Top medical journals in a bitter battle over statins

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medwebThe editors of the UK's two top medical journals are at war over statins. The British Medical Journal and The Lancet have taken opposing views amid criticism that the UK’s Committee on Publication Ethics's 'refusal to investigate the growing concerns of senior UK scientists'.

Larry Husten, medical journalist and editor of CardioBrief writes in MedPage Today that the bitter fight has its origins in the 2014 publication in the British Medical Journal of two articles that were highly critical of statins.

Professor Rory Collins of Oxford University, a leading statin trialist, demanded that the BMJ retract the article. After a lengthy investigation by an independent committee the BMJ declined to retract the articles, though it did issue corrections.

Husten says that The Lancet recently became involved when it published a 30 page review article by Collins and colleagues seeking to demonstrate that the benefits of statins have been underappreciated and the adverse effects of statins have been overstated by both the medical community and the public.

In a related comment, The Lancet editor Dr Richard Horton, aligned himself with Collins and supported an effort by Collins and others to seek sanctions against the BMJ from the UK’s Committee on Publication Ethics (COPE), decrying what he described as "COPE's refusal to investigate the growing concerns of senior UK scientists".

Husten writes that the latest salvo in the battle comes from the BMJ in response to Horton's comment.

The BMJ said that Horton's characterisation of COPE's response was "inaccurate" and it published for the first time COPE documents relating to the controversy. And, Husten says, the documents from COPE, published online by the BMJ, make clear that a COPE panel did investigate the issue but did not agree with Collins and his supporters. The COPE panel "found that neither paper met the COPE criteria for retraction." COPE also rejected the idea that it was unethical or inappropriate to publish articles critical of statins:

"Without having an opinion on one or other side of the debate on the use of statins and their side effects, it is clear that this is a topic on which there is a considerable range of opinion and no purpose is served by censoring either side of the debate."

"We hope that publication of the documents relating to the complaint will serve to correct the public record," said Fiona Godlee, editor-in-chief of BMJ. Husten says that the supporting documents released by the BMJ also clearly indicate that Collins refused invitations from Godlee to publish his concerns about the disputed papers in BMJ.

Husten writes that the BMJ also published an editorial comment by Dr Harlan Krumholz of Yale University on the statin controversy. (Krumholz was a member of the independent BMJ committee that investigated whether the BMJ should retract the disputed 2014 articles.)

Krumholz, though generally supportive of statins, points out limitations in the trials and calls for independent verification of the data. "In the end," he wrote, "the sharing of these data by the trialists may do more to advance their interpretation of the data and promote consensus than anything else they could do."

Also appearing on the BMJ website is a blog post by Dr Richard Lehman, who questioned the blithe dismissal of statin side effects. "Muscle pain and fatigability are not a figment of misattribution and public misinformation," he wrote.

"They are too prevalent and recurrent in people who desperately want to stay on statins. Rather than discount a widely observed phenomenon, we should ask why there is such a mismatch with reporting in the trials."

Husten writes that Lehman further observed: "The main adverse effect of statins is to induce arrogance in their proponents. The evidence for this class of drugs is massive and the areas of controversy are quite small. Most of the current debate consists of throwing blame at the BMJ for creating public doubt about statins in two short articles. So it has become an argument about communicating evidence to the public and to individuals, and this is something the Lancet authors seem to think should be done by authoritative persuasion …"

Husten writes that he had invited Collins and Horton to respond to the BMJ statement.

 

The ongoing fracas speaks to a larger issue hovering over this controversy – the growing calls for an independent review of statin trial data, something Godlee herself has called for, says a The Source for Interventional Cardiovascular News and Education (TCTMD) report. The Lancet review was meant to “bring an end to a dangerous debate”, but, she says, “not everyone agrees.

“Though the benefits of statins for secondary prevention or in people at high risk of cardiovascular disease are undisputed, proposals to offer them to large numbers of people at lower risk remain controversial, much to the frustration of the statin trialists who authored the Lancet review,” Godlee says.

The report says she points to Krumholz editorial, which highlights some of the limitations of the existing data, including the dearth of data on people older than 80 years, uncertainty about how comparable adverse event data across trials are, and the paucity of head-to-head comparisons of individual statins. There is also uncertainty about whether the trials are applicable to current patients with cardiovascular disease, Krumholz suggests.

“Independent third party scrutiny of the statins trial data remains an essential next step if this increasingly bitter and unproductive dispute is to be resolved,” Godlee says. “I have now written to England’s chief medical officer, Sally Davies, asking her to call for and fund an independent review of the evidence on statins. As Krumholz concludes, sharing the individual patient-level data from the statins trials would send ‘a strong message that no single person or group should have exclusive access to data’ that are so important for public health.”

Although Collins’ group, the Cholesterol Treatment Trialists’ Collaboration, has announced that it is undertaking a detailed review of adverse events using trial data, Krumholz is quoted in the report as saying: “I don’t think you could consider them independent … since they were funded to do many of the trials.”

 

The controversy is creating uncertainty among people taking statins or who might need to consider doing so and Professor Peter Weissberg, medical director at the British Heart Foundation attempts, in a report in The Guardian, to answer the question of whether they are as controversial as stories suggest.

Weissberg writes: “Statins lower the amount of bad (low-density lipoprotein) cholesterol in your blood, and the higher your cholesterol, the greater the risk of a heart attack. If you have a gene defect that causes a very high cholesterol level – a condition called familial hypercholesterolaemia (FH) – then you are at very high risk of a heart attack.

"Before statins, doctors were virtually powerless to prevent such heart attacks because there were no drugs that were effective at reducing cholesterol without causing intolerable side effects. Statins changed all that.

“Now people with FH can take a statin and expect to live a normal lifespan. Similarly, if you have suffered a heart attack, regardless of your cholesterol level, there is abundant uncontested evidence that taking a statin will reduce your risk of a further heart attack or stroke. So where is the problem?

“The problem arises when we consider giving a statin to healthy people, who have no apparent cholesterol gene defect or evidence of heart disease, in the hope it will prevent a future heart attack. This is when doctors start to worry about the risk-to-benefit ratio. If a doctor is going to prescribe a statin for a healthy individual to protect against future heart disease, he or she wants to be pretty certain the drug won’t do more harm than good because, unfortunately, all drugs have side effects.”

Weissberg writes: “So you and your doctor need to know three things – what are your chances of having a heart attack or stroke in the next few years without any treatment? How much would that risk be reduced if you took a statin? And what is the likelihood of a serious side effect?

“By noting down some simple facts such as your age, gender, whether you smoke, your blood pressure, your cholesterol level and family history, your doctor can calculate your risk of suffering a heart attack or stroke in the next 10 years. Evidence on benefits and side effects comes from clinical trials designed to impartially quantify the benefits and risks of taking a statin.”

Weissberg writes in the report the combined evidence from many such trials shows that statins reduce the risk of a heart attack or stroke even in those with relatively low cholesterol levels. But, because most people with low cholesterol levels are at relatively low risk of a heart attack, many people would need to be treated to prevent one of them from having a heart attack. This would not be a problem if there were no risks associated with taking a statin.

So what are the risks, he asks? “Studies have identified three potentially serious but very rare risks. People taking statins are at slightly increased risk of developing type 2 diabetes. This seems to occur in people on the verge of developing it anyway, and despite the onset of diabetes those people are still at lower risk of heart attack or stroke in the future than they would be without a statin.”

He says: “There is also a small increased risk of a haemorrhagic stroke – a bleed into the brain – but this risk is more than offset by the reduced risk of a stroke – caused by a blocked artery – if you take a statin, so your overall risk of a stroke is reduced.

“The third risk is that statins can definitely cause a condition called myopathy which is characterised by muscle pain and evidence of muscle damage on blood tests. Very rarely, if the treatment is not stopped, this can progress to a potentially fatal condition called rhabdomyolysis. But if the treatment is stopped, the symptoms stop too. Patients are warned to watch out for muscle pains when they start taking a statin and, not surprisingly, many do complain of muscle pains. But few of them have actual myopathy. Placebo-controlled trials have shown that when patients are told to watch out for muscle pains, almost as many taking a placebo report experiencing them as do those taking the active drug. It is this phenomenon that has led to the perception that statin side-effects are common, which they are, but it does not mean they are unsafe.

“So what should you do? If you are at high risk, take a statin. The risks of not taking one – a heart attack or a stroke – far outweigh risks associated with the drug. If you are not in this category, ask your GP to assess your risk then discuss the best way to reduce it. For many this will mean a change in lifestyle and diet, not a statin. If your doctor recommends a statin and you experience a side-effect, they can usually be resolved by reducing the dose or swapping to another brand.”

Weissberg writes: “Clinical trials tell us that, at a population level, statins are safe and effective. But only you and your doctor can decide if they are right for your needs. Be guided by your doctor rather than by what you might read or hear elsewhere.

 

Comments from a briefing on The Lancet review include from:

Professor Alan Boyd, president of the faculty of pharmaceutical medicine at the Royal College of Physicians, said: “When a new medicine is initially approved for use in patients there is only limited information about its longer term benefits and risks. For all medicines this information only becomes available with the passage of time and widespread prescribing to patients. This article by Rory Collins and his colleagues is an excellent example as to how such information is arrived at.

“The article itself is an excellent review of the long term benefits and risks that are now considered to be associated with the use of statins over a thirty year period. It brings together data from multiple randomised controlled clinical trials that have been conducted with statins since they were first introduced as prescription medicines in the late 1980s.

"From this analysis it is clear that statins do reduce the risk of having major cardiovascular events and that these benefits also are long lasting with prolonged use of the medicine. In addition, this review article is definitive in stating that the main adverse effects that occur with the use of statins are now very well established and characterised and in most cases will resolve when the treatment is stopped.

"This statement now goes against the many other articles that have warned about the serious side effects that statins could cause and that suggested that they should be used with caution in patients and that the risks outweighed the benefits.

“This article now firmly establishes the benefit risk profile of statins. Although it has taken thirty years to arrive at this point, it has demonstrated the public health benefit of the use of this class of drugs and lays to rest the views held previously about the risks involved with them. It is a good example of the practice of pharmaceutical medicine and the collective use of multiple controlled studies bringing benefits to patients and should be extremely helpful to prescribers and healthcare authorities.”

Dr June Raine, director of the UK's Medicines and Healthcare Products Regulatory Agency’s vigilance and risk management of medicines division, said: “The benefits of statins are well established and are considered to outweigh the risk of side-effects in the majority of patients.

"The efficacy and safety of statins has been studied in a number of large trials which show they can lower the level of cholesterol in the blood and reduce cardiovascular disease and can save lives. Trials have also shown that medically significant side effects are rare.

“Medicine safety and effectiveness is of paramount importance and under constant review. Our priority is to ensure that the benefits of medication outweigh the risks. Any new significant information on the efficacy or safety of statins will be carefully reviewed and action will be taken if required.

“Information on potential side effects can be accessed through the patient information leaflets and any suspected side effects reported to us through our warning system, the Yellow Card Scheme, are publicly available on our website.

“If you have any questions about your medicine, please speak to your GP or healthcare professional”

Dr Tim Chico, reader in cardiovascular medicine and consultant cardiologist at the University of Sheffield, said: “This paper summarises the risks and benefits of statins, and highlights the damage done by irresponsible or uninformed scare stories that exaggerate their risks.

"Many people are reluctant or completely opposed to taking statins but cannot explain why, other than they feel statins are dangerous or ineffective, neither of which is correct. Most inaccurate messages about statins come from observational studies. Scientific journals and newspaper articles are littered with observational studies that are later shown to be incorrect, but they get reported on because they make interesting headlines and confirm people’s existing biases.

“The current study restricts itself to summarising comprehensively the findings from properly conducted, randomised controlled trials, where patients received statin or placebo pills, with neither patient nor doctor knowing which they were taking. Although even these studies aren’t without disadvantages, they are the only reliable evidence on which to base the benefits and risks of a particular treatment.

“I often meet people who don’t want to take statins yet are happy to take other drugs with greater risks of side effects, or take supplements with no benefit at all. Statins have been unfairly demonised, and this prevents a sensible discussion of the risks and benefits of their use. Statins can cause side effects, but the chance of developing these is low, while the effects of suffering the heart attack that a statin might have prevented can be fatal or life-long.

“It is clear that statins reduce the risk of a heart attack, not completely, but sufficiently to recommend taking them in people with a higher risk of heart disease. Statins also increase the risk of some side effects, particularly muscle pain, bleeding into the brain and diabetes. As a doctor, it’s not my role to tell people to take any drug; my job is to tell people openly the risks and benefits of a particular treatment and for them to decide for themselves. Unfortunately, the confusion over the risks of statins means many people have made up their mind without being told the proper facts.

“Some critics of statins justify their position by saying that a healthy lifestyle can reduce the risk of heart disease more than statins, and it is true that much more should be done to improve our diet, exercise habits and other factors such as smoking and obesity. However, these are complex and difficult factors to alter, and doctors have only a limited ability to help our patients improve their lifestyle.”

Professor David Webb, professor of therapeutics & clinical pharmacology, University of Edinburgh, and president, British Pharmacological Society, said: “In recent years, those of us who manage the large number of patients at excess risk of heart disease and strokes have been fighting an uphill battle to persuade them to take statins, a class of medicines that have been repeatedly shown to save lives.

"The problem has largely related to concerns about muscle aches and potentially more serious side effects (muscle damage, diabetes and haemorrhagic stroke) that have been very well publicised on the internet. Many patients who have much to benefit from statins, and many of those at more modest risk, have been persuaded not to take them because of exaggerated claims of harm, and some research suggesting that the benefits have been overestimated. It is likely that many lives have been lost, based on a received view that statins are dangerous and ineffective.

“This comprehensive review, by a broad group of leading international academics, of robust and unbiased evidence from randomised controlled trials and systematic reviews, confirms that statins are both effective and cost effective, and that the benefit rises with the level of pre-treatment risk. It also confirms that any rare harms are substantially outweighed by solid benefits, in terms of a reduction of heart attacks and strokes.

“So long as the public still have trust in experts, this work provides the evidence needed to justify providing the substantial cardiovascular protection to patients that they deserve.”

Professor Jeremy Pearson, associate medical director at the British Heart Foundation, said: “This comprehensive review reiterates the life saving benefits of statins, which vastly outweigh the rare side effects associated with the medicine. Evidence, from many objective clinical trials, shows that statins are a safe and effective way of reducing heart attack and stroke risk. And there is certainly no debate that people who have had a heart attack or stroke should be taking statins to reduce their risk of another, potentially deadly event.

“Medicine should be guided by evidence and this review will help clinicians to consider the available evidence and judge its strengths and weaknesses. Clinicians, and particularly GPs, play a vital role in advising patients so it’s important that if a person has concerns about their medication, they discuss this with their GP first.”

Professor Sir John Tooke, former president of the Academy of Medical Sciences and chair of the ‘How can we all best use evidence to judge the potential benefits and harms of medicines’ oversight group, said: “This study has added much needed clarity into the heated debate on the safety and efficacy of statins. Most importantly it highlights the relative value of different ways of generating evidence.

“It is essential that patients and the public have access to the best evidence when it comes to making decisions about the management of their health, whether these concern lifestyle changes or the use of medication. Clear, accurate and trustworthy information is vital to empower people to make treatment choices.

“This review provides a clear summary of the evidence to date which will help healthcare professionals and patients have more informed conversations about the benefits and harms of statins.

“Following a request from the Chief Medical Officer, the Academy has been exploring the best ways of generating and communicating evidence about the benefits and harms of medicines, and how to ensure this evidence is trustworthy so that all stakeholders – patients, the public but also healthcare professionals – can use it to inform their decisions about medicines.

“Throughout our evidence gathering for the project we have repeatedly heard calls for communications about scientific evidence to present absolute risk and so I am pleased to see that this study has presented data in this way.”

MedPage Today report The Lancet review BMJ Harlan M Krumholz editorial BMJ letter BMJ Fiona Godlee editorial Richard Lehman blog TCTMD material The Guardian report Science Media Centre material

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