Is the editor of the BMJ suffering from statin-induced amnesia?

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].

Then in 2013, the same Cochrane group updated their data and concluded thatoverall 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 in October 2013 questions the evidence on which this U-turn appeared 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 relevant appraisal would be simply to calculate if, compared to placebo, statins actually reduce the risk of health outcomes.

The BMJ authors used the data from the CTT meta-analysis and found thatrisk of death was not reduced by statins at all. So, the CTT authors had extrapolated the data in a way that showed a benefit that actually does not exist in reality.

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 were 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], in which she writes

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 ofindustry sponsored clinical trials too often obscures.

At one point, Fiona Godlee remarks:

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

And now a curious thing has happened. On 27th January, the BMJ published an article co-authored by two of the original Cochrane authors (along with a general practitioner) [6]. The piece examines the risk of a hypothetical male patient, and the benefits and risks to him of taking a statin. The piece is relentlessly positive in its appraisal of the benefits of statins, and does much to attempt to allay any fears we may have about risks.

Here’s some excerpts (I have removed references for ease):

Adverse events and stopping treatment because of [statins] are common, but occur at similar rates in treated and control groups in clinical trials (17% and 12% respectively), making it difficult to ascribe these events to statins.

Reports of reduced energy, fatigue, depressed mood, and reduced quality of life show inconsistent findings.

Myositis (a ≥10-fold rise in normal levels of creatine kinase) is caused by statins, but myalgia (muscle pain without raised creatine kinase) is not linked with statin use.

The authors conclude:

Patients may expect not to be harmed in any way by preventive treatment with statins, and their views of trade-offs between benefit and possible harms will likely determine the wider use of statins.

I am not the only person to have noticed what seems to be quite a biased tone in the latest BMJ piece. Here’s a response from three New Zealand doctors who articulate well the issues [7] (as above, I have removed the scientific references for ease).

Enthusiasm for the use of statins comes through strongly in the paper by Ebrahim et al. It reads more as a “YES” in a head to head piece about the use of statins and does not convey the ongoing controversy around many aspects of when and how to use statins for primary prevention.

We note a number of references to the National Institute for Health and Care Excellence guidance. More recent American guidelines now recognise the absence of evidence to support any particular arbitrary LDL target in primary prevention. The authors’ suggestion of using ezetimibe in conjunction with a statin when LDL is not controlled is therefore redundant. More importantly, there is no evidence that ezetimibe improves meaningful clinical outcomes either with or without statins in any population.

We were also surprised at the authors’ presentation of statins’ adverse effects on muscle. Their statement that “Myositis (a >10-fold rise in normal levels of creatine kinase [CK]) is caused by statins, but myalgia (muscle pain without raised CK) is not linked with statin use” seems to minimise this adverse effect. For a patient who develops muscle pain whilst taking a statin, whether their CK is raised beyond an arbitrary threshold is unimportant, the question is whether or not the pain is linked to their medication. This adverse effect is well-established and has been described in more recent studies than the quoted 2008 review which in fact did not conclude that statins do not cause muscle pain without raised CK. The distinction between myositis and myalgia in this context is thus obfuscatory. There is ample evidence from cohort, adverse events report data, and case reports to suggest myalgia without enzyme alteration is a problem, and is not rare.

A person (in this context they aren’t patients until we start labelling them as high risk) considering whether to take a statin for primary prevention needs to understand their estimated cardiovascular risk, and be given a personalised estimate of the magnitude of the benefits and harms of the available risk-reducing non-pharmacological and pharmacological interventions. Our role is to provide appropriate and personalised advice on the range and size of possible benefits and harms for all interventions (lifestyle and medications) to inform these shared decisions. (10) A shared decision making approach facilitates informed choices based onassessment, understanding and prioritisation of benefits and harms. This approach may particularly benefit those penalised by previous threshold guidelines: young people with low 5 or 10 year, but high lifetime, combinedrisk can opt for earlier treatment, and conversely some healthy elderly people (whose main risk factor is simply age) may choose to opt out of rigid guideline-driven unilateral treatment decisions. None should face pressure by practitioners fearing professional or financial censure for not following a one size fits all cut-off approach to treatment. These principles have been adopted in advice recently released by the New Zealand Ministry of Health (11) which includes a recommendation to adopt a shared decision making model.

Given that the overwhelming majority of those who take statins for primary prevention will not derive any benefit from them, it is crucial that decisions to initiate lifetime therapy are informed by a clear presentation and discussion of the best available evidence.

Remember, this most recent pro-statin piece [6] appears in the BMJ, which only a few weeks before, carried a piece which highlighted the potential bias in the statin literature and the problems with how statin studies are often undertaken and reported. This most recent piece gives plenty of soothing reassurances about the safety of statins, and yet back in October the editor of the BMJ was alluding to the potential problems with relying on industry-derived data. Is the editor of the BMJ suffering from a sudden bout of statin-induced amnesia, I wonder?

References:

1. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1:CD004816.

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.

6. Ebrahim S, et al. Statins for the primary prevention of cardiovascular disease
BMJ 2014;348:g280

7. Hudson B, et al. Rapid response published 30 January 2014

10 Responses to Is the editor of the BMJ suffering from statin-induced amnesia?

  1. Ellie Winslow 7 February 2014 at 12:11 pm #

    You and Malcolm Kendrick have so much in common re statins, you ought to join forces somehow and leverage your impact!

    • Fiona 7 February 2014 at 3:24 pm #

      Yes, Ellie. I recommend people to read Dr Kendrick’s blog out today, ‘A sorry little patient tale’.

    • DWS 7 February 2014 at 4:09 pm #

      I agree, and also Beatrice Goulomb, who has been doing a lot of work regarding medical fraud, and statins. And she has some scathing talks on youtube regarding the overall fraud in the medical industry.

  2. Z.M. 7 February 2014 at 1:04 pm #

    Also, what about the trials included in the 2013 meta-analysis? There are not many quality trials in primary prevention.

    I don’t understand the inclusion of small statin trials (e.g. ACAPS) which were never designed to evaluate mortality outcomes.

    The ASCOT-LLA trial was truncated with unclear mortality benefit. The trial was stopped early at 3.3 years and the mortality curves seem almost identical at this point, yet the ASCOT paper reports a 13% reduction in total mortality. What is going on there?

    Why include the flawed and truncated JUPITER trial with unclear data, but excluded the ALLHAT trial for which data was available on the primary prevention population? Although it was non-blinded, the ALLHAT trial was also the only trial in primary prevention which actually used total mortality as the primary endpoint.

    The Japanese MEGA Study used an open-labeled design together with a diet intervention which could introduce bias as explained by other Japanese researchers – http://www.ncbi.nlm.nih.gov/pubmed/23221235

    Dr.Briffa, any thoughts on these issues?

  3. Larry Silverstein 7 February 2014 at 1:12 pm #

    Hi,

    We have reached a stage in medicine today, where the patient cannot trust his GP, when he prescribes not one, but two statins to patients who have never had a heart attack, but who have mild hypertension.

    I know one person who keeps getting the prescription, but doesn’t take the statins. It seems the Drug companie’s sales reps are “pushing” the GPs to prescribe their drugs and feeding them selective research , which shows how great the drug is. The REAL research is being done on “HUMAN GUINEA PIGS”, who are trusting their GP and innocently take the drugs believing they are going to improve their health, when in fact they could be causing serious damage to other organs in their body.

    It would seem Ms Godless has been “got at” & is doing a favor by allowing the pro-statin article.

    All I know is, that patients don’t have the same trust in their GPs as they used to have!

    How does the Hippocratic Oath go, “I will neither give a deadly drug to anybody if asked for it, nor will I make a suggestion to this effect”.

  4. Sheulee 7 February 2014 at 2:10 pm #

    How cheery Rufus Hound is stepping up to defend our NHS, right with you and I can hear Claire Rayner cheering…but how sodding complex are the issues when its our NHS making people sicker. Doh. And I just had a disorientating dehumanising 5 day in patient stay – three people did the holy trinity of wearing a name badge, introducing themselves and asking how to pronounce my tricky first name. I love you NHS but some stuff needs fixing. Starting with stopping unnecessary medication, and soon, there’s money to be saved as well as nasty side effects avoided. Maybe doling out fewer medications might even help morale…Thank you John et al for keeping on top of all the skew. Regards, an ex GP.

  5. Richard David Feinman 7 February 2014 at 4:59 pm #

    Great analysis but there’s an additional critical point and that is whether a meta-analysis is worth anything at all. In a meta-analysis you pool different studies to see if more information is available from the combination. As such, if it is good for anything, which is questionable, it is for small under-powered studies where you hope that putting them together might point you to something that you didn’t see. It is a kind of Hail Mary last ditch play. It is not intended for large studies. Most important, if a study has failed to show an effect, adding another study that has shown no effect will not improve things.

    I discussed Jakobsen’s meta-analysis on saturated fat in my blogpost at http://wp.me/p16vK0-8t and pointed out that almost all of the studies failed to show an effect of replacing saturated fat with carbohydrate or with PUFA and yet the authors came up with an answer. How is this possible? Well, as Dr. Briffa points out the Cochrane Group are self-appointed experts and if you can get away with that, then there’s no telling what you can get away with.

    But, think about the benefit to the lipophobes. With meta-analysis, no experiment ever fails, no principle is ever disproved — statins prevent heart attacks, sugar causes heart attacks, cholesterol causes heart attacks, red meat causes heart attacks — it doesn’t matter how many studies show no effect. One winner and you can do a meta-analysis. Just one more expensive trial and we’ll show that saturated fat is bad.

    The principle is that doctors prefer a large study that is bad to a small study that is good but the idea that the simply adding more subjects will make a study more reliable is absurd. Most of us think that if the phenomenon has big variability, then mixing studies will reduce reliability. And in science, it is expected that if your results contradict previous experiments, you will provide evidence as to the cause of the differences. What did they do wrong. And do the authors of the original study agree that the meta-analysis is right and they were wrong? Not if you don’t ask them.

  6. Axel F 7 February 2014 at 9:24 pm #

    Thanks for bringing up this discussion Dr. Biriffa. How to use statins to prevent heart disease in healthy individuals is one of the most important questions facing modern medicine today.

    Sometimes even the most respected medical journals get it wrong. A recent meta-analysis of the use of statins for elderly people could have made a huge impact – if the calculations had been right. But they weren’t…. http://www.docsopinion.com/2014/01/07/statins-for-elderly-people-was-the-message-corrupted/

  7. William L. Wilson, M.D. 7 February 2014 at 11:30 pm #

    For a complete review of the reasons not to trust studies done by drug companies (and the journals that publish them), I suggest reading Peter Gotzsche’s excellent book “Deadly Medicines and Organized Crime”. Dr. Gotzsche is the leader of the Nordic Cochrane Centre and has been involved in looking at the drug industry from both the inside and outside. His perspective is very troubling.

  8. Jessica Alvarez 5 June 2014 at 6:40 pm #

    Hi Dr. Briffa

    This is a classic example of FINANCE masquerading as science. Peer review is a very flawed process with enormous problems. Peer review doesn’t mean much of ANYTHING. It is NOT the arbiter of what is true. MUCH junk gets by the referees.

    Add to this, the system can and DOES get abused, too, and doctors can act like ” gate keepers.”

    In science, what matters is THIS:

    When someone else finds your work interesting….. And THEY take it up…And they perform experiments of ” A1A quality”…. And it WORKS….. And then it gets to be done more and more and more and more….. Add to this when there are several different independent test methods developed to test it – all getting the same result……. ( as in the case of Dark Matter) THEN it becomes part of the cannon of science. Then your confidence grows and grows.

    THAT is what matters.

    Isaac Newton’s ” Principia Mathematica ” was not at all peer reviewed, yet is some of the finest science ever conducted on this planet.

    This doctor, Fiona Godleee , looks exactly as I imagined her- a stuffy , stubborn , dogmatist with a poor understanding of science.

    In science we force our views and beliefs to conform to the evidence of reality – no matter how uncomfortable it is for us. Dr. Godlee forces the evidence of reality to conform to her beliefs…..

    Sincerely,
    Jessica

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