Cholesterol-lowering statin drugs remain the most prescribed drugs in Australia, with almost 23 million prescriptions written for the top 3 drugs in this class (atorvastatin, rosuvastatin and simvastatin) in the 2016-17 financial year.
A meta-analysis of clinical trials published in JAMA Cardiology on 1 August 2018 found that statins and other cholesterol-lowering drugs significantly reduce the risk of major vascular events (such as heart attacks). For each 1 mmol/L drop in low density lipoprotein cholesterol (LDL-C), the risk of an event dropped by 21%.
Of course, that’s a relative risk reduction. The numbers look far less impressive when presented in terms of absolute risk reduction.
For example, a 75 year old diabetic man who smokes and has high blood pressure might have a 30% risk of having a heart attack in the next year. If he takes a statin which lowers his LDL-C by 1 mmol/L, his risk will now be 26.7%. At the other end of the risk spectrum, a 45 year old nondiabetic woman with normal blood pressure might have an 8% risk of having a heart attack in the next year; taking a statin which reduces her LDL-C by 1 mmol/L will reduce her risk to 7.1%.
Another major concern with using clinical trial data to make decisions about your own medical care was pointed out in an editorial accompanying the meta-analysis: clinical trials are not well designed to detect rare but serious adverse effects, for several reasons.
Firstly, participants in clinical trials are carefully selected to be ‘perfect patients’. People with conditions that affect their ability to metabolise drugs, such as liver or kidney disease, are excluded, as are elderly people who metabolise drugs less efficiently regardless of health status. Women are underrepresented in clinical trials of statins, largely because premenopausally, women’s risk of cardiovascular disease is low, and it takes many years after menopause for it to catch up with men’s risk – by which time women are more likely to be excluded from clinical trials because of their age. And finally, participants in clinical trials are usually only taking the drug that is under study, not a ‘drug cocktail’.
But once a drug is approved, it is prescribed to people who are not perfect patients – they may be younger or older than the trial participants, be taking multiple medications whose interactions have not been studied, and have illnesses which influence how the new drug impacts them.
Secondly, clinical trials frequently include ‘run-in periods’, in which the drug is given to participants before the ‘official’ beginning of the clinical trial. In one study of the efficacy of simvastatin, the Heart Protection Study, 36% of participants were excluded from the trial at the end of the run-in period. The study’s authors claimed that “the run-in period was to assess the LDL-lowering responsiveness of each individual” – which looks suspiciously like rigging the game in the first place by selecting participants who are more likely to have a favourable response to the drug. However, since the majority of those who were excluded either chose not to participate or were not compliant with the medication regime, it is likely that the run-in period was also used to identify and exclude from the trial participants who were more likely to have ADRs, in order to make the drug appear safer than it actually is.
Thirdly, clinical trials are not adequately powered to detect rare adverse events. Simply put, you can never enrol enough people in a trial, or follow them up for long enough, to identify all the uncommon but serious side effects. Hence, these are only detected by post-marketing surveillance – reporting of adverse events once the drug is released onto the market.
Unfortunately, a systematic review of the extent of under-reporting of adverse drug reactions (ADRs) in both primary care and hospital settings, found a staggering 94% under-reporting rate of ADRs overall, and an 85% under-reporting rate for serious and severe ADRs. Even more frighteningly, 5 of the 8 hospital-based studies found a median under-reporting rate for more serious or severe ADRs of 95%, meaning that only 5% of ADRs that could seriously harm or even kill patients were reported.
The disinclination of doctors to consider that a patient’s symptoms may be due to an ADR, and to report it to surveillance systems, is no doubt the primary major reason why, as the author of the editorial in JAMA Cardiology pointed out,
“The association of diabetes with statin use was not fully described until 23 years after lovastatin approval and millions of patients had received statins.”
Aside from an increased risk developing type 2 diabetes, statin use is associated with multiple ADRs, ranging from common and distressing to severe and incapacitating. These include:
- Muscular symptoms such as pain, aches, stiffness, weakness, fatigue, cramping and tenderness, which occur in 10.5% patients, usually within 1 month of commencing statin therapy.
“Muscular pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work.”
- An increased risk of back disorders including spondylosis (degeneration of the spinal column) and intervertebral disc disorders. In a US study, statin users with an average age of 52 had 1.27 times the odds of being diagnosed with back disorders after stating to take statins, with a number needed to harm of 17 – which means that for every 17 people taking a statin, one would develop a back disorder that they otherwise would not have suffered.
- Increased risk of idiopathic inflammatory myositis (IIM). An Australian study published in July 2018 found that people diagnosed with IIM, an autoimmune disease which causes debilitating muscle inflammation, were almost twice as likely to have taken statins as matched controls – that is, people with similar characteristics to the IIM patients, who had not developed this condition.
- Cognitive impairment including reduced attention, working memory, and overall mental efficiency. Between 0.1 and 1% of people taking statins will experience cognitive impairment, which can significantly reduce quality of life.
Informed consent involves discussing the known risks and benefits of a proposed treatment, as well as the alternatives to it. But how many people who have been prescribed a statin have been given enough information to make an intelligent decision that takes into account their risk of suffering both the illness the drug is supposed to prevent, and the ADRs it may cause, as well as their personal values in relation to these risks?
A British study found that even patients who had just been discharged from a coronary care unit would not take a drug that reduced their absolute risk of suffering another cardiovascular even by less than 20%, while those with no history of cardiovascular disease would not take a drug that offered an absolute risk reduction of less than 30%. Yet no statin offers risk reductions anywhere near this level for the overwhelming majority of patients who are prescribed the drug, given that their absolute risk is far less than 30% in the first place.
On the other hand, decades of research by luminaries including Dr Dean Ornish and Dr Caldwell Esselstyn, among others, has established that a low-fat plant-based diet is highly effective at reducing the risk of cardiovascular events, with the only side effects being good ones: weight loss, increased energy, and easier bowel movements, for starters!
Statin drugs have their place, and for some individuals, the benefits of treatment may truly outweigh the risks. But anyone who has been prescribed a statin without being told their likelihood of benefitting from the drug in absolute risk reduction terms, the potential adverse reactions they may suffer, and the potential alternative of adopting an Ornish- or Esselstyn-style diet and lifestyle program, has been denied their fundamental right to informed consent.
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