November 10, 2020

expert reaction to two studies looking at cholesterol, cardiovascular disease and statins in older people

Two studies published in The Lancet look at cholesterol, cardiovascular disease, and statins in older people.

Prof Sir Nilesh Samani, Medical Director at the British Heart Foundation, said:

“Many clinical trials have shown that statins reduce heart attacks and strokes, but question marks have remained about how helpful they are in older people.  This new research not only shows that statins provide significant benefits in people over the age of 75, but that this age group could benefit the most as their risk of heart disease is higher.

“Patients should not be denied a statin simply because of their age.  Any decision to start taking a statin should be based on a conversation between a patient and their GP, which will take into account an individual’s risk and likely benefit.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“These studies appear to me to be statistically sound, and between them, they do make a case for considering a greater role for cholesterol-reducing treatment in older adults (aged at least 70 or 75).  But in considering their findings, there are some issues to take into account, particularly about the primary prevention study in Denmark (by Mortensen and Nordestgaard).

“The first point I’d raise about the Danish study is that it’s observational.  For people in all the age groups they considered, and particularly the 70-79 and 80-100 groups, it does provide very clear evidence that the higher their LDL (‘bad’) cholesterol level was, the greater their risk of a heart attack.  The evidence that higher LDL cholesterol is associated with cardiovascular disease (CVD) more generally isn’t quite as clear, but I do find it pretty convincing.  What’s more awkward is that it is not so clear how far the high LDL cholesterol levels actually cause the heart attacks, strokes, and so on.  Because the study is observational, there are many differences between the people with low and high cholesterol levels, apart from their cholesterol measurements.  These other differences might, in part at least, be the actual cause of the differences in heart attack risk.  The researchers did make some statistical adjustments to allow for such differences in factors that are known to be related to the risk of heart disease and strokes, and there was still clear evidence of increased risk of heart attacks and CVD after these adjustments.  But they cannot adjust for every possible difference.  Given what is known from many other studies about associations between LDL cholesterol levels and diseases of the heart and circulation, I would find it very surprising if the cholesterol levels don’t come into cause and effect at all, but there has to remain a certain amount of doubt about how far they explain risk differences.

“The second issue concerns the estimates of how many people, in different age groups, would need to be treated with statins for five years to prevent one heart attack or one episode of CVD.  As the researchers themselves point out, these estimates are not based on observing what happened if the people in this study are put on statins.  They are based on a statistical model that makes assumptions, based on other studies, of how much the risk of a heart attack or a CVD event would be reduced if the people took moderate-intensity statins.  Those estimates are ‘tuned’ to the numbers of heart attacks and CVD events, and the cholesterol levels, actually observed in this population, but they still use the assumptions from other studies about the reductions in risk.  However, the new research also estimated, for instance, the size of the difference in heart attack risk between two groups that differ in their LDL cholesterol level by 1 mmol/L.  For people aged 70-79, for example, the risk is estimated to be about 25% higher in the group with higher cholesterol than in the group with lower cholesterol.  Because of the way percentages work, that means that the risk in the lower cholesterol group is about 20% lower than the risk in the higher cholesterol group.  But the model that the researchers used for estimating the effect of statins assumes that the risk would be 30% lower in the lower cholesterol group, not 20% lower, if their lower cholesterol was achieved by taking statins.  This might indicate that, for this population, the assumed reductions in heart attack risk from taking statins are a bit high.  There are several reasons why that might be the case – or maybe it isn’t really the case at all, and the risk differences estimated in the study look smaller than they really are because they are partly masked by some other factor.

“So maybe this is just a fussy statistician’s nit-pick – but I’d suggest it may not be.  If the risk reductions from statins really are smaller than the researchers assumed, then the numbers of people that would have to be treated to avoid one heart attack would be larger than the researchers estimated – and arguably they are already quite large.  For instance, to avoid one heart attack in five years in people in this population aged 70-79, the researchers estimated that 145 of them would need to be treated with moderate intensity statins for five years.  If the reduction in risk from statins is rather less than the researchers assumed, more than the 145 would need statin treatment to avoid the one heart attack.  That number would be over 200 if statins actually reduce the heart attack risk by 20% rather than 30% for each 1 mmol/L reduction in LDL cholesterol.  Maybe that’s still a good balance of risks and benefits, given that a lot of evidence indicates that adverse effects from statins are pretty rare.  But the comment by Professor Raal and Dr Mohamed that accompanies these two papers points out that older patients may already be taking several different medications for different health conditions, and that there are several issues concerned with such patients having to take large numbers of pills each day.  It suggests that many different aspects must come into balancing the benefits and risks of prescribing statins for older patients.”

Paper 1: ‘Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70–100 years: a contemporary primary prevention cohort’ by Martin Bødtker Mortensen and Børge Grønne Nordestgaard was published in the Lancet at 09:00 UK time on Tuesday 10 November 2020.

DOI: 10.1016/S0140-6736(20)32233-9

Paper 2: ‘Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials’ by Baris Gencer et al was published in the Lancet at 09:00 UK time on Tuesday 10 November 2020.

DOI: 10.1016/S0140-6736(20)32332-1

Declared interests

Prof Kevin McConway: “I am a Trustee of the SMC and a member of the Advisory Committee, but my quote above is in my capacity as a professional statistician.”

None others received.