Allowing patients to see that most of the side effects they had attributed to a statin were no less with a placebo convinced half to go back on the lipid-lowering drugs, the SAMSON trial showed with a clever design.
The N-of-1 trial randomized 60 patients to alternating 1-month periods of 20-mg atorvastatin, placebo, and an empty pill bottle in a blinded fashion for 1 year, with daily symptom check-ins on a smartphone app.
Mean symptom intensity on a 100-point scale was higher when people were taking a pill — 8.0 during no-tablet months compared with 15.4 on placebo and 16.3 on the statin (both P<0.001) — but without a significant difference between placebo and the statin (P=0.39).
Comparing individual patients to their own results, placebo actually looked more than twice as bad for symptoms as statins due to some outliers among the patients, reported James Howard, PhD, of Imperial College London, at the virtual American Heart Association (AHA) virtual meeting and online in the New England Journal of Medicine.
Pooling the results across patients, 90% of the symptoms could be attributed to the so-called nocebo effect (0.90 ratio of placebo symptoms beyond those on no treatment to statin symptoms beyond those of no treatment).
Once provided the data, 30 of the 60 patients — all of whom had previously quit taking a statin due to side effects that emerged within 2 weeks of starting it — successfully restarted a statin and were on it 6 months later.
“SAMSON leaves no doubt that patients really do get side effects from statin tablets,” Howard said, but while “very real, they are mainly caused by the act of taking tablets, not the statin.”
That statin-related complaints are a problem of perception will not come as news to clinicians, commented Steven Nissen, MD, of the Cleveland Clinic. His prior GAUSS-3 trial had showed in 2016 that 60% of intolerable muscle symptoms reported with multiple statins actually didn’t stem from the statin in about 60% of patients based on a blinded placebo challenge for enrollment purposes.
“It does give a pretty consistent message that a lot of statin-intolerant patients can, in fact, tolerate a statin if you try hard enough,” he told MedPage Today.
In the clinic, an N-of-1 challenge might be useful for individual patients but challenging, Nissen noted.
“It’s very encouraging, it shows that it’s a strategy that we could potentially employ,” he said. “The problem of course is you have to consent people to do this. That’s problematic. How many doctors are going to do an informed consent in order to get a patient to do this? How easily can you get placebos for atorvastatin? There are practical problems with doing this in clinical practice.”
While “very elegantly done,” the trial didn’t use a washout period between treatments, which might have biased the findings to the null, commented Salim Virani, MD, PhD, of Baylor College of Medicine in Houston and American College of Cardiology Prevention of Cardiovascular Disease Council chair.
Also, “in practice, many patients develop symptoms later than 2 weeks, so these findings cannot be generalized to them,” cautioned AHA session discussant Francine Welty, MD, PhD, of Beth Israel Deaconess Medical Center in Boston. She noted that in the SEARCH trial, nearly all of the people with genetic predisposition to statin-induced toxicity who developed myalgias did so beyond the first month of treatment.
“Non-drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time,” she stated.
SAMSON’s findings shouldn’t make physicians dismissive of statin-related muscle or other symptom complaints, Virani argued.
“Even if we go by these results, there is 10% of the effect that is related to statin therapy,” he told MedPage Today. Accept the patient’s symptoms, then talk about what to do now, he suggested from his experience running a dyslipidemia clinic. “Reassure the patients that almost all of these side effects are reversible, [explain] what are the benefits of taking statin therapy, work with the patient, have a positive attitude.”
Those discussions take time but are worthwhile, he said, pointing to the potentially life-saving effects for high-risk individuals and the fact that so many of the participants were willing to go back on statins.
Howard agreed, arguing that physicians need to take these complaints head-on. The usual strategy of trying a different statin is reasonable, but starting them at a low dose and working up may actually contribute to the nocebo effect by sending the message that you do expect side effects at some dose, he pointed out.
These findings suggest that the most powerful antidote is to explain the evidence and what the real expectations are, he told reporters at a press conference. “We may need to be a little more optimistic about statins…because the nocebo effect can only really rear its head if the patients are expecting to feel worse.”
Last Updated November 15, 2020
The study was funded by the British Heart Foundation.
Howard disclosed support from Wellcome Trust.
Virani disclosed support from the Department of Veterans Affairs, World Heart Federation, and Tahir and Jooma family.