To make an informed choice about statins, here is what you should know

News that there may be errors in the algorithms used to calculate statin prescription will leave cardiology clinics and surgeries fighting through the mist of the latest statin controversy. In 25 years of medical practice, the class of drugs known as statins seems consistently to have provoked more controversy than any other. Why?

Epidemiological studies since the 1970s have shown clearly that the higher the blood cholesterol, the higher the risks of heart attack. However, even a series of such observations is not sufficient to show a causative relation between blood cholesterol and cardiovascular risk; still less that therapeutically lowering cholesterol would translate into any outcome benefit. That would require evidence from a randomised placebo-controlled clinical trial, and ideally more than one.

So how does the biomedical community (scientists, clinicians and the pharmaceutical industry) approach the challenge of showing that a treatment works? To test the effects of a drug requires a defined population and an outcome that can be quantified in a practical time frame to allow statistical comparisons between those receiving placebo and those receiving the active drug. As in the case of statins, it is logical, therefore, to design the first trials to treat patients who are perceived to be at high risk of the measurable event; not least because, from a statistical point of view, the size (and therefore cost) of the trial will depend on (a) the frequency of the measured event and (b) the magnitude of the treatment effect — so focusing on high-risk patients makes sense. 

I remember clearly hearing the results of the landmark Scandinavian Simvastatin Survival Study as a trainee cardiologist in London in 1994. This clinical trial studied 4,444 patients with both prior heart attack and high cholesterol (even after lifestyle advice and modification). The results were startling: over the five and a half years median follow-up period, simvastatin lowered total cholesterol by 25 per cent. In the placebo group 256 patients (12 per cent) died compared with 182 (8 per cent) in the simvastatin group. So, the risk of death was reduced by about a third. In other words, for every 100 patients treated for about five years after a heart attack, four people who would otherwise have died did not. The probability that this was a ‘chance’ result (ie wrong) was less than one in 1,000. 

Death is obviously the most robust quantifiable end point of all — but there were commensurate reductions in heart attack risk and the need for heart operations. Whether one thinks that these results are numerically impressive or not is to some extent subjective. In most areas of medicine, a mortality reduction of around one third with a daily tablet would be considered unusually effective. 

Over the next 20 or so years a series of trials sequentially extended the demonstration of statin efficacy to populations that were at lower baseline risk and had lower starting levels of cholesterol. Overall, the results were clear and consistent: lowering LDL-cholesterol with statins reduces cardiovascular risk, but the magnitude of the reduction depends on the patient’s risk — the higher the risk, the more there is to gain, which is not surprising. 

Accordingly, pretty much anyone who has had a heart attack or who has coronary artery disease will find themselves in a category of patients for which statin efficacy has been shown in trials. So how come the controversy? As more trials emerged, the indications for statins increased. The groups considered eligible for prescriptions of statins expanded and the seemingly ever-changing goal posts may have raised suspicions about the motivation of both the pharmaceutical industry and of the prescribing physicians. Indeed, the medical profession has not been good at communicating with the public about how clinical trials work, the inevitably changing landscape of clinical evidence, the nature and magnitude of the projected benefits (or lack of them) and, crucially, where the uncertainties lie.

So what about the uncertainties? For the most part these start where the margins of the clear evidence base start to fray and partially informed (albeit well-intentioned) speculation begins. In part, this is where risk calculators (like QRISK2) and guidelines come in — to plug the gap where trial data are lacking. Current algorithms such as QRISK2 combine a number of variables including age, cholesterol, blood pressure, smoking history, family history etc and compute a 10-year risk of cardiovascular events. Equipped with this type of individualised assessment of risk, it is possible for bodies such as NICE to make recommendations for treatment with carefully considered but ultimately arbitrary thresholds.
An important topic of debate in this area is the question of ‘lifetime risk’. We know that atherosclerosis, the process of artery ‘furring-up’ that underlies heart attack and many strokes, starts in early life (certainly by the 20s) and progresses over many years. We know this from postmortem examination of the hearts of people who died prematurely eg in road accidents. So, extrapolating from the trial evidence, one line of thought is to make interventions that delay progression of atherosclerosis from a relatively early stage in order to ameliorate lifetime risk of cardiovascular disease. However, since clinical trial data require measurable events in a manageable time frame, a long-term benefit of this approach will be difficult to show.   

So what to do? Given a high lifetime risk of coronary disease and the early onset of the process, one could take a view that an individual, even in early life, should be able to prospectively survey their future risk and make a decision on their approach to interventions that may ameliorate that risk before it reaches a high level. This would include lifestyle modification but could also include preventive treatment, eg with statins. Clearly healthy, symptom-free patients taking drugs over long periods requires very careful consideration of the potential risks and benefits.

My larger points are that: (1) a given individual, properly equipped with knowledge of the risks and benefits of a treatment, and in consultation with their physician, should be able to make informed choices (and to revisit and revise them as the evidence accumulates) and (2) a more robust understanding of both the processes of medical decision-making and the extent and nature of the body of evidence, including its gaps and deficiencies, will leave patients less susceptible to the shock waves of new or unexpected findings and less exposed to the manipulative sensationalism that characterises some lay reporting, particularly, it seems, when it come to statins. 

Dr Robin Choudhury is professor of cardiovascular medicine at the University of Oxford, consultant cardiologist at the John Radcliffe hospital and clinical director of the Oxford Acute Vascular Imaging Centre.

  • Michael Rose

    Statins have also been seen to reduce Brain Mass Loss in MS. Bonus, if you happen to be on them in the first place.

  • CrossCourt2

    It’s less debatable whether statins benefit those who already had a heart attack. It’s more debatable, whether it will benefit those that have not had a heart attack. I would be interested in any new studies that focuses on this group.

  • FDL

    Solid Evidence Backs Heart Attack Prevention Initiative

    May 05, 2016

    NEW YORK (Reuters Health) – An overview of systematic reviews shows that high-quality evidence underlies the choice of drugs in the Million Hearts Program for primary prevention of atherosclerotic cardiovascular disease, according to researchers.

    As Dr. Mark D. Huffman explained in an email to Reuters Health, “The Centers for Disease Control and Prevention and Department of Health and Human Services created its Millions Hearts Program to prevent one million heart attacks and strokes by 2017.”

    The program, he added, “emphasizes ABCS, including Aspirin, Blood pressure lowering drugs, Cholesterol lowering drugs, and Smoking cessation to achieve this ambitious goal. Our paper uses a transparent method to summarize information from previous systematic reviews to evaluate the safety and efficacy of these commonly used drugs to prevent heart attacks and strokes.”

    In an April 27 online paper in JAMA Cardiology, Dr. Huffman, of Northwestern University Feinberg School of Medicine, Chicago, and colleagues noted that they settled on 35 systematic reviews of randomized clinical trials. Of these, 15 covered aspirin, four included blood pressure lowering therapy, 12 were on statins, and the remaining four reviewed tobacco-cessation drugs.

    “We found high-quality evidence supporting the use of aspirin, statins, and blood pressure lowering drugs to prevent heart attacks and strokes and for tobacco-cessation drugs to nearly triple abstinence rates,” Dr. Huffman said.

    In particular, compared to placebo, the relative risk of atherosclerotic cardiovascular disease was 0.90 with aspirin and 0.75 with statins. With blood pressure lowering therapy, the relative risk for coronary heart disease was 0.84 and for stroke it was 0.64.

    “Medications like aspirin carry an increased risk for side effects,” Dr. Huffman continued, “including major bleeding, while statins are generally safe. Side effects have not been reported as clearly in systematic reviews of blood pressure lowering or tobacco-cessation drugs.”

    Commenting on the findings by email, Dr. Joseph Yeboah of Wake Forest Baptist Health, Winston-Salem, North Carolina, told Reuters Health, “Unfortunately risk-benefit ratios of these methods/approaches are not uniform across the spectrum of characteristics in the general asymptomatic community dwelling adult population.”

    Dr. Yeboah, who has conducted research in the field, added, “While the benefits of blood pressure lowering and smoking cessation may tip the risk-benefit ratio balance toward generalized application for primary prevention of atherosclerotic cardiovascular disease, caution should be exercised with aspirin and statin use due to very significant side effects that may grossly outweigh any benefits in segments of primary atherosclerotic cardiovascular disease prevention populations.”

    The Center for Medicare and Medicaid Innovation supported this research. Two coauthors reported disclosures.

    JAMA Cardiol 2016.

  • Donald H. Marks

    I remain not completely convinced. See the link for the JAMA article “Healthy men should not take statins” by Dr Redberg, editor of the Archives of Internal Medicine April 2012 advising healthy men with high cholesterol to stay away from statin anti-cholesterol drugs, pointing out there is no mortality benefit.

    • David_Bailey

      Right – and one thing that statins clearly do, is cause muscle problems. I got severe cramps plus additional weakness in my polio leg after taking Simvastatin for 3 years. I didn’t initially assume that the statin was responsible, and neither did my doctor (that is part of their danger) but after three periods without statins, it became perfectly obvious that the cramps were more severe while I was taking statins. After 9 months without statins I can walk properly again! I have been 3 years now without statins, and there has been no recurrence – I take that is nearly proof that statins did this to me.

      What amazed me, was that talking with others of about my age (63 at the time) stories of statin horrors abound, but mostly these happen soon after starting the drug, and so are quickly recognised.

  • Paul Halan

    The anecdotal evidence are nothing short of horror stories. The scientific studies do conclude a significant number of subjects have adverse effects when taking statins. When prescribing statins GP’s should have follow-up consultations to determine if there are any differences in a persons’ behaviour. Not only from the patients’ observations but also observations from significant others.
    Here’s my story. My cholesterol has been high all my life. My mother and brother have had high cholesterol all their lives. My GP prescribed me Rosuvastatin 20mg tablets. The GP said, “if anyone is a candidate for statins it’s you as your body is not processing cholesterol efficiently”, I said, ” I’ve had high cholesterol all my life and if my body wasn’t processing my cholesterol as it should wouldn’t my cholesterol build-up and continually increase?” This was dismissed and I began my statin nightmare. I religious took the Rosuvastatin tablets and my cholesterol dropped to “normal” levels. What I wasn’t aware of was my mood as the change was so gradual. After a year I did start to notice that my mood became depressive. I was struggling with everyday life and began convincing myself that there was no purpose in life. My wife noticed the changes but never discussed it with me, and I never discussed it with her as I thought it was a passing phase or a mid-life crisis (I’m 51 years old). Over the course of the next year I sunk deeper and deeper in to depression. Several times I considered suicide. It got so bad I was praying to God to give me a sign for a reason to carry on. By Christmas 2016 I was determined to commit suicide on New Year’s Eve as I just couldn’t continue any longer. Two days later I saw strange lights in the sky, was this my sign from God? Two days from then my wife came across a warning about statins in one of her chat rooms. I did some research on google and read a Psychiatric Study that found a significant number of subjects experienced depression. This was caused by the use of statins. As the cholesterol lowered it interfered with the production of serotonin in the brain. I also read several anecdotal experiences and could relate as I was experiencing the same adverse effects. The last day of the year I stopped the medication. There was no change initially but when I awoke on the 8th day I was looking at myself and realised I was back to my old-self, gosh, I was so happy. My wife got her husband back and I got my life back. Two years of my life was wasted and tortured. Three months later (23rd, March 2017) I have not had one bad day.
    Please, please approach statins with caution. If you have to take them make sure you are adequately supervised and supported to identify any changes in your regular life.