Another randomized trial, on the heels of the recently published SAMSON, has concluded — many would say confirmed — that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.
Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.
The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be due to a nocebo effect; that is, they are attributed to the drugs — perhaps due to negative expectations — but not actually caused by them.
The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study due to such symptoms, or in patient quality of life.
The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online February 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine, United Kingdom.
“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the UK non-profit Science Media Centre.
“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Smeeth, who is senior author on the trial publication.
Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced — depending on what they learned in the trial — to stay on the drugs.
It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”
But there was a “slight caveat,” Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”
Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.
“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Smeeth said.
“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield, United Kingdom, in a Science Media Centre press release on StatinWISE.
Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
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Rechallenge Is Possible
Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.
“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol but not involved with StatinWISE.
“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”
And, Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician–patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.
“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, told theheart.org | Medscape Cardiology.
“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.
“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin-intolerant, they really should fail three statins, which would be a very good standard.”
In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80% to 90% of patients who believe they are statin-intolerant due to muscle symptoms are actually not statin-intolerant at all.
“I think a massive amount of it is supratentorial,” Moriarty, who was not part of StatinWISE, told theheart.org | Medscape Cardiology. It comes directly from “what they heard, what they read, or what they were told — and at their age, they’re going to have aches and pains.”
Value of the N-of-1 Trial
Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins due to muscle symptoms to give the drugs another chance.
In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.
So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except — as previously reported — it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.
StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Chico added in the Science Media Centre release.
“I often encounter people who have a firmly held view that statins cause muscle pains even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment’,” he said.
Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.
More efficient and useful, Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”
He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
No Statin Effect on Muscle Symptoms
Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.
The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% CI, –0.36 to 0.14; P = .40).
Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio (OR) of 1.11 (99% CI, 0.62 – 1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77 – 1.94).
Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were due to “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug — 9% and 7%, respectively — throughout the 1-year study.
“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.
“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”
StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.” Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from GlaxoSmithKline and AstraZeneca. Stone reports no industry relationships or other disclosures. Nissen reports that his center has received funding for clinical trials from AbbVie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Pfizer, The Medicines Company, Silence Therapeutics, Takeda, and Orexigen; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Chico had no conflicts. Moriarty declared no relevant conflicts of interest. Samani had no disclosures.
BMJ. 2021;372:n135. Full Text