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PubMed2005

The influence of guidelines on the use of statins: analysis of prescribing trends 1998-2002.

AIMS: To monitor statin prescribing trends over time in order to determine whether prescribers were influenced by study results and/or clinical guidelines in terms of type and dosage of statin prescribed. METHODS: The GMS (General Medical Services) prescription database in Ireland was used to identify a cohort of patients, prescribed statins, in order to investigate prescribing trends from January 1998-December 2002. Statin prescribing rates for patients with ischaemic heart disease and diabetes were compared with rates in the general GMS population. Logistic regression analysis was used in patients with ischaemic heart disease and diabetes and adjusted odds ratios and 95% confidence intervals presented. RESULTS: Increased statin prescribing over time was noted (test for linear trend P < 0.0001). Pravastatin was the most frequently prescribed, followed by atorvastatin; simvastatin and fluvastatin showed lower rates of prescribing. Atorvastatin showed the greatest increased rate over time. An increase in the overall dose prescribed (test for trend P < 0.01) was chiefly due to increases in pravastatin dose, but doses were still below those recommended from clinical trials. Statins were prescribed more frequently in patients with ischaemic heart disease and diabetes, 44% (95% CI 43-45%) compared with the total GMS population, 7.7% (95% CI 7.6-7.8%), by December 2002. However, statins were only prescribed to 52% (95% CI 51-53%) of ischaemic heart disease patients and 40% (95% CI 39-41%) of patients with diabetes by December 2002. Patients aged 45-64 years were more likely to receive statins, compared with those aged 65 years and older. CONCLUSION: These findings suggest that the beneficial effects of statins shown in clinical studies may not be achieved in practice.

Adolescent↗
PubMed2005

Persistence and determinants of statin therapy among middle-aged patients for primary and secondary prevention.

AIMS: Statins have been shown to significantly reduce morbidity and mortality in patients with coronary artery disease (CAD), and also in patients with dyslipidaemia when statins are taken regularly. Middle-aged patients have the highest level of forecasting benefit and little is known about persistence rate of these therapies in a real-life setting. The objective was to evaluate the persistence rate of middle-aged patients initiating a statin therapy and its relation with several determinants for primary and secondary prevention. METHODS: A cohort was reconstructed using the RAMQ databases. All patients aged 50-64 years-old who received at least one statin prescription between 1 January, 1998 and 31 December, 2000 for a new intention of treatment for dyslipidaemia were included in the cohort and followed up until 30 June, 2001. The date of the first prescription of statin was defined as the index date. There were 4316 patients in the secondary prevention (CAD diagnosis) and 13,642 patients in primary prevention cohort. The cumulative persistence rate was estimated using Kaplan-Meier, and Cox regression models were used to estimate the hazard ratio of ceasing statins. RESULTS: We found that persistence with statins had fallen to 71% after 6 months of treatment, and had declined to 45% after 3 years in the secondary prevention cohort; the corresponding figures were 65% and 35% in the primary prevention cohort. Our results suggest that patients with dyslipidaemia in primary prevention compared with those in secondary prevention (HR: 1.18; 1.11-1.25) are less likely to be persistent. Patients with other cardiovascular risk factors such as age (HR: 0.99; 0.98-0.99), diabetes (HR: 0.84; 0.79-0.90), hypertension (HR: 0.76; 0.72-0.80) were most likely to be persistent with statins. We observed lower persistence in patients who have used the greatest number of pharmacies and prescribing physicians. CONCLUSION: This analysis indicates that barriers to persistence occur early in the therapeutic course. Overall persistence with statins is low, and particularly among patients with few other cardiovascular risk factors.

Cohort Studies↗
PubMed2005

Suboptimal choices and dosing of statins at start of therapy.

AIM: To assess dosing and determinants of the choice of statins among starters of statins. METHODS: Data were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category. RESULTS: In 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 +/- 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 +/- 0.56 DDDs) and atorvastatin (1.43 +/- 0.59 DDDs) received higher doses (P < 0.001), whereas users of fluvastatin (0.78 +/- 0.37 DDDs) and cerivastatin (0.81 +/- 0.30 DDDs) received lower doses (P < 0.001). Patients already using CYP3A4 inhibitors more frequently received fluvastatin (OR = 1.80; 95% CI 1.11, 2.94), metabolized by non-CYP3A4 pathways, and atorvastatin (OR = 1.62; 95% CI 1.06, 2.47), which is metabolized by CYP3A4, than simvastatin. Statin doses were not adjusted when prescribed to patients using CYP3A4 inhibitors. CONCLUSIONS: Many patients starting statin therapy did not receive a statin of first choice. The coadministration of potentially interacting drugs may have led to a change in statin choice, but not in dosage lowering. These findings suggest that the quality of statin therapy could be improved.

Choice Behavior↗
PubMed2005

Socioeconomic gradient in use of statins among Danish patients: population-based cross-sectional study.

AIMS: Socioeconomic inequalities in statin use are a public health concern but they may also confound observational studies of statins' effectiveness. We conducted a population-based cross-sectional study in Denmark to examine the association between socioeconomic status (SES) and statin use. METHODS: We obtained data on socioeconomic status of all persons in North Jutland County, Denmark, between 1995 and 1999 from the Prevention Registry at Statistics Denmark. Data on filled statin prescriptions were identified through the County Prescription Database. We compared the 1-year prevalence proportions of statin use for different socioeconomic groups, adjusted for age and urbanization. Separate analyses were done for patients with a history of cardiovascular disease as recorded in the County Hospital Discharge Registry. RESULTS: Among men with cardiovascular disease, statin use in 1995 was higher in those with the highest socioeconomic status (adjusted relative prevalence proportion (RPP) among top managers 1.86, 95% CI: 1.17-2.96), and lower among retired men (RPP (95% CI) 0.63 [0.43-0.93] in old-age pensioners, and 0.66 [0.45-0.98] in the early retired), when compared with basic-level workers. The socioeconomic differences in statin use among men decreased in magnitude over time but remained throughout the study period. We found no clear social gradient in statin use among women. CONCLUSIONS: Even in a health care system that claims to ensure a high degree of equity in medical care, we found clear indications of a socioeconomic gradient in statin use among men in the years after the launching of these drugs.

Adolescent↗
PubMed2005

Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.

Statins are the treatment of choice for the management of hypercholesterolaemia because of their proven efficacy and safety profile. They also have an increasing role in managing cardiovascular risk in patients with relatively normal levels of plasma cholesterol. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy. The chemical structures of statins govern their water solubility, which in turn influences their absorption, distribution, metabolism and excretion. Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have elimination half-lives of 1-3 h. Atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds, with elimination half-lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P(450) system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin are relatively hydrophilic and not significantly metabolized by cytochrome P(450) enzymes. All statins are selective for effect in the liver, largely because of efficient first-pass uptake; passive diffusion through hepatocyte cell membranes is primarily responsible for hepatic uptake of lipophilic statins, while hydrophilic agents are taken up by active carrier-mediated processes. Pravastatin and rosuvastatin show greater hepatoselectivity than lipophilic agents, as well as a reduced potential for uptake by peripheral cells. The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing low-density lipoprotein cholesterol, followed by atorvastatin, simvastatin and pravastatin. As a class, statins are generally well tolerated and serious adverse events, including muscle toxicity leading to rhabdomyolysis, are rare. Consideration of the differences between the statins helps to provide a rational basis for their use in clinical practice.

Clinical Trials as Topic↗
PubMed2004

Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex.

Statins have been reported to lower the risk of developing Alzheimer's disease; however, the mechanism of this potentially important neuroprotective action is not understood. Lowering cholesterol levels does not appear to be the primary mechanism. Statins have pleiotropic effects in addition to lowering cholesterol, and statins may act on several different pathways involving distinct gene expression patterns that would be difficult to determine by focusing on a few genes or their products in a single study. In addition, gene expression patterns may be specific to a particular statin. To understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with lovastatin, pravastatin, and simvastatin. Furthermore, brain statin levels were determined using liquid chromatography/tandem mass spectrometry. These studies revealed 15 genes involved in cell growth and signaling and trafficking that were similarly changed by all three statins. Overall, simvastatin had the greatest influence on expression as demonstrated by its ability to modify the expression of 23 genes in addition to those changed by all three drugs. Of particular interest was the expression of genes associated with apoptotic pathways that were altered by simvastatin. Reverse transcription-polymerase chain reaction experiments confirmed the microarray findings. All three drugs were detected in the cerebral cortex, and acute experiments revealed that statins are relatively rapidly removed from the brain. These results provide new insight into possible mechanisms for the potential efficacy of statins in reducing the risk of Alzheimer's disease and lay the foundation for future studies.

Animals↗
PubMed2005

Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomised trials.

OBJECTIVE: To compare the social and demographic profiles of patients who receive statin treatment after myocardial infarction and patients included in randomised trials. To estimate the effect of statin use in community based patients on subsequent all cause mortality and cardiovascular recurrence, contrasting effects with trial patients. DESIGN: Observational cohort study using a record linkage database. SETTING: Tayside, Scotland (population size and characteristics: about 400,000, mixed urban and rural). SUBJECTS: 4892 patients were discharged from hospital after their first myocardial infarction between January 1993 and December 2001. 2463 (50.3%) were taking statins during an average follow-up of 3.7 years (3.1% in 1993 and 62.9% in 2001). MAIN OUTCOME MEASURES: All cause mortality and recurrence of cardiovascular events. RESULTS: 319 deaths occurred in the statin treated group (age adjusted rate 4.1 per 100 person years, 95% confidence interval 3.2 to 4.9), and 1200 in the statin untreated group (12.7 per 100 person years, 11.1 to 14.3). More older people and women were represented in the population of patients treated with statins than among those recruited into clinical trials (mean age 67.8 v 59.8; women 39.6% v 16.9%, respectively). The effects of statins in routine clinical practice were consistent with, and similar to, those reported in clinical trials (adjusted hazard ratio for all cause mortality 0.69, 95% confidence interval 0.59 to 0.80; adjusted hazard ratio for cardiovascular recurrence 0.82, 0.71 to 0.95). CONCLUSIONS: The community effectiveness of statins in those groups that were not well represented in clinical trials was similar to the efficacy of statins in these trials.

Cohort Studies↗
PubMed2006

Impact of statin therapy on clinical outcomes in chronic heart failure patients according to beta-blocker use: results of CIBIS II.

BACKGROUND: HMG-CoA reductase inhibitors (statins) are widely prescribed in patients with established systolic chronic heart failure (CHF). However, there is considerable controversy regarding their benefit in this setting. We therefore conducted a post-hoc analysis of outcomes according to statin use within the Second Cardiac Insufficiency Bisoprolol Study of the beta-blocker, bisoprolol, in NYHA classes III-IV systolic CHF patients (left ventricular ejection fraction <35%), receiving background ACE inhibitor and diuretics. METHODS: Analysis of clinical outcomes was performed according to baseline use of statins and subsequent randomisation to placebo or bisoprolol. Cumulative incidence curves for clinical events were constructed using the Kaplan-Meier method and tested for significance by log-rank statistic. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Two hundred and twenty-six of 2,647 patients were receiving statins at baseline (8.5%). Patients were well-matched in the 4 study groups at baseline for gender, weight, NYHA class and LVEF, however statin/bisoprolol patients were significantly younger (p < 0.05). Statin use at baseline was associated with a significant survival benefit compared with no statin use (p < 0.005, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.39-0.94). This benefit remained after adjusting for other significant predictors of survival (p < 0.05, HR = 0.60, 95%CI = 0.39-0.94). A significant interaction effect was noted with bisoprolol, survival being greatest in the statin/bisoprolol group (p < 0.001, HR = 0.14, 95% CI = 0.03-0.60). Survival was 98.3% in the statin/bisoprolol group, 82.1% in the statin/placebo group, 87.2% in the no statin/bisoprolol group and 82.8% in the no statin/placebo group. The statin/bisoprolol group was also associated with fewer cardiovascular (p < 0.005) and sudden deaths (p < 0.0005) compared with other groups. CONCLUSIONS: Despite the post-hoc, non-randomised nature of this analysis, these observations suggest that statin use appears to be beneficial in CHF. Furthermore, there appears to be a favourable interaction between statins and beta-blockade within the Second Cardiac Insufficiency Bisoprolol Study cohort. Prospective studies of statins are required to definitively address the role of these agents in established CHF.

Adrenergic beta-Antagonists↗
PubMed2002

Preprocedural statin medication reduces the extent of periprocedural non-Q-wave myocardial infarction.

BACKGROUND: Stenting-related myocardial injury has been recognized as a frequent and prognostically important event, the extent of which depends on microcirculatory impairment in association with platelet aggregation, inflammation, and increased oxidative stress. Recent studies underscored the non-lipid-lowering effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with antithrombotic, antiinflammatory, and antioxidative aspects. Thus, we tested the hypothesis that preprocedural statin therapy is associated with a reduction in the extent of stenting-related myocardial injury. METHODS AND RESULTS: We stratified 296 consecutive patients who were undergoing stenting of a de novo stenosis according to the preprocedural status of statin therapy (229 statin-treated and 67 control patients). Incidence of periprocedural myocardial injury was assessed by analysis of creatine kinase (CK; upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men) and cardiac troponin T (cTnT; bedside test; threshold 0.1 ng/mL) before and 6, 12, and 24 hours after the intervention. Relative to control patients, the incidence of CK elevation >3x ULN was more than 90% lower in statin-treated patients (0.4% versus 6.0%, P=0.01). Statin therapy was the only factor independently associated with a lower risk of CK elevation >3x ULN (OR: 0.08, 95% CI: 0.01 to 0.75; P=0.03). The overall incidences of CK and cardiac troponin T elevation were slightly lower in statin-treated than in control patients (14.4% versus 20.9%, P=0.3, and 17.9% versus 22.4%, P=0.5, respectively). CONCLUSIONS: Preprocedural statin therapy is associated with a reduction in the incidence of larger-sized, stenting-related myocardial infarctions. Prospective, randomized trials are warranted to further assess this cardioprotective effect of statins in coronary intervention.

Biomarkers↗
PubMed2000

Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription.

BACKGROUND: Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function. METHODS AND RESULTS: To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production. CONCLUSIONS: Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.

Actins↗
PubMed2005

Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report.

BACKGROUND: No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. METHODS AND RESULTS: We evaluated 137 patients with HF and an EF > or =0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21+/-12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, beta-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P=0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153+/-45 versus 98+/-33 mg/dL, P<0.01). After statin therapy, LDL cholesterol levels fell to a similar level (101+/-32 mg/dL) as in patients not receiving statins (98+/-33 mg/dL). After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (adjusted relative risk of death [95% CI] 0.20 [0.06 to 0.62]; P=0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P=0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P=0.082). CONCLUSIONS: Statin therapy may be associated with improved survival in patients with HF and a normal EF.

Adult↗
PubMed2003

Early vascular benefits of statin therapy.

Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration. Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment. These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid lowering properties of statins.

Anti-Inflammatory Agents↗
PubMed2003

Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials.

BACKGROUND: Statins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol. REVIEW METHODS: PubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events. RESULTS: Different statins at a range of doses reduced total cholesterol by 17-35% and LDL-cholesterol by 24-49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained. CONCLUSIONS: Statins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg.

Atorvastatin↗
PubMed2005

Differential effects of statins on relevant functions of human monocyte-derived dendritic cells.

Statins were shown to possess immunomodulating properties, but the mechanisms of statin effects on the immune system are poorly understood. We analyzed the influence of statins on professional antigen-presenting dendritic cells (DC). Immature DC were cultivated from monocytes of healthy donors. DC maturation was induced by lipopolysaccharide (LPS; 1 microg/mL). Unstimulated and LPS-stimulated DC were treated with simvastatin or atorvastatin (0.1-1 microM). The expression of CD40, CD83, CD86, and human leukocyte antigen-DR on unstimulated and LPS-stimulated DC was reduced significantly by statins, and the expression of Toll-like receptor 2 (TLR2) and TLR4 on LPS-stimulated DC was enhanced temporarily. Statins caused a significant reduction of endocytosis of fluorescein isothiocyanate-dextran by DC. Statins significantly inhibited the basal secretion of interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor alpha from unstimulated DC, and their release from LPS-stimulated DC was enhanced. In mixed leukocyte reaction, preincubation of LPS-stimulated DC with statins significantly suppressed their clustering with T cells and their ability to induce T cell proliferation, CD71, and CD25 up-regulation on T cells and the secretion of interferon-gamma and IL-2 from T cells. In conclusion, this study showed that statins suppressed endocytosis, basal secretion of proinflammatory cytokines, and the ability of DC to induce T cell proliferation, activation, and T helper cell type 1 differentiation. However, statin preincubation of LPS-stimulated DC caused a further increase in their secretion of proinflammatory cytokines.

Antigen Presentation↗
PubMed2004

Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study.

OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

Aged↗
PubMed2006

Statin treatment and adherence to national cholesterol guidelines after ischemic stroke.

BACKGROUND: National cholesterol guidelines have defined high vascular risk individuals as those who could potentially benefit most from statin therapy. The authors aimed to determine the rate of statin use, its predictors, and the achievement of national guideline target lipid goals among ischemic stroke survivors. METHODS: The authors abstracted data from the Vitamin Intervention for Stroke Prevention (VISP) study database from the United States and Canada to incorporate into algorithms for initiating statin therapy according to the National Cholesterol Education Program (NCEP) guidelines for high-risk individuals. The authors applied these algorithms to all study subjects. Univariate as well as multivariate associations for target lipid levels and statin implementation were then evaluated utilizing pertinent demographic, clinical, and laboratory data. RESULTS: Of 2,894 subjects in the analysis dataset, 38% were women; 71% were recruited in the United States and 29% in Canada. Of 769 high-risk subjects, 262 (34%) had a low-density lipoprotein (LDL) level > or =130 mg/dL and 124 of these (47%) were not on statin. Among those high-risk persons on statin treatment, only 42% had an LDL < or =100 mg/dL. Subjects in the overall cohort were more likely to be on a statin if they were treated in the United States or had a history of hypertension or coronary artery disease. CONCLUSIONS: Approximately one out of three guideline-eligible high vascular risk ischemic stroke patients in this study had low-density lipoprotein cholesterol concentrations above qualifying levels for pharmacologic therapy, but half of these patients were not taking a statin, and of those receiving statin treatment, less than half were within recommended lipid goals.

Adult↗
PubMedDate not supplied

Safety issues with statin therapy.

OBJECTIVE: To describe the most important potential adverse effects related to statin therapy, discuss mechanisms of toxicity and drug interactions, and suggest approaches for enhancing safety with statin therapy. DATA SOURCES: Large-scale clinical trials, government databases and papers, and recent studies of statin safety. STUDY SELECTION: By the author. DATA EXTRACTION: By the author. DATA SYNTHESIS: The number of patients requiring intensive therapy with statins to achieve lipid goals is climbing, and as the number grows, so does the potential for adverse effects with these agents. The most detrimental adverse effects of statins are hepatotoxicity and myopathy. Liver dysfunction induced by statins is rare and usually mild, with asymptomatic transaminase elevation or acute cholecystitis. Progression to liver failure is exceedingly rare, and transaminase elevations is usually reversible with dose reduction. Statin-associated myopathy is generally a concern when patients have more than one risk factor for muscle syndromes, such as an elderly patient with poor renal function. Drug interactions represent an additional concern, especially for atorvastatin, lovastatin, and simvastatin, all of which are metabolized by the important 3A4 isoenzyme of the cytochrome P450 system of the liver. CONCLUSION: The benefits of all available statins for the treatment or prevention of cardiovascular disease outweigh any potential risks of therapy. For patient groups most susceptible to adverse effects, such as the elderly and those on multiple medications, clinicians should consider the use of statins that are least likely to interact with other medications.

Chemical and Drug Induced Liver Injury↗
PubMed2007

Probable statin-induced testicular pain.

OBJECTIVE: To describe a case of a patient experiencing testicular pain on 3 occasions after taking 3 different statins. CASE SUMMARY: A 54-year-old man with hyperlipidemia was started on lovastatin therapy. His other medications included aspirin, levothyroxine, buspirone, and atenolol. Seven months after starting lovastatin, the patient experienced testicular discomfort that resolved upon discontinuation of the drug. Afterward, he started simvastatin and again experienced testicular discomfort. The simvastatin was changed to atorvastatin, and the pain resolved. However, 3 months after starting atorvastatin, the patient developed testicular pain, which resolved after the drug was stopped. During each of the episodes, the patient's pain increased when he was sitting, driving, or wearing tight clothing. The Naranjo probability scale indicates that statins probably caused the patient's pain. DISCUSSION: Testicular pain is rarely caused by medications. Product labeling for statins does not list urinary adverse events as common. However, labeling for atorvastatin and pravastatin lists rare urologic adverse effects. A literature search did not reveal any previously reported cases of testicular adverse effects from statins. However, statins have been shown to inhibit cholesterol synthesis in the testis. Some data indicate that statins reduce serum testosterone concentrations, but other data indicate that statins have no effect on sex hormones or spermatogenesis. Data are also available indicating that aspirin might affect testosterone concentrations and testicular function. It is difficult to know whether either of the above hormonal mechanisms was associated with our patient's testicular discomfort, but the time course and challenge/rechallenge aspects of the case suggest that the statins were the cause. CONCLUSIONS: Urologic adverse effects of statins rarely occur but should not be overlooked by medical providers.

Atorvastatin↗