September 5, 2018

expert reaction to study on use of statins in older people

Researchers, publishing in the BMJ, have reported that statins do not have a protective effect against cardiovascular disease in healthy adults between the ages of 75 and 84.

Prof. Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said:

“Old age itself – particularly reaching the age of 80 and above – puts people at increased risk of a heart attack or stroke. This risk can be heightened by factors such as high cholesterol, diabetes and high blood pressure, even in those who are otherwise seemingly healthy.

“Regardless of age, those who have suffered a heart attack or stroke will benefit from taking a statin. Previous clinical trials – which are a better measure than observational studies like this – have also suggested that statins can contribute to a reduction in risk of a heart attack or stroke in elderly people who are not at significant risk of heart disease. However, further trials are needed to better understand how effective they are in this age group.

“In line with current guidance, the most important thing is that GPs have a discussion with their elderly patients to help them understand their personal risk of a heart attack or stroke, so they can make an informed decision about taking statins alongside other methods of reducing their risk.”

Prof. Liam Smeeth, Professor of Clinical Epidemiology, London School of Hygiene and Tropical Medicine.

“I do have major reservations about this study for two reasons. Firstly the issue of confounding. People are prescribed statins because they and their doctors are concerned about their high risk of cardiovascular disease. This means that people who are and are not prescribed statins are likely to be different. Specifically, people who are prescribed statins will tend to have a higher risk of cardiovascular events and mortality, and this difference is likely to bias any efforts to assess the effects of statins. This is called confounding and is always a potentially major issue in observational studies of drug effects. While the authors did what they could to try and adjust for such differences, the likelihood of them capturing all possible confounding is small. What makes this doubly difficult is that such uncaptured confounding is invisible: by definition we can’t see or measure it, even though it can have a big impact on the study results.

“My second issue is around power. The authors conclude that the beneficial effects of statins “reduced beyond the age of 85 years and disappeared in nonagenarians”, clearly implying evidence of no effect. In fact in these oldest age groups, the correct interpretation would be “lack of evidence” because power was low.

“The two issues really come together in the oldest age groups. For someone in their 80s to start a statin strongly suggests that they and their doctor are seriously worried about a high risk of vascular events. Without the statin, it is likely the people selected to take a statin would be at markedly higher risk.”

Dr June Raine, Director of The Medicine and Healthcare products Regulatory Agency’s (MHRA) Vigilance and Risk Management of Medicines (VRMM) Division said: 

“The benefits of statins are well established and are considered to outweigh the risk of side-effects in the majority of patients. The efficacy and safety of statins has been studied in a number of large trials which show they can lower the level of cholesterol in the blood and reduce cardiovascular disease and can save lives.

“For prevention of cardiovascular disease, statins are authorised in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, in addition to correction of other risk factors and other cardioprotective therapy.

“Trials have also shown that medically significant side effects are rare. The known side effects of statins are provided in the product information for healthcare professionals and Patient Leaflet which is provided with the medicine.

“Medicine safety and effectiveness is of paramount importance and under constant review. Our priority is to make sure the benefits of medication outweigh the risks. Any new significant information on the efficacy or safety of statins will be carefully reviewed and action will be taken if required.

“If you have any questions about your medicine, please speak to your GP or healthcare professional.”

Prof. Tim Chico, Professor of Cardiovascular Medicine and Honorary Consultant Cardiologist, University of Sheffield, said:

“Due to it’s design this study cannot tell us whether or not statins reduce death or cardiovascular disease in older people. The press release is unhelpfully worded and suggests that the results of this study show there is no benefit of statin treatment when this conclusion is not justified.

“The study examined many thousands of people and compared those who had been prescribed statins with those who had not. Because doctors are presumably not randomly prescribing statins, this means there must be some differences between the patients in each group, otherwise why would they be prescribed different drugs? All this study can show is whether or not there is a relationship between statin prescription (no one knows whether people took the tablets or not, which is another weakness of the study) and future health problems. Although it doesn’t show that statin prescription is associated with death in non-diabetics, but is associated with reduced deaths in diabetics, neither of these associations are proven to be anything to do with the statin. To do so requires a randomised trial, although there are already a number of these which show that statins do reduce the risk of cardiovascular disease and death in certain types of people.

“This study doesn’t help me decide whether or not an elderly person should go on a statin, which as always should be a joint decision between patient and doctor based on a clear and open discussion about what benefits and risks are involved and include discussion about the other ways risk of cardiovascular disease can be reduced, such as physical activity and diet.”

Dr Ajay Gupta, Senior Clinical Lecturer in Clinical Trials, and Cardiovascular Medicine at Queen Mary University of London, said:

“This is an observational study on older patients with no pre-existing vascular disease (heart attacks or strokes or other similar illnesses), who have been prescribed a statin for the ‘first time’.

“Like all such observational studies, it answers only a few questions, but raises several more.  What it shows is that a new prescription of a statin reduces deaths, heart attacks and strokes amongst those who are younger than 85 years and suffering with diabetes; but it failed to show any benefits amongst the others. More importantly, it shows there is no signal of any harm or excess adverse effects with the use of statin in this age group. It provides a platform for to study this area more intensely, and amongst this rapidly growing group of patients

“When we compare these findings, with the current knowledge and literature, the findings on diabetic sub-group are consistent with the prevailing evidence, and the newer findings of a little benefit on commencing a statin for first time in older patients (who are otherwise healthy) raises a further question: why should chronological age makes a difference in the statin efficacy? And, why the findings are neutral compared to the unequivocal benefits shown in other studies in those below age of 75? Is it that because the older patients in this study have been provided the benefits of a statin too late? Whether in this group, the disease is so established that statin use now shows little benefit? These questions needs answers, and perhaps a new trials on this uncharted area would be useful!”

Prof. Colin Baigent, Director Medical Research Council Population Health Research Unit University of Oxford, said:

“This problem with this type of study, which used routine health records, is that is a very unreliable way to determine the effects of statins on the risk of heart attacks and strokes. The only suitable method is a clinical trial where people are allocated to a statin or to no statin entirely at random. We already have quite a bit of evidence from clinical trials of statin therapy that recruited some elderly people. These trials show clearly that statins prevent heart attacks and stroke in those over 75 – and that the benefits are similar irrespective of whether a person has had a previous heart attack or stroke.  These same trials also show that statins are just as beneficial in those without diabetes as they are in those with the disease. Wider use of statins in the elderly would therefore be expected to help prevent substantial numbers of heart attacks and strokes in the elderly, and older people who think that they might benefit from a statin should discuss this possibility with their GP.”

Prof. Kausik Ray, Professor of Public Heath, Imperial College London, said:

“Observational data have a lower level of evidence in all guidelines. They do not replace randomised trails where the only thing different between treatment groups is the treatment. Irrespective of statistical adjustment with observational studies they are just that observational. As the authors themselves say. “This was an observational study, so no firm conclusions can be drawn about cause and effect, and the authors cannot not rule out the possibility that some of their results may be due to unmeasured (confounding) factors.”

“In RCTs there are only a modest number of elderly patients, therefore data have to be pooled using meta-analyses. There are at least two well done meta-analyses of primary prevention in the elderly which show reductions in non-fatal MI and stroke but not mortality. Now if you are a fit and well elderly individual the thought of an MI or stroke and the disability and your dependence on others resulting from such an event might be such that you wish to consider preventative therapies such as BP reduction and lipid lowering therapy. It is reasonable to assume that if someone is healthy and/ or adverse risk factors has managed to get to 80 then there are other likely protective factors that have prevented them from developing cardiovascular disease. Thus whilst not necessarily mandated a discussion could/ should be had on a case by case basis of the potential benefit and a discussion of potential side effects with each patient.”

“This paper does not provide any information one way or another beyond RCTs. If we did not have RCTs then this paper would be hypothesis generating but it’s not even that. There is an ongoing prospective RCT which is in Australasia called SATREE which will also be recruiting through the UK and Europe in the future which will be the largest prospective RCT in the elderly with about 10 000 patients.”

Prof. Peter Sever, Professor of Clinical Pharmacology & Therapeutics, Imperial College London, said:

“ “This was an observational study, so no firm conclusions can be drawn about cause and effect, and the authors cannot not rule out the possibility that some of their results may be due to unmeasured (confounding) factors”.

“This a very common problem with observational studies, the outcomes of which are frequently not confirmed by randomised controlled trials. Particularly in the elderly with comorbidities the lack of randomisation can create substantial bias and the problem of confounding is a serious issue.”

*Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study by Ramos et al. will be published in The BMJ at 23:30 UK time on Wednesday 5th September, which is also when the embargo will lift. 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/statins/

Declared interests

Prof. Liam Smeeth: “Liam Smeeth holds research grants at the London School of Hygiene and Tropical Medicine from MRC, Wellcome, BHF, Diabetes UK, NIHR and GSK (unrelated to any specific drug).  He is the principal investigator of the NIHR funded Statinwise trial that is seeking to establish whether statins cause muscle pain. He is a Trustee of the British Heart Foundation (unpaid).”

Dr June Raine: “No conflicts of interest”

Prof. Tim Chico: “No conflicts”

Dr Ajay Gupta: “I have no direct conflicts of interests to declare in context of this manuscript.  In last 3 years, I have received reimbursement for the travel expenses incurred to attend a conference each from Servier inc and Pfizer. I am associated with the ASCOT legacy study, which is an investigator led study that was received part funding by an independent grant from Pfizer”

Prof. Colin Baigent:  “I jointly coordinate, with Professor Rory Collins, the Cholesterol Treatment Trialists’ Collaboration meta-analysis of all large-scale randomized trials of statin-based treatments. CTSU has received funding from the pharmaceutical industry to conduct randomized trials, including trials of statin therapy, but this work is conducted independently of the source of funding and the trials are sponsored by the University of Oxford.”

Prof. Kausic Ray: “I have consulted for companies that make cholesterol modifying medications and for therapies related to diabetes.”

Prof. Peter Sever: “Received grant funding and honoraria for speakers bureau from Pfizer”

None Others Received