Muscle Pain Reported Mostly by Those Aware They're on Statins: ASCOT-LLC Analysis

Fran Lowry

May 05, 2017

LONDON, UK — When prescribing a statin, doctors should be aware of the nocebo effect, judging from an analysis of adverse events on and off active therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA)[1].

In the trial, conducted from 1998 to 2005 with both double-blinding and an open-label phase, an excess rate of muscle-related adverse events appeared only when patients and their doctors were aware that statin therapy was being used, according to a new analysis.

"In our study, we are unable to show any difference in side-effect profiles between placebo and the statin, so we cannot attribute side effects that are reported in observational studies as being due to the drug," senior author Dr Peter Sever (Imperial College London, UK) told heartwire from Medscape.

The upshot is that "most patients who complain of minor side effects on statins, particularly muscle aches and pains, can no longer attribute this specifically to the statin," he said.

"They are experiencing something called the nocebo effect, widely recognized in medicine, that can result when doctors make their patients aware that some side effects may occur with the tablets they are prescribing. There is a real chance that the patients will then develop those side effects."

The ASCOT-LLA follow-up analysis was published May 2, 2017 in the Lancet.

Truth Between the Extremes

According to Dr Steven Nissen (Cleveland Clinic, Cleveland, OH), the issue of patients thinking they have muscle aches and pains as a result of their statin use "comes from patients doing too much surfing on the internet, and they come up with this idea."

On the other hand, Nissen, who wasn't connected with the analysis, said it would also be wrong to claim that muscle aches on statins are virtually never a real phenomenon.

"There are flaws in this analysis," he told heartwire . "First of all, it's a 20-year-old study that used the lowest dose available of atorvastatin. Many of the people who have symptoms are going to have them at the higher doses, so that's one issue.

"The truth is somewhere between the extremes," Nissen said. "I think the truth here is that there are people who have statin-associated muscle symptoms, but it's certainly not everybody, and the nocebo effect is real and does occur in some people."


The original objective of the trial was to determine the best combination of drugs to treat hypertension, but the ASCOT investigators decided to add a lipid-lowering arm to include patients with high cholesterol in addition to elevated blood pressure.

Patients aged 40 to 79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol 6.5 mmol/L or lower who were not taking a statin or fibrate, had no history of MI, and were not being treated for angina were randomized to receive atorvastatin 10 mg daily (n=5101 patients) or placebo (n=5079 patients) in the randomized double-blind placebo-controlled phase of the trial.

This phase continued for 3 years and was halted when the benefits for patients on atorvastatin became so apparent that it was considered unethical to continue having patients receive placebo.

At this point, patients continued in the blood-pressure portion of ASCOT and were asked if they would also like to receive atorvastatin. Roughly two-thirds of the patients said yes, and one-third said no. This unblended, nonrandomized phase was done between December 2002 and June 2005.

Sever and his team included 9899 patients in the analysis of this phase: 6409 patients (65%) on atorvastatin and 3490 (35%) on placebo, with a median follow-up of 2.3 years.

In addition to muscle-related adverse events, the investigators also looked at erectile dysfunction, cognitive impairment, and sleep disturbance.

As the group reported, during the blinded phase of the trial, reports of muscle-related adverse events and erectile dysfunction were similar in both statin and placebo groups. Reports of cognitive dysfunction were extremely rare.

The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than placebo (149 per year for atorvastatin patients compared with 210 for placebo patients).

There was an excess of renal and urinary adverse events among patients randomized to atorvastatin (481 per year) vs 392 per year in patients randomized to placebo.

By contrast, during the nonblinded, nonrandomized phase, muscle-related symptoms were 41% more common among people taking atorvastatin compared with those who opted not to take the statin (1.26% vs 1.00% per year; P=0.006).

"Prevention of Intolerance Is Paramount"

The study is highly relevant "in support of the fact that statins do not significantly increase the risk of muscle pain," write Dr Juan Pedro-Botet (Hospital del Mar, Barcelona, Spain) and Dr Juan Rubiés-Prat (Universitat Autònoma de Barcelona, Spain) in an accompanying commentary[2].

They agree that the excess of muscle-related adverse effects associated with atorvastatin therapy that was seen only in the nonblinded phase of the trial is consistent with a nocebo effect.

"Given that the statins are among the best evidence-based lipid-lowering tools available and suitable for many patients, prevention of intolerance is paramount. Thus, physicians should alert their patients to possible statin-associated side effects without raising negative expectations. Furthermore, they should encourage patient understanding of the rationale for statin treatment, which could optimize and facilitate shared decision making on statin therapy," they conclude.

Other Limitations

Nissen had further reservations about the ASCOT-LLC analysis, beyond the use of less-than-contemporary atorvastatin dosages. Another "is that these were casually reported symptoms, sort of spontaneous adverse-event reporting. If you want to know whether people have statin-associated muscle symptoms, you have to have a formal process for querying people about their symptoms. The investigators did not do that. There's no rigor in the way the data were collected," Nissen said.

"The study was not done with the idea of collecting information on statin-associated symptoms, which means that there may have been lots of people in the study who had symptoms that were never written down," he said.

Nissen called attention to a "much more rigorous" study that he headed, GAUSS 3, in which "we went about systematically collecting the information. And we did in fact see that there were a lot of people who had the nocebo effect, but there were also people who had real symptoms," he said.

"If people complain about statins, we always try to work with them, reassure them. We try different statins, we try adjusting the doses, we do everything we can because these drugs obviously have very important benefits. You don't give up because patients complain idly about a symptom."

The study was funded by Pfizer, Servier Research Group, and Leo Laboratories. Sever reports that his institution held a grant for the conduct of ASCOT in the UK and Ireland; he has also received speaker's honoraria from Pfizer and Amgen and is a recipient of the National Institute for Health Research Senior Investigator Award and supported by the BioMedical Research Centre Award to the Imperial College Healthcare National Health Service Trust. Disclosures for the coauthors are listed in the paper. Pedro-Botet reports receiving lecture honoraria from AstraZeneca, Esteve, Ferrer, Merck, Mylan, and Sanofi. Rubies-Prat reports no relevant financial relationships. Nissen reports receipt of grants from Amgen, Pfizer, Esperion, Lilly, AstraZeneca, the Medicines Company, Takeda, Orexigen, Novo Nordisk, and Novartis.

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