A regular series on the latest clinical studies from around the world – and what they mean ‘in practice’ – compiled and written by Clare GP Dr Ray O’Connor
1. Cardiovascular Health
What are the benefits of healthy elderly people taking aspirin regularly? Aspirin is an antiplatelet agent that has been used in low doses (75-100mg/d) for the prevention of cardiovascular events. It continues to be widely used for primary and secondary prevention of stroke. Its major adverse effect is an increased bleeding tendency.
The objective of this trial1 was to establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin. The study was a secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin.
The participants were 19,114 older adults (56.4 per cent females with a median age of 74 years, community-dwelling), living in Australia or the US. They were free of symptomatic cardiovascular disease and were followed up for a median of 4.7 years. 9,525 individuals received aspirin and 9,589 individuals received placebo. The main outcome was stroke.
The main finding was that aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke. However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin compared with those receiving placebo.
The conclusion was that low-dose aspirin may have no role for the primary prevention of stroke and that caution should be taken with use of aspirin in older persons prone to head trauma (eg, from falls).
Aspirin is known to be associated with increased risk of GI bleeding, especially in the elderly. Another secondary analysis from the same ASPREE study2 looked at the risk of anaemia in those taking aspirin.
It was found that taking a 100-mg dose of aspirin each day was associated with a 20 per cent higher risk of anaemia compared with a placebo. The incidence of anaemia was about 51 events per 1,000 person-years in the aspirin group and 43 events in the placebo group.
Participants who received daily aspirin also tended to have a larger decrease in ferritin levels—a measure of overall iron stores—and in haemoglobin concentration over three and five years, respectively.
Both of these results make it difficult to justify giving aspirin as prevention to healthy elderly.
Predicting Atrial Fibrillation
Lifestyle risk factors are a modifiable target in atrial fibrillation (AF) management. The relative contribution of individual lifestyle risk factors to AF development has not been described. Development and validation of an AF lifestyle risk score to identify individuals at risk of AF in the general population were the aims of this study.3 It used data from the UK Biobank and Framingham Heart Study, which are large prospective cohorts with outcomes measured over 10 years.
Incident AF was based on ICD 10 coding. Prior AF was excluded. Cox proportional hazards regression identified independent AF predictors, which were evaluated in a multivariable model. The result was the development of the HARMS2-AF score. The score is calculated as follows (parameter followed by score in brackets): Hypertension (4); Age 60-64 (1); 65+ (2); Raised BMI of 30 or more (1); Male gender (2); Sleep apnoea (2); Smoking (1); Alcohol 7-14u/wk (1); >15u/wk (2). The probability of remaining free of AF based on the score is shown in the chart below.
Diet and CVD and all-cause mortality
Unhealthy diets have been ranked as a major factor for death and cardiovascular disease (CVD) globally. The aim of this study was to develop a healthy diet score that is associated with health outcomes and is globally applicable using data from the Prospective Urban Rural Epidemiology (PURE) study and replicate it in five independent studies on a total of 245,000 people from 80 countries. The consistency of the associations of the score with events was examined in five large independent studies from 70 countries.4
The healthy diet score was developed based on six foods each of which has been associated with a significantly lower risk of mortality [i.e. fruit, vegetables, nuts, legumes, fish, and dairy (mainly whole-fat); range of scores, 0–6]. The main outcome measures were all-cause mortality and major cardiovascular events.
During a median follow-up of 9.3 years in PURE, compared with a diet score of ≤1 points, a diet score of ≥5 points was associated with a lower risk of mortality, CVD, myocardial infarction, and stroke. These findings applied to all world regions, especially in countries with lower income where consumption of these foods is low.
- Cloud G et al. Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People. Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open. 2023;6(7):e2325803. doi:10.1001/jamanetworkopen.2023.25803.
- Harris E. Daily Dose of Aspirin Linked With Anemia in Older People. JAMA. 2023;330(3):210. doi:10.1001/jama.2023.11954.
- Segan L et al. New-onset atrial fibrillation prediction: the HARMS2-AF risk score. European Heart Journal (2023) 00, 1–11. https://doi.org/10.1093/eurheartj/ehad375.
- Mente A et al. Diet, cardiovascular disease, and mortality in 80 countries. European Heart Journal (2023) 00, 1–20. https://doi.org/10.1093/eurheartj/ehad269.
Hearing loss and dementia
Hearing loss is associated with increased cognitive decline and incident dementia in older adults. The ACHIEVE study1 aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. It was a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70–84 years with untreated hearing loss and without substantial cognitive impairment, that took place at four community study sites across the USA.
Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and follow-up was every six months. The primary endpoint was three-year change in a global cognition standardised factor score.
Analysis was by intention to treat. The findings were that hearing intervention did not reduce three-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort.
These findings suggest that a hearing intervention might reduce cognitive change over three years in populations of older adults at increased risk for cognitive decline, but not in populations at decreased risk for cognitive decline.
Daytime napping and brain volume
Daytime napping has been associated with cognitive function and brain health in observational studies. However, it is unknown whether these associations are causal. This study from the UK Biobank2 looked at the relationship between habitual daytime napping and cognition and brain structure. The authors concluded that there was a modest causal association between habitual daytime napping and larger total brain volume. More research is needed on the topic.
Hormone Replacement Therapy and Dementia
Dementia affects more women than men worldwide. Even when controlling for differences in survival rates, the incidence of dementia among women is higher compared with that of men, suggestive of risk factors related to the female sex. This was a nationwide, nested case-control study based in Denmark, using national registries.3 The aim was to assess the association between use of menopausal hormone therapy and dementia development according to type of hormone treatment, duration of use, and age at usage.
The authors studied 5,589 incident cases of dementia and 55,890 age matched controls.These were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy. The findings were that compared with people who had never used treatment, people who had received oestrogen progestin therapy had an increased rate of all cause dementia (hazard ratio 1.24).
Increasing durations of use yielded higher hazard ratios, ranging from 1.21 for one year or less of use to 1.74 for more than 12 years of use. Oestrogen-progestin therapy was positively associated with development of dementia for both continuous and cyclic regimens.
As this was an observational study, the authors cautiously conclude that further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.
Monoclonal Antibody Treatment for Dementia Prevention
Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer’s disease have had mixed results. This study tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer’s disease.
In this prospective, placebo-controlled trial4, persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (indicating no cognitive impairment), a score on the Mini–Mental State Examination of 25 or more (range, 0 to 30), and elevated brain amyloid levels on positron-emission tomography (PET) were enrolled.
A total of 1,169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60 per cent were women, and 75 per cent had a family history of dementia. At 240 weeks, the mean change in Preclinical Alzheimer Cognitive Composite (PACC) were not statistically different, thus cognitive decline was not slowed.
- Lin F et al. Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial. www.thelancet.com Published online July 18, 2023. https://doi.org/10.1016/S0140-6736(23)01406-X.
- Paz V et al. Is there an association between daytime napping, cognitive function, and brain volume? A Mendelian randomization study in the UK Biobank. Sleep Health: Journal of the National Sleep Foundation. https://doi.org/10.1016/j.sleh.2023.05.002.
- Pourhadi N et al. Menopausal hormone therapy and dementia: nationwide, nested case-control study. BMJ 2023;381:e072770. http://dx.doi.org/10.1136/bmj-2022-072770.
- Sperling R et al. Trial of Solanezumab in Preclinical Alzheimer’s Disease. N Engl J Med. doi: 10.1056/NEJMoa2305032 (published on July 17, 2023, at NEJM.org).
Physical Activity (PA)
PA is the gift that just keeps on giving. There have been several studies again reinforcing the beneficial effects of PA. My favourites are summarised here.
PA and Type 2 Diabetes (T2D) prevention
Although 30 min/day of moderate-intensity PA is suggested for preventing T2D, the current recommendations exclusively rely on self-reports and rarely consider the genetic risk. This prospective cohort study study1 examined the prospective dose-response relationships between total/intensity-specific PA and incident T2D accounting for and stratified by different levels of genetic risk.
It was based on 59,325 participants in the UK Biobank (mean age=61.1 years). During a median follow-up of 6.8 years, there was a strong linear dose-response association between moderate-to-vigorous-intensity physical activity (MVPA) and incident T2D, even after adjusting for genetic risk. Compared with the least active participants, the Hazard Ratios (HRs) for higher levels of MVPA were: 0.63 for 5.3–25.9 min/day, and 0.26 for >68.4 min/day. The authors also suggest that there may be no minimal or maximal threshold for the benefits.
PA and pain
PA might influence the risk or progression of chronic pain through pain tolerance. This study2 aimed to assess whether habitual leisure-time PA level and PA change affects pain tolerance longitudinally in the population.
The study sample was 10,732 community-based Norwegian people. Of these, 51 per cent were women. The findings were that being physically active at either of two time points of the study measured 7–8 years apart was associated with higher pain tolerance compared to being sedentary at both time-points. Pain tolerance increased with higher total activity levels, and more for those who increased their activity level during follow-up.
PA and falls
Another study investigated associations between leisure-time physical activity (LPA) and injurious falls in older women, and explored modification of associations by physical function and frailty.3 The study population was Australian Women born during 1946–51.
The findings were that Participation in LPA as recommended by World Health Organization (150–300min/week) was associated with lower odds of injurious falls. The authors also urge caution when promoting general physical activity among people with physical limitation or frailty.
PA and cancer prevention
Finally, a brief report from the UK Biobank Study looked to evaluate the dose-response association of device-measured daily vigorous intermittent lifestyle physical activity (VILPA) with incident cancer, and to estimate the minimal dose required for a risk reduction of 50 per cent of the maximum reduction.4
During a mean follow-up of 6.7 years (149,650 person-years), 2,356 total incident cancer events occurred, 1,084 owing to PA-related cancer. Almost all (92.3 per cent) of VILPA was accrued in bouts of up to one minute. Daily VILPA duration was associated with outcomes in a near-linear manner, with steeper dose-response curves for PA-related cancer than total cancer incidence.
Compared with no VILPA, the median daily VILPA duration of bouts up to one minute (4.5 minutes per day) was associated with an HR of 0.80 for total cancer and 0.69 for PA-related cancer. Findings were similar for VILPA bout of up to two minutes. Thus, small amounts of VILPA were associated with lower incident cancer risk and may be a promising intervention for cancer prevention in populations not able or motivated to exercise in leisure time.
- Luo M et al. Accelerometer-measured intensity-specific physical activity, genetic risk and incident type 2 diabetes: a prospective cohort study. Br J Sports Med Epub ahead of print: [June 5, 2023]. doi:10.1136/bjsports-2022-106653.
- Årnes AP, Nielsen CS, Stubhaug A, Fjeld MK, Johansen A, Morseth B, et al. (2023) Longitudinal relationships between habitual physical activity and pain tolerance in the general population. PLoS ONE 18(5): e0285041. https://doi.org/10.1371/journal.pone.0285041.
- Kwok W et al. Physical activity and injurious falls in older Australian women: adjusted associations and modification by physical function limitation and frailty in the Australian Longitudinal Study on Women’s Health. Age and Ageing 2023; 52: 1–10. https://doi.org/10.1093/ageing/afad108.
- Stematakis E et al. Vigorous Intermittent Lifestyle Physical Activity and Cancer Incidence Among Nonexercising Adults The UK Biobank Accelerometry Study. JAMA Oncol. doi:10.1001/jamaoncol.2023.1830. Published online July 27, 2023.