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17th October 2022
The anti-viral drug remdesivir was the first medicine against COVID-19 to be recommended for authorisation in the European Union for adults and adolescents (from 12 years of age and weighing at least 40 kilograms) with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at the start of treatment). However, according to the summary of product characteristics of the drug, remdesivir should not be used in patients with eGFR < 30 mL/min. Nevertheless, death from COVID-19 has been reported to be as high as 30.5% among haemodialysis patients highlighting the need to improve the prognosis of this patient cohort after infection with the virus. In an observational study of 48 haemodialysis patients infected with COVID-19, when remdesivir was given at a dose of 100 mg 4 hours before the dialysis sessions, there were no significant effects on liver function tests. In addition, more than two-thirds of patients showed an improvement in oxygen requirement and the duration of hospital stay was reduced to a mean of 5.5 days.
With a suggestion that the drug was potentially safe and likely to be effective in patients with reduced renal function, for the present study, Korean researchers examined use of the drug in hospitalised patients receiving haemodialysis. The drug was given at a loading dose of 100 mg and then 50 mg for the next 2 to 4 days depending on the patient’s status. The primary outcome was a composite of in-hospital mortality, use of a high-flow nasal cannula or transfer to an intensive care unit.
Haemodialysis patients and COVID-19 outcomes
A total of 118 patients with a mean age of 68.5 years (66.1% male) were included in the analysis and of whom, 44 (37.3%) received remdesivir.
The composite primary outcome occurred in 2.3% of the remdesivir group and 13.5% of those not given the drug (p = 0.042). In addition, disease worsening was also lower (6.8% vs 20.3%, p = 0.049) in the remdesivir group.
In regression analysis, remdesivir use was independently associated with a lower occurrence of the primary outcome (adjusted odds ratio, aOR = 0.01, 95% CI 0.001 – 0.31, p = 0.009) and disease severity worsening (aOR = 0.08, 95% CI 0.02 – 0.42, p = 0.003).
The authors also reported no anaphylaxis or hypersensitivity reactions to the drug and that the incidence of liver enzyme elevation during hospitalisation did not significantly differ between the groups (22.7% vs 17.6%, p = 0.494).
They concluded that remdesivir was safe to use in haemodialysis patients and was associated with better clinical outcomes and a reduced risk of disease worsening.
Lim JH et al. Clinical Effectiveness and Safety of Remdesivir in Hemodialysis Patients with COVID-19 Kidney Int Rep 2022
11th March 2022
Undertaking muscle-strengthening activities, independently of aerobics, reduces the risk of cardiovascular disease (CVD), total cancer and all-cause mortality. This was the main finding from a meta-analysis by researchers from the Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Miyagi, Japan.
Increasing muscle strength is recognised as a marker of good health and the World Health Organization recommends regular muscle-strengthening activity for all age groups. The importance of muscle-strengthening activities was highlighted in a 2018 review which concluded that higher levels of upper- and lower-body muscular strength are associated with a lower risk of mortality in the adult population, regardless of age and follow-up period. Moreover, grip strength, which is a marker for overall strength, has also been found to be an independent predictor of all-cause mortality and cardiovascular diseases.
Although aerobic activities have become an established route for reducing both CVD and all-cause mortality risk, the relationship with muscular strength has been less well studied. For the present analysis, the Japanese team looked at the strength of the association between muscle-strengthening activities and the risk of CVD, cancer and mortality in adults. In addition, they were wanted to determine the dose-response relationship with health outcomes and also whether there were synergistic benefits from combing muscle strengthening and aerobic activities.
The team searched all the major databases from inception to 2020 for studies which considered the health outcomes from muscle strengthening activities in those without severe health conditions such as cancer at baseline.
Muscle strengthening activities and health outcomes
A total of 16 studies were included in the final analysis which covered all-cause mortality (8), CVD (9), total cancer (7), type 2 diabetes (5) and site-specific cancers (2). The number of participants varied between 3809 to 479,856 and the median duration of follow-up was 25.2 years and included patients 18 to 97 years of age.
Among studies which considered all-cause mortality, muscle-strengthening activities were associated with a 15% reduced risk of death (Relative risk, RR = 0.85, 95% CI 0.79 – 0.93, p < 0.001). With respect to the duration of activities, the lowest RR was seen at 40 minutes/week (RR = 0.83, 95% CI 0.79 – 0.86). Combing muscle and aerobic activities led to a 40% lower mortality risk (RR = 0.60, 95% CI 0.54 – 0.67) compared to no activity.
For CVD, there was a 17% lower risk from undertaking muscle-strengthening exercises (RR = 0.83, 95% CI 0.73 – 0.93) and the lowest relative risk occurred with training for at least 60 minutes/week (RR = 0.82, 95% CI 0.76 – 0.90).
Finally, muscle-strengthening activities led to a 12% lower risk of total cancer incidence (RR = 0.88) and a 17% lower incidence of diabetes (RR = 0.83).
Discussing their findings, the authors noted that there was a J-shaped relationship between muscle-strengthening activities and all-cause, CVD and total cancer mortality, with the greatest benefit (i.e., highest risk reduction) after 30 to 60 minutes/week of activities.
They concluded that the greatest benefit was accrued from combining muscle and aerobic activities although added the caveat that since the available data are currently limited, further studies are required to increase the certainty of the evidence.
Momma H et al. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies Br J Sports Med 2022
Giving baricitinib for 10 days to patients hospitalised with severe COVID-19 led to a 13% reduced risk of death compared with those in receipt of standard care. This was the main finding of the RECOVERY trial group at Oxford University, UK.
During the pandemic, several studies identified that a hyper-inflammatory response induced by the virus is a major cause of disease severity and death. Furthermore, data also indicates that glucocorticoids such as dexamethasone, can modulate this inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Another factor which mediates inflammation in COVID-19 is interleukin-6, a cytokine produced by macrophages that induces a pro-inflammatory response and is often found to be elevated infected patients. Baricitinib is a Janus Kinase (JAK) inhibitor and licensed for the treatment of both rheumatoid arthritis and atopic eczema. The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases. Consequently, inhibition of this pathway with drugs such as baricitinib, represent a potentially useful therapeutic option for patients with COVID-19. In fact, there is already some evidence that while baricitinib does not reduce disease progression in COVID-19, it is associated with a mortality benefit.
For the current trial, which is available as a preprint, the RECOVERY team evaluated the effectiveness of baricitinib in a large number of patients, to further strengthen the evidence base for the drug. Patients were eligible for inclusion to the study if they had either confirmed or suspected COVID-19 and where their attending physician believed that inclusion did not pose a risk to the patient, e.g., because of their medical history. Eligible patients were randomised 1:1 to either usual care plus baricitinib (10 mg daily for 10 days or until discharged if this was sooner) or usual care only. The primary outcome was 28-day all-cause mortality and secondary outcomes included time to discharge from hospital and a composite outcome of invasive mechanical ventilation or death among those not mechanically ventilated at the point of randomisation.
Baricitinib and mortality
A total of 8156 patients were included with 4148 (mean age 58.5 years, 66% male) randomised to baricitinib. Upon entry to the study, 95% of participants were receiving corticosteroids and 23% tocilizumab.
Among those allocated to baricitinib, the primary outcome occurred in 12% compared to 14% in the usual care group (adjusted rate ratio, RR = 0.87, 95% CI 0.77 – 0.98, p = 0.026). This reduction was similar (although non-significant) when adjusted for those with a confirmed positive PCR test (RR = 0.90, 95% CI 0.79 – 1.02).
In the baricitinib group, there was a lower risk of progression to the composite secondary outcome (RR = 0.90, 95% CI 0.81 – 0.99).
The authors concluded that their large randomised trial provided further and more robust evidence for the beneficial effects of baricitinib and support the use of the drug for patients hospitalised with COVID-19.
RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. MedRxiv 2022
8th February 2022
The mortality in heart disease patients has been found to be lowest for those with a body mass index (BMI) between 25 and 35 and which is higher that the level recommended in prevention guidelines. This was the conclusion of the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) study by researchers from the Department of Medical Sciences, Uppsala Clinical Research, Sweden.
According to the World Health Organization (WHO), overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. Obesity is measured using BMI values and WHO defines someone as overweight if their BMI is greater than or equal to 25 and obese if their BMI is greater than or equal to 30. Based on these criteria, WHO estimates that in 2016, 39% of adults (18 years and older) were overweight and 13% were obese. Moreover, elevated BMI levels have been associated with numerous diseases and metabolic abnormalities including hyper-insulinaemia, insulin resistance, hypertension, dyslipidaemia, coronary heart disease and certain malignancies. However, despite the potential adverse cardiovascular sequelae associated with obesity, many studies and meta-analyses have demonstrated an obesity paradox in that the overweight and mildly obese having a better prognosis than do their leaner counterparts with the same level of cardiovascular disease.
The relationship between BMI and cardiovascular outcomes is therefore not straight forward and this relationship was further confused by the results of a 2019 study which concluded that while obesity was independently associated with increased risk for long-term mortality among patients with stable coronary artery disease, being overweight did not appear to confer an additional mortality risk.
For the present study, the Swedish team examined the association between BMI and mortality in heart disease patients based on data from the STABILITY study, a randomised, placebo-controlled trial evaluating the phospholipase A2 inhibitor in patients with stable coronary heart disease. Patient’s BMI was measured at baseline and the associations with cardiovascular outcomes were evaluated by Cox regression analysis with multivariable adjustments of several factors including gender, age, prior myocardial infarction, renal dysfunction, smoking status etc. The primary outcomes of interest were the composite of cardiovascular death, myocardial infarction and stroke whereas a secondary outcome was all-cause mortality.
Mortality in heart disease patients during follow-up
The study included 15,785 patients with a mean age of 64.9 years (18.7% female) and who were followed up for a mean of 3.7 years. In total, 1.5% of participants had a BMI < 20, 19.4% a BMI of 20 – 25, 42.8% a BMI of 25 – 30, 25.1% a BMI of 30 – 35 and 11.2% a BMI > 35.
In fully adjusted models, among those with the lowest BMI (< 20), there was a more than doubling of the risk of all-cause mortality (Hazard ratio, HR = 2.27, 95% CI 1.60 – 3.22), cardiovascular death (HR = 2.26) and heart failure (HR = 2.51) compared to those with a BMI of 25 – 30 which served as the reference point. Similarly, all-cause mortality was higher among those with a BMI of 20 – 25 (HR = 1.21) and cardiovascular mortality (HR = 1.26).
For the most obese patients (BMI > 35), the risk of all-cause mortality was higher than the reference group (HR = 1.18) and as was the risk for cardiovascular mortality (HR = 1.23).
In discussing their findings, the authors noted how mortality in heart disease was effectively U-shaped, i.e., the highest risks were in those with both the lowest and highest BMI values. They calculated that the lowest risk was for those with a BMI of 27 which was considered as ‘overweight’ in guidelines which advocate an ideal BMI of 20 to 25, suggesting how their data indicated that a slightly higher BMI was optimal.
Held C et al. Body Mass Index and Association With Cardiovascular Outcomes in Patients With Stable Coronary Heart Disease – A STABILITY Substudy J. Am Heart Assoc 2022
9th September 2021
It is well established that physical activity is associated with health benefits such as a lower risk of coronary heart disease, stroke and type 2 diabetes. One widely accepted means of quantifying physical activity is the number of steps/day although this metric is not generally included in national physical activity guidelines. However, while a 2019 review noted an inverse relationship between daily steps and positive health outcomes such as all-cause mortality and cardiovascular events, it concluded that more independent studies are required before these observations can be translated into public health guidelines. This is despite a 2020 review concluding that walking an additional 1000 steps/day can help lower the risk of all-cause mortality and cardiovascular disease morbidity. In addition, while there is some evidence that an increased intensity of physical activity is associated with greater health benefits, it is unclear whether the number of steps/day and step intensity positively impact on mortality.
In trying to establish whether both the number of steps/day and intensity affected mortality, a team from the Institute for Applied Life Sciences, University of Massachusetts, US, conducted a prospective study in middle-aged Black and White adults. Participants were recruited from the Coronary Artery Risk Development in Young Adults (CARDIA) study which included a balanced sample by race (e.g., Black and White), sex, age and education levels from four different locations across the US. Participants were asked to wear an ActiGraph 72164, which measures the number of free-living steps/days, for 7 consecutive days during waking hours. Based on the number of recorded steps, participants were then grouped as low (<7000 steps/day), moderate (7000–10,000) and high (>10,000). They quantified step intensity as daily minutes at 100 steps/min or more, which indicates moderate intensity. The primary outcome was all-cause mortality and the results were adjusted for several covariates including smoking status, race, body mass index, alcohol intake and a measure of diet, the healthy eating index.
There were 2110 participants recruited with a mean age of 45.2 years (57.1% female), of whom 42.1% were of Black ethnicity. Individuals were followed-up for a period of 20 years. Compared with those in the low step group, there was a significantly lower mortality in those in the moderate group (adjusted hazard ratio, aHR = 0.28, 95% CI 0.15 – 0.54). Interestingly, among those taking a higher number of steps/day, the reduction in risk was less (aHR = 0.45, 95% CI 0.25 – 0.81), indicating no potential mortality benefit from taking more than 10,000 steps/day.
Subgroup analysis revealed no difference in risk reductions among Black (aHR = 0.30) or White participants (aHR = 0.37), for those in the moderate step groups or between the sexes, aHR = 0.28 (women) and aHR = 0.42 (men). Furthermore, the step intensity did not affect mortality estimates.
The authors concluded that taking at least 7,000 steps/day during middle-age was associated with a lower mortality risk but that step intensity had no impact.
Paluch AE et al. Steps per Day and All-Cause Mortality in Middle-aged Adults in the Coronary Artery Risk Development in Young Adults Study. JAMA Netw Open 2021
6th September 2021
Coronary heart diseases are the leading global cause of death and responsible for an estimated 17.9 million lives lost each year. The idea that influenza might contribute to the development of myocardial infarction (MI) and subsequent death, comes from autopsy studies of patients who died during influenza epidemics. In fact, a recent analysis of 364 hospitalisations for acute MI, confirmed a significant association between respiratory infections, especially influenza and MIs. It is therefore possible that administration of an influenza vaccination as both a primary or secondary preventative measure, could improve cardiovascular disease outcomes. However, a Cochrane review from 2015, concluded that among those with cardiovascular disease, influenza vaccination may reduce mortality and combined cardiovascular events but that more and higher-quality evidence is necessary to confirm these findings.
This need for more high-quality evidence was the reason for the Influenza vaccination After Myocardial Infarction (IAMI) trial undertaken by researchers from the Faculty of Health, Department of Cardiology, Orebro University, Sweden. The team hypothesised that influenza vaccination would reduce the incidence of death, further MIs and stent thrombosis, in patients with a recent MI or with high-risk coronary disease, which included those with stable coronary artery disease and 75 years of age or older with additional risk factors. Eligible patients for the trial were those with either ST-elevation myocardial infarction (STEMI) or non-STEMI. Patients were excluded if they had received an influenza vaccination during the previous 12 months. Participants were then randomised 1:1 to either influenza vaccine or placebo (saline) within 72 hours of their MI. The primary endpoint of interest was a composite of all-cause death, MI, or stent thrombosis at 12 months.
There were 2571 individuals with a mean age of 59.9 years (81% male) randomised to either arm. Overall, 54.5% of participants were admitted with STEMI and 45.2% with non-STEMI and 8 with stable coronary artery disease. Over the following 12 months, the primary outcome occurred in 5.3% of those vaccinated and 7.2% of those in the placebo group (hazard ratio, HR = 0.72, 95% CI 0.52 – 0.99, p = 0.04). The mortality rates were 2.9% (influenza vaccine) and 4.9% placebo (HR = 0.59, 95% CI 0.39 – 0.90, p = 0.014). In addition, within the influenza vaccination group, 2% experienced a subsequent MI compared to 2.4% in the placebo group (p = 0.57). None of the patients with stable coronary artery disease died.
Discussing their findings, the authors noted how the early administration of influenza vaccination led to a reduced risk of death compared to placebo. They concluded that the provision of influenza vaccination should form part of the in-hospital treatment received by patients following a myocardial infarction.
Frobert O et al. Influenza Vaccination after Myocardial Infarction:
A randomised, Double-Blind, Placebo-Controlled, multi-center Trial. Circulation 2021
27th August 2021
According to the World Cancer Research Fund, colorectal cancer (CRC) is the third most commonly cancer in men and the second most common cancer in women. Moreover, the most recent data from 2018, shows that worldwide, there were over 1.8 million new cases of CRC. The relationship between cancer and hypertension is uncertain although in a retrospective study of over 25,000 cancer patients, new onset hypertension was found in a third of individuals. This relationship might be related to the vascular endothelial growth factor (VEGF) proteins, which are mediators of angiogenesis and lymphangiogenesis in tumours and have been found to be elevated in patients with hypertension. It is conceivable therefore, that the use of anti-hypertensives may exert a protective effect in those with cancer. This was the theory behind a retrospective study of patients with CRC undertaken by a team from the University of Virginia, School of medicine, Virginia, US. They examined a Medicare database which contained patient demographic information for those with cancer. They focused on patients with CRC aged 65 years and older but excluded those with any stage of CRC prescribed anti-hypertensives prior to the cancer diagnosis. The researchers extracted data on the clinical characteristics of CRC including stage and tumour grade and examined adherence to anti-hypertensive therapy based on the proportion of days covered (PDC), which is a measure of adherence with values greater than 0.80 used to define patients who are adherent to their anti-hypertensive therapy. All classes of anti-hypertensives were included and the period of follow-up started 1 year after the initiation of blood pressure lowering therapy. The primary outcome was CRC-specific mortality and the team used hazard regression models to examine the association between the use of individual anti-hypertensives and mortality.
A total of 13,982 patients were included in the analysis. A range of factors were found to be associated with CRC mortality including male gender (hazard ratio, HR = 1.07, 95% CI 1.03 – 1.13) and interestingly, being single, rather than married (HR = 1.08). The use of anti-hypertensives was associated with a decreased CRC-specific mortality (HR = 0.79, 95% CI 0.75 – 0.83). Furthermore, there was a significant association between adherence to treatment (i.e., those with a PDC greater than 0.80 and decreased mortality (HR = 0.94, 95% CI 0.90 – 0.98). Among the different types of drugs, significant associations were found for only angiotensin enzyme converting enzyme inhibitors (HR = 0.84), beta-blockers (HR = 0.87) and thiazide diuretics (HR = 0.83).
In discussing these results, the authors were cautious that these novel findings would need to be researched further as a potential tool to improve cancer-related mortality. However, they concluded that anti-hypertensive medications might represent a promising pathway to supporting patients with CRC.
Balkrishnan R et al. Associations between initiating antihypertensive regimens on stage I–III colorectal cancer outcomes: A Medicare SEER cohort analysis. Cancer Med 2021
9th July 2021
Excessive systemic inflammation and which is characterised by increased levels of various interleukins including interleukin-6 (IL-6), has become a key feature of COVID-19 infection. The interleukin-6 antagonists that have received most attention are the monoclonal antibodies, tocilizumab and sarilumab, which either bind directly to IL-6 or its membrane bound receptor. Whether or not there is an overall mortality benefit from the use of interleukin-6 antagonists in those hospitalised with COVID-19 remains uncertain. Some studies have found there to be a benefit whereas other have found no obvious benefit and others still have concluded that there remains some doubt over the relative harms and benefits of these treatments. Given the ambiguity of the available data, a team from the World Health Organisation, undertook a meta-analysis of studies in which IL-6 antagonists were used in patients hospitalised with COVID-19. The overarching aim of the analysis was to determine the association between the administration of IL-6 antagonists and 28-day mortality compared to usual care. Eligible trials were those in which patients had been randomly assigned to an IL-6 antagonist or usual care. The primary outcome was set as all-cause mortality, 28 days after treatment randomisation. However, the team also considered both the class effect and the two individual IL-6 antagonists, tocilizumab and sarilumab separately. A secondary outcome was the comparison of IL-6 antagonists versus corticosteroids.
A total of 27 eligible trials were included in the meta-analysis and at the time, 9 were fully published and the remainder available only as preprints. Tocilizumab was studied in 19 trials and administered to 4299 patients whereas sarilumab was given to 2073 patients. The median patient age across all trials was 62 years and a third (33%) of patients were female. In the trials, most patients were receiving respiratory support at randomisation. After 28 days of treatment, there were 1407 deaths among patients allocated to interleukin-6 antagonists and 1158 deaths in those assigned to usual care. This gave rise to a summary odds ratio (OR) of 0.86 (95% CI 0.79 – 0.95, p = 0.003) corresponding to an absolute reduction in mortality of 22% for the intervention. For tocilizumab, summary OR was 0.83 (95% CI 0.74–0.92, p < 0.01) although the summary OR for sarilumab was not significant (OR = 1.08, 95% CI 0.86–1.36). In comparison with corticosteroids, the summary OR was 0.77 (95% CI 0.68–0.86) for tocilizumab and 0.92 (95% CI 0.61–1.38) for sarilumab.
The authors noted that while there were apparent differences in mortality between the two interleukin-6 antagonists, this was possibly because sarilumab trials had been conducted earlier in the pandemic when the use of corticosteroids was not part of standard care. Nevertheless, they concluded that the use of interleukin-6 antagonists was associated with a lower 28-day mortality compared with usual care.
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalised for COVID-19. A Meta-analysis. JAMA 2021