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

BACKGROUND: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. OBJECTIVES: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. DESIGN: A series of 200 double-blinded N-of-1 trials. SETTING: Participants were recruited from 50 general practices in England and Wales. PARTICIPANTS: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. MAIN OUTCOME MEASURES: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful. RESULTS: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. CONCLUSIONS: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. FUTURE WORK: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. LIMITATIONS: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Statins are one of the most commonly prescribed drugs in the UK. There is strong evidence that they are effective in safely reducing heart disease; however, there is some doubt about whether or not statins cause muscle pain, stiffness or weakness. This research has been carried out to understand the effect of statins on muscle symptoms. To answer our question, we asked 200 volunteers from across England and Wales to participate in the study. Patients who joined the study either had recently stopped taking statins because of muscle symptoms or were considering stopping because of muscle symptoms. Patients who participated were randomly assigned to a sequence of six 2-month treatment periods during which they received either statins or a placebo. Neither patients nor their general practitioner knew which tablet they were receiving. This helped to reduce bias in the data. At the end of each treatment period, patients were asked to report any muscle symptoms, or any other symptoms, that they experienced. The key result of this work is that patients reported no difference, on average, in their muscle symptoms between periods of taking a statin and periods of taking a placebo. We also assessed the impact on the patient's quality of life by looking at how statins affected the following areas: general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. As with muscle symptoms, there was no evidence of a difference between statin and placebo periods. The majority of patients who finished the trial decided to continue using statins after the trial. Future research should be carried out to assess different statin doses, as higher doses are often used following a heart attack. In addition, further work is needed to see how the approach we used could be adopted into everyday clinical care.

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

OBJECTIVE: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. DESIGN: Series of randomised, placebo controlled n-of-1 trials. SETTING: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. PARTICIPANTS: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. MAIN OUTCOME MEASURES: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. RESULTS: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. CONCLUSIONS: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. TRIAL REGISTRATION: ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.

Frequent attendances at emergency departments in England.

BACKGROUND: A small proportion of patients referred to as 'frequent attenders' account for a large proportion of hospital activity such as ED attendances and admissions. There is a lack of recent, national estimates of the volume of frequent ED attenders. We aimed to estimate the volume and age distribution of frequent ED attenders in English hospitals. METHOD: We included all attendances at all major EDs across England in the financial year 2016-2017. Patients who attended three times or more were classified as frequent attenders. We used a logistic regression model to predict the odds of being a frequent attender by age group. RESULTS: 14 829 519 attendances were made by 10 062 847 patients who attended at least once. 73.5% of ED attenders attended once and accounted for 49.8% of the total ED attendances. 9.5% of ED attenders attended three times or more; they accounted for 27.1% of the ED attendances. While only 1.2% attended six times or more, their contribution was 7.6% of the total attendances. Infants and adults aged over 80 years were significantly more likely to be frequent attenders than adults aged 30-59 years (OR=2.11, 95% CI 2.09 to 2.13, OR=2.22, 95% CI 2.20 to 2.23, respectively). The likelihood of hospital admission rose steeply with the number of attendances a patient had. CONCLUSION: One in 10 patients attending the ED are frequent attenders and account for over a quarter of attendances. Emergency care systems should consider better ways of reorganising health services to meet the needs of patients who attend EDs frequently.

Increase in the vascular residence time of propranolol-loaded nanoparticles coated with heparin.

Propranolol-HCI incorporated nanoparticles prepared with a blend of a polyester and a polycationic polymer and coated or not with a low molecular weight heparin by electrostatic interactions were prepared by emulsification followed by solvent evaporation. The mean diameter was 388 and 357 nm for coated and uncoated nanoparticles, respectively, and the entrapment efficiency ranged from 20 to 32%. Coated nanoparticles were negatively-charged, whereas uncoated nanoparticles displayed a positive zeta potential (+30 mV). After intravenous administration to rabbits of propranolol-HCI solution and propranolol-loaded nanoparticles coated or not with heparin, pharmacokinetic data revealed that coated nanoparticles exhibited a prolonged blood residence time. It can be concluded that the hydrophilic layer of heparin at the surface of nanoparticles conferred stealth properties which probably reduce the phagocytosis process and avoid immediate uptake by the mononuclear phagocytic system.

Preparation and characterization of propranolol hydrochloride nanoparticles: a comparative study.

The water-in-oil-in-water (w/o/w) emulsification process is the method of choice for the encapsulation inside polymeric particles of hydrophilic drugs such as proteins and peptides which are high molecular weight macromolecules. Our objective was to apply this technique in order to formulate nanoparticles loaded with both a hydrophilic and a low molecular weight drug such as propranolol-HCl. Nanoparticles were prepared using a pressure homogenization device with various polymers (poly--caprolactone, poly(lactide-co-glycolide), ethylcellulose) and different amounts of drug and were compared in terms of particle size, encapsulation efficiency and drug release. Higher encapsulation efficiencies were obtained with both PCL (77.3%) and PLGA (83.3%) compared to ethylcellulose (66.8%). The in vitro drug release was characterized by an initial burst and an incomplete dissolution of the drug. When decreasing the polymer/drug ratio, the release appeared more controlled and prolonged up to 8 h. It can be concluded that nanoparticles prepared by w/o/w emulsification followed by solvent evaporation might be potential drug carriers for low molecular weight and hydrophilic drugs.

Anticoagulant activity of heparin following oral administration of heparin-loaded microparticles in rabbits.

Heparin-loaded microparticles, prepared according to the double emulsion method with biodegradable (PCL and PLGA) and nonbiodegradable (Eudragit RS and RL) polymers used alone or in combination, with or without gelatin, were characterized in vitro and in vivo after oral administration in rabbits. The entrapment efficiency and the release of heparin were determined by a colorimetric method with Azure II. The antifactor Xa activity of heparin released in vitro after 24 h was assessed. After oral administration of heparin-loaded microparticles in rabbits, the time course of modification of the clotting time estimated by the activated partial thromboplastin time (APTT) was followed over 24 h. Microparticles with a size ranging from 80 to 280 microm were obtained. Heparin entrapment efficiency as well as heparin release depended on both the nature of the polymers and the presence of gelatin. The Eudragit polymers increased the drug loading but slowed down the heparin release, whereas gelatin accelerated the release. No change in clotting time was observed after oral administration of gelatin microparticles. Heparin-loaded microparticles prepared with blends of PLGA and Eudragit displayed a prolonged duration of action characterized by a twofold increase in APTT and a enhancement of absorption. This study demonstrated the feasibility of encapsulating heparin within polymeric particles, and the significant increase in APTT confirmed the oral absorption of heparin released from polymeric microparticles.

In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits.

BACKGROUND: Owing to its short half-life and lack of oral absorption, heparin has to be administered by the parenteral route. An oral heparin formulation, however, would avoid the disadvantages of parenteral injections and would consequently be highly desirable for patients. Polymeric nanoparticles (NPs) prepared with biodegradable poly-epsilon-caprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) and nonbiodegradable positively charged polymers (Eudragit RS and RL), used alone or in combination, were evaluated in vitro and in vivo after a single oral administration of heparin-loaded NPs in rabbits. METHODS AND RESULTS: After oral administration of heparin-loaded NPs in rabbits (600 IU/kg), increases in both anti-factor Xa activity and activated partial thromboplastin time (aPTT) were detected with each formulation. Moreover, the anti-Xa activity was detected for a longer period than when a heparin solution was administered intravenously. A peak concentration of 0.16+/-0.01 IU/mL and an average aPTT of 24 seconds (2-fold increase) were obtained 7 hours after oral dosing of Eudragit RL/PCL NPs containing heparin, exhibiting an absolute bioavailability of 23%. CONCLUSIONS: The significant increases in anti-factor Xa activity and aPTT confirmed the oral absorption in rabbits of heparin released from polymeric NPs.