“Doctor, should I take a cholesterol lowering drug?” Although it sounds simple, it is one of the most difficult questions I face in my office. “What are the risks?” “What are the side effects?” Will I have to take it for the rest of my life? Patients are often anxious to know the right answers. These are important issues. And, generally, they don’t get a simple answer. They get a speech.
People are usually not keen on taking drugs if they feel well. Although the title of this blog refers to a patient who is wondering whether a drug might help him, a more common situation would be a patient who is reluctant to take a drug. “Doctor, do you really think I need to take a medication to lower my cholesterol? Aren’t there other ways to lower it? ”
Lately, more and more people are saying: “No I don’t want to take a drug to lower my cholesterol. I’ve heard that they are useless. Besides, I read on the internet that cholesterol does not cause heart disease. They say it’s all a big lie.”
Let me start by trying to simplify the issue a bit. For patients with a history of heart attack or myocardial infarction (MI), coronary artery disease (CAD) or stroke, there is very strong evidence that treatment with a statin drug reduces the risk of death and new cardiovascular events. Studies also show that patients with diabetes benefit from statin therapy. So, often, the decision is not very difficult. Clinical guidelines are very clear on this. These patients should be treated with statins because the evidence for their benefit in secondary prevention is very strong.
Having said that, how about healthy people with no history of cardiovascular disease or diabetes. Should they take statin drugs if their blood cholesterol is high? Or, let me rephrase the question; Should they take statins, even if their cholesterol is normal? According to recent news headlines they should. And, not only if their cholesterol is high, but if their general risk for heart disease is elevated.
These recommendations are based on findings from a recent metaanalysis of 27 trials involving 175,000 people, some of whom were at low risk of heart problems. The study, recently published in The Lancet, received a lot of attention because the results show that a huge part of the population may benefit from statin therapy. The researchers said the positives greatly exceeded any side-effects from taking the drugs, such as muscle weakness, diabetes and depression.
Borislava Mihaylova, of the University of Oxford, lead author of the study, said: “In the UK, current practice is generally to give people a statin only if they have had or are considered to be at “high risk” of having a heart attack or a stroke. This study shows that the benefits of statins extend to a much lower-risk group of people than previously thought.”
Professor Colin Baigent, from the Medical Research Council, said: “It is not just about treating raised cholesterol after middle-age. The benefits of statins in people who are currently healthy, but are for some reason at increased risk of a heart attack or stroke, are substantial, and much greater than any of the known risks. People who are at increased risk, perhaps because they are overweight, or smoke, or have high blood pressure, would be better off with lower cholesterol, even if their cholesterol is not considered to be particularly high.”
Professor Baigent believes the routine use of statins would lead to 10,000 fewer heart attacks and strokes a year, including 2,000 fewer deaths in the UK. The small cost of the drugs would be outweighed by NHS savings due to the reduced number of heart attacks and strokes.
The scientists say the imminent revision of NHS guidelines on the use of statins should be used to widen those eligible for routine therapy. At present, statins are restricted to those with at least a 20 percent risk of having a heart attack or stroke over the next ten years. However, a commentary in the Lancet says most over-50s are likely to be at higher risk of cardiovascular disease, and so it would be ‘pragmatic’ to use age to prescribe statins instead of costly medical tests.
This all sounds quite simple and really fantastic. By taking one tablet a day, a huge number of the population may be able to reduce their risk of heart attack and stroke. From a health-economic viewpoint this is also great because, according to the statistics, fewer heart attacks will save tax payers money. Almost to good to be true!
But, could there be a downside to all this. So far, muscle pain, has been the most commonly reported side effect of statin therapy. Other uncommon side effects are muscle damage, liver damage, digestive problems, rash or flushing. Recently, however, other side effects have been highlighted. Thus, statin therapy has been associated with the risk of developing diabetes and neurological side effects such as memory loss and confusion. The possible association between statin use and the onset of diabetes mellitus is definitely of concern as recently pointed out by Professor Eric Topol from San Diego, California.
A recently published randomized study indicates that the side effects of statin therapy may be more common than previously thought. The study enrolled 1016 subjects (692 men; 324 women) with LDL levels of 115 to 190 mg/dL and no cardiovascular disease or diabetes who were randomized to two well known statin drugs, or placebo for six months. The results showed a significant adverse effect on energy and fatigue with exertion associated with statin use, which was more common in women than men. The authors also point out that there was a significant relation between the reduced energy reported and actual activity, which could in turn lead to an increase in cardiovascular clinical events.
“These findings are important, given the central relevance of energy and functional status to well-being,” the authors write. They add: “These effects, germane to quality of life, merit consideration when prescribing or contemplating use of statins, particularly in groups without expected net morbidity/mortality benefit, extending to ‘high-risk’ primary prevention and women and elderly persons (including those with coronary artery disease).”
The paper’s first author, Golomb commented: “Statins are fine in patient populations where a mortality benefit has been shown—ie, men under 70 with heart disease or primary-prevention patients with raised C-reactive protein (CRP) or who smoke. But I would think twice for other groups. Primary-prevention patients who don’t smoke or don’t have raised CRP are far more likely to experience an adverse effect than to have a cardiac event. “She estimated that fatigue could affect between 20% and 40% of patients taking statins. “Observational data suggest the effect tracks with the potency of the agent, so it may be more of an issue with the newer, more potent statins,” she added.
Cholesterol lowering drugs in primary prevention – A closer look at the scientific data
Epidemiologic studies have found a graded relationship between the total cholesterol concentration and coronary risk. This relationship is much stronger for individuals with known coronary heart disease (CHD) than those without manifestations of such disease. Data from Pekannen, J, Linn, S, Heiss, G, et al, N Engl J Med 1990; 322:1700
According to the lipid hypothesis, lowering of blood cholesterol will reduce the risk of cardiovascular disease. Let’s take a closer look at the scientific data that have tested this hypothesis. If you don’t like all the details, you can jump to the final chapter of this article.
Effects of diet and lifestyle. Lifestyle modifications may reduce levels of LDL-cholesterol (LDL-C). However, no studies have shown that this translates into less risk of heart disease or death. The Multiple Risk Factor Intervention Trial (MRFIT) studied 12,866 high-risk men. An intervention that included dietary advice to reduce cholesterol levels did not significantly reduce mortality due to cardiovascular disease nor all-cause mortality.
Drug treatment.The first trials with cholesterol lowering drugs in primary prevention were performed in the late seventies and early eighties, before the so-called statin era. Some of them showed significant reductions in cardiovascular events although there was not a significant effect on mortality. However, there was a disturbing increase in mortality due to other reasons than heart disease among patients receiving active drug therapy. The higher death rate from noncardiac causes raised a concern regarding the safety of cholesterol-lowering therapy, particularly in a relatively low-risk population.
The West of Scotland Coronary Prevention Study (The WOSCOPS trial) was published in 1995. It was designed to evaluate the effect of pravastatin (40 mg/day) for five years on the rate of MI and death due to CHD in 6.595 men with elevated cholesterol, but no prior history of heart disease. These were the main criteria for inclusion of patients
- Men aged 45 to 64 years.
- Total cholesterol concentration above 252 mg/dL (6.5 mmol/L) on initial screening.
- LDL -C above 155 mg/dL (4.0 mmol/L) on visits two and three and above 174 mg/dL (4.5 mmol/L) but below 232 mg/dL (6.0 mmol/L) on one occasion after dietary therapy for four weeks.
The results, based upon intention to treat principles, can be summarized as follows:
- Nonfatal heart attack or death due to CHD — 31 percent relative risk reduction (p<0.001).
- Nonfatal MI — 31 percent risk relative risk reduction (p<0.001).
- All cardiovascular deaths — 32 percent relative risk reduction (p = 0.033).
- Total mortality — 22 percent relative risk reduction (p = 0.051).
The reduction in nonfatal MI or CHD death was from approximately 9.4 to 6.4 percent at six years. Thus, the absolute benefit was 3 percent, ie, for every 100 patients treated, three did not have a coronary event at six years. In addition, it was estimated that the number needed to treat to prevent one death over five years was 146 patients. Another important observation was that, in contrast to the earlier primary prevention trials, there was no difference in noncardiovascular death.
These observations were extended in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which showed that lovastatin reduced the incidence of a first major coronary event in low-risk men and women without clinical evidence of cardiovascular disease and LDL-C levels near the average for the general population. For every 1000 men and women treated with lovastatin for five years, 19 major coronary events, 12 myocardial infarctions, and 17 coronary revascularizations could be prevented. No effect was seen on all-cause mortality. The total absolute benefit was approximately 2 percent, meaning that 50 patients had to be treated for five years to prevent one event.
Similar results were seen in the ASCOT-LLA, which studied atorvastatin (10 mg) in men and women with relatively normal serum cholesterol levels but with high blood pressure and at least three additional cardiac risk factors.Patients with diabetes appeared to receive less benefit from atorvasatin than patients without diabetes. This result contrasts with findings in the AFCAPS/TexCAPS trial and several secondary prevention trials.
The JUPITER trial of rosuvastatin 20 mg daily in healthy adult men and women with elevated C-reactive protein levels (hs-CRP) and LDL-C levels below 130 mg/dL (3.4 mmol/L) found a marked reduction in the primary endpoint of first major cardiovascular events and for all-cause mortality. This trial was stopped early for benefit which may exaggerate the true level of benefit, particularly for the primary endpoint. This study received huge attention due to the fact that the population selected did not have a significantly elevated cholesterol. However, for the first time, patients with signs of inflammation (elevated hs-CRP levels) were shown to benefit from satin therapy.
Taken together, these trials suggest that statin therapy for primary prevention is effective over a wide range of baseline LDL-C levels and lipid profiles and carries a similar relative risk reduction to statin therapy in secondary prevention. The absolute magnitude of benefit, however, is typically lower than in secondary prevention. Thus, the so-called number needed to treat, in order to prevent an event, is much higher in primary than secondary prevention.
Should I take a cholesterol lowering drug?
Let’s go back to the metaanalysis published last May in the Lancet. What is the absolute risk reduction with statin therapy in patients with no history of heart disease and less than 10% risk of a cardiovascular event over five years? For every 1 mmol/L reduction in LDL-C there is an absolute reduction in major vascular events of about 11 per 1000 over 5 years.
What do these numbers really mean for the individual patient? It is often difficult to apply statistics to real life. Let’s say that I am a low risk patient and my LDL-cholesterol is 3.7 mmol/L. My doctor prescribes a statin and I decide that I will take it every day for the next five years. My LDL-C goes down to 2.7 mmol/L while I’m taking the drug. This treatment is going to make it one percent less likely for me to have a coronary event or a stroke during those five years, compared to If I do not take the drug.
Well, this does not appear impressive at all. Knowing about the possible side effects, I would probably not be interested in drug treatment. However, although the efficacy of the drug is measured in number of events, it is possible that the drug influences some underlying pathohpysiological mechanism that might be of benefit for me. There are indeed some studies indicating that statin therapy may reduce the progress of atherosclerosis in human arteries.
If we look at the numbers from the WOSCOPS trial, treatment with pravastatin for six years would reduce the likelihood of having a vascular event by three percent during six years. These numbers are a bit higher, probably because the typical WOSCOPS patient generally had higher risk.
Then, how about high risk patients? Who are they? Should they be treated with statins. Suppose I am a 52 year old high risk patient, a smoker with high blood pressure, with a father who had an MI in his fifties and an LDL-C of 4.7 mmol/L. In this case I might embrace the idea of taking a statin as it could statistically lower my risk considerably. In this case I am much more likely to benefit from satin therapy than if I was a low risk patient. On the other hand, I would probably benefit much more by quit smoking.
Earlier this year, The European Society of Cardiology, published new European Guidelines on cardiovascular disease prevention in clinical practice. These are the key messages concerning blood lipids:
- Increased plasma cholesterol and LDL-C are among the main risk factors for cardiovascular disease.
- Hypertriglyceridaemia and low HDL cholesterol are independent cardiovascular risk factors.
- Statin therapy has a beneficial effect on atherosclerotic cardiovascular outcomes.
According to these recent guidelines, the indication for statin therapy in primary prevention depends on the patient’s total risk for cardiovascular events. Such a risk assessment is generally based on the blood levels of cholesterol and presence or absence of other risk factors, sch as smoking and high blood pressure. “Cholesterol lowering therapy depends on initial levels of risk: the higher the risk, the greater the benefit. There are no differences in beneficial effects of cholesterol lowering between men and women and between younger and older age groups, even individuals 75 years of age, although the benefits in healthy women are not proven.”
However, despite indicating an uncertainty about women, no distinction is made in the guidelines, between treatment recommendations for men and women. A 2004 analysis of thirteen studies showed that for women without CVD, lipid lowering does not affect total or CHD mortality. “Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively. For women with known cardiovascular disease, treatment of hyperlipidemia is effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization, but it does not affect total mortality”.
Finally, let me touch en the health-economic angle. Bear with me because my knowledge of economics is less than basic. Some studies have indicated that statin therapy in low risk patients is not cost effective. However, the results of the recent metaanalysis, published in the Lancet, have been used to argument that treatment of low risk patients may indeed be cost effective.
Let me quote Professor Baigent again: “It is not just about treating raised cholesterol after middle-age. The benefits of statins in people who are currently healthy, but are for some reason at increased risk of a heart attack or stroke, are substantial, and much greater than any of the known risks. People who are at increased risk, perhaps because they are overweight, or smoke, or have high blood pressure, would be better off with lower cholesterol, even if their cholesterol is not considered to be particularly high. The routine use of statins would lead to 10,000 fewer heart attacks and strokes a year, including 2,000 fewer deaths in the UK. The small cost of the drugs would be outweighed by NHS savings due to the reduced number of heart attacks and strokes”.
Somehow, the idea of using drugs to to counter the effects of smoking, unhealthy eating and lack of exercise, does not appeal to me. Furthermore, forcing people to take drugs in order to reduce health costs seems odd, to say the least. If health authorities want to spend money on prevention, they might as well use them to promote healthy lifestyle and educate people about risk factors, lifestyle, nutrition, healthy and unhealthy foods. Such an approach, however, would have to start already in childhood.
A positive reward system sometimes works well, at least in dog training. Maybe, instead of forcing low risk individuals to take statins, authorities could reward them for not smoking and staying away from obesity. A regular visit with a nurse, once a month, where you would have to prove that your weight has not gone up, and that you have not smoked. If you are approved, you will get your monthly pay-check. Just an idea!