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Editorials

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

Re: Adverse effects of statins

Dr Abramson et al’s original assertion that “18% of statin treated patients had discontinued therapy (at least temporarily) because of statin related adverse events” (in reference to Zhang et al’s study) was incorrect, as was Dr Malhotra’s similar claim. The actual figure was 17.4 %, and referred to the incidence of side effects (rather than the percentage of individuals stopping statins due to side effects). It is right that these errors are acknowledged, but would a correction not have done? Why has Professor Sir Collins demanded a retraction of the articles when their main points remain unchallenged? And why is Fiona Godlee even contemplating retraction in this instance when there, as it stands, appears to be no case to answer?

I agree that it is right to be somewhat circumspect about Zhang et al’s findings, given their observational nature. It is certainly true that they seem out-of-step with the findings from randomised controlled trials (as Professor Sir Collins points out). However, as Fiona Godlee quite rightly tells us, there are reasons why randomised controlled trials (RCTs) may significantly underestimate the adverse effects of statins.

With respect to this, she writes: “However, generalising from clinical trials to wider populations may be problematic because of patient selection; for example, exclusion of older patients, patients with co-morbid conditions or potential drug-drug interactions, and women. In addition, when compared with the full clinical study reports, published accounts of clinical trials in medical journals report only a minority of adverse events.”

It is perhaps worth bearing in mind that that there are yet many more ways by which statin RCTs may end up ‘missing’ adverse effects. These include the facts that:

1. Commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects. One pointer to this is that diabetes diagnoses have only been documented in a very small minority of statin trials.

2. Many trials do not state clearly how and how often adverse effects were assessed. Because of this, it far from certain that all adverse events have been recognised and logged appropriately.

3. Trial volunteers tend to be enthusiastic individuals, and may therefore be less likely to report side effects than patients in routine clinical practice.

4. Many trials have a ‘run-in’ period where individuals are given a placebo to help ensure adequate compliance with medication. This can cause studies to be ‘enriched’ with highly motivated individuals who, again, may be less likely to complain of side-effects.

5. One major statin trial, [1] (The Heart Protection Study - headed by Professor Sir Collins) employed a run-in period which subjected all potential participants to the active drug. Individuals with evidence of adverse events were excluded, which obviously means a higher percentage of ‘statin tolerant’ individuals made it into the study proper.

6. Several studies are of short duration and, worse still, may have been subject to early termination (something which tends to downplay harm and exaggerate benefits).

7. In many trials, adverse effects are only deemed to have occurred if there’s been extreme deviation from normal biochemistry (for example, judging that myopathy has occurred only when creatinine kinase levels are 10 times the upper limit of normal or higher). Setting the bar this high obviously works to depress side effect rates.

Interestingly, a recent review paper on statin side-effects acknowledged six distinct reasons why RCTs may not be relied upon to provide an accurate assessment of statin side effects. Oddly, acknowledgment of these very real issues did not stop the authors confidently stating that: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.” [2] Because of the shortcomings of the research, there is no way they could make such a claim. The authors’ own multiple misgivings about the research in this area were somehow ‘lost’ in their abstract (and in the media).

I note that that the BMJ reported this study at length [3], and in particular relayed the predominantly ‘statins are safe’ line taken in the media by lead author Dr Judith Finegold. However, the report includes no caveats at all about the study's findings and issues no cautions at all regarding their obvious unreliability.

Some might argue that the ‘crime’ here is similar in nature and of similar importance to public health as the omissions of Drs Abramson and Malhotra.

I understand that Professor Sir Collins has steadfastly refused to put his concerns regarding the articles by Drs Abramson and Malhotra to the Editor in writing for publication. Is it normal for individuals with complaints about BMJ content to be granted a meeting with the Editor after refusing to submit a formal response? Perhaps Fiona Godlee will clarify what the protocol is here?

I would like to know because I (and perhaps others) sometimes read information in the BMJ that I believe is inaccurate and/or misleading. Let me start with the BMJ report of the Finegold paper [3]. Fiona Godlee is rightly concerned that some may possibly suffer from being put of starting or continuing to take statins. However, in failing to communicate the unreliability of the conclusions of the Finegold paper, many may have been given a false sense of security, and are now at risk of adverse effects from statins. For this reason, I believe caveats about the evidence should have been highlighted in the report, so that doctors and patients were in a better position to make an informed choice about the appropriateness of statins. In light of this, I believe at least a correction is warranted. However, some may argue that the omissions are of such importance to public health that a full retraction of the article is in order.

I am very concerned that many individuals may have been put needlessly at risk by the BMJ’s one-sided presentation of the Finegold study. I am asking now for the opportunity to meet with Fiona Godlee so that I can put my concerns to her and make my case for correction or retraction. I am assuming that I (and others) can expect the same treatment that has been afforded to Professor Sir Collins. If not, why not?

References:

1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.

2. Finegold JA, et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European Journal of Preventive Cardiology 2014;21(4):464-74

3. Wise J. Statins may have fewer side effects than is claimed, meta-analysis finds BMJ 2014; 348:g2151

Competing interests: I am a paid author, journalist and speaker, and in my work regularly express views that question conventional wisdom regarding the cholesterol hypothesis and the appropriateness of mass medication with statins.

20 May 2014
John Briffa
Practising Doctor and Writer
N/A
Woolaston House, 17-19 View Road, London, N6 4DJ