'Conclusive' Proof Statins Are Safe and Effective

A recent study published in The Lancet has been reported (by the journal) as providing conclusive proof that statins are safe and effective in the long-term. The Lancet also produced a podcast on their website and published a commentary to accompany the study.

The results of this study, along with the associated podcast and commentary have been presented in a way that is extremely favourable to statins. However, there is an obvious fundamental flaw with this study that, in my opinion, has not been adequately discussed.

The new study relates to a follow-up of the Heart Protection Study (HPS), which was a statin clinical trial that ran for just over 5 years. At the end of this study the researchers continued to monitor the participants for a further 5 years. 

During the follow-up period, increasing numbers of people who were in the original placebo group started to take a statin. By the end of the study, the number of people taking a statin in each group was the same. 

The table below shows how many people (as a percentage) were taking a statin in each group.

 

Obviously, the study was no longer comparing a statin against a placebo – it was comparing statins against statins. Just to make it even more confusing; we do not even know which statin people took during the follow-up period and at what dosage.

This did not stop the researchers describing the results of this study as definitive evidence in favour of statins. 

Most doctors who prescribe statins will not have the time to read the full study and will have to rely on the summary and the podcast. This will leave them with an interpretation of these results that is heavily skewed in favour of statins.  

As far as I am concerned, the fact that just as many people in the placebo group took a statin is enough to nullify this study. However, there are several additional issues. 

All of the people included in this study are categorised as having very high risk. Almost half had already had a heart attack, and everyone else had either other forms of cardiovascular disease or conditions that would place them at high risk.  All of the evidence from statin clinical trials has consistently shown that any 'benefit' varies greatly according to the level of risk the trial participants have. Therefore, if any statin benefits were found during this study, it is simply unthinkable to try and extrapolate this to the general population or the majority of people who take statins.

In addition, the study report and commentary describe the results in terms of relative percentages. This is a very common problem with statin clinical trials. The relative percentage is meaningless to patients and it grossly exaggerates any suggested 'benefit'. For example, in terms of vascular related deaths a risk reduction of 18% is quoted for the initial trial period. However, the real risk reduction in absolute terms was 1.7%. 

Incidently, this 1.7% risk reduction in vascular related deaths reduced to 0.1% during the follow-up period. Therefore, there is not any real evidence to support the claim that the 'benefits' of statins increase if a person starts taking the statin earlier in life. 

It is also worth mentioning that statins have a wide range of adverse effects (some very serious) that were not included in this study. 

References:

Reuters: Cholesterol drugs safe, even after a decade of use. 23 November 2011

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002; 360:7-22

Heart Protection Study Collaborative Group. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20 536 high-risk individuals: a randomised controlled trial. ; published online Nov 23.

Kohli, P and Cannon, CP Statins and safety: can we finally be reassured?Lancet 2011;  published online Nov 23

At Last, the Tide has Turned!

Statins have been in the media a lot again this week and finally at least some of the facts are starting to get out. It has all been prompted by a review conducted by the Cochrane Collaboration. This review concluded that for many people who take statins, the risks for adverse effects outweigh any benefits.

This will be of no surprise to anyone who has looked into this subject, and the media reports do not go far enough, but at least some of the issues regarding statins are now starting to reach the general public.

The news reports do not go far enough because they still suggest that cholesterol is a risk factor for heart disease. After all this time it still absolutely amazes me that so many doctors have not bothered to take even the most casual look at the evidence.

British Heart Foundation Continues to Support Statins

Here is the latest headline from the British Heart Foundation (BHF):

“Research by BHF-funded scientists has shown that when it comes to cholesterol, ‘lower seems to be better’ for protecting us against heart attacks... The researchers looked at the effects of increasing the dosage of statins, a medicine that reduces cholesterol. They showed that a bigger drop in cholesterol – from more intensive treatment with statins – cut risks even more.”

This refers to a study just released in the Lancet. This study, and the media hype that the BHF have created about it, is nothing more than an attempt to confuse and mislead people.

If you read the headlines and the summary report you could certainly be forgiven for thinking that statins are wonder drugs and cholesterol really is humanity’s nemesis. This study did indeed find a reduction in heart attacks associated with more intensive use of statin drugs. However, there are at least four major reasons why the results are misleading.

The first reason is that the reduction in risk quoted in the interpretation of the study refers to a reduction in LDL cholesterol that is not normally seen in real life. This exaggerates the perceived benefits.

The interpretation refers to reductions in LDL levels of 2-3 mmol/l. The authors state that this reduction in LDL cholesterol would reduce the risk of a vascular event (such as a heart attack) by 40-50 percent.

Well, LDL cholesterol is typically around 2-3 mmol/l anyway, so the suggestion that it could be reduced by 2-3 mmol/l is nonsense – most people would have to be clinically dead to achieve this drastic reduction. So, the suggested risk reduction is completely academic and for most people could never happen.

The second reason is that, as usual, relative percentages are used instead of absolute percentages. This problem is ubiquitous in statin clinical trials and I have commented on it many times before. The risk reductions of 40-50 percent are relative percentages, which can only mislead people. In real terms, the percentages come down to single digits or less.

The third reason is that, as usual, the issue of deaths from all causes is not addressed. Statins can reduce the risk of suffering a heart attack or other cardiovascular event, but at the same time, these drugs can also increase the risk of dying from other causes, and overall, there is usually no net benefit.

There is not much point in taking an expensive medication if the risk for one disease is reduced at the cost of increasing the risk for another disease within the same time period.

I called the BHF today and asked them for the data concerning deaths from all causes. The press office said they didn't know, but they did kindly send me the full report for the study.

In this trial, the risk of dying from any cause was reduced from 2.3 percent to 2.1 percent. So, in real terms, the benefit of more intensive statin use equates to a risk reduction of just 0.2 percent.

But even this meagre 0.2 percent risk reduction may not be experienced by real people who take statins. This issue relates to the fourth problem with this study.

The forth reason why the results are misleading is that the analysis did not distinguish between people at a lower risk for a heart attack and people at a higher risk.

Around 7 million people are taking statins in England alone, and in America it is estimated that more than 20 million people may be taking them. The vast majority of these people are taking statins for primary prevention. This means that they do not have cardiovascular disease but are given the medications in the hope of preventing future disease.

To date, there is no convincing evidence that statins provide any net benefit to people when they are taken for primary prevention - they do not reduce the overall death rate. This was the conclusion of the latest analysis in the Archives of Internal Medicine.

The analysis that the BHF are supporting includes data from higher risk groups - the results do not represent the majority of people who currently take a statin.

Medical Director of the British Heart Foundation Supports Cholesterol Hypothesis

Yesterday there was an article in the Daily Mail newspaper titled Statins: Should You Be Taking Them?

Professor Peter Weissberg attempts to present a case for the use of statins. Professor Weissberg is the medical director of the British Heart Foundation.

The first thing to notice about Professor Weissberg’s comments is that he avoids mentioning any actual data for the benefit of cholesterol-lowering statins.

There are numerous comments made by Weissberg that I would take issue with. For instance, he states that the average cholesterol level in the UK is:

 “high compared to, say, China, where it is 3.2mmol/l and where there are significantly fewer cases of heart disease”

While this comment about China is correct, it should be looked at in the context of other data published by the British Heart Foundation.

 

For example, the average cholesterol level for women in the U.K. is the 12th lowest on a scale of 45 countries. A similar pattern is found for men in the U.K., who are the 15th lowest on the same scale of 45 countries. Despite this, the U.K. of course has one of the highest rates of heart attacks in the world.

Cholesterol levels in the UK have been declining for some time. For example, between 1994 and 2006 the percentage of men aged 65 to 74 with ”high” cholesterol decreased from 87 percent to 54 percent. Despite this, the rate of coronary heart disease for this age group stayed about the same. Other age groups have experienced an increase in the rate of heart disease as the number of people with “high” cholesterol has decreased.

Ticino in Switzerland has the highest cholesterol level of all regions studied in the World Health Organisation MONICA project. The region has the highest percentage of men with cholesterol levels above 7.8mmol/l. They eat more saturated fat than men in the U.K. Yet they have one of the lowest rates of heart attacks. 

Men in Moscow, have one of the lowest rates of high cholesterol, but they have a much higher rate of heart attacks than men in Ticino. 

Men in Glasgow, U.K. have lower cholesterol levels than men in Ticino, but their rate of heart attacks is more than two and half times greater. 

All of this data is published by the British Heart Foundation and is available from their statistics website www.heartstats.org. 

Some time ago the British Heart Foundation published a booklet about lowering cholesterol. This booklet contained a diagram showing that 46 percent of people in the U.K. who had died of heart disease had 'high' cholesterol. Of course, this means that more than half of the people who die of heart disease do not have “high” cholesterol: they have low cholesterol.

Ever Wondered Why Statin Drug Trials Are Stopped Early?

All clinical trails involving cholesterol-lowering statin drugs have been relatively short in duration. Usually they run for about 5 years and sometimes only for 2 years. There are no published trials to show the long-term effects of statins, however, patients are being asked to take statins for several decades. 

This may seem slightly trivial, but it really isn't. How long a drug is consumed can have a significant effect on the risk/benefit balance. Especially where statins are concerned – since any benefit of statins already hangs by a thread. 

Some adverse effects of statins can occur quickly (like muscle aches and pains) and others (like diabetes) may take longer to develop. The full extent of the adverse effects associated with statins is not seen in just 5 years – it would take much longer to see the full effects.

So, drug companies can effectively choose the duration of the trial that will show their drugs in the best possible light. Drug companies also have a history of not publishing studies that show their drugs to be ineffective or harmfull – well lets face it, they are a business at the end of the day, with immense pressures to increase profits for shareholders.

The fact that no longer-term studies have been published on statins should make us very concerned. At the very least, our health authorities (who are supposed to protect us) should be asking for at least one long-term trial. We know that money is not an issue, because the drug companies keep doing more and more relatively short trials. Instead of this repetition we could have a longer trial that might tell us something new. 

In 2008, the results of the JUPITER trial were published. This trial attracted a lot of media attention around the world and I have commented on it several times before. In summary, the statin used only managed to reduce deaths from all causes by a mere 0.55 percent (despite the nonsensical relative percentages that the drug company put out to the media to exaggerate the results).

One of the many interesting aspects of the JUPITER trial is that it was stopped early. It was stopped after just 1.9 years. 

I have always suspected that this trial was stopped early because if it was allowed to continue even the miniscule 0.55 percent benefit would disappear.

A few days ago, a study was published in the Journal of the American Medical Association (JAMA), that looked at the effects of stopping trials early. This study found that trials stopped early almost always show much better results for the drug being tested than if the trial was allowed to run its full duration. 

In fact, the JAMA study showed that any drug benefits may be doubled by stopping the trial early. This means that the 0.55 percent reduction in deaths found in the JUPITER trial would have almost completely disappeared if the trial was allowed to run its full course.

The statin used in the JUPITER trial caused more people to develop diabetes, and all statins cause a long list of other adverse effects (some of which result in permanent damage). Knowing this, was it wise for the FDA to approve the wider use of statins based on the results of the JUPITER trial?

References:   

Bassler, D et al. randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010; 303(12):1180-7

Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine 2008; 359:2195–2207