Randomized Controlled Trial

. 2021 Feb 24:372:n135.

doi: 10.1136/bmj.n135.

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Emily Herrett¹, Elizabeth Williamson², Kieran Brack³, Danielle Beaumont³, Alexander Perkins², Andrew Thayne³, Haleema Shakur-Still³, Ian Roberts³, Danielle Prowse³, Ben Goldacre⁴, Tjeerd van Staa⁵, Thomas M MacDonald⁶, Jane Armitage⁷, Jon Wimborne⁸, Paula Melrose⁸, Jayshireen Singh⁹, Lucy Brooks¹⁰, Michael Moore¹¹, Maurice Hoffman¹², Liam Smeeth¹; StatinWISE Trial Group

Collaborators, Affiliations

Collaborators

StatinWISE Trial Group:
Rebecca Harmston, Brian MacKenna, David Symes, John Norrie, Nicholas Mills, Hannah Castro, Nabila Youssouf, Collette Barrow, Sergey Kostrov, Hakim Miah, Eve Thacker, Melissa Baldey, Eleanor Sowerby, Nicola Harding, Gail Timcke, Alison Macleod, Karen Lomax, Nigel Wells, Emma Pierre, Tom Baker, Carla Bratten, Karen Forshaw, Daniel Clark, Selina Fox, Rachel Hubbard, David Crichton, Nabeel Alsindi, Mandy Hayes, Keith Peter Elliot, Robin Fox, Jane Stanford, Emily Ackland, George Strong, Debbie Kelly, Dev Malhotra, Dipti Gandhi, Gillian Foster, Diane Exley, Dawn Brayford, Theresa Nuttall, Clare Corbett, Nicola Anderton, Gwyn Hughes, Sian Turner, Sarah Roberts, David Brown, Susan Fairhead, Karen Sutcliffe, Mark Boon, Paula Dirienzo, Kay Ellor, Hasan Chowhan, Amy Townrow, Tracey Rowles, Debbie Hipps, Geoffrey Perry, Amanda Ayers, Rebecca Cooper, Sara Harley, Lesley Parsons, Ann Selby, Regan Hood, Elizabeth Zoon, Lucy Wraith, Vicky Peterson, Jackie Pretty, Narinder Dhillon, John Wearne, Sandra Moss, Kate Maitland, Catherine Edge, Susan Brown, Stuart Mackay-Thomas, Heather Pearson, Ewan Deas, Lesley Yelland, Helen Jones, Stephen Rogers, Ian Huckle, Carsten Dernedde, Caroline Mansfield, Heather Leishman, Jordan Howard, Chris Wright, Mark Ashworth, Satinder Kumar, Catarina Guerreiro, David Hartley, Sally Gordon, Carolyn Forrest, Andy Gibson, Laura Howe, John Whitwell, Irwin Nazareth, Letitia Coco-Bassey, Kate Walters, Jaqueline Mburu, Crystal Chetwood, Lynne Dowding, Alison Williams, Nikki Richards, Mini Nelson, Emma Chadwick, Helen Mingaye, Mehul Mathukia, Jacqueline Mburu, Anna Swinburn, Janeth Tomakin, Valentina Valasevich, Hywel Jones, Joanne Bannister, Emma Edwards, Morag McDowall, Beverley Hall, Helen Permain, Nigel Peacock, Carol Harrison, Lorraine Parsons, Chuin Kee, Paula McLaren, Sherard Le Maitre, Helen Nash, Stephanie Evans, Rachel Evans, Stephen Miller, Pooja Agarwal, Oliver Booth, Victoria Mayhew, Alison Peat, Maqsood Manzur, Umesh Chauhan, Lesley Miller, Katie O'Connell-Binns, Simon Wetherell, Sam Moon, Sarah Bland, Julia Leach, Mark Sloan, Christine Shepherd, Ross Dyer-Smith, Maarten Derks, Karen Read, Jodie Button, Martin Hadley-Brown, Sandra Smith, Caroline Hutson, Barbara Stewart, Karen Norcott, Andrew Slattery, Davinder Singh, Rose Fells, Susie Foster, Liz Tomlinson, Michaela Coutts, Kathryn Morgan, David Cowling, Joanna Beldon, Caite Guest, Bruce Helme, Daniel Tacagni, Nikki Davies, Angela Sanders, Paul Harris, Angela Juhasz, Anne Jenkins, Kirsteen Rakin, Tracey Hayward-Allingham, Samantha Kirby, Kumani Jeyarajah, Beata Guss, Dorota Daukszewicz, Yesim Ozcan, Jaisun Vivekanandaraja, Preeti Pandya, Stella Oldham, Lindsey Roberts, Julie Fuller, Murtaza Khanbhai, Jonathan Barnett, Veridiana Toledo, David Collier, Anne Zak, Rebecca James, Yasmin Choudhury, Mary Feely, Manish Saxena, Julian Shiel, Julia Colclough, Elizabeth Butterworth, Alison Crumbie, Jill Barlow, Nicola Jayne Pascall

Affiliations

¹ Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
² Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
³ Clinical Trials Unit, Department of Population Health, London School of Hygiene and Tropical Medicine, London, UK.
⁴ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
⁵ Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK.
⁶ MEMO Research, University of Dundee, Dundee, UK.
⁷ Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸ Bay Medical Practice, York Bridge Surgery, Morecambe, UK.
⁹ NIHR Clinical Research Network, Guy's Hospital, London, UK.
¹⁰ Keats and Hampstead Group Practice, London, UK.
¹¹ School of Primary Care and Population Sciences, University of Southampton, Southampton, UK.
¹² Patient member of the trial steering committee appointed by NIHR, London, UK.

PMID: 33627334
PMCID: PMC7903384
DOI: 10.1136/bmj.n135

Randomized Controlled Trial

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Emily Herrett et al. BMJ. 2021.

. 2021 Feb 24:372:n135.

doi: 10.1136/bmj.n135.

Authors

Collaborators

StatinWISE Trial Group:
Rebecca Harmston, Brian MacKenna, David Symes, John Norrie, Nicholas Mills, Hannah Castro, Nabila Youssouf, Collette Barrow, Sergey Kostrov, Hakim Miah, Eve Thacker, Melissa Baldey, Eleanor Sowerby, Nicola Harding, Gail Timcke, Alison Macleod, Karen Lomax, Nigel Wells, Emma Pierre, Tom Baker, Carla Bratten, Karen Forshaw, Daniel Clark, Selina Fox, Rachel Hubbard, David Crichton, Nabeel Alsindi, Mandy Hayes, Keith Peter Elliot, Robin Fox, Jane Stanford, Emily Ackland, George Strong, Debbie Kelly, Dev Malhotra, Dipti Gandhi, Gillian Foster, Diane Exley, Dawn Brayford, Theresa Nuttall, Clare Corbett, Nicola Anderton, Gwyn Hughes, Sian Turner, Sarah Roberts, David Brown, Susan Fairhead, Karen Sutcliffe, Mark Boon, Paula Dirienzo, Kay Ellor, Hasan Chowhan, Amy Townrow, Tracey Rowles, Debbie Hipps, Geoffrey Perry, Amanda Ayers, Rebecca Cooper, Sara Harley, Lesley Parsons, Ann Selby, Regan Hood, Elizabeth Zoon, Lucy Wraith, Vicky Peterson, Jackie Pretty, Narinder Dhillon, John Wearne, Sandra Moss, Kate Maitland, Catherine Edge, Susan Brown, Stuart Mackay-Thomas, Heather Pearson, Ewan Deas, Lesley Yelland, Helen Jones, Stephen Rogers, Ian Huckle, Carsten Dernedde, Caroline Mansfield, Heather Leishman, Jordan Howard, Chris Wright, Mark Ashworth, Satinder Kumar, Catarina Guerreiro, David Hartley, Sally Gordon, Carolyn Forrest, Andy Gibson, Laura Howe, John Whitwell, Irwin Nazareth, Letitia Coco-Bassey, Kate Walters, Jaqueline Mburu, Crystal Chetwood, Lynne Dowding, Alison Williams, Nikki Richards, Mini Nelson, Emma Chadwick, Helen Mingaye, Mehul Mathukia, Jacqueline Mburu, Anna Swinburn, Janeth Tomakin, Valentina Valasevich, Hywel Jones, Joanne Bannister, Emma Edwards, Morag McDowall, Beverley Hall, Helen Permain, Nigel Peacock, Carol Harrison, Lorraine Parsons, Chuin Kee, Paula McLaren, Sherard Le Maitre, Helen Nash, Stephanie Evans, Rachel Evans, Stephen Miller, Pooja Agarwal, Oliver Booth, Victoria Mayhew, Alison Peat, Maqsood Manzur, Umesh Chauhan, Lesley Miller, Katie O'Connell-Binns, Simon Wetherell, Sam Moon, Sarah Bland, Julia Leach, Mark Sloan, Christine Shepherd, Ross Dyer-Smith, Maarten Derks, Karen Read, Jodie Button, Martin Hadley-Brown, Sandra Smith, Caroline Hutson, Barbara Stewart, Karen Norcott, Andrew Slattery, Davinder Singh, Rose Fells, Susie Foster, Liz Tomlinson, Michaela Coutts, Kathryn Morgan, David Cowling, Joanna Beldon, Caite Guest, Bruce Helme, Daniel Tacagni, Nikki Davies, Angela Sanders, Paul Harris, Angela Juhasz, Anne Jenkins, Kirsteen Rakin, Tracey Hayward-Allingham, Samantha Kirby, Kumani Jeyarajah, Beata Guss, Dorota Daukszewicz, Yesim Ozcan, Jaisun Vivekanandaraja, Preeti Pandya, Stella Oldham, Lindsey Roberts, Julie Fuller, Murtaza Khanbhai, Jonathan Barnett, Veridiana Toledo, David Collier, Anne Zak, Rebecca James, Yasmin Choudhury, Mary Feely, Manish Saxena, Julian Shiel, Julia Colclough, Elizabeth Butterworth, Alison Crumbie, Jill Barlow, Nicola Jayne Pascall

Affiliations

¹ Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
² Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
³ Clinical Trials Unit, Department of Population Health, London School of Hygiene and Tropical Medicine, London, UK.
⁴ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
⁵ Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK.
⁶ MEMO Research, University of Dundee, Dundee, UK.
⁷ Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸ Bay Medical Practice, York Bridge Surgery, Morecambe, UK.
⁹ NIHR Clinical Research Network, Guy's Hospital, London, UK.
¹⁰ Keats and Hampstead Group Practice, London, UK.
¹¹ School of Primary Care and Population Sciences, University of Southampton, Southampton, UK.
¹² Patient member of the trial steering committee appointed by NIHR, London, UK.

PMID: 33627334
PMCID: PMC7903384
DOI: 10.1136/bmj.n135

Abstract

Objective: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins.

Design: Series of randomised, placebo controlled n-of-1 trials.

Setting: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018.

Participants: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms.

Interventions: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo.

Main outcome measures: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods.

Results: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins.

Conclusions: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment.

Trial registration: ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the National Institute for Health Research and London School of Hygiene and Tropical Medicine for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

**Fig 1**
Recruitment and participant flow. *Seven of these 46 participants never received treatment (one withdrew consent, one had intolerable symptoms, one had clinical concerns, and four for other reasons). †152 participants were included in the secondary analysis (one participant completed the patient questionnaire in two periods but the primary outcome in only one)

See this image and copyright information in PMC

Comment in

StatinWISE sheds new light on statin-related muscle symptoms.
Liuzzo G, Patrono C. Liuzzo G, et al. Eur Heart J. 2021 May 7;42(18):1726-1727. doi: 10.1093/eurheartj/ehab220. Eur Heart J. 2021. PMID: 33961023 No abstract available.

References

1. Fulcher J, O’Connell R, Voysey M, et al. Cholesterol Treatment Trialists’ (CTT) Collaboration . Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397-405. 10.1016/S0140-6736(14)61368-4 - DOI - PubMed
1. Cholesterol Treatment Trialists’ Collaboration . Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393:407-15. 10.1016/S0140-6736(18)31942-1 - DOI - PMC - PubMed
1. Collins R, Reith C, Emberson J, et al. . Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61. 10.1016/S0140-6736(16)31357-5 - DOI - PubMed
1. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123. 10.1136/bmj.f6123 - DOI - PubMed
1. Malhotra A. Saturated fat is not the major issue. BMJ 2013;347:f6340. 10.1136/bmj.f6340 - DOI - PubMed

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Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Collaborators

Affiliations

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

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Medical

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