I assume it is every pharmaceutical company’s dream to market a drug that people take for a lifetime to cut the risk of certain diseases or simply to delay the process of aging or prolong life. Indeed statins, drugs that are often used to lower blood cholesterol, have commonly been marketed as such wonder drugs. Although primarily used among people with cardiovascular disease (CVD), from a business perspective it would surely be much more interesting if their use became widespread as a preventive measure among the majority of healthy individuals.
Although scientific evidence supports the use of statin drugs for certain groups of individuals, advertisement and other marketing procedures appear to have facilitated their use among people who probably derive no benefit from their use. Unfortunately, the medical profession has played along in this process, not surprisingly because many doctors believe that these drugs have transformed cardiovascular medicine.
Generally, a physician will receive more critique from his/her colleagues for not treating a patient who may derive benefit from statin therapy than for treating a patient who will likely not benefit. In many countries around the world, about 25-30 percent of adults are taking statin drugs. Although many specialists believe there are a number of high-risk individuals who are not receiving therapy, many low-risk individuals who derive very little benefit are also being treated.
Statins are potent inhibitors of cholesterol biosynthesis and lower the concentration of LDL cholesterol. Most specialists believe that the lowering of LDL-cholesterol matters most when it comes to treating heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. The non-cholesterol lowering effects of statins are often termed their “pleiotropic effect.” Among the pleiotropic effects of statins is an anti-inflammatory effect. It is not known whether the clinical benefits of treatment with statins are due to the reduction of LDL-cholesterol alone, to inflammation inhibition, or to a combination of both processes.
Clinical trials of statin therapy have addressed patients with cardiovascular disease as well as healthy individuals with increased risk for heart disease. The evidence of statins for secondary prevention, such as after a heart attack, is much stronger. Statins significantly reduce the risk of a second heart attack and they lower mortality. The higher the risk of disease the greater the potential benefit for any preventive measure, and the easier it is to measure the benefit in clinical trials.
A meta-analysis published 2012 indicates that statins reduce the risk of vascular events among healthy individuals with a relatively low cardiovascular risk. The authors concluded that “this benefit greatly exceeds any known hazards of statin therapy.” However, another recent meta-analysis shows that statins increase the risk of diabetes and the frequency of abnormal liver function tests. The increased risk of diabetes is about 9%, and it is estimated 250 patients need to be treated with a statin for one case of diabetes to be diagnosed.
I often wonder how to best inform individual patients about the role of statins in cardiovascular prevention. Almost every day I am faced with the decision on whether to treat or not to treat. I also receive a number of e-mails and comments through my website from people who are having a hard time deciding whether they should take statins or not. Unfortunately, I’m only able to answer a fraction of those and usually only in general terms.
Statins for Healthy People
I’m not going to discuss statin treatment for patients who have been diagnosed with cardiovascular disease because the evidence is strongly in favor of treatment. My concern is for the healthy individual who may be prescribed statins for years, risking side effects, and possibly deriving a very small or possibly no benefit.
Deciding whether to prescribe statins in primary prevention is a typical example of when “shared decision making” or “patient centered care” should be employed. Shared decision making is a collaborative process that allows patients and their providers to make health care decisions together, taking into account the best scientific evidence available, as well as the patient’s values and preferences.
Shared decision making honors both the provider’s expert knowledge and the patient’s right to be fully informed of all care options and the potential harms and benefits.
So, to inform individuals on the effects of statin therapy, the physician has to start teaching them about clinical trials. I’m not going to spend to much time on that here, but let me reflect shortly on the issue of “absolute” and “relative ” risk reduction.
Let’s say that a trial on statin therapy among high-risk men randomized to a statin drug or placebo for six years showed that 6 percent in the statin group had a cardiovascular event (heart attack or death of cardiovascular causes), but 9 percent in the placebo group. This is actually what The West of Scotland Coronary Prevention Study (The WOSCOPS trial) showed. The risk of an event is 3 percent less over six years if you take a statin drug compared to if you don’t. This is “absolute” risk reduction. However, 6 percent is 33 percent lower than 9 percent. Thus, “relative” risk reduction is 33 percent. Understandably, this is usually what the pharmaceutical companies highlight in their marketing efforts.
Randomized clinical trials are not perfect. You can tweak the numbers one way or the other, depending on what picture you want to paint. For example, if I were a patient I would like to ask my doctor: “What is the likelihood of escaping an event over six years if I don’t take a statin drug?” According to the above study, the answer is 91 percent. On the other hand, if I take a statin drug for six years the likelihood of escaping an event is 94 percent. Not a big difference, is it? The absolute difference is the same as before, 3 percent.
However, if you are a fan of “relative” risk like the pharmaceutical companies, the likelihood of escaping an event if you take a statin is increased only by 3.3 percent. These are indeed very small numbers keeping in mind that the relative risk of having a statin induced diabetes is 9 percent. So, obviously, it all depends on how the physician presents the available data to the patient.
Is There a Difference Between Men and Women?
The question whether women benefit from statins in primary prevention depends on how the trials are interpreted. In her book, The Truth About Statins, Dr. Barbara Roberts criticizes the use of the term “need for revascularization” as a cardiovascular event in clinical trials.
Most of the statin trials count hard end-points such as nonfatal heart attack and cardiac death. However, many use composite end points that are softer, often including “need for revascularization” which basically is the number of times the patient was referred to bypass surgery or stent treatment. This “need” is usually determined by the person’s physician, not the physician carrying out the study, and there is wide variability in the alacrity with which physicians decide whether or not to refer a patient for revascularization. Dr. Roberts points out that if this end point is omitted from the major trials on statins in primary prevention which have included women, and only hard end points used, there is no significant effect of statins compared with placebo among women.
The Number Needed to Treat (NNT) is often used to describe the efficacy of certain treatments. It is the number of patients you need to treat to prevent one additional bad outcome (death, stroke, etc.). For example, if a drug has an NNT of 5, it means you have to treat five people with the drug to prevent one additional bad outcome.
In their meta-analysis published in JACC (Journal of The American College of Cardiology) 2012, William J Kostis and coworkers concluded that statins are effective among both men and women, in primary as well as secondary prevention. In an accompanying editorial, Dr. Lori Mosca discusses some of the problems associated with addressing the effects of statins in primary prevention by meta-analysis. Firstly, within each primary prevention population, there may be a substantial difference in risk. Secondly, the authors did not have enough data to critically evaluate adverse side effects. Thirdly, concerns have been raised about the long term safety of statins for primary prevention, both in men and women, due to a potential increased risk of incident diabetes. Fourthly, women without CVD have a lower risk for mortality and CVD than men without CVD. Therefore the absolute benefit of statins will typically be less for women than men, suggesting it might be appropriate that women receive statins less frequently than men in the setting of primary prevention.
In October 2012 William J Kostis responded with a letter in JACC providing interesting results from an additional meta-analysis examining absolute risk reduction, where they looked at the primary end-point of the respective studies. For women, the number needed to treat (NNT) over a 4-year period was 148 for primary prevention. In men, the corresponding NNT over a 4-year period was 43.
Thus, looking at the numbers with regards to absolute risk reduction, the difference between men and women is quite striking. In primary prevention, the NNT for women almost four times higher than for men. This confirms the suggestion that it “might be appropriate that women receive statins less frequently than men in the setting of primary prevention.” Furthermore, a recent observation indicated that the risk of diabetes associated with statin therapy might be higher among women than men.
The Bottom Line
Giving unnecessary and potentially harmful treatment to people is bad medical practice. It goes against one of the oldest and most important general rules of medicine, “first do no harm.” Statins are used by about 25 percent of Americans 45 years and older. Between six and seven million people in the UK take statin drugs every day. The widespread use of these drugs is partly due to effective marketing by pharmaceutical companies.
The largest part of those who take statins is healthy individuals. For any therapy with such widespread use, the evidence of efficacy has to be substantial, and the risk of serious side effects has to be close to zero. This is not the case for statin use among healthy people.
However, it is important to keep in mind that among healthy individuals taking statin drugs, there are high-risk individuals who may benefit more than others. The decision on when to treat and not to treat can indeed be quite complex. It is a typical situation where shared decision making should be employed, allowing the patient to have a say in the final decision.