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Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence.

ABSTRACT: INTRODUCTION:Statins reduce the incidence of cardiovascular disease (CVD) and cause few adverse effects. Half of patients prescribed statins discontinue treatment due to perceived intolerance. Placebo-controlled (blinded) n-of-1 trials have shown people with perceived intolerance that the statin does not cause adverse events and most resume treatment. However, blinded n-of-1 trials are impractical to deliver in routine practice. Tackling Statin Intolerance using n-of-1 trials (TaSINI) will test the feasibility of a general practitioner (GP)-delivered behavioural intervention endorsing an unblinded n-of-1 trial to increase adherence to statins relative to usual care. METHODS AND ANALYSIS:TaSINI is a feasibility randomised controlled trial with a nested qualitative substudy. Ninety primary care patients who have discontinued statins due to intolerance or refused treatment will be randomised to an unblinded n-of-1 trial, a blinded n-of-1 trial (positive control) or usual care (negative control). Participants randomised to usual care will be advised to take statin therapy to prevent CVD. In both n-of-1 trial arms, GPs will deliver a behaviourally informed intervention that accessibly explains the benefits of statins, the prevalence of adverse effects and endorse the benefit of experimenting with medication. Participants will alternate between 4?weeks of medication and no medication (unblinded arm) or randomly sorted active and placebo (blinded arm) and will record adherence, symptoms and symptom attributions throughout. After 6?months, GPs will feedback symptom data during active/inactive treatment periods. All participants will be asked if they would like to initiate statin treatment. Measures of feasibility will be met if 4% of invited patients enrol, 50% of participants randomised to n-of-1 trials engage with the experiment and 25% more participants initiate statin in the unblinded n-of-1 arm than in usual care. ETHICS AND DISSEMINATION:This study has been granted ethical approval by North of Scotland Research Ethics Service. The results will be written up for publication and show whether to progress to an effectiveness trial where the primary outcome would be differences in low-density lipoprotein concentration.

SUBMITTER: Tudor K

PROVIDER: S-EPMC7044821 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence.

Tudor Kate K Brooks Jenny J Howick Jeremy J Fox Robin R Aveyard Paul P

BMJ open 20200212 2

<h4>Introduction</h4>Statins reduce the incidence of cardiovascular disease (CVD) and cause few adverse effects. Half of patients prescribed statins discontinue treatment due to perceived intolerance. Placebo-controlled (blinded) n-of-1 trials have shown people with perceived intolerance that the statin does not cause adverse events and most resume treatment. However, blinded n-of-1 trials are impractical to deliver in routine practice. Tackling Statin Intolerance using n-of-1 trials (TaSINI) wi ...[more]

PMID: 32051312

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Project description:Randomised control trials are regarded as the gold standard for evaluating the effectiveness and efficacy of healthcare interventions with thousands of trials published every year. Despite significant investment in infrastructure, a staggering number of clinical trials continue to face challenges with retention. Dropouts could lead to negative consequences-from lengthy delays to missing data that can undermine the results and integrity of the trial. Summarising evidence from non-randomised evaluations of retention strategies could provide complementary information to randomised evaluations that could guide trialists to the most effective ways of increasing retention of participants in clinical trials.The following electronic databases will be searched for relevant studies: EMBASE, MEDLINE, the Cochrane Controlled Trials Register, and Cochrane Methodology Register and the search will be limited to English-published studies during the last 10 years to increase relevance to current trials. Non-randomised studies (observational studies) including a comparison of two or more strategies to increase participant retention in randomised trials or comparing one or more strategies with no strategy will be included. The primary outcome will be the proportion of participants remained at the primary analysis as determined in each retention study.This review aims to gather and evaluate evidence on the effect of retention strategies examined in non-randomised studies. It is imperative to collect evidence from obseravational studies to infer whether or not these studies could be considered a practical way to complement or even replace a broadly favourable randomised design. If we find that non-randomised studies to be included in this review are of high quality with adequate control of biases, we will recommend to trialists and others not to rely exclusively on randomised studies and to give meticulous attention to the plentiful evidence that can be obtained from non-randomised studies. Should the results of this review suggest that evaluating retention strategies in observational studies provides insufficient evidence to trialists planning their retention strategies, we will be able to say that there is little point in conducting non-randomised studies and that they would do better to invest their time and resources in a randomised evaluation if possible. Where a non-randomised study design is chosen, the review authors will offer recommendations to trialists and others regarding how to ensure that these studies are conducted in a way that can minimise the risk of bias and increase confidence in the findings.PROSPERO 2017: CRD42017072775 .

Project description:BackgroundAlthough statins are often discontinued when myalgia arises, a causal relationship may not always exist. How well-tolerated statins are when rechallenge is blinded and controlled is unclear.Methods and findingsWe performed a systematic review and meta-analysis (PROSPERO CRD42023437648) to evaluate the success of statin rechallenge versus matched placebo in those who were previously statin intolerant. Our primary outcome was intolerance; our secondary outcome was the myalgia or global symptom score. Medline, Embase, CINAHL Plus, Scopus, and CENTRAL were searched from inception to May 1, 2023. Eligible trials were randomized controlled trials with parallel or crossover designs examining statin rechallenge in statin-intolerant adults. Two independent reviewers selected studies, extracted data, and assessed risk of bias (Cochrane Collaboration's risk-of-bias tool 1). Relative risk (RR) and mean difference (MD) were estimated using fixed effect Mantel-Haenszel statistics. Of 1,941 studies screened, 8 met our inclusion criteria (8 to 491 participants from Asia, Europe, North America, and Oceana). Compared to placebo, intolerance was more common in statin users [325/906 (36%) vs 233/911 (26%), RR 1.40, 95% CI, 1.23 to 1.60, I2 = 0%, 7 trials, number needed to harm 10] and there was no statistically significant difference in myalgia or global symptom score on a 100-point scale [MD 1.08, 95% CI, -1.51 to 3.67, I2 = 0%, 5 trials]. Limitations include only 1 trial asking participants about intolerable symptoms (vs inferring intolerance from discontinuation or trial withdrawal); the small number of trials; the possibility of attrition bias; and the potential for carryover effects in crossover/n-of-1 trial designs.ConclusionsOf those previously intolerant of statins who were rechallenged with a statin and compared to placebo recipients, medication intolerance was more common amongst statin recipients. However, there was no significant difference in mean myalgia or global symptom score between statin and placebo, and only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo.

Project description:INTRODUCTION:This project focuses on how frailty is addressed in primary healthcare (PHC) and will evaluate the effectiveness of a multifactorial intervention (considering the appropriateness of the pharmaceutical prescription, the nutritional care provided and the exercise intervention) for persons with frailty, in terms of improving their functional capacity and reducing the incidence of adverse events related to frailty. The final evaluation will be made at 12 months' follow-up. METHODS AND ANALYSIS:Pragmatic multicentre cluster randomised controlled clinical trial, single blind with two arms: multifactorial intervention in PHC versus usual follow-up. The randomisation unit is the patient list and the analysis unit is the patient. In addition, a cost-effectiveness study and a qualitative study will be carried out, the latter based on semistructured interviews and focus groups. Two hundred persons (100 per study branch) all aged ?70 years, presenting frailty, but functionally independent and resident in the community, will be recruited. A baseline evaluation will be carried out prior to the intervention, with follow-up at 6 and 12 months. The main study variables considered will be functional capacity and incidence of adverse events; the secondary variables considered will be the patients' sociodemographic characteristics, nutritional status, level of physical activity and drug consumption, together with data on comorbidity, cognitive and affective status and health-related quality of life. Data will be analysed according to the intention-to-treat principle using a 5% significance level. ETHICS AND DISSEMINATION:The study will at all times be conducted in strict accordance with the provisions of the Declaration of Helsinki and with the national legislation regulating patients' autonomy. All patients recruited will be asked to provide written informed consent before taking part in the clinical trial. On completion of the study, the principal investigator expects to publish the results of this research in a peer-reviewed open access scientific journal. TRIAL REGISTRATION NUMBER:ISRCTN17143761.

Project description:IntroductionAlthough statins are commonly used for prevention of cardiovascular disease, there is limited evidence about statin-related adverse effects in older people. Statin-related adverse events (AEs), especially the statin-associated muscle symptoms (SAMS), are the most common reasons for their discontinuation. Therefore, it is important to determine the risk of SAMS in the older population. We will undertake a systematic review and meta-analysis primarily focusing on the risk of SAMS and secondarily targeting myopathy, rhabdomyolysis, AEs and serious AEs, dropouts due to SAMS in run-in period, related permanent discontinuation rate of statins and creatine kinase level, among older people who received statins for primary prevention.Methods and analysisThis study has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols statement. We will include randomised controlled trials in which statin was compared with placebo with at least 1 year follow-up among older adults aged ≥65. This review is an update of a Cochrane systematic review that included the articles published before 2012. Cochrane Central Register of Controlled Trials, Medline OvidSP and Embase electronic database searches will be performed to identify relevant articles, limiting the publication date from 1 January 2012 to 13 February 2017. There will be no language limitation. Two independent reviewers will screen titles and abstracts and full text in duplicate. Risk of bias and evidence quality will be assessed using the Cochrane Collaboration's tool and the Grading of Recommendations Assessment, Development and Evaluation approach, respectively. A meta-analysis using pooled data will be undertaken, if appropriate. We will also perform metaregression and subgroup analyses to identify sources of heterogeneity.Ethics and disseminationThis study is exempt from ethics approval due to the anonymous and aggregated data used. The outcomes will be disseminated by conference presentations and published in a peer-reviewed journal.Trial registration numberCRD42017058436.

Project description:IntroductionStatins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in the absence of statin myopathy. Discrepancies between data from observational studies, which suggest statins are associated with excess muscle symptoms, and from randomised trials, which suggest no such excess, have caused confusion. N-of-1 trials offer the opportunity to establish whether muscle symptoms during statin use are caused by statins in particular individuals.Methods and analysisThis series of 200 randomised, double-blinded N-of-1 trials in primary care will determine (1) the effect of statins on all muscle symptoms and (2) the effect of statins on muscle pain that is perceived to be statin related. Patients who are considering discontinuing statin use due to muscle symptoms and those who have discontinued in the last 3 years due to such symptoms will be recruited. Participants will be randomised to a sequence of six 2-month treatment periods during which they will receive atorvastatin 20 mg per day or matched placebo. On each of the last 7 days of each treatment period, participants will rate their muscle symptoms on a Visual Analogue Scale (VAS).At the end of their trial, participants will be shown numerical and graphical summaries of their own symptom data during statin and placebo periods. The primary analysis on the aggregate data from all participants will be a linear mixed model for VAS muscle symptom score, comparing scores during treatment with statin and placebo.Ethics and disseminationThis trial received a favourable opinion from South Central-Hampshire A Research Ethics Committee. Results will be published in a peer-reviewed medical journal. Dissemination of results to patients will take place via the media, website (statinwise.lshtm.ac.uk) and patient organisations.Trial registration numberISRCTN30952488.

Dataset Information

Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence.

Publications

Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence.

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