Background
It has been known since the 1960s that people who suffer a heart attack are more likely to have higher blood levels of cholesterol than those who don't (Prospective Studies Collaboration, 2007). In a few families, a genetic mutation leads to individuals having very high levels of blood cholesterol (familial hypercholesterolaemia). This often leads to heart attacks and other forms of atheromatous arterial disease occurring at a much earlier age than in the general population.
There are different sub-types of cholesterol. Research has shown that arterial disease is particularly associated with high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C). These findings were quickly applied to the treatment of individuals with a high risk of vascular disease: in a process known as secondary prevention, those who had already had a heart attack or angina were prescribed cholesterol-lowering drugs in order to prevent vascular harm. Those people who had a strong family history of early vascular disease or who had familial hypercholesterolaemia were treated similarly (primary prevention).
However, early treatments with drugs such as colestyramine and colestipol were dogged by problems with side effects even though they were somewhat effective in reducing both serum cholesterol levels and later vascular events,.
In the 1970s it was discovered that another class of drugs which inhibit the hepatic enzyme hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase) are effective at lowering serum cholesterol (Sternberg, 2006). These drugs, commonly known as statins, were subsequently marketed in a variety of forms - simvastatin, lovastatin, atorvastatin, rosuvastatin, etc. Because of their greater effectiveness and apparent greater tolerability compared to older lipid-lowering agents (see below) they became the drugs of choice for the treatment of hypercholesterolaemia in both primary and secondary prevention (Baigent et al, 2005).
Which patients should definitely receive statins?
There is a settled medical view (European Society of Cardiology, 2016; NICE Cardiovascular Disease Guideline [CG181] 2014, updated 2016) that people who have already suffered a definite vascular event (such as an ischaemic stroke, myocardial infarction, retinal embolism causing amaurosis fugax, etc.) or who have symptoms that indicate atheromatous arterial disease (such as stable or unstable angina, or peripheral vascular disease) should be offered a range of measures to reduce their vascular risk. These measures fall into three groups -
(1) lifestyle advice related to smoking cessation, exercise, diet, alcohol consumption and so on;
(2) investigation and treatment of associated conditions such as hypertension and diabetes mellitus;
(3) preventative drugs (also known as chemoprophylaxis), including anti-platelet agents and statins.
Although good lifestyle advice is 'primary prevention' for all sorts of health conditions, these measures in patients with a known vascular problem come under the heading of 'secondary prevention'. The same approach is taken with those who appear to have familial hypercholesterolaemia, namely people who have a total cholesterol concentration more than 7.5 mmol/litre and a family history (in a close relative) of premature coronary heart disease, or people with a total cholesterol concentration of more than 9.0 mmol/litre or a non-HDL cholesterol concentration of more than 7.5 mmol/litre even in the absence of a first-degree family history of premature coronary heart disease.
So far as statins are concerned, the evidence in favour of their use in secondary prevention comes from several clinical trials carried out in the 1990s: for example, in the 4S trial (Scandinavian Simvastatin Survival Study Group, 1994) total mortality was reduced in the simvastatin group such that, of 100 people given simvastatin 8 people died compared to 11 or 12 out of 100 in the placebo group. So far as death from coronary heart disease, specifically, is concerned, between 8 and 9 people in every 100 died after being given placebo compared to 5 given simvastatin. Subsequent research has suggested that more intense lipid lowering in higher-risk people is more effective than less intense treatment (Cholesterol treatment Trialists, 2010).
Statins in primary cardiovascular disease (CVD) prevention
Although screening for cardiovascular risk is not part of a national screening programme in the UK and has not formally been recommended by the UK National screening committee, it has become increasingly common for asymptomatic individuals to be offered CVD screening, using the implicit justification that coronary heart disease and stroke are leading causes of death and disability in the population. Individuals are selected for screening opportunistically, usually when they attend primary care for some unrelated reason, or as part of a programme of general health checks promoted by Public Health England, and those who are deemed to be at increased risk are then offered advice and chemoprophylaxis to protect against adverse CVD events.
Thus, for example, NICE (2016) recommends that "people older than 40 should have their estimated CVD risk reviewed on an ongoing basis". Risk assessments commonly take the form of the calculation of a combined risk score based on such things as age, sex, family history, smoking habit, blood pressure and serum cholesterol level, both for total cholesterol and for LDL-C. The combined score is then used to derive a percentage risk, for that individual, of a significant CVD event over the succeeding year, five-year period or ten-year period (see, for example, Hippisley-Cox J, Coupland C and Brindle P, 2017).
If someone has at least a 20 out of 100 risk of CVD events in the next ten years then he/she will be offered advice about how to make the lifestyle changes described above in relation to exercise, weight, diet, smoking etc. in order to prevent an adverse CVD occurrence, if they haven't done so already. These people will also be offered statins.
Why is the use of statins in primary CVD prevention controversial?
In order for any form of pharmaceutical prophylaxis to be acceptable it needs to be effective, largely free of significant adverse effects and cheap. The debate about the value of statins for primary prophylaxis centres on their effectiveness in lower-risk people and the frequency and severity of their side-effects.
Are statins effective?
It has been reported that prescribing statins at doses that effectively reduce LDL-C blood levels by at least half seem to halt progression or even contribute to regression of coronary atherosclerosis (Nissen et al, 2006), although this is a 'proxy' or surrogate measure rather than a guarantee of a reduction in the endpoint of less deaths and disability.
Baigent et al (2005), in a meta-analysis of fourteen statin trials involving over 90,000 subjects, reported that there was a small reduction in all-cause mortality per 1 mmol/L reduction in LDL cholesterol: for every 100 people given a statin for one year there were between 8 and 9 deaths compared to 10 in every 100 given a placebo. This reflected a reduction in deaths from all vascular causes, from 6 per 100 to 5 per 100. The proportional reduction in major vascular events was greater when larger reductions in LDL cholesterol were achieved.
This meta-analysis, though reasonably persuasive overall, includes trials involving subjects with widely differing levels of baseline CVD risk and it is hard to obtain substantial amounts of data for subjects at low risk. The same group have subsequently published a meta-analysis in which they were able to obtain individual participant data from twenty-two trials of the use of statins (Cholesterol Treatment Trialists' Collaborators, 2012). In this paper they reported that statin therapy reduced the 5-year incidence of major coronary events, coronary revascularisations, and ischaemic strokes by about 20 in every 100 per 1·0 mmol/L reduction in LDL cholesterol, and that additional reductions in LDL cholesterol obtained with more intensive statin regimens further reduced the incidence of these major vascular events.
The benefits of statin therapy were seen across all risk groups. However, in the group of subjects with the lowest risk (5-year risk of major vascular events lower than 100 per thousand) the authors report that "each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years."
Given that the absolute rate of events in this group was already low at 57 per 1000 over 5 years, this means that statins would reduce the risk to 46 per 1000, assuming that the average reduction in LDL cholesterol was about 1 mmol/l. Thus it seems that the effectiveness of statins in low-risk individuals is modest. (Readers wishing to see this information displayed in graphical form may wish to consult the page on Statins for Primary Prevention of Cardiovascular Diseases on the website of the Harding Center for Risk Literacy).
Further support for the view that low-risk people may not benefit from being prescribed statins comes from the paper by Byrne, Cullinan and Smith (2019): in this paper the authors review the change in eligibility for statin prophylaxis in European guidelines on cardiovascular disease prevention published in 1987 versus those published in 2016, using data from a national cohort of older people in Ireland. They found that the proportion of their sample of over 50s who would have been eligible for statins increased from 8% based on the 1987 guidelines to 61% with the 2016 guidelines. The broadening of the diagnostic criteria over this period meant that increasingly lower risk people became eligible for treatment and the number of people that would need to be treated (NNT) to prevent one major cardiovascular event also went up substantially: 40 people at the lowest risk in the 1987 guidelines compared with 400 of those at the lowest risk in the 2016 guidelines.
These authors then examined three published reviews which fully disaggregated primary prevention data from secondary data; the reviews included people taking statins for between one and five years and they had an average age between 62 and 69 years. Byrne and colleagues found that there were significant reductions among those taking statins in all-cause mortality (relative risk 0.91, 95% confidence interval 0.85 to 0.97), vascular deaths (0.85, 0.77 to 0.95), major coronary events (0.71, 0.65 to 0.77), and major vascular events (0.75, 0.70 to 0.80).
However, the net benefit or absolute risk reduction achieved with statins depended on a person’s baseline risk of developing cardiovascular disease, based on traditional risk factors. When subjects were stratified in this way, the estimated effects of statins on most outcomes were not statistically significant.
Are statins likely to cause significant adverse effects?
The NHS website lists a number of symptoms which occur commonly in people taking statins, including nose bleeds, sore throat, runny nose, headache, nausea, bowel disturbances and an increased risk of diabetes. Side-effects which are thought to be most likely to be statin-specific are related to skeletal muscle and include muscle aches and pains and rhabdomyolysis.
The frequency and importance of these effects are contentious: the CTT (2012) paper reports that "statin therapy is associated with a small increased risk of myopathy (excess incidence of about 0·5 per 1000 over 5 years) and, more rarely, of rhabdomyolysis (excess incidence of about 0·1 per 1000 over 5 years)". Other authors have reported a more negative picture: Abramson et al (2013, corrected 2014) describe a review of more than 100 000 subjects studied over 8 years; in this group 174 per 1000 had a statin-related adverse effect documented. In about 590 per 1000 of these the statin was discontinued, at least temporarily, with a total figure for statin discontinuations of 90 per 1000.
It is also worth noting the comment by Byrne and colleagues (2019) that studies reporting results that are favourable to the pharmaceutical industry may be more likely to be published and may under-report harms. Overall, however, the long-term safety of statins does not appear to be a significant issue (see Harding Center for Risk Literacy pages, above).
There is also a problem concerning the 'nocebo' effect: statins have acquired a reputation for causing muscle pain. It has been observed that subjects in clinical trials who are given an inert comparator substance instead of a statin may also report muscle aches, leaving room for debate about whether such pains are actually due to a specific chemical effect of statins. A study reported in November, 2020 called the SAMSON study (Wood et al) described the results of giving a statin, an inert placebo or no tablets at all to people who had previously stopped taking statins because of side effects. They found that the reported frequency of muscle side effects was almost as high when the subjects were taking the placebo as when they were taking the statin and concluded that about 90% of the apparently harmful effect of statins on muscle pains was indeed due to a nocebo effect.
Are statins cheap?
Yes - the average annual cost of treatment with simvastatin, 40mg daily is under £10 and of atorvastatin, 40mg daily is a little over £12 (Regional Drug and Therapeutics Centre, Newcastle, Cost Comparison Charts, January 2019).
What advice should patients receive?
There is a strong case for advising the use of statins in people who have already had a documented vascular event or who have known vascular disease such as angina or peripheral arterial disease. In those who experience adverse effects from a statin, problems can often be resolved by lowering the dose or switching to another type of statin. Although persistent symptoms are sometimes a problem, there is no evidence that statins confer any other long term health risks such as an increased risk of cancer.
The case for opportunistic screening is less clear. People who have clinical markers of risk (age over 40, male, smokers, family history of premature vascular events, etc) often have have their CVD risk estimated using an evidence-based risk tool such as SCORE or QRISK-3. Expert groups generally recommend that if someone's 10-year CVD risk exceeds 10% (10 in 100 chance of having a heart attack or stroke in the next 10 years) a doctor, usually the patient’s GP, should discuss measures to reduce CVD risk with the person and if their risk level is more than 20%, they should be offered statins as part of a package of measures.
It can be argued that there is a strong case for improving the information given before starting statins, so that a proper shared decision is made for what is in fact a predicted risk of disease complications rather than an actual symptomatic condition, especially as the medical response includes offering a planned lifelong medication.
In people who are at very low risk (which includes most of the general population in middle age) the situation is much less clear: perhaps for the sake of simplicity doctors easily fall into the trap of believing that the decision to offer, prescribe or take a medication is based on the binary of 'it works' vs 'it doesn’t work'. The threshold levels of 10% and 20% are therefore helpful in giving a sense of gradation of risk. Decision aids help too (for example, those provided by NICE, or by the Harding Center for Risk Literacy - see above).
However, we can still be misled into thinking that informed consent is a matter of giving 'objective' information which can be rationally analysed by the autonomous individual to come to a 'free' decision. People, however, are not either as free or autonomous as one might idealise. All of us are easily 'nudged' in particular directions by our faith in the authority of those around us. A culture of suspicion might lead people to choose not to follow doctors' advice (for example, as is sometimes the case with vaccinations). A culture of belief, influenced by the covert forces of vested interests – such as drug companies and those with jobs and status - might lead many members of the general public to be enthusiastic about other medical interventions.
Practising doctors are privileged to be able to 'know' their patients personally to some extent, and so to be able to have a personal and adult conversation about what risk and benefit might look like for the individual. Unfortunately, pressures of time can sometimes reduce this conversation to a simple recommendation based on a threshold being met.
If the medical profession is to retain the trust of society in the long run, we should aspire to being more nuanced and balanced in our recommendations, and also sympathetic towards the decisions of patients when they, inevitably, may not be in line with our own personal or 'guideline' preferences. The reality is that the use of any medications, including statins, contains many uncertainties for any individual.
It is sad that deaths from cardiovascular causes have stopped declining despite the rise in statin prescriptions (Mensah et al, 2017). Whilst we cannot conclude anything directly about causation, this finding should at least flag up that there are other factors which are of greater significance than statins alone. Doctors should fully respect individuals’ decisions not to take a statin, even if they provide more directive counselling for the secondary prevention and at higher levels of risk.
When should statins be discontinued?
Apart from those people who are statin intolerant despite changes of dose and formulation, the other group in whom this question arises are people of advanced age and/or with severe, life-limiting illnesses: many such people are keen to reduce the load of medical interventions. Preventative medications, of which statins are one, require years of concordance for the person to benefit. Some people may therefore be keen to discuss reducing medication load, including statins.
Addendum
In September, 2019 Sir Norman Lamb, the Chair of the House of Commons Select Committee on Science and Technology, called on the government to ask its newly-appointed Chief Medical Adviser to conduct a review into the use of statins so that the various views of those who are in favour of, or against, more widespread use of statins could be reconciled.
Roger Fisken and James May
6th November, 2019
References
Abramson JD, Rosenberg HG, Jewell N, Wright JM (2013). Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123.
Abramson JD, Rosenberg HG, Jewell N, Wright JM (2014). Should people at low risk of cardiovascular disease take a statin? Correction. BMJ 2014;348:g3329.
Baigent C, Keech A, Kearney PM et al. (2005). Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366 (9493):1267–78.
Byrne P, Cullinan J, Smith S (2019). Statins for primary prevention of cardiovascular disease. BMJ 2019;367:l5674.
Cholesterol Treatment Trialists' Collaboration (2010). Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 376 (9753); 1670-1681.
Cholesterol Treatment Trialists' Collaboration (2012). The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380: 581-90.
European Society for Cardiology (2016). 2016 European Guidelines on cardiovascular disease prevention in clinical practice. The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European Journal of Preventive Cardiology 2016, Vol. 23(11) NP1–NP96.
Hippisley-Cox J, Coupland C, Brindle, P (2017). Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ 2017;357:j2099.
Mensah GA, Wei GS, Sorlie PD et al. (2017). Decline in Cardiovascular Mortality
- Possible Causes and Implications. Circulation Research 2017;120:366-380.
National Institute for Healthcare and Clinical Excellence (NICE) (2016). Cardiovascular disease: risk assessment and reduction, including lipid modification. Clinical guideline [CG181] Published date: July 2014 updated September 2016.
Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 295:1556–1565.
Prospective Studies Collaboration (2007). Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 370 (9602); 1829-1839.
Scandinavian Simvastatin Survival Study Group (1994). Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344 (8934); 1383-1389.
Sternberg, D. (2006). An interpretive history of the cholesterol controversy, part V: The discovery of the statins and the end of the controversy. Journal of Lipid Research. 47: 1339–1351.
Wood FA, Howard JP, Finegold JA et al. (2020) N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. NEJM; 383:2182-2184. DOI: 10.1056/NEJMc2031173.