAR T cell treatment was significantly better than many of the others, in fact, loncastuximab, pola-BR, and tafasitamab were all shown to have no significant difference in efficacy to CAR T cell therapy after adjustment for the median number of prior lines of treatment in the meta-regression analysis.
The authors concluded that tafasitamab showed a trend of best efficacy and that CAR T cell therapy was no more effective than tafasitamab, loncastuximab or pola-BR. However, because of the high level of heterogeneity, the authors called for randomised controlled trials to confirm their findings.
Citation
Kim J et al. Comparison of Several Salvage Treatments of Relapsed/Refractory Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta‐Analysis. Abstract 2986 ASH conference 2022
20th December 2022
Use of aprocitentan in patients with treatment-resistant hypertension provides a superior reduction in systolic blood pressure compared to placebo with a sustained action four weeks after discontinuation according to the results of a randomised, double-blind trial by Australian and US researchers.
The incidence of hypertension, which is a major factor for cardiovascular disease, appears to be on the increase. In a 2021 study, the number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 million women and 317 million men in 1990 to 626 and 652 million respectively in 2019. Resistant hypertension has been defined as above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a diuretic. In fact, the prevalence of resistant hypertension has been found present in 10.3% of the general population. One potential pharmacological target for patients with resistant hypertension is blockage of endothelin, which is a powerful vasoconstrictor peptide derived from the endothelium. Initial studies with a selective endothelin type A antagonist, darusentan, in patients with resistant hypertension, showed that the drug provided additional reduction in blood pressure in patients who had not attained their treatment goals with three or more antihypertensive drugs. Early studies with aprocitentan, which is an orally active, dual endothelin receptor antagonist, found that it was well tolerated and that there were no clinically significant findings for any safety variable. Moreover, in a dose ranging study in patients with essential hypertension, compared to lisinopril 20 mg, aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office blood pressure. This led the authors to conclude that their findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension.
In the current study, researchers undertook the PRECISION trial, that recruited patients with a sitting systolic blood pressure of 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts. The first was a 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. In part 2, all patients received aprocitentan 25 mg and in the final part, which was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary endpoint was the change in unattended office systolic blood pressure from baseline to week 4 and the secondary endpoint, the blood pressure changes from withdrawal baseline to week 40.
Aprocitentan and treatment outcomes
A total of 730 participants with a mean age of 61.7 years (59.3% male) were included in part 1 and of whom, 577 (94%) completed part 3 of the study. At screening, between 62 and 65% of participants were receiving > 4 antihypertensive agents.
The change in systolic blood pressure at 4 weeks was -15·3 mm Hg for aprocitentan 12·5 mg, -15·2 mm Hg for aprocitentan 25 mg, and -11·5 mm Hg for placebo. In both cases, the difference compared to placebo was statistically significant (p = 0.0042 and 0.0046) for the 12.5 and 25 mg doses respectively. There was also a significant reduction in diastolic blood pressure (-3.9 mmHg and – 4.5 mmHg) for the 12.5 and 25 mg doses.
After 4 weeks of withdrawal, the office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 – 7·9, p < 0·0001).
In terms of adverse effects, the most frequent were mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the initial 4-week double-blind phase, leading to treatment discontinuation in seven aprocitentan patients.
The authors concluded that for patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.
Citation
Schlaich MP et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 2022
Use of a purified eicosapentaenoic acid (EPA) formulation in patients with coronary artery disease prescribed statins, reduced the incidence of adverse cardiovascular outcomes such as myocardial infarction and stroke compared to a control group not taking the formulation, according to the findings of a study by Japanese researchers presented at the American Heart Association (AHA) conference in Chicago.
Statin therapy leads to a reduction of cardiovascular events in both primary and secondary prevention. Since no treatment is fully effective in all patients, one therapy that has attracted interest over many years has been the omega-3 polyunsaturated fatty acids (PUFAs). However, recent studies with PUFAs have been contradictory with one trial in patients with elevated triglyceride levels despite the use of statins, finding that the risk of ischaemic events, was significantly lower among those who received 2 g of icosapent ethyl twice daily (a highly purified EPA) than among those who received placebo. In contrast, a second trial, again in statin-treated patients, concluded that the addition of omega-3 to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events.
Due to these contrary findings, The Japanese team sought greater clarity of the role of PUFAs and presented data from the Randomized Trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy – statin and EPA (RESPECT-EPA) trial. Participants, all of whom had chronic coronary artery disease and were treated with statin therapy, were randomised to highly purified EPA (1800 mg/day) or control groups (i.e., no EPA therapy) and the primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischaemic stroke, unstable angina pectoris, and clinically indicated coronary revascularisation. A further inclusion criterion was a low EPA/arachidonic acid ratio (< 0.40).
Highly purified EPA and cardiovascular outcomes
A total of 2506 participants with a mean age of 68 years (17% female), of whom 45% had diabetes, were included and randomised to the highly purified EPA (icosapent ethyl 1800 mg daily, n = 1,249) or control and followed for 5 years.
The primary outcome occurred in 10.9% of the icosapent ethyl group vs. 14.9% of the control group (p = 0.055). For the secondary outcomes, sudden cardiac death, myocardial infarction, unstable angina, or coronary revascularisation, this occurred in 8.0% in the icosapent ethyl group vs. 11.3% in the control group (p = 0.031). However, there was a higher incidence of gastrointestinal disorders in the icosapent ethyl group (3.4% vs 1.2%, p < 0.001).
The authors concluded that among Japanese patients with chronic coronary artery disease and treated with statin therapy, icosapent ethyl may be associated with a reduction in adverse cardiovascular outcomes.
Citation
Bavry AA et al. Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid – RESPECT-EPA. Presented at the American Heart Association Scientific Sessions, Chicago, IL, November 6, 2022
PCSK9 inhibitor persistence in patients with familial hypercholesterolaemia (FH) appears to be very high over time and associated with achievement of low-density lipoprotein cholesterol (LDL-C) goals as well as an improvement in quality-of-life according to an analysis of clinical practice data by Spanish researchers.
Familial hypercholesterolaemia is associated with premature atherosclerotic cardiovascular diseases and is inherited as an autosomal dominant trait. Due to the presence of dysfunctional low-density lipoprotein (LDL) receptors because of a genetic mutation, serum LDL-C levels are considerably increased from birth. Within the general population, a recent meta-analysis of 62 studies estimated a pooled FH prevalence of 1:311. According to the 2019 ESC/EAS Guidelines for the management of dyslipidaemias, patients with FH are categorised as being at very high risk of cardiovascular disease. Consequently, the guidelines recommend a therapeutic regimen that achieves ≥50% LDL-C reduction from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). In addition, studies have suggested that the use of a PCSK9 inhibitor led to a 54.9% mean reduction in LDL-C from baseline in those with severe heterozygous FH. Nevertheless, information on the persistence or adherence to treatment with PCSK9 inhibitors in patients with FH, which is required to reduce the burden of atherosclerotic disease over time, is lacking. In the current study, researchers set out to examine the persistence to treatment, efficacy and impact on quality of life of PCSK9 inhibitor use in FH patients within a real-world clinical setting.
The researchers used data from the Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART), an open, prospective study in genetically defined FH patients in Spain. They included patients on stable lipid-lowering therapy and who were managed and with a PCSK9 inhibitor (PCSK9i), although the choice of which agent was decided by the treating clinician. For the study, researchers measured persistence as the % of patients staying on a PCS9Ki at the end of each year of follow-up and quality of life was assessed with the EuroQol 5D.
PCSK9 inhibitors persistence and effectiveness over time
A total of 696 patients with a median age of 56.4 years (46% female) were included and followed for a median of 3.7 years with the median baseline LDL-C being 3.8 mmol/L. Background lipid lowering therapy was a statin and ezetimibe in 74.6% of cases and statin monotherapy in 17.5% of cases.
During the follow-up, persistence with PCSK9i was 96.1% for the whole period. At the last follow-up visit, the median LDL-C had reduced by 58%. In addition, at the last follow-up visit, 48% of patients had achieved the 2019 ESC/EAS LDL-C goal.
There were also improvements in quality of life after the first year and this remained stable over time.
The authors concluded that there was long-term persistence with PCSK9i in patients with FH patients within a clinical practice setting and that use of a PCSK9i vastly increased attainment of LDL-C goals.
Citation
Alonso R et al. Persistence with long-term PCSK9 inhibitors treatment and its effectiveness in Familial Hypercholesterolemia: data from the SAFEHEART study. Eur J Prev Cardiol 2022
Widespread state medical marijuana legalisation in the US is associated with a lower rate of opioid dispensing and pain-related hospital events among some adults receiving treatment for newly diagnosed cancer according to an analysis by US researchers.
Pain is an extremely common cancer symptom with a 2022 meta-analysis of 12 studies (10 with breast cancer and 2 lung cancer) patients, finding a pooled pain prevalence rate of 40%. Although paracetamol and non-steroidal anti-inflammatory drugs are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder, strong opioids are the mainstay of analgesic therapy in treating moderate to severe cancer-related pain. Nevertheless, with tightened regulations leading to a decrease in opioid prescribing across the United States, evidence points to a decline in opioid use among end-of-life care in those with cancer although there has been a rise in pain-related emergency department visits, suggesting that end of life cancer pain management may be worsening. Although medical marijuana has been studied and found to be efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids, a 2016 review suggested that while marijuana may have the potential for refractory cancer pain, much of the data are based on animal data, small trials, or are outdated.
With the potential to help patients with cancer pain, in the current study, US researchers set out to assess the associations between medical marijuana legalisation and opioid-related and pain-related outcomes for adult patients receiving cancer treatment. The team used data from national commercial claims between 2012 to 2017. The researchers assessed several measures including the proportion of patients having 1 or more days of opioids and 1 or more pain-related emergency department visits or hospital events, during the 6 months after a new cancer diagnosis.
Medical marijuana and opiate use
A total of 38,189 patients with newly diagnosed breast cancer, 12,816 with colorectal cancer (55.4% male) and 7,190 (51.1% female) with lung cancer were included in the analysis.
Medical marijuana legalisation was associated with a reduction in the rate of 1 or more opioid days from 90.1% to 84.4% (difference = 5.6, 95% CI 2.2 – 9.0, p = 0.01) among breast cancer patients. For colorectal cancer patients, there was also a reduction, this time from 89.4% to 84.4% (difference = 4.9, 95% CI 0.5 – 9.4, p = 0.03). Finally, opioid use reduced from 31.5% to 22.1% (difference = 9.4, 95% CI 0.8 – 17.9, p = 0.03) among patients with lung cancer with recent opioids.
Medical marijuana legalisation was also associated with a reduction in the rate of 1 or more pain-related hospital events from 19.3% to 13.0% (difference = 6.3, 95% CI 0.70 – 12.0, p = 0.03) among patients with lung cancer with recent opioids. However, the difference for the other two forms of cancer was not significant.
The authors concluded that medical marijuana legalisation was associated with a lower rate of opioid dispensing and pain-related hospital events among some adults receiving treatment for newly diagnosed cancer.
Citation
Bao Y et al. Medical Marijuana Legalization and Opioid- and Pain-Related Outcomes Among Patients Newly Diagnosed With Cancer Receiving Anticancer Treatment. JAMA Oncol 2022
19th December 2022
An AI model which uses data derived from a single chest X-ray, is able to predict the 10-year risk of death from a heart attack or stroke, stemming from atherosclerotic cardiovascular disease (ASCVD) according to the results of a study presented at the Radiological Society of North America (RSNA) conference 2022.
The term ‘deep learning’ refers to a subset of machine learning, which is essentially a neural network with three or more layers which attempt to simulate the behaviour of the human brain — albeit far from matching its ability—allowing it to “learn” from large amounts of data. Among patients with cardiovascular disease, risk assessment is a critical step in the current approach to primary prevention of atherosclerotic cardiovascular disease (ASCVD). Knowledge of the 10-year risk for atherosclerotic cardiovascular disease identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat for both statins and antihypertensive therapy. The current assessment of risk relies on a limited set of risk factors, namely, age, sex, systolic blood pressure, antihypertensive treatment, total and HDL-cholesterol, diabetes, and cigarette smoking. However, according to Jakob Weiss, a radiologist affiliated with the Cardiovascular Imaging Research Center at Massachusetts General Hospital and who was involved in the RSNA study, ‘variables necessary to calculate ASCVD risk are often not available, which makes approaches for population-based screening desirable adding that, ‘as chest X-rays are commonly available, our approach may help identify individuals at high risk.’
In the current study, Dr Weiss and his team, developed the AI model (referred to as CXR-CVD) using 147,497 chest radiographs (CXR) from 40,643 participants from the PLCO cancer screening trial and which was trained to predict cardiovascular mortality from a single CXR image. In addition, the team undertook independent testing in a second separate cohort of 11,430 outpatients potentially eligible for primary prevention and with no prior major adverse cardiovascular events (MACE). The prognostic value of the AI model was compared to the established ASCVD risk score in a subset of 2,401 (21%) patients and for whom, the variables necessary to calculate ASCVD risk were available. The primary outcome was observed 10- year incident MACE and both hazard ratios (HR) and c-statistics were estimated using Cox proportional hazards regression.
AI Model prediction of cardiovascular risk
A total of 11,430 patients with a mean age of 60.1 years (42.9% male) were included in the independent testing dataset. Over a median follow-up of 10.3 years, there were 9.6% MACE events documented.
Using the AI model, there was a significant association with MACE in statin eligible patients (HR = 2.03, 95% CI 1.81 – 2.30, p < 0.001) and after adjustment for cardiovascular risk factors, this association remained significant (HR = 1.63, 95% CI 1.43 – 1.86, p < 0.001).
In the subgroup of patients for whom all the necessary ASCVD variables were available, the performance of the AI model was similar (c-statistic = 0.64 vs. 0.65; p = 0.48) to but also additive to, the ASCVD risk score (HR = 1.58, 95% CI 1.20 – 2.09, p = 0.001).
The authors concluded that using a single routine CXR image, the AI model was able to predict 10-year incident MACE with similar performance and incremental to the established clinical standard. They added that since CXR images are commonly available, our approach may help identify individuals at high risk for cardiovascular disease, prompting risk factor assessment and targeted prevention.
Citation
Weiss J et al. Deep Learning to Predict 10-year Cardiovascular Risk from Chest Radiographs. Presented at the RSNA 2022.
A retrospective study presented at the Radiological Society of North America (RSNA) 2022, of patients with a history of COVID-19 infection found that several weeks after an acute infection with the virus, there was a statistically significant higher level of liver stiffness compared to non-infected control patients.
Liver stiffness (LS) is closely associated with hepatic fibrosis in patients with chronic liver disease but is also increased in patients with acute hepatitis, acute liver failure and cholestasis. In fact, LS (which is expressed in kilopascals, kPa) is a rapid and excellent screening test for liver cirrhosis and which can be measured non-invasively with shear wave elastography. Previous work has shown that the presence of LS ≥ 9.6 kPa, is associated with more severe COVID‐19 disease hence liver stiffness can be used as a marker of fibrosis. However, whether LS persists over time and leads to liver damage is uncertain.
In the study presented at the RSNA, researchers from Massachusetts General Hospital in Boston, used ultrasound shear wave elastography (SWE) to compare LS in patients with and without COVID-19 infection. The researchers created three patient cohorts: the first cohort were COVID-19 patients, with a confirmed and positive PCR test result at least 12 weeks before their SWE; the second cohort was a pandemic, random control group who underwent elastography during the COVID-19 pandemic but with no history of COVID-19; the final group comprised a random sample of pre-pandemic patients. The team set the primary endpoint as the average difference in median Young’s modulus between post-COVID-19 patients and controls after adjusting for age, sex and time period in a linear regression model.
Liver stiffness differences between the groups
There were 131 patients with a mean age of 55.5 years (51.1 % female) included in the study, 31 of whom had tested positive for COVID-19 and scans were undertaken an average 44 weeks after participant’s infection with the virus.
After statically adjusting for age, sex, and time period, COVID-19 infection was associated with an average increase in median Young’s modulus of 1.71 kPa (95% CI 0.67 – 2.75, p = 0.002). In addition, COVID-19 participants had higher median liver stiffness compared to contemporaneous controls (median = 7.68 vs 5.99 kPa, p <0.001). However and somewhat unexpectedly, pre-pandemic controls had higher median stiffness compared to post-pandemic controls (median = 7.01 kPa, p = 0.56).
The researchers concluded that COVID-19 infection is associated with increased liver stiffness which may reflect lasting liver injury following infection.
However, in a press release from the conference, one of the researchers, Dr Firouzeh Heidari said that ‘we don’t yet know if elevated liver stiffness observed after COVID-19 infection will lead to adverse patient outcomes‘ adding that ‘we are currently investigating whether the severity of acute COVID-related symptoms is predictive of long-term liver injury severity.’
Citation
Heidari F et al. Lasting Liver Injury Following COVID-19 Infection Measured by Ultrasound Shear Wave Elastography. RSNA Conference 2022
According to a press release by drug manufacturer Lilly, donanemab provides a greater level of brain amyloid clearance compared to aducanumab at 6 months.
Brain amyloid-β deposition is a hallmark used to define Alzheimer’s disease. Moreover, in March 2022, the Food and Drug administration (FDA) in the US, approved the first in vitro diagnostic test for early detection of amyloid plaques associated with Alzheimer’s disease. The FDA added that a positive test was consistent with the presence of amyloid plaques, similar to what would be seen in a PET scan and that a negative result is consistent with a negative amyloid PET scan result, reducing the likelihood that a patient’s cognitive impairment was due to Alzheimer’s disease, enabling physicians to pursue other causes of cognitive decline and dementia.
The current data announced by Lilly, comes from the TRAILBLAZER-ALZ 4 trial, which was a randomised, open-label phase 3 study designed to compare donanemab (DM) with aducanumab (AM) on amyloid plaque clearance in participants with early, symptomatic Alzheimer’s Disease. In the trial, donanemab and aducanumab were administered via intravenous infusions every four weeks for up to 18 months.
Donanemab efficacy
In the co-primary outcomes, brain amyloid plaque clearance, defined as achieving brain amyloid plaque levels of <24.1 Centiloids, was achieved in 37.9% of DM-treated participants compared with 1.6% of AM-treated patients at 6 months. In the intermediate tau subpopulation, 38.5% of DM-treated participants reached brain amyloid clearance compared with 3.8% of AM-treated participants by 6 months. In a key secondary outcome, DM reduced brain amyloid levels vs. baseline by 65.2% compared with 17.0% for AM at 6 months. In an exploratory outcome, donanemab, but not aducanumab treatment significantly reduced plasma P-tau217 at 6 months compared to baseline.
In terms of safety, amyloid-related imaging abnormalities were the most common treatment emergent adverse event in both groups and occurred with a similar frequency (25.4% vs 26.1%, DM vs AM).
Although only 6-month data is currently, available, the press release describes how TRAILBLAZER-ALZ 4 is an on-going study and results from 12 or 18 months will be presented once available.
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