Statin Induced Myopathy and Myalgia: Time Trend Analysis and Comparison of Risk Associated with Statin Class from 1991–2006

BACKGROUND: Statins are widely used as a cholesterol lowering medication, reduce cardiovascular mortality and morbidity in high risk patients; and only rarely cause serious adverse drug reactions (ADRs). UK primary care databases of morbidity and prescription data, which now cover several million people, have potential for more powerful analytical approaches to study ADRs including adjusting for confounders and examining temporal effects. METHODS: Case-crossover design in detecting statin associated myopathy ADR in 93, 831 patients, using two independent primary care databases (1991-2006). We analysed risk by drug class, by disease code and cumulative year, exploring different cut-off exposure times and confounding by temporality. RESULTS: Using a 12 and 26 week exposure period, large risk ratios (RR) are associated with all classes of statins and fibrates for myopathy: RR 10.6 (9.8-11.4) and 19.9 (17.6-22.6) respectively. At 26 weeks, the largest risks are with fluvastatin RR 33.3 (95% CI 16.8-66.0) and ciprofibrate (with previous statin use) RR 40.5 (95% CI 13.4-122.0). AT 12 weeks the differences between cerivastatin and atorvastatin RR for myopathy were found to be significant, RR 2.05 (95% CI 1.2-3.5), and for rosuvastatin and fluvastatin RR 3.0 (95% CI 1.6-5.7). After 12 months of statin initiation, the relative risk for myopathy for all statins and fibrates increased to 25.7 (95% CI 21.8-30.3). Furthermore, this signal was detected within 2 years of first events being recorded. Our data suggests an annual incidence of statin induced myopathy or myalgia of around 11.4 for 16, 591 patients or 689 per million per year. CONCLUSION: There may be differential risks associated with some classes of statin and fibrate. Myopathy related to statin or fibrate use may persist after a long exposure time (12 months or more). These methods could be applied for early detection of harmful drug side effects, using similar primary care diagnostic and prescribing data

Clinical evaluation of rosuvastatin in heart transplant patients with hypercholesterolemia and therapeutic failure of other statin regimens: short-term and long-term efficacy and safety results

[Abstract] We conducted an observational study of 30 heart transplant recipients with serum low-density lipoprotein cholesterol (LDL-c) >100 mg/dl despite previous statin therapy, who were treated with rosuvastatin 10 mg daily (5 mg in case of renal dysfunction). Serum lipids, creatine phosphokinase (CPK), bilirubin, and hepatic enzymes were prospectively measured 2, 4, and 12 weeks after the initiation of the drug. Clinical outcomes of patients who continued on long-term rosuvastatin therapy beyond this 12-week period were reviewed in February 2015. Over the 12-week period following rosuvastatin initiation, serum levels of total cholesterol (TC) and LDL-c and the ratio TC/high-density lipoprotein cholesterol (HDL-c) decreased steadily (P < 0.001). Average absolute reductions of these three parameters were –48.7 mg/dl, –46.6 mg/dl, and –0.9, respectively. Seventeen (57%) achieved a serum LDL-c < 100 mg/dl. No significant changes from baseline were observed in serum levels of triglycerides, HDL-c, hepatic enzymes, bilirubin, or CPK. Twenty-seven (90%) patients continued on long-term therapy with rosuvastatin over a median period of 3.6 years, with no further significant variation in lipid profile. The drug was suspended due to liver toxicity in 1 (3.3%) patient and due to muscle toxicity in 2 (6.7%) patients. All adverse reactions resolved rapidly after rosuvastatin withdrawal. Our study supports rosuvastatin as a reasonable alternative for heart transplant recipients with hypercholesterolemia and therapeutic failure of other statin regimens

Pravastatin for early-onset pre-eclampsia:a randomised, blinded, placebo-controlled trial

Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds

SAFETY EVALUATION OF STATIN IN YOGYAKARTA, INDONESIA

Background : The 3-hydroxy-3-methylglutaryl-coenzyme (HMG-Co-A) reductase inhibitors, also known as statins, are the most effective class of drugs for lowering serum Low-Density Lipoprotein cholesterol (LDL-c)concentrations. They are first-line agents for patients who require drug therapy to reduce serum LDL-c concentrations. Although these drugs have been very successful in managing the cardiovascular health of many patients, there are also potential adverse effects that have been identified. The most common adverse effects reported include muscle pain or weakness that can progress to rhabdomyolysis and mortality. If detected early, statin-related symptoms are reversible after withdrawal of the statin. Objective : This research was aimed to know the safety of statin used at Public Hospitals in Yogyakarta. Method : This research was observational study with retrospective data collected. The target population are all of diabetes mellitus, cardiovascular and stroke patients that recorded on the medical record of Public Hospitals in Yogyakarta during 2 months. Results : There were 28 patients who used simvastatin and 8 patients who used atorvastatin, experienced adverse effects of statins (n=157). Headache was the most adverse effect which was experienced by the patients. However rhabdomyolysis was not found in this reasearh. Interaction between simvastatin and nifedipine resulted more adverse effects such as headache, insomnia and abdominal pain than with other drugs. Conclusions : Simvastatin, rosuvastatin and atorvastatin were well tolerated use in Yogyakarta, Indonesia. Only 22.9% from 157 patients experienced the adverse effects of statin. Adverse effects because of the interaction between simvastatin and other drugs were experienced by 8.92% patients. The result of this study need to be confirmed with additional study with larger sample sizes and vigilant surveillance to abolish the toxicity of the statin

Statin-Associated Muscular and Renal Adverse Events: Data Mining of the Public Version of the FDA Adverse Event Reporting System

OBJECTIVE: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank-order of the association. METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. RESULTS: Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non-acute renal failure or for an increase in blood creatinine level. CONCLUSIONS: Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin-associated adverse events

Gene-by-Environment Interaction of Hepatic Xenobiotic Transporter Polymorphisms and Nonalcoholic Steatohepatitis on Drug Disposition and Toxicity

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease and is the hepatic manifestation of metabolic syndrome. The overall rate of NASH is on the rise globally, and currently approximately 1.5-6.45% of the population is afflicted with this disease(Z. M. Younossi et al., 2016). The progression of NASH is known to result in the dysregulation of many genes, including those that are responsible for ADME processes. These changes can alter the disposition of xenobiotics and result in adverse drug reactions (ADRs). Since ADRs are becoming increasingly frequent, with nearly 1 in 20 hospital patients experiencing ADRs in the United States(Bourgeois, Shannon, Valim, & Mandl, 2010), determining the factors that contribute to variations in drug response is increasingly important. Additionally, genetic polymorphisms are known to cause pharmacokinetic variations, and many of them have been extensively researched for their impacts on patient response. Less known, however, is how genetic polymorphisms and chronic liver disease interact, and how that interaction may increase patient risk for ADRs. As the goal of precision medicine is to provide the right dose to the right person at the right time, determining how factors like disease state can interact with genetic polymorphisms to alter pharmacokinetics can provide a better basis for individualized dosing. The purpose behind this study was therefore to utilize a methionine- and choline-deficient (MCD) rodent model to determine the gene-by-environment interactions of hepatic xenobiotic transporter polymorphisms and NASH on the disposition and toxicity of pharmaceutical compounds. To identify the impact of these gene-by-environment interactions, pharmacokinetic studies were designed to investigate the alterations to drug distribution that occurred with NASH in combination with disruptions of hepatic uptake and efflux transporters and to determine the underlying mechanism behind pharmacokinetic alterations during disease progression. The results in the MCD rodent model of NASH found a synergistic interaction between polymorphisms of both hepatic uptake and efflux transporters and NASH that lead to changes in plasma retention and biliary excretion of probe substrates. The comparison between biliary excretion of SN-38 in wild-type and Bcrp-/- rats demonstrated this synergistic interaction, as no alterations were found in biliary AUCs until the combination of the disease and genetic disruption, where biliary excretion significantly decreased. A similar interaction was demonstrated in a study investigating the gene dose of Oatp1b2 and NASH on pravastatin disposition, where the combination of full genetic Oatp1b2 knockout along with NASH was necessary to see dramatic increases in plasma AUC and tissue concentrations. Finally, in order to identify the underlying mechanism by which NASH alters pharmacokinetics, the disposition of sorafenib-glucuronide was determined in wild-type, Oatp1a/1b cluster knockouts, and Mrp2 knockouts, with and without MCD diet. By comparing the changes to plasma AUC and liver concentrations in these groups, the disruption to hepatocyte hopping that occurs during NASH was made quantifiable. In summation, these data identify synergistic gene-by-environment interactions of hepatic xenobiotic transporter polymorphisms and NASH, the alterations that these interactions cause to drug disposition, and the mechanism by which NASH causes pharmacokinetic changes through disruption of hepatocellular shuttling

Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments

Adverse drug events due to drug-drug interactions can be prevented by avoiding concomitant use of causative drugs; therefore, it is important to understand drug combinations that cause drug-drug interactions. Although many attempts to identify drug-drug interactions from real-world databases such as spontaneous reporting systems have been performed, little is known about drug-drug interactions caused by three or more drugs in polypharmacy, i.e., multiple drug-drug interactions. Therefore, we attempted to detect multiple drug-drug interactions using decision tree analysis using the Japanese Adverse Drug Event Report (JADER) database, a Japanese spontaneous reporting system. First, we used decision tree analysis to detect drug combinations that increase the risk of rhabdomyolysis in cases registered in the JADER database that used six statins. Next, the risk of three or more drug combinations that significantly increased the risk of rhabdomyolysis was validated with in vivo experiments in rats. The analysis identified a multiple drug-drug interaction signal only for pitavastatin. The reporting rate of rhabdomyolysis for pitavastatin in the JADER database was 0.09, and it increased to 0.16 in combination with allopurinol. Furthermore, the rate was even higher (0.40) in combination with valsartan. Additionally, necrosis of leg muscles was observed in some rats simultaneously treated with these three drugs, and their creatine kinase and myoglobin levels were elevated. The combination of pitavastatin, allopurinol, and valsartan should be treated with caution as a multiple drug-drug interaction. Since multiple drug-drug interactions were detected with decision tree analysis and the increased risk was verified in animal experiments, decision tree analysis is considered to be an effective method for detecting multiple drug-drug interactions.This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions

Are non-allergic drug reactions commonly documented as medication “allergies”? A national cohort of Veterans\u27 admissions from 2000 to 2014

Purpose: Adverse drug reactions (ADRs) including medication allergies are not well-described among large national cohorts. This study described the most common documented medication allergies and their reactions among a national cohort of Veterans Affairs (VA) inpatients. Methods: We evaluated inpatient admissions in any VA Medical Center from 1 January 2000 to 31 December 2014. Each admission was linked with allergy history preceding or upon admission. Individual drugs were aggregated into drug class category including: penicillins, sulfonamides, angiotensin converting enzyme (ACE) inhibitors, opiates, HMG-CoA reductase inhibitors (“statins”) and non-steroidal anti-inflammatory inhibitors (NSAID). Results were reported in aggregate and over time. Results: Approximately ~10.8 million inpatient admissions occurred from 2000 to 2014. We found the most commonly reported allergy drug classes were penicillins (13%, n = 1 410 080), opiates (9.1%, n = 984 978), ACE inhibitors (5.7%, n = 618 075) sulfonamides (5.1%, n = 558 653), NSAIDs (5.1%, n = 551 216) and statins (3.6%, n  = 391 983). Several allergy histories increased over time including opiates (6.2 to 11.2%), ACE inhibitors (1.3 to 10.2%), statins (0.3 to 7.3%) and NSAIDs (3.9 to 6.0%). Rash was the most commonly documented reaction on reports for penicillins (25.5%, n = 371 825), sulfonamides (25.6%, n = 165 954) and NSAIDs (10.3%, n = 65 741). The most common reaction for opiates was nausea/vomiting (17.9%, n = 211 864), cough/coughing for ACE inhibitors (41.0%, n = 270 537) and muscle pain/myalgia for statins (34.1%, n = 186 565). Conclusions: We report that penicillins and opiates are the most commonly documented drug allergies among VA inpatients, but other drug classes such as ACE inhibitors, statins and NSAIDs are becoming increasingly common. Clinicians also commonly document non-allergic ADRs in the allergy section such as cough or myalgia. Copyright © 2016 John Wiley & Sons, Ltd