Two studies published on line on 10 November 2020 in The Lancet journal suggest that older adults are at greater risk of cardiovascular events than younger people, and benefit at least as much from cholesterol-lowering medications. The papers provided new evidence on whether LDL cholesterol-lowering therapies, including statins, can reduce the rate of major cardiovascular events in older people.

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Atherosclerosis, a disease of the arteries characterised by the deposition of fatty material on their inner walls, starts early in life and develops slowly over decades before suddenly giving rise to clinical diseases (such as myocardial infarction and atherosclerotic cardiovascular disease) later in life. Blood vessels narrow progressively when fat gets deposited in their inner walls. There is experimental evidence from animal studies, epidemiological linkage in cohort studies, unbiased genetic evidence and randomised controlled trial evidence all highlighting the role of LDL cholesterol as a central driving force for this process.

For these reasons, LDL cholesterol is the primary treatment target in all major guidelines for both primary and secondary prevention.

When have we to start cholesterol lowering treatments; at a very early age? It seems that specialists advocate looking at these treatments benignly at least from age 40.

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The first study

The first study, an observational one, led by Professor Børge Nordestgaard of the Copenhagen University Hospital, Denmark, was designed to assess primary prevention of cardiovascular events– meaning that participants did not already have clinical signs of heart disease when they joined the study.

Researchers analysed data from 91,131 people aged 20 to 100 years who were not taking statins or other cholesterol-lowering medication, and were enrolled in the Copenhagen General Population Study (CGPS) between 2003 and 2015. Of those people, 10,592 participants were aged 70 to 79 years, and 3,188 participants were aged 80 to 100 years.

During the follow up period of 7.7 years and the study recorded 1515 first-time heart attacks and 3389 cases of cardiovascular diseases. The researchers have also recorded the LDL cholesterol levels, for each individual. To evaluate the potential benefit of statins for each age group, the authors estimated the number of people who would need to be treated (NNT) with a moderate-intensity statin therapy to prevent one incidence of heart attack in five years.

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Results

The study concluded that people aged over 70 years had the highest incidence of heart attack and cardiovascular disease of any age group. Thus, heart attacks per 1,000 people per year irrespective of LDL cholesterol levels: Age 80-100, 8.5; age 70-79, 5.2; age 60-69, 2.5; age 50-59, 1.8; age 20-49, 0.8.

Older people might gain the greatest benefits from treatment of moderate-intensity statin therapy, compared to younger people. A physician would need to treat 42 people aged 80 to 100 for 5 years to prevent one cardiovascular disease event. The corresponding figures were 88 for those aged 70 to 79 years, 164 for those aged 60 to 69 years, 345 for those aged 50 to 59 years, and 769 for those aged 20 to 49 years.

A physician would need to treat 80 individuals aged 80 to 100 with a moderate intensity statin for 5 years to prevent one heart attack. The figures were 145 persons for people aged 70 to 79, 261 for persons aged 60 to 69, 439 for those aged 50 to 59, and 1,107 for those aged 20 to 49.

The incidence of cardiovascular disease also increased with age and rising LDL cholesterol levels and was highest in people aged 80 to 100 (at the highest LDL cholesterol levels, >5 mmol/L, the rates of cardiovascular disease in 1,000 people per year for each age group were:

• Age 80-100, 37.1
• Age 70-79, 14.6
• Age 60-69, 6.4
• Age 50 to 59, 5.4
• Age 20-49, 4.6

In people aged 80-100 years with the highest levels of LDL cholesterol, there were 37.1 cases of cardiovascular disease per 1,000 people each year.)

The risk of heart attack in the overall population was increased by 34% for every 1 mmol/L rise in LDL cholesterol. The effect was amplified with increasing age, such that people aged 80 to 100 years with elevated LDL cholesterol levels had the highest absolute risk of heart attack (at the highest LDL cholesterol levels, >5 mmol/L, the rates of heart attacks in 1,000 people per year for each age group were:

• Age 80-100, 13.2
• Age 70-79, 6.6
• Age 60-69, 3.1
• Age 50 to 59, 3.1
• Age 20-49, 3.3

For example, in people aged 80-100 years with the highest levels of LDL cholesterol, there were 13.2 heart attacks per 1,000 people each year.)

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Meta-analysis on LDL lowering treatments

In the second study published in the same issue of The Lancet, researchers led by Professor Marc Sabatine, from Brigham and Women’s Hospital, Boston, Mass., USA, carried out a meta-analysis and systematic review of 24 trials and five individual randomised-controlled trials.

The researchers included data from 244,090 participants in the analysis: 21,492 people aged at least 75 years. Just over half of participants aged 75 years or older were from trials of statin therapies (54.7%, 11, 750/21, 482), 28.9% were from trials of the cholesterol-lowering drug ezetimibe (6, 209/21, 482) and the remaining 16.4% were from trials of PCSK9 inhibitors (3, 533/21, 482), which are another class of drugs prescribed to lower cholesterol. The average time of study follow-up ranged from 2.2 to 6 years.

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Results

There was no difference in the magnitude of the risk reduction in major vascular events between statins and other cholesterol-lowering medications in the older age group.

Older individuals have higher rates of major cardiovascular events than younger people overall, and in this study, rates were almost 40% higher in those aged 75 years and older. The authors say this means it is expected that treating people aged over 75 years with cholesterol-lowering therapies is likely to particularly prevent large numbers of cardiovascular events.

Professor Marc Sabatine, lead author of the study, from Brigham and Women’s Hospital, Boston, Mass., USA, clarified in a press release-

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now their benefits for older people have remained less certain. Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and non-statin therapy, in elderly people.”

The authors acknowledge some limitations to their study. The definitions of cardiovascular events differed slightly between trials. However, the authors added that these minor differences may not affect the clinical implications of their findings. Additionally, older patients who are included in clinical trials might not be representative of everyday practice, because people who already have multiple medical conditions or are unable to attend follow-up visits would not typically be enrolled in a clinical trial.

Professor Frederick Raal, University of the Witwatersrand, South Africa, who was not involved in the study, wrote in a linked comment-

“As the authors acknowledge, although lipid-lowering therapy was efficacious in older patients, we should not lose sight of the benefit of treating individuals when they are younger. The average age of patients in all the trials analysed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established. Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis rather than try to manage the condition once fully established or advanced.”

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Experts’ comments

Responding to Science Media Centre, London, Prof Kevin McConway, Emeritus Professor of Applied Statistics, the Open University, acknowledged that these studies appear 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.” he cautioned.

Professor McConway brought forward a second issue that 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.” he clarified.

“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.”

Professor McConway gave numerical examples to buttress his views. According to him, 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.” Professor McConway rightly reflected on the complexities to be considered.

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.”

The press release from the Lancet pointed out a limitation of the first study. It only included people of white European origin living in a high-income country, so it is not clear if the results would apply to other ethnic groups or people living in low-income settings.

In a paper published in the Indian Journal of Medical Research (Oct 2013) Dr Enas A.Enas, Coronary Artery Disease in Asian Indians (CADI) Research Foundation, Lisle, IL, USA and others have stated that “early and aggressive statin therapy offers the greatest potential for reducing the continuing epidemic of CAD among Indians.”

The authors asserted that “the updated 2013 Cochrane review has put to rest all lingering doubts about the overwhelming benefits of long-term statin therapy in primary prevention by conclusively demonstrating highly significant reductions in all-cause mortality, major adverse cardiovascular events (MACE) and the need for coronary artery revascularisation procedures (CARPs)”.

The Cochrane review was based on 18 randomised controlled trials with 19 trial arms (56,934 patients) dating from 1994 to 2008. All were randomised control trials comparing statins with usual care or placebo. The mean age of the participants was 57 years (range 28 - 97 years), 60.3% were men, and of the eight trials that reported on ethnicity, 85.9 % were Caucasian. However, the duration of treatment was a minimum one year and with follow-up of a minimum of six months. Is that sufficient?

The American Board of Internal Medicine (ABIM) Foundation in its “Choosing Wisely Initiative” has stated that for older people, there is no clear evidence that high cholesterol leads to heart disease or death.

“In fact, some studies show the opposite—that older people with the lowest cholesterol levels actually have the highest risk of death” they added.

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Will they revise this stand in light of The Lancet papers?

“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,” as recommended by Prof Sir Nilesh Samani.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph.D from University of Leeds, UK, he is a medical physicist with specialization in radiation safety and regulatory matters. He was a Research Associate in the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.