A recent Cochrane review of the use of cholesterol-lowering statin drugs in primary prevention has sparked some controversy.  The controversy is not so much over what the data says, but in what conclusions to draw from the data.

Statin drugs have been surrounded by controversy for a number of reasons. On the one hand they demonstrably lower cholesterol, and the evidence has shown that they also reduce the incidence of heart attacks and strokes. The data on whether or not they reduce mortality has been less clear, although this latest data actually supports that claim. However, statins have also been blockbuster drugs for pharmaceutical companies and this has spawned concerns (some might say paranoia) that drug companies are pushing billions of dollars worth of marginally effective drugs onto the public.

So are statins a savior or a scam? Life does not always provide nice clean answers to such simple dichotomies. The evidence clearly shows that statins work and are safe. However, pharmaceutical companies do like to present their data in the best light possible, and they need to be watched closely for this. The recent review does call them on some practices that might tend to exaggerate the utility of statins. Finally, the real question comes down to – where should we draw the line in terms of cost-benefit of a preventive measure like statins.

Let’s look as this recent review of the data to see what it actually shows.

First, for context, this Cochrane review looked specifically at statins for primary prevention – prevention of vascular events (mainly heart attacks, strokes, and overall mortality) in those who are at low risk for heart disease and who have not already had any vascular event. The evidence for statins for secondary prevention, after a heart attack, is more robust – decreasing risk of a second heart attack by about one-third. This makes sense, and is generally what we see. The higher the risk of disease the greater the potential benefit for any preventive measure, and the easier it is to measure this benefit in clinical trials.

Further, as the risk of the disease becomes smaller, the risk-benefit ratio and cost-benefit ratio of preventive measures goes down. At some point the side effects from the treatment become greater than the risk of the disease being prevented. Generally clinical trials divide risk into two broad categories – primary prevention and secondary prevention. However, in reality there is a spectrum of risk. A person without a history of a vascular event may still be at high risk if they have a lot of risk factors – hypertension, age, high cholesterol, diabetes, and smoking. And of course, since statins are cholesterol lowering agents, high cholesterol at baseline is a reasonable marker for the potential of benefit from statins.

Statins also have to be compared to other measures – like diet and exercise – for relative effectiveness and cost-effectiveness. No one doubts that it would be best if every patient had a healthy diet and weight and exercised regularly. Some argue that statins should be reserved for those who fail these lifestyle interventions, or who have genetically high cholesterol refractory to diet and exercise. The reality is that it is very difficult to get individual patients to change their behavior. In fact, a recent Cochrane review concluded:

Interventions using counselling and education aimed at behaviour change do not reduce total or CHD mortality or clinical events in general populations but may be effective in reducing mortality in high-risk hypertensive and diabetic populations. Risk factor declines were modest but owing to marked unexplained heterogeneity between trials, the pooled estimates are of dubious validity. Evidence suggests that health promotion interventions have limited use in general populations.

This is not very encouraging. Clearly we need to work on societal interventions and improving patient interventions to achieve a healthier lifestyle as a society. But also it is clear that lifestyle intervention is not a quick or easy fix, and so there will continue to be a role for medical intervention in vascular prevention.

Statins for Primary Prevention

When the Cochrane reviewers looked at the evidence for primary prevention they found that many trials included patients at high risk, or did not measure LDL levels. Essentially they felt that the data was contaminated in such a way as to exaggerate the benefit for primary prevention. Their review sought to correct those biases. They reviewed the data from 14 trials involving 34 272 patients. What they found was that total mortality had a relative risk reduction of 17%, risk of heart attacks was reduced by 28%, and strokes by 22%. In low risk patients the number needed to treat in order to prevent one death per year was 1000. The review also did not show any additional adverse events in those treated vs placebo groups.

The authors do not challenge the legitimacy of these results. The data is fairly robust – there is a reduction in risk of death and vascular events from statins in primary prevention. Study author, Dr. Shah Ebrahim, is quoted by Heartwire as saying:

“If you look at the hard end points of all deaths and coronary deaths, the effects are consistent with both benefit and with the play of chance. But importantly, the absolute benefits are really rather small—1000 people have to be treated for one year to prevent one death. It is probably a real effect, but it means a lot of people have to be treated to gain this small benefit. As we don’t know the harms, it seems wrong-minded to me to treat everyone with a statin. In these circumstances, lifestyle changes and stopping smoking would be far preferable.”

And that is where the controversy comes in. Other researchers think the authors are making conclusions that go beyond their own evidence. Heartwire also quoted Dr. Colin Baigent, a clinical researcher from Oxford, as saying:

“I object to the conclusions they have drawn from their review. They say there is not good evidence of benefit, but their own data show significant reductions in deaths and cardiac events. They didn’t show any increase in adverse events in their review, but they then say the benefit is not worth the risk. That doesn’t make sense.”

This does make for an interesting science-based medicine conversation. In this case the two sides largely agree on the data, but differ in terms of how to apply that data to the practice of medicine. This, I feel, can be a very constructive controversy. This is exactly the kind of question that should be agonized over by experts. While I think the Cochrane reviewers are displaying a negative bias against statins, they do provide balance to the pro-statin bias of pharmaceutical companies who sell statins. In the end, the data is out there and practitioners and patients will be better informed in making decisions about statin use. I am concerned about media reporting of this issue. It is easy to oversimplify the take-home message as “statins do not work” and I have already read commentaries quoting this study to support that position.

My read of this evidence is that there is solid evidence that statins have a real benefit for primary prevention. This benefit is small, which is exactly what I would predict for a preventive measure in a low-risk population. The data also show that statins are safe. The major risk is for the development of an inflammatory muscle disease, but that is very rare. For interventions that prevent death – that lower mortality – I think even small benefits are worthwhile. Further, having a heart attack or stroke, even if it is not a fatal event, has a very negative effect on quality of life. Taken together, one person per year out of several hundred taking statins for primary prevention will avoid a heart attack, stroke, or death. From a purely medical point of view, that sound pretty good to me.

What seems reasonable is to use statins for primary prevention in those who have some risk factors for vascular disease, in patients with genetically high cholesterol, and in those with high cholesterol or significant risk factors in whom lifestyle counseling has not yielded adequate results. Try diet and exercise first – and always in conjunction with medication, but statins are a reasonable choice in selected patients, even for primary prevention. We could use more studies to better delineate where to draw that line, but that will be difficult as any difference in outcome is likely to be slight and therefore massive trials will be needed to get statistically significant results.

Cost effectiveness is a tougher issue, because we then have to arbitrarily decide what a human life is worth in terms of medical expense. This issue has become more acute as health-care costs rise and everyone is looking for ways to cut back. What I have not seen is a calculation of the cost of statins for primary prevention vs the cost savings from reduced vascular events. Having a stroke or heart attack is expensive, and pays for a lot of prevention. The question is – exactly where is the line crossed in terms of the vascular risks of the population being treated.

The good news is that many statins are now becoming available as generics, with a marked reduction in cost. There is already a Spanish analysis showing that the availability of generics is making statin treatment more cost effective.

Conclusion

This recent Cochrane review of statin use for primary prevention supports the conclusion that statins are safe and effective in reducing vascular events and overall mortality even in primary prevention. The benefits are statistically small, which is expected for a preventive measure in a low risk population. It is still unclear where to draw the line in terms of which patients should receive statins, but these data will help practitioners and patients make individualized decisions about cholesterol management and vascular prophylaxis.

Because this is ultimately a judgment call, the results of this study can be spun to a variety of conclusions. The study authors chose to present an overall negative conclusion – that the effect size is too small to be worth it. While other experts, looking at the same data, have come to the opposite conclusion – that statins are worth it. It is important to emphasize that the debate is not about whether or not statins have a real effect – they do, but about the cost-benefit of statins as an intervention for primary prevention.

One could also argue that Cochrane reviewers, given that their purpose is to provide objective and thorough reviews of existing evidence for specific clinical questions, should take a more neutral approach to interpreting the data. This is not the first Cochrane review discussed on SBM that can be criticized for taking a decidedly biased approach to the evidence in their conclusions. This should prompt some soul-searching, in my opinion, on the pat of the Cochrane collaboration.