‘Nocebo effect’ may explain many cases of statin intolerance: SAMSON
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Patients who developed symptoms within 2 weeks of statin initiation reported similar side effects while on placebo, suggesting a large proportion of burden owed to the nocebo effect, according to findings from the SAMSON trial.
According to research presented at the virtual American Heart Association Scientific Sessions, when this nocebo effect was revealed to these patients, who had initially discontinued statin therapy due to adverse effects, half were open to resuming treatment.
“We frequently see patients who have stopped taking statins due to the side effects. Yet, studies actually show that more than half of patients abandoned statins completely within 2 years of starting them; and yet, in placebo-controlled trials, no more people stopped statins than stopped placebos,” James P. Howard, PhD, Wellcome Trust PhD Fellow and cardiology registrar at Imperial College London, said during his presentation. “So, we designed a study to solve this contradiction because a patient who is suffering side effects from statin tablets gains no help from the experience of thousands of other people in placebo-controlled trials because their key question is, ‘Why is this happening to me?’”
The study was simultaneously published in The New England Journal of Medicine.
For this double-blind, three-group, n-of-1 trial, investigators enrolled 60 patients (mean age, 66 years; 58% men; 90% white) who had previously discontinued statins due to side effects that occurred within 2 weeks of therapy initiation of treatment to determine whether symptoms attributed to discontinuation were caused by a statin or placebo.
Participants were given four bottles of atorvastatin 20 mg, four bottles of a placebo and four empty bottles, with each bottle taken for a 1-month period according to a random sequence.
Via smartphone app, participants reported daily symptom scores, which ranged from 0, or no symptoms, to 100, the worst imaginable symptoms.
“If the side effects were caused by the statin molecules, the placebo months would have been down at the level of the empty months. But if the side effects were caused by the nocebo effect, then the placebo would be just as bad as the statin,” Howard said during the presentation. “We also wanted to see if taking part in SAMSON could directly help our patients. So, we asked each of them 6 months after they finished this trial if they had been able to go back onto clinical status, which they had previously believed they needed to abandon for good.”
Symptom severity
Overall, the mean reported symptom severity scores were:
- 8 for no treatment (95% CI, 4.7-11.3);
- 15.4 for placebo (95% CI, 12.1-18.7); and
- 16.3 for statin therapy (95% CI, 13-19.6).
Investigators found that difference in symptom severity reported for placebo compared with statin therapy was not clinically significant (P < .388); however, side effect severity was significant for both stain and placebo compared with no treatment (P for both < .001).
According to the results, the calculated nocebo ratio was 0.9.
“What does SAMSON tell us? SAMSON leaves no doubt that patients rarely do get side effects from statin tablets, [but] 90% of this burden is elicited by placebo tablets too,” Howard said during the presentation. “Therefore, the most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking tablets and not the statin contained within.”
Understanding nocebo and resuming therapy
In addition, 6 months after the conclusion of the trial, half of all participants resumed statin therapy.
“Regarding what SAMSON will change; first, patients need to be taken seriously when they report side effects,” Howard said. “Second, because this n-of-1 design has built-in no-tablet periods, participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect, and this led to half of them happily restarting statins. Finally, we hope that this novel study will be able to help our patients and other researchers answer questions about medications in their own fields. We believe that SAMSON could be a truly seminal trial design.”
Discussant Francine K. Welty, MD, PhD, associate professor of medicine at Harvard Medical School and cardiologist at Beth Israel Deaconess Medical Center, said during the press conference: “The most important implication is those with symptoms within 2 weeks of starting the statins should be reassured that about half will be able to successfully restart. In practice, many patients do develop symptoms later than 2 weeks, so these findings cannot be generalized to them. For example, in the SEARCH trial, 85% to 90% develop their myalgias after the first month of treatment.
“There was also no wash-out period between each 1-month treatment arm,” Welty said. “If subjects developed symptoms during atorvastatin and then went to placebo, there is possibility that there was carryover of symptoms into the placebo arm.”
Reference:
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Kim Allan Williams Sr., MD, MACC, FAHA, MASNC, FESC
SAMSON was very encouraging to me in that I have had some fairly good results working with people who are statin intolerance to find a dose to get them to tolerate it. One technique I use is to turn the computer screen toward the patient and have them watch me Google two words, statin and mortality. When you hit the images, all these Kaplan-Meier plots show up. I explain to them what a Kaplan-Meier plot is, and they see this huge difference. There is one that pops up on familial hyperlipidemia and illustrates using 12-year outcomes a massive death rate if you're not on a statin and excellent survival if you are. Then there are other little graphs showing how people who stopped statins died; how if you are on a high-dose statin, you're better off than on a moderate dose, which is better than a low dose. All of this is right there where the patient can see it.
Then for the last few years, since the data came out from Medicare that it was going to be bankrupt in 2026, I actually tell the patient that one of the major contributors to that is statins, because you could not have anticipated the reduction in death from them.
After seeing those two things, people always try the next dose of statin. What I did not know until now was that I was unknowingly reducing the nocebo effect. I was changing their attitude.
It really does prove to us that attitude matters and that we ought to be thinking of that whenever we have adherence issues with any drug, but particularly statins.
In SAMSON, when patients were given the empty bottles, they were okay. When they were given a statin, they had problems if they were statin-intolerant. But if they received a placebo pill that looked like a statin, 90% of them were going to have pretty much the same problems. That is a striking piece of knowledge, that it is not the drug, it is the pill. We need to change that from the inside. We need to get people to feel like this medication is going to save their life.
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Pradeep Natarajan, MD
Statins remain among the most commonly prescribed medication classes in the world, and the risk for muscle adverse effects is well recognized. In most randomized controlled trials, such symptoms are reported in both placebo and statin arms at largely similar rates. However, in practice, patients are only prescribed statins, not placebos, and often experience various symptoms, but it can be challenging to prove that the symptoms are not due to the statin. Aspiring to do no harm and having an increasing armament of cholesterol-lowering medicines, physicians and patients may either avoid cholesterol-lowering medicines altogether or move on to a different class.
The SAMSON study now tests whether a small group of patients who report statin-associated adverse events also develop the same symptoms on placebo using random monthly crossover sequences over 12 months. The trial showed that 90% of these patients also had symptoms with placebo. This study indicates that statin-associated side effects are real but are less common than currently understood. While placebos are not recommended to vet putative statin-associated adverse effects in clinical practice, this observation may reassure physicians and patients to pursue statin rechallenges in most scenarios.
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Howard JP, et al. LBS.04: Fish oil, fancy drugs and frustrations in lipid management. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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