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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