Both Statins and Placebos Produce ‘Very Real’ Side Effects: SAMSON

 

(UPDATED) Patients taking statins for LDL cholesterol-lowering experience very real side effects from treatment, but the vast majority also report side effects from a placebo, according to the results of the SAMSON trial. With a little effort, though, half of patients who stopped treatment due to statin-associated side effects were successfully restarted on therapy.

The unique, n-of-1 clinical trial testing the nocebo effect of statin therapy, which was presented today during the late-breaking clinical trial session at the virtual American Heart Association 2020 Scientific Sessions, has very clear clinical implications, say researchers. 

“SAMSON leaves no doubt that patients really do get side effects from statin tablets,” lead investigator James Howard, MB BChir (Imperial College London, England), said during a morning press conference. “Ninety percent of this burden is elicited by the placebo tablet, too, and therefore, the most important message from SAMSON is that side effects from statins are very real, but they are mainly caused by the act of taking tablets and not by the statin contained within them.”

Howard stressed that patients “need to be taken seriously” when they complain about side effects, but said n-of-1 efforts, in SAMSON as well as in the doctor’s office, can clearly show patients they are reporting symptoms even when they are a taking a placebo. “Because this n-of-1 design has built in ‘no-tablet’ periods, participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. Half of them happily restarted statins,” he explained.

Kim Williams, MD (Rush University Medical Center, Chicago, IL), past president of the American College of Cardiology, called SAMSON fascinating, noting that he often conducts n-of-1 studies in practice, particularly around dietary interventions. Side effects related to statin therapy are a critical issue because the drugs save lives only if patients take them.

“If you have an indication for a statin and you don’t take it—it doesn’t matter what the reason is, whether you forgot, the doctor didn’t know the guidelines, insurance companies wouldn’t cover it, or if you have statin-associated muscle symptoms—the mortality rate is higher,” Williams told TCTMD. “So this trial is really important to get into the hearts and minds of doctors and patients, to understand that a lot of what we’re facing with statins is real.”

Similarly, Douglas S. Jacoby, MD (University of Pennsylvania Perelman School of Medicine, Philadelphia), who wasn’t involved in the study, said there is a substantial drop off in statin adherence even in patients who have had an MI, with less than half still taking the drug after 1 year. “Some people don’t believe there is a benefit [with statins], but that’s not most people,” he said. “Most people, they’re either afraid of statins or they’ve had side effects. There is a real problem with side effects out there.”

Overall, the nocebo effect observed in SAMSON line up with his clinical experience. 

“Fundamentally, people do have reactions to pills, and we know that placebo pills give people side effects,” he told TCTMD. “I have patients that can feel different on a brand name drug versus the generic. I have patients that do well on one generic and then another generic is filled by the pharmacy and they have side effects to that. All of this and the drug itself has stayed the same. I think this is a very clever study. I like how they did it. It’s good to have this proof behind us, but I think if you were going to bet [on the results], this is what you’d probably bet on.” 

SAMSON’s Strengths

Speaking with the media, Howard also pointed out that statin adherence remains extremely poor beyond 1 and 2 years. Despite this, there is no evidence of increased stoppages/withdrawals from treatment in the randomized, controlled clinical trials. With that contradiction in mind, the group designed the Self-Assessment Method for Statin Side Effects or Nocebo (SAMSON) trial “because the patient who is suffering side effects on statins gains no help from the experience of thousands of other people in the placebo-controlled trials,” he said.

Side effects from statins are very real, but they are mainly caused by the act of taking tablets, and not by the statin contained within them. James Howard

In total, 60 patients (mean age 65 years) with indications for statin therapy who stopped treatment within 2 weeks of initiation because of side effects were included in the study. Most patients in the trial (77%) were treated for primary prevention and had tried, on average, at least two statins before stopping treatment altogether. The main reasons for statin discontinuation were muscle aches (60%), fatigue/tiredness (15%), and cramps (10%). 

As part of the trial, all patients received four bottles of atorvastatin 20 mg, four bottles of a placebo tablet, and four empty bottles. Each bottle was used for 1 month according to a random sequence and patients were asked to track their symptom intensity daily using a smartphone application. The symptom scores ranged from zero (no symptoms) to 100 (severe symptoms), and if patients considered their symptoms too harsh they could stop taking the tablets for that month.

The mean symptom score for patients taking no tablets was 8.0, which was significantly lower than the scores of those taking atorvastatin and placebo. For the patients taking statins and those taking placebo, the mean symptom scores were 16.3 and 15.4, respectively, a difference that was not statistically significant. The calculated nocebo proportion—the ratio of symptoms experienced on placebo compared with symptoms on atorvastatin—was 0.90, meaning that 90% of symptom burden from statins was also elicited by placebo.

Six months after the completion of the trial, and after they had received information about their reported symptoms while on placebo, 30 of the 60 patients were successfully restarted on statin therapy.

Francine Welty, MD, PhD (Beth Israel Deaconess Medical Center, Boston, MA), who commented on the study during the late-breaking session, said that patients who develop symptoms within 2 weeks of starting should be reassured that there is a 50% chance they’ll be able to successfully restart treatment. However, she noted that many patients develop symptoms beyond that 2-week window and the SAMSON results can’t be generalized to them. For example, in SEARCH, roughly 85% of patients developed myalgia after the first month of treatment, she said.

Patients Aren’t Lying

To TCTMD, Amit Khera, MD (University of Texas Southwestern Medical Center, Dallas, TX), who served as moderator during the morning press conference and late-breaking trial session, said muscle aches, fatigue, and other side effects are relatively common with treatment. As a preventive cardiologist, he encounters many patients who are “ready to have this fight” over statin therapy and potential downsides.  

“If you look at the literature, about one in 10 patients develop side effects,” he said. “It is a very big problem considering the millions of patients on statins. My approach is usually what many people do: looking for secondary causes, then trying a different statin at a lower dose and then working my way up, or maybe trying a nonstatin agent. [With SAMSON], what we’re getting is a completely different strategy.”

In this n-of-1 trial, investigators tackled side effects “head-on” with patients to demonstrate that a lot of their symptoms were the result of their own negative perceptions, said Khera. “It’s a very different way to approach it,” he said. The SAMSON data, he added, provide more information he can bring to the shared decision-making discussion regarding statin therapy.

Howard told TCTMD that if a patient develops side effects with a statin, switching them to another drug or a lower dose is a very reasonable approach. However, in doing so, physicians are creating an impression that at some dose the patient isn’t going to feel particularly great, he said.

“The worry is that our trial data shows that probably most statin side effects, maybe not all but most, may be this nocebo effect and you may be fueling that,” said Howard. If physicians explained the evidence and fostered positive or optimistic expectations about treatment, many of these side effects wouldn’t arise. “The nocebo effect can only rear its head if the patient is expecting to feel worse, just as the placebo effect will only work if people are expecting to feel better.”

This trial is really important to get into the hearts and minds of doctors and patients, to understand that a lot of what we’re facing with statins is real. Kim Williams

Williams agreed, noting that all physicians need to be aware of the nocebo effect and be prepared to deal with it. “If your uncle had a problem with a statin and you knew about it, you start looking for that side effect,” he said. “That expectation crosses over from the statin to the placebo. It’s kind of shocking in a way, but this is human behavior. The mind can somaticize symptoms based on expectations.”

In his practice, Williams said at least one in five patients report statin-related side effects. The historical statin trials, he noted, all included a run-in period, which partly explains why the rates are so much lower compared with real-world practice. When a patient develops side effects on a statin, Williams does try another drug, or maybe the same drug at a lower dose or lower frequency, but he pointed out the clinical guidelines largely emphasize high-intensity statin therapy to slash LDL cholesterol for the majority of patients. When all this fails to resolve side effects—and that includes checking for secondary causes, such as hypothyroidism or low vitamin D levels—he turns to the PCSK9 inhibitors. 

Jacoby, a preventive cardiologist and lipidologist, frequently treats patients referred to him for statin-associated side effects. For those who have tried a statin but stopped because of muscle pain or weakness, among other reasons, Jacoby tells patients the side effects aren’t dangerous, just a nuisance, but that the option is there to try different medications to lower the risk of future MI and other ASCVD events.

“We agree that we’re going to try things together and then we talk about what we’re going to try,” said Jacoby. There are multiple statins available on the market, and patients might react poorly to one but not another. Like Williams, he’ll frequently start at the lowest possible dose. Ezetimibe, and the PCSK9 inhibitors are generally tolerated much better than statins and those agents, he said, are also very good options for patients.

“We set very aggressive goals in our preventive cardiology program,” said Jacoby. “In secondary prevention patients, those with known cardiovascular disease, I often target their LDL-cholesterol levels below 55 mg/dL. When I target these very aggressive LDL levels, more than one-third, probably closer to half, are also on a nonstatin agent in addition to statins, with ezetimibe and PCSK9 inhibitors the most common ones.”

SAMSON investigators initially planned to recruit just 50 study participants but they had an overwhelming response when the British Heart Foundation advertised the trial in their newsletter.

“We were so inundated with people wanting to take part, to find out for themselves whether they did truly have statin side effects, that we recruited 60 patients, more than we anticipated,” said Howard. “We only had to stop then because we ran out of placebo tablets.”