N-of-1 (Single-Patient) Trials for Statin-Related Myalgia

Joy TR, Monjed A, Zou GY, et al. 
Ann Intern Med. 2014;160(5):301-310-310.

Background

Statin-related myopathy includes myalgia (muscle symptoms without creatine kinase (CK) elevation), myositis (muscle symptoms with CK elevation) and rhabdomyolysis [1]. Although reported rates vary, statin-related myopathy appears to be common. It is clinically important because it may lead to patients discontinuing a therapy with proven cardiovascular benefits.
No highly specific diagnostic test exists, and CK levels are only slightly increased, if at all [2]. Myalgia and changes in CK levels  may also occur for other reasons. Muscle biopsies are invasive and may not be congruent with symptoms or CK elevations [3,4]. Hence, diagnosis of statin-related myalgia is often difficult, and primarily dependent on patients’ and physician’s impressions of causality during open-label statin therapy. This may lead to false conclusions that statins cause myalgia.
N-of-1 trials are single-patient, randomised, multiple crossover, blinded comparisons of an active vs. placebo treatment, and are the most effective way to limit biases in individual patients because each patient is his or her own control [5]. Thus far, this type of trial has not been used for statin-related myalgia.
This is a proof-of-conduct study to assess the feasibility and potential value of n-of-1 trials for statin-related myalgia, in patients who had previously developed myalgia within 3 weeks of open-label statin use. Each trial lasted up to 33 weeks and comprised of a maximum of 3 statin and placebo treatment pairs, assigned in a random order. Treatment periods were separated by a 3-week washout interval.

Main results

• In individual trials, 7 out of 8 patients did not show statistically greater myalgia symptoms on the visual analogue scales (VAS) myalgia score on statin vs. placebo treatment. One patient met the prespecified clinically significant difference for the VAS myalgia score, which did not reach statistical significance.
• No significant differences were seen for secondary outcomes between the two treatments.
• Combined analysis of eight n-of-1 trials revealed no statistically significant differences between statin and placebo treatment for myalgia VAS, symptom-specific VAS and pain interference score (PIS).
• Statistically greater discomfort was seen on the pain severity score (PSS) with statins vs. placebo, but the mean difference did not meet the prespecified clinically significant difference.
• No statistically significant differences in CK and liver enzyme levels were seen between statin and placebo.
• 5 of the 7 patients requiring statin therapy after conclusion of the trial resumed statin treatment.

Conclusion

This proof-of-concept study of n-of-1 trials found no clinically significant differences in myalgia or other pain measures in patients with statin-related myalgia.
The n-of-1 trial approach can identify patients with clearly statin-caused symptoms. Also, it may prevent patients from withdrawing from a treatment they need, because it allows to differentiate if myalgia is due to statins or other causes.
Although n-of-1 trials require highly motivated patients, it may provide a useful method to ascertain the unbiased occurrence of myalgia in patients in whom open-label statin rechallenge or statin switch may have suffered from confounding factors.

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References

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2. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163:553-64.
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