Statin associated muscle symptoms (SAMS): strategies for prevention, assessment and management.

INTRODUCTION: Statins are the cornerstone for atherosclerotic cardiovascular disease risk reduction with recognized efficacy in primary and secondary prevention. Despite this, they remain underutilized due to concerns regarding adverse effects. Statin-associated muscle symptoms (SAMS) are the most frequent cause of medication intolerance and discontinuation with a prevalence estimated at 10%, regardless of causality, with the consequence of increased risk of adverse cardiovascular outcomes. AREAS COVERED: This clinical perspective reviews recent developments in mechanisms underlying the pathogenesis of statin myopathy, the role of the nocebo effect in perception of statin intolerance, and explores diverse components endorsed by international societies in establishing a statin intolerance syndrome. Non-statin drug alternatives that reduce low-density lipoprotein-cholesterol are also discussed, with emphasis on therapies with established effects on cardiovascular outcomes. EXPERT OPINION: Ultimately, a patient-centered clinical approach to managing SAMS is proposed to optimize statin tolerability, achieve guideline-recommended therapeutic goals and improve cardiovascular outcomes.

Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?

BACKGROUND: Statin-associated muscle symptoms (SAMS) are common. Rechallenge with the same statin (same-statin rechallenge) has recently been included as part of a proposed scoring index for diagnosing SAMS, but data regarding tolerability and efficacy of same-statin rechallenge, compared with other strategies, is minimal. In this study we evaluated the tolerability, percent change in low-density lipoprotein cholesterol (LDL-C), and proportion of patients achieving their LDL-C targets among 3 common management strategies-same-statin rechallenge, switching to a different statin (statin switch), and use of nonstatin medications only. METHODS: We performed a retrospective analysis of 118 patients referred to our tertiary care centre for management of SAMS, defined as development of muscle-related symptoms with 2 or more statins. Baseline and last follow-up lipid parameters were documented. Patients were classified as tolerant of a strategy if, at their last follow-up, they remained on that strategy. RESULTS: After a median follow-up of 17 months, most (n = 79; 67%) patients were able to tolerate a statin. Tolerability was similar among the 3 treatment strategies (71% same-statin rechallenge vs 53% statin switch vs 57% for nonstatin therapy only; P = 0.11). Those in the same-statin rechallenge and statin switch groups achieved greater LDL-C reductions compared with those who only tolerated nonstatins (-38.8 ± 3.4% vs -36.4 ± 2.9% vs -17.3 ± 4.5%; P = 0.0007). A greater proportion of patients in the same-statin rechallenge group achieved their target LDL-C compared with those in the nonstatin therapy only group (50% vs 15%; odds ratio, 6.8; 95% confidence interval, 1.5-40.7; P = 0.04). CONCLUSIONS: Among individuals with a history of SAMS, most will tolerate statin therapy. Same-statin rechallenge was highly tolerable and efficacious. Thus, same-statin rechallenge might warrant increased utilization.

Simvastatin prescribing patterns before and after FDA dosing restrictions: a retrospective analysis of a large healthcare claims database.

BACKGROUND: Muscle-related events, or myopathies, are a commonly reported adverse event associated with statin use. In June 2011, the US FDA released a Drug Safety Communication that provided updated product labeling with dosing restrictions for simvastatin to minimize the risk of myopathies. OBJECTIVE: Our objective was to describe prescribing patterns of simvastatin in combination with medications known to increase the risk of myopathies following updated product labeling dosing restrictions in June 2011. METHODS: A retrospective observational analysis was carried out, in which administrative claims data were utilized to identify prescribing patterns of simvastatin in combination with calcium channel blockers (CCBs) and other pre-specified drug therapies. Prescribing patterns were analyzed on a monthly basis 24 months prior to and 9 months following product label changes. Incidence of muscle-related events was also analyzed. RESULTS: In June 2011, a total of 60% of patients with overlapping simvastatin-CCB claims and 94% of patients with overlapping simvastatin-non-CCB claims were prescribed an against-label combination. As of March 2012, a total of 41% and 93% of patients continued to be prescribed against-label simvastatin-CCB and simvastatin-non-CCB combinations, respectively. The most commonly prescribed dose of simvastatin was 20 mg (39%). Against-label combinations were most commonly prescribed at a simvastatin dose of 40 mg (56%). Amlodipine was the most commonly prescribed CCB in combination with simvastatin (70%) and the most common CCB prescribed against-label (67%). CONCLUSIONS: Despite improvements in prescribing practices, many patients are still exposed to potentially harmful simvastatin combinations. Aggressive changes in simvastatin prescribing systems and processes are needed to improve compliance with FDA labeling to improve medication and patient safety.

Preclinical assessment of a polyspecific antivenom against the venoms of Cerrophidion sasai, Porthidium nasutum and Porthidium ophryomegas: Insights from combined antivenomics and neutralization assays.

A polyspecific antivenom is used in Central America for the treatment of envenomings by viperid snakes. This antivenom is generated in horses hyperimmunized with a mixture of venoms from Bothrops asper, Crotalus simus and Lachesis stenophrys. The present study analyzed the ability of this antivenom to neutralize the venoms of three Central American viperid species of the 'Porthidium group', i.e. Porthidium nasutum, Porthidium ophryomegas and Cerrophidion sasai, formerly classified as Cerrophidion godmani. In addition, the immunorecognition of the components of these venoms was assessed by immunoaffinity antivenomics. The antivenom proved effective in neutralizing the lethal, hemorrhagic, myotoxic, phospholipase A(2) (PLA(2)) and proteinase activities of the three venoms, albeit exhibiting quantitative differences in the values of the Median Effective Doses (ED(50)). Excepting for certain low molecular mass bands corresponding to disintegrins, and some PLA(2)s and PI-metalloproteinases, Western blotting and immunoaffinity chromatography revealed immunorecognition of most Porthidium and Cerrophidion venom proteins. In agreement with in vivo neutralization assays, immobilized antivenom IgGs showed higher immunocapturing activity of toxins from both Porthidium taxa than from C. sasai. Overall our results demonstrate a significant paraspecific protection of the Costa Rican polyspecific antivenom against the three venoms sampled. They also stress the need to search for novel ways to enhance the immune response of horses against several weakly immunogenic venom components.

Biomechanical and nonfunctional assessment of physical capacity in male ICU survivors.

OBJECTIVES: ICU admission is associated with decreased physical function for years after discharge. The underlying mechanisms responsible for this muscle function impairment are undescribed. The aim of this study was to describe the biomechanical properties of the quadriceps muscle in ICU survivors 12 months after ICU discharge. DESIGN: Case-control study with consecutive inclusion of ICU survivors and age- and sex-matched controls. SETTING: Patients were treated at a mixed 18-bed ICU at a tertiary care university hospital and tested at a biomechanical university laboratory. PATIENTS: We included 16 male ICU patients (Acute Physiology and Chronic Health Evaluation II score 20 ± 7, mean ± SD), who had stayed in the ICU >72 hrs and survived to 12 months and 15 age- and sex-matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An extensive battery of biomechanical tests, including maximum, fast, and endurance contractions, was administered during isometric knee extensions while simultaneously recording surface electromyography (quadriceps and hamstrings). Compared to controls, ICU survivors had reduced maximal voluntary torque (22%, 179 ± 64 Nm vs. 230 ± 57 Nm, p = 0.03), absolute rate of force development (50%, 868 ± 372 Nm/sec vs. 1739 ± 470 Nm/sec, p < 0.001) and relative rate of force development (32%, 512 ± 260% maximum voluntary contraction/sec vs. 754 ± 189% maximum voluntary contraction/sec, p < 0.01), and endurance time (40%, 136 ± 84 sec vs. 226 ± 111 sec, p < 0.02). Rate of force development, but not maximal voluntary torque, was significantly reduced after adjusting for muscle mass. Electromyography data indicated no impairment of motor activation strategy or central motor drive. Also, no difference in reaction time was found between patients and controls. CONCLUSIONS: ICU survivors had reduced rate of force development and muscular endurance 1 yr after ICU discharge. Our data indicate that the functional deficits experienced by ICU survivors originate in muscle tissue rather than the nervous system. Also, increased attention to velocity-orientated exercise during rehabilitation of ICU patients may have the potential to better physical outcome after critical illness.

Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment.

HMG-CoA reductase inhibitors ('statins') represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant interindividual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of statin myopathy. The identification of patients with an increased proclivity to statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of statins.

Placement of silicone sheeting at decompressive craniectomy to prevent adhesions at cranioplasty.

Adhesion formation between dura mater and cortex, and the overlying temporalis muscle and galea following decompressive craniectomy, can make subsequent cranioplasty difficult and adds to the risks of the procedure. We describe the implantation of sterile silicone sheeting at decompressive craniectomy to prevent adhesion formation and facilitate subsequent cranioplasty, potentially reducing surgical time, improving outcome and reducing risk.

An assessment of statin safety by muscle experts.

The National Lipid Association's (NLA) Muscle Safety Expert Panel was charged with the duty of examining the definitions, causative factors, and management of statin myopathy. The Panel was asked to use its evidence-based findings to form recommendations in response to a series of specific questions posed by the Task Force. The panel was composed of a clinical cardiologist, an exercise physiologist and skeletal muscle expert, and an expert in preventive cardiology who also examined skeletal muscle complications of statin use.