October 30, 2019
Controversy around the use of statins for the primary prevention of cardiovascular disease is once again in the news, with a new analysis suggesting that statin use in low-risk patients "may be an example of low value care (having little benefit and potential to cause harm) in these patients and, in some cases, represent a waste of healthcare resources," researchers conclude.
The analysis was published online in the BMJ on October 16.
The researchers, who were led by Paula Byrne, PhD, National University of Ireland Galway, say there is uncertainty about whether the benefits of statins outweigh the harms for primary prevention and whether widespread statin use can be justified from a societal perspective.
Nevertheless, clinical guidelines have expanded the eligibility criteria over time, and in many countries the majority of people taking statins do so for primary prevention.
"We wanted to look at who is using statins and why, and investigate the benefits in the people who are actually taking them, particularly those who have not got established heart disease where there is debate as to the usefulness of statins," Byrne explained.
For their analysis, the researchers examined the effects of changes to European guidelines on cardiovascular disease prevention from 1987 to 2016 using data from a national cohort of older people in Ireland.
"Of those aged over 50 in this database, 30% were using statins — two thirds for primary prevention," Byrne said. "Three quarters of women on statins were taking them for primary prevention compared with just over half of men. As so many people are taking statins for primary prevention, we need to be really clear of their benefits in this population."
Applying guideline recommendations from various times over the past 30 years to the Irish cohort, the researchers found that according to the 1987 guidelines 8% of their population would have been eligible for statins, but by 2016 the guidelines were recommending much greater use of statins so that 61% of the cohort were eligible for the drugs. "That is a huge increase," Byrne commented.
The researchers then went looking for what evidence there was to support use of statins in primary prevention patients.
"We found that although there have been many studies and meta-analyses of statin treatment there is little evidence separating out the primary and secondary populations," Byrne noted.
They found three systematic overviews that reported on primary prevention patients separately — two reviews from the Cholesterol Treatment Trialists' (CTT) Collaboration that were considered to be one dataset because they analyzed the same data; and two other reviews by Mora et al and Ray et al.
The researchers calculated that based on 1994 guideline recommendations for use of statins, the number needed to treat (NNT) to prevent one cardiovascular event in the primary prevention population was 40, which Byrne said was "quite a reasonable number."
But when applying the 2016 guidelines to the data, they found an NNT of 400. "So we are getting far less bang for our buck with the 2016 guidelines," Byrne noted.
Small Benefits Effect Choice
The researchers give examples of two primary prevention patients who would have very different absolute benefits of taking statins. One is a 65-year-old man who smokes, does not have heart disease, but has high total cholesterol levels, raised blood pressure, and an estimated 38% absolute risk of having a major coronary event in the next 10 years. He could expect an absolute risk reduction of about 9% (NNT = 11) from taking a statin.
The second example is a 45-year-old woman who does not smoke and has raised total cholesterol levels and slightly raised blood pressure. She has a 10-year risk of 1.4%, but her absolute risk reduction by taking a statin would be just 0.6% (NNT = 166).
"Indeed, our analysis suggested that none of those classified as low or moderate risk in primary prevention would reach the levels of risk reduction that patients say would justify taking a daily preventive medicine," they write.
When the benefits are of such a small magnitude, the decision to take a medication may rest on any potential harms caused by the drugs, Byrne says.
"Some clinicians and patients may desire a reduction in risk of cardiovascular disease, regardless of whether the benefit is small," the authors write. "For others, the impact of potential adverse effects heavily influences their decision making, and even modest estimates of harms caused by daily medication could negate the benefits of statins."
But they point out that data on adverse effects from some of the relevant studies have not been made available for independent analysis, and there is a high level of uncertainty as to what the harms are.
"The CTT estimates that for every 10,000 patients treated with statins for 5 years, there would be five cases of myopathy, 50 to 100 new cases of diabetes, and five to 10 hemorrhagic strokes," Byrne said.
"Other data has suggested that frequency of myopathy is much higher — at about 530 cases per 10,000 patients treated for 5 years," she added. "Also, myopathy is a high bar for defining muscle symptoms — what a person thinks is muscle pain probably is muscle pain. We need access to the data so it can be independently scrutinized to try and estimate this more accurately."
She maintains that patients need to be able to make their own decisions on the benefits and the harms. "But for that to be possible, we need better data on both the benefits and the harms in the primary prevention population. We also need more trials in low-risk individuals with sufficient power to look at subgroups such as women and older people where there is even more uncertainty."
Better communication of the uncertainty about the benefits and harms of statins in these low-risk patients would take the pressure off general practitioners (GPs) in terms of prescribing these drugs, Byrne says. "There needs to be more transparency around this uncertainty, which would empower both doctors and patients to make better decisions," she concludes.
Conclusions 'Not Surprising'
Commenting on this latest analysis, Metin Avkiran, MD, associate medical director at the British Heart Foundation (BHF), said, "The conclusions are not surprising and align with what we know already, based on the evidence from numerous independent clinical trials."
"The evidence from clinical trials going back more than two decades shows that statins are an effective way of people reducing their risk of a heart attack. We already know that the benefits are even greater for people who have already had a heart attack or stroke," he said.
"An important area of debate here relates to the magnitude of benefit provided by statin treatment in people who are at relatively low risk and whether that benefit outweighs the risk of side effects. For people who fall into this category, the decision on whether to take statins should be based on discussion with their GPs," Avkiran said.
"We recognize people's concerns about statin side effects and we want patients and their doctors to be able to make informed, evidence-based decisions about taking and prescribing these medicines."
The BHF is doing its part by funding researchers to gather, analyze, and make available all the individual participant data from large clinical trials into statins, he added. "Putting an end to this debate should help to stop conflicting reports, which can put people off taking potentially life-saving drugs that they have been prescribed for good reason."
Byrne and Avkiran have disclosed no relevant financial relationships.