Recently I was the author, and co-signee, of a letter sent to NICE (the National Institute for Care and Health Excellence) asking that their recommendations on primary prevention of cardiovascular disease should be withdrawn. Mainly the advice on the use of statins for those at low risk of a heart attack, or stroke. Those in the UK may have seen a bit a stir in the media.
Others who signed this letter included: Sir Richard Thompson, Chairman of the Royal College of Physicians, Dr. Clare Gerada, past president of the Royal College of General Practitioners and Dr. Kailash Chand – deputy chairman of the British Medical Association. [I have included this letter for you to read, if you wish]
So, we are not talking about a bunch of mavericks here – apart from me, of course. When people who are as much a part of the ‘establishment’ as this are willing to put their names to such a letter then you know that people are getting very concerned. Very concerned indeed.
NICE wrote back to me saying that their guidance was completely wonderful and that nothing should change [I paraphrase, but not by much]. This was pretty much as expected. However, in parallel with this letter, the organisation that represents all GPs in the UK (the General Practitioner’s Committee of the BMA) voted unanimously to reject the NICE guidelines. This happened in May.
Now, very recently, the Annual Representative Meeting (ARM) of the British Medical Association debated the NICE guidelines. The motion put to the meeting was,as follows:
‘This meeting believes that in any advisory committee of NICE, when guidance on any drug is issued it must be made clear that none of the members must have a financial interest in pharmaceutical companies which manufacture the drugs’.
Here is the speech made by Kailash Chand to the meeting:
‘Chairman, Representative Body (RB). This is a chosen motion for a purpose. Some of you will have been very concerned about the general direction of travel by NICE, others will have been concerned simply by the issue of conflict of interest.’
This motion calls for clarity in the role of the pharmaceutical companies and their relationship with those individuals who hold positions of considerable influence on the advisory committees of the NICE, which describes and defines what many consider to be best practice.
This motion is NOT seeking to discredit people who advise NICE or indeed to diminish the Institute itself, which has a vital role in interpreting complex modern clinical evidence.
In fact, it is precisely because we should value the Guidance provided by NICE, that it is absolutely essential for it to carry the TRUST and complete CONFIDENCE of the profession. Guidance which has the power to influence our everyday practice, and against which many of us are performance managed must be based on the highest principles of INTEGRITY and TRANSPARENCY.
It is possible that those involved in an advisory capacity to NICE believe that they are able to manage their conflicts of interest, but it is absolutely imperative that NICE should not only be free of even subliminal influence from the pharmaceutical industry, but perhaps even more importantly, be SEEN to be completely independent and not reliant on partial data disclosure of pharmaceutical industry trial data.
Today, we see a lack of confidence from the profession in NICE’s capacity to analyse data and provide reliable advice, when only selective trial information from drug trials is made available.
Recently, the conference of LMCs unanimously passed a motion calling upon NICE to defer a decision to recommend a reduction of the threshold for prescribing statins for primary prevention in the general population.
The BMJ, the Cochrane Institute and indeed this Conference last year called upon the pharmaceutical companies to release ALL data, as a means to increase transparency and to allow more independent verification of results. In fact NICE itself has joined this coalition to call for access to this data, yet continues to place itself in a position of advising with access to only limited information – the pharmaceutical industry have widely ignored these calls for transparent disclosure.
We know that pharma sponsored trials are twice as likely to produce positive results for a drug, and we also know that only half of trials are available in a published form for peer review. This excludes trials which may be stopped prematurely or have end points altered by the sponsors.
Earlier this year the Cochrane Review concluded that the early evidence which had shaped the advice from NICE before the Flu pandemic, had been flawed and had resulted in an exaggerated impression of the usefulness of these medications. The absence of transparency in the process by which data was released and then interpreted has been deeply regrettable. Some have called it a gross betrayal.
So, please support this motion. It is a call for NICE to review its methods where advisory boards may be populated by individuals with links to industry. NICE needs to recognise that those of us tasked to implement its guidance must have full confidence in the transparency and integrity of those individuals providing advice. NICE must be beyond reproach. It should not just be SEEN to be independent, it MUST be independent.
Otherwise its advice which most of us have to implement or adhere to, will continue to affect the lives of millions of patients.
This motion was passed unanimously.
Once again, NICE is under fire. This time from the entire medical profession, and those who represent them. It seems that doctors are deeply concerned about the medical evidence. They feel it has been corrupted, and that those who sit on the guideline committees are, themselves, under the influence of the pharmaceutical industry.
Hoorah. Will anything change? I shall keep throwing rocks, or course. Now a few more powerful rock throwers are joining in. Perhaps the citadel will crumble.
Letter sent to NICE:
Professor David Haslam, Chairman
National Institute for Health and Care Excellence
10 Spring Gardens
London, SW1A 2BV
cc. The Right Honourable Jeremy Hunt, MP
Secretary of State for Health
Department of Health
Richmond House 79 Whitehall
London, SW1A 2NS
10th June. 2014
Concerns about the latest NICE draft guidance on statins
We are concerned about your draft guidance on CV risk for discussion and debate. We would ask for a delay until our concerns are addressed. Whilst we agree with much of the guidance, our concerns focus on six key areas: medicalization of healthy individuals, true levels of adverse events, hidden data, industry bias, loss of professional confidence, and conflicts of interest
The draft guidance recommends offering statin treatment for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD.
1. Medicalisation of five million healthy individuals.
Firstly, we believe that the benefits in a low risk population do not justify putting approximately five million more people on drugs that will then have to be taken lifelong.
The important questions for clinicians and for patients include: (1) does treatment of elevated cholesterol levels with statins in otherwise healthy persons decrease mortality or prevent other serious outcomes? (2) What are the adverse effects associated with statin treatment in healthy persons? (3) Do the potential benefits outweigh the potential risks? Recent papers have suggested that statin therapy should not be recommended for men with elevated cholesterol who are otherwise healthy.2
Furthermore, Atorvastatin 20mg is also recommended as the first-line treatment. This appears counter intuitive, as Atorvastatin has never been demonstrated to reduce mortality for primary prevention any clinical study. (3b)
2. Conflicting levels of adverse events
In emphasising the cost per Quality Adjusted Life Year (QALY), NICE is clearly making a major assumption that the key issue is mortality reduction, and that statins lead to very few adverse effects. We would question this very strongly.
The levels of adverse events reported in the statin trials contain worrying anomalies. For example, in the West of Scotland Coronary Prevention Study (WOSCOPS, the first primary prevention study done), the cumulative incidence of myalgia was 0.06% in the statin arm, and 0.06% in the placebo arm3.
However, the METEOR study found an incidence of myalgia of 12.7% in the Rosuvastatin arm, and 12.1% in the placebo arm4. Whilst it can be understood that a different formulation of statin could cause a different rate of myalgia, it is difficult to see how the placebo could, in one study, cause a rate of myalgia of 0.06%, and 12.1% in another. This is a two hundred fold difference in a trial lasting less than half as long.
Furthermore, the rate of adverse effects in the statin and placebo arms of all the trials has been almost identical. Exact comparison between trials is not possible, due to lack of complete data, and various measures of adverse effects are used, in different ways. However, here is a short selection of major statins studies.
AFCAPS/TEXCAPS: Total adverse effects losartan 13.6%: Placebo 13.8%
4S: Total adverse effect simvastatin 6%: Placebo 6%
CARDS: Total adverse effects atorvastatin 25%: Placebo 24%
HPS: Discontinuation rates simvastatin 4.5%: Placebo 5.1%
METEOR: Total adverse effects rosuvastatin 83.3%: Placebo 80.4%
LIPID: Total adverse effects 3.2% Pravastatin: Placebo 2.7%
JUPITER: Discontinuation rate of drug 25% Rosuvastatin 25% placebo. Serious Adverse events 15.% Rosuvastatin 15.5% placebo
WOSCOPS: Total adverse effects. Pravastatin 7.8%: Placebo 7.0%
Curiously, the adverse effect rate of the statin, it is always very similar to that of placebo. However, placebo adverse effect rates range from 2.7% to 80.4%, a thirty fold difference.
3. Hidden data
Without access to the raw data, it is difficult to understand how statin related adverse events, and placebo related adverse events can mirror each other so precisely, whilst the absolute rates can vary thirtyfold (almost three thousand per cent). These data most certainly require analysis by a third party with appropriate expertise.
A further serious concern is that the data driving NICE guidance on statins comes almost entirely from pharmaceutical company funded studies. Furthermore, these data are not available for review by independent researchers, only those who work for the Oxford Cholesterol Treatment Trialists Collaboration (CTT).
The CTT has commercial agreements with pharmaceutical companies which apparently means that they cannot release data to any other researchers who request to see it. Which, in turn, means that the latest reviews of the data by NICE and also by the Cochrane group are totally reliant on the CTT 20121 meta-analysis analysis of this concealed data?
4. Industry bias
The overdependence on industry data raises concerns about possible biases. Extensive evidence shows that industry funded trials systematically produce more favourable outcomes than non- industry sponsored ones.5,6
Notably, only one major non-industry funded study on statins has been done. ALLHAT-LLP. The main findings were summarised: ‘Although pravastatin has been shown in multiple large clinical trials to reduce CHD morbidity and mortality, NO benefit was demonstrated in ALLHAT-LLT, the largest clinical event trial of pravastatin published to date.’ (6b)
True levels of adverse events
We are also concerned that the rate of adverse effects in post-marketing studies is, in most cases, far higher than that found in the pre-marketing studies. In part this is due to the fact that the clinical trial populations studied in premarketing trials are highly selected. Furthermore, industry sponsored trials include pre-randomisation run-in periods where those who fail to tolerate statins are excluded.RCT patientsmay therefore not represent the population that will actually take the drugs in the real world. RCTs may thus grossly underestimate adverse effects such as myopathy or cognitive impairment,7 and fail to detect drug interactions e.g. amlodipine and statins.
Important findings from some other non-industry sponsored studies
A double blind randomised controlled trial that compared 1016 low risk patients receiving simvastatin 20 mg or pravastatin 40 mg with placebo showed that both drugs had a significant adverse effect on energy/fatigue exercise score with 40% of women reporting reduced energy or fatigue with exertion.9 Reducing exercise capacity in a healthy group when physical inactivity is a major contributor to the development of cardiovascular disease is extremely counterproductive.
A large observational study involving 153,840 postmenopausal women aged between 50 and 80 years enrolled in the Women’s Health Initiative study found that statins were associated with a 48% increased risk of developing diabetes.8
Potential psychiatric symptoms including depression, memory loss, confusion, and aggressive reactions have also been associated with statin use.(10)
Erectile dysfunction, to take another significant adverse effect, is not mentioned in the statin trials. Yet, when it was specifically looked for, around 20% of men appeared to be affected.(11)
5. Loss of professional confidence
We are also concerned that GPs feel that this guidance is a ‘step too far. It is instructive to note that a survey of 511GPs carried out by Pulse magazine revealed that ‘….almost six out of ten (57%) oppose the plan to lower the current 10-year risk threshold for primary prevention, while only 25% support it. Furthermore, 55% would not personally take a statin or recommend a family member does so based on a 10% 10-year risk score.’ (11b)
More recently the General Practitioners Committee (GPC), which negotiates on behalf of GPs in the UK passed the following resolution: ‘In light of the Cochrane review of the effectiveness of antiviral influenza treatments, the GPC will request that NICE refrain from recommending a reduction to the current treatment threshold for primary prevention of cardiovascular disease with statin therapy unless this is supported by evidence derived from complete public disclosure of all clinical trials’ data’ (11c)
Asking GPs to meet targets that they feel uncomfortable with risks a damaging split within the profession, and a loss of confidence among the public, who are likely to recognise increasingly that GPs are being asked to prescribe statins despite feeling it is inappropriate.
6. Conflicts of Interest (real and perceived)
We are also seriously concerned that 8 members of NICE’s panel of 12 experts for its latest guidance have direct financial ties to the pharmaceutical companies that manufacture statins. Furthermore, some members of the guideline panel are also involved in next generation, more expensive, cholesterol lowering drugs, which are not yet on the market. If cholesterol lowering becomes established in low risk people, the indications for these new cholesterol lowering drugs such as the ApoB Antisence drugs and PCSK9 inhibitors will probably expand as well. We feel that parties with industry conflicts should not be participants in generating recommendations regarding drug use that will influence medical care across the population.
We fear that the CTSU could be perceived as having a major conflict of interest in the area of cardiovascular disease prevention/lipid modification, which has an impact on the Unit’s perceived objectivity. We strongly urge that other researchers, for example, the Cochrane Stroke Group and Cochrane Heart Group, should be able to scrutinize and assess all the data that the CTT has utilised over the years to produce their extremely influential studies.
CTT is a part of the Clinical Trials Service Unit (CTSU) in Oxford, which has carried out many very large studies on statins, and other lipid modification agents with pharmaceutical company support, and has received hundreds of millions in funding over the years. To consider just one such study (REVEAL). REVEAL is being funded by Merck Sharp & Dohme, which developed anacetrapib. A grant of £96 million towards the cost of this multi-million dollar study has been provided to the University of Oxford.
We are concerned that financial conflicts of interest and major commercial bias may have corrupted the database on statins, resulting in an underestimate of the incidence of statin side-effects. Unless all of the data are made available it is impossible to establish a cost per QALY, as there may be DALYs [disability adjusted life years] not accurately accounted for.
We call for all of the data from the clinical trials to be made available to credible researchers, for example, the Cochrane Stroke and Heart Groups. We believe that there is a need for a more robust post-marketing analysis of suspected adverse effects from statins prescribed in a community setting.
To conclude we urge you to withdraw the current guidance on statins for people at low risk of cardiovascular disease until all the data are made available. The potential consequences of not doing so are worrying: harm to many patients over many years, and the loss of public and professional faith in NICE as an independent assessor. Public interests need always to be put before other interests, particularly Pharma.
Sir Richard Thompson, President of the Royal College of Physicians
Professor Clare Gerada, Past Chair of the Royal College of General Practitioners and Chair of NHS Clinical Transformation Board
Professor David Haslam, General Practitioner and Chair of the National Obesity Forum
Dr J S Bamrah, Consultant Psychiatrist and Medical Director of Manchester Mental Health and Social Care Trust
Dr Malcolm Kendrick, General Practitioner and Member of the British Medical Association’s General Practitioners sub- Committee
Dr Aseem Malhotra, London Cardiologist.
Dr Simon Poole, General Practitioner
David Newman, Assistant Professor of Emergency Medicine and Director of Clinical Research, Mount Sinai School of Medicine, New York
Professor Simon Capewell, Professor of Clinical Epidemiology, University of Liverpool
References (may require site registration or membership to access)
1: Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C: ‘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. 2012 Aug 11;380(9841):581-90. May 17.
2: Redberg RF, Katz MH. Healthy Men Should Not Take Statins. JAMA. 2012;307(14):1491-1492. doi:10.1001/jama.2012.423.
4: John R. Crouse, MD; Joel S. Raichlen, MD; Ward A. Riley, et al: ‘Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis’: The METEOR Trial JAMA. 2007;297(12):1344-1353. doi:10.1001/jama.297.12.1344
5: Smith R. Conflicts of interest: how money clouds objectivity. J R Soc Med 2006;99:292-7.
6: Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. Jama 2003;289:454-65.
7: Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf 2013:12:327-37.
8: Culver AL, Ockene IS, Balasubramanian R, Olenzki BC, Sepavich DM, Wactawski-Wende
J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s
Health Initiative. Arch Intern Med 2012;172:144-52.
9: Tatley M, Savage R. Psychiatric adverse reactions with statins, fibrates and ezetimibe implications for the use of lipid-lowering agents. Drug Safety 2007;30:195-201.
10: Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial. Arch Intern Med. 2012;172(15):1180-1182. doi:10.1001/archinternmed.2012.2171.
11: Solomon H1, Samarasinghe YP, Feher MD, et al: ‘Erectile dysfunction and statin treatment in high cardiovascular risk patients.’ Int J Clin Pract. 2006 Feb;60(2):141-