INTRODUCTION
There is debate over the frequency and causal relationship between statins and muscle-related adverse events (MRAEs).1 Postmarketing observational studies have suggested such symptoms are very common, affecting around 20% of patients. However, meta-analyses of randomized trials have recorded a far lower incidence of MRAEs (around 5%), with no suggestion of a clear causal relationship.1,2
Some have posited that the discrepancy in rates of adverse events may in part be due to inadequate data collection in trials.1 This could occur if passive approaches (relying on spontaneous reports from patients) to MRAE data collection were used, as is common in trials, instead of proactive approaches (e.g., standardized checklists).3,4
METHODS
We requested internal company trial documents from regulators—clinical study reports (CSRs), trial protocols, and blank case report forms—to determine if and how MRAEs were prospectively assessed in randomized trials of statins. We obtained these trial documents through freedom of information requests to the European Medicines Agency and Health Canada for all clinical trials of atorvastatin, rosuvastatin, fluvastatin, and simvastatin.5 We included all blinded, placebo-controlled randomized trials irrespective of year.
For all included studies, we assessed each study’s inclusion and exclusion criteria to determine whether participants may have been precluded from participating in a trial because of treatment-related adverse events, either historically or through pre-randomization run-in procedures.
We examined study protocols and blank case report forms to determine whether study investigators were instructed to survey MRAEs and their severity. We also recorded whether rhabdomyolysis, myalgia, and other MRAEs were specifically reported in trial results. Any investigation of creatine phosphokinase (CPK) levels was noted. Data extraction was performed in duplicate, with discrepancies resolved through discussion. Our dataset is publicly available (10.5281/zenodo.5196179).
RESULTS
We obtained and screened documents for 85 trials; 23 trials of 4 statins met our inclusion criteria. The median number of randomized participants of the 23 trials was 175, and the median female percentage was 38%. Two trials excluded individuals with a history of MRAEs. A further 19 trials allowed clinician judgment about the appropriateness of patient eligibility (e.g., “Patients with other significant abnormalities that the investigator feels may compromise the patient’s safety or successful participation in the study must not be entered into the study.”).
Twelve trials had a placebo run-in period; five trials had an active run-in period. All trials recorded the intensity and duration of adverse events (Table 1). However, only one trial had a dedicated MRAE surveillance and reporting system, and 17 trials examined CPK levels linked to MRAE reporting.
Table 1.
MRAE Data Collection and Reporting Across Trials
| No. (%) | ||||
|---|---|---|---|---|
| Atorvastatin | Rosuvastatin | Fluvastatin | Simvastatin | |
| Trials assessed | 6 | 2 | 11 | 4 |
| Data collection during the trial | ||||
| Methods for recording AEs (any type) | ||||
| Intensity of AEs assessed | 6 (100%) | 2 (100%) | 11 (100%) | 4 (100%) |
| Duration of AEs assessed | 6 (100%) | 2 (100%) | 11 (100%) | 4 (100%) |
| Methods for recording MRAEs | ||||
| CPK lab assessment | 6 (100%) | 2 (100%) | 5 (45%) | 4 (100%) |
| MRAE symptom specific data collection | 0 (0%) | 1 (50%) | 0 (0%) | 0 (0%) |
| Trial reporting | ||||
| Trial results availablea | 6 | 1 | 9 | 3 |
| Musculo-skeletal events reported by typeb | ||||
| Any MRAE | 6 (100%) | 1 (100%) | 7 (78%) | 3 (100%) |
| Rhabdomyolysis | 0 (0%) | 0 (0%) | 0 (0%) | 1 (33%) |
| Muscle pain (myalgia) | 3 (50%) | 1 (100%) | 6 (67%) | 3 (100%) |
| Unspecified joint pain/disorder | 5 (83%) | 1 (100%) | 6 (67%) | 2 (67%) |
| Leg pain/disorder | 3 (50%) | 0 (0%) | 6 (67%) | 2 (67%) |
| Miscellaneous pain | 0 (0%) | 1 (100%) | 6 (67%) | 3 (100%) |
aThe following studies were excluded from the ‘Trial reporting’ section of this table due to incomplete data, redacted information related to AEs, or lack of access to trial results: JUPITER, Study No. 6, Study No. 12, and 4S trial
bA trial was only counted in the tally if it reported at least 1 event of a given type. Trials reporting zero events as well as trials that did not report on the given type were not counted in the tally
Seventeen trials reported at least one type of MRAE (Table 1). Most MRAEs were generally not defined. Unspecified joint pain/disorder, leg pain/disorder, and miscellaneous pain were the most commonly reported MRAEs from the included statin trials, besides rhabdomyolysis and myalgia.
DISCUSSION
While the majority of trials 89% (17/19) reported at least one type of MRAE, only one trial had proactive methods for soliciting these data, suggesting the vast majority of trials used passive methods for MRAE data collection. Passive methods are known to undercount adverse events,6 and may help explain the lower reporting of MRAEs in trials compared to clinical experience. In addition, the use of active drug run-ins in trials (particularly for atorvastatin) would further diminish the ability of those trials to detect the frequency of MRAEs.
Our results underscore the importance of critical appraisal of trial design and data collection methods from CSRs, and simultaneously the vulnerability of any meta-analysis that skips this step.
Amongst all clinical trial data held by regulators for four major statins, only one trial proactively collected data regarding MRAEs, indicating that regulators lacked high-quality evidence necessary to make an informed assessment about the true incidence of MRAEs. Given the clinical importance of the question, regulators should warn about this gap in the knowledge base and encourage future trials to address this data gap.
Acknowledgements
Not applicable
Author Contribution:
All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Doshi, Jefferson
Acquisition of data: all authors
Analysis and interpretation: all authors
Drafting of the manuscript: all authors
Critical revision of the manuscript for important intellectual content: all authors
Administrative, technical, or material support: Doshi
Supervision: Doshi
Data availability
Data extractions are freely available in the Zenodo repository (10.5281/zenodo.5196179).
Declarations
Conflict of interest
PD has received travel funds from the European Respiratory Society (2012) and Uppsala Monitoring Center (2018); grants from the FDA (through University of Maryland M-CERSI; 2020), Laura and John Arnold Foundation (2017-22), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014-16), Cochrane Methods Innovations Fund (2016-18), and UK National Institute for Health Research (2011-14); was an unpaid IMEDS steering committee member at the Reagan-Udall Foundation for the FDA (2016-2020); and is an editor at The BMJ. KH was supported in 2020 by the FDA of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award U01FD005946 totaling US$5,000 with 100% funded by FDA/HHS. The project contents are those of KH and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS, or the U.S. Government. TJ was in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews (2015 to 2018). In 2014 to 2016, he was a member of three advisory boards for Boehringer Ingelheim. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products for which he receives fees (current). TJ is a relator in a False Claims Act lawsuit on behalf of the United States that involves sales of Tamiflu for pandemic stockpiling. If resolved in the United States favour, he would be entitled to a percentage of the recovery. TJ is coholder of a Laura and John Arnold Foundation grant for development of a RIAT support centre (2017 to 2022) and Jean Monnet Network Grant, 2017 to 2020, for The Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018 to 2022). TJ consulted for Illumina LLC on next-generation gene sequencing (2019 to 2020). TJ was the consultant scientific coordinator for the HTA Medical Technology programme of the Agenzia per i Servizi Sanitari Nazionali (AGENAS) of the Italian MoH (2007 to 2019). TJ is Director Medical Affairs for BC Solutions, a market access company for medical devices in Europe. TJ was funded by NIHR UK and the World Health Organization (WHO) to update Cochrane review A122, Physical Interventions to interrupt the spread of respiratory viruses. TJ is funded by Oxford University to carry out a living review on the transmission epidemiology of COVID-19. Since 2020, TJ receives fees for articles published by The Spectator and other media outlets. TJ was part of a review group carrying out Living rapid literature review on the modes of transmission of SARS CoV 2 (WHO Registration 2020/1077093 0) - 2020-2021. He is a member of the WHO COVID 19 Infection Prevention and Control Research Working Group for which he receives no funds. TJ is funded to co-author rapid reviews on the impact of COVID restrictions by the Collateral Global Organisation. ST indicates no COI.
Footnotes
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References
- 1.Maningat P, Breslow JL. Needed: pragmatic clinical trials for statin-intolerant patients. N Engl J Med [Internet] 2011;365(24):2250–1. doi: 10.1056/NEJMp1112023. [DOI] [PubMed] [Google Scholar]
- 2.Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med [Internet]. 2011;78(6):393–403. doi: 10.3949/ccjm.78a.10073. [DOI] [PubMed] [Google Scholar]
- 3.Mayo-Wilson E, Fusco N, Li T, Hong H, Canner JK, Dickersin K, et al. Harms are assessed inconsistently and reported inadequately part 1: systematic adverse events. J Clin Epidemiol [Internet] 2019;113:20–7. doi: 10.1016/j.jclinepi.2019.04.022. [DOI] [PubMed] [Google Scholar]
- 4.Mayo-Wilson E, Fusco N, Li T, Hong H, Canner JK, Dickersin K, et al. Harms are assessed inconsistently and reported inadequately Part 2: Nonsystematic adverse events. J Clin Epidemiol [Internet] 2019;113:11–9. doi: 10.1016/j.jclinepi.2019.04.020. [DOI] [PubMed] [Google Scholar]
- 5.Jefferson T, Demasi M, Doshi P. Statins for primary prevention: what is the regulator’s role? BMJ Evid Based Med [Internet]. 2020 10.1136/bmjebm-2019-111321 [DOI] [PubMed]
- 6.Wernicke JF, Faries D, Milton D, Weyrauch K. Detecting treatment emergent adverse events in clinical trials : a comparison of spontaneously reported and solicited collection methods. Drug Saf [Internet] 2005;28(11):1057–63. doi: 10.2165/00002018-200528110-00006. [DOI] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
Data extractions are freely available in the Zenodo repository (10.5281/zenodo.5196179).