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the British Medical Journal announced that remarks made in two BMJ articles about the side-effects of statins had been withdrawn [1].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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Read the complete article here.

Researchers pronouncing ‘statins are safe’ are undermined by their own observations - Briffa

Researchers pronouncing ‘statins are safe’ are undermined by their own observations

By Dr John Briffa on 13 March 2014

 

Listen to most ‘key opinion leaders’ talk about statinsand you will hear soothing reassurances about their safety. Yet, my experience as a doctor suggests that adverse effects such as fatigue and muscle pain occur more commonly than ‘official statistics’ suggest. However, a study published this week claims to provide evidence that, for the most part, statin side effects are ‘imagined’ [1].

In this research, the adverse effect rates from statins was compared with those seen in individuals taking placebo (dummy) pills in a total of 29 studies. The conclusion was that apart from increasing the risk of diabetes, statins don’t generally have any more adverse effects than placebo. The actual words the authors use in their conclusion are: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.”

This is confident, seemingly ‘evidence-based’ stuff, indeed. However, these findings do appear to me to be at odds with what I and many other doctors observe in real life: that a significant number of people who take statins have side-effects that resolve (sometimes slowly) on discontinuation of their medication. Of course, as the authors of this most recent study allude to, these side-effects may be nothing more than a negative placebo response – sometimes referred to a ‘nocebo’ response.
However, is there anything about the way statin trials may be designed and conducted that could jeopardise our ability to get accurate data on the adverse effects of these drugs?

Several explanations are possible. First, commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects. One pointer towards this is that, although evidence of liver damage is documented in the majority of trials, diabetes diagnoses were only documented in three of the 29 trials assessed in the recent study.

Second, 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 were ‘caught’ and logged appropriately.

Third, some trials’ exclude patients with severe diabetes, kidney failure or high blood pressure. In reality, though, these individuals may come to be prescribed and take statins.

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

Fifth, 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.

Finally, many trials excluded patients on medication sharing the same liver metabolic pathway as statins (e.g. fibrates and macrolide antibiotics). Patients on such drugs, in the real world, might well suffer higher rates of pharmacologically mediated effects.

I make no secret of the fact that I think the benefits of statins are over-hyped and that the adverse effects are generally downplayed. As a result, a cynical observer might read my reservations here and think ‘well, he would say that’.

But, here the kicker: those six issues I detail above were plucked from the very same study that trumpets the safety of statin [1]. Much of what is written in this section of the post was actually lifted verbatim from the study.

So, by the authors’ own admission, there are many reasons why the adverse effect rates seen in statin studies may not accurately reflect the rates seen in the real world. But then how can the authors conclude 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.”

The reality is the deficiencies of the studies do not allow the authors (or anyone) to conclude that at all. The authors’ pronouncement on safety is utterly undermined by their own admissions about the incompleteness and untrustworthiness of the study data.

The opening line of the study is this: “Patients and doctors need clear reliable information
about benefits and risks to make informed decisions.” The only clear thing about the risks of statins, to my mind, is that there isn’t much clarity. Making bold pronouncements on the safety of statins without us having the facts is potentially misleading, and may cause many to come to considerable harm, needlessly.

References:
1. 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 March 12, 2014

Beware: new cholesterol lowering drugs coming - Kendrick

Beware: new cholesterol lowering drugs coming

by Dr Malcolm Kendrick

‘…across the gulf of space, minds that are to our minds as ours are to those of the beasts that perish, intellects vast and cool and unsympathetic, regarded this earth with envious eyes, and slowly and surely drew their plans against us.’ War of the Worlds

An era is coming to an end. Statins, the world’s most widely prescribed and profitable drugs, have, with the exception of Crestor (rosuvastatin), all come off patent and their price has plummeted. Good news for NHS accountants: not so good for company profits.

So a supposedly new, improved, much safer and more effective generation of cholesterol lowering drugs will soon be available at a doctor’s surgery near you. At least that will be the general tone of the marketing. With 80% of the population suffering from “high” cholesterol, according to guidelines drawn up by consultants with links to drug companies, there is obviously a huge need. (For an account of how seriously we should take this “need” see Dr John Briffa’s post.)

This is obviously a great opportunity for the companies but it also faces them with a fascinating dilemma. Statins have been relentlessly promoted as the most beneficial l class of drugs ever, protecting not just against cardiovascular disease but also Alzheimer’s and Parkinson’s and being virtually side-effect free into the bargain.

An alarming press release

But if the companies are going to persuade those NHS accountants and cash-strapped GP commissioning bodies to start paying serious prices for the new drugs, they need to persuade them that statins actually had a serious problem all along but it is one that can be avoided by buying the new products.

Recently I received a press release by email that was the first sign that this process is already underway. It was a warning about something called P9 which, had I been a loyal statin believer, I would have found pretty alarming. After explaining how statins worked by targeting an enzyme known as HMG-CoA in the liver, the email went on to tell me this:

“However, statin treatments have been shown to actually stimulate the production of PCSK9, which is counterproductive, possibly damaging to the liver, and ultimately limits the treatment’s ability to lower LDL cholesterol levels.”

Why weren’t we told about this risk before?

What on earth is PCSK9, you and the medical statin believers might well ask. And if it is not only able to damage the liver but also render the whole purpose of taking a statin self-defeating, why haven’t we been told about it before?

Here was a classic marketing ploy; tell you about a problem and immediately offer a solution in the form of a drug that is able to block the production of damaging PCSK9. The full name of these new drugs is proprotein convertase subtilisin/kexin type 9 inhibitors.

And it’s not the only dauntingly high tech-new cholesterol lowering drug that could be coming your way in the not too distant future. For the sake of completeness here is a list of nearly all the new compounds waiting in the wings. Some will undoubtedly founder on the rocks of side effects that are just too dangerous, never to be seen again.

Other new drugs in the race

• Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors)
• Antisense oligonucleotides (ASOs) targeting the production of apolipoprotein B-100 (apoB-100)
• Microsomal triglyceride transfer protein inhibitors
• Squalene synthase inhibitors
• Peroxisome proliferator-activated receptor agonists
• Thyroid hormone receptor agonists

For the moment though my money for the first out of the gate are the PCSK9 inhibitors, which I will call P9 inhibitors. So what exactly are they? Well P9 is an enzyme that is found mainly in the liver. It binds to receptors that remove the “bad” LDL (low density lipoprotein) cholesterol and destroys them after they have taken just one LDL molecule out of circulation, meaning that they can’t be reused to remove more LDL.

But if you block P9, you allow LDL receptors to continue removing LDL merrily from the bloodstream, so LDL levels fall dramatically. In fact P9 inhibitors appear to lower LDL far more effectively than statins which, if you sign up to the belief that the lower your cholesterol goes the more protection you get, this can only be another major benefit.

The new statin combo

What’s clever about this is that it avoids taking on statins directly. Given how familiar doctors are with them, how most believe in them and how cheap they are, a head on attack would be doomed to failure.  The manufacturers know, damn well, that doctors are not just going to stop using statins, so their P9 inhibitors will be positioned to sit alongside statins, allowing them to work, supposedly, even more safely.  At first anyway.

But there is more to this press release and I could pick it apart for hours, marvelling at the ability to say so much – in so few words. But let’s just focus on the phrase…’possibly damaging to the liver’ in relation to statins. Now, I know that statins do damage the liver – to a greater or lesser degree. Liver enzymes in the blood (a sign of liver damage) are often raised to three times normal levels – sometimes more.

But why not focus on the side-effect that is most clearly recognised with statins?  Namely muscle damage and pain. This is the true Achilles heel of statins. Yet the press release talks about liver damage…

Danger to your liver

The most likely reason is that P9 inhibitors have been found to cause liver problems themselves in both animal studies and phase 1 studies on human volunteers. Knowing their mechanism of action, it is more than likely that PCSK9 blocking agents could damage the liver. If you over-ride negative feedback mechanisms, the body doesn’t like it very much, as you will be overloading cells with toxic waste products. Enzymes to break down LDL receptors are there for a reason.

So, we can expect P9 inhibitors are going to cause liver damage. However, by attacking statins for causing liver damage, the pharmaceutical companies will be hoping to mask the most serious adverse effect of the new drug. The words used to defuse concerns about this problem will be something along the lines of. ‘With our P9 inhibitor we have seen mild elevations of liver enzymes in clinical studies. However, they are similar to those caused by statins, are reversible and cause no long-term damage.’ Blah, blah….  ‘Move along, nothing to see here.’

This fear is not just based on a vague unease that if you block a feedback mechanism in the body you are probably heading for disaster. It is also based on the fact that, if the companies developing P9 inhibitors are already blaming statins for causing liver damage, they are doing to hide their own problems behind a smokescreen. You heard it here first.

I also predict that severe liver damage problems will take years to emerge. In most people the liver is pretty resilient – it takes a lot of alcohol and a lot of time to destroy it. I fear that clinical studies will not be long enough to demonstrate this effect –before the drugs are launched and widely prescribed. I can say all this because it is what has happened with damaging block buster drugs in the past, such as the anti-inflammatory Vioxx and and the diabetes drugs Avandia.

My predictions for P9 inhibitors:

• They will be widely promoted as the new statins
• Pfizer, or Merck, will buy out the patent to one of the new products (they may have already done this)
• They will be launched without any long-term studies to show they actually cut your chance of dying from a heart attack. They will be approved purely on the basis that they lower cholesterol/LDL cholesterol.
• They will make billions upon billions in the first two years and be hailed around the word as a new generation in cholesterol lowering. The chief executives of the companies selling these drugs will be paid massive bonuses
• Key Opinion Leaders (‘experts’) will promote them ruthlessly at major conferences and press launches
• Reports of a high level of liver damage/deaths will  start to emerge
• The companies will deny there is a problem and attack anyone who says there is one
• They will start to be withdrawn from the market two to three years after launch
• There will be lawsuits
• The companies will be fined a small fraction of the profits they made from hyping the drugs
• It will emerge that the problems with liver damage were known by the companies many years before the drugs were launched but not many people will be interested by then, as the next generation of lipid lowering agents will be arriving
• No-one will be held accountable

Yes, the great Nostrokendrickos has spoken.
In the meantime remember that ‘Something unpleasant this way comes’.
Disclosure: I do not believe that a raised LDL/cholesterol level causes heart disease.
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Read the complete article here.

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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Read the complete article here.

Academic takes a well-aimed swipe at cholesterol drug ezetimibe - Briffa

Academic takes a well-aimed swipe at cholesterol drug ezetimibe

Aug, Fri 24th, 2012  By : Dr John Briffa

 

I am not particularly enthusiastic about cholesterol management. I don’t believe that the role cholesterol has in cardiovascular disease is as is popularly stated. But more importantly, when we use drugs to manage cholesterol the results are, by and large, disappointing. For example, treatment with statins does not save lives in people without a prior history of heart attack or stroke. Even in people at higher risk of cardiovascular disease, the great majority of treated individuals over a few years will not benefit. And then we have the problems of side effects.

The popularity of cholesterol management strategies in many way hinges on the idea that (LDL) cholesterol is bad, and lowering it is good. Yet, the scientific literature is littered with evidence that does not support either of these contentions. For example, we have evidence linking higher cholesterol levels with improved health outcomes and longevity in the elderly. We also have plenty of evidence which shows that cholesterol reduction will not always benefit health, and may in fact pose hazards here.

A case in point here concerns the drug ezetimibe. This medication reduces cholesterol, but unlike statins (which reduce cholesterol production in the liver), ezetimibe blocks the absorption of cholesterol from the gut. It’s generally very effective at reducing cholesterol levels, and because of this, the Food and Drugs Administration (FDA) licensed ezetimibe for use in the treatment of raised cholesterol in 2002. Since then, ezetimibe has gone to rack up sales in the order of $4 billion dollars annually.

Ezetimibe was licensed on the basis of its ability to lower cholesterol. At this time, no study has been published that it had benefits on health. So, what’s happened since? Well, there’s been a few studies that have looked at ‘clinical’ endpoints or disease processes (such as the build-up of plaque in the arteries), and the results have been far from encouraging.

For example, 2008 saw the publication of the so-called ENHANCE study which found that adding ezetimibe to simvastatin (a statin) led to an increase in the thickness of artery walls in the neck compared to simvastatin alone (though the difference was not statistically significant). The results of this trial were delayed by 2 years and had to be forced out of the manufacturers by the US Government.

Other studies have not only found no benefit, they’ve revealed worsening outcomes. In one study, treatment with ezetimibe was associated with (statistically significant) worsening of the narrowing of the arteries in the legs [1]. And then we have the inconvenience of the trials which link ezetimibe use to an increased risk of dying from cancer [2], which some researchers (in the pay of ezetimibe’s manufacturers) put down to ‘chance’, even though the data shows that the association is highly unlikely to be due to chance, and in all likelihood is a real effect.

Casual conversations with members of the medical profession reveal to me that the issues with ezetimibe are largely unrecognised, though there have been signs in the scientific literature that we are at last seeing some awareness of the issues. I came across a piece published recently in the journal Expert Opinion in Pharmcotherapy written by Dr Sheila Doggrell of the University of Queensland in Australia [3]. Dr Goggrell has reviewed the evidence and concludes this:

“…ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice.”

It is perhaps relevant that Dr Doggrell is an academic, which perhaps gives her the tools to take a cool hard look at the data and come to her own conclusions. Despite not being a clinician she is acutely aware that the only important thing is the impact ezetimibe has on health (not cholesterol levels). It’s an approach that I think more clinicians could do with adopting.

References:
1. West AM, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;218(1):156-62
2. Peto R, et al. Analyses of cancer data from three ezetimibe trials. NEJM 2008;359(13):1357-66
3. Doggrell SA. The ezetimibe controversy – can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin Pharmacotherapy 2012;13(10):1469-80
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Emphasis of bold text added by me - bd. Read thecomplete article here.

Another industry funded statin study that smacks of bad science and bias - Briffa

Another industry funded statin study that smacks of bad science and bias

Aug, Wed 15th, 2012 By : Dr John Briffa

 

‘JUPITER’ is the name given to a study which tested the effectiveness of the statin drug rosuvastatin (Crestor). The effects of rosuvastatin were compared with placebo in a large group of individuals free from a history of cardiovascular disease (such as previous heart attack or stroke) [1]. Testing in this setting (what is known as ‘primary prevention’) generally yields less beneficial results than in individuals with known cardiovascular disease (‘secondary prevention’). Despite being deemed at relatively low risk, the individuals treated with rosuvastatin saw significant improvements in some outcomes (more on this later), and the study got a lot of positive media and medical attention as a result.

One slight fly in the ointment that emerged from this study was the fact that those treated with a statin had a significantly increased risk of developing type 2 diabetes. Other studies have also found statins can up the risk of this condition. So, last week a study was published [2] in the Lancet medical journal, in which the original JUPITER authors looked again at their data to, supposedly, assess whether or not the benefits of rosuvastatin outweighed any risk from diabetes.

The authors found that the enhance risk of diabetes was only seen in individuals with at least one major risk factor diabetes. They go on to tell us that in this group, treatment with statins led to 54 new cases of diabetes being diagnosed. However, all is well because the group treated with statins also had 134 fewer ‘vascular events’.

The term ‘vascular’ event, however, covers a multitude of ills, including unstable angina (heart pain that comes on in an unpredictable fashion), non-fatal heart attacks, non-fatal strokes, fatal heart attacks, fatal strokes, and ‘revascularisations’ (e.g. insertion of a stent or bypass surgery). An outcome that is made up of lots of different outcomes is sometimes referred to as a ‘composite endpoint’. There is at least some doubt about the appropriateness of using composite endpoints to judge the effectiveness of medical interventions.

To begin with, the wider the net is cast, the more likely benefit will be seen, and the more likely the benefits will be deemed to be ‘statistically significant’. Also, some of the outcomes that are of limited relevance clinically (e.g. unstable angina) can occur frequently. This can skew the statistics in favour of finding ‘significant’ results, even though the clinical significance is debatable. The risk of the most important outcomes (such as fatal heart attacks and overall risk of death) may be reduced only a small amount or not at all.

Some researchers have raised the idea that drug companies and researchers may ‘game’ (deliberately manipulate) the design of studies by using composite endpoints in a way which inflates the apparent benefits of a drug [3].

In this latest regarding the impact of rosuvastatin on diabetes risk seen in the JUPITER study, the authors seem keen to remind us of the benefits of statins using a composite endpoint. However, analysis of adverse effects are limited to one outcome (diabetes). This basic technique really does much to stack the odds in favour of ending up a favourable end result.

I have seen many, many statin studies which use composite end points for benefits. Never, though, have I seen one which uses composite endpoints for adverse effects. In addition to increasing diabetes risk, statins have the potential to precipitate a range of other adverse effects including muscle pain, muscle damage, liver damage and kidney damage. How about lumping all those and other effects together to see how that ‘benefits’ and ‘risks’ stack up then?

There’s more than a whiff of bias here. Is there any other evidence that the authors of the study were biased and committed, perhaps, to finding positive results for rosuvastatin? I believe so.

In the abstract (summary) of the study, the authors are keen to point out that in individuals statins reduced the risk of venous thromboembolism (e.g. clots in the veins of the legs known as deep vein thrombosis) by about half. They also tell us that in people with or without risk factors for diabetes statins reduced overall risk of death by 17 and 22 per cent respectively. These are impressive statistics perhaps. But what the authors neglect to tell us, though, is that none of these outcomes was ‘statistically significant’, which means the ‘benefits’ the authors laud were much more likely to be due to chance than any genuine effect from taking statins.

It’s unlikely that any of us will be too surprised to learn that the original JUPITER study and this latest poor excuse of a paper were funded by the company that makes rosuvastatin (AstraZeneca).

References:
1. Ridker PM, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207
2. Ridker PM, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. The Lancet 2012;380(9841):565-571
3. Kip KE, et al. The Problem With Composite End Points in Cardiovascular Studies – The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention. J Am Coll Cardiol. 2008;51(7):701-707
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Read the full article here.

The Polypill has never been proven to benefit anyone - Briffa

It’s easy to fall for the polypill hype, but the reality is this medication has never been proven to benefit anyone

There’s been a ton of press over the last couple of days regarding a study of what is termed the ‘polypill’ – a combination medication conceived more than a decade ago with, supposedly, the prevention of heart disease and stroke in mind. The original ‘formulation’ combined blood pressure- and cholesterol-lowering medications, along with aspirin and vitamin B12. From time to time in the scientific literature we have seen studies which purport to support the idea of polypill taking for disease prevention. And the latest of these was published this week. Here, in short, is the study design and what it showed. After that, I’ll offer my own interpretation of the data.

This latest study tested the impact of a polypill comprising the following drugs:

• amlodipine (blood pressure lowering medication) – 2.5 mg
• losartan (blood pressure lowering medication) – 25 mg
• hydrochlorothiazide (blood pressure lowering medication) – 12.5 mg
• simvastatin (a statin) – 40 mg

The medication was given for 12 weeks to men and women aged 50 and over. At another time, they took a placebo for 12 weeks. In this sense, individuals acted as their own ‘controls’ in this study.

Individuals were selected for the study on the basis of two criteria:

1. They needed to be currently taking at least one of the medications in the polypill
2. They needed to be aged 50 or over

The impact on blood pressure and cholesterol levels was assessed. The polypill did bring significant reductions here. The authors estimate from the degree of reductions here that heart disease and stroke would be reduced by 72 and 64 per cent respectively. Impressive numbers. There’s talk of this extending life by a decade or more.

But here’s the thing: this study simply can’t be used to judge whether the polypill prevent cardiovascular disease and delays death. These ideas are based on speculation based on the idea that lowering blood pressure and cholesterol translates into significant benefits for health. Yet, as I explored most recently here and here, blood pressure and statin medications are generally very ineffective for the purposes of disease prevention and preventing death. Most people who take these drugs just won’t benefit.

This is particularly the case when individuals are deemed to be at low risk of cardiovascular disease. Normally, medication is prescribed on the basis of, say, blood pressure or cholesterol levels. But not in this study: here people were selected on the basis of age, irrespective of perceived risk. Of course it’s possible that some might benefit from the polypill, but it’s also likely that many more will not.

And of course the drugs in the polypill are not without risk. Any one of these medications on its own might cause problems, but the risk is magnified when medication are taken in combination. The design of the study (individuals had to be on at least one of the drugs in the polypill prior to the study) essentially preselects for individuals who, compared to members of the general population, are more likely to tolerate the medication being tested. So, risk of side-effects in the study population would be generally lower than we would expect to see in real life.

But, all of this is a diversion from the main point that we simply cannot predict the value of a drug on its impact on so-called ‘surrogate markers’ such as blood pressure and cholesterol. I mean, who would have predicted that ezetimibe, a potent cholesterol-lowerer, would never be shown to have benefits for health, or that the drug torcetrapib (which lowers ‘bad’ cholesterol and raises ‘good’ cholesterol) happens to increase the risk of people dying?

If we want to know how effective the polypill is, we need to test its impact on health. What impact does the polypill have on risk of heart disease, stroke and overall risk of death? We just don’t know because this latest study does not tell us. There are four previous polypill studies in the literature, and none of them look at these critically important ‘end points’ or ‘outcomes’ either.

The lead author of the latest study is David Wald, son of Professor Sir Nicholas Wald, co-inventor of the polypill. Professor Wald and a colleague (Professor Malcom Law) hold a polypill patent. I suspect they have at least some desire to cash in on their invention. But if they want to do that, why not test the polypill in a way which does not lead to wild speculation but cool hard facts? Perhaps if the polypill was properly studied we’d get to see that, like so many drugs, the ‘expected’ benefits fail to materialise. Maybe it’s better to keep the dream alive with a string of studies and articles that allow rampant speculation and uber-enthusiasm but simply fail to tell us what we really need to know.

References:
1. Wald DS, et al (2012) Randomized Polypill Crossover Trial in People Aged 50 and Over. PLoS ONE 7(7): e41297. doi:10.1371/journal.pone.0041297
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Please read the complete article here.
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Sept 8, 2014 -  An FDA advisory committee looks at a new cardiovascular polypill about which FDA staff expressed serious reservations http://1.usa.gov/1CNj7AM
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Shocking Swedish ‘science’ - Briffa

Shocking Swedish ‘science’

Over the last few years there has been something of a diet revolution going on in Sweden. It appears that increasing numbers of Swedes are eschewing the conventional advice to eat a low fat, high carbohydrate diet, and instead are opting for something altogether lower in carb and higher in fat – the so-called ‘low-carb/high-fat (LCHF) diet. Interest in this way of eating was particularly sparked by Dr Annika Dahlqvist, and more recently has been championed by Dr Andreas Eenfeldt over at dietdoctor.com.

So significant has this shift been, that it’s reported that about a quarter of Swedes have given LCHF a go, and the country has suffered from something of a butter shortage lately.

However, not everyone is happy about this dietary trend. Just this week saw the publication of a study in Nutrition Journal which laments it [1]. The study, conducted by Swedish researchers, assessed trends in food consumption in the north of Sweden, along with weight and cholesterol levels, from 1986 to 2010.

First of all, though, let’s be clear on two things:
1. The data regarding dietary intake was self-reported – something which is known to be fraught with inaccuracy.
2. The data is epidemiological in nature, which means it can never tell us anything more that the associations between things, and certainly not that one thing is causing another.

Anyway, the researchers point our attention to the fact that fat intakes fell from 1986-1992. At this time, by the way, and through the study period as a whole, average weight was climbing. So what does that say, on the face of it, for the effectiveness of low-fat eating for weight control?

But then fat intakes started to rise in 2002 for women and 2004 for men. The concern that comes loud and clear in the paper is that this was paralleled by a rise in cholesterol levels which the authors describe as a ‘deep concern’. However, by their own admission, cholesterol levels didn’t start to climb until 2007. The inference is that increased fat intake led to the rise in cholesterol. But are we really expected to believe that it took 3-5 years for cholesterol to rise in response to an increase in saturated fat intake? That doesn’t seem quite right to me.

Also, while overall fat and saturated fat were increasing, other changes in the diet were occuring too. For example, the Swedes drank progressively more wine, and ate more rice and pasta too. But there is no mention in the study that there is a possibility that these foodstuffs might contribute to changes in cholesterol levels (or weight).

Another problem is that this sort of study is based on averages from a population. We cannot tell, therefore, what’s happening on an individual level. Is it possible, for instance, that those who adopted a LCHF diet lost weight while those who did not gained, overall? We’ll never know. Even if we did, it would not matter much seeing as, as we discussed before, this was a big old epidemiological study anyway, which will really never enlighten us about anything much at all.

And why does any rise in cholesterol matter anyway? Well, in the minds of the researchers, raised cholesterol will inevitably translate into an increased risk of cardiovascular disease.
The authors also cite this evidence:

Evaluations of 14 randomized trials of statins have concluded that a reduction of LDL cholesterol by 1 mmol/L leads to a 12% reduction in all-cause mortality and a 19% reduction in CHD mortality [2]. The suggestion here, if cholesterol-lowering is good, raised cholesterol must be bad.

There’s a couple of problems with this thinking, though. First of all, the study they quote was based on data obtained from studies of cholesterol-lowering drugs (statins). Lowering cholesterol with drugs is not the same as lowering it through diet, and one cannot extrapolate from one to the other.
Secondly, there’s a very good chance, in my opinion, that statins don’t even work through cholesterol reduction. For example, they reduce the risk of stroke, even though cholesterol does not appear to be an important risk factor for stroke. They also appear to reduce the risk of heart disease in people with normal or low cholesterol levels. Further evidence for the fact the statins probably do not work through cholesterol reduction comes from a ton of evidence which shows that many approaches which improve cholesterol do not have broad benefits for health including fibrates, resins, torcetrapib, ezetimibe, hormone replacement therapy and, last but by no means least, dietary change (lower fat or fat modification).

But let’s get back to basics for a moment. Does saturated fat cause cardiovascular disease? Major recent reviews of the evidence suggest not [3-5]. It should be noted that this evidence is epidemiological in nature, so we can’t be certain that saturated fat does not cause problems from this evidence. However, the lack of an association between saturated fat and cardiovascular disease strongly suggests that eating more of it is unlikely to be a problem.

Are the authors aware of this evidence? Maybe, maybe not. What they do is, first of all, cite the deeply flawed work of Ancel Keys. Then they go on to state this:

However, a recent review on the role of fats and fatty acids on human health concluded that the relationship is more complex [6]. Trans fatty acids increase the risk, fish or n-3 long-chain polyunsaturated fats decrease the risk, but the data are conflicting or insufficient to convict or free total fat intake or other fat fractions with respect to CVD risk. Thus, further research is needed, especially focusing on long-term dietary intake.

Notice, absolutely no mention of saturated fat here at all.

And what of the more reliable intervention studies? What happens when individuals adopt a diet lower in fat or change fat consumption in a supposedly healthier direction? Well, a recent huge meta-analysis [7] of this evidence showed:

Reduction of dietary fat, modification of dietary fat, or both did not reduce the risk of death due to cardiovascular disease.

Reduction of dietary fat, modification or dietary fat, or both did not reduce overall risk of death.

The authors of this study report that there was evidence that reduction and/or modification of fat led to a significant reduction in risk of ‘cardiovascular events’ (basically a collection of fatal and non-fatal heart attacks and strokes). However, there’s a couple of things worth bearing in mind here:
First of all, dietary fat change did not lead to a significant reduction in risk of either heart attack or stroke when taken in isolation. Also, some of the studies used in the analysis did not just employ changes in dietary fat, but other strategies too (for example, nutritional supplements were given to the treated group). This obviously makes it impossible to discern what elements of the treatment were effective. Crucially, when such studies were removed from the analysis, overall risk of cardiovascular events was not lowered at all.

In other words, the best available evidence (intervention studies) tells us that modifying our diet in the way that the Swedish authors would us believe is healthy has, in fact, no benefits for health. Of course, the natural logical conclusion to draw from this is that a move to a higher fat diet is not inherently harmful.

Of course you won’t learn any of this from the ‘study’ itself, nor the way it’s been reported. Here’s a typical example. And here’s a quote from the study’s lead author from the article I’ve linked to – Professor Ingegerd Johansson of the University of Umea:

…these results of this Swedish study demonstrate that long-term weight loss is not maintained and that this diet increases blood cholesterol, which has a major impact on risk of cardiovascular disease.

The first idea simply cannot be concluded from this study. And there’s a pile of evidence to suggest that the second assertion is just plain wrong. And this from a professor, no less. Someone needs to give this professor a lesson in science.

References:
1. Johansson I, et al. Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden. Nutrition Journal 2012, 11:40
2. Baigent C, et al: Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005, 366:1267–1278.
3. Mente A, et al. A Systematic Review of the Evidence Supporting a Causal Link Between Dietary Factors and Coronary Heart Disease. Arch Intern Med. 2009;169(7):659-669
4. Siri-Tarino PW, et al. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease Am J Clin Nutr 2010;91(3):535-46
5. Skeaff CM, et al. Dietary fat and coronary heart disease: summary of evidence from prospective and randomised controlled trials. Annals of Nutrition and Metabolism 2009;55:173-201
6. Food and Agriculture Organization of the United Nations (FAO): Fats and fatty acids in human nutrition. Report of an expert consultation. Rome: FAO Food and nutrition paper 91; 2010. ISBN ISBN 978-92-5-106733-8.
7. Hooper L, et al. Reduced or modified dietary fat for preventing cardiovascular disease.
Cochrane Database Syst Rev. 2011 Jul 6;7:CD002137
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Read the full article here.

Statins for healthy people? Hang on a minute…

Statins for healthy people? Hang on a minute…

I’ve had a few emails today alerting me to reports of a study concerning the use of statins in healthy individuals. The study in question is a meta-analysis (grouping together of similar studies) of statin trials [1]. Part of this meta-analysis involved assessing the impact of statin therapy in individuals deemed to be at relatively low risk of cardiovascular events such as heart attacks and strokes. One of the stand-out findings of this study is that statins led to a statistically significant reduction in risk of ‘major vascular events’. This was even true for individuals at less than 10 per cent risk of vascular events over a 5-year period. This has led to the suggestion that statins used might be widened to even people at low risk of cardiovascular problems.

Before we swallow this idea, though, it is perhaps a good idea to see just how effective statins were found to be in this meta-analsysis. First of all, what is meant by ‘major vascular events’? Actually, this is a term that includes many different potential outcomes including fatal and non-fatal heart attacks and strokes and ‘revascularisation’ procedures (such as placing tubes called stents in the coronary arteries). When a lot of different outcomes are grouped together, it makes it much more likely that a ‘statistically significant’ results will emerge.

When the outcomes are narrowed a little, the results are less impressive. For example, when we look at risk of death from any vascular event (a heart attack or stroke), we find that statins did not reduce risk in individuals deemed to be at low risk (<10 per cent over 5 years). This, by the way, was even true for those who had known vascular disease.

The ‘positive’ findings from this study have, as is often the case, been expressed as reductions in relative risk. The risk of vascular events overall was 21 per cent lower for each 1 mmol/l (39 mg/ml) reduction in levels of low density lipoprotein cholesterol (LDL-C). However, when overall risk is low, then a relative risk reduction might not amount to much in real terms.

We’re told by the authors this meta-analysis that treating with statins prevented 11 major vascular events for every 1000 people treated for a period of 5 years. Put another way, 91 people would need to be treated for 5 years to prevent one major vascular event. Or in other words, only about 1 per cent of people treated with statins for 5 years will benefit (and about 99 per cent won’t).

Overall, lowering LDL-C by 1 mmol/l was found to reduce the risk of death by 9 per cent over a 5-year period. Again, this might sound like a positive finding to some, but the actual reduction in risk of death was 0.2 per cent per year. What this means is that at this level of cholesterol reduction, 500 individuals would need to be treated with statins for a year for one person to have his/her life saved.
The authors of this meta-analysis give us some soothing reassurances about the fact that the benefits of statins vastly outweighing the risks of adverse events such as myopapthy (muscle pain and weakness). They quote of the excess incidence of myopathy as 0.5 cases per 1000 people over 5 years. However, the source they quote is based on diagnosing myopathy once the marker for muscle damage (creatine kinase) is at least TEN TIMES the upper limit of normal. Many individuals will have significant pain and weakness with much lower levels of creatine kinase. Statins are also linked with adverse effects on the liver and kidneys, and increase risk of diabetes too.

Despite the very positive interpretation of the data by the study authors and the media, this meta-analysis shows us again what previous evidence has revealed: statins are highly ineffective in terms of improving health and saving lives. And their risks are generally downplayed.

Collectively, the authors of the meta-analysis are referred to as the Cholesterol Treatment Trialists’ (CTT) Collaborators, including researchers from Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University. The conflicts of interest statement which accompanies this paper informs us that: “Some members of the writing committee have received reimbursement of costs to participate in scientific meetings from the pharmaceutical industry.” I suppose this may account, at least in part, for a data interpretation that appears so heavily biased towards statins.

References:
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 epub 17th May 2012
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Read the full atricle here.http://www.drbriffa.com/2012/05/18/statins-for-healthy-people-hang-on-a-minute/

Why statin side effects are likely to be much more common than official statistics suggest

 Why statin side effects are likely to be much more common than official statistics suggest

By : Dr John Briffa

In the UK, the most popular ‘drugs bible’ goes by the name of the British National Formulary (BNF). Within its pages is found a wealth of information about pills and potions that are available over-the-counter and by prescription, including indications and advice of dosages. A significant proportion of the pages in the BNF are taken up with information about contraindications (situations where the drug should be avoided or used with caution) and side-effects. This information is now to be found as part of the packet insert which comes with medication. I’ve known many, many people to read this information and decide that they’ll give the medication a miss.

One class of medication with a range of known side-effects are the statins. These cholesterol-reducing drugs are known to have the potential to cause symptoms such as muscle pain and fatigue, as well as cause damage to organs such as the liver and kidneys. About a year ago I was at a medical lecture, and one (doctor) member of the audience commented that he felt his patients experienced side effects from taking statins far more commonly than official statistics suggested. My own experience supports this observation.

Could there be an explanation for this phenomenon?

One explanation has to do with the design of statin studies. Quite often, individuals who are in poor health and perhaps at increased risk of side-effects are automatically barred from entering a study. Yet, in the real world, even people who are poor candidates in this respect may end up being prescribed a statin. Individuals with a history of problems such as muscular pain or damage to the liver or kidneys (all of which can be exacerbated by statins) are typically excluded from studies too, further reducing the chance that side-effects will arise.

Even those who make it through this screening process, however, may be subjected to what is known as an ‘run in’ period prior to the study. Here, individuals may be treated with a statin with idea being that individuals who are ‘non-compliant’ (do not take their medication as instructed) are weeded out. However, the run-in period also affords the researchers the opportunity to detect individuals who are susceptible to statin side-effects and stop them getting into the study proper.

In other words, in formal studies participants are often at a significantly lower risk of side-effects than those in the general population.

Another problem with conventional studies is how side-effects are defined. Muscle pain is a quite-frequent side-effect of statins. In extreme cases, statins can cause a break-down of muscle tissue known as ‘rhabdomyolysis’ which can have potentially fatal consequences. In some studies, the focus has been on rhabdomyolysis, which means less severe side-effects such as muscle pain or fatigue may ‘go missing’.

Another way in which the bar for side-effects can be set very high concerns the blood parameters used to detect damage. For instance, in a recent study muscle damage was only deemed to have occurred when muscle enzyme levels (a marker for muscle damage) were at least 5 times the upper limit of normal [1]. In this same study, liver damage (another potential hazard of statins) was only deemed to have occurred when liver enzymes were at least 3 times the upper limit of normal. In both cases, a more logical approach would be to regard a rise of any amount above the top end of the normal range as abnormal and significant. This would be more how it is in actual clinical practice.
The elimination of individuals prone to side-effects and the setting of the bar very high for abnormalities help explain why the side-effects from statins seem much more common in the real world than officially quoted statistics.

However, even in the real world, there might be under-recognition of the damage statins can do. That’s because, quite often, doctors will dismiss the idea that statins might be the cause for someone’s symptoms, even when scientific evidence supports such as link. For more on this, see here.

References:
1. Nicholls S, et al. Effect of Two Intensive Statin Regimens on Progression of Coronary Disease. NEJM 2011;365(22):2078-87
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Read the complete article here.

Scientists sometimes shift the scientific goalposts

Dr. John Briffa

Scientists sometimes shift the scientific goalposts

Posted on 10 August 2011

It’s easy to believe that statins have dramatic life-saving properties. The reality is, however, that for the majority of people who take them, they don’t. In the biggest and best review published to date, statins were not found to reduce overall risk of death in individuals with no previous history of cardiovascular disease [1]. What this study shows is that for great majority of people who take statins, the chances of them saving their life are, essentially, nil (just so you know).

Of course, you wouldn’t expect everyone to take this finding lying down. A number of people responded to this study with letters to the journal in which it appeared, attempting to cast doubt on its findings. None of it amounted to much, but I thought I would focus on one response, which in my view demonstrates how some scientists and doctors attempt to shift the scientific goalposts to make their point and suit their ends.

The response came from Drs Gabriel Chodick and Varda Shalev [2]. The main thrust of their objections come in the form of three studies that were included in the review referred to above that they claim have ‘major limitations’. Here’s what they say about each of these studies:

“…their meta-analysis included 3 studies with major limitations: a significant decrement in low-density lipoprotein cholesterol levels over the study period in the placebo arm (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]), old age at therapy initiation (Pravastatin in Elderly Individuals at Risk of Vascular Disease [PROSPER] Study), and incomplete information on low-density lipoprotein cholesterol levels over the follow-up period (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]). All these studies showed negative results; their inclusion would have biased against finding a benefit to statin treatment.”

With regard to the first study, what Drs Chodick and Shalev seem to be saying is that the control group (the group treated with placebo rather than statin) saw natural reductions in cholesterol, so the benefits of taking a statin did not to show up. However, the impact that statins had on cholesterol levels relative to a control group is not important – the only important thing is the impact statins had on health (and, in particular, overall risk of death). This is also true for the last study highlighted by Drs Chodick and Shalev.

As regard the second study, it’s not clear why the advanced years of participants would be a barrier to determining the effectiveness of statins. Actually, the elderly are known to be at particularly high risk of cardiovascular disease, meaning that if anything, this population would, theoretically, be generally most likely to benefit from statin therapy.

In summary: none of Drs Chodick and Shalev’s objections hold any water at all. But they don’t stop there. Here’s the final paragraph from their letter.

“Also, randomized controlled trials are often characterized by limited follow-up periods. Therefore, all-cause mortality benefits may not be apparent in randomized controlled trials among a primary prevention population. It would be informative in this regard to take into account the results of large observational studies with longer follow-up periods to better capture the benefits of statins in primary prevention patients.”

What they’re saying here is that clinical trials don’t go on long enough to detect benefits. It’s better, in their mind, to revert to longer studies that are observational (also known as ‘epidemiological’) in nature. However, such studies look at associations between things, but can never be used to prove the benefits of statins. Only intervention studies can do this.

So, what the authors of this letter are effectively saying is that we should ignore the best evidence we have in favour of quite-useless epidemiological evidence.

One of the authors of this letter is, in fact, an epidemiologist, and really should know better. But then again, both of the authors work for a company that assists drug companies in, among other things, ‘reducing the time to market’ and the writing and submission of scientific articles for publication.

See here for more details. It’s a clear conflict of interest, of course, and perhaps goes some way to explain why they make apparently spurious objections to existing evidence and appear to be calling for an approach that can never really get to the truth.

References:
1. Ray KK, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65 229 participants. Arch Intern Med. 2010;170(12):1024-1031
2. Chodick G, et al. Statins and all-cause mortality in high-risk primary prevention: a second look at the results. Arch Intern Med. 2010;170(22):2041-2
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Read the full article here.