In patients who previously discontinued statins due to side effects, nocebo effect was present
A Three-arm N-of-1 Trial With Statin, Placebo and Tablet Free Periods, to Verify Side Effects and Identify Their Cause: The SAMSON trial
Presented during the AHA Scientific Sessions 2020 by James Philip Howard, Imperial College London, UK.
Introduction and methods
Studies showed that more than half of patients stop taking statins within two years of initiation. Yet, in placebo-controlled trials, no more patients stop taking statins compared to patients stopping placebo. A patient suffering from side-effects from statins gains no help from data on thousands of patients in placebo-controlled statin trials Therefore, the SAMSON study was performed to examine this contradiction.
In SAMSON, 60 patients who stopped taking statin due to intolerable side effects were included. They were given 4 months medication bottles containing statins 20 mg, 4 containing placebo and 4 empty bottles. They took each of these treatments during one month in a prespecified randomized order. Symptoms were reported on a scale 1-100 on their smartphone. Symptom burden was expected to be low during period of empty bottles, intermediate during intake of placebo and high during statin use. If side effects were caused by the nocebo effect, symptom burden would be as high as with statins. Ratio of levels of symptoms burden by statins vs. placebo was calculated to determine the nocebo effect; the nocebo proportion. In addition, 6 months after the SAMSON trial, participants were asked whether they were back on statin treatment.
Patients with symptoms arising within 2 weeks were enrolled to ensure symptoms would recur during study treatment period. Patients with any symptoms that led to discontinuation (not necessarily muscle symptoms) were eligible.
- Levels of symptoms was substantially higher during the statin period compared to the no treatment period (P<0.001). However, level of symptoms was also substantially higher during the placebo period compared to the no treatment period (P<0.001) and there was no difference in symptom level between the statin period and the placebo period (P=0.368).
- The calculated nocebo proportion was 0.90.
- Six months after the trial, 50% of participants were back on statin treatment.
The SAMSON trial showed that patients really do get side-effects from statin tablets, but 90% of symptom burden in patients who previously discontinued statins is elicited by placebo tablets too. The authors stated that side effects by statin tables are mainly caused by the act of taking tablets, not what is in them. Finally, they said that the n-of-1 design comprising active treatment, placebo and no treatment may help explore etiology symptoms.
The discussant Francine Welty, MD, PhD (Boston, MA, USA) discussed some limitations of the study, such as lack of a washout between the treatment arms and limitation of enrolment of subjects who developed symptoms within 2 weeks on a statin (non-drug related side effects of medications are often greater during the initial weeks of treatment). Furthermore, she wondered whether a longer duration of treatment may have resulted in a greater difference between placebo and statin.
- Our reporting is based on the information provided during AHA Scientific Sessions 2020 -