Statin advice from the Wizard of Oz

by Jerome Burne

There is a whiff of the Wizard of Oz about the advice on statins that we’ve been getting for years. It comes in the form of ringing pronouncements from behind a curtain that all is well; that these drugs have been tested and found to be greatly efficacious and totally safe. Unfortunately it is now clear that no one, other than the Wizard, his assistants and the munchkins who make the statins, have been able to see how they arrive at that conclusion since the curtain conceals the data.

What actually happened to individual patients during the big trials run by the drug companies is for wizard eyes only. This was the topic of a HeathInsightUK post a couple of weeks ago (The house of statin secrets) and followed up last week in the Daily Mail (Millions of healthy Britons to be prescribed drugs GPs say they won’t take). Others bloggers such as HIUK contributor Malcolm Kendrick and cardiologist Dr Aseem Malhotra have also been raising questions about the reliability of the pronouncement issuing from behind the curtain.

This proved too much for a very senior wizard Professor Sir Rory Collins who warned in the Guardian on Saturday that thousands would die if doctors kept “creating misleading levels of uncertainty” about statins. Making people “unjustifiably suspicious” of these drugs was going to lead to deaths because people would stop taking them. This is authoritarian medicine at its most magisterial.

We need transparency

It is certainly a long way from the evidence based approach to medicine advocated by Dr Ben Goldacre, set out in great detail in his book Bad Pharma. He rightly believes that we need transparency from drug companies so that independent researchers can see all the information about patients they gathered in their trials because, as he makes very clear, the companies are far too ready to juggle with statistics and spin or simply hide unfavourable results.

This would of course mean independent researchers such as Drs Kendrick and Malhotra picking over the data and quite possibly “creating levels of uncertainty” when the raw data and the conclusions didn’t match up. But then that is what science is all about.

Unfortunately there is not much chance of that happening at the moment as far as the data on a large number of statin trials held by the Oxford-based Clinical Trialists (CTT) Collaboration is concerned. This is the research organisation Professor Sir Rory Collins heads. The evidence that underpins his pronouncements about the safety and effectiveness of statins is firmly behind the curtain. It is of course possible that all his conclusions are built on rock-solid data and totally valid, but while nobody else can see it, this is faith-based medicine.

The European Medical Association (EMA), which licences drugs in Europe, certainly doesn’t believe that we should rely on faith in the pharmaceutical companies’ integrity. It bases its licencing decisions on the full results of trials run by drug companies, not just the published ones. In 2010 it announced that it was going to encourage transparency by making clinical trial data available on demand for every drug it had reviewed. Since then it has released over 1.9 million pages of this detailed information on how patients responded.

Raised Eyebrows

It’s hard to disagree with this initiative – although a couple of drug companies disagree so strongly that they are taking the EMA to court over it, but that is another story – and many top UK doctors have signed up a campaign called Alltrials that is pushing for something similar here. Dr Goldacre is of course heavily involved. So there were raised eyebrows when his name showed up as one of the authors on a widely reported paper published last week which found that statins had virtually no side-effects.

The surprise – schadenfreude in some quarters -was due to the fact that the evidence for this comforting conclusion all came from published trials run by the drugs companies with no attempt to gather the kind of detailed data his book was vehement in demanding. So has Dr Goldacre now transmogrified into a junior wizard behind the curtain?

On the one hand he has put up a blog which admits that the data on which his trial’s conclusions were based were “flawed” but defends its publication on the grounds that it is “a useful illustration of how… to gather side-effects data from trials”.

On the other hand, despite the flawed data, the paper makes a pretty radical recommendation that can only be of considerable benefit to the manufacturers, and possibly harmful to patients. It says that patient information leaflets for statins should be rewritten to make it clear that your chance of suffering a genuine side effect is very small. This is a recommendation based on unexamined drug company data that has been shown many times in the past to be highly unreliable.

How to get favourable results

What is useful about both Goldacre’s blog and the published paper is the detailed list they contain of ways in which trials can be set up to produce favourable results, largely by excluding many of the patients who would actually be getting the drugs in the real world. This is a dejargonised version of what the paper says:

First, the drug companies paying for the trials may have little interest in checking carefully for possible side effects. For example a biomarker for liver damage is checked in most trials although it rarely indicated a problem, but only three out of 29 trials reported new cases of diabetes.

Second, many trials don’t give any details about how side-effect reports were actually collected or how often.

Third, some trials exclude patients with disorder such as severe diabetes, kidney failure or hypertension, many of who would be likely to be given statins in the real world.

Fourth people who volunteer for trials are often chosen because they are enthusiastic and so may be less likely to report side effects and less likely to stop taking the drugs than real world patients.

Fifth many trials in our meta-analysis had a period before the trial had actually started when patients were just given a placebo to find out which ones took their pill regularly. Those who didn’t were excluded from the real trial. The result would be a those remaining would be much more highly motived than those who would get the drug in the real world.

Finally, another group who were often excluded from trials, also making them unrepresentative, were those already on a drug that affected the liver in a similar way such as certain antibiotics – just the ones who could be expected to report more side effects.

Time to go back to Kansas

In his post-publication blog Dr Goldacre also mentions the various ways patients can be selected for trials to produce more favourable results (Statins have no side-effects? This is what our study really found). He then goes on to clarify the information you need to make a judgement if the published results from a trial reflect what actually goes on.

This is something called the “Clinical Study Report (CRP) about a trial: these are very long and detailed documents that give a huge amount of detail about the methods and results of a trial, and they’re important, because methodological flaws can often be glossed over in the brief report on a clinical trial that appears as an academic journal paper.”

Dr Goldacre then illustrates the importance of CRPs with some German research which found that 87% of the Clinical Study Reports gave a complete account of the side-effects found in trials compared with just 26% in the published versions of those trials.

So a simple question to Sir Rory Collins: Please sir when can we see the CRPs of the 29 clinical trials you have behind the CTT’s curtain? If they were brought out it would be likely to cause a rapid return to Kansas and the real world.

 

Jerome Burne

Jerome Burne

Jerome Burne is the editor of HealthInsightUK. He is an award-winning journalist who has been specialising in medicine and health for the last 10 years and now works mainly for the Daily Mail. His most recent book “10 Secrets of Healthy Ageing” was written with nutritionist Patrick Holford. He blogs at “Body of Evidence” – jeromeburne.com. 2015: Finalist for 'Blogger of the Year' award from Medical Journalists' Association.

9 Comments

  • If we are to give potentially harmful drugs to large numbers of people, many of whom are currently reasonably healthy, then it is imperative that the drugs are not harmful. With statins, that ‘lack of harm’, or side effects, is under some dispute. So there is a second requirement that the ‘lack of harm’ is absolutely clear and transparent to the public and especially to those who are prescribed the drug. This is manifestly not happening. So, in my opinion, they fail on at least one test, and probably a second.

    As for Goldacre, I am perplexed. He seems to be an enigma with contradictions. There is something intellectually unsatisfactory about him. There seem to be contradictions in the Alltrials setup as endorsed by GSK. The point about access to data is that we want to be able to see if pharma has been cheating again by fiddling the stats. And yet, as I understand it, the data is only released to researchers with a proper funded trial or review etc. I am unhappy about the whole thing which looks as if it might morph into yet another exercise in hiding, not revealing, problems with a drug.

  • Has Goldacre published much research of this type? I’m left wondering whether he’s spent years sermonising without a lot of direct experience. Maybe he’s now found that doing good research is a demanding task. His sort-of, kind-of repudiation of the work of which he is a co-author does him no credit at all. I don’t suppose his co-authors were thrilled either.

    “Our paper on the side effects of statins used the right method to address an important issue, but our data was flawed” says he. My own rule was that if I decided my data were shonky I didn’t publish. Simples.

    • As far as I am aware, this is the first peer reviewed paper Goldacre has published as a co-author. His other output are the two ‘popular science’ books “Bad Science” (in which he demonises complementary medicine in its many guises) and “Bad Medicine” (in which he demonises the dodgy practices of pharma in fiddling the results of trials). The second only seems to dwell upon the effectiveness claims of pharma and curiously avoids much mention of the harms that have arisen by virtue of getting dangerous drugs onto the market.

      For a much better assessment of the harms done by pharma, a thorough read of Dr David Healy’s blog, or the related blog Risk.com is much more of an eye-opener.

      I get the impression that Goldacre did a Cochrane course in the production of systematic reviews/meta-analyses and was knocked out by the apparent, and rather misleading, elegance of the mechanistic processes of Evidence Based Medicine. Then he wrote Bad Science in a flurry of starry-eyed enthusiasm. But then he began to see some of the flaws in the way the system is gamed by pharma. The result of some (but not all) of the scales falling from his eyes was his second book.

      Now that he has shifted from clinical medicine to research, he seems to have realised (as you say) that it is all rather difficult to get real data from real patients to produce clear cut results. Hence his rather woolly defence of his own paper.

      The ultimate irony is that he spent an awful lot of time debunking the kind of things that epidemiologists produce and which are reported in newspapers in Bad Science; and now here he is, having become an epidemiologist, and having his paper reported (and possibly sensationalised) in a newspaper. How the mighty are fallen!

  • Editorial

    Indeed – be intersting to see how this all plays out. Also it doesn’t say much for the practice of evidence based medicine that the most widely used drug in the world with (possibly) the largest number of clinical trials devoted to establishing its safety and effectiveness have still not clearly done either. And now that nearly all are off patent probably never will.

  • My bad reaction to Simvastatin (in my polio leg) happened after 3 years of taking the drug – so I am pretty sure it would never have featured in any trial.

    Because Simvastatin had seemed so harmless up until then, I stopped and started three times to confirm that it really was Simvastatin that was doing the damage. Indeed, it was extremely lucky that I even remembered that statins can produce muscle problems!

    This suggests to me that doctors need to collect side effect statistics far more rigorously, and to be aware that drugs can produce bad reactions years after starting.

  • You are not alone, see below websites for further information:

    General information including articles written by other doctors on the website of former American Astronaut and Medical Doctor, Duane Graveline M.D.: http://www.spacedoc.com/

    Testimonials of patients talking about their experiences, side effects, etc. with statins, many of these people have been permanently disabled even after ceasing taking the statin:

    http://www.spacedoc.com/board/viewforum.php?f=1

    http://www.askapatient.com/comparedrugs.asp?class=HYPERLIPIDEMIA – Cholesterol Lowering Drugs (HYPERLIPIDEMIA):Compare drugs

    https://www.statineffects.com/info/ – The UCSD Statin Study group, headed by Beatrice A. Golomb, MD, PhD

    http://www.chicagotribune.com/health/sc-health-1225-pharm-20131227,0,2271702.story – Cholesterol drugs can interfere with exercise

    http://articles.mercola.com/sites/articles/archive/2012/10/15/statin-drugs-on-coronary-disease.aspx – Confirmed Again: Statin Drugs Accelerate Cardiovascular Disease

    http://www.naturalnews.com/muscle_damage.html#ixzz2pBZbNzmB – Statins can cause muscle damage without necessarily exhibiting pain symptoms

    Best of luck in your recovery.

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