(Updated, May 2, May 4)
–The authors say muscle problems with statins are an example of the ‘nocebo’ effect.
A new study helps debunk the widespread belief that statins cause muscle-related pain and weakness in large numbers of patients. The “nocebo effect” may be the cause of the epidemic of muscle pain among statin users, say the study investigators and outside commentators.
There are few more broadly relevant and contentious questions in modern medicine than who should take statins. Observational studies and anecdotal reports indicate that adverse events in people taking statins are common. As many as 20% of people who take statins report some sort of problem. But in randomized controlled trials of statins reports of adverse events have been similar in the placebo and active treatment groups, suggesting little or no pharmacologic adverse effect. (All parties agree that statins can cause the rare and extremely serious adverse effect of rhabdomyolysis in about 1 in 10,000 patients, and that statins also cause a small increase in the risk of developing diabetes, though the clinical implications of the later finding are still unclear.)
Now a new report in the Lancet compares the rate of side effects in a group of patients both during and after their participation in a randomized controlled trial, the ASCOT-LLA trial. During the trial more than 10,000 patients were blinded to treatment assignment. After the trial was completed participants were invited to take part in a followup study in which they were offered open-label statin treatment.
During the randomized portion of the study there was no difference in the rate of muscle-related symptoms between the two groups: 2.03% per year in the atorvastatin group versus 2% in the placebo group. In the open-label followup study, in which about two-thirds of the patients were taking atorvastatin, there was a small but statistically significant larger percentage of patients in the atorvastatin group who reported muscle-related symptoms: 1.26% per year versus 1.00% per year (hazard ratio 1.41, CI 1.10–1.79, p=0.006).
“Just as the placebo effect can be very strong, so too can the nocebo effect.,” said Peter Sever (Imperial College London), lead author of the study, in a press release. “This is not a case of people making up symptoms, or that the symptoms are ‘all in their heads’. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm. What our study shows is that it’s precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them.”
The authors speculated that they may have underestimated the nocebo effect, since ASCOT-LLA was performed between 1998-2005, “before claims that statin therapy causes high rates of side-effects had become as common as they are now.”
Statin critics have argued that adverse event rates in trials have been lower than real life because most trials have enrolled patients who have already been shown to tolerate statins. But, write Juan Pedro-Botet, Juan Rubiés-Prat (Barcelona), in an accompanying editorial, in ASCOT-LLA “no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.”
Rita Redberg (UCSF) doesn’t think that a nearly 20-year-old trial can address the situation today. She repeated her call for the Cholesterol Treatment Trialists (CTT) to release the patient-level data of their trials. “I think if they truly want to contribute to the discussion of the incidence of statin related adverse events in clinical trials, they should make the CTT held trial data publicly available, as Rory Collins said he would do two years ago, but has not happened.” Collins is a leader of the CTT and a co-author of the new Lancet paper.
In their conclusion the study authors chastised the media: “The widespread media coverage that has arisen from claims that statin therapy causes side-effects in up to one fifth of patients, and the failure to correct such misleading claims rapidly and fully, has led to patients at high risk of major vascular events with established cardiovascular disease stopping their statin therapy. Such reductions in statin use have been estimated to result in thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided. Seldom in the history of modern therapeutics have the substantial proven benefits of a treatment been compromised to such an extent by serious misrepresentations of the evidence for its safety. We hope that the demonstration in the ASCOT-LLA of not only the absence of adverse effects of statin therapy on muscle-related and other AEs, but also the effect of ascertainment bias in non-blinding studies (which have been the basis of many of the misleading claims), will help to counter the adverse effect on public health of exaggerated claims about statin side-effects.”
The editorialists agreed that patient reports about muscle pain “might result from patients’ perceptions about statins in light of negative press reports of statin use or even poor understanding of warnings about statin-associated side-effects.”
Given the established cardiovascular benefits of statins, they write, “clinicians should be fully informed about potential nocebo effects, including patients’ previous knowledge or perceptions of statin therapy, and discuss the evidence… with patients.”
Asked to comment on the study, Harlan Krumholz (Yale University) said that “the evidence is growing regarding the safety of statins. They remain one of the most remarkable breakthrough drugs ever produced…. Vigilance in evaluating drug effects, especially in popular drugs, must continue – but this study shows just how hard it can be to disentangle adverse effects from perceptions of adverse effects.”
Marilyn Mann, a highly respected patient advocate, offered the following comment: “Patients often experience muscle symptoms while taking a statin. This study adds to the evidence that these symptoms are often not caused by the statin. However, it is rarely productive for a patient to simply be told that the drug isn’t causing the symptoms the patient is feeling. Rather, patients and their doctors need to work together over a period of time to try to determine whether the symptoms are related to the statin. Drug discontinuation followed by rechallenge is often successful. In addition, many people can tolerate a lower dose, a different statin, or a different dosing schedule. In some cases, other cholesterol drugs are an option.”
Update:
Rita Redberg sent the following additional comment:
“I would just add that I find this publication of the adverse event rate in this 15 year old trial of low dose (10mg) atorvastatin in mostly white, middle aged men, adds little to our knowledge of side effects of statins as used today. The current guidelines recommend high dose statins, which have higher incidence of all side effects. In addition, the ASCOT LLA trial had a run-in period which would have removed the patients who complained of aches and pains. The 2003 Lancet paper states “After the 4-week run-in period, we confirmed eligibility and consent for randomisation. “ This is contrary to the statement of the editorialists. The rate of muscle pains in placebo and statin group in the trial was about 2%, much lower than in other trials and noted in clinical practice.”
Update (May 4):
I asked Peter Sever to clarify the question about the ASCOT-LLA run-in period. He informed me that “the original ASCOT run in was a period during which we collated details of eligibility notably lipid profiles. Statins were not administered prior to randomisation.”
Bullcrap. I had serious muscle pain before I knew statins might be the cause. Pain went away when the statins went away. My doctor said, “Statins aren’t for everyone.”
Does anyone take you serious anymore?
“write Juan Pedro-Botet, Juan Rubiés-Prat (Barcelona), in an accompanying editorial, in ASCOT-LLA “no run-in period existed to exclude patients intolerant to therapy””
Rita Redberg: “The 2003 Lancet paper states “After the 4-week run-in period, we confirmed eligibility and consent for randomisation. “ This is contrary to the statement of the editorialists.”
Who is telling the truth here?
My GP was trying to persuade me to take statins. “Why, I have even persuaded my father to take them.” I pressed him on the point and he admitted that the old boy’s dose had had to be halved because of the muscle pain.
So I suppose I learned that statins can cause pain and that the effect is dose-related.
Anyway, about their beneficial effects, if any: is there a good rule of thumb about their benefits for non-symptomatic patients? Do they, let us say, extend the life of 10% of patients by a year? Of 1% by a week? What?
dearieme,
Benefit: Most likely none whatsoever.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800759/figure/OPENHRT2015000343F3/
Thank you for the link. ” … only a minority of the cohort (7%) gain any lifespan from a lifetime of preventative therapy …” That suggests to me that a sensible line of enquiry would involve trying to identify the 7% so that the other 93% need not take on the disadvantages of statins without any compensating advantages.
If there are no discernible characteristics capable of identifying the 7% then I’d rather doubt the claim.
dearieme,
Perhaps this will eventually help find the 7%:
http://www.drjohnm.org/2017/05/the-future-of-predicting-heart-disease-may-be-in-your-genes/
Honestly the cardiology field has turned into a joke and largely by their own hands. Failure after Failure (Apo1 Milano, HDL boosters, self-absorbing stents, PCSK9) after they were all touted as game changers. And now this. Seriously?
Larry,
Excellent summary as usual. Your ability to get varying expert opinions on the topic in a concise format is unique.
I find it remarkable that Rita Redberg is dismissing the findings based on a “run-in period” that didn’t exist.
Have you been able to get her response to the fact that there was no run-in period on statins?
For all the zealous statin-haters chiming in here: as a clinician I know that statin associated muscle symptoms are real but also that the nocebo effect is very powerful. Sorting these out in an individual patient requires considerable time and effort.
There are some GLARINGLY obvious problems with this research as stated by Dr Amitava Banerjee, Senior Clinical Lecturer in Clinical Data Science and Honorary Consultant Cardiologist, UCL:
~ First, this study only considers one statin (atorvastatin). Two other commonly used statins in the UK are simvastatin and rosuvastatin and further study is required in these statins.
~ Second, this is a primary prevention trial, i.e. in people who are at risk (e.g. smokers, diabetics, high blood pressure) but have not had a heart attack. The dose of atorvastatin is low (10mg) and therefore we cannot generalise the results to use of statins in people who have had heart attack or stroke (‘secondary prevention’) where higher doses (typically 80mg of atorvastatin).
~ Third, this is research based in the UK and Scandinavia and the results are not necessarily applicable to other populations, especially other ethnic groups.
~ Finally, the trial was conducted 15 years ago. There have been changes in the proportion of individuals who are taking statins, increasing age and comorbidities in the population with potential for interactions with other drugs which an individual may be taking. All this further research is necessary before we start changing side effect leaflets for statins.
NOTE:
As disclosed by the Lancet, funding for this latest slaphappy “nocebo effect” statin study was provided by the folks who make the drug — Pfizer Inc, along with Servier Research Group and Leo Laboratories.
I think they sponsored the original trial long ago. Pharma companies now have little interest in statins because they are generic.
Replying to Larry Husten…
As noted in my previous comment, the text of your story really needs to inform your readers of the fact that the original ASCOT-LLA Lipitor/atorvastatin study, and the current followup study, were both funded by a group of multinational pharmaceutical corporations: Pfizer Inc (which owns Lipitor/atorvastatin); Servier Laboratories; and Leo Pharma.
Further to this point, it is patently (pardon the pun) absurd for you to state in the comments section: “Pharma companies now have little interest in statins because they are generic”. To wit, Lipitor/atorvastatin is still a blockbuster selling drug which generated nearly two billion USD global revenue for Pfizer in 2016. Plus, there is still, literally, billions more being made by multiple other drug companies who are manufacturing the generic atorvastatin.
Of course, newly patented lipid-lowering drugs, chiefly the PCS9 inhibitors, are of paramount interest to pharma business. Thus, the existing body of research on lipid-lowering via statin drugs is of tremendous ongoing value since it can continue to be data-mined to yield increasingly outlandish reports about the benefits — and now the alleged absolute harmlessness — of past, present and future lipid-lowering therapies.
Meanwhile back at the ranch, Pfizer continues to be deluged with several thousand lawsuits over harm from Lipitor/atorvastatin side-effects. As recently reported by Reuters, this will be far bigger than other mass lawsuits of its kind: “For one, Lipitor is the best-selling prescription drug of all time, racking up global sales of more than $130 billion since it went on the market in 1996. More than 29 million patients in the United States have been prescribed the drug, suggesting there is a vast pool of potential plaintiffs”.
So, yeah, it’s safe to say that Pfizer and all other statin/lipid-lowering stakeholders are still SUPER interested in torturing the research data to disprove evidence of any potentially litigious side-effects. In the case at hand, the tool of choice is the ‘nocebo’ effect — which maintains that people develop genuine negative symptoms as a consequence of finding out that they are taking a drug which may cause side-effects. Pfizer is currently purveying this defense in the court of public opinion, in preparation for a court of law. I’m sorry to say that your column (“Rigorous Study Debunks Alarms That Statins Cause Muscle Problems”) appears to be useful in this process.
I’m sorry but this is an extremely biased and one-sided attack. Please address the details of the study if you wish to be taken seriously.
Replying to Larry Husten…
I appreciate that you have taken the time to give feedback and I acknowledge that my comments have a strong point of view. However, I trust that my remarks are no more “biased and one-sided” than numerous others here on this thread. Moreover, my opinion is not an uninformed opinion, nor is inaccurate. And it is certainly not irrelevant to discuss the undue influence of industry funding and other vested interests within the context of contemporary medical research.
Indeed, a number of expert commentators are questioning the validity of this current study, given that it is a reanalysis of data from a 20 year old trial (ASCOT-LLA) that was designed to compare two antihypertensive strategies (inclusive of 10mg Lipitor/atorvastatin) for the prevention of CHD. Others have more bluntly questioned why researchers suddenly decided to data dredge a dated study – which was NOT designed to look at adverse effects as a primary end-point – to prove that statins do not have any adverse effects. Others have also noted that the original ASCOT-LLA study and the current reanalysis are both funded by three pharmaceutical companies — including Pfizer, which is currently being sued over adverse effects from the drug Lipitor/atorvastatin that the new reanalysis now attributes to the nocebo effect. It has been said that he who pays the piper calls the tune.
You have suggested that I focus more on the “details of the study” and I do have a couple of further thoughts and questions to offer.
To recap: ASCOT-LLA was a two stage clinical trial with two groups of participants in each stage. It began with an initial blinded phase that was followed up by an unblinded phase. During the initial blinded phase, neither of the two groups of participants knew whether they were taking a statin drug or a placebo. During the followup unblinded phase of observation, both groups fully knew that they were either receiving, or not receiving, a statin.
The ‘nocebo’ effect proposes that people manifest a higher rate of side-effects when they know that they are taking a drug that may cause side-effects. In keeping with this theory, one would then expect to see a considerable increase in muscle-related side-effects among the drug treatment group during the unblinded phase of the ASCOT-LLA study. But that is NOT what happened. Instead, reports of muscle-related problems DECREASED, from 2.03% to 1.26% (for an overall decline of 38%), within the drug treatment group when the study shifted from the blinded to the unblinded phase. At the unblinded phase, however, we do also see that the rate of muscle-related problems in the drug treatment group is somewhat higher relative to the non-treatment group (1.26% vs 1.00%) — a finding that the current authors now wish to attribute to the nocebo effect. But, if the presumed nocebo effect was really at work, why wasn’t there also a simultaneous increase in the rate of muscle related problems within the treatment group itself. Again, why was there a DECREASE of 38%? And what does this portend for the credibility of a nocebo effect at any stage of the study?
Medscape also just did a story about this study and, if I may say, it is relatively well-rounded and even-handed. I’m not a huge fan of Steve Nissen (who’s had more than his fair share of industry funding), but he does have some nifty things to say about the flaws of this current study: http://www.medscape.com/viewarticle/879613#vp_1
Regarding how the side-effects data was collected in the original ASCOT-LLA trial, Nissen said: “These were casually reported symptoms, sort of spontaneous adverse-event reporting. If you want to know whether people have statin-associated muscle symptoms, you have to have a formal process for querying people about their symptoms. The investigators did not do that. There’s no rigor in the way the data were collected…The study was not done with the idea of collecting information on statin-associated symptoms, which means that there may have been lots of people in the study who had symptoms that were never written down”. Nissen doesn’t say ‘garbage in, garbage out’, but that may be one possible interpretation.
FWIW, Larry, I have followed your columns closely for several years and your body of work is usually at an extraordinarily high level. May I ask why you are confident that the original ASCOT-LLA side-effects data is of sufficient rigor for the current reanalysis to “debunk alarms that statins cause muscle problems”, as you have stated?
“Given the established cardiovascular benefits of statins, ” what are they?????