Participants meeting the following criteria are included: people aged 75 years and older being treated with statins as primary prevention for CV events, who provide informed consent.
After randomization, patients in the statin-cessation strategy are instructed to withdraw their treatment. In the comparison strategy, patients continue their statin treatment at the usual dosage. The cost-effectiveness of the statin-cessation strategy compared to continuing statins will be estimated through the incremental cost per quality-adjusted life years QALYs gained at 36 months, from the perspective of the French healthcare system.
Overall mortality will be the primary clinical endpoint. Period effects were explored in sensitivity analyses. To assess differences between data collection methods, the primary analysis was repeated adjusting for the data collection method and allowing the treatment effect and the residual variance to vary by the data collection method. The binary measure of whether the participant reported having or not having muscle symptoms during that treatment period with participants contributing one response per period until completion or withdrawal was analysed with a logistic mixed model with random participant and treatment effects.
This binary measure was then combined with the follow-up question about attribution, to obtain one binary measure of whether the participant reported having muscle symptoms that could not be attributed to another cause eg, strenuous exercise. This binary measure was analysed with a similar logistic mixed model. Secondary outcomes of the effect of the statin on other aspects of life were analysed similarly to the primary outcome, omitting the autoregressive correlation structure.
We recorded the number and proportion of participants who decided to continue to use statins three months after their treatment ended month We used graphical and descriptive summaries to explore how withdrawals and adherence related to the statin and placebo periods. In patients who had not withdrawn before the start of the trial, a multinomial model was used to compare the probabilities of participants withdrawing during a placebo period, withdrawing during a statin period, or completing the trial.
Analyses were repeated restricting to withdrawals because of intolerable symptoms. All analyses were prespecified. A data monitoring committee oversaw the study. A StatinWISE patient involvement group was involved in trial design, specifically the packing and distribution of the drug, design of the data collection tools, and the content and wording of patient documents. Patient representatives provided active input into the interpretation and presentation of the results.
We recruited participants between 20 December and 5 April , and the last participant follow-up was on 5 July Mean age was Median total cholesterol concentration was 5. The participants included in the primary analysis contributed measurements during statin periods and symptom score measurements during placebo periods. Each of these measurements contributed to the primary analysis. The mean number of scores per participant was Appendix figure 3 shows the distribution of symptom scores across all periods.
Recruitment and participant flow. The observed mean muscle symptom score on the visual analogue scale was lower during statin treatment periods mean 1. Participants contributed different numbers of periods to the analysis and so the estimated treatment effect was not identical to the crude difference in means.
We found no evidence that the effect of statins on the primary outcome was modified by the method of data collection appendix table 2. We found no evidence of an effect of statins on the occurrence of muscle symptoms overall odds ratio 1. For the other secondary outcomes general activity, mood, ability to walk, normal work, relationships with other people, sleep, and enjoyment of life , we found no differences in symptom scores measured on the visual analogue scale between the statin and placebo periods table 3.
Participants contributed multiple periods to these summaries and so the odds ratio cannot be directly calculated from these fractions. Odds ratios above 1 indicate higher odds on statins. Each analysis includes all participants with at least one measurement for that outcome during a placebo period and at least one measurement during a statin period. One additional participant provided secondary outcome data through our questionnaire than provided primary outcome data.
Values greater than zero indicate more symptoms on statins. One participant did not attend. Table 4 shows the reasons for withdrawal. Overall, few participants withdrew because of muscle symptoms. Appendix figure 4 shows the mean symptom scores for those who withdrew versus those that did not withdraw. Among the participants who had not withdrawn before the start of the trial, our multinomial models showed no evidence of a difference in the probability of withdrawals during a statin period compared with a placebo period, either overall risk ratio 0.
Adherence reported by participants was confirmed by verification of the number of pills remaining in the returned drug treatment packs. During the trials, 13 serious adverse events were recorded; none was considered attributable to the study drug treatment. 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 were found.
This series of n-of-1 trials recruited participants who were considering stopping or had stopped their statin treatment because of muscle symptoms.
We found no differences in the frequency or severity of muscle symptoms between the statin and control periods. Also, we found no differences for the effect of muscle symptoms on aspects of daily life general activity, mood, ability to walk, normal work, relationships with other people, sleep, and enjoyment of life between the statin and control periods. Missing outcome data were equally distributed between the statin and placebo periods, making it unlikely that muscle symptoms contributed to missed outcome data collection.
We found no evidence of a difference in withdrawals between the statin and placebo periods but StatinWISE was not powered to detect a difference in withdrawals between periods, and our estimates did not exclude a difference.
This highly selected population of participants had identified themselves at the start of the study as experiencing symptoms when taking statins that were severe enough to stop treatment. Our findings support the limited evidence from one small n-of-1 trial and large systematic reviews and meta-analyses of randomised trials that have not established a clear effect of statins on muscle symptoms in the absence of myopathy.
Our data also agree with findings from a smaller cohort of patients with idiopathic inflammatory myopathies whose myalgia was not aggravated by statins. Our findings clearly indicated that most patients taking statins did not experience symptoms causally related to their statin, highlighting the importance of blinding when assessing adverse effects.
Observational studies have reported adverse effects on muscle, 26 and the experience of muscle symptoms when taking statins in clinical practice causes patients to stop treatment.
The large proportion of our participants who intended to restart treatment with statins after their trial is in line with observational data showing that rechallenge with statins can be tolerated by most patients. A common criticism of large placebo controlled trials of statins is that patients most likely to experience side effects are not included. StatinWISE included only patients who had experienced symptoms during treatment with statins.
Also, in some larger trials, participants were not asked specifically about muscle symptoms and their intensity; in StatinWISE, patients were asked directly about the intensity of their muscle symptoms. We minimised bias and confounding by collecting data on muscle symptoms in a series of double blind trials, with randomised statin and placebo treatments.
Within subject designs tend to have greater statistical power, which was increased by repeated measurements in each treatment period, allowing us to investigate differences between statins and placebo with greater precision.
The design also allowed us to feed back information to participants about whether their muscle symptoms occurred more frequently during the statin or placebo period, so that they could decide whether to continue treatment with statins. In conducting this series of trials, we allowed participants to determine whether their symptoms were likely to be caused by statins.
In this real world, general practice setting, we have shown the potential of these studies to be used in everyday clinical practice. The n-of-1 trial could be adopted by clinicians who are looking to establish the best course of treatment for patients, in general practice or outpatient settings, who present with muscle symptoms associated with statins.
Of the randomised participants, 86 did not complete the whole trial, of whom 49 did not provide sufficient data to contribute to the primary analysis. Adherence was similar for the statin and placebo periods, and the trial was adequately powered to account for this level of attrition. We did not measure levels of creatine kinase in participants who withdrew from the study so we do not know what proportion of participants had biochemical evidence of muscle effects. For simplicity, we assessed the effect of one statin, atorvastatin 20 mg, on muscle symptoms.
Our results, therefore, might not apply to higher doses of atorvastatin or to other statins. Although we intended to collect outcomes with web based methodology, over half of the participants preferred to report their symptoms on paper or by telephone.
Our two month treatment periods were designed to be long enough to allow the previous treatment to washout, and to allow the current treatment to have an effect. It is possible, however, that this time period was not long enough for some of our patients, and that the scores on the visual analogue scale were affected by treatment from the previous period. The analysis of our series of n-of-1 trials found no overall effect of statins on muscle symptoms in participants selected on the basis of having experienced severe muscle symptoms but no important increases in levels of enzymes during previous treatment with statins.
The lack of effect in patients completing the trial, combined with the low number of withdrawals owing to muscle symptoms, suggests a nocebo effect among users of statins, or of high tolerance to blinded rechallenge. Treatment with statins for those at high risk has potential health benefits that are lost by those who stop treatment.
The availability of n-of-1 trial packs in clinical care would allow patients and clinician to replicate this study in individuals, for any statin and at any dose to suit clinical needs, in primary care or in lipid clinics. Our results suggest that most patients would restart treatment after such a trial.
Future work could focus on conducting n-of-1 trials for other types of statins and higher doses, and for other drugs which are associated with transient adverse effects. A causal link between statins and rare but severe muscle adverse effects is well characterised but the causal effect of statins on less severe muscle symptoms, such as stiffness, pain, and weakness, is uncertain.
Widely publicised results of unblinded observational studies has led to many patients stopping treatment, believing their muscle symptoms are caused by statins, thus increasing morbidity and mortality from cardiovascular disease. Blinded, randomised n-of-1 trials can provide evidence of the role of statins in muscle symptoms. In a series of randomised, placebo controlled n-of-1 trials, no overall effect of statins on the frequency or severity of muscle symptoms was found in participants who had previously reported severe muscle symptoms when taking statins.
The n-of-1 trial could be a powerful clinical tool for clinicians and patients to determine how best to investigate muscle symptoms associated with statins. A sensitive literature search was performed to identify all relevant RCTs, with no time or language limits. Thirteen reports of RCTs were included in this study. The median score was 11 interquartile range IQR 8 to The most underreported items were those related to trial design, title and abstract, allocation concealment, implementation of the randomization sequence, and blinding.
Other important items, such as the one related to the description of the inclusion criteria, also had low adherence. Peer Review reports. When assessing the effects of an intervention for a specific clinical condition, randomized controlled trials RCTs are considered the preferable source of evidence to support its use [ 1 ].
Well-designed, well-conducted, and well-reported RCTs provide the most unbiased data for reducing the uncertainties around effects of an outcome of interest and for improving the reliability of findings [ 1 ].
To ensure their transparency and reproducibility, the International Committee of Medical Journal Editors ICMJE recommends the use of reporting guidelines that aim to improve the quality of the reports from studies on healthcare [ 3 , 4 ]. The statement was published in [ 5 ], updated in , and consists of a checklist of 25 items that guide the reporting of essential items of a RCT [ 4 ].
The CONSORT checklist is divided into six sections: title and abstract one item , introduction one item , methods ten items , results seven items , discussion three items , and other information three items. Assessing published trials for their completeness—i. We searched for studies including type 1 or 2 diabetic patients, regardless of age and sex.
Participants with or without diabetic retinopathy were considered, depending on the therapeutic or preventive purpose of the related RCT. We considered the diagnosis of diabetic retinopathy by any criteria previously validated. We included RCTs with parallel, cross-over or cluster designs. We only included complete and published studies. Protocols were not included. As comparators we considered other interventions, no intervention, or placebo.
We performed a sensitive search strategy without language, date, or publication status restrictions, using relevant descriptors and indexed terms in all databases.
The full search strategies for each database are presented in Additional file 1. We conducted additional searches in the clinical trial registries ClinicalTrials. We also performed a manual search from reference lists of all included studies and review articles for additional studies. We contacted field specialists about unpublished or ongoing studies that could fulfill our inclusion criteria. The selection of studies was performed by two authors VM and RP independently.
The first step of the selection was the reading of titles and abstracts. All potentially relevant studies were taken to a second step that consisted of a full text reading. All studies that fulfilled our inclusion criteria were included for critical appraisal. A third author RR was consulted if disagreement occurred in any step of the selection process. Selection was performed using Rayyan software [ 7 ]. Two authors VM, RR, or LL independently extracted data on results of the included studies and transfered data to an a priori developed sheet.
We confirmed the adherence to the 25 items and scored each item as: 0 no adherence or 1 full adherence. Search strategies retrieved references. After the selection process, 13 reports of RCTs fulfilled the eligibility criteria and were included [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].
The results section items items 13 to 19 had a median of four items judged adequate IQR 4 to 5 Fig. Table 1 presents the number of times that each item was judged adequate. Inadequate reporting by a scientific study, especially involving experimentation in humans, is scientific misconduct and is associated with resource waste. Adequate reporting means transparency and improves reproducibility [ 23 , 24 ].
The most underreported items in our study are related to the methods section. Overall, the methods sections were poorly reported and the results and discussion sections were better reported. As in other areas of health research, the reproducibility of clinical studies on diabetic retinopathy seems to be impaired by poor reporting. The low quality of reporting affects the synthesis of evidence in systematic reviews as well. Our study has some limitations. The CONSORT checklist was proposed as a reporting guideline tool for writing, rather than a tool for the evaluation of already published reports.
Nevertheless, the effect of this limitation on our results was probably null since no cluster trials were retrieved by the search strategy. However, this does not mean that previous RCTs should not adhere to reporting recommendations, because the checklist was already available in and reviewed in
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