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Patients unaware of statin use report no increase in muscle-related symptoms
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Muscle pain and weakness reported by statin users is more likely to be caused by the nocebo effect than by statins directly, according to new data from the ASCOT-LLA study.
Adverse events related to muscles were less likely to be reported by patients and doctors when they were masked to statin use than when they were unmasked to it, the researchers reported in The Lancet.
“Just as the placebo effect can be very strong, so too can the nocebo effect,” Peter Sever, FRCP, from the National Heart and Lung Institute, Imperial College London, said 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.”
Sever and colleagues analyzed 10,180 patients with hypertension and at least three other CV risk factors from the blinded randomized phase of the ASCOT-LLA study of atorvastatin 10 mg vs. placebo, and 9,899 patients from the unblinded nonrandomized phase of the study.
The researchers compared adverse events, including muscle symptoms, erectile dysfunction, sleep disturbance and cognitive impairment, in the blinded phase vs. the unblinded phase. Median follow-up was 3.3 years in the blinded phase and 2.3 years in the unblinded phase.
During the blinded phase, there was no difference between the atorvastatin and placebo groups in muscle-related adverse events (atorvastatin, 2.03% per year; placebo, 2% per year; HR = 1.03; 95% CI, 0.88-1.21) or erectile dysfunction (atorvastatin, 1.86% per year; placebo, 2.14% per year; HR = 0.88; 95% CI, 0.75-1.04), whereas sleep disturbance was lower in the atorvastatin group (1% vs. 1.46%; HR = 0.69; 95% CI, 0.56-0.85), and there were too few cases of cognitive impairment from which to draw conclusions, the researchers wrote.
Other adverse events were similar between the groups during the blinded phase except for renal and urinary adverse events, which were higher with atorvastatin vs. placebo (1.87% per year vs. 1.51% per year; HR = 1.23; 95% CI, 1.08-1.41).
In the unblinded phase, muscle-related adverse events were reported more often in those taking statins vs. those not taking statins (1.26% per year vs. 1% per year; HR = 1.41; 95% CI, 1.1-1.79), according to the researchers.
Other adverse events were similar between the groups during the unblinded phase except for musculoskeletal and connective tissue disorders (statin, 8.69%; no statin, 7.45%; HR = 1.17; 95% CI, 1.06-1.29) and blood and lymphatic system disorders (statin, 0.88% per year; no statin, 0.64% per year; HR = 1.4; 95% CI, 1.04-1.88).
“We know that statins can prevent a significant number of [MIs] and strokes,” Sever said in the release. “We know that there is a small increase in the risk of diabetes, and at high doses there is a very small increase in myopathy, but overall the benefits greatly outweigh the harms. Widespread claims of statin intolerance still prevent too many people from taking an affordable, safe and potentially lifesaving medication.”
In a related editorial, Juan Pedro-Botet, MD, from the lipid and vascular risk unit at
Hospital del Mar in Barcelona, Spain, and Juan Rubiés-Prat, MD, from the department of medicine at Universitat Autònoma de Barcelona, wrote: “Clinicians should be fully informed about potential nocebo effects, including patients’ previous knowledge or perceptions of statin therapy, and discuss the evidence for [statin-associated muscle symptoms] with patients.”
They concluded that: “Given that statins are among the best evidence-based lipid-lowering tools available and suitable for many patients, prevention of intolerance is paramount. Thus, physicians should alert their patients to possible statin-associated side effects without raising negative expectations. Further, they should encourage patient understanding of the rationale for statin treatment, which could optimize and facilitate shared decision making on statin therapy.” – by Erik Swain
Disclosure: Pedro-Botet reports receiving lecture honoraria from AstraZeneca, Esteve, Ferrer, Merck, Mylan and Sanofi. Rubiés-Prat reports no relevant financial disclosures. Sever reports receiving speakers’ honoraria from Amgen and Pfizer. Please see the full study for a list of the other researchers’ relevant financial disclosures.
Perspective
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Joseph S. Alpert, MD
These findings absolutely confirm what I thought for a very long time. The incidence of muscle-related adverse events is low, and these events were reported much less when the patients were blinded than when they were told they were on a statin.
Patients come in having read that statins may give them muscle aches or pains. However, musculoskeletal issues are the No. 1 reason why people go to their primary care doctor. These are extremely common, especially in elderly individuals, who often wake up with cramps, aches or pains. It’s one of the prices paid for achieving an advanced age. There are many reasons for these issues aside from statins.
While some other adverse events were more common among those taking statins, the incidences were low and the absolute differences were tiny.
Statin adherence is a huge problem. Fifty percent of patients with STEMI stop their statin within the first year, even though this is the drug that stands to make them last longer, with less chance of another MI, than any other drug we give them. I recently wrote an editorial in the American Journal of Medicine about the importance of encouraging high-risk patients to continue their statin therapy (Alpert JS. Am J Med. 2017;doi:10.1016/j.amjmed.2016.12.046). While some patients say they don’t want to put chemicals in their body, the reality is that taking these medicines is the best way to live longer and reduce the chance of MI.
I have seen some patients who have had tons of muscle aches and pains while on statin therapy, and have tried different statins and couldn’t tolerate them. But it’s a very small minority. My strategy for patients initially intolerant to statins is to give them 5 mg of rosuvastatin on Monday, Wednesday and Friday. It doesn’t produce as big an effect as if they took it every day, but very often, that quiets down the muscle aches or pains to a tolerable level.
To combat the nocebo effect, doctors should tell their patients about this study. Expectations of harm can often increase the likelihood of harm. Patients should be told not to expect muscle cramps from statins, because less than one in 50 people on statins get them, and many people not on statins get them. Help them realize the science has shown this is a very uncommon side effect. In fact, statins are well-tolerated, and a patient is more likely to see his or her grandchildren graduate from college if he or she takes them.
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Rita F. Redberg, MD, MSc
These findings do not change my opinion on the safety of statin therapy. I don’t think they reflect the experience of patients. Muscle-related adverse events in this study are much lower than reported in randomized trials and observational studies, as well as in clinical experience.
In the ASCOT study, the researchers didn’t actually ask about muscle-related adverse events at any of the follow-up visits. They wrote, “specific questions related to any putative adverse events were not asked at these visits.” It seems this is a case where if you don’t ask, you’re not going to get the information. In addition, they had several different definitions for muscle-related adverse events. What they’re highlighting seems to be one small category of them. They also report musculoskeletal and connective tissue disorders occurred in approximately 8% of patients in the blinded phase. That must have been a broader category, different from what they were reporting prominently.
If statin intolerance is a problem, the solution is to take a lower dose or not take a statin at all. We know that side effects increase with higher doses. In primary prevention, I believe most people are better off without statins, but if a patient who could clearly benefit from them is intolerant, the goal is to take as low a dose as possible and try different preparations.
Any time people take pills, they feel side effects, but we can’t discount what people are feeling. A lot of people report muscular-related side effects with statins — often more than 50% in observational studies — and I don’t think it’s the nocebo effect. A few years ago, the same group of researchers led a session at the European Society of Cardiology Congress on PCSK9 inhibitors, and they said a reason they were interested in PCSK9 drugs was the rate of muscle-related side effects in statins was so high, on the order of 40% to 50%. By any measure, the rates reported in the current study are extraordinarily low.
If we want to have a rich discussion of adverse effects from statins, the Cholesterol Treatment Trialists should make their data publicly available. They said they would do so several years ago, and we are still waiting for that.
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