Literature Review

Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer. Insights From Large Randomized Statin Trials

Article· Literature ReviewinJournal of the American College of Cardiology 50(5):409-18 · July 2007with 45 Reads
Abstract
We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer. Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated. Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression. In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23). Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.

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  • ... In the last year, this approach was extended by new ACC guidelines also to patients at high CV risk in primary prevention, such as those with type 2 diabetes (ATP-IV) [8]. Two meta-analyses addressed the issue of the impact of using higher vs. lower intensity statin therapy on liver toxicity [37,38]. In the first, performed in 23 statin treatment arms with 309,506 person-years of follow-up, raise of liver enzymes increased significantly with higher statin dose while there was no significant relationship between LDL-C reduction and hepatotoxicity [37]. ...
    ... Two meta-analyses addressed the issue of the impact of using higher vs. lower intensity statin therapy on liver toxicity [37,38]. In the first, performed in 23 statin treatment arms with 309,506 person-years of follow-up, raise of liver enzymes increased significantly with higher statin dose while there was no significant relationship between LDL-C reduction and hepatotoxicity [37]. The Authors concluded that the risk of statin associated liver enzyme elevation is not related to the magnitude of LDL lowering but is more likely determined by drug-and dose-specific effects [37]. ...
    ... In the first, performed in 23 statin treatment arms with 309,506 person-years of follow-up, raise of liver enzymes increased significantly with higher statin dose while there was no significant relationship between LDL-C reduction and hepatotoxicity [37]. The Authors concluded that the risk of statin associated liver enzyme elevation is not related to the magnitude of LDL lowering but is more likely determined by drug-and dose-specific effects [37]. Similar results were obtained in a second meta-analysis of RTCs comparing higher vs. lower intensity therapy [38]. ...
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    Non-alcoholic fatty liver disease is an emerging liver disease in Western countries and the most frequent cause of incidental elevation of serum liver enzymes. Dyslipidaemia is frequently observed in patients with non-alcoholic fatty liver disease, and treatment of dyslipidaemia plays a critical role in the overall management of these patients. Moreover, coronary artery disease remains the most common cause of death. Statins are effective lipid-lowering agents, associated with a lowering the risk of cardiovascular events in several interventional randomized clinical trials. However, statins are often underused in patients with non-alcoholic fatty liver disease and many physicians are concerned about the prescription of statins to patients with unexplained persistent elevation of liver enzymes or active liver disease. Based on currently available data, statin therapy, at low-to-moderate doses, seems to be safe and has low liver toxicity. Treatment of dyslipidaemia in patients with non-alcoholic fatty liver disease is recommended and may also improve liver function tests. In these patients, the risks of not taking statins could outweigh the risks of taking the drug. Conversely, the usefulness of statins for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is still a matter of debate and randomized clinical trials of adequate size and duration are required.
  • ... Dose Response Drug interactions arise when drugs inhibit metabolic pathways of statins, compete for metabolism with statins, or cause similar or A range of sources support a dose relation for many statin AEs interacting toxicity. Additionally, apparent interactions may arise (table II) [37,168,171,172,[176][177][178][179][180][181][182][183][184][185](although there may exist AEs that are when drugs serve as markers for existing problems that signal not dose dependent). Meta-analyses of RCTs comparing lower vulnerability to AEs. versus higher potency statins are of greatest relevance among the Several widely used statins – atorvastatin, simvastatin, and clinical trial data because these examine similar patients (within lovastatin (and previously cerivastatin, now off the market) – are the same study) placed on drugs of different potencies. ...
    ... [327] (– Meta-analysis of head-to-head RCTs of higher vs lower potency statins showed significant increase in LFT elevation with higher dose statins: @BULLET LFT (transaminase) elevation OR 2.7 (95% CI 1.5, 5.0) with higher vs lower dose statins. [179] The effect appeared to be greater for hydrophilic statins (pravastatin, the most hydrophilic, is actively taken up into the liver) @BULLET LFT elevation (alanine or aspartate aminotransferase ≥3 times the ULN) OR 4.5 (95% CI 3.3, 6.2) with intensive vs nonintensive statin therapy [177] – In a different study design, looking not at dose, but LDL-C reduction, for any 10% LDL-C reduction, rates of elevated LFTs increased significantly with higher dose statins [182] – although the percent LDL-C reduction was not related. For many reasons, this type of study is less interpretable from a dose-response standpoint a Rhabdomyolysis – Excess rhabdomyolysis cases involving cerivastatin primarily involved high-potency use and/or combination with gemfibrozil, which increases the effective dose [171,172,180] – Drugs that inhibit CYP3A4 system and thereby increase statin concentrations (e.g. ...
    ... (However, the power of these studies to detect such an association was low. Also, LDL-C reduction is a problematic metric (see table IV, footnote b), and more so across trials since sample differences can swamp dose effects [182] a ) – In the SEARCH trial in which 12 064 subjects were randomized to 20 or 80 mg simvastatin, there were 49 cases of " definite myopathy " in the simvastatin 80 mg group and 2 in the simvastatin 20 mg group. [190] b There were 49 cases of " incipient myopathy " in the simvastatin 80 mg group and 6 in the simvastatin 20 mg group. ...
    Article
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    HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
  • ... risk of liver test abnormalities and that monitoring was not warranted in patients taking a low-to-moderate dose other than at the onset of therapy [63]. Another meta-analysis of 75,317 subjects addressed the issue of effect of higher vs. lower intensity statin therapy on liver toxicity [64]. It included 23 statin arms for 0.9-6 years of follow-up. ...
    ... notes: CaRE-cholesterol and recurrent events; ldl-C-low-density lipoprotein cholesterol; lipid-long-term intervention with pravastatin in ischemic disease; RCTs-randomised controlled trial; WoSCopS-West of Scotland coronary prevention study. Meta-analysis Number of RCTs Patients Duration Drug used Liver toxicity prospective pravastatin pooling project [59] 3 (lipid/CaRE/ WoSCopS) 19,768 5 years pravastatin 40 mg no excess of liver function abnormalities denus et al. [63] 13 49,275 48 weeks-6 years pravastatin 40 mg only fluvastatin associated with odds of having liver test abnormalities lovastatin 30-45 mg Simvastatin 30 mg Fluvastatin 40-80 mg alsheikh-ali et al. [64] 23 statin arms 75,317 0.9-6 years lovastatin 20-80 mg drug-and dose-specific effects are more important determinants of liver toxicity than magnitude of ldl-C lowering ...
  • ... risk of liver test abnormalities and that monitoring was not warranted in patients taking a low-to-moderate dose other than at the onset of therapy [63]. Another meta-analysis of 75,317 subjects addressed the issue of effect of higher vs. lower intensity statin therapy on liver toxicity [64]. It included 23 statin arms for 0.9-6 years of follow-up. ...
    ... notes: CaRE-cholesterol and recurrent events; ldl-C-low-density lipoprotein cholesterol; lipid-long-term intervention with pravastatin in ischemic disease; RCTs-randomised controlled trial; WoSCopS-West of Scotland coronary prevention study. Meta-analysis Number of RCTs Patients Duration Drug used Liver toxicity prospective pravastatin pooling project [59] 3 (lipid/CaRE/ WoSCopS) 19,768 5 years pravastatin 40 mg no excess of liver function abnormalities denus et al. [63] 13 49,275 48 weeks-6 years pravastatin 40 mg only fluvastatin associated with odds of having liver test abnormalities lovastatin 30-45 mg Simvastatin 30 mg Fluvastatin 40-80 mg alsheikh-ali et al. [64] 23 statin arms 75,317 0.9-6 years lovastatin 20-80 mg drug-and dose-specific effects are more important determinants of liver toxicity than magnitude of ldl-C lowering ...
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    apollo Hospitals, new delhi, india; c lipid association of india, new delhi, india; d Medicine, The Tamil nadu dr MgR Medical University, Chennai, india; e Snn Specialities Clinic, Chennai, india; f Clinical lead for lipids and CVd prevention, Royal Free nHS Foundation Trust Hospital, london, UK; g department of Cardiology, g. B. pant Hospital, new delhi, india; h Fortis Hospital, new delhi, india; i department of Endocrinology, indraprastha apollo Hospital, new delhi, india; j Centre for Cardiac Sciences, Kokilaben dhirubhai ambani Hospital, Mumbai, india; k nephrology Research, Fortis Escort, Kidney & Urology institute, new delhi, india; l george institute of global Health, new delhi, india; m Fortis-C-doC Centre of Excellence for diabetes, Metabolic diseases and Endocrinology, new delhi, india; n department of Medicine, Maulana azad Medical College & attached Hospital, new delhi, india; o department of neurology, indraprastha apollo Hospitals, new delhi, india; p department of nephrology, indraprastha apollo Hospitals, new delhi, india; q department of Rheumatology, indraprastha apollo Hospitals, new delhi, india; r division of Clinical & preventive Cardiology, Medanta Heart institute, Medanta Hospital, gurugram, india; s department of Cardiology, Medanta Hospital, gurugram, india; t non-invasive Cardiology, Max Super Speciality Hospital, Saket, new delhi, india; u Royal Free london nHS Foundation Trust, london, UK; v department of Cardiology, Max Healthcare institute ltd., Saket, new delhi, india; w department of Endocrinology, pt. BdSpgiMS, Rohtak, india; x department of Cardiology, King george's Medical University, lucknow, india; y department of Cardiology, all india institute of Medical Sciences, new delhi, india; z department of Endocrinology, artemis Hospital, gurugram, india; aa department of internal Medicine, Sahyadri Speciality Hospital, pune, india; ab department of Cardiology, indraprastha apollo Hospitals, new delhi, india; ac department of Endocrinology & Metabolism, aiiMS, new delhi, india; ad department ABSTRACT These Lipid Association of India (LAI) recommendations refer to specific patient populations. They follow the previously published LAI part 1 recommendations. These part 2 LAI recommendations focus on specific patient groups. These include patients with heart failure, chronic kidney disease, non-alcoholic fatty liver disease, cerebrovascular disease, thyroid disorders, inflammatory joint diseases, familial hypercholesterolaemia and human immunodeficiency virus infection. We also consider women, the elderly and post-transplantation patients. The current recommendations are based, as much as possible, on available data from Indian populations.
  • ... Nello studio HPS, che ha interessato 20.000 pazienti, l'incidenza di cancro è stata del 7,9% nel gruppo che assumeva statina e del 7,8% nel gruppo che assumeva placebo. Per contro, nel 2007, una metanalisi [19] di 23 RCT ha documentato un'associazione significativa fra il rischio di cancro e i più bassi valori di colesterolo LDL raggiunti con la somministrazione di statine . Nell'agosto 2008 il dato è stato confermato [20] analizzando i dati di 15 RCT, per un totale di 96.840 pazienti . ...
  • ... Statins have been used for decades in the primary and secondary prevention of CVD among children and adults, males and females, diabetics and nondiabetics , who are at moderate to high risk of CVD [2] . Statins are known to have a good safety record but are associated with side effects, the most common of which are related to muscle [3],[4],[5],[6],[7] . The ubiquity of statin usage has focused attention on their side effects because, although relative rates of adverse events are low, the absolute numbers affected are high. ...
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    Statin therapy has demonstrated remarkable efficacy in reducing mortalities associated with cardiovascular diseases through preventing myocardial infarction and ischaemic stroke. Despite the proven benefits of statins in this context, there are growing concerns among patients and physicians on the safety of short-term and long-term use and their adverse effects, especially muscle toxicity, resulting in non-adherence and withdrawal of the treatment. Reports and publications on a variety of statin-associated side effects, with major focus on myopathy as the most commonly reported side effect, were reviewed. The incidence, diagnosis, prevention and management of statin-induced adverse effects are outlined in this updated review to highlight the importance of statin use in high-risk populations, and to reduce the rate of under-prescription and withdrawal of the treatment. Key points: Side effects of statins, including muscle aches, diabetes and liver function test abnormalities, are increasingly recognised. Statin-related muscle side effects have recently been systematically classified. Rare autoimmune phenomena related to statin therapy, including necrotising myopathy, interstitial lung disease and lupus-like reactions, are now recognised. Statins increase the risk of transition to diabetes in susceptible individuals with the metabolic syndrome. There is little systematic evidence to link cognitive impairment with statin therapy.
  • ... Statin use has been found to be associated with an elevated risk of being diagnosed with a high grade prostate cancer (Nordstrom et al., 2015). Another study found an inverse relationship between LDL cholesterol levels and cancer incidence in patients on statins (Alsheikh-Discovery Medicine, Volume 20, Number 112, December 2015 Statin Use as Anti-cancer Therapy Ali et al., 2007 ). The PROSPER trial studied pravastatin in the elderly at risk for vascular disease. ...
    Article
    Statins, the most commonly prescribed class of drug, have demonstrated effects beyond cholesterol reduction including anti-tumor and immunomodulatory properties. Several epidemiological studies have suggested an anti-neoplastic effect of statins evidenced by reductions in cancer incidence and cancer-related mortality. Clinical trials on statins as part of therapy for cancer have generated interest in the oncology community. Statins have been investigated for a variety of cancers, early and late stage, and in combination with chemotherapy and radiation. So far promising results have been reported with statin use in pediatric brainstem tumors, early stage breast cancer, hepatocellular carcinoma (HCC), colorectal cancer (CRC), refractory or relapsed multiple myeloma (MM), and refractory acute myeloid leukemia (AML). There is still much investigation to be completed to determine which subtypes of patients benefit from statin therapy, how statins may potentiate other anticancer approaches, and the appropriate dosing schedule to use.
  • ... Статины являются основой современной терапии по коррекции нарушений липидного обмена и показаны большинству больных с высоким риском сердечно-сосудистых осложнений [1]. Многолетний клинический опыт применения статинов убедительно показал, что длительная терапия статинами в целом достаточно безопасна [2][3][4][5][6]. Менее ясен вопрос о безопасности длительной терапии статинами у больных с исходно нарушенной функцией печени. ...
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    Aim. To assess the potential of ursodeoxycholic acid (UDCA) in the prevention of liver dysfunction in patients with cardiovascular diseases (CVD) and high risk of cardiovascular events (CVE) with indications for statins use.Material and methods. Patients (n=262, age 60.1±8.9 years) took statins for secondary prevention of CVE in observational cohort study. The follow-up duration was 6 months. UDCA was recommended for all patients because of liver diseases and/or biliary tract. Some of the patients with high treatment compliance strictly followed recommendations to take UDCA, and another part of the patients with low treatment compliance did not take UDCA. Comparison of these groups allowed highlighting UDCA effects.Results. Controlled lipid-lowering therapy in combination with UDCA resulted in a significant reduction in total cholesterol (TC) and low density lipoprotein cholesterol levels after 6 months of follow-up to 4.3 mmol/L and 2.3 mmol/L, respectively (p<0.001). Deterioration in the dynamics of alanine-aminotransferase (ALT), aspartate aminotransferase (AST), creatinphosphokinase (CPK) and gamma glutamine transferase (GGT), as well as increase in serum bilirubin was not found. Moreover, in general significant decrease in ALT, AST, GGT and alkaline phosphatase (p<0.001) was observed, the levels of total serum bilirubin and CPK did not change at the end of the study (p=0.65 and p=0.16, respectively). Taking UDCA simultaneously with statins led to additional reduction in TC and low density cholesterol compared with statin monotherapy (p=0.01).Conclusion. One of the affordable and effective ways to deal with a wider statin use in patients with liver and biliary tract disorders is their co-administration with UDCA.
  • ... The literature on cholesterol and cancer has demonstrated an inverse relationship between total serum cholesterol levels and incident cancer [49]. There are a number of studies suggesting that an excessively low level of total cholesterol might be an increased risk for cancer mortality505152535455. Recently, some studies have reported that lower levels of LDL-C are associated with higher rates of incident cancers [56]. ...
    Article
    Purpose: In recent years, the potential risk of cancer associated with statin use has been a focus of much interest. However, it remains uncertain whether statin therapy is associated with cancer risk. To examine the association between statin use and the risk of cancer, we conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database of claims constructed by a database vendor (The Japan Medical Data Center Co., Ltd, Tokyo, Japan [JMDC]). Methods: Relevant reports in the FAERS, which included data from the first quarter of 2004 through the end of 2012, were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals and was calculated using the case/non-case method. Additionally, signals were detected via the information component (IC) using the IC025 metric. Furthermore, event sequence symmetry analysis (ESSA) was applied to identify the risk of cancer following treatment with statins over the period January 2005 to July 2013. Results: In the FAERS database analyses, significant signals for colorectal cancer and pancreatic cancer were found for statins as a class. In the ESSA, significant associations between statin use and colorectal cancer and pancreatic cancer were found, with adjusted sequence ratios (95% confidence intervals) of 1.20 (1.08-1.34) and 1.31 (1.13-1.53), respectively, at an interval of 48 months. Conclusions: Multi-methodological approaches using different algorithms and databases suggest that statin use is associated with an increased risk for colorectal cancer and pancreatic cancer.
  • ... They also found no difference in muscle pain or weakness between participants treated with simvastatin 40 mg OD or placebo for 5 years or in the number who discontinued treatment due to musculoskeletal problems [39]. Adverse reactions increase at higher doses [51]; hence we chose to use 40 mg OD in our present study. The incidence of fatal rhabdomyolysis has been estimated at 0.12% per 1 million prescriptions on the basis of data derived from the US Food and Drug Administration databases and the National Prescription Audit Plus [50]. ...
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    Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid ß (Aß, coded on chromosome 21) deposition and therefore delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs). Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. Methods TOP-Cog was a feasibility/pilot double-blind RCT of 12 months simvastatin 40mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E ε4, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre-randomisation and 12 months post-randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework approach to determine recruitment motivators/barriers, and participation experience. Results We identified 181 (78%) of the likely eligible Down syndrome population, and recruited 21 (11.6%), from an area with a general population size of 3,135,974. Recruitment was highly labour intensive. Thirteen (62%) completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. Conclusion A full-scale RCT is feasible. It will need 37% UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population.
  • ... For instance, utilization of moderate/ high-intensity statins is a common method for achieving the LDL-C goal. However, increasing the intensity of statins may lead to a high risk of adverse events, which results in low compliance and thus unsatisfactory goal attainment [7][8][9] . Moreover, in China, there is only one category of statin , simvastatin, which happens to be a low-intensity statin, on the National Essential Drugs List [10]. ...
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    Background: Hyperlipidemia is a common disease in China. Although 88.9 % of the Chinese population taking lipid-lowering medications has already used a statin, only 61.5 % of the population has reached the goal of low-density lipoprotein cholesterol. Thus, many patients in China seek help from Traditional Chinese Medicine. Yirui capsules are an innovative Chinese Medicine which are designed to improve the blood lipid state in patients with hyperlipidemia. However, there is still a lack of high-quality evidence from clinical trials to support the application. Therefore, we designed a clinical trial to evaluate the safety and efficacy of Yirui capsules for use by patients with hyperlipidemia. Methods/design: This is a multicenter, randomized, double-blinded, placebo-controlled trial. Based on lifestyle modification therapy, eligible patients will randomly be assigned to the Yirui capsule or the placebo group. The primary outcome is the percentage of participants who reach the goal of 30 % low-density lipoprotein cholesterol decline at treatment end-point. The secondary outcomes include the changes from baseline to treatment endpoint in low-density lipoprotein cholesterol, total cholesterol, triglyceride, high-density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B, non-high-density lipoprotein cholesterol, MOS 36-Item Short-Form Health Survey scoring, total and individual item scoring of symptomatic grading and quantifying scale, and body mass index. Discussion: The main ingredients of the Yirui capsule are perilla oil, Folium Ginkgo (Yinxingye), Radix Salviae miltiorrhizae (Danshen), Fructus Crataegi (Shanzha), Rhizoma Alismatis (Zexie), and Radix Notoginseng (Sanqi), which are expected to improve the blood lipid state. This randomized placebo-controlled trial will comprehensively evaluate the effectiveness and safety of Yirui capsules against hyperlipidemia in the hope of providing a new adjunctive Chinese medicine option for clinical practice in dyslipidemia treatment. Trial registration: ChiCTR-IOR-15006496 . Registered on 29 May 2015. Protocol version: WXJ.YRJN-HBT-V1.0 (21 Jan 2015).
  • ... However in Simvastatin group statically significant reductions were found among T.BIL, but statically significant elevation was found among ALP in female and reduction in male and more elevation found in ALP in patients >60 years comparing with other age groups. Review of the literature demonstrated controversial effects of Simvastatin on cholesterol and hepatic function, some studies reported an elevations of liver parameters during Simvastatin therapy[12,[19][20][21][22][23]whereas others studies showed that Simvastatin has no effect on liver parameters[24,25]. Regarding the fluctuation group, in general for all patients there was significant effect on the lipid parameters less than the use of Simvastatin or Fluvastatin separately. ...
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    Objective: The study was aimed to evaluate Simvastatin and Fluvastatin effects on patients with hypercholesterolemia. Methods: For 6 months, 141 patients administered Simvastatin (GpA), 100 administered Fluvastatin (GpB) and 100 fluctuated between them (GpC). Post treatment, in GpA, Triglycerides, total Bilirubin (T.BIL), Cholesterol and Low Density Lipoprotein (LDL) were significantly reduced. Alkaline Phosphatase (ALP) and Alanine Aminotransferase (ALT) elevated reduced in females and elevated in males. T.BIL reduced in both males and females. Results: In GpB, Glutamyltransferase elevated and Cholesterol and LDL reduced. Albumin elevated in females and reduced in males and the opposite in Triglycerides. Significant difference between age groups in Albumin, Globulin, and ALT was found. In GpC, Asprtate Aminotransferase (AST) elevated and ALT, Cholesterol, Triglycerides and LDL reduced in all patients. Albumin and ALT elevated in males and reduced in females. Significant difference between age groups in Albumin, T.BIL and AST was found. Conclusions: Fluvastatin or simvastatin had variable effects on lipid parameters in patients with hypercholesterolemia and associated with mild effect on liver. Simvastatin was more effective to reach antihypercholesterolemic goal. Effects were related to gender, age and continuation on the same medication. Patients lab data periodic monitoring during therapy is useful to reach antihypercholesterolemic goal and observe any serious liver parameters elevation.
  • ... secondary prevention)789. While these trials provide evidence for secondary prevention of coronary heart disease, statins have been plagued by conflicting evidence of potential associations with higher all-cause mortality including cancer, trauma and suicide, as well as adverse physical, psychological, and cognitive effects10111213141516. More recently, controversies surrounding statins stem from a lack of consensus in the scientific community as to the benefits of statins for primary prevention in the absence of established coronary artery disease17181920. ...
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    Background: The ACC/AHA released new guidelines in December of 2013 for treatment of high blood cholesterol to simplify identification and treatment of patients most likely to benefit from statins. These guidelines may result in more patients receiving statin therapy, and at younger ages. In 2012, the U.S. Food and Drug Administration (FDA) mandated warnings for all statin drugs for possible adverse effects on cognitive performance. Statins can be classified as having greater lipophilic or hydrophilic solubility properties with lipophilic statins more readily crossing the blood brain barrier, and possibly differentially inducing detrimental cognitive effects. Objective: We sought to analyze generalizability of the FDA statin class warning. Methods: De-identified publicly-available data were analyzed from the FDA Adverse Event Reporting System (AERS) in relation to reports of cognitive dysfunction (primary outcome), and by type of statin (lipophilic, hydrophilic) versus " control " drugs used in the general population. Results: Significantly higher proportional reporting ratios (PRRs) were observed for lipophilic statins, which more readily cross the blood-brain barrier, (range: 1.47-3.51) compared to hydrophilic statins (range: 0.69-1.64). However, fluvastatin, lovastatin, and pitavastatin (lipophilic) had relatively few adverse reports. The signal of higher risk of cognitive dysfunction was observed for the lipophilic statin atorvastatin (PRR = 2.59, 95% confidence interval: 2.44-2.75) followed by simvastatin (PRR = 2.22, 95% confidence interval: 2.04-2.31). Hydrophilic statins (rosuvastatin, pravastatin) showed essentially no evidence suggestive of heightened risk of cognitive dysfunction. Fluvastatin, lovastatin, and pitavastatin had relatively few adverse reports, and no evidence of a higher proportion of cognitive dysfunction reports compared to the control drugs in aggregate (PRR range: 0.22 to 1.48). Conclusions: Inconsistent with the FDA class warning, highly lipophilic statins with specific pharmacokinetic properties (atorvastatin, simvastatin) appear to confer a significantly greater risk of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic solubility properties.
  • This article provides needed perspective on statin efficacy and safety in individuals under 40, 40-75, and >75 years of age. In those under 40, statins are primarily used for treatment of severe hypercholesterolemia, often familial, and they are well tolerated. In middle-aged adults, statins have strong evidence for benefit in primary and secondary prevention trials; however, in primary prevention, a clinician-patient risk discussion should precede statin prescription in order to determine appropriate treatment. In those over 75, issues of statin intensity and net benefit loom large as associated comorbidity, polypharmacy, and potential for adverse effects impact the decision to use statins with RCT data strongest in support of use in secondary prevention.
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    3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the key enzyme in cholesterol synthesis. Statins are used in treatment of hypercholesterolemia as inhibitors of HMG-CoA reductase. Cancer cells overexpress HMG-CoA reductase enzyme. Recent studies have demonstrated that statins may inhibit the proliferation of human breast cancer cells. Statins have proangiogenic effects in low therapeutic concentrations and angiostatic effects in higher concentrations. Statins induce apoptosis and reduce cell invasiveness in various cell lines, including malignant glioma, neuroblastoma and myeloid leukemia. The chemopreventive activity of statins against cancer is suggested to depend on inhibition of cholesterol synthesis together with their antioxidant and anti-inflammatory properties.
  • Article
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    Cardiovascular disease (CVD) is estimated to remain as the main cause of death in developed nations over the next 30 years, with increased prevalence in the older population. This is because the observed decline in the incidence of CVD owing to improvements in prevention has now been counterbalanced by the increased shift toward an older and thus more fragile population. Statin treatment reduces cardiovascular morbidity and mortality in middle-aged adults. However, few studies have included older individuals, particularly those aged 80 years or over. The adverse effects associated with high doses of statins and their interactions with other drugs may give rise to more problems in the elderly population. Evidence remains limited regarding the overall benefit of starting statin therapy in adults aged 80 and over; so that clinical judgment remains necessary in making the decision to use them. In this review, we present available evidence from randomized clinical trials, as well as relative community and post-approval data directly applicable to the management of CVD in the elderly, in both primary and secondary prevention. Also discussed is the latest evidence regarding the putative protective effects of statins on senile dementia and the relationship between statin treatment and cancer.
  • Article
    Statins are the most common medications prescribed for treatment of lipid disorders to reduce cardiovascular risk. In this chapter, the types and classes of statins are presented. The major statin trials conducted over the last 30 years are then summarized, with an emphasis on the relation of statin use with cardiovascular disease mortality. Statin doses, metabolism, drug interactions, side effects are then summarized. The chapter concludes with the approach to the patient with statin intolerance.
  • Chapter
    In the United States, 790,000 people sustain a myocardial infarction annually or one every 40 s (Mozaffarian et al. Circulation 131:e29–322, 2015). Of these, 114,000 will be fatal. Atherosclerosis is a complex, multifactorial disease. Over the course of the past five decades, numerous prospective observational cohort studies have established beyond any doubt that risk for atherosclerotic disease is driven by a number of risk factors, which include dyslipidemia, hypertension, insulin resistance and diabetes mellitus, obesity, cigarette smoking, and age (Stamler et al. JAMA 256:2823–2828, 1986; Castelli Can J Cardiol 4:5A–10A, 1988; Assmann et al. Eur Heart J 19:A2–11, 1998; Goldbourt et al. Br Med J Clin Res Ed 290:1239–1243, 1985; Verschuren et al. JAMA 274:131–136, 1995). The greater the burden of risk factors, the higher the likelihood for developing such manifestations of atherosclerosis as coronary artery disease (CAD), carotid artery disease, and peripheral arterial disease. Atherosclerotic disease is unequivocally associated with increased risk for myocardial infarction, stroke, renal artery disease and renal insufficiency, claudication and lower extremity amputation, and death. Progressive accumulation of lipid in arterial walls resulting in luminal obstruction is a cardinal structural manifestation of atherosclerotic disease. Arresting this process of lipid infiltration and retention is an important goal in modern cardiovascular medicine. Dyslipidemia is highly prevalent in the United States (Toth et al. J Clin Lipidol 6:325–330, 2012). Even when patients are treated, they tend to be undertreated leaving them with significant residual risk for developing atherosclerotic disease and sustaining both primary and secondary acute cardiovascular events (Toth Resid Staff Physician 53:s1–s7, 2007; Punekar et al. Clin Cardiol 38: 483–491, 2015; Punekar et al. Curr Med Res Opin 33:869–876, 2017).
  • Article
    Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
  • Article
    Statins belong to the best-investigated drugs and their effectiveness in secondary and primary prevention of cardiovascular events is beyond dispute. There has been controversial discussion of their safety and tolerability. In clinical practice, many patients present symptoms of myalgia. However, severe muscular side effects are very rare. Most statin-intolerant patients who stop statin therapy because of adverse effects can be successfully restarted on statins. Statins are associated with an increased risk of liver function tests but discontinuation due to this reason is uncommon. The risk for newly diagnosed diabetes mellitus is increased but this is counterbalanced by cardiovascular risk reduction. Cancer risk is not increased. Simvastatin and pravastatin seem safer and more tolerable than other statins. There are numerous contraindications and intercations which makes statin prescription a responsible task.
  • Article
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    Beta-blockers such as propranolol and labetalol is known to induce toxic myopathy because of their partial beta-2 adrenoceptor agonistic effect. Nebivolol has the highest beta-1 receptor affinity among beta-blockers and it has never been reported to induce rhabdomyolysis until now. We report a patient who developed rhabdomyolysis after changing medication to nebivolol. A 75-year old woman was admitted to our hospital because of generalized weakness originating 2 weeks before visiting. Approximately 1 month prior to her admission, her medication was changed from carvedilol 12.5 mg to nebivolol 5 mg. Over this time span she had no other life style changes causing rhabdomyolysis. Her blood chemistry and whole body bone scan indicated rhabdomyolysis. We considered newly prescribed nebivolol as a causal agent. She was prescribed carvedilol 12.5mg, which she was previous taken, instead of nebivolol. She was treated with hydration and urine alkalization. She was fully recovered and discharged.
  • Article
    Objectives The aim of this study was to assess the relationship between hypercholesterolemia (HC) and clinical events through a percutaneous coronary intervention (PCI) registry. Background HC is a well-known independent risk factor for long-term cardiovascular events after PCI. However, it has been reported to be associated with a lower risk of adverse events in patients with cancer or acute coronary syndrome. Methods We analyzed the relationship between HC and adverse events in patients treated with everolimus-eluting stents (EESs) through the Tokyo-MD PCI study (an all-comer, multicenter, observational registry). The propensity score method was applied to select two groups with similar baseline characteristics. Results The unadjusted population included 1,536 HC patients and 330 non-HC patients. Propensity score matching yielded 314 matched pairs. After baseline adjustment, the outcomes of HC patients were significantly better than those of the non-HC patients with respect to the primary endpoint, which was a combination of mortality from all causes, nonfatal myocardial infarction (MI), nonfatal neurological events, and major bleeding (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.39-0.81; p=0.002), and the secondary endpoints, which included a combination of mortality from all causes, nonfatal MI, and nonfatal neurological events (HR 0.59, 95% CI 0.39-0.88; p=0.01), and major bleeding (HR 0.42, 95% CI 0.20-0.88; p=0.02). A subgroup analysis showed age as an interaction factor for the primary endpoint (interaction p=0.035). Conclusion HC was associated with better outcomes in patients who underwent EES implantation, even after baseline adjustment.
  • Article
    Aim. To study the opinion of doctors about the possibility of statins prescription to patients with cardiovascular diseases and concomitant chronic liver diseases.Material and methods. Сross-sectional questioning of the random sample of physicians was performed. Results. 70 physicians (internists - 61.4%, cardiologists - 20.0%, neurologists - 5.7%, endocrinologists - 4.3%, and others) were interviewed. Work experience in the specialty of doctors was 25 years (14; 32.5). 22.9% of doctors completely exclude the possibility of statins prescription to patients with cardiovascular disease if they have concomitant liver disease. 70% of physicians consider it possible to use statin therapy in patients with liver disease, but only under certain conditions. Only a third of them, mostly internists, are ready to prescribe statins under condition of acceptable initial transaminase changes, and almost half of these doctors consider it possible to use statin therapy in patients with concomitant liver diseases only when serum transaminase levels are normal.Conclusion. The physicians often and sometimes unreasonably find it impossible to use statin in patients with cardiovascular diseases and concomitant chronic liver diseases.
  • Article
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    Aim. To evaluate the differences between a group of patients treated with ursodeoxycholic acid (UDCA) during the study period and a group of patients not treated with UDCA by pseudo-randomization using Propensity Score Matching.Material and methods. 262 patients aged 60.1±8.9 years, taking statins for the secondary prevention of cardiovascular complications were included into a 6-month observational cohort study. The UDCA intake was recommended to all the patients due to the presence of liver and/or bile duct diseases. One part of the patients strictly followed medical recommendations and used UDCA, while the other part of the patients wasn’t taking UDCA. This allowed comparing the effect of UDCA in these groups.Results. Propensity Score Matching method allowed forming two groups of patients of 52 people each with similar main clinical and demographic characteristics. A more significant decrease in the levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) (up to 4.0 mmol/L and 1.92 mmol/L, respectively; p<0.001) after 6 months was found in patients treated with lipid-lowering therapy in combination with UDCA as compared with patients without UDCA (up to 4.52 mmol/L and 2.6 mmol/L, respectively; p<0.05). No ALT, AST, CPK, LDH activity deterioration and no bilirubin serum level increase was found. Due to statin treatment the target levels of LDL-C by the end of the study were achieved in 31% of the patients of UDCA-group. Target levels of LDL-C were not achieved in any of the patients of the group without UDCA (p<0.001). There was demonstrated a high adherence to UDCA therapy.Conclusion. Combined therapy with statins and UDCA is effective and safe in patients with high cardiovascular risk and concomitant liver disease. Co-administration of statins with UDCA is promising in the treatment of hyperlipidemia in patients with low tolerance to statins. However, additional controlled studies are required.
  • Chapter
    Adhering to a healthy dietary pattern—specifically the modernized Mediterranean diet—may be critical to reduce breast cancer (BC) risk in high-risk women and in women who wish to decrease their BC risk. In the context of the Mediterranean diet, it is important to increase plant and marine n-3 and decrease plant and animal n-6. High flavonoid intake—which increases n-3—should be encouraged as it is associated with lower BC risk. To reduce insulin resistance and diabetes—which are associated with an increased BC risk—women should increase fiber consumption and favor low-GI foods. Women should choose organic foods because of their effect on the n-3/n-6 ratio and because they contain fewer contaminants—and lower levels of each contaminant—in particular endocrine disruptors. Finally, any drug thought to increase diabetes and/or BC risk—in particular, the statins and certain antihypertensive medications—should be prohibited. To lower blood pressure or to decrease the risk of cardiovascular disease, physicians do have lifestyle strategies, and it would be tragically unwise to persist in prescribing anticholesterol statins and antihypertensive drugs in women wishing to decrease their BC risk.
  • Article
    Aim: Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Methods: Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. Results: A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the 7 available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the 2 independent risk factors of SILI (OR and 95% CI: 1.93, 1.08-3.35, P = 0.025, and 1.73, 1.07-2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after re-challenge of other statins. Conclusion: High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study.
  • Article
    Full-text available
    Use of statin therapy in patients with type 2 diabetes mellitus (T2DM) has been recommended by most clinical guidelines. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among T2DM patients. It has been proved that statins are effective for primary or secondary CVD prophylaxis. Reports have highlighted the underutilization of statins in clinical practice and the suboptimal adherence to guideline recommendations. This review article points to summarize the current evidence confirming the role of statins in T2DM patients and to provide an overview of factors that may affect statins' prescribing patterns and compliance in clinical practice. Initiatives to enhance statin therapy prescribing should recognize the comprehensive nature of the prescribing process. Attempts to assure proper statin prescribing and utilization can help in achieving better clinical outcomes of statin therapy.
  • Article
    Statin therapy is very effective and safe for preventing and treating cardiovascular disease regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Throughout the world patients frequently discontinue statin therapy without medical advice due to perceived side effects, and consequently increase their risk for cardiovascular events. In the case of statin intolerance it may be advisable to change the dose, change to a different statin, try alternate-day statin therapy, or, if intolerance is associated with all statins even at the lowest dose, then non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.
  • Article
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    One of the most frequent causes of hospital admissions in older adults is the devastating condition known as congestive heart failure. Characterized by disabling symptoms of difficulty breathing, fatigue, and swelling of the extremities, congestive heart failure also increases the risk of early demise. Fortunately, scientists have discovered that the mitochondrial energizer coenzyme Q10 (CoQ10) can offer powerful assistance to those challenged with congestive heart failure, improving the heart's pumping ability and even reducing the need for medications. Since CoQ10 levels are depleted by aging and statin medications and tend to be low in those with congestive heart failure, achieving optimal blood levels of CoQ10 may be an important strategy for safeguarding cardiac health. What is CoQ10? It has been 50 years since Fred Crane discovered CoQ10 in 1957.1 Since that time, scientists have discovered what this extraordinary molecule is and what it does in settings of both health and disease. It is important to clarify that a coenzyme should not be confused with an enzyme (a protein that accelerates a biochemical reaction). A coenzyme is a simple molecule (many vitamins are coenzymes) that is essential for the normal function of specific enzyme systems in our cells. Coenzyme Q10 is the cofactor or coenzyme for three large enzyme systems that are essential for 90% of cellular energy production. Because the heart muscle uses more energy than any other tissue and normally has the highest concentration of CoQ10, it is very sensitive to CoQ10 deficiency. Coenzyme Q10 is well established to be a clinically relevant first-line antioxidant in our defense system against excess oxidative stress. It is the only fat-soluble antioxidant that is synthesized by our body and is capable of regeneration back to its reduced or antioxidant form through normal cellular enzyme systems. Its location in the lipid mitochondrial membranes is particularly important, as mitochondria are the major site of free-radical production, and CoQ10 is an excellent free-radical scavenger.
Literature Review
  • Article
    Summary Background Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. Methods We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4·0 mmol/L to 9·0 mmol/L. Follow-up was 3·2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Findings Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0·85, 95% CI 0·74-0·97, p=0·014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0·81, 0·69-0·94, p=0·006). Stroke risk was unaffected (1·03, 0·81-1·31, p=0·8), but the hazard ratio for transient ischaemic attack was 0·75 (0·55-1·00, p=0·051). New cancer diagnoses were more frequent on pravastatin than on placebo (1·25, 1·04-1·51, p=0·020).
  • Article
    Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5·5-8·0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo.Over the 5·4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0·70 (95% Cl 0·58-0·85, p=0·0003). The 6-year· probabilities of survival in the placebo and simvastatin groups were 87·6% and 91·3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0·58, 95% Cl 0·46-0·73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0·66 (95% Cl 0·59-0·75, p<0·00001), and the respective probabilities of escaping such events were 70·5% and 79·6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p<0·00001) in the risk of undergoing myocardial revascularisation procedures.This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.
  • Article
    background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a com- posite of death from any cause, myocardial infarction, documented unstable angina re- quiring rehospitalization, revascularization (performed at least 30 days after randomiza- tion), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P
  • Article
    Context Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups.Objective To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least 1 additional CHD risk factor.Design and Setting Multicenter (513 primarily community-based North American clinical centers), randomized, nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).Participants Ambulatory persons (n = 10 355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes.Intervention Pravastatin, 40 mg/d, vs usual care.Main Outcome Measures The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included nonfatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer.Results Mean follow-up was 4.8 years. During the trial, 32% of usual care participants with and 29% without CHD started taking lipid-lowering drugs. At year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care; among the random sample who had LDL-C levels assessed, levels were reduced by 28% with pravastatin vs 11% with usual care. All-cause mortality was similar for the 2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P = .88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual care. CHD event rates were not significantly different between the groups (RR, 0.91; 95% CI, 0.79-1.04; P = .16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual care.Conclusions Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention. Figures in this Article The important etiologic role of circulating levels of low-density lipoprotein cholesterol (LDL-C) in the development of atherosclerotic coronary heart disease (CHD) is well established. Numerous randomized trials in the 1970s and 1980s affirmed that lowering LDL-C levels with diet and/or drugs, such as bile acid sequestrant resins and fibrates, reduced CHD event rates.1 However, the total cholesterol reductions attained in these trials were modest (approximately 10%), and the correspondingly modest reductions in CHD mortality were offset by small increases in noncardiovascular mortality, with no net effect on overall mortality.1 In the mid-1980s, a new potent and well-tolerated class of drugs, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) provided the means to conduct randomized trials in which total cholesterol reductions of 20% and greater could be sustained long-term. These trials also allowed questions about the overall benefits and risks of cholesterol lowering to be effectively addressed. The lipid-lowering trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)2 (ALLHAT-LLT) was originally envisioned as a free-standing double-blind trial to evaluate the effects of cholesterol lowering with a statin drug in a population that was older and more inclusive than those studied in prior trials. After successful completion of the Cholesterol Reduction In Seniors Program (CRISP),3 a 2-year feasibility study, the concept was modified and incorporated into ALLHAT as a randomized, nonblinded trial comparing pravastatin treatment with a usual care control group in a moderately hypercholesterolemic subset of the planned 40 000 ALLHAT participants. The principal objectives of the ALLHAT-LLT were to evaluate the impact of large sustained cholesterol reductions on all-cause mortality in a hypertensive cohort with at least 1 other CHD risk factor and to assess CHD reduction and other benefits in populations that had been excluded or underrepresented in previous trials, particularly older persons, women, racial and ethnic minority groups, and persons with diabetes.2 Emphasis on primary care settings was deemed important because of the study's substantial implications for these providers and their patients. Despite the publication of more than 20 long-term statin trials4- 13 since ALLHAT began in 1994 and the publication of the National Cholesterol Education Program (NCEP) Adult Treatment Panel Guidelines (ATP III)14 in 2001, ALLHAT-LLT remains the second largest long-term statin trial and addresses a unique population. This article presents results of the pravastatin vs usual care comparison for all-cause mortality and CHD end points in ALLHAT-LLT. Results of the ALLHAT antihypertensive trial appear in an accompanying article.15
  • Article
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    Context.— Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons.Objective.— To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels.Design.— A randomized, double-blind, placebo-controlled trial.Setting.— Outpatient clinics in Texas.Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile).Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated fat, low-cholesterol diet.Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death.Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups.Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention. Figures in this Article EPIDEMIOLOGICAL observations have demonstrated consistently a strong positive, continuous, independent, graded relation between plasma total cholesterol (TC) and the incidence of coronary heart disease (CHD). This relation covers a wide range of cholesterol concentrations, including those considered normal or mildly elevated.1- 3 In the Multiple Risk Factor Intervention Trial follow-up of screened men, 69% of deaths from CHD in the first 6 years of follow-up occurred in subjects with TC values between 4.71 and 6.83 mmol/L (182-264 mg/dL).4 In the first 16 years of the Framingham Heart Study, 40% of participants who developed a myocardial infarction had a TC level between 5.17 and 6.47 mmol/L (200-250 mg/dL).5 Large end point studies have demonstrated conclusively that effective cholesterol-lowering treatment can substantially reduce myocardial infarction and other coronary events. In the Scandinavian Simvastatin Survival Study the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduced total mortality in patients with CHD by 30% because of a 42% reduction in deaths from CHD.6 Subsequently, pravastatin was shown to reduce fatal and nonfatal coronary events in patients with7 and without8 CHD. However, it is unknown whether benefit from reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD (primary prevention) extends to individuals with average serum cholesterol levels, women, and older persons. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) targeted a cohort of generally healthy middle-aged and older men and women with average TC and LDL-C levels and with below-average high-density lipoprotein cholesterol (HDL-C) levels. The primary end point analysis was the incidence of first acute major coronary events, defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. The inclusion of unstable angina was a unique feature of this study, and its inclusion as a primary end point reflects the increasing frequency of unstable angina as the initial presentation of CHD in the United States.9
  • Article
    BACKGROUND: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.
  • Article
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    ABSTRACT Context.— Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. Objective.— To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. Design.— A randomized, double-blind, placebo-controlled trial. Setting.— Outpatient clinics in Texas. Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated fat, low-cholesterol diet. Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.
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    A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.
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    In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P<.001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein—cholesterol level (24% to 40%), increased high-density lipoprotein—cholesterol level (6.6% to 9.5 %), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein—cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P<.001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia. (Arch Intern Med. 1991;151:43-49)
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    Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.
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    To examine the relation between low serum total cholesterol concentrations and causes of mortality. Cohort study of men followed up for an average of 14.8 years (range 13.5-16.0 years). One general practice in each of 24 British towns. 7735 men aged 40-59 at screening selected at random from the 24 general practices. Deaths from all causes, cardiovascular causes, cancer, and non-cardiovascular, non-cancer causes. During the mean follow up period of 14.8 years there were 1257 deaths from all causes, 640 cardiovascular deaths, 433 cancer deaths, and 184 deaths from other causes. Low serum cholesterol concentrations (< 4.8 mmol/l), present in 5% (n = 410) of the men, were associated with the highest mortality from all causes, largely due to a significant increase in cancer deaths (age adjusted relative risk 1.6 (95% confidence interval 1.1 to 2.3); < 4.8 v 4.8-5.9 mmol/l) and in other non-cardiovascular deaths (age adjusted relative risk 1.9 (1.1 to 3.1)). Low serum cholesterol concentration was associated with an increased prevalence of several diseases and indicators of ill health and with lifestyle characteristics such as smoking and heavy drinking. After adjustment for these factors in the multivariate analysis the increased risk for cancer was attenuated (relative risk 1.4 (0.9 to 2.0) and the inverse association with other non-cardiovascular, non-cancer causes was no longer significant (relative risk 1.5 (0.9 to 2.6); < 4.8 v 4.8-5.9 mmol/l). The excess risks of cancer and of other non-cardiovascular deaths were most pronounced in the first five years and became attenuated and non-significant with longer follow up. By contrast, the positive association between serum total cholesterol concentration and cardiovascular mortality was seen even after more than 10 years of follow up. The association between comparatively low serum total cholesterol concentrations and excess mortality seemed to be due to preclinical cancer and other non-cardiovascular diseases. This suggests that public health programmes encouraging lower average concentrations of serum total cholesterol are unlikely to be associated with increased cancer or other non-cardiovascular mortality.
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    Elevated mortality has been reported at extremes of the serum total cholesterol distribution, with increased coronary mortality reported at high total cholesterol levels and increased cancer and non-cardiovascular/non-cancer mortality at low total cholesterol levels. The authors used data collected on 1,959 males aged 35-69 years from the fourth Framingham Study examination to analyze the relations between total serum cholesterol levels and 409 coronary deaths, 325 cancer deaths, and 534 other deaths for a 32-year follow-up. Age- and risk factor-adjusted Cox regressions were computed. Nonlinear (U-shaped) relations were investigated with the use of quadratic regression and with dummy variables using the 160-199 mg/dl group as the comparison group. Subset analyses investigated the relation in smokers and men who drank > or = 14 alcoholic drinks per week. All analyses were repeated removing those with existing cardiovascular disease and cancer and those who died during the first 5 years of follow-up. A significant U-shaped relation with all-cause mortality was noted, as were an inverse relation to cancer mortality and a monotonic increasing relation with coronary disease mortality. In subset analyses, the association of low serum cholesterol (< 160 mg/dl) with cancer mortality was observed in men who smoked cigarettes. Compared with the 160-199 mg/dl group, the relative risk was 3.72 (p = 0.0001, 95% confidence interval 1.91-7.25). Studies of the relation of low total serum cholesterol levels, cigarette smoking, and cancer are needed.
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    In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.
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    Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. A randomized, double-blind, placebo-controlled trial. Outpatient clinics in Texas. A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.
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    Richard CPasternak, Sidney CSmith, C.NoelBairey-Merz, Scott MGrundy, James ICleeman, ClaudeLenfant. (2002) ACC/AHA/NHLBI clinical advisory on the use and safety of statins11When citing this document, the American College of Cardiology, American Heart Association, and National Heart, Lung and Blood Institute would appreciate the following citation format: Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Advisory on the Use and Safety of Statins. J Am Coll Cardiol 2002;40:568–73.22This document is available on the Web sites of the ACC (www.acc.org), the AHA (www.americanheart.org), and the NHLBI (www.nhlbi.nih.gov/guidelines/cholesterol).. Journal of the American College of Cardiology 40, 567-572 CrossRef
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    Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE). To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI. Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil. A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L). Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years. Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups. Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group. Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.