Statins, Yes More on Statins

An interesting paper in the BMJ examines the effects of statins specifically in people over the age of 75.[1] It finds that while they reduce cardiovascular mortality in people with diabetes, they have no such protective effect in people over the age of 75 who do not have diabetes. The study was based on a retrospective cohort of nearly 50,000 people over 65 years old from a routine database in Spain.

This result seems at variance with the limited evidence beyond the age of 75 in randomised trials. The interesting question relates to possible bias in non-randomised evidence. Database studies, in addition to possible confounders not included in the model, can suffer from survival bias. This subtle, but important, bias results from a control group that misses out people who would have survived to take the intervention in the intervention group.  This study mentions this form of bias, in one sentence, but does not say much more about it, though they did apply something called prescription time-distribution matching.  I did not fully understand this but take it to be a method to mitigate survival bias.

Taken in the round, I think this study leaves the jury out as far as statins in older people are concerned. One thing it does confirm is that statins have a bigger net benefit in people with diabetes than in age-controlled, non-diabetic people.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Ramos R, Comas-Cufí M, Martí-Lluch R, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018; 362: k3359.

Can Diet Help Maintain Brain Health?

A recent study in the journal of Neurology looked at the long-term effects high fruit and vegetable intake had on a person’s cognitive function.[1] The authors were able to research and follow-up 27,842 US men over a 26 year period. These men were middle-aged (mean age of 51 years) and were or had been health professionals.

Every four years, from 1986 to 2002, they completed questionnaires looking at their eating habits, and then completed subjective cognitive function questionnaires in 2008 and 2012. Logistic regression of the data found significant individual associations between higher intakes of vegetables (around six servings a day compared to two), fruits (around three servings a day compared to half) and fruit juice (once a day compared to less than once a month) and lower odds of moderate or poor subjective cognitive function. These associations remained significant after adjusting for non-dietary factors and total energy intake, though adjusting for dietary factors weakened the association with fruit intake. Daily consumption of orange juice (compared to less than one serving per month) was associated with much lower odds of poor subjective cognitive function, with an adjusted odds ratio of 0.53 (95% CI 0.43-0.67). Meanwhile the adjusted odds ratios for vegetables were 0.83 (05% CI 0.76-0.92) for moderate, and 0.66 (0.55-0.80) for poor subjective cognitive function. The authors also found that high intake of fruit and vegetables at the start of the study period was associated with a lower risk of poor subjective cognitive function at the end of the study. Although the study does not prove a causal link, the fact that the association lasted the length of the study support the idea that vegetable and fruit consumption may help avert memory loss.

— Peter Chilton, Research Fellow

Reference:

1. Yuan C, Fondell E, Bhushan A, Ascherio A, Okereke OI, Grodstein F, Willett WC. Long-term intake of vegetables and fruits and subjective cognitive function in US men. Neurology. 2018.

An Aspirin A Day to Keep the Doctor Away?

Many healthy elderly people take a daily dose of aspirin as a preventive measure, often in order to lower their risk of cardiovascular illness. But is this practice beneficial? A series of three analyses in the New England Journal of Medicine suggests not.[1-3] The ASPREE study looked at more than 19,000 healthy elderly individuals, randomly assigning half to receive a daily aspirin, and half to receive a placebo, and followed them for a median of 4.7 years. There was no significant difference between the groups with regards to disability-free survival (p=0.79),[1] or risk of cardiovascular disease,[2] but there was a higher rate of major haemorrhage seen in those taking aspirin (hazard ratio 1.38, 95% CI 1.18-1.62).[1] Further, the authors found that the risk of any-cause mortality was 12.7 (per 1,000 person-years) in those taking aspirin, compared to 11.1 in those taking placebo – a hazard ratio of 1.14 (95% CI 1.01-1.29).[3] The main cause of the excess mortality was cancer-related death: 3.1% of those taking aspirin vs. 2.3% of those taking placebo (hazard ratio 1.31, 95% CI, 1.10-1.56).

Previous trials of aspirin have shown a protective effect with regards to cancer-related death,[4] suggesting these results should be interpreted cautiously, and that longer term follow-up could be informative.

It is important to note that these were healthy individuals, with no history of cardiovascular disease, dementia or disability, and who had not been previously prescribed aspirin by their doctor.

— Peter Chilton, Research Fellow

References:

1. McNeill JJ, Woods RL, Nelson MR, et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. New Engl J Med. 2018.
2. McNeill JJ, Wolfe R, Woods RL, et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. New Engl J Med. 2018.
3. McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. New Engl J Med. 2018.
4. Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011; 377: 31-41.

Does Pet Ownership Make Us Healthier?

Like many of us, I love animals, and am crazy about both dogs and cats. It is almost hard to describe how much I love them. But is this all very good for me? I mean, dogs can bite, cats scratch, and all animals can transmit infections. On the other hand, they are psychotropic; cuddly, warm and attentive. Some evidence suggests that people who keep pets are healthier than those without.

However, a rather dismal paper in the BMJ puts paid to all of that.[1] According to an analysis of a large cohort study of aging individuals, those who own pets do no better than those who do not. They are no stronger, happier or otherwise healthier than people without pets. Still, I would like to live with a cat or dog.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Batty GD, Zaninotto P, Watt RG, Bell S. Associations of pet ownership with biomarkers of ageing: population based cohort study. BMJ. 2017; 359: j5558.

A Heretical Suggestion!

The locus of health care is moving increasingly towards the community. In high-income countries (HIC) the greatest burden of health falls to frail elderly people with multiple chronic diseases. Hospital is often bad news for such people, both from a psychological and physical point of view.[1] There are good arguments for avoidance of admissions, and for increasing care provision in the community in HICs. In low- and middle-income countries (LMICs) there are also good arguments for community care. The WHO estimates that over three-quarters of all care could be most appropriately delivered in the community. The Declaration of Alma Ata and the Bamako Initiative from the United Nations both support the development of community care for LMICs. In this News Blog I wish to probe this subject more deeply. I will argue that community care is entirely appropriate for preventive outreach care. However, I will argue that we should re-examine the case for promoting community over hospital settings for demand-led care, especially in deprived urban environment.

My re-examination of this subject came about as a result of recent tours of eight slums within Nigeria, Kenya, Pakistan and Bangladesh. While all of these areas have a strong need for supply-side preventive care in the community, I have come to question the wisdom of trying to develop demand-led care within slum localities. My misgivings are based on a number of personal observations and from a reading of the relevant literature.

On site observations suggest that local residents prefer to use hospital facilities, even when this is less convenient than a more accessible community clinic. Some, but not all, slums are reasonably well supplied by local clinics. These clinics are usually staffed by medical officers or nurses rather than doctors. In many cases they have been provided by NGOs. I have observed that these clinics do not have many clients. When I draw attention to this, I am often told that this is because I have come at a quiet period. However, when I probe more deeply, I learn that the outpatients departments of nearby hospitals receive the bulk of the patients. Certainly that is my impression on visits to hospitals in LMICs where outpatient departments ‘heave’ with patients. This finding triangulates with work that colleagues and I have carried out in India under MRC sponsorship.

Not only do local residents seem to prefer hospital-based outpatient’s care, but my reading of the literature suggests that they are right to do so. Working with colleagues, I am carrying out a review of the quality of care provided in local settings in LMICs. The literature shows that such care is almost universally of a low standard, irrespective of whether the provider is private or public. Care given by doctors is generally better than that given by non-medical personnel, but even so is of a poor standard when delivered in the community. The quality of care across both settings is a topic of enquiry in the NIHR Unit on Health Service Provision in Slums that I direct. However, I suspect that the hospital will come out on top.

The corollary of the above, rather preliminary findings, is that we should be cautious about wholesale, and perhaps ideologically-driven, policies to deliver demand-based healthcare coverage in community settings  in low-income urban environments. Pending further research I hypothesise that it may be better to improve access and quality in hospital settings, at least in the first instance. Before taking fixed positions on these important issues we need to understand more about access to healthcare at the demand-side, the quality of such healthcare, and the most-cost effective approaches to driving up the quality of health care.

Please note that all of the above remarks apply to healthcare at the demand-side. That is to say, where a person has sought care for a perceived health problem. We fully support outreach primary preventive services to ensure vaccination, detect malnutrition, and ensure that people stick to their HIV and other treatment regimes.

Box A. Section VI of the Declaration of Alma-Ata

“Primary health care is essential health care based on practical, scientifically sound and socially acceptable methods and technology made universally accessible to individuals and families in the community [emphasis added] through their full participation and at a cost that the community and country can afford to maintain at every stage of their development in the spirit of selfreliance and self-determination. It forms an integral part both of the country’s health system, of which it is the central function and main focus, and of the overall social and economic development of the community. It is the first level of contact of individuals, the family and community with the national health system bringing health care as close as possible to where people live and work, and constitutes the first element of a continuing health care process.”

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Intensive Care Harmful in Elderly Patients. NIHR CLAHRC West Midlands News Blog. 7 December 2017.

Corroboration of Previous Reports on Vitamin D and on Coffee

In recent News Blogs we have provided evidence that vitamin D and calcium are useless in preventing osteoporotic fractures in elderly people with no obvious risk factors.[1] [2] This is now powerfully corroborated in a paper in JAMA by Zhao, et al.,[3] who carried out a systematic review and meta-analysis involving over 50,000 participants. They found absolutely no beneficial or harmful effects of either vitamin D or calcium or a combination of the two compared to placebo in reducing the risk of either vertebral hip or other non-vertebral fractures. The absolute risk difference was zero with an upper confidence limit of 0.01. Hopefully this puts the matter to bed once and forever.

Likewise a recent umbrella review in the BMJ [4] corroborated previous news blogs on the generally health promoting effects of coffee.[5] It would appear that these benefits are also seen in equal measure with de-caffeinated coffee, suggesting that it is the other components of coffee that benefit health.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.
2. Lilford RJ. Yet Another Null Result on Vitamin D and Calcium Supplementation in Older Women. NIHR CLAHRC West Midlands News Blog. 5 May 2017.
3. Zhao J-G, Zeng X-T, Wang J, et al. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA. 2017; 318(24): 2466-82.
4. Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ. 2017; 359: j5024.
5. Lilford RJ. Should You Keep Drinking Coffee? NIHR CLAHRC West Midlands News Blog. 1 September 2017.

A Calming Scent

In a previous News Blog we looked at a study investigating associations between body odour and attractiveness to strangers.[1] But what about the smell of someone we already love? A recent study randomly assigned 96 women to smell the scent of either their partner, a stranger, or a neutral unworn shirt, before exposing them to stress through a standardised mock job interview and an unanticipated mental arithmetic task.[2] The results found that women exposed to their partner’s scent perceived lower levels of stress both before and after the stressor task (though not during). Further women exposed to a stranger’s scent had higher levels of cortisol throughout the study, which is released in response to stress.

Perhaps providing worn clothing from a loved one could be a useful coping strategy for people who have been separated, for example, in elderly patients in care homes.

— Peter Chilton, Research Fellow

References:

1. Lilford RJ. The Scent of a Woman – Not as Important as Once Thought. NIHR CLAHRC West Midlands News Blog. 24 November 2017.
2. Hofer MK, Collins HK, Whillans AV, Chen FS. Olfactory Cues From Romantic Partners and Strangers Influence Women’s Responses to Stress. J Person Soc Psychol. 2018; 114(1): 1-9.

Intensive Care Harmful in Elderly Patients

An intervention to promote use of intensive care in elderly patients (over age 75) was evaluated in a cluster RCT of 20 French hospitals.[1] The intervention worked in the narrow sense that it did increase the rate of admission to the intensive care unit (ICU) (by nearly 70%). But did this result in improved survival? Not at all – in fact there was a statistically significant increase in death rates in the hospitals randomised to have lower thresholds for ICU care; both in hospital (18% increase) and at 6 months (16% increase). So a conservative policy dominates – it is both less expensive and more effective in old people. But this paper should make one think – how effective is ICU for other groups of patients? Apart from looking after people who need a breathing machine, is ICU really an effective treatment at all? It is highly invasive and intrusive. I am not a therapeutic nihilist, but one does have to wonder. Perhaps we should design a less intensive form of intensive care? Such an approach could be evaluated in RCTs before advocating global use of the current standard ICU model in high-income countries. Let me annoy my colleagues by proposing a hypothesis. ICU types think that it is the monitoring and fiddling with vital signs that saves lives. I think the main effect is better diagnosis – because patients are scrutinised carefully by highly trained people, conditions are spotted that would otherwise be missed. Just a thought!

I would like to thank News Blog reader Gus Hamilton for drawing my attention to this article.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Guidet B, Leblanc G, Simon T, et al. Effect of Systematic Intensive Care Unit Triage on Long-term Mortality Among Critically Ill Elderly Patients in France: A Randomized Clinical Trial. JAMA. 2017; 318(15): 1450-9.

Antioxidants and Age-Related Macular Degeneration

It is estimated that around 5% of the general population suffer from age-related macular degeneration (AMD),[1] where extracellular material known as drusen accumulate under the retina at the back of the eye and which can eventually lead to blurred or a loss of vision. It has been suggested that antioxidants may help prevent or delay development of AMD in people who do not suffer the condition by protecting the retina against oxidative stress, but it is unclear as to whether this is the case.

A systematic review in the Cochrane Database by Evans and Lawrenson looked at the effectiveness of antioxidant supplements as treatment in people who already had AMD,[2] and found that taking a multivitamin antioxidant vitamin may delay the progression of AMD when compared to a placebo or no treatment (odds ratio 0.72, 95% CI 0.58-0.90). The authors also conducted a systematic review looking at whether there was an association between taking antioxidant vitamins (carotenoids, vitamin C, vitamin E) or minerals (selenium, zinc) and the development of AMD in people without AMD.[3] Five RCTs were included, with a total of 76,756 individuals without AMD. These studies all looked at the use of various supplements against placebo. Generally, the various studies found that there was no effect of supplements on development of AMD, while in some cases there was evidence of an increased risk (see table below).

Comparison	No. of studies	Disease	Risk Ratio (95% Confidence Interval)
Vitamin E vs. placebo	4	AMD	0.97 (0.90-1.06)
		Late-stage AMD	1.22 (0.89-1.67)
Beta-carotene vs. placebo	2	AMD	1.00 (0.88-1.14)
		Late-stage AMD	0.90 (0.65-1.24)
Vitamin C vs. placebo	1	AMD	0.96 (0.79-1.18)
		Late-stage AMD	0.94 (0.61-1.46)
Multivitamin vs. placebo	1	AMD	1.21 (1.02-1.43)
		Late-stage AMD	1.22 (0.88-1.69)

— Peter Chilton, Research Fellow

References:

1. Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012; 96(5): 752-6.
2. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000254.
3. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000253.

Sniffing Out Trouble

The scent of freshly baked bread; the smell of a recently-mown lawn on a summer’s breeze; the aroma of an open bottle of wine – people often take particular delight in smell. But as we get older our olfactory function starts to decline. Interestingly, previous research has shown that adults with dementia have more difficulty distinguishing smells, compared to adults without dementia. However, we do not know whether this olfactory dysfunction is predictive of subsequent dementia.

A longitudinal study of 2,906 US adults aged 57-85 measured their ability to identify five odours (rose, leather, orange, fish and peppermint) using a validated test, then looked at the incidence of dementia five years later.[1] They found that adults who had difficulty identifying the smells at baseline were more than twice as likely to have developed dementia by the five year follow up (odds ratio = 2.13, 95% CI 1.32-3.43). This was after controlling for age, sex, race and ethnicity, education, comorbidities, and cognition at baseline. Further, more errors in identification was associated with greater probability of dementia diagnosis (p=0.04). Unfortunately, as the authors admit, they did not control for confounders already associated with olfactory function, such as smoking or depression.

It is hoped that using such an odour identification test will be an efficient and cost-effective addition to current examinations that assess an individual’s risk of dementia, thereby allowing early interventions and give individuals more time to plan for their future. It may also be a useful tool for early diagnosis of Parkinson’s disease, which is also associated with olfactory dysfunction.

— Peter Chilton, Research Fellow

Reference:

1. Adams DR, Kern DW, Wroblewski KE, McClintock MK, Dale W, Pinto JM. Olfactory Dysfunction Predicts Subsequent Dementia in Older U.S. Adults. J Am Geriatr Soc. 2017.