When Unblinded to Statin Therapy, Patients’ Muscle-Related Adverse Events Shoot Up: ASCOT Analysis


ROME, Italy—In the latest study to question statin side effects, use of the drugs was not associated with an increased risk of muscle-related adverse events compared with placebo when patients and physicians involved in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) were blinded to the study treatment.

However, when the trial was completed and treatment unblinded, individuals who continued with statin therapy in the observational, nonrandomized extension of ASCOT were significantly more likely to report muscle-related side effects compared with those not on statins.

“So, what do we make of these findings?” asked lead investigator Ajay Gupta, MD (Imperial College, London, England). “These data suggest there is no evidence for increased adverse events associated with the use of statins. The reported excess of muscle-related adverse events in observational studies is possibly due to confounding by knowledge of the use of statins among patients and physicians alike, and compounded by the widespread adverse media publicity. [This] is the so-called ‘nocebo’ effect.

The observational data differ sharply from the findings from randomized, controlled clinical trials, said Gupta. For example, in one large meta-analysis of 26 randomized statins trials, there was no significant increased risk of muscle-related adverse events among patients treated with statin therapy. Comparatively, observational studies have suggested that as many as one in five patients treated with statins develop some sort of side effect, the vast majority of adverse events being muscle-related.

Presenting the analysis at the European Society of Cardiology Congress 2016 in Rome, Italy, Gupta added that recent studies have suggested there has been a reduction in the uptake of statins, including in patients at high risk for cardiovascular events, while other studies have shown patients are not sticking with the lipid-lowering therapy. “Some of this can be attributed to a recent spurt of adverse publicity,” said Gupta. “Most of these media reports are based on the observational data and anecdotal case reports.

ASCOT Stopped Early for Clinical Benefit

In ASCOT, 10,305 patients eligible for lipid-lowering therapy were randomized to treatment with atorvastatin 10 mg or placebo. The blinded, randomized arm of the study ran for 3.3 years, at which time statin therapy reduced the risk of death from coronary heart disease and nonfatal MI by 36%. At the completion of the lipid-lowering arm of ASCOT, which was stopped early because of the benefit of atorvastatin, patients were followed as part of the blood pressure-lowering arm of the trial and offered statin therapy. Of these patients, two-thirds in the statin and placebo arms began treatment with atorvastatin 10 mg while the remaining one-third were nonusers. The nonrandomized, observational extension ran for 2.2 years.

In the blinded, randomized phase of ASCOT, there was no significant increase in definite or probable muscle-related adverse events, nor were there increases in the risks of erectile dysfunction or cognitive impairment. Gupta noted that the number of cognitive events in both arms was too small to make confident judgements about the risk of statin therapy on this endpoint. Sleep disturbances were significantly reduced in the statin-treated patients, however.

In contrast, there was a 41% increase in muscle-related adverse events among 6,409 statin users in the unblinded extension study when compared with 3,490 non-statin users (HR 1.41; 95% CI 1.10-1.79). In the extension arm, there was no effect of statin therapy on the risk of sleep disturbances, erectile dysfunction, or cognitive impairment.

During the clinical trial update session, Gupta noted that a recent study by Anthony Matthews, MD (London School of Hygiene and Tropical Medicine, England), and colleagues, which was reported by TCTMD, showed that high-profile, negative media reports suggesting statins are associated with side effects have resulted in an increase in primary- and secondary-prevention patients stopping their statin. With ASCOT, however, the trial was conducted in an era before statins were so scrutinized in the media, so researchers were unable to link the muscle-related adverse events with negative stories.

Speaking with TCTMD, Richard Chazal, MD (Lee Memorial Health System, Fort Myers, FL), who co-chaired ESC session with David Wood, MD (Imperial College, London), said the issue of myalgia in statin-treated patients is “extremely common” in clinical practice. The onset of muscle pain is confounded by the age of the patients, many of whom are at the stage in life where aches and pains are common. The randomized, blinded data from ASCOT—showing no evidence of muscle-related or other adverse events—is consistent with multiple randomized trials.

“But in contrast, the second part, the unblinded aspect of ASCOT, is consistent with clinical practice and what we see in real life, and that is we have a significant number of patients who have symptoms like this,” said Chazal. “But a lot of this [occurs] before you even start them on statins, such as patients that have already decided they are intolerant to statins based on something they’ve read that is not science-based, or is based on advice they’ve gotten from people.”

Chazal, the current president of the American College of Cardiology, said he even uses a personal anecdote when dealing with statin-reticent patients. Shortly after he started taking a statin, he developed severe muscle cramps in his lower leg over the first couple of days. Cognizant of the published data and intent on being on a statin, he persevered, and the cramping went away. “My point of the story is if I had stopped the statin after the second [cramping] episode and it didn’t recur, I’d have put my hand on the bible and sworn I was intolerant to statins.”

The ASCOT data, he said, will also help in his discussions with patients concerned about muscle pain, particularly those individuals who really need to be treated with statin therapy. In his practice, true statin intolerance is extremely rare, he said, noting that patients with muscle pain can be switched to another agent, have their dosage lowered, or even stopped and successfully rechallenged with the same drug.

“It takes time to have these conservations,” Chazal acknowledged, but he noted his patients are receptive to the discussion highlighting the benefits of statins and the rarity of true intolerance.

In response to the public concern about statin safety driven by the observational studies and media coverage, even the venerable Cholesterol Treatment Trialists’ (CTT) Collaboration have launched a new meta-analysis to assess the relative and absolute risk of adverse events with statin therapy.

 


 

 

 

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Sources
  • Gupta A. The influence of blinding and un-blinding on statin related adverse events (AEs): new evidence from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Presented at: European Society of Cardiology Congress 2016. August 28, 2016. Rome, Italy.

Disclosures
  • The ASCOT analysis was supported by a research grant from Pfizer and the Foundation for Circulatory Health.

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