The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 14/49/159. The contractual start date was in April 2016. The draft report began editorial review in October 2019 and was accepted for publication in March 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

© Queen’s Printer and Controller of HMSO 2021. This work was produced by Herrett et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Background

Statins effectively reduce cardiovascular disease (CVD) in primary and secondary prevention among men and women across all age groups. 2,3 Meta-analyses have demonstrated the safety of statins. 4 Although severe adverse effects are rare, statins are known to be associated with a small increase in the risk of myopathy (absolute excess risk 1 case per 10,000 people treated per year), which can progress to more severe rhabdomyolysis (0.2 cases per 10,000 people treated per year). 4 Although the association between statins and these severe muscle disorders is well characterised, uncertainty persists about less severe muscle symptoms. Many people strongly believe that statins commonly cause muscle symptoms such as stiffness, pain and weakness. 5–7

This perception has been driven by unblinded observational studies7,8 and exacerbated by media reports worldwide. 9–11 The lack of blinding in observational studies means that patients taking a medication expect to experience adverse effects12 and, therefore, reporting of symptoms may be higher than in a comparable statin-free population. This phenomenon, the ‘nocebo’ effect, can lead to bias in unblinded studies. Because some patients think that their muscle symptoms are caused by statins, discontinuation is common,7–11,13 which leads to increased CVD and mortality14 and a substantial public health burden.

Study design

The trial protocol has been previously published25 and parts of the published article are reproduced throughout this report. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. This includes minor additions and formatting changes to the original.

StatinWISE was a series of randomised, double-blind, placebo-controlled N-of-1 trials. The overall duration of the trial was 1 year for each participant and comprised six 2-month treatment periods (three of placebo and three of active treatment) in a randomly allocated order (Figure 1).

FIGURE 1.

The trial overview. This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Procedures

The trial treatment consisted of once-daily oral administration of 20-mg atorvastatin capsules, which was compared with a matching placebo (microcrystalline cellulose). The treatment phase of the trial consisted of six treatment periods of 8 weeks’ duration each (i.e. 56 daily capsules). During each treatment period participants received 20 mg of atorvastatin or placebo. A blinded placebo, identical in size, colour, smell and packaging to the active statin, was chosen to prevent knowledge of treatment from affecting symptom scores.

All treatment packs were stored in a temperature-monitored room with temperature-controlled refrigeration units at the London School of Hygiene & Tropical Medicine. Each 8-week supply of allocated treatment was posted to the patient by the trial team. Patients were contacted to ensure that they had received the correct treatment pack and to confirm the date when they would start the new treatment period. Alternatively, patients could access the trial electronic data capture (EDC) system themselves and enter their treatment pack number and start date.

The start date that was entered into the EDC system was used to calculate the dates for data collection for that treatment period. Reminder notifications for sending the next treatment pack were also generated by the EDC system, and the next treatment pack would be sent by the trial team. Patients were provided with prepaid stamped envelopes to return each treatment pack once completed. Patients were also given written instructions (included on the inside of the treatment pack) on how to take the study medication. A freephone telephone number was provided for patients to call if they had any questions.

Patients were asked to take one capsule orally once daily at a time of day that was convenient to them, and to try to take it at a similar time each day. If patients suffered any difficulties when taking the capsules, changing the time of the day that the medication was taken was an initial option offered to them. Stopping the medication with a short treatment break was also offered to patients if they were experiencing any adverse symptoms. Patients were advised to consult their GP if symptoms persisted.

Adherence to the study was monitored as part of the data collection. Monitoring returned packs for drug accountability against the reported data collection was also undertaken.

Dose selection

Atorvastatin is recommended by the current National Institute for Health and Care Excellence (NICE) guidelines for lipid modification,26 and 20 mg is the recommended dose for primary prevention of CVD. Atorvastatin is also recommended by NICE for secondary prevention;26 for patients with a high risk of adverse events (our patient population), a dose of < 80 mg is recommended.

Outcome measures

The primary outcome was self-reported muscle symptoms, defined as pain, weakness, tenderness, stiffness or cramp to the body of any intensity. The primary outcome was measured each day using a validated visual analogue scale (VAS) (range 0 to 10 cm)27 for the last 7 days of each treatment period. We aimed to collect symptoms using a web-based database or mobile phone app (application), but our patient representatives recommended that participants should also be permitted to submit their scores over the telephone or by paper questionnaire. Participants reporting by telephone were asked to score their symptoms on an analogue severity scale and, thus, did not use a VAS. Measuring symptoms during only the last week of each 2-month treatment period was designed to avoid any carryover effect.

Secondary outcomes were collected on the last day of each 2-month treatment period. These included whether or not patients reported that they believed their symptoms were caused by the study medication, the site of muscle symptoms and VAS scores for the effect of their muscle symptoms on general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life, and any other symptoms that the patient believes were attributed to the study medication. Adherence to study medication was self-reported and verified by a count of returned treatment packs containing the trial medication. Three months after the end of the final treatment period, we determined if the participant continued or ceased statin treatment and the relationship to their primary outcome, as well as whether or not patients found their own trial result helpful in making the decision about future statin use.

Number of participants needed

A feasibility study in the Clinical Practice Research Datalink indicated that, on average, 35 patients per practice per year would be eligible to take part in the trial. We anticipated an average uptake of 15% among primary care patients invited to participate in our trial. Therefore, we estimated that we would need to invite approximately 1300 patients from over 50 general practices to the trial to achieve our recruitment target of 200 patients.

Sample size

A sample size of 64 participants provides approximately 90% power to detect a treatment effect of at least 10 mm, assuming a type I error of 5%. Allowing for loss to follow-up of 40% of participants through the trial inflates the required sample size to 107 participants.

Period effects (changes in underlying VAS pain score because of factors other than randomised treatment, e.g. seasonal, activity related), variability in individual statin effects across patients, imperfect adherence to the assigned treatment and potential non-normality of the distribution of VAS pain scores were investigated by further detailed simulations. These factors all have the effect of decreasing power, thus increasing the sample size required. An approximate 80% increase in the sample size required in the absence of these effects provided approximately ≥ 90% power across a plausible range of these potential effects; thus, we determined that a final sample size of 200 was required.

Randomisation and masking

Randomisation codes were generated and held securely by the clinical trials unit (CTU) information technology (IT) team at the London School of Hygiene & Tropical Medicine, which was independent of the StatinWISE trial management team, maintaining the blinded processes. Eight treatment sequences were defined (Table 1) and given an equal corresponding range of values between 0 and 1. Then, a series of random numbers between 0 and 1 were generated and matched to a treatment sequence, producing the randomisation list. The codes were made available to a Good Manufacturing Practice-certified clinical trial supply company (Sharp Clinical Services, Rhymney, UK) for the treatment packs to be manufactured in accordance with the randomisation list that was established in sequence from 1001 to 1200 in the EDC system.

Patients were randomly allocated to receive a sequence of blinded placebo or atorvastatin treatment by the research nurse/general practice trial team and entered into the EDC system and associated with a treatment sequence allocation. Treatment blocks were stratified to ensure that (1) all participants received one period of statin and placebo in their first two treatment periods (in a random order) and (2) no participant would be allocated to three sequential periods of the same treatment. Treatments were therefore allocated in three paired blocks (statin–placebo or placebo–statin) of treatment, with patients completing six treatment periods of 8 weeks’ duration each (i.e. 56 daily capsules). Each individual was randomly allocated (with equal probability) to one of the eight sequences (see Table 1).

Atorvastatin and the placebo were in capsule form and identical in appearance. DBcaps® capsules (Capsugel^®, Morristown, NJ, USA), which have a unique locking mechanism to help with assuring the integrity of the blind, were used for overencapsulation of both the atorvastatin and the placebo treatments. The treatment packs were packaged in boxes of six, in line with the eight sequence options as per the randomisation code. Patients were recruited and allocated a sequence in order of entry on to the EDC system (see Table 1). Patients, general practice staff and trial staff were blind to the allocation in each period.

A visually matched placebo was chosen as an appropriate comparator for two reasons. First, patient expectation of symptoms when on statins is likely to affect their experience of symptoms. A placebo control should minimise bias arising from knowledge of allocation. Second, withholding statin treatment from patients during placebo treatment periods is justified because the trial recruited patients who had recently stopped using statins (and, therefore, were not currently receiving any benefit from statins) and those who wished to discontinue. If patients in the trial tolerate the active treatment periods with few symptoms, then this trial is likely to increase their use of statins in the long term.

Data collection

This trial was co-ordinated from the CTU at the London School of Hygiene & Tropical Medicine and conducted at GP practices in England and Wales.

Baseline data were collected and entered online to the trial database provided by the London School of Hygiene & Tropical Medicine CTU. Follow-up data were collected directly from each patient at the end of each 2-month period.

Patients were allowed to choose the method of data collection that was most suitable for them from the following:

• Bespoke mobile phone app that required patients to use their own smartphone.

• Online database using a computer, mobile phone or tablet.

• Paper forms that they received by post at the same time as their trial treatment and that they could complete themselves or with the help of a trial team member by telephone if they so requested. Trial staff would telephone the patient on each data collection day and complete the questionnaire based on the patient’s answers.

A sensitivity analysis was performed to assess any evidence of symptom scores varying between participants using different data collection methods.

For patients with a smartphone who chose to submit outcome data using the trial’s bespoke mobile app, the GP, principal investigator (PI) or research nurse helped the patient to install and set up the app. The GP, PI or research nurse also gave a demonstration to ensure that the patient understood how to use it. Each GP, PI or research nurse had access to the internet so that the patient could download the app without using their own mobile network (ensuring that download of the app was free of charge to the patient).

The GP or research nurse also showed the patient how to complete the symptoms data for the baseline form using their preferred method. Any questions were addressed at this stage. Once baseline procedures were completed and the patient was confirmed as being eligible and consented, the patient would then be allocated to a randomly selected sequence of treatments.

A screening log was used to record all patients who were identified as potentially eligible using the research site database, including those who were ineligible and those who declined participation. The screening log remained at the relevant research site and only anonymised information regarding number of screened patients and number and reasons for screen failure was shared with the CTU.

Data outlined on only the baseline, follow-up, end-of-trial and adverse events data forms were collected as part of the trial database.

Patients reporting intolerable symptoms

The GP remained the first point of contact for patients during the trial for their care. Intolerable muscle symptoms were to be reported to the GP, who provided clinical care as directed by the appropriate NICE guidelines. Figure 2 shows the decision-making pathway for the GP and the patient in the case of patients reporting intolerable symptoms.

FIGURE 2.

Intolerable symptoms pathway. Note that withdrawal from the trial at any time is possible (the patient should visit their GP and complete a withdrawal form). This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

If patients experienced intolerable muscle symptoms and who did not want to be withdrawn early from the trial, the GP was asked to confirm that the patient still met the trial eligibility criteria. Patients who continued to meet the eligibility criteria could be offered the following options by the GP, depending on the GP’s clinical judgement:

• continue with current treatment

• reduce the frequency of tablet use to every other day rather than daily

• stop for that treatment period and resume at the start of the next period.

Patients who withdrew from treatment temporarily or permanently were asked to inform the study team and report symptoms at the time of stopping, and to continue to submit outcome data for their current treatment period.

Statistical methods

Full details of the statistical analysis methods and the plan can be found on the project page (www.journalslibrary.nihr.ac.uk/programmes/hta/1449159/#/documentation; accessed May 2020).

Protocol changes

Prior to any patients being randomised to the trial, an addition was made to the exclusion criteria: excluding any patients with any contraindications to the summary of product characteristics for 20 mg of atorvastatin.

Adverse events were also changed to be reported if they met the outlined criteria for a serious adverse event on the protocol, and not only those resulting in a hospitalisation/death.

After an initial slow period of recruitment, an advertising campaign was launched to promote the trial in GP practices. Patients could contact the CTU at the London School of Hygiene & Tropical Medicine directly, expressing their interest in participating. They would then be sent a letter requesting their GP’s details. The CTU would then contact the GP for confirmation of the patient’s suitability for the trial. Patients would then be screened at William Harvey Heart Centre at Barts and The London School of Medicine and Dentistry, Queen Mary University of London. The recruitment pathway for the trial was subsequently updated to incorporate this process, as well as amendments made to the patient information sheet. However, only one patient was recruited via this pathway. The recruitment period was also extended after recruitment began, although working to the same sample size.

The consent form was also amended so that consent to participate in the optional genetic study was captured on a separate form to that of consent to participate in the trial itself.

Patient and public involvement

Three patient representatives were on the Trial Steering Committee (see Appendix 1). A StatinWISE patient involvement group provided feedback on the trial design, patient information sheet and data collection tools. Their input and views shaped aspects of the design, specifically around the logistics of drug postage and return, the drug packaging, the phrasing of questions for the outcome measures, the format of the data collection tools that were patient facing, and the content and wording of the patient information sheet. The group continued to be involved throughout the course of the trial, including providing substantial input into the individual participants’ results feedback document. Patient representatives also provided active input into the interpretation of the results and their presentation. They will also play an important role in designing materials for dissemination.

Approvals

StatinWISE was given a favourable opinion by the South Central Hampshire Research Ethics Committee (16/SC/0324) and regulatory approval (17072/0009/001-0001).

Role of the funding source

The trial was funded by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The writing committee had full access to all data in the study and had final responsibility for the decision to submit for publication.

Recruitment and participant flow

Two hundred patients were recruited between December 2016 and April 2018. The first patient was enrolled on 20 December 2016 and the last patient’s last follow-up took place on 5 July 2019.

Baseline data

The median age was 69.5 years [interquartile range (IQR) 63–76 years] and 115 (57.5%) participants were male (Table 2). Fourteen participants (7.0%) were current smokers, 105 (52.5%) were ex-smokers, 33 (16.5%) had diabetes and 140 (70.0%) had a history of CVD. The mean total cholesterol level was 5.4 mmol/l [standard deviation (SD) 1.4 mmol/l].

Table 3 shows the numbers of participants allocated to each sequence of treatment over the six trial periods.

Data collection methods

Table 4 shows the details of the method chosen to collect outcome data. Around half of the participants chose to collect data using the paper form. A total of 88 participants (44%) chose to fill in the online form and 17 participants (8.5%) submitted data by telephone.

Numbers analysed

Figure 3 describes participant flow through the trial. A total of 151 out of 200 (75.5%) randomised participants provided one or more VAS measurements in a placebo period and one or more in a statin period and are therefore included in the primary analysis. A total of 86 (43.0%) participants did not complete the whole trial (two died, four were lost to follow-up and 80 withdrew).

FIGURE 3.

Recruitment and patient flow. This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

For the primary analysis of the daily muscle symptom scores, the linear mixed model was fitted on 151 participants, who contributed 5214 individual symptom score measurements (placebo, n = 2576; statin, n = 2638). The mean number of scores per participant was 34.5 (range 8–42). In period 1, 164 participants (82.0%) provided at least one daily report of muscle symptoms, which dropped to 149 participants in period 2 (74.5%) and 115 in period 6 (57.5%).

Outcomes

Primary outcome

Among the 151 patients who reported at least one primary outcome measure during a statin period and at least one primary outcome measure during a placebo period, there was no evidence of a difference in mean muscle symptom scores between statin and placebo periods (Figure 4; estimated mean difference statin minus placebo –0.11, 95% CI –0.36 to 0.14; p = 0.398). The observed mean muscle symptom score was lower during statin treatment periods (mean 1.68, SD 2.57) than during placebo periods (mean 1.85, SD 2.74).

FIGURE 4.

Box plot of mean difference in primary outcome (VAS daily symptom scores), comparing statin with placebo.

The effect of statins on the primary outcome was not modified by the method of data collection (Table 5). Figures 5 and 6 display summaries of the primary outcome measure (i.e. VAS scores) by period and randomisation sequence. Figure 5 shows the trajectory of mean scores (daily patient VAS scores are averaged across the week and an overall mean is then calculated for each period in each sequence). Figure 6 shows the trajectory of median scores (daily patient VAS scores are summarised for each period by the median and the overall median is then calculated for each period in each sequence). To indicate variability of the outcome measure, Figure 6 also shows the IQR.

TABLE 5 - Estimated treatment effect from a linear mixed model allowing the statin effect to vary by data collection method chosen

The p-value for the interaction shows a joint test for the three interaction parameters (i.e. testing the null hypothesis that statin effect does not vary by data collection method).

This table has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Data collection method	Estimated mean difference	95% CI	p-valuea
Statin (method: online)	0.008	–0.358 to 0.373	0.968
Statin interaction parameters			0.594
App	–0.065	–0.704 to 0.574
Paper	–0.159	–0.676 to 0.358
Telephone	–0.681	–1.680 to 0.318
Collection method
Online	Reference
App	0.563	–0.223 to 1.349	0.161
Paper	0.604	–0.081 to 1.289	0.084
Telephone	1.949	0.352 to 3.545	0.017
Constant	1.441	1.053 to 1.829	< 0.001

FIGURE 5.

Trajectory plot of mean VAS scores by randomised sequence. (a) PSPSPS; (b) PSPSSP; (c) PSSPPS; (d) PSSPSP; (e) SPPSPS; (f) SPPSSP; (g) SPSPPS; and (h) SPSPSP.

FIGURE 6.

Trajectory plot of median VAS scores with IQRs by randomised sequence. (a) PSPSPS; (b) PSPSSP; (c) PSSPPS; (d) PSSPSP; (e) SPPSPS; (f) SPPSSP; (g) SPSPPS; and (h) SPSPSP.

Table 6 provides descriptive summaries of the primary outcome by allocated sequence across the three paired treatment blocks.

TABLE 6 - Summary of the primary outcome (daily VAS symptom scores)

Median of mean daily VAS scores across each period.

Period	Placebo		Statin		Difference (statin – placebo)
	Number of participants	Mediana (25th, 75th percentiles)	Number of participants	Mediana (25th, 75th percentiles)	Number of participants	Mediana (25th, 75th percentiles)
All patients with reported scores
1 and 2	158	0.4 (0, 3.9)	155	0.2 (0, 2.4)	145	0 (–1, 0.6)
3 and 4	121	0.6 (0, 3.2)	128	0.8 (0, 3.4)	118	0 (–0.4, 0.6)
5 and 6	115	0.3 (0, 3.4)	116	0.1 (0, 2.8)	115	0 (–0.5, 0.1)
Patients with at least one report in a statin period and at least one in a placebo period (i.e. included in the primary analysis)
1 and 2	147	0.4 (0, 3.8)	148	0.4 (0, 2.4)	145	0 (–1, 0.6)
3 and 4	121	0.6 (0, 3.2)	128	0.8 (0, 3.4)	118	0 (–0.4, 0.6)
5 and 6	115	0.3 (0, 3.4)	116	0.1 (0, 2.8)	115	0 (–0.5, 0.1)

Withdrawals

Overall, 80 patients (40%) withdrew from the trial before the end of the 12-month treatment period. A total of 16 of these 80 patients (20%) withdrew informed consent, 32 (40%) reported intolerable muscle symptoms, 14 (17.5%) withdrew because of clinical concerns raised by their GP and 18 (22.6%) withdrew for other or unknown reasons. Of the 80 withdrawals, 34 (42.5%) were during a statin period, 39 (49.75%) during a placebo period and seven (8.75%) after randomisation but prior to any study medication being taken.

More participants withdrew because of intolerable symptoms during a statin period (n = 18) than because of intolerable symptoms during a placebo period (n = 13). Conversely, the number of participants withdrawing because of clinical concern was greater during a placebo period (n = 9) than during a statin period (n = 4).

Figure 7 shows the withdrawal of patients broken down by treatment period and randomised sequence.

FIGURE 7.

Withdrawals for each treatment period by randomised sequence. P, placebo; P1, period 1; P2, period 2; P3, period 3; P4, period 4; P5, period 5; P6, period 6; S, statin.

Adherence

Participant-reported adherence was confirmed through verification of the number of pills remaining in returned medication packs. Adherence to the study medication was high, with the proportion of participants reporting taking their study medication ‘every day’ or ‘most days’ being at least 80% during each period among participants who had not yet withdrawn (Figure 8).

FIGURE 8.

Adherence to study medication by period and sequence for (a) all recruited participants; and (b) those who had not yet withdrawn. This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

This figure has been reproduced from Herrett et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Of the 114 patients who completed the full six treatment periods, 113 received their results during an end-of-trial discussion (56.5% of randomised participants) (one participant did not attend). At 15 months, 58 (51.3%) of these 113 participants had a prescription for statins, 74 (65.5%) said that they intended to resume statins and 99 (87.6%) said that their trial had been helpful (Table 12).

Adverse effects

During the trials there were 13 serious adverse events but none was considered attributable to the study medication. There were two fatal events (one during statin treatment and one after the end of treatment) and 11 non-fatal events (five during statin treatment and six during placebo).

No emergency treatment unblinding was needed.

Comparison with other literature

StatinWISE, along with the concurrent SAMSON trial,35 are the first large-scale N-of-1 trials to investigate the effect of statins on muscle symptoms. Our findings largely support evidence from large systematic reviews and meta-analyses of randomised controlled trials, which have shown no effect of statins on muscle symptoms in the absence of myopathy,3,4,22 despite being powered to have detected extremely rare and serious side effects of statins (e.g. rhabdomyolysis, myopathy, haemorrhagic stroke and diabetes4). An ongoing meta-analysis36 is investigating adverse event data from statin trials, aiming to provide a complete understanding of any other statin side effects. Although our trial cannot exclude the possibility of side effects among a minority of participants, it clearly indicates that the majority of patients taking statins do not experience symptoms because of their statin, and highlights the importance of blinding when assessing side effects.

Observational studies have frequently reported muscle side effects,37 and patients’ experience of muscle symptoms during statin use frequently causes them to discontinue use. Various explanations have been offered for the high frequency of symptoms found in observational studies and clinical practice. First is the nocebo effect, in which expectations of adverse effects may have led patients to attribute muscle symptoms occurring during statin use to the statins themselves. 12 Second, muscle aches and pains are common among the age group taking statins, and so occur by chance during statin use, causing patients to misattribute their pain to statins. 38 Lack of randomisation and blinding in observational studies means that spurious effects of statins are more likely. Given the proportion of patients who intended to resume statin use after their trial, our result is also in agreement with observational data showing that statin re-challenge can be tolerated. 39,40

Strengths

We collected data on muscle symptom side effects of statins as a primary outcome, in the setting of a blinded, placebo-controlled series of trials with randomised order of treatments to minimise bias and confounding. The within-patient design created superior power that was boosted in our study by repeated measurements in each treatment period, thus allowing us to investigate differences between statin and placebo with more precision.

Owing to the within-participant trial design, we were able to feed back to individual participants about whether their muscle symptoms occurred more frequently with statins or placebo and allowing them to decide for themselves whether or not to continue on statin treatment.

In delivering this series of trials, we have created a diagnostic tool allowing patients to empirically evaluate whether or not their symptoms are caused by statins. The N-of-1 trial is a complex design, but was made easy for patients as trial medications were delivered directly to patients through the post. This pathway of care could be adopted by clinicians who are looking to establish the best course of treatment for patients who present with statin intolerance.

Limitations

Although the overencapsulated statin and placebo were identical in appearance, we cannot exclude the possibility that a determined participant may have opened the capsules and unblinded themselves based on taste.

Of the 200 randomised participants, 86 did not complete the trial, of whom 49 did not provide sufficient data to contribute to the primary analysis. Adherence was similar between statin and placebo periods, and the trial was adequately sized to account for this level of dropout. Although overall withdrawals were not related to statin or placebo periods, withdrawal due to intolerable symptoms was more common during statin periods, and although it is recommended that GPs measure creatine kinase among patients experiencing such symptoms, this was not part of our trial protocol.

For simplicity and pragmatism, the trial assessed the effect of statins on muscle symptoms using 20 mg of atorvastatin only, so we are unable to extrapolate our results to other types of statins, to other dosages or to other outcomes that have been suggested to be statin related. 41

Although we intended to collect outcomes using web-based methodology, over half of the participants preferred to report their symptoms on paper or by telephone.

Generalisability

Our results are generalisable to patients who are considering discontinuing statins or have already discontinued statins due to muscle symptoms, and who are willing to re-challenge or participate in an N-of-1 trial. The N-of-1 methodology is applicable to other clinical situations in which the causal effect of a drug on a transient symptom is questioned.

Implications for practice

The evidence from our series of N-of-1 trials suggests that this methodology could be a useful tool to aid decision-making about future statin use and encourage patients to find out whether or not statins are causing their symptoms.

General practitioners who are managing patients who believe that they are experiencing muscle symptoms as a result of the statin that they are taking should be aware that the majority of StatinWISE participants did not experience a difference in symptoms between statin and placebo, although a small proportion did have more muscle symptoms during statin treatment.

Recommendations for future research

1. We would recommend that series of N-of-1 trials be undertaken for other types of statins, higher dosages and non-muscle symptoms that are frequently attributed to statins. In particular, we would recommend this methodology among patients with existing CVD who require higher statin doses than tested in our series of N-of-1 trials.

2. We would recommend that N-of-1 trials be used in the context of transient symptoms that occur during the use of other medications.

Contributions of authors

Emily Herrett (https://orcid.org/0000-0002-9425-644X) (Assistant Professor) was involved in the design, conduct, analysis and reporting phases.

Elizabeth Williamson (https://orcid.org/0000-0001-6905-876X) (Associate Professor of Medical Statistics) was involved in the design, conduct, analysis and reporting phases.

Kieran Brack (https://orcid.org/0000-0002-8100-8949) (StatinWISE Trial Manager) was involved in the design and conduct phases.

Alexander Perkins (https://orcid.org/0000-0002-9817-2390) (StatinWISE Trial Manager) was involved in the conduct, analysis and reporting phases.

Andrew Thayne (https://orcid.org/0000-0002-9702-1662) (Data Assistant) was involved in the design, conduct and reporting phases.

Haleema Shakur-Still (https://orcid.org/0000-0002-6511-109X) (Professor of Global Health Clinical Trials) was involved in the design, conduct, analysis and reporting phases.

Ian Roberts (https://orcid.org/0000-0003-1596-6054) (Professor of Epidemiology and Public Heath) was involved in the design, conduct, analysis and reporting phases.

Danielle Prowse (https://orcid.org/0000-0002-7470-4823) (Assistant Data Manager) was involved in the design and conduct phases.

Danielle Beaumont (https://orcid.org/0000-0002-2530-9608) (Senior Trial Manager/Research Fellow) was involved in the design and conduct phases.

Zahra Jamal (https://orcid.org/0000-0002-3817-6795) (Trial Assistant) was involved in the reporting phase.

Ben Goldacre (https://orcid.org/0000-0002-5127-4728) (Senior Clinical Research Fellow) was involved in the design and reporting phases.

Tjeerd van Staa (https://orcid.org/0000-0001-9363-742X) (Professor in Health e-Research) was involved in the design and reporting phases.

Thomas M MacDonald (https://orcid.org/0000-0001-5189-6669) (Professor of Molecular and Clinical Medicine) was involved in the design phase.

Jane Armitage (https://orcid.org/0000-0001-8691-9226) (Professor of Clinical Trials and Epidemiology) was involved in the design phase.

Michael Moore (https://orcid.org/0000-0002-5127-4509) (Trial Steering Committee Chairperson) was involved in the design, conduct and reporting phases.

Maurice Hoffman (https://orcid.org/0000-0002-8860-4786) (Patient Representative on the Trial Steering Committee) was involved in the conduct and reporting phases.

Liam Smeeth (https://orcid.org/0000-0002-9168-6022) (Professor of Clinical Epidemiology) was involved in the design, conduct, analysis and reporting phases.

Publications

Herrett E, Williamson E, Beaumont D, Prowse D, Youssouf N, Brack K, et al. Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care. BMJ Open 2017;7:e016604.

Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ 2021;372:n135.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

Trial Steering Committee

Michael Moore, Maurice Hoffman, Rebecca Harmston, Brian MacKenna, David Symes, Haleema Shakur-Still and Liam Smeeth.

Data Monitoring Committee

John Norrie (a member of the NIHR HTA and Efficacy and Mechanism Evaluation Editorial Board), Nicholas Mills and Hannah Castro.

Protocol Committee

Emily Herrett, Elizabeth Williamson, Danielle Beaumont, Danielle Prowse, Nabila Youssouf, Kieran Brack, Jane Armitage, Ben Goldacre, Tom MacDonald, Tjeerd van Staa, Ian Roberts, Haleema Shakur-Still and Liam Smeeth.

Trial Co-ordinating Team

Liam Smeeth (Chief Investigator), Elizabeth Williamson (Statistician), Alexander Perkins (Trial Manager), Andrew Thayne (Data Assistant), Haleema Shakur-Still (CTU Co-director), Ian Roberts (CTU Co-director), Danielle Prowse (Assistant Data Manager), Danielle Beaumont (Senior Trial Manager), Nabila Youssouf (Trial Manager), Kieran Brack (Trial Manager), Collette Barrow (Trial Administrator), Sergey Kostrov (IT Systems Officer) and Hakim Miah (IT Manager).

Trial Collaborators

Please see Appendix 4 for a list of GP practices involved in the research.

The following staff were involved in the trial at the GP practices:

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 and Nicola Jayne Pascall.