The phenomenon of non-adherence to statin therapy is well known. Reasons for discontinuation include elevated hepatic or muscular enzymes, neurological symptoms, and muscular symptoms collectively referred to as statin-associated muscle symptoms (SAMS).1 SAMS seems to occur less frequently in randomized control trials than in observational studies. These results suggest that SAMS may be attributable to other causes than the pharmacological effects of the statin – including the nocebo effect2.
Clinicians are first encouraged to rule out factors associated with an increased risk of statin intolerance.1 In addition, the likelihood of causality should be carefully considered based on regional distribution and characteristics of the complaint1. Finally, the clinician must ascertain that symptoms began within 4 weeks of initiating the statin. If so, the next step is to implement a dechallenge – rechallenge protocol. This involves withdrawal of the drug for a period of 4 weeks. Symptoms are expected to cease if the statin is the true cause for the SAMS. Next, the statin is re-initiated, and the patient is monitored for recurrence of the same symptoms.
Researchers from Imperial College London provided new insight into SAMS in their correspondence to New England Journal of Medicine.2 They designed a n-of-1 trial of atorvastatin, a placebo, or no treatment to evaluate side effects (Clinical Trials.gov: NCT02668016). A total of 60 patients who had previously discontinued statin therapy due to SAMS were enrolled in the trial. Each participant received four bottles containing a month’s supply of atorvastatin, four bottles containing a month’s supply of a placebo, and four empty bottles. Patients consumed bottle contents for one month at a time in accordance with a randomly generated sequence. They reported any perceived muscular symptoms, including severity.
The primary end point was the “nocebo ratio.” This ratio’s numerator is symptom intensity with placebo minus the symptom intensity with neither statin nor placebo. The denominator is symptom intensity with a statin minus the symptom intensity with neither statin nor placebo. After pooling individual patient data, the nocebo ratio was calculated to be 0.90.
Symptom severity was rated from 0 (no symptoms at all) to 100 (worst imaginable). Among all 60 patients, the mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months, and 16.3 during statin months.
Patient expectations of statin treatment
In patients who had discontinued their statins due to SAMS, 90% of the symptoms reported while taking the statin were also reported with taking the placebo (= nocebo effect). Of the 60 participants in the trial, half (30) were able to successfully restart statins. Four others planned to do so, and one was uncontactable.
The remaining 25 who were off statins did not plan to restart them. Of these 25, 18 were still hesitant due to side effects. Four others reported that their cholesterol levels had improved such that they no longer required a statin. One stated that their cholesterol level was unresponsive to a statin. One other had received a new diagnosis of a progressive neurodegenerative disorder. Finally, one reported simply that they were “too old” to restart a statin.
Interestingly among all 60 patients, the mean symptom intensity was 8.0 during no-tablet months (95% CI, 4.7 to 11.3), 15.4 during placebo months (95% CI, 12.1 to 18.7; P<0.001 relative to no-tablet months), and 16.3 during statin months (95% CI, 13.0 to 19.6; P<0.001 relative to no-tablet months. When symptom intensity was compared between statin and placebo months, there was no significant difference (P=0.39). Thus, many patients demonstrated a nocebo effect whereby their symptoms were likely the result psychological impact perhaps due to a negative expectation of statin treatment.
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Author: Kelly Schoonderwoerd