‘Nocebo’ effect explains 90% of symptoms in patients who quit statins because of side effects
Presenters: James Philip Howard, PhD, MB and Francine K. Welty, MD, PhD
An “n-of-1” study of patients who discontinued statin therapy because of side effects reveals similar intensity of symptoms between placebo and atorvastatin, both of which were significantly greater than symptom severity experienced during a no-tablet period. The findings from the Self-Assessment Method for Statin Side-effects Or Nocebo study (SAMSON) demonstrate a significant nocebo effect that, when explained to patients, enabled half of them to successfully restart a statin.1
Many people who start statins abandon them, yet placebo-controlled trials do not show excess withdrawals in the statin arms, said presenter James Philip Howard, PhD, MB, fellow at Imperial College in London, UK.
“SAMSON certainly leaves no doubt that patients really do get side effects from statin tablets, but what SAMSON shows us is that 90% of their symptomatic burden is elicited by placebo tablets, too,” he said. “Because this trial 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 our patients happily restarting statins.”
SAMSON enrolled 60 patients who discontinued statins because of any intolerable side effect that arose within 2 weeks of initiation. Patients were given four 1-month medication bottles containing atorvastatin 20 mg, four containing placebo, and four containing nothing (empty). These were taken in a specified randomized order, 1 per month, over 1 year. There was no washout period between arms. A smartphone was used to rate symptom severity daily on a scale of 1 to 100: if symptoms became intolerable, the tablets could be stopped for that month.
The mean age of participants was 65, and 77% were taking statins for primary prevention. Participants tried a median of 2 statins before abandoning treatment. Muscle aches were the reason for abandoning statin treatment in 65% of cases.
There were 71 stoppages of tablets, 31 while on placebo (median days to stop, 18) and 40 while on atorvastatin (median days to stop, 17).
The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001 vs no-tablet months), and 16.3 during statin months (P < .001 vs no-tablet months; P < .388 vs placebo months). The nocebo proportion (the ratio between incremental symptom severity while taking a placebo and the incremental symptom severity) was 0.9.
Of the 60 participants, 59 responded to a follow-up questionnaire at 6 months, at which time 30 of the 60 resumed taking a statin, 4 had planned to do so, and 1 was not able to be contacted, leaving 25 who did not plan to restart, 18 of whom stated side effects as the reason.
“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 the tablets, not by the statin that is contained within them,” said Dr. Howard.
In practice, many patients develop symptoms later than 2 weeks, so these findings cannot be generalized to them, and limiting enrollment to those who developed symptoms within 2 weeks of starting a statin could have biased the findings toward a nocebo effect, said discussant Francine K. Welty, MD, PhD, associate professor of medicine, Harvard Medical School, Boston.
Because statin stoppage increases the risks of stroke, myocardial infarction, and total mortality, management of side effects to permit treatment persistence is important, she said. Supplementing patients with vitamin D whose vitamin D level is below 30 ng/mL has been shown to improve statin tolerance.2
The Cleveland Clinic experience supports alternate dosing (ie, 2 to 3 times per week), she noted.3 In patients treated with alternate dosing, total mortality was 2% at 8 years, and similar to daily dosing, compared with 7% in those who discontinued statins (P = .08).
“In those who awaken at night with cramps, try morning dosing, because the cramps may occur during the day and may be less likely to affect lifestyle,” said Dr. Welty.
References
- https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AHA20&id=2195
- Saxon DR, Eckel RH. Statin intolerance: a literature review and management strategies. Prog Cardiovasc Dis 2016; 59(2):153–164. doi:10.1016/j.pcad.2016.07.009
- Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic Experience. Am Heart J 2013; 166(3):597–603. doi:10.1016/j.ahj.2013.06.004
Dr. Howard has disclosed no relevant relationships. Dr. Welty has disclosed financial interests (grant, research support, advisor, or review panel member) with Boehringer Ingelheim.