78. Statins…….Is the Edifice Beginning to Crumble?

The BMJ has recently announced that it is withdrawing statements which suggest that adverse effects occur as a response to treatment with statins in 18-20% of patients (1). The background is that an article in the BMJ (2) which was published in October 2013 questioned the evidence behind new proposals to extend the routine use of statins to people at low risk of cardiovascular disease. In this, it was argued that the benefits of statins in low risk people were less than has been claimed and the risks are greater. They cited evidence that side-effects of statins occur in 18-20% of people. Subsequently a correction was published which explained that although the 18-20% figure was based on statements in the referenced observational study by Zhang and colleagues—which said that “the rate of reported statin-related events to statins was nearly 18%,”(3). The BMJ article did not reflect necessary caveats and did not take sufficient account of the uncontrolled nature of the data produced by Zhang and colleagues.

The BMJ was alerted to the error by Sir Rory Collins, professor of medicine and epidemiology at Oxford University, who was also head of the CTT Collaboration, whose data was reanalysed in the article. Collins visited the editor and raised the issue in the media. Despite several requests to send a rapid response or a letter for publication, Collins refused to do so. He was not satisfied with the publication of a correction and demanded that the article (and another one which had also quoted the same figures) should be retracted.

Fiona Godlee, the editor of the BMJ considers that retraction is not justified because the incorrect statements were secondary to the primary focus of the article. Nevertheless because she believes she is not totally disinterested, she has referred this issue to an independent group to give an objective view.

Incidentally Rory Collins is certainly not a disinterested party because of his critical role in the CTT Collaboration, which itself has been subject to severe criticism (4).

The rapid responses in which the BMJ allows any individual to respond immediately are a very good indication of the reaction to any specific paper. With respect to this issue, these are very revealing. Here is a selection(5):

“How can there be any doubt about the frequent adverse side effects of taking statins when so much money has been spent on epidemiological research and worldwide promotion of extensive use? “

Ellen Grant, retired physician and gynaecologist

“Doctors do not ask patients about the adverse effects of any drugs they prescribe, never mind statins. If you mention any side effects to them they do not fill in any forms to notify relevent bodies. They do not care. I was on statins and had very bad problems with muscle weakness and tiredness.”

Edward Maszka, retired NHS patient

“Adverse effects are routinely assessed using observational data. This is considered the reference (‘gold’) standard in adverse effects reporting by the United States Food and Drug Administration …. and others. Indeed too many investigations to count have found that RCTs in general, and industry funded RCT publications in particular, are unable to act as arbiters or predictors of adverse effects in clinical practice. …..Dr. Abramson and Dr. Malhotra were therefore both correct in their statements, based on the most reliable and appropriate data yet published on the adverse effect rate of statins. (New onset diabetes, generally a result of statins for 2%, is typically not recognized as a statin adverse effect and thus was likely unreported or under-reported in their source data, making an 18- 20% estimate either correct or an underestimate).

It is a mistake to correct or retract these statements. The appointed independent panel will, I hope, have the expertise and courage to confirm and reinforce their important and accurate statements. “

David Newman, Physician/Researcher, Icahn School of Medicine at Mount Sinai, NY USA

“The claims by Abramson and Malhotra that “18% of statin treated patients had discontinued therapy because of statin related events” is syntactically wrong, but not a particularly egregious error. Many far worse errors exist in the published medical literature without hide nor hair of a correction, let alone an editorial retraction…..

Correction of the minor error in the two papers is an appropriate editorial response. Demanding an editorial retraction on the grounds of a minor error looks like bullying by those who seek to uphold their position free from criticism rather than fairly argue their case in a public forum. Godlee and the independent review should have the courage to stand up against such demands and allow publication to stand.”

John Dalton, Safety Consultant, Cumbria

“……these rates derived from clinical records may under-estimate the true incidence of side effects in people taking statins because not all patients with side effects will inform their doctor and not all doctors will enter a relevant diagnostic code in the patient’s electronic medical record.”

Azeem Majeed, Professor of Primary Care Mariam Molokhia, Kings College, London, Imperial College, London

“Two years ago I was prescribed 40mg Simvastatin. Within twelve hours of taking the first pill I was barely able to climb my stairs due to profound weakness and exhaustion. I took a half tablet 24 hours after the first (just for fun) and was rendered bed-bound for another 24 hours. The adverse effects gradually reduced over the following five days or so and there were no lingering symptoms.I would be highly unlikely to willingly take any statin in the future, irrespective of my lipid levels.”

Peter Todd, retired biomedical scientist

“It is no surprise that the incidence of side effects is lower in clinical trials, as they only randomise patients who complete a run in phase with the drug. Patients who have side effects are excluded from the trials. So trial data is useless in assessing the potential of any drug to cause adverse effects. Why do we not just ask the audience I.e. Gp’s for their guess as to the true rate of significant side effects. My guess would be around 25%. Let’s have a vote.”

Edmund Willis, GP, Brigg

“I find it surprising and disappointing that Professor Collins has chosen to raise his concerns in the media rather than through published correspondence in the British Medical Journal. To sensationalise the argument outside proper scientific channels will fuel patient concerns rather than allay them. I would also like to know whether Professor Collins has directly or indirectly received funding from any manufacturers of statins -which, of course, requires a conflict of interest statement in the medical, though not the popular press.”

Andrew Bamji, Retired Consultant Rheumatologist, Rye who suffered significant statin musculoskeletal side-effects which lasted for some years after cessation

“It is in fact Dr. Collins, head of the CTT collaboration and of the HPS study who should be taken to task in this debate about adverse effects for not releasing mortality data about women. 22 years ago in BMJ he and others asked for larger all-cause mortality studies regarding sub-groups [Medline 1633527] and after over $m100 from his sponsor for the HPS studies, the 4 mortality curves [men, women, diabetic and not] still have never been published for the first HPS. They should, with error bars.

Dr. Collins avoided female all-cause deaths in CTT by only reporting “proportional coronary heart disease mortality” [in Medline 16214597] and this without the mortality data from ASCOT-LLA [atorvastatin vs placebo] that we know ended with 2 more non-fatal “events” in women on statin. Not even the latest meta-analysis [Kostis, Medline 22300691] could dislodge the female death data from ASCOT. These are reporting scandals Dr. Collins should correct, with numbers needed to treat, per year of statin use.

Taking only the placebo-controlled trials in Kostis, we have about 100,000 patient-years and there was no all-cause mortality benefit for women, something known since Walsh and Pignone(1) and discussed here(2).

1. Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. AMA. 2004 May 12;291(18):2243-52. Medline 15138247

2. Vos E, Rose CP, Biron P.Point: why statins have failed to reduce mortality in just about anybody J Clin Lipidol. 2013 May-Jun;7(3):222-4. Medline 23725922But”

Eddie Vos, Forensic Engineer, Canada

“Within a day of starting the treatment I experienced muscle pains which I had not experienced before. From the explanatory leaflet I gathered that this was a common initial response, and would quickly go away. I continued the prescribed treatment and my condition deteriorated so that by the fifth day I was incapacitated to the extent that I could not leave the house. I had difficulty getting up and down stairs , and in rising from a chair. I gathered that such side effects were reversible if the treatment was not prolonged and so I stopped. Within 48 hours the side effects subsided and I returned to the condition I had previously enjoyed. I declined my GP’s suggestion to try a different statin because the experience, to me, had been so adverse, even frightening.

Some time later I started to experience awkwardness in walking; I developed a jerky gait which I took to be due to trouble with my feet. My chiropodist/podiatrist referred me to my GP, who diagnosed peripheral neuropathy. This condition, he told me, is usually associated with diabetes or heavy drinking: in my case there was no obvious precursor condition, but I have wondered if it might be in some way related to that brief course of Simvastatin which was so rapidly disabling.

At Christmas last year I met an old friend, a couple of years my junior. Talk within the group somehow turned to the subject of statins, and Ron said he had been recommended by his GP to take them. He was not aware of my experience: his objection, he said, was the result of seeing their effects on fellow members of his golf club, golfers who had played for years but who now, after going onto statins, could no longer complete even a few holes.”

Horace Bennett, Retired Chartered Engineered, London

“In my opinion 20% is still a very conservative figure when it comes to adverse effects from statins.
I’m a member of many forums and actually run a support group for people who have suffered and are suffering severe side effects from statins. I can assure the medical profession there are thousands suffering and in my estimation the figure is more 50% or higher. Unfortunately some suffer completely unaware that it’s the statin causing their ‘ muscle and joint pain’ depression’ memory loss, myopathy , neuropathy etc.

At the moment there is nothing we can do apart from try and support and advise each other, it’s unfortunate that many doctors do not recognise that the problems their patients are having are due to the statins they’re taking.

I tell every member in my group and others to inform MHRA and fill in ‘ yellow card’ apart from that our hands are tied and we have to leave our health in the hands of those who do listen and are trying to help us by keeping this in the media.
Please don’t let the drug companies win, keep fighting for us as our voices can’t be heard as we’re buried deep and hidden in statistics.”

Sonya Young, Company Secretary, Princes Risborough

“Muscular adverse effects are very common with statins. The 2011 Cochrane review of statins for the primary prevention of cardiovascular disease reported a risk ratio of 1.03 for muscle pain, i.e. 3% more patients developed muscle pain on drug than on placebo (1). However, industry-funded randomised trials are notoriously unreliable when it comes to the harms of drugs (2). A publicly-funded randomised trial from 2012 that studied the impact of statins on energy and exertional fatigue got results that could be interpreted as 20% of the men and 40% of the women experiencing a worsening in either energy or exertional fatigue (3).

I therefore wonder why Sir Rory Collins has bullied the BMJ in a most unacademic fashion for having published a paper that reported a similar incidence of harms based on a cohort study (4). He has even called for a retraction of the paper, just like drug companies have often done when a paper appeared that could threaten their sales (2). Collins and his colleagues publish meta-analyses based on company data to which no one else has access because of the confidentiality clauses Collins and colleagues have accepted.

I believe science ceases to exist when no one else than those who have conflicts of interest are allowed to see the data.

1. Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013;1:CD004816.
2. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013.
3. Golomb BA, Evans MA, Dimsdale JE, et al. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012; 172: 1180–2.
4. Abramson JD, Rosenberg HD, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123.”

Professor Peter Gøtzche, Nordic Cochrane Centre, Copenhagen

CONCLUSION

What we have here is an avalanche of opposition to the actions of Rory Collins. It is evident that he is absolutely isolated with no support worth mentioning. By nitpicking about a relatively trivial mistake he has actually released a flood of information which when taken together provides convincing evidence that the side-effects of statins is a much greater problem than Collins and many of his colleagues have been prepared to admit. This incident is arguably one of the most outstanding examples of an “own goal” scored in academia in recent years.

Above all, it is now evident that there must be a fundamental review of the use of statins. For years the benefits have been played up and the adverse effects played down. Decisions on when statins should be prescribed have been based on a cost-benefit analysis which has been totally false. Collins has attempted to use the media to his advantage but his efforts have backfired spectacularly. The availability of this information in the BMJ presents the media with an opportunity to expose the skullduggery that goes on in the background which results in the gross over usage of drugs. If only the politicians could be persuaded to get to grips with this issue, the NHS could save enormous sums of money and much suffering would be avoided.

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