Adverse effects of statins
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3306 (Published 15 May 2014) Cite this as: BMJ 2014;348:g3306
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I have two observations to make on the statin wars.
Firstly: if there is any uncertainty at all about the risks and benefits of statins – and there is - then we have failed to competently implement the most basic principles of evidence based medicine. Statins are the single most commonly prescribed class of treatment in the developed world, taken by tens if not hundreds of millions of patients every day. That would be more than enough clinical experience to resolve any research questions, if we were competently identifying all outstanding uncertainties, and conducting well-designed trials to answer those questions in routine clinical care [1]. We need better data; better dissemination of that data; and better communication of that data, in ways that help people make decisions which reflect their wishes. Statins should be the crowning glory of evidence based medicine, our perfection incarnate: instead, they are a mess.
Secondly: while disputes over individual numbers are important, the leading protagonists in the statin wars seem, above all, to be suffering under a grand delusion that all patients think like they do. On the one hand, we have clinicians and researchers insisting that no sane patient would refuse a safe simple treatment that reduces their chances of a heart attack by one in 200; on the other, we have clinicians and researchers insisting that one in 200 is a laughable and trivial benefit, which no sensible patient could ever care about.
In reality, all patients are different, and we all – as doctors or as patients - weigh up different factors differently. Some want longevity at any cost; some think taking a pill every day is an affront to their independence. Some think aching muscles are a trivial niggle; some think that side effects - even when mild, well-documented, and carefully discussed - are proof that their doctor is a reckless idiot.
When we offer statins, or any preventive treatment, we are practicing a new kind of medicine, very different to the doctor treating a head injury in A&E. We are less like doctors, and more like a life insurance sales team: offering occasional benefits, many years from now, in exchange for small ongoing costs. Patients differ in what they want to pay now, in side effects or inconvenience, and how much they care about abstract future benefits. Crucially, the benefits and disadvantages are so closely balanced that these individual differences really matter.
Because of that, this new kind of medicine needs perfect information. We need clean, clear data showing the risks and benefits of preventive treatments, on real world outcomes, beyond any reasonable doubt, at every level of risk, and for as many subgroups as possible. We need shared decision making products that are universally available, carefully validated, and seamlessly integrated into routine clinical care, to help all patients make their own truly informed decisions. Lastly, we need to recognise that different patients have different priorities: different to each other and, sometimes, very different to our own.
Ben Goldacre
Research Fellow in Epidemiology
London School of Hygiene and Tropical Medicine
ben.goldacre@lshtm.ac.uk
[1] Staa T-P, Goldacre B, Gulliford M, et al. Pragmatic randomised trials using routine electronic health records: putting them to the test. BMJ. 2012;344(feb07 1):e55-e55. doi:10.1136/bmj.e55.
Competing interests: I have a Wellcome Clinical Research Training Fellowship and receive income from talking and writing for public and professional audiences about problems in science and medicine.
Dear Editor,
This letter is the collective statement of the Russian Formulary Committee. Our organization has now been working for 18 years, advising once the Ministry of Health, Russian Academy of Medical Sciences, and now functioning as a professional society.
With all due respect to the NICE and the scientific advice provided by the NICE to UK physicians we tend to disagree with the advice prepared in relation to statin use in low risk populations.
1. The prospective decision of NICE is based on the external review of the industry data, not open for the scrutiny by specialists, and thus it is a decision which may not be totally trusted.
2. The introduction of the mass treatment/prevention program leads to the risk of serious and less serious side effects. Unfortunately, knowledge about the frequency of the side effects of statins is very approximate. One of the causes of the insufficient knowledge is the underreporting in trials and trials’ design to minimize the side effects.
3. The NNT in the low risk population is high by definition. Thus, the prospective introduction of the ‘recommended’ statin treatment for the low risk population is a high risk decision, the decision of high risk of doing more harm, than good.
4. The decision to recommend statin therapy in low risk population will lead to the introduction of ‘box ticking’ to get the quality rating and additional payment. This system is mimicked in many jurisdictions. Millions of people around the world may be harmed because of a dubious UK NICE decision.
5. The UK NHS is famous for being serious about rational health care spending. The cost of mass statin treatment is enormous. There are other problems to address in the NHS, as we understand, but we trust NICE - they know it better. In the same time, the introduction of mass statin treatment in NHS will flash a green light to other health systems, less affluent and more corrupted, including the Russian one. It is why we express our opinion.
6. The representation of the numerical mistake in the BMJ article as a major deception of the public is misleading and should be opposed with all seriousness. In some modern non-democratic countries attacks on independent media are frequently started from the representation of some text as immoral, or non-patriotic, or irresponsible, etc. only to justify financial or administrative pressure.
Competing interests: No competing interests
Thank you Dr Abbasi for your confirmation; I am sure organisations like the Patients Association and Cure the NHS will keep this in mind.
I the meantime, how about the BMJ campaigning on increasing tax or limiting availability of sugar rich alcoholic drinks(including wines) and beverages using high fructose corn syrup? This strikes me as a equally valid response to the 10% statin debate.
I presume your journal is not financially supported by these companies?
Competing interests: No competing interests
Dear editor,
Following your recent editorial about adverse effects of statins (1), we analysed the official information available in France for healthcare professionals and patients, about a relatively new adverse effect of this class: the diabetogenic effect.
The European Medicines Agency (EMA) acknowledged the diabetogenic effect of statins in March 2012. That date, the EMA demanded that summaries of product characteristics (SmPC) and package leaflets (PL) for all statins should be modified (2). A common text was written for the pharmaceutical firms and statins as a whole (3). The American Food and Drug Administration came to the same conclusions in February 2012 and transmitted the same request to US firms (4).
We therefore analysed the French SmPCs and PLs, all of them being on the website of the national medical products agency (Agence Nationale du Médicament et des produits de Santé, ANSM) (5).
During the 3 days following the ANSM database update on the 25th april 2014, we found 227 generic proprietary drugs and 34 brand name drugs containing a statin (6). SmPCs and PLs were not available online for 5 generic proprietary drugs and 1 brand name drug.
Of the 255 available SmPC, only 133 (52%) mentioned the diabetogenic effect of statins. With no exception, PLs were updated when and only when SmPCs were. Table 1 below show detailed results per statin.
More than 2 years after the EMA demand, nearly one SmPC/PL out of two had not been updated. The oldest molecules’data (pravastatin, simvastatin and fluvastatin) were the least updated.
SmPCs are crucial to healthcare professionals, as they form the basis of every other available information on drugs. PLs are also very important to patients’ information. However, despite the French law modifications following the benfluorex affair, official information on adverse effects of drugs is still unreliable (7).
In this context, we may find unsurprising that since 2012, no information at all has been sent from the ANSM to French healthcare professionals about the diabetogenic effect of statins, despite the fact that these drugs are prescribed to more than 6.4 million patients (8).
We feel that the French drug regulatory agency should take an urgent step to enforce its own decisions about health care professionals’ and patients’ information.
Dr Stambach Frédérick, GP at Haute-Vienne in France, stambach.fred@orange.fr; competing interests: None
Dr Nicot Philippe, GP, expert for the Haute autorité de santé, and vice-president of the FORMINDEP association; competing interests: None
Dr Doubovetzky Jean, GP and senior writer for Prescrire journal, competing interests: None
References
1.Godlee F. Adverse effects of statins. BMJ 2014;348:g3306. Available at: http://www.bmj.com/content/348/bmj.g3306
2.EMA alert March 2012 - Pharmacovigilance Working Party (PhVWP) Monthly report December 2011 plenary meeting - WC500120115.pdf [Internet]. [quoted 9th Apr 2014]. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/01/WC50...
3.Transparency Commission. HAS – Recommendations of the Transparency commission about the Crestor – put online on 15th April 2014 [Internet]. 2014. Available at: http://www.has-sante.fr/portail/upload/docs/evamed/CT-13465_CRESTOR_PIS_...
4.FDA. Drug Safety and Availability > FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs [Internet]. [quoted 20th March 2014]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
5.ANSM. Index of proprietary pharmaceutical drugs [Internet]. [quoted 15th May 2014]. Available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php#result
6.Stambach F. The diabetogenic effect of statins, first reports and literature review [Internet] [Thèse d’exercice]. [France]: Faculté de médecine de Limoges; 2014. Available at: http://www.voixmedicales.fr/wp-content/uploads/2014/05/Th%C3%A8se-v5_5_1....
7.Law n° 2011-2012 of 29th December 2011 relating to the reinforcement of sanitary security of medicines and health products | Legifrance [Internet]. [quoted 26th Apr 2014]. Available at: http://www.legifrance.gouv.fr/affichTexte.do;jsessionid=?cidTexte=JORFTE...
8.Assurance Maladie. Usages des statines [Internet]. Point d’information; 2013. Available at: http://www.urml-oi.net/infos_temps_2013/Usage_statines_mai_2013.pdf
Competing interests: No competing interests
Dear Professor Sir Iain Chalmers,
Sorry to here you have been taking a statin and have been getting severe muscle pains. Why don't you have some of the relevant tests carried out by Biolab, London and Acumen laboratory, Devon to see what is going on in your cells?
The commonest treatable deficiencies are of zinc and magnesium and essential fatty acids and also Co-enzyme Q10. Acumen's ATP profile shows more reasons for mitochondrial dysfunction which is are usually treatable.
Thank goodness there is more to aid life than just often flawed epidemiology.
Competing interests: No competing interests
Dr de Silva will be pleased to know that he is able to complain to the Press Complaints Commission about The BMJ. We are certainly open to criticism, nor do we hesitate to criticise when we believe it to be justified.
Competing interests: No competing interests
Randomized, placebo controlled withdrawal/discontinuation trials are uncommon. The first time I became aware of this research strategy was when Archie Cochrane's unit in Cardiff addressed uncertainty about whether to continued prescription of diuretics was justified in some older people for whom they had been prescribed. Those about whom this question had been raised were randomly allocated either to continue on diuretics or to placebo.
I think this research strategy may be relevant to discussions about the variety of postulated side effects of statins. It is clear from the current debate about the frequency of side effects attributable to statins that the quality of reporting of possible side effects is very variable, perhaps particularly in large multicentre trials sponsored by industry.
A more scientifically efficient research strategy for identifying side effects attributable to statins might be to invite people who wonder whether their symptoms are caused by statins to participate in randomized, placebo controlled withdrawal/discontinuity trials. Such trials, each involving a few thousand symptomatic patients at most, should not be difficult to set up, and useful information could be produced without long term follow up. They could provide estimates of the extent to which symptoms improve after random allocation to either (continued) statin or to placebo.
Although such trials could not provide patients considering whether to start taking statins with estimates of the likelihood that they will experience adverse effects, they would provide patients experiencing symptoms with relevant evidence about whether their symptoms could be expected to be relieved by stopping statins.
I have been wondering for some time whether the unexplained, intermittent, severe muscle pains in my right upper arm are caused by the 40 mg of simvastatin I have been taking every day for the past few years. I would welcome better information to inform my judgements about my (life long) medication and its possible unwanted effects. I hope I will be invited to participate in the controlled trials that are needed to provide the information.
Competing interests: No competing interests
Like Klim McPherson,1 my experience is of the effects of hormonal contraceptives and HRT. For many decades I have been detailing numerous faults in epidemiological studies.2,3 Even the WHI HRT study underestimated the dangers of taking hormones because most women had taken either contraceptive or menopausal hormones before being randomised to take hormones or placebos. This inevitably underestimates increases in cancers and strokes, heart attacks and venous thrombosis and mental illness caused by ever use of hormones.
It is the same with statin trials. If everybody is taking statins then who are the never users for controls? Some statin trials may have excluded or disregarded patients with muscle weakness. The Oxford/FPA contraceptive drug study excluded women who stopped taking oral contraceptives in the first five months,2 although I had already published in the 1960s that the first year drop-out rate matched the first year incidence of headaches and matching increases in angiogenesis.3
Worst of all, drug company sponsored studies seem not to have any investigations of the most revealing cell chemistry – either before drugs are started or during “treatment”. The fact that John McLaren-Howard’s brilliant biochemical tests have been developed and carried out without any large scale finance is a disgrace. McLaren-Howard’s ATP profile tests reveal that mitochondrial dysfunction causes fatigue.6 There is no need for confusion if doctors behave like doctors instead of robots mislead by number crunching.
1 McPherson K. Concerns about the latest NICE draft guidance about statins. Re: Adverse effects of statins. BMJ 2014 16 June.
2 Dr Ellen Grant, The Bitter Pill / Elm Tree Hamish Hamilton, Great Britain 1985.
3 Dr Ellen Grant, Sexual Chemistry Reed Books, London 1994.
4 Vessey M, Doll R, Peto R et al. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosoc Sci 1976;8:373-427.
5 Grant ECG. Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968;3:402-5.
6 Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int J Clin Exp Med. 2013;6:1-15.
Competing interests: No competing interests
I wonder if the BMJ is covered by the Press Complaints Commission? I guess the general press don't have the same conflicts of interests brought on by relying on advertisements for newer drugs which (unlike statins) I have not usually seen criticised in the BMJ and Lancet.
Competing interests: No competing interests
Re: Adverse effects of medical journalism
Dr Goldacre suggests that doctors as a whole have not risen to the challenge of moderating for their patients the risks and benefits of statins due to the lack of clarity of information provided to them.
Could I suggest that the problem lies with medical journalists, who have tended to be biased towards controversial research findings (usually based on panic), without describing the bigger context (for example harm caused by non intervention), and potential conflicts of interests of the authors and journals concerned.
In my opinion, medical journalists have also tended to be sanctimonious and patronising about doctors working at the coal face, who see many more patients, and have a better informed view on how patients see choices open to them.
Competing interests: No competing interests