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Original Research |

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

Tisha R. Joy, MD; Alaa Monjed, MD; Guang Yong Zou, PhD; Robert A. Hegele, MD; Charlotte G. McDonald, MD, MSc; and Jeffrey L. Mahon, MD, MSc
[+] Article and Author Information

From Schulich School of Medicine and Dentistry, Robarts Clinical Trials, and Robarts Research Institute, Western University, London, Ontario, Canada.

Note: All authors had access to the data and take responsibility for the analysis and reported findings.

Acknowledgment: The authors thank Leanne Vanderhaeghe and Christopher Reynaert of the Pharmacy Department at St. Joseph's Hospital for their help with the conduct of this trial, especially the generation of randomization schemes, purchase and compounding of active and placebo capsules, and dispensing of study medications. The authors also thank research assistants Lynda Bere and Patricia Rosas-Arellanos and the patients who participated.

Grant Support: In part by the Program of Experimental Medicine (Dr. Joy) and the Department of Medicine (Drs. Joy and McDonald) from Western University, London, Ontario, Canada.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1921.

Reproducible Research Statement:Study protocol: Available from Dr. Joy (e-mail, tisjoy@hotmail.com). Statistical code: Available from Dr. Zou (e-mail, gy.zou@robartsinc.com). Data set: Not available.

Requests for Single Reprints: Tisha R. Joy, MD, Western University, Schulich School of Medicine and Dentistry, B5-107, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada; e-mail, tisjoy@hotmail.com.

Current Author Addresses: Drs. Joy, McDonald, and Mahon: Western University, Schulich School of Medicine and Dentistry, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.

Dr. Monjed: Al-hejra Street, PO Box 463, Makkah, Saudi Arabia.

Dr. Zou: Robarts Clinical Trials, PO Box 5015, 100 Perth Drive, London, Ontario N6A 5K8, Canada.

Dr. Hegele: Vascular Biology, Robarts Research Institute, 1511 Richmond Street North, London, Ontario N6A 5B7, Canada.

Author Contributions: Conception and design: T.R. Joy, C.G. McDonald, J.L. Mahon.

Analysis and interpretation of the data: T.R. Joy, A. Monjed, G.Y. Zou, J.L. Mahon.

Drafting of the article: T.R. Joy, J.L. Mahon.

Critical revision of the article for important intellectual content: T.R. Joy, R.A. Hegele, C.G. McDonald, J.L. Mahon.

Final approval of the article: T.R. Joy, A. Monjed, G.Y. Zou, R.A. Hegele, C.G. McDonald, J.L. Mahon.

Provision of study materials or patients: T.R. Joy, R.A. Hegele, C.G. McDonald.

Statistical expertise: G.Y. Zou.

Obtaining of funding: T.R. Joy, C.G. McDonald.

Collection and assembly of data: T.R. Joy, A. Monjed, R.A. Hegele.


Ann Intern Med. 2014;160(5):301-310. doi:10.7326/M13-1921
Text Size: A A A

Background: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation.

Objective: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results.

Design: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791)

Setting: Tertiary care lipid clinic.

Patients: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels.

Intervention: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo.

Measurements: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm).

Results: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months.

Limitation: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation.

Conclusion: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability.

Primary Funding Source: Western University, London, Ontario, Canada.

Topics

statins ; myalgia

Figures

Grahic Jump Location
Figure 1.

Study design.

The study duration was 33 wk. After the baseline assessment at time 0, patients had 3 pairs of active drug (3 wk) and placebo (3 wk) exposures. Randomly assigned treatment pairs comprised 2 treatment periods (active therapy or placebo) separated by a 3-wk washout period. Treatment pairs were also separated by washout periods. A complete n-of-1 trial comprised 3 treatment pairs. Clinic visits occurred at baseline and at the end of each treatment period (solid arrows). Baseline scores for the visual analogue scales and Brief Pain Inventories were collected at time 0. Patients then completed these questionnaires at days 7, 14, and 21 in each treatment period.

Grahic Jump Location
Grahic Jump Location
Figure 3.

VAS myalgia scores for each n-of-1 trial, based on treatment period.

The VAS myalgia scores for patients 1 to 8 are presented according to each treatment period (active [solid circle, solid line] and placebo [solid square, dotted line]). A full n-of-1 trial consisted of 6 treatment periods (3 active and 3 placebo). Treatment periods were 3 wk in duration. The VAS myalgia scores were completed at the end of each week in the treatment periods. Higher VAS myalgia scores signify greater muscle pain. Patient 6 crossed over early during treatment period 1, resulting in only 2 VAS myalgia scores for that period. Patient 7 forgot to complete 1 of 3 VASs for myalgia in treatment period 6, and patient 8 discontinued the n-of-1 trial after completing 5 treatment periods. VAS = visual analogue scale.

Grahic Jump Location

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References

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Comments

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Re: N-of-1 (Single-Patient) Trials for Statin-Related Myalgia
Posted on April 1, 2014
Oladimeji Akinboro, MD, MPH, Linda Williams, MD, Daniel Pomerantz, MD, MPH
Montefiore New Rochelle Hospital, New Rochelle, New York
Conflict of Interest: None Declared
We read with great interest, the multiple single case (N-of-1) trials of statin-related myalgia reported by Joy et al. (1).

3-week treatment periods were employed for intervention and placebo administration, respectively, in randomized sequences with intervening 3 week wash-out periods. However, prior studies suggest that the onset of statin-induced myalgia occurs within weeks to months of starting therapy, with a mean period of 6 months reported in a review by Hansen et al (2, 3). The mean period for resolution of symptoms was 2 months in that review (2). The question, therefore, arises as to whether the 3-week treatment and intervening washout periods employed in this study were long enough for the development and resolution, respectively, of statin-related myalgias and/or myopathy among the study participants.

Visual analogue scales and a pain inventory were administered once a week during each treatment period. Recall bias cannot therefore be excluded, though such bias is likely to be non-differential for either intervention or placebo treatment periods. Future N-of-1 trials may leverage the availability of wireless devices for real-time reporting of symptoms transmitted over secure networks (4). Such real-time reporting can also facilitate the analysis of the data for periodicity of symptoms such as diurnal variations.

Paired t-tests were employed in the individual-level analysis of each N¬-of-1 trial. This analytic approach ignores the serial temporal correlation of the reported outcomes, which are likely to be greater between treatment periods that are closer in time (4). In addition, considering that each participant had only 3 paired treatment periods, it was not shown if the statistical assumptions that underlie the use of parametric methods, such as paired t-tests, were reasonably satisfied in this analysis.

Intervention, randomization sequence, and results were reported for each patient. However, the baseline characteristics of individual patients were summarized, rather than reported at the individual level. Considering that there were only 8 final participants, the presentation of their individual level baseline characteristics would have been quite informative to the reader in facilitating a more robust assessment of the study results vis-à-vis relating each individual participant’s baseline characteristics to her/his results.

In conclusion, Joy et al. have shown the N-of-1 trial methodology to be a scientifically-rigorous and practical approach for individualizing treatment decisions regarding statin therapy among patients who report statin-related myalgias. Future trials may consider longer treatment and washout periods. They may also utilize secure wireless technologies for real-time reporting of symptoms.


REFERENCES
1. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon, JF. N-of-1 (Single-Patient) Trials for Statin-Related Myalgia. Ann Intern Med. 2014;160(5):301-310.
2. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 Patients With Statin-Associated Myopathy. Arch Intern Med. 2005;165:2671-2676.
3. Bruckert E, Hayem G, Dejager S, Yau C, Be´gaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients— the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-14.
4. Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med . 2011 March ; 8(2): 161–173.
In Response
Posted on June 13, 2014
Tisha R. Joy, MD, Guang Yong Zou, PhD, Jeffrey L. Mahon, MD, MSc
Western University, London, Ontario, Canada
Conflict of Interest: None Declared

We thank Akinboro and colleagues for their commentary.
We agree that our decision to restrict each treatment exposure and washout phase to 3 weeks meant that our n-of-1 trials could not reliably detect statin-related muscle symptoms taking more than 3 weeks to develop and/or resolve (1). To minimize this, we chose patients who previously developed myalgia within 3 weeks of starting a statin, and we used the same statin in the n-of-1 trial that the patient associated with myalgia during open-label treatment (1). Our rationale for choosing a 3 week washout between treatment exposures has been provided (1). We note in the study by Hansen et al (2) that one-third of patients reported symptoms within a month of statin initiation. As well, in a study of 354 patients with statin-related muscle symptoms, Cham et al found that myalgia symptoms recurred within a median time of 2 weeks upon statin re-challenge (3). We believe that our n-of-1 trials reliably assessed possible statin-related myalgia in patients with a shorter symptom history. As Akinboro and colleagues suggest, we cannot generalize our findings to patients with a longer history of symptoms, though we remain doubtful that n-of-1 trials for patients with possible statin-related myalgia that develop or resolve more than 3 weeks after starting or stopping a statin will be practicable (1). Parenthetically, and based on the small number of n-of-1 trials we did, we wonder whether the incidence of myalgia that is truly caused by statins, and the time it takes for myalgia symptoms to clear, have been overestimated in previous cohort studies of patients receiving open-label statin treatment.
We agree with Akinboro and colleagues that there is potential for recall bias within our n-of-1 trials but that, more importantly, such bias was equally applicable to placebo and active treatment periods. We also agree that secure wireless technologies for real-time reporting of symptoms is an attractive technology worth exploring in the context of n-of-1 trials.
We used the paired t-test to analyze data from each n-of-1 trial based on published guidelines (4). It is true that the assumptions underlying the t-test may not be strictly satisfied in our case, but the t-test is well-known to be robust to violation of assumptions (5). We also note that use of nonparametric tests would yield even less significant p-values than those we obtained using the t-test, thereby providing stronger evidence for our conclusion.
Individual baseline characteristics for patients who completed the n-of-1 trials are given in the Table.

The visual analogue scales range from 0 to 100 mm, with higher scores indicating worse pain or symptomatology. The pain severity and pain interference scores range from 0 to 10, with higher scores indicating worse pain severity and pain interference, respectively.

Subject

Age

(years)

Gender

(M/F)

VAS Myalgia

Score, mm

Symptom-Specific VAS score, mm

Pain Severity Score

Pain Interference Score

1

56

F

0

0

1.75

0

2

76

F

36

37

4.25

3.28

3

65

F

12

10

2

1.28

4

62

M

2

13

2

1.29

5

71

F

29

0

4.75

2.71

6

62

F

18

0

3

2.29

7

78

F

12

6

2

0

8

62

F

0

0

3.25

8.71

 

 

 

 

 

 

 

 

 

 

 

 

 

Abbreviations: F, female; M, male; VAS, visual analogue scale.


References:

1. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-10.
2. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165(22):2671-6.
3. Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-associated muscle-related adverse effects: a case series of 354 patients. Pharmacotherapy. 2010;30(6):541-53.
4. Guyatt G, Sackett D, Adachi J, et al. A clinician's guide for conducting randomized trials in individual patients. CMAJ. 1988;139(6):497-503.
5. Heeren T, D'Agostino R. Robustness of the two independent samples t-test when applied to ordinal scaled data. Stat Med. 1987;6(1):79-90.



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Summary for Patients

Treatment Trials to Determine Whether Statins Are the Cause of a Patient's Discomfort

The full report is titled “N-of-1 (Single-Patient) Trials for Statin-Related Myalgia.” It is in the 4 March 2014 issue of Annals of Internal Medicine (volume 160, pages 301-310). The authors are T.R. Joy, A. Monjed, G.Y. Zou, R.A. Hegele, C.G. McDonald, and J.L. Mahon.

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