Benefits of statins explored

“Thousands of deaths could be prevented a year if people at risk of heart attack or stroke are prescribed more powerful statins,” the Daily Mail reported. The newspaper said that intensive use of statins lowers cholesterol levels even further than standard therapy, cutting the risk of heart attack and stroke by a further 15%.

The news report is based on a large meta-analysis of recent studies looking at the effectiveness of statins. A major strength is its size, involving data from 170,000 patients in 26 randomised trials, and this indicates that the results are probably reliable. It is important to point out that this research applies only to people at high risk of heart disease and stroke.

Also, while the study looked at the safety of intensive statin therapy, it did not investigate whether it increased the incidence of myopathy - a painful condition that involves muscle weakness and damage, and a recognised side effect of statins. The researchers advise that more intensive cholesterol-lowering therapy should involve combining different types of more potent statins, rather than just increasing the dose of simvastatin, which is most commonly prescribed.

The bottom line is that people who are concerned about the effectiveness of their treatment should consult their doctor, rather than try to increase their dosage themselves.


Where did the story come from?

The newspapers have mainly reported on a meta-analysis published in The Lancet medical journal. BBC News also referred to a randomised trial published in the same journal.

The meta-analysis was carried out by researchers from the University of Oxford and the University of Sydney. It was funded by the UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council and National Heart Foundation. Most of the original trials included in the analysis were funded by the pharmaceutical industry.

Several newspapers and the BBC covered the research. The findings were generally reported accurately but the significance of the results may have been exaggerated.

Headlines from the Daily Mail and Daily Express referred to a ‘new wonder statin’ and a ‘new wonder drug’, which could be misleading as the statins in these trials are already in use. Several sources correctly pointed out that some statins are associated with muscle weakness and damage, and these may not be suitable for prolonged use at high doses. The Telegraph also reported one expert as warning that the results only applied to high-risk individuals.


What kind of research was this?

Previous research has established that statins reduce the risk of adverse events such as coronary death, heart attack and stroke, through lowering levels of low density lipoprotein (LDL) cholesterol (‘bad’ cholesterol).

The researchers say that standard statin regimes (e.g. 20-40mg of simvastatin daily) typically reduce LDL cholesterol by about one-third.

In this study, they wanted to test their theory that larger reductions in LDL cholesterol through more intensive statin treatment would reduce risk even further. They designed their analysis to test the safety and effectiveness of more intensive stain therapy to lower cholesterol further.

This was a meta-analysis, a type of study that uses statistical methods to combine evidence from existing studies to give an overall measure of the effectiveness of an intervention. The advantage of a meta-analysis is that because it looks at several studies, it has higher statistical power and its estimate of effectiveness is likely to be more reliable than the findings of any single study.

However, a meta-analysis is a statistical examination of other clinical studies. Therefore, it is only as good as the studies it includes and if the studies themselves vary too much in their designs it will not be valid to combine their results.


What did the research involve?

The researchers were part of a large consortium of cholesterol researchers and had access to the data from all the eligible trials. The eligible trials they included in their meta-analysis were all randomised controlled trials looking at the effect of statin therapy on lowering LDL cholesterol, up to the end of 2009. The studies had to have at least 1,000 participants and to have carried out treatment for at least two years.

The results were divided into trials that compared different intensities of statin therapy and trials that compared statin therapy with placebo. This resulted in five trials comparing different intensities of statin therapy in a total of 40,000 participants. There were 21 trials comparing statin therapy with placebo, in a total of 130,000 participants.

For each type of trial, the researchers calculated both the average reduction in risk of events such as coronary death heart attack and stroke, and the average risk reduction per 1.0 mmol/L LDL cholesterol, one year after each trial began.

The individual trial results were combined in statistical analyses. The researchers then assessed whether more intensive statin therapy has adverse effects, such as higher risk of cancer. They also tested whether it increased the risk of muscle damage (rhabdomyolosis), a known, rare, side effect of statins.


What were the basic results?

The researchers found that in the five trials of intensive therapy versus standard therapy, more intensive statins produced:

* an overall further reduction of 15% in first major vascular events (95% confidence interval [CI], 11 to 18%)
* a 13% further reduction in coronary death or non-fatal heart attack (95% CI 7 to 19%)
* a 19% further reduction in revascularisation (procedures to improve blood supply to the heart) (95% CI 15 to 24%)
* a 16% further reduction in ischaemic stroke (95% CI 5 to 26%)
* an average further risk reduction (RR) in cholesterol of 0.51mmol/L after one year

These further reductions in risk were similar to the reductions found in the 21 trials comparing statins with a placebo treatment, per 1.0mmol/L reduction in cholesterol. This supports their conclusions that there was a similar reduction in risk however the data was examined. When both types of trial were combined, similar proportional reductions in major events per 1.0mmol/L LDL were found in all types of patients studied, including those with LDL cholesterol lower than 2mmol/L.

Across all 26 trials, deaths from all causes were reduced by 10% for every 1.0 mmol/L reduction in LDL (RR 0.90, 95% CI 0.87 to 0.93), largely reflecting a drop in deaths from cardiac causes.

More intensive statins were not associated with increased deaths due to cancer or other non-cardiac causes or the incidence of cancer at low cholesterol levels.


How did the researchers interpret the results?

The researchers say that more intensive statin therapy leads to further reductions in LDL cholesterol, safely resulting in a lower risk of heart attack and stroke. Each 1.0 mmol/L reduction in cholesterol reduced the annual rate of these events by just over a fifth. They suggest that reducing LDL cholesterol by 2 to 3 mmol/L would reduce risk of heart attack and stroke by 40-50%.

The researchers suggest that these benefits may be achieved with less chance of side effects such as muscle weakness, with the newer more potent statins such as rosuvastatin, or by combining standard doses with other cholesterol-lowering therapies, rather than by increasing doses of generic statins.


Conclusion

This is an important study. It shows that among high-risk patients, lowering LDL cholesterol with high dose statin therapy reduces the risk of adverse outcomes such as heart attack and stroke more than standard statin treatment. The reduction in risk is in direct relation to the reduction in cholesterol levels.

There are some points to note:

* Although this analysis looked at some adverse outcomes, such as cancer and haemorrhagic stroke, it did not compare the incidence of more minor side effects - in particular, muscle weakness - between intensive and standard treatment.
* Of the five trials comparing different intensities of statin therapy, only two had found statistically significant differences between the therapies. However, the researchers say that after looking at the absolute reduction in LDL cholesterol achieved, the results of these five trials are compatible with one another, meaning that they did not consider this a serious limitation.
* The researchers argue that the more potent, more expensive statins might achieve greater reductions in cholesterol with lower rates of side effects compared with generic statins. This point is not directly addressed by this study. This question of which statin is better, if there is one, will need further analysis in direct trials that compare these drugs against each other.

Overall, the benefits of statins are not in dispute for people at high risk of heart disease or stroke and this study supports this. Patients interested in what the ideal level of cholesterol might be (the target for them) should consult their health practitioner as this will depend on their overall level of risk.
Links to the headlines

New wonder statin 'could save thousands' at risk of heart attacks or strokes. Daily Mail, November 9 2010

More potent statins 'could save thousands'. The Daily Telegraph, November 9 2010

Statin increase 'will save lives'. BBC News, November 9 2010

Statin is new wonder drug. Daily Express, November 9 2010
Links to the science

Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. The Lancet, Published Online November 9

Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants n 26 randomised trials. The Lancet 2010, Published Online November 9