Statins for the primary prevention of cardiovascular disease
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g280 (Published 27 January 2014) Cite this as: BMJ 2014;348:g280
- Shah Ebrahim, professor of public health and policy1,
- Fiona C Taylor, managing editor, Cochrane Heart Group1,
- Peter Brindle, general practitioner2
- 1Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Health, London WC1E 7HT, UK
- 2Avon Primary Care Research Collaborative, Bristol Clinical Commissioning Group, Bristol BS1 3NX, UK
- Correspondence to: F C Taylor fiona.taylor{at}lshtm.ac.uk
- Accepted 8 January 2014
A 55 year old former financial services manager attended a cardiovascular risk check, which showed he had a 15% risk of suffering a major cardiovascular event in the next 10 years.1 He asks his general practitioner whether he needs a statin given his risk. His risk factors are being overweight; moderate smoker; blood pressure 150/90 mm Hg; and serum total cholesterol concentration 5.5 mmol/L, high density lipoprotein cholesterol 1.2 mmol/L, low density lipoprotein cholesterol 3.5 mmol/L, triglycerides 1.7 mmol/L.
What are statins?
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, involved in cholesterol biosynthesis. Low density lipoprotein (LDL) cholesterol concentration is lowered by reducing its production in the liver and increasing removal from the circulation.2 Lowering blood levels of LDL cholesterol, a major risk factor for cardiovascular disease, reduces the chances of having cardiovascular disease. Statins also have anti-inflammatory effects, improve endothelial function, and reduce thrombus formation, but these effects may not be independent of cholesterol lowering or reduce cardiovascular disease risk.3 Expert committees promote their use on a global scale,4 5 6 7 and statin prescribing and expenditure have risen rapidly. In England, prescriptions for statins rose fivefold from 2001 to 2011 to £61m a year (£544 average annual cost per person).8
How well do they work?
Statins are indicated for secondary prevention of cardiovascular disease. The Cholesterol Treatment Trialists Collaboration reviewed data from 27 clinical trials of statins (170 000 participants) for both primary and secondary prevention and reported a 20% relative risk reduction per 1 mmol/L reduction in LDL cholesterol concentration for major vascular events. These beneficial effects were seen in both men and women, at ages from <60 to >70 years, in people with and without cardiovascular disease, in those at high and low cardiovascular disease risk, in diabetics, and in those with average levels of blood cholesterol.9
A Cochrane systematic review of statins for primary prevention of cardiovascular disease included 18 trials (56 934 participants, most with one or more cardiovascular disease risk factor).10 It found that statins lowered cardiovascular disease risk by 27% (table⇓). The median level of cardiovascular disease risk observed in the control groups of the trials was equivalent to 15% over 10 years (the same as the current case). Over five years, the number needed to treat (NNT5) to avoid one cardiovascular event was 50. The NNT5 for people at 10%, 20%, and 30% predicted cardiovascular event risk over 10 years were 74, 37, and 25 respectively. These compare with NNT5 values of between 12 and 34 in secondary prevention.
Effects of statins on from trials in primary prevention6
How safe are they?
Use of statins by low risk patients has been criticised on the grounds that their benefits do not outweigh their harms12 and debated.13 14 However, all cause mortality in people taking statins with no pre-existing cardiovascular disease is reduced (table⇑), indicating that any unintended life threatening effects are outweighed by their beneficial impact on cardiovascular disease, although this evidence is not strong.15 Earlier concerns about cancer risk are unfounded.16 However, other unintended effects are not comprehensively reported in systematic reviews or trials.17
Adverse events and stopping treatment because of them are common, but occur at similar rates in treated and control groups in clinical trials (17% and 12% respectively),10 making it difficult to ascribe these events to statins. Reports of reduced energy, fatigue, depressed mood, and reduced quality of life show inconsistent findings.18 19 20 Myositis (a ≥10-fold rise in normal levels of creatine kinase) is caused by statins, but myalgia (muscle pain without raised creatine kinase) is not linked with statin use.21 In two large, well conducted, observational analyses using national primary care datasets, the numbers needed to harm for incident myositis associated with five years of statin treatment were between 9022 and 250.23 Rhabdomyolysis—an extreme form of myositis that can be serious if not detected and treated early—may be caused by statins but is very rare.24 Myositis and other adverse effects are more common with aggressive lowering of cholesterol levels by means of potent statins such as rosuvastatin or higher doses of statins (such as doubling of usual doses).25
Statins are associated with an increased risk of developing type 2 diabetes,11 26 especially at higher doses.27 Only two primary prevention trials reported on type 2 diabetes outcomes, with a pooled relative risk of 1.18 (95% confidence interval 1.01 to 1.39). This result is consistent with a larger meta-analysis that included both primary and secondary prevention trials, which found that treating 255 people for four years would cause one case of diabetes, but this would be offset by avoiding more than five major vascular events (table⇑).11 This increased risk of diabetes was related to baseline fasting glucose levels among trial participants.28
Haemorrhagic stroke was not increased by use of statins in a meta-analysis of randomised trials (odds ratio 1.08 (95% confidence interval 0.88 to 1.32)).29 Large observational primary care datasets found no strong evidence that statins were associated with an increased risk of Parkinson’s disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, or infections, and confirmed the evidence from randomised trials of no increased risk of cancer.22 23 Other possible adverse effects of statins (cataracts, depression, and peripheral neuropathy) and possible benefits (on bone mineral density, cognition, and macular degeneration) have not been confirmed in randomised trials.20
Patients may expect not to be harmed in any way by preventive treatment with statins, and their views of trade-offs between benefit and possible harms will likely determine the wider use of statins.30
How are statins taken?
The National Institute for Health and Care Excellence (NICE) guidelines recommend that, before starting a statin, all patients should have a comprehensive assessment of their cardiovascular risk factors and secondary causes of dyslipidaemia considered (see box 1).31 Patients should be advised to deal with modifiable risk factors before starting statins. Current NICE guidance uses a threshold of ≥20% for 10 year risk of cardiovascular disease for using statins. People at lower cardiovascular risk may also benefit, however,9 and the new American College of Cardiology/American Heart Association guideline has lowered its treatment threshold to a predicted 7.5% for 10 year cardiovascular risk.32
Box 1: Monitoring statins in practice
Baseline measurements
Fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides
Blood glucose, renal function, and liver function tests (transaminases)
Thyroid function tests to exclude hypothyroidism as a cause of dyslipidaemia
Repeated measurements
NICE considers that it is unnecessary to make repeated measures of blood lipid profiles routinely
Liver function should be measured within 3 months of starting treatment and at 12 months, but not again unless clinically indicated
Indications for creatine kinase measurements
Measure this in patients complaining of muscle symptoms (pain, tenderness or weakness)
Refer if concentration is raised ≥5 times above the upper limit of normal range
If concentration is raised <5 times above the upper limit, symptoms should be monitored carefully and creatine kinase measurement repeated a month later. If still raised, reduce the statin dose and recheck creatine kinase a month later. If symptoms persist or creatine kinase levels remain high, specialist advice should be sought
Creatine kinase should not be routinely monitored in asymptomatic people being treated with a statin
What are the precautions?
General contraindications to prescribing statins include women during pregnancy and breast-feeding, previous hypersensitivity reactions to a statin, active liver disease, renal failure, and heavy drinkers (50+ units a week). Both the USA and UK drug regulatory agencies have issued safety alerts advising blood glucose monitoring in patients at risk of developing diabetes and taking statins.33 34 However, based on current evidence, statins should not be avoided in patients with pre-existing diabetes who are at high risk of cardiovascular disease.
Drug interactions
Many drugs are metabolised by the cytochrome P450 isoenzyme system, which also metabolises statins, and consequently drug-drug interactions may occur.35 Patients with renal disease, HIV infection, and organ transplants are more prone to interactions. A wide range of drugs have been implicated in interactions. Patients treated with these drugs should be monitored for possible side effects, such as muscle pain and gastrointestinal symptoms (see box 2). Patients taking simvastatin should be advised to avoid drinking grapefruit juice. Lower doses of statins are less likely to provoke clinically important interactions.
Box 2: Statins and interacting drugs36
Macrolide antibiotics—Erythromycin, clarithromycin, telithromycin
Azole antifungals—Itraconazole, ketoconazole, posaconazole
Protease inhibitors—Amprenavir, indinavir, nelfinavir, ritonavir, saquinavir
Immunosuppressive drugs—Ciclosporin
Fibrates—Gemfibrozil
Cardiovascular drugs—Amiodarone, verapamil, diltiazem, amlodipine, ranolazine, warfarin
Antidepressant drugs—Nefazodone
Other drugs—Sildenafil, danazol
How cost effective are statins?
For primary prevention of cardiovascular disease, cost per QALY is variable depending on the level of cardiovascular disease risk, age, and cost of statins, with NICE supporting their use in people with predicted 10 year cardiovascular risk of >20%.6 The costs per QALY were based on NHS costs in 2004 when most statins were still in patent. These estimates need updating given the large reductions in their costs.
How do statins compare with other drugs and interventions?
Statins are not the only means of reducing risk of cardiovascular disease. People at high cardiovascular risk can reduce their risk by making lifestyle changes (see figure⇓ and case outcome).
If a statin is not tolerated, switching to an alternative statin and starting at a low dose may work. Fibrates (bezafibrate, ciprofibrate, fenofibrate, gemfibrozil) lower cholesterol, but evidence of clinical effectiveness is limited. NICE recommends use of ezetimibe when statins are contra-indicated or not tolerated, or in conjunction with a statin when LDL cholesterol concentration is not controlled by optimal statin therapy.31 Combination statin and fibrate treatment may be used when blood triglyceride levels are raised and are not controlled with a statin alone. However, evidence of clinical benefits from combination treatment is limited and side effects (such as muscle pain) are common.
Nicotinic acid, plant sterols and stanols, anion exchange resins, and omega 3 fatty acid supplements are not recommended by NICE for cholesterol lowering in primary prevention.
Case outcome
Stopping smoking would reduce the patient’s predicted 10 year cardiovascular disease risk from 15% to 11%. If he takes a statin instead and gains the typical 1 mmol/L reduction in LDL cholesterol level, this too would reduce his predicted cardiovascular disease risk to 11% (see figure⇓). Stopping smoking and taking a statin would reduce this further to 9%
As he is overweight and hypertensive, a programme of alcohol reduction, increased physical activity, and attending a weight reduction course might achieve a lower blood pressure and would combat other cardiovascular risk factors not included in the risk score. Adding a statin to these lifestyle measures would, on average, almost halve his risk to 8% (assuming he does not revert to his adverse lifestyle as the statin is now “doing the job”) with an NNT5 of approximately 60 for cardiovascular disease events.
His predicted 10 year cardiovascular disease risk is lower than the NICE threshold of ≥20%; treating him with a statin would go against current English guidance.
Predicted cardiovascular disease risk (percent) over 10 years for given characteristics based on QRISK Intervention software1
Tips for patients
You can reduce your chances of having a heart attack or stroke
The common risk factors are smoking, high blood pressure, raised blood cholesterol (circulating fat in the bloodstream), and lack of exercise. All of these can be improved with beneficial results
Consider checking your own risk and seeing what effect lifestyle changes could have on reducing your risk (see http://qintervention.org/). Decision making tools such as the Mayo Clinic’s (http://statindecisionaid.mayoclinic.org/index.php/statin/index) and the National Prescribing Centre’s (www.npc.nhs.uk/therapeutics/cardio/cd_lipids/resources/pda_Lipids.pdf) may help you to weigh up the risks and benefits of taking statins
Statins lower your cholesterol level and reduce your chances of having a heart attack or stroke
There is no evidence that statins cause cancer or dementia or increase your risk of dying from other diseases
Statins may increase your chance of developing diabetes, particularly if you are obese, physically inactive, and have a family history of diabetes. Even then, the benefits of taking statins outweigh the smaller risk of developing diabetes
People with diabetes benefit from taking statins
If you get muscle pains while taking a statin you should consult your GP, who may want to do a blood test and may reduce your statin dose or advise taking it on alternate days
Statins are more effective if taken in the evening on going to bed
Grapefruit juice should be completely avoided if you are taking simvastatin as it can worsen the side effects, but this is not such a problem with atorvastatin
Statins have to be taken every day and for the foreseeable future – they won’t work if you don’t take them
Some drugs must be avoided or used with caution when taking statin. Consult your GP before taking any other drugs with a statin
Notes
Cite this as: BMJ 2014;348:g280
Footnotes
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic for this series, please email us at practice@bmj.com.
Contributors: FCT planned and wrote the first draft. SE interpreted the data and redrafted the manuscript where required. PB contributed to the drafting and revision of the manuscript. All authors gave final approval of the article. SE is responsible for the overall content and acts as guarantor.
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and we have no relevant interests to declare. PB was involved in the development of QRISK.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).