Wednesday January 19 2011
The benefits of statins do not outweigh the risks for everyone
“Up to three million people are taking statins needlessly,” says The Daily Telegraph. It reports that a comprehensive study suggests statins are “ineffective in many cases and could be doing more harm than good”.
The news story is based on a review of trials of statins in people who had not (yet) suffered a cardiovascular event such as a heart attack or stroke. There was some evidence that statins reduced the risk of dying from any cause, and the risk of any cardiovascular outcome. However, the trials and review have several limitations, including some indications that adverse events within the trials were not recorded.
It is important to point out that the benefit of statins in people with cardiovascular disease, who have already suffered a heart attack or stroke, or who are considered to be at high risk of an event, is not in question here.
This review supports the need for careful consideration of the overall cardiovascular risk of the individual when deciding whether to prescribe a statin. In higher-risk populations, the benefits of a drug often clearly outweigh the risks. However, when lower-risk populations are considered, this balance can often tip the other way. The results here do not support the widespread use of statins in people at low risk of cardiovascular events.
Where did the story come from?
The news reports follow a Cochrane systematic review conducted by researchers from the London School of Hygiene and Tropical Medicine and the University of Bristol.
The main conclusion of this review is that there is a lack of quality evidence to support the use of statins in people with low cardiovascular risk. This has been generally reflected in the articles by The Daily Telegraph, the Daily Mirror and the Daily Express. However, the Daily Mail’s headline (“Statins 'may cause loss of memory and depression'”) is incorrect. The researchers’ main concern is that there is not enough reporting of adverse events, not that there is evidence for any particular harm.
What kind of research was this?
This Cochrane systematic review and meta-analysis investigated whether statins lower blood cholesterol, thereby reducing cardiovascular risk in people without a history of coronary heart disease (known as “primary prevention”). There is already clear evidence of their benefit in people who have already suffered a heart attack or stroke (known as “secondary prevention”).
A high quality systematic review that searches the medical literature to identify all relevant randomised controlled trials of a particular intervention is the most reliable method of assessing the evidence of its safety and effectiveness. Systematic reviews do have some inherent limitations, in that they rely on individual studies with varied quality, methods, outcomes and follow-up.
What did the research involve?
The researchers searched medical databases for all randomised controlled trials of at least 12 months of statin treatment compared with placebo or usual care, with at least another six months follow-up. To be eligible, trials had to have focused mainly on primary prevention, with less than 10% of the participants having a history of cardiovascular disease. Trials that also investigated other drug treatments were allowed if both the experimental group and control groups took them. The main outcomes that the researchers were interested in were:
- death from any cause
- fatal or non-fatal cardiovascular events
- fatal or non-fatal heart attack or stroke
Secondary outcomes of interest were changes in blood cholesterol, need for revascularisation procedures, adverse effects and quality of life effects. The individual trials were assessed for quality and risk of bias and the trial results were combined, taking into account the variability between study populations, interventions and follow-up (heterogeneity).
What were the basic results?
Fourteen randomised controlled trials met the inclusion criteria. These were in a total 34,272 people who had been followed for between one and five years, equating to 113,000 patient-years of follow-up. The average age of the participants was 57 and 66% were male. The trials were dated 1994-2006 and conducted mostly in Europe, the USA and Japan.
Eleven trials recruited patients with specific conditions that put them at higher cardiovascular risk. In eight of the trials this was raised blood lipids (fat levels), but others included populations with diabetes or hypertension. All trials tested the effectiveness of a statin compared with placebo, of which the most common statin used was pravastatin 10-40mg per day (the drug used in nine trials). Five trials also included advice, counselling or information on lifestyle behaviour, such as smoking cessation, diet and exercise.
Overall, eight trials reported data on death from any cause. A total of 2.8% of the overall study population in these eight trials died during follow-up. Risk of death from any cause was reduced by about 17% (relative risk 0.83, 95% CI 0.73 to 0.95) by statins.
Three large trials demonstrated that statins reduced the risk of any fatal or non-fatal cardiovascular event (relative risk 0.70, 95% CI 0.61 to 0.79).
Regarding secondary outcomes, there was evidence that statins reduced the need for revascularisation interventions (RR 0.66, 95% CI 0.53 to 0.83). Cholesterol levels reduced in all trials, but the studies were too different to allow the results to be combined for this outcome, mostly because of different statins and doses across the studies.
There was no evidence of any significant harm caused by statins, with no difference in rate in the statin and placebo groups, though the trials had all variously reported adverse effects (ranging from cancer to muscle pain). There was no reliable data to allow assessment of the effect on individuals’ quality of life.
How did the researchers interpret the results?
The researchers conclude that statins reduced death from any cause, any cardiovascular event and the need for revascularisation. There was also no evidence that adverse events increased with statins. However, they caution that there is also evidence of “selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease”. More details of these are given in the conclusion.
The researchers say that when these things are considered together, there is only “limited evidence” that primary cardiovascular prevention with statins is cost-effective and improves quality of life. They advise caution in the prescription of statins for people who are at low cardiovascular risk.
This review examined the use of a statin for primary prevention in people who have not yet suffered a cardiovascular event, and whose risk of having one varied considerably. It is important to point out that the benefits of statins in people with established cardiovascular disease and who have already suffered a heart attack or stroke, or who are considered to be at high risk of suffering a cardiovascular event, is not in question.
In high-risk populations, the benefits of a drug that prevents disease often clearly outweigh the risks (such as side effects on health and quality of life). However, in lower-risk populations, this balance often begins to tip the other way and the size of the drug’s benefits compared to its harms can become negligible. This is particularly the case with drugs such as statins, where a relatively large proportion of the population are at low cardiovascular risk, some with raised cholesterol but having no other risk factors. There are also feasibility and cost issues to consider when giving a drug to such a potentially large population.
Although there was some evidence of a reduction in death from any cause, any cardiovascular outcome, and need for revascularisation with no increased risk of adverse events, the researchers acknowledge several limitations to this review and the trials within it. These included:
- The small number of individual cardiovascular events (e.g. stroke or heart attack) that actually occurred during the trials. When separate disease outcomes are quite rare, researchers in the individual trials often compensate for this by instead recording the occurrence of any one of a defined set of outcomes (e.g. all strokes, all heart attacks, all cases of peripheral arterial disease that occurred within the trial, combined all together in one endpoint). The trial then has better ‘power’ to calculate the risk of this ‘composite endpoint’ in the intervention group compared with the control group, than it would have for examining the risk of a single outcome, such as a heart attack. Some of the trials did not even report the numbers that experienced outcomes individually and only reported the numbers with the composite outcome. Therefore it is difficult for the reviewers to gain an accurate picture of whether or not taking a statin has any effect on the person’s risk of suffering a heart attack, or suffering a stroke, as individual disease outcomes.
- Some of the trials included people with previous cardiovascular events (i.e. it was not a pure primary prevention population). The researchers only included new studies that had less than 10% secondary prevention populations, but they also included data from previous systematic reviews in their current review, some of which may not have been so stringent in which studies they analysed.
- It is possible that some of the trials suffered from selective reporting of outcomes, particularly adverse events. The researchers point out that eight of the trials did not report adverse effects at all.
- Two of the large trials were stopped early due to an observation of benefit in the statin arm. This may lead to an overestimation of the treatment effect.
- As the researchers indicate, all but one trial had received funding from the pharmaceutical industry, which may potentially allow for biased reporting.
- The trials included predominantly white, middle-aged populations. Their results may not be applicable to people outside of these groups.
Overall, this review supports the need for careful consideration of the overall cardiovascular risk profile of the individual when deciding whether to prescribe a statin. As the authors of this review conclude, the evidence does not support the widespread use of statins in people at low risk of a cardiovascular event (expected annual risk of death from any cause below 1%, or expected annual risk of any cardiovascular event below 2%).
The findings of the review also highlight the need for further quality trials when statins are used in primary prevention populations, which give full reporting of outcomes.