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.
ABSTRACT: Statins 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.This 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.This 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.ISRCTN30952488.
Project description: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.
Project description:It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR]?=?0.89, 95% CI 0.78-1.01, p?=?0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72-1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76-1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR?=?0.93 [95% CI 0.82-1.07], p?=?0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR?=?0.98, 95% CI 0.80-1.20, p?=?0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Please see later in the article for the Editors' Summary.The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Project description:Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
Project description:INTRODUCTION:Although 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 ANALYSIS:This 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 DISSEMINATION:This 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 NUMBER:CRD42017058436.
Project description:Acute coronary syndrome (ACS) is characterised by increased effector cells and decreased regulatory T-cells (Tregs). Statins have been shown to be clinically beneficial in ACS patients. This effect could be mediated via the induction of Tregs in ACS patients. The aim of this systemic review and meta-analysis was to evaluate whether statin therapy enhances the frequency of Tregs determined by CD4+CD25+FOXP3+ in this subset of patients. A comprehensive search of PubMed and Embase was performed. Studies were restricted to randomised controlled trials that quantified CD4+CD25+FOXP3+ cell frequency by flow cytometric analysis before and after statin treatment in adults diagnosed with ACS. A minimum of at least two of the conventional markers to identify Tregs was compulsory. Four randomised controlled trials studies (439 participants) were included, all with low-to-moderate risk of bias. Pooled data showed a significant increase in Treg frequency after statin therapy in ACS patients. A further meta-regression and subgroup analysis also showed a negative dose-related effect, and a statin type-related effect (rosuvastatin versus atorvastatin), respectively. The results confirmed that statins positively alter the frequency of Tregs, which may indicate a potential mechanism of their therapeutic effect. However, there was a risk of information bias due to the markers used to identify Tregs, which was not fully explored, therefore, further randomised controlled trials should utilise markers of Tregs, such as the FOXP3 locus (Treg-specific demethylated region), for identification.
Project description:Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied.The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69).These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.
Project description:To explore the risk of industry sponsorship bias in a systematically identified set of placebo controlled and active comparator trials of statins.Systematic review and network meta-analysis.Open label and double blind randomised controlled trials comparing one statin with another at any dose or with control (placebo, diet, or usual care) for adults with, or at risk of developing, cardiovascular disease. Only trials that lasted longer than four weeks with more than 50 participants per trial arm were included. Two investigators assessed study eligibility.Bibliographic databases and reference lists of relevant articles published between 1 January 1985 and 10 March 2013.One investigator extracted data and another confirmed accuracy.Mean absolute change from baseline concentration of low density lipoprotein (LDL) cholesterol.Study level outcomes from randomised trials were combined using random effects network meta-analyses.We included 183 randomised controlled trials of statins, 103 of which were two-armed or multi-armed active comparator trials. When all of the existing randomised evidence was synthesised in network meta-analyses, there were clear differences in the LDL cholesterol lowering effects of individual statins at different doses. In general, higher doses resulted in higher reductions in baseline LDL cholesterol levels. Of a total of 146 industry sponsored trials, 64 were placebo controlled (43.8%). The corresponding number for the non-industry sponsored trials was 16 (43.2%). Of the 35 unique comparisons available in 37 non-industry sponsored trials, 31 were also available in industry sponsored trials. There were no systematic differences in magnitude between the LDL cholesterol lowering effects of individual statins observed in industry sponsored versus non-industry sponsored trials. In industry sponsored trials, the mean change from baseline LDL cholesterol level was on average 1.77 mg/dL (95% credible interval -11.12 to 7.66) lower than the change observed in non-industry sponsored trials. There was no detectable inconsistency in the evidence network.Our analysis shows that the findings obtained from industry sponsored statin trials seem similar in magnitude as those in non-industry sources. There are actual differences in the effectiveness of individual statins at various doses that explain previously observed discrepancies between industry and non-industry sponsored trials.
Project description:This study aimed to identify a mechanism for statin-induced myopathy that explains its prevalence and selectivity for skeletal muscle, and to understand its interaction with moderate exercise. Statin-associated adverse muscle symptoms reduce adherence to statin therapy; this limits the effectiveness of statins in reducing cardiovascular risk. The issue is further compounded by perceived interactions between statin treatment and exercise. This study examined muscles from individuals taking statins and rats treated with statins for 4 weeks. In skeletal muscle, statin treatment caused dissociation of the stabilizing protein FK506 binding protein (FKBP12) from the sarcoplasmic reticulum (SR) calcium (Ca2+) release channel, the ryanodine receptor 1, which was associated with pro-apoptotic signaling and reactive nitrogen species/reactive oxygen species (RNS/ROS)-dependent spontaneous SR Ca2+ release events (Ca2+ sparks). Statin treatment had no effect on Ca2+ spark frequency in cardiac myocytes. Despite potentially deleterious effects of statins on skeletal muscle, there was no impact on force production or SR Ca2+ release in electrically stimulated muscle fibers. Statin-treated rats with access to a running wheel ran further than control rats; this exercise normalized FKBP12 binding to ryanodine receptor 1, preventing the increase in Ca2+ sparks and pro-apoptotic signaling. Statin-mediated RNS/ROS-dependent destabilization of SR Ca2+ handling has the potential to initiate skeletal (but not cardiac) myopathy in susceptible individuals. Importantly, although exercise increases RNS/ROS, it did not trigger deleterious statin effects on skeletal muscle. Indeed, our results indicate that moderate exercise might benefit individuals who take statins.
Project description:Statin-induced myopathy is a common side-effect but its mechanisms in human skeletal muscle have never been explained satisfyingly. We exposed 25 different primary human muscle cell lines to either a lipophilic or a hydrophilic statin, quantified cholesterol, mevalonate, proliferation, differentiation, and performed a comprehensive transcriptome and proteome analysis. We found reduced mevalonic acid (MVA) and cholesterol levels demonstrating incorporation of statins into the cells. Statins also significantly impaired proliferation and differentiation. Using an integrated pathway analysis approach with transcriptome and proteome data from statin-treated human primary myotubes, we modelled a novel statin-induced metabolism network for human muscle cells. This analysis confirmed the effect of statins on cholesterol biosynthesis but also uncovered alterations of acetyl CoA-dependent lipid and fatty acid metabolism Overall design: Human primary human myoblasts were treated with 2 different statins under fusion conditions.
Project description:BACKGROUND: Muscle effects are the most common reported adverse effects of 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins). However, in placebo-controlled trials the incidence of muscle pain is most often similar for placebo and active control groups. OBJECTIVE: We sought to evaluate whether statin use was associated with a higher prevalence of musculoskeletal pain in a nationally representative sample. METHODS: Cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Participants were 3,580 adults > or =40 years without arthritis who were interviewed at home and examined in a mobile examination center. Participants were asked about sociodemographic characteristics, health conditions, medication use, and musculoskeletal pain. Height, weight, blood pressure, ankle brachial index, and cholesterol were measured. MEASUREMENTS AND MAIN RESULTS: Prevalence and adjusted odds ratios (OR) of any musculoskeletal pain and musculoskeletal pain in 4 different anatomical regions (neck/upper back, upper extremities, lower back, and lower extremities) by statin use during the last 30 days. Among statin users (n = 402), 22.0% (95%CI 18.0-26.7%) reported musculoskeletal pain in at least 1 anatomical region during the last 30 days, compared with 16.7% (95%CI 15.1-18.4%) of those who did not use a statin. Compared to persons who did not use statins, those who used statins had multivariable-adjusted odds ratios (95%CI; p value) of 1.50 (1.07-2.11; p = .01) for any musculoskeletal pain, 1.59 (1.04-2.44, p = .03) for lower back pain, and 1.50 (1.02-2.22, p = .03) for lower extremity pain. CONCLUSION: Musculoskeletal pain is common in adults > or =40 years without arthritis. In this nationally representative sample, statin users were significantly more likely to report musculoskeletal pain.