Dr John Briffa's response to the BMJ's withdrawal of comments.

My reaction to the BMJ’s withdrawal of statements relating to the safety of statins

By Dr John Briffa on 21 May 2014

 

You may have noticed that there’s a bit of a ‘fight’ going on over the cholesterol-reducing class of drugs known as ‘statins’. I am simplifying here, but there are essentially two opposing camps. In one corner, there are those doctors and researchers who hold the view that the statins should be given to pretty much all adults from middle-age, and there is little to be concerned with regarding their safety. In the other corner, there are those who believe that statins do no good at all for the vast majority of people who take them, and that the side-effects are more common that ‘official statistics’ suggest.
The fight went up a notch last week when the editor of the British Medical Journal announced that remarks made in two BMJ articles about the side-effects of statins had been withdrawn [1]. One of the articles was written by Dr John Abramson from Harvard Medical School and colleagues, and principally questioned whether extending statin use to those at lower risk (as has been suggested by the National Institute of Health and Care Excellence) will save lives [2].  According to their analysis, it won’t. The other piece was written by UK cardiologist Dr Aseem Malhotra, and principally questioned the role of saturated fat in heart disease [3].

In both articles, the authors referred to a study [4] that found that 17.4 per cent of people taking statins had adverse effects as a result attributed to statins. In the articles this figure was expressed as 18 per cent or ‘about 20 per cent’ which, apparently, was the first error. However, other issues, according the BMJ, was that the authors claimed that the 17.4 figure related to the percentage of people who stopped statins (at least temporarily) due to side-effects – this is not correct (it represented the percentage of people who had adverse effects). Also, the study in question was ‘observational’ in nature, which means that we don’t know if the adverse effects are due to statins or are the result of the ‘nocebo’ effect (like a placebo effect, only with negative effects rather than positive). The Editor of the BMJ, Fiona Godlee, tells us in her editorial that the caveats concerning the observational nature of these findings should have been made.

Both the articles made it through the peer-review process, so how did these errors come to be picked up? Well, apparently, they were brought to the attention of Fiona Godlee by Professor Sir Rory Collins, who heads up what is known as the Cholesterol Treatment Trialists (CTT) collaboration based in Oxford, UK. The CTT holds data on statin studies and periodically assesses it to tell us that statins are safe and very effective.

However, the CTT has in the past made grand claims about the effectiveness of statins that are based on the extrapolation of data (rather than actual data). Plus, as some have pointed out, the CTT refuses to release its data for independent inspection. The CTT can basically say what it likes about the effectiveness and safety of statins, but no-one can challenge what it says because no-one else has access to its data.

Apparently, Professor Sir Collins was invited by Fiona Godlee to put his concerns in writing for publication but he refused. He and Fiona Godlee met, and this set the ball rolling which culminated in the withdrawal detailed above. However, apparently this is not enough for Professor Sir Collins: he is demanding retraction of both articles, even though he has not challenged the main points raised in the articles. Fiona Godlee has set up an investigation to determine whether or not the articles should be retracted.

I have written to the BMJ in the form of an online ‘rapid response’ that was posted yesterday. You can read my response here.

In my response I accept that errors were made, but ask if a simple correction might have done.
Professor Sir Collins bases his assertions regarding the safety of statins on data from randomised controlled trials, like the ones analysed by the CTT. However, there are many reasons why randomised controlled trials may not adequately identify and report adverse effects from statins. Fiona Godlee acknowledges this herself and lists some of the issues, and I add to that list in my response. In all, there are about a dozen reasons why randomised trials stand to ‘miss’ adverse effects.

I also raise the issue of a recent study which appeared to confirm the safety of statins [5]. The study also detailed many reasons why results from clinical trials are an unreliable assessor of side effects. The study was reported in the BMJ [6], but the report included none of the caveats listed in the paper (or any other ones). As I explain to the Editor, these omissions may lull individuals into a false sense of security, and put people at unnecessary risk of adverse effects of statins, some of which can be serious.

One might argue that the ‘crime’ committed by the BMJ is roughly equivocal to the ones perpetrated by Drs Abramson and Malhotra. I point this out to Fiona Godlee in my response, and request a meeting with Fiona Godlee to discuss my concerns. After all, why should I not be afforded similar privileges as Professor Sir Collins”

You can read the response in full here. If you agree with the sentiments expressed in it, please click on the ‘thumbs up’ symbol to the right of the response to log your agreement.

References:
1.    Godlee F. Adverse effects of statins. BMJ 2014;348:g3306
2.    Abramson JD, Rosenberg HD, Jewell N, Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ2013;347:f6123
3.    Malhotra A. Saturated fat is not the major issue. BMJ2013;347:f6340
4.   Zhang H, et al. Discontinuation of statins in routine care settings. Ann Intern Med 2013;158:526-34
4.    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
5.    Wise J. Statins may have fewer side effects than is claimed, meta-analysis finds BMJ 2014; 348:g2151
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It’s not about statins – it’s about censorship - Zoë

It’s not about statins – it’s about censorship

Written by Zoë on May 19, 2014

Two very serious things happened last week – one in Australia and the other in the UK, although both are about information on line, so they have global impact…

Catalyst – Australia
Last October, two programmes aired on ABC television under the “Catalyst” banner (Catalyst is like Horizon – a science/investigation kind of programme). The first programme was called “Heart of the Matter Part 1 – Dietary Villains” and it aired on 24th October 2013. A transcript and copy has been preserved by someone on line. You can currently see it here, but I’m not sure for how long. The transcript of the programme is also available on this link. In essence – this programme challenged the widely held view that saturated fat causes heart disease.

The second programme aired on 31st October 2013 and, again, it can currently be seen here (video and transcript). This programme was called “Heart of the Matter Part 2 – Cholesterol drug war.”
Those who stand to gain from the diet-heart-cholesterol hypothesis did not want these programmes aired. There were calls for the second programme to be cancelled, after the first programme had been shown. The person making these demands, professor Emily Banks, admitted that she “didn’t have a lot of detail” about the cholesterol programme, but wanted it pulled anyway.

Both programmes aired. Catalyst is the only science show on Primetime Australian TV and it pulled in approximately 1.5 million viewers. That’s approximately half the number of people who take statins in Australia, by the way.

Barely had the closing credits run before the pro-statin brigade swung into action. A formal complaint was lodged with the body that reviews “Audience and consumer affairs” and a few months later, the findings were published in a 49 page document. In between airing and publication, Catalyst – producers and presenter (Maryanne Demasi) – were pretty much paralysed from doing further work by the demands placed upon them by the investigation.

You can read the full report. You may like to wait for a Dr Malcolm Kendrick blog – due any time now – where he summarises all the complaints made against the two programmes and those rejected and upheld. Nothing was upheld against the first programme on dietary fat and yet this has been pulled. For the second programme on cholesterol, I lost count of the judgements that recorded “no breach” of any of the codes – 16 I think. There was 1 breach upheld – and 1 alone. This is on P46 of the 49 page report.

The investigation concluded that in one part of one programme the presentation favoured an anti-statin view more than a pro-statin view. The report did not recommend that the programme be removed from the ABC web site and condemned to the scrap heap. You can see the recommended remedy on p4 of the report “We suggest it would be appropriate for additional material to be made available on the special ‘Heart of the Matter’ program website.” And that’s about it. Yet this programme has also been pulled – ABC have caved in to the pressure placed upon them by statinators. The intention of those who promote statins was no doubt to ensure that a programme like this is never aired, touched or conceived of again. They didn’t want this one to air. Tragically, they have almost certainly achieved their aim.

I tweeted the irony of the judgement – that the pro-statin bias prevails 365 days a year and yet 1 hour of a TV programme, where one small part was slightly less than balanced towards both pro and anti-statin views, is silenced – for bias! This isn’t about statins. It’s about censorship.

UK – BMJ
In the UK, in the same week, same drug, we also experienced censorship. Only this time, thanks to the robustness of BMJ editor-in-chief Fiona Godlee, we experienced only a small censorship – for now anyway.

On 15th May, Fiona Godlee published this editorial in the BMJ Godlee noted that, in October 2013, the BMJ “published an article by John Abramson and colleagues that questioned the evidence behind new proposals to extend the routine use of statins to people at low risk of cardiovascular disease. Abramson and colleagues set out to reanalyse data from the Cholesterol Treatment Trialists’ (CTT) Collaboration. Their contention was that the benefits of statins in low risk people were less than has been claimed and the risks greater.”

Godlee continued, “In their conclusion and in a summary box they said that side effects of statins occur in 18-20% of people. This figure was repeated in another article published in the same week in The BMJ by Dr Aseem Malhotra. The BMJ and the authors of both these articles have now been made aware that this figure is incorrect, and corrections have been published withdrawing these statements. The corrections explain 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%”. The BMJ articles did not reflect necessary caveats and did not take sufficient account of the uncontrolled nature of Zhang and colleagues’ data.”
Godlee had been alerted to ‘the error’ by Rory Collins, head of the Cholesterol Treatment Trialists (CTT) Collaboration, whose data were reanalysed by Abramson and colleagues. Godlee says in her editorial that Collins visited her at The BMJ in early December and then took the matter up in the UK media towards the end of March 2014.

The Guardian article references Collins as follows: “The Oxford academic said the side-effect claims were misleading and particularly damaging because they eroded public confidence. “We have really good data from over 100,000 people that show that the statins are very well tolerated. There are only one or two well-documented [problematic] side effects.” Myopathy, or muscle weakness, occurred in one in 10,000 people, he said, and there was a small increase in diabetes.”

The challenges that the Guardian should have made:
The Guardian should have ascertained how independent/conflicted their source was. These are the two pertinent questions:

1) How much, Professor Collins, have you/your department/your charity/your family – whatever outlets you have – received directly and/or indirectly from the pharmaceutical industry during your lifetime?

2) You head the CTT. Why will the CTT not release Serious Adverse Effect data (and raw data generally) from clinical trials so that researchers, doctors and patients can fully understand the side effects of statins? How can you claim that statin side effects are negligible when you won’t share the data?

The Guardian should have done their own (simple) research into statin side effects. Here are two pertinent questions:

1) If side effects are as rare as you say, why does the patient leaflet for Lipitor – the most lucrative statin, indeed the most lucrative drug ever in the history of mankind, state the following:

“Common side effects (may affect up to 1 in 10 people) include:
• inflammation of the nasal passages, pain in the throat, nose bleed
• allergic reactions
• increases in blood sugar levels (if you have diabetes continue careful monitoring of your blood sugar levels), increase in blood creatine kinase
• headache
• nausea, constipation, wind, indigestion, diarrhoea
• joint pain, muscle pain and back pain
• blood test results that show your liver function can become abnormal“

2) If diabetes is to be dismissed so lightly, why is the diabetes statins lawsuit gathering pace in the US? (Google diabetes statins lawsuit) and why is “increases in blood sugar levels” listed as one of the common side effects in the patient warning leaflet?

Funding
The web of funding around Collins, CTT, CTSU (Clinical Trial Service Unit) has proved astoundingly difficult to get to the bottom of. I had a bit of a breakthrough recently and came across a declaration of interest for Colin Baigent – CTT secretariat and close senior colleague of Collins. Check page five for current and recent grants. The following have been awarded to Colin Baigent and Rory Collins, (with other names mentioned alongside):

Merck & Schering	£39 MILLION (2002-2011)
Merck	£52 MILLION (2005-2013)
British Heart Foundation	£9 MILLION (2005-2013) (Where does the BHF get that kind of money?) & then another grant from the BHF for £2.7 MILLION (2004-2013) & then a couple more for several hundreds of thousands of pounds.
Medical Research Council	£13.8 MILLION (2008-2013) (Check the most recent appointees to the MRC - a Senior Vice President of Pfizer and Executive Vice President of Astra Zeneca).
Bayer	A mere £965,000
John Wyeth Ltd	£500,000
Novartis	£350,000

That’s £114 MILLION before you get into the small change.

Censorship
ABC has caved in, despite no judgement requiring them to do so. Godlee has asked a third party to review both articles to see if the current revisions are sufficient, or to decide if the two articles should be pulled. Collins wants both articles to be retracted. As Godlee points out: Malhotra’s article is primarily about saturated fat – it merely references the Zhang article, which Collins is not happy about and the Abramson article is primarily about the fact that the CTT data failed to show that statins reduced the overall risk of death in people with a <20 10="" an="" available.="" be="" cardiovascular="" disease.="" fact="" important="" is="" of="" openly="" p="" risk="" this="" to="" which="" year="">I have no doubt that Collins would like these two articles deleted from the records forever. For him it may be about the statins that have funded him/his department/wherever to the tune of over one hundred million pounds. For the rest of us it’s about censorship.
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BMJ exposes ways we have been misled over the ‘benefits’ of statins - Briffa

BMJ articles exposes the ways we have been misled over the ‘benefits’ of statins

By Dr John Briffa on 1 November 2013   

 

The ‘Cochrane Collaboration’ is an international collective of researchers whose self-proclaimed role is to provide accurate and robust assessments of health interventions. The group specialises in ‘meta-analyses’: the grouping together of several similar studies on interventions including drug therapies.
In 2011, Cochrane researchers assessed the evidence relating to statin use in individuals at low risk of cardiovascular disease (defined as a less than 20 per cent risk over 10 years), and concluded that there was limited evidence of overall benefit [1]. I appeared on Channel 4 news to discuss this publication and the issues surrounding it, and you can see the discussion here.

Earlier this year, the same Cochrane group updated their data and concluded that overall risk of death and cardiovascular events (e.g. heart attack or stroke) were reduced by statins in low risk individuals, without increasing the risk of adverse events (including muscle, liver and kidney damage) [2]. It seems the Cochrane reviewers had had quite some change of heart. A paper published in the BMJ on 22 October questions the evidence on which this U-turn appears to have been made [3].

The authors of the BMJ piece note that although the 2013 meta-analysis included four additional trials, these trials did not substantially change the findings. The change in advice was actually based on another meta-analysis, published in 2012, conducted by a group known as the Cholesterol Treatment Trialists’ (CTT) collaboration [4].

Among other things, the CTT authors concluded that, in low risk individuals, for each 1.0 mmol/l (39 mg/dl) reduction in LDL-cholesterol, statins reduce overall risk of death and heart attack by about 9 per cent and 20 per cent respectively. The conclusion was that statins have significant benefits in low risk individuals that greatly exceeded known risks of treatment.

However, the CTT authors took the odd step of calculating the benefits of statins according to a theoretical reduction in LDL-cholesterol levels. A much more realistic appraisal would be simply to calculate if, compared to placebo, statins actually reduce the risk of health outcomes.
The BMJ authors use the data from the CTT meta-analysis and found that risk of death was not reduced by statins at all. So, the CTT authors had used had extrapolated the data in a way that showed a benefit that actually does not exist in reality.

And what of the claim that statins reduce the risk of cardiovascular events such as heart attack or stroke? The data shows that about 150 low-risk individuals would need to be treated for five years to prevent one such event (i.e. only about one in 750 individuals will benefit per year).

They also draw our attention to the impact of statin treatment on ‘serious adverse events’. This outcome can be improved by statins as a result of, say, a reduced number of heart attacks, but worsened through side effects such as muscle or liver damage. The BMJ authors note that the CTT review did not consider serious adverse events (a major omission). Without knowing more about this, though, we simply cannot make a judgement regarding the overall effect of statins, and whether the net effect is beneficial or not. Interestingly, of three major trials that were included in the CTT review that assessed overall serious adverse effects, none found overall benefits from statin treatment.
So, while the CTT authors seem to have over-hyped the benefits of statins, they seem at the same time to have been quite keen to steer clear of talk of their very real risks and the absence of evidence foroverall benefit.

The BMJ authors draw our attention to the fact that every single trial included in the CTT was industry funded. Such trials are well known to report results more favourably and perhaps downplay risks than independently funded research. The BMJ authors cite specific ways in which the adverse effects of drugs seen in clinical trials can be ‘minimised’. These include:

• The exclusion of individuals from trials with known health issues likely to be exacerbated by statins or signal susceptibility to statin side effects (such as liver, kidney and muscle disease).
• The use of a ‘run-in’ period before the study starts which detects and then excludes individuals who do not tolerate statins.
• The possibility that individuals ‘drop out’ from the study because of side effects, meaning that the incidence of some side effects can be ‘lost’ from the data.
• Failure of the study investigators to assess and monitor adverse events such as muscle damage and changes in brain function.
• Failure to properly ascertain or report adverse events.

It is noted that the Cochrane authors admit the reporting of adverse effects in studies is generally poor, but also state that it’s unlikely statins have major life-threatening hazards. The authors of the BMJ piece are not convinced, though, writing: “[The] large discrepancies between the frequency of adverse events reported in commercially funded randomised controlled trials included in the CTT meta-analysesand non-commercially funded studies show that determination of harms cannot be left to industry alone.”

The BMJ piece is accompanied by an editorial from the journal’s editor, Fiona Godlee [5]. Her comment on this issue starts:

None of this does much to bolster confidence in the published literature.

Godlee goes on to write:

Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available. AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA.

If I were to summarise, I’d say that, at best, there seems to be a degree of complacency regarding the veracity of statin data on the part of both the CTT and the Cochrane researchers. There is a sense that they are happy to present the ‘positive’ findings in the best possible light, and at the same time seem relaxed about the clear gaps we have in our knowledge about potential harms. The fact that statins appear to have no overall benefit in those at low risk of cardiovascular disease should not go unacknowledged, either.

Worse still, we have evidence that drug trials can be designed, conducted and reported in ways that obscure the truth. And sometimes, even when we have data that can help us make informed decisions about the appropriateness of a treatment, some drug companies will fight tooth and nail to prevent that data seeing the light of day.

This sort of subterfuge may be good for sales and share price, but it is almost certainly bad for our collective health. On this point, the BMJ authors state than instead of doctors following guidelines and prescribing statins for individuals at low risk of cardiovascular disease, they should explain the magnitude of benefits and uncertainties regarding harm. In addition, they might also discuss the fact that the vast majority of cardiovascular disease risk is linked with lifestyle factors such as smoking, diet and physical activity. Fiona Godlee backs this approach, but states that the benefits of lifestyle change are: “something that the dominance of industry sponsored clinical trials too often obscures.”
Personally, I am delighted that the misdeeds of drug companies and some researchers can now be exposed in this way, and in a high-profile medical journal at that. In the past, I think there was much more opportunity for the industry and its hired hands to mislead us. Greater transparency means that the industry as a whole is getting more of what I believe it deserves: our contempt.
References:
1. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1:CD004816.
Medline
2. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev2013;1:CD004816.
3. Abramson JD, et al. Should people at low risk of cardiovascular disease take a statin?
BMJ 2013;347:f6123
4. Cholesterol Treatment Trialists’ (CTT) Collaborators. 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. The Lancet 2012;380(9841):581–90.
5. Godlee F. Statins for all over 50? No BMJ 2013;347:f6412.
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BMJ editor casts doubt on veracity of statin trials funded by the statin makers - Godlee

Statins for all over 50? No

Fiona Godlee, editor, BMJ

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6412 (Published 23 October 2013)                                         Cite this as: BMJ 2013;347:f6412    

 

Should you prescribe statins to everyone over the age of 50, even those at low cardiovascular risk? A new Cochrane review seems to suggest that you should. An article in this week BMJ cries caution (doi:10.1136/bmj.f6123).

Current guidance from the UK’s National Institute for Health and Care Excellence (NICE) and the American Heart Association recommends statins only when the 10 year risk of cardiovascular disease is 20% or greater. But since these guidelines were written, a large meta-analysis of individual patient data reached a different conclusion. Published in the Lancet in 2012, the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis found that statins significantly reduced major cardiovascular events and all cause mortality in people at low risk, a benefit which, the paper said, “greatly exceeds any known hazards of statin therapy.”

As John Abramson and colleagues explain, it’s this meta-analysis that led the Cochrane reviewers to embrace the idea that statins should be used far more widely, even perhaps to everyone over 50, as a Lancet editorial suggested at the time.

But Abramson and colleagues’ detailed critique of the CTT meta-analysis should give us pause. Their own analysis of the data finds no evidence of a reduction in all cause mortality or in the total number of serious events. They also highlight the failure of the trials included in the CTT analysis to adequately report important harms of statin treatment, including myopathy and diabetes. They conclude that broadening the use of statins to low risk individuals “will unnecessarily increase the incidence of adverse events without providing overall health benefits.”

There is a concern underlying their critique that will be familiar to BMJ readers. It is that all of the trials included in the CTT meta-analysis were funded by the manufacturer of the statin being studied. They list the various ways in which these trials might have exaggerated the benefits of statins and minimised the harms, and they summarise what low risk patients need to know. Top of the list is the benefit of lifestyle change, something that the dominance of industry sponsored clinical trials too often obscures.

None of this does much to bolster confidence in the published literature. Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available (doi:10.1136/bmj.f1636). AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA (doi:10.1136/bmj.f4728).

As for a way forward, I can’t improve on the list of solutions proposed by Richard Lehman when emailing out his journal review blog this week (http://bit.ly/HcKvjy): “All phase 3 trials to be designed and conducted independently of manufacturers, using the best available comparator. Research priorities to be determined by patients (James Lind Alliance). Value-based pricing. All data available from all trials, with meta-data: IPD [individual patient data] level for qualified independent centres. Big increase in comparative effectiveness research, much more research into non-pharmacological treatments.”

Notes

Cite this as: BMJ 2013;347:f6412

Footnotes

• Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest

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Emphasis added.

Read the complete article here.