Blinded placebo-controlled trials may top the hierarchy of scientific evidence, but unblinded personal N-of-1 experiments may be just as effective at increasing statin uptake, new research suggests.
“What it does is sort of harnesses the way that people — and we don’t like it as physicians — actually do their own experiments,” Paul Aveyard, PhD, University of Oxford, United Kingdom, said. “What we’re doing is saying, okay, let’s work together on this but let’s do it scientifically, so that you yourself can draw sound conclusions on whether the medicine is really causing side effects.”
To achieve this, the researchers enrolled 93 patients (mean age, 73.9 years; 43% male) who stopped or refused statins despite clinical indications and randomly assigned them to primary-care-physician delivered behavioral counseling with either an unblinded or blinded N-of-1 trial or to usual care without counseling.
The unblinded group alternated between atorvastatin 20 mg for 4 weeks and then off for 4 weeks for 6 months, whereas the blinded group received capsules in 4-week blocks that included either an encapsulated atorvastatin tablet or filler only. Patients reported symptoms on each day of the last week of each 4-week period.
Counseling included information designed to address participants’ concerns about statins by endorsing statins’ cardiovascular benefits, explaining their mechanism of action, and the prevalence of adverse events in clinical trials versus routine practice.
In all, 28 of the 36 unblinded patients and 28 of 37 in the blinded group attempted the N-of-1 experiment, and 71% and 82%, respectively, completed the 6-month study and received physician feedback.
As reported in Circulation Cardiovascular Quality Outcomes, nearly half, or 45%, of patients restarted or began statins in the N-of-1 trial groups, compared with 20% of control subjects (95% CI, 5% to 43%; P = .041).
There was no difference in uptake between the unblinded (44%) and blinded (46%) groups (95% CI, –20% to 24%; P = .86).
This may be because adverse events, including pain, were equally common when on versus off statins, the authors suggest. Participants reported symptoms on 3 or 4 days in total on and off statins in the unblinded (mean, 3.3 and 3.8 days, respectively) and blinded (3.4 and 3.5 days, respectively) groups. Mean pain and interference scores were very low, at 0.3 out of 10 and similar between groups.
Participants who completed daily reports reported having physical symptoms on one-fifth of the days: 20.4% of days on statins and 22.3% of days off statins in the unblinded group, and 20.9% and 22.4% of days, respectively, on and off statins in the blinded group.
Unblinded patients attributed nearly half the symptoms to the statin when on statins but only a fifth of symptoms to statins when off the drug. They were also more certain of their attributions than in the blinded group.
Several blinded trials have failed to show an excess of adverse effects with statins compared with placebo. The recent N-of-1 SAMSON study, for example, reported that 90% of symptoms attributed to statins were due to the nocebo effect, or the act of taking the pills rather than any pharmacologic effect.
“If a physician can persuade people to take statins because SAMSON shows them that it makes no difference whether they’re on statins or placebo, they get the same amount of side effects, then they don’t need this,” Aveyard said. “But people will say that’s all very well, but I take a statin and I experienced side effects from it.”
He also noted that unblinded experiments bypass the need for placebos, which are out of reach for the ordinary clinician at, £13,000 (US$18,000) to create encapsulated placebos for 36 patients.
“So in the trial, we tested the blinded, as it were, full-on best way of doing it against the cheap and cheerful way of just alternating medication on and off,” he said. “And it seems to be working. But the key thing is that people have to monitor their symptoms, even when they’re off medication, because that way they realize they still get symptoms.”
The authors conclude that the results suggest patient concerns about statin tolerability stem mainly from misattributing symptoms to statins, rather than nocebo effects.
An accompanying editorial points out that SAMSON suggests otherwise and that the nocebo effect may explain why up to 50% of patients taking statins have stopped them within 2 years, despite blinded randomized trials.
“We applaud Tudor et al for showing that we can help many patients who have stopped statins due to side effects with an unblinded approach. This is certainly easier and cheaper to run than the trials that preceded it. However, this is at the price of being able to tease out the true etiology of what our patient is experiencing,” James Howard, PhD, MRCP, a SAMSON investigator, and Skanda Rajasundaram, BMBCh, Imperial College London, write.
The editorialists note that atorvastatin is available in 10, 20, 30, 40, 60, and 80 mg tablets, but question whether future licensing laws could require a small number of 0 mg tablets be created as well.
“These tablets could then be prescribed by doctors, have their labels removed, and serve as cheap and perfect placebos for patient-run N-of-1 trials using a simple symptom diary,” they say. “Until then, maybe unblinded trials are the next best solution.”
Aveyard acknowledged the study wasn’t adequately powered to detect a difference between the blinded and unblinded arms, but said the aim was to set the stage for a larger feasibility trial in the United Kingdom.
“It’s all very well knowing that unblinded interventions help people using statins, but what can the practicing cardiologist, general internist, family practitioner do about that? Absolutely nothing. They can’t get hold of placebos,” he said. “So, we’ve got to find different ways of doing this and that’s what the unblinding was about. This gives us enough of a signal to take this unblinded arm into a full-scale trial to see whether indeed we get people to use statins long-term.”
The study was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the NIHR Oxford and Thames Valley Applied Research Collaboration (ARC). Coauthors Kate Tudor, Jenny Brooks, and Paul Aveyard are in part funded by the Oxford BRC and Oxford ARC. Howard and Rajasundaram report having no relevant financial relationships.
Circ Cardiovasc Qual Outcomes. Published online June 14; 2022. Full text, Editorial
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