Safety Of Statin Treatment Research Articles

Efficacy and Safety of Statin Treatment in Children with Familial Hypercholesterolemia: Outcomes of 20 Years of Experience

Background: The objective of this retrospective cohort study was to present the experience of 20-year-long comprehensive care of pediatric patients with familial hypercholesterolemia (FH) in a single academic center. Methods and Results: The study included 84 children aged 1–18 years with FH. For the whole study group, 535 medical visits were recorded. The mean follow-up period was 33.6 months. Molecular testing performed in 55 children (65%) provided genetic confirmation of the diagnosis in 36 children (43%). Twenty-seven children (32%) were treated pharmacologically with statins. Follow-up during the treatment averaged 29 months. Treatment with statins was associated with a mean reduction in total cholesterol and LDL-cholesterol levels of 24 and 33% from the baseline. Symptoms of statin intolerance occurred incidentally and did not require amendment in the treatment protocol. Significantly higher values of body weight, height, and BMI were found only among girls older than 10 years who were treated with statins. Conclusions: These data confirm a high efficacy and a good safety profile of statin treatment in children with FH, demonstrating no harm to physical development. However, there is a need for further cause-and-effect research regarding associations between long-term treatment with low-cholesterol, low-fat diets, statin therapy, and excessive weight gain.

Simvastatin reduced infiltration of memory subsets of T lymphocytes in the lung tissue during Th2 allergic inflammation

Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.

Effectiveness and Safety of Statin Therapy in Children: A Real-World Clinical Practice Experience

BackgroundStatin use for hypercholesterolemia in children is predominantly reported from short-term clinical trials. In this study, we assess the efficacy and safety of statin treatment in clinical pediatric practice. MethodsRecords of all patients who began statin treatment at age <18 years and remained on statins for >6 months from 5 pediatric lipid clinics were reviewed. Information at baseline and from all clinic evaluations after statin initiation was recorded, including lipid measurements, statin drug/dose, safety measures (anthropometry, hepatic enzymes, creatine kinase levels), and symptoms. Lipid changes on statin therapy were assessed from baseline to 6 ± 3 months and from 6 ± 3 months to last follow-up with a mixed-effects model, using piecewise linear splines to describe temporal changes, controlling for repeated measures, sex, and age. ResultsThere were 289 patients with median low-density lipoprotein cholesterol (LDL-C) of 5.3 mmol/L (interquartile range [IQR]:4.5–6.5) and mean age of 12.4 ± 2.9 years at statin initiation. Median duration of therapy was 2.7 years (IQR: 1.6–4.5) with 95% on statins at last evaluation. There were significant decreases in total cholesterol, LDL-C, and non–high-density lipoprotein cholesterol (non–HDL-C) from baseline to 6 ± 3 months (P < 0.001) and from 6 ±3 months to last follow-up (P < 0.001). Triglycerides and HDL-C were unchanged but the triglyceride to HDL-C ratio decreased significantly by late follow-up. At final evaluation, median LDL-C had decreased to 3.4 mmol/L (IQR:2.8–4.2). No patient had statins discontinued for safety measures or symptoms. ConclusionsIn real-world clinical practice, intermediate-term statin treatment is effective and safe in children and adolescents with severe LDL-C elevation.

Clinical efficacy and safety of statin treatment after carotid artery stenting

Objective The randomized controlled trail was carried out to investigate the influence of statin pre-treatment on clinical efficacy of carotid artery stenting (CAS). Methods 160 eligible patients were randomly divided into statin group (n = 82) and control group (n = 78). The patients in statin group received 40 mg atorvastatin daily 7 days before operation. Major endpoints included transient ischemic attack (TIA), stroke, death, myocardial infarction (MI), and other cardiac adverse events within 30 days after CAS. Results Preoperative baseline information was similar between the statin and control groups (p > 0.05 for all). Within 48 h after operation, the occurrence rate of CIN (3.66% vs 8.97%, p = .019) and new infarction (4.88% vs. 14.10%, p = .045) were significantly lower in statin group than in control group. 30 days after CAS, the incidences of TIA (12.20% vs. 26.92%, p = .018), ischemic stroke (6.10% vs. 16.67%, p = .034), and other cardiac complications (7.32% vs. 19.23%, p = .026) were also significantly lower in statin group, than in the control group. Multiple analysis demonstrated that statin use exerted protective effect against ischemic stroke (OR = 0.038, 95% CI = 0.003–0.543, p = .016) and other cardiac complications (OR = 0.208, 95%CI = 0.063–0.694, p = .011). Conclusion Pre-treatment with statin is an effective and safe strategy to prevent from perioperative complications and to improve postoperative outcomes in patients undergoing CAS.

Rationale for the use of statins in liver disease.

The evolution of chronic liver injuries from benign and manageable dysfunction to life threatening end-stage liver disease with severe complications renders chronic liver disease a global health burden. Because of the lack of effective medication, transplantation remains the only and final curative option for end-stage liver disease. Since the demand for organ transplants by far exceeds the supply, other treatment options are urgently required to prevent progression and improve end-stage liver disease. Statins are primarily cholesterol-lowering drugs used for primary or secondary prevention of cardiovascular diseases. In addition to the primary effect, statins act beneficially through different pleiotropic mechanisms on inflammation, fibrosis, endothelial function, thrombosis, and coagulation to improve chronic liver diseases. However, concerns remain about the efficacy and safety of statin treatment because of their potential hepatotoxic risks, and as of now, these risks impede broader use of statins in the treatment of chronic liver diseases. The aim of this review is to comprehensively describe the mechanisms by which statins improve prospects for different chronic liver diseases with special focus on the pathophysiological rationale and the clinical experience of statin use in the treatment of liver diseases.

Ischemic heart disease: effectiveness and safety of statin treatment in a malaysian tertiary healthcare facility

Purpose: To determine the effectiveness and safety of statins in ischemic heart disease (IHD) patients in a Malaysian tertiary hospital. Methods: This cross-sectional observational study was conducted at Universiti Kebangsaan Malaysia (UKM) Medical Center, Kuala Lumpur, Malaysia and patients were included if they were diagnosed with IHD and treated on statins for three months, or had IHD with no statins prescribed. Results: A total of 72 patients admitted to the medical ward due to IHD were enrolled in this study. Fifty three of them were statin users and 19 patients had no history of statin treatment. The most commonly used statin was lovastatin (n = 42, 79.2 %), atorvastatin (n = 5, 9.4 %), simvastatin (n = 3, 5.7 %) and rosuvastatin (n = 3, 5.7 %). Risk factors found in the study population were dyslipidaemia (n = 52, 72 %), hypertension (n = 58, 80.1 %), diabetes (n = 36, 50 %), advanced age (n = 63, 87.5 %), smoking (n = 19, 26.4 %) and family history (n = 16, 22.2 %). Patients that were on statin were more likely to achieve targeted LDL-C levels compared to those that did not achieve LDL-C levels (χ 2 = 7.25, p = 0.007). There were also no difference in liver enzyme values between statin users and non-statin users. Conclusion: This study provides information regarding safety and efficacy of statins in the local population and the need for a more stringent approach in achieving targeted lipid levels in IHD patients. Keywords: Effectiveness of statins, Safety of statin, Ischemic heart disease, Cardiovascular, Liver enzymes, Hypretension, Diabetes

Beyond confusion and controversy, can we evaluate the real efficacy and safety of cholesterol-lowering with statins?

A strong controversy has emerged about the reality of safety and efficacy of statins as stated by company-sponsored reports. However, physicians need credible data to make medical decisions, in particular about the benefit/harm balance of any prescription. This study aimed to test the validity of data on the company-sponsored statin trial by comparing them over time and then comparing statins with each other. Around the years 2005/2006, new stricter Regulations were introduced in the conduct and publication of randomized controlled trials (RCTs). This would imply that RCTs were less reliable before 2006 than they were later on. To evaluate this, we first reviewed RCTs testing the efficacy of statins versus placebo in preventing cardiovascular complications and published after 2006. Our systematic review thereby identified four major RCTs, all testingrosuvastatin. They unambiguously showed that rosuvastatin is not effective in secondary prevention, while the results are highly debatable in primary prevention. Because of the striking clinical heterogeneity and the inconsistency of the published data in certain RCTs, meta-analysis was not feasible. We then examined the most recent RCTs comparing statins to each other: all showed that no statin is more effective than any other, including rosuvastatin. Furthermore, recent RCTs clearly indicate that intense cholesterol-lowering (including those with statins) does not protect high-risk patients any better than less-intense statin regimens. As for specific patient subgroups, statins appear ineffective in chronic heart failure and chronic kidney failure patients. We also conducted a MEDLINE search to identify all the RCTs testing a statin against a placebo in diabetic patients, and we found that once secondary analyses and subgroup analyses are excluded, statins do not appear to protect diabetics. As for the safety of statin treatment – a major issue for medical doctors – it is quite worrisome to realize that it took 30 years to bring to light the triggering effect of statins on new-onset diabetes, manifestly reflecting a high level of bias in reporting harmful outcomes in commercial trials, as has been admitted by the recent confession of prominent experts in statin treatment. In conclusion, this review strongly suggests that statins are not effective for cardiovascular prevention. The studies published before 2005/2006 were probably flawed, and this concerned in particular the safety issue. A complete reassessment is mandatory. Until then, physicians should be aware that the present claims about the efficacy and safety of statins are not evidence based.

Long-term efficacy and safety of statin treatment beyond six years: A meta-analysis of randomized controlled trials with extended follow-up

Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5–6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47,296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7–14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85–0.96; P=0.0009), cardiovascular mortality (0.87, 0.81–0.93; P<0.0001) and major coronary events (0.79, 0.72–0.86; P<0.00001) was observed in favour of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74–0.93; P=0.001), cardiovascular mortality (0.81, 0.69–0.95; P=0.01) and major coronary events (0.77, 0.63–0.95; P=0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95–1.04; P=0.79), deaths from cancers (1.00, 0.93–1.07; P=0.98) and non-cardiovascular mortality (0.95, 0.90–1.00; P=0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms.

Pitavastatin and Atorvastatin Double-Blind Randomized ComPArative Study among HiGh-Risk Patients, Including ThOse with Type 2 Diabetes Mellitus, in Taiwan (PAPAGO-T Study)

BackgroundEvidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.Methods and ResultsBetween July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = −35.0 ± 14.1% and atorvastatin group = −38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (−37.1 ± 12.9% vs. −38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A1C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.ConclusionBoth pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.Trial Registration ClinicalTrials.gov NCT01386853 http://clinicaltrials.gov/ct2/show/NCT01386853?term=NCT01386853&rank=1

Does the Benefit from Statin Therapy Extend Beyond 5 Years?

Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the "in-trial" periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.

Efficacy and safety of statin treatment for cardiovascular disease

Efficacy and safety of statin treatment for cardiovascular disease

Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial.

SummaryBackgroundFindings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.Methods20 536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393.FindingsDuring the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19–28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89–1·02]) or vascular mortality (0·98 [0·90–1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92–1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92–1·11]) or to non-vascular causes (0·96 [0·89–1·03]).InterpretationMore prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment.FundingUK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.

The Failure of Immunomodulation Therapy in Heart Failure: Does the Statins &amp;#x201C;Paradigm&amp;#x201D; Prove the Rule?

Inflammation is an important process and an underlying mechanism involved in atherogenesis as well as the clinical manifestations following coronary artery disease (CAD). Evidence suggests that chronic heart failure (CHF) is associated with an increased inflammatory process. Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), interleukin-1 (IL-1) and adhesion molecules are elevated in states of CHF and are related to long term prognosis. Statins are among the most effective compounds reducing morbidity and mortality in patients with, or at increased risk of, CAD. Efficacy and safety of statin treatment has not been validated in patients with CHF. Several studies have reported that statins could be beneficial in patients with CHF. In addition, the beneficial effects of statins have been largely attributed to their anti-inflammatory properties. However, recent randomized, double-blind, placebo-controlled trials reported that statins did not affect clinical outcomes in patients with CHF of any cause. These data support the notion that current immunomodulation approaches in heart failure are not successful. Thus, more large scale clinical trials are required to evaluate the impact of statins on immune imbalance and its restoration in patients with CHF.

Pharmacogenetics of HMG-CoA Reductase Inhibitors: Optimizing the Prevention of Coronary Heart Disease

The statins are the most important group of drugs for lipid-lowering therapy in the prevention of coronary heart disease. Greater reductions in LDL-cholesterol appear to be associated with greater benefits but the clinical efficacy and safety of statin treatment varies considerably from person to person because of a combination of phenotypic and genotypic factors. Pharmacogenetic studies have investigated the relationship between common genetic variants and the lipid responses to statin therapy and adverse events, and some candidate genes related to the pharmacodynamics and pharmacokinetics of different statins have been identified. Some of these genetic variants show a different frequency in different ethnic groups. This field of pharmacogenetic research is receiving considerable attention and many new findings have been reported recently. Pharmacogenetic and pharmacogenomic studies of statin therapy are likely to provide a bet- ter understanding of the effects of these drugs and to help with prediction of the most appropriate drug and dosage for each individual and whether the addition or substitution of other lipid modifying drugs may be necessary to achieve the most safe and effective prevention of coronary heart disease.

The case for statin therapy in chronic heart failure

Both primary and secondary prevention studies have provided a wealth of evidence that statin therapy effectively reduces cardiovascular events. However, this general statement on the efficacy and safety of statin treatment has not been validated in patients with chronic heart failure (CHF). Recently, numerous statin trials have reported analysis on CHF parameters and numerous CHF trials have performed analysis on baseline statin use. In this article, we will review the currently available evidence from a pathophysiological as well as clinical perspective, building a case for and against the use of statins in CHF. From a pathophysiological perspective, we will discuss the known association of cholesterol and mortality, the ubiquinone, and the endotoxin-lipoprotein hypothesis. From a clinical perspective, we will discuss the observational studies, subgroup analysis of large randomized controlled trials, prospective randomized trials in CHF patients, and the future perspectives of the large European statin studies focussing on the statin therapy in CHF.

ＨＭＧ‐ＣｏＡ還元酵素阻害薬Ｐｒａｖａｓｔａｔｉｎ服用患者におけるリスクファクターと血清脂質値に関する調査

Purpose: HMG-CoA reductase inhibitors (statins) have been widely used in the treatment of hypercholesteremia in Japan as well as in Western countries. Although statins have been shown to be effective in the prevention of coronary heart disease (CHD) in high-risk patients, the potential benefit of statins on the overall mortality has not been proven in subjects at lower risk for CHD. In this study, we investigated the risk factors and serum cholesterol concentrations in patients given pravastatin.Methods: Patients who were given pravastatin during the period from June 2002 until May 2003 in the Hamamatsu University Hospital were studied. Data for height, body weight, age, gender, smoking and history of diabetes mellitus, hypertension and CHD in the patients were collected from their case records. Serum cholesterol concentrations were determined before and after the treatment with pravastatin. The ethics committee in the Hamamatsu University approved this study.Results: There were 213 male (37.4%) and 356 female (62.6%) patients given pravastatin. The mean age of the patients was 63.9 yrs, and % of the patients aged under 50 yrs was 10.7%. Seventy-seven % of the patients had no history of CHD. Female patients without smoking, diabetes mellitus, hypertension and CHD constituted 17% of all patients. Total and LDL cholesterol levels in all groups were significantly decreased by 17.6% and 25.5%, respectively, after the administration of pravastatin. Treatment with pravastatin was started at the lower total cholesterol levels in male patients or patients with CHD than in female patients or patients without CHD.Conclusion:Our results suggest that significant numbers of patients with a low risk for CHD were prescribed the statins, and that placebo-controlled large-scale trials should be conducted to demonstrate the benefit and safety of statin treatment on overall mortality in Japan.