Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects .
There was no evidence of any serious harm caused by statin prescription .
Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life .
Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta- analysis indicate that these benefits are similar in people at lower ( < 1 % per year ) risk of a major cardiovascular event .
AUTHORS ' CONCLUSIONS Reductions in all-cause mortality , major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins
BACKGROUND Reducing high blood cholesterol , a risk factor for cardiovascular disease ( CVD ) events in people with and without a past history of CVD is an important goal of pharmacotherapy .
Statins are the first-choice agents .
Previous review s of the effects of statins have highlighted their benefits in people with CVD .
The case for primary prevention was uncertain when the last version of this review was published ( 2011 ) and in light of new data an up date of this review is required .
OBJECTIVES To assess the effects , both harms and benefits , of statins in people with no history of CVD .
Low-Dose Combined Therapy with Fluvastatin and Cholestyramine in Hyperlipidemic Patients
Table . SI Units and Drugs Many reports have shown the efficacy of the combination of bile-absorbing resin and 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor ( statin class ) therapies [ 1 - 4 ] . Primarily , this resin-statin treatment regimen has been targeted to patients with low-density lipoprotein ( LDL ) cholesterol levels greater than 6.47 mmol/L ( > 250 mg/dL ) , a population presumably enriched with familial hypercholesterolemic patients . Consequently , dosages have been large , with both the statin and resin agents administered at the upper ends of their respective dosing ranges . However , this group of markedly hypercholesterolemic patients does not represent the typical person identified through the adult National Cholesterol Education Program guidelines . For the considerably larger pool of persons with LDL cholesterol between 4.14 mmol/L and 6.21 mmol/L ( 160 mg/dL and 240 mg/dL ) , a safe , convenient , well-tolerated , and effective dosing method is essential . Low-dose combination therapy is thought to be beneficial because long-term compliance is enhanced and safety maximized while efficacy is preserved . It has been suggested that side effects with statin agents are dose-dependent , thereby implying a benefit with routine use of lower dosing . In contrast , side effects attributed to resin are equivalent at varying doses within the usual dosing range [ 5 , 6 ] . Thus , the benefit of lower resin dose would be confined to enhanced palatability and tolerability . The overall cholesterol lowering with such a low-dose combination , however , still remains unknown . Fluvastatin sodium ( Lescol , S and oz ; East Hanover , New Jersey ) , a new water-soluble cholesterol-lowering agent that acts through the inhibition of HMG-CoA reductase , is the first entirely synthetic HMG-CoA reductase inhibitor and differs structurally from the fungal derivatives of compactin [ 7 ] . Fluvastatin has a distinctive biopharmaceutical profile ; it has a high rate of absorption that is not influenced by food intake , possesses no circulating active metabolites , is 98 % protein-bound , does not cross the blood-brain barrier , has a systemic half-life of 30 minutes , and is 95 % excreted by the liver [ 8 ] . We evaluated the LDL cholesterol-lowering efficacy of various combinations of low-dose resin and statin treatments , using cholestyramine ( Questran Light ; Bristol ) and fluvastatin . The study population included mostly patients with hypercholesterolemia who would , according to the new National Cholesterol Education Program guidelines for adults ( LDL cholesterol > 4.91 mmol/L [ > 190 mg/dL ] or LDL cholesterol > 4.14 mmol/L [ > 160 mg/dL ] with two risk factors ) , be advised to receive medication . Methods The study protocol was design ed by mutual consent of the investigators and S and oz Research Institute , with all data collected by the investigators subject to review and analysis by S and oz Research Institute . The interpretation of the data in this article is based on the mutual consent of all su bmi tting authors . All patients were consecutively r and omized based on a diagnosis of hypercholesterolemia confirmed during drug washout with an LDL cholesterol level of at least 4.14 mmol/L ( 160 mg/dL ) , despite dietary intervention , and a plasma triglyceride level of no more than 3.39 mmol/L ( 300 mg/dL ) . Persons were excluded if they had a history of homozygous familial hypercholesterolemia , secondary hyperlipidemia , liver disease , renal disease , diabetes , myocardial infa rct ion or angioplasty within 6 months of study entry , or uncontrolled hypertension . The patients ' mean age was 54.1 years ; 54 % were male ; 95 % were white and 3 % were black . The treatment groups did not differ in baseline demographic characteristics . The study was approved by the institutional review boards for human research of all participating institutions . Informed consent was obtained from all patients . Treatment Plan This study consisted of a 6-week , single-blind , placebo washout period followed by a 24-week , double-blind treatment period divided into three phases ( Figure 1 ) . Patients were withdrawn from hypolipidemic therapy for at least 4 weeks ( 1 year for probucol ) before entry into the washout period . In addition , patients were instructed by a registered dietitian to follow a cholesterol-lowering diet ( American Heart Association or National Cholesterol Education Program step 1 ) for at least 8 weeks before entry into the washout period and throughout the study , and a Food Record Rating score of 15 or less was required for study entry [ 9 ] . Patients with  aspartate aminotransferase or alanine aminotransferase values greater than 1.5 times the upper limit of laboratory normal during the washout period were excluded from the study . Figure 1 . Study design and numbers of patients initially assigned to each treatment group . At the end of the placebo washout period , patients who satisfied all entry criteria entered the 24-week , double-blind treatment period , which consisted of three 8-week phases . For the first 8 weeks ( phase 1 ) , patients were assigned r and omly into six groups receiving blinded study medication : two groups receiving placebo ; two receiving 10 mg of fluvastatin ; and two receiving 20 mg of fluvastatin . In phases 2 and 3 of the study , one placebo group , one 10-mg fluvastatin group , and one 20-mg fluvastatin group received open-label cholestyramine in addition to the blinded study drug , whereas the other three groups remained on fluvastatin or placebo monotherapy for the rest of the trial . In phase 2 , the dose of cholestyramine added to the regimen of patients in the three combination groups was 4 g twice daily . In phase 3 , the dose of cholestyramine was increased to 8 g twice a day for these patients . Blinded medication was taken once daily at bedtime , approximately 4 hours after the evening meal . Patients receiving open-label cholestyramine took their medication just before breakfast and dinner . Compliance with all treatment regimens was assessed by pill or packet count . Study Evaluations Patients were assessed every 2 weeks during the placebo washout period and every 4 weeks during the 24-week treatment period . Dietary compliance was determined by Food Record Rating scores derived from dietary records collected throughout the study [ 9 ] . Twelve-hour fasting blood sample s were obtained at each visit for lipid determinations , which were done by a central laboratory ( Medical Research Laboratories ; Cincinnati , Ohio ) . Low-density lipoprotein cholesterol was calculated according to the Friedewald formula [ 10 ] . Total cholesterol , high-density lipoprotein cholesterol , and plasma triglycerides were measured on a 737 Hitachi analyzer ( Boehringer Mannheim Diagnostics ; Indianapolis , Indiana ) with microenzymatic procedures [ 11 ] fully st and ardized , and part 3 was monitored through the National Heart , Lung , and Blood Institute and Centers for Disease Control and Prevention Lipid St and ardization Program [ 12 , 13 ] . Safety was evaluated at baseline and at intervals throughout the study . These evaluations included measurements of blood pressure and pulse ; physical , ophthalmologic , and electrocardiographic examinations ; and routine laboratory tests . Investigators were asked to assess , in a blinded fashion , each adverse event and laboratory abnormality for a potential relation to blinded study drug administration , based on their clinical experience and judgment . Statistical Analysis All statistical comparisons were made using two-tailed tests at the P < 0.05 level . Data were pooled across all clinical centers for analysis . The Statistical Analysis System ( SAS Institute , Inc. ; Cary , North Carolina ) software was used for all analyses . All confidence intervals are 95 % and represent the difference in mean percent change from baseline between two treatment groups of interest . For each patient , the baseline lipid value was defined as the average of the week 2 and week 0 lipid measurements during the washout phase . In evaluating efficacy by treatment phase , lipid results were calculated as the averages of the values for weeks 4 and 8 , weeks 12 and 16 , and weeks 20 and 24 . For end-point analyses , the end point was defined as the last active treatment phase visit for which lipid data were available . One-way analysis of variance models were used to compare the mean percentage change in total cholesterol , LDL cholesterol , high-density lipoprotein cholesterol , and triglycerides between the treatment groups . In each model , we did tests of significance of the percentage change from baseline within each group and of differences in mean percentage change between treatment groups . In determining safety , a newly occurring abnormality was defined as an abnormality reported during the active treatment period but not reported during the placebo washout period , and a worsening abnormality was an abnormality that worsened from the placebo washout period to the active treatment period . The number of patients with newly occurring or worsening abnormalities in each treatment group was determined , and the proportions were compared using the Fisher exact test . Results Of 460 patients from nine study centers screened , 224 met study criteria and were r and omized into the double-blind treatment period of this study ; 203 completed all phases of treatment . Fifteen ( 10 % ) of 150 fluvastatin-treated patients and 6 ( 8 % ) of 74 placebo- or cholestyramine-treated or both ( that is , non-fluvastatin-treated ) patients were dropped during the double-blind treatment period . Five fluvastatin-treated patients ( 1 receiving concomitant cholestyramine ) and 1 placebo-treated patient ( receiving concomitant cholestyramine ) dropped out because of adverse events . These events , each of which occurred in one patient , were angina , myalgia , stomatitis and glossitis , heartburn and indigestion , elevated transaminase levels , and alopecia . Of these , only the instance of stomatitis and glossitis was judged by the investigator to be definitely related to the drug . One patient
Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects .
There was no evidence of any serious harm caused by statin prescription .
Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life .
Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta- analysis indicate that these benefits are similar in people at lower ( < 1 % per year ) risk of a major cardiovascular event .
AUTHORS ' CONCLUSIONS Reductions in all-cause mortality , major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins
BACKGROUND Reducing high blood cholesterol , a risk factor for cardiovascular disease ( CVD ) events in people with and without a past history of CVD is an important goal of pharmacotherapy .
Statins are the first-choice agents .
Previous review s of the effects of statins have highlighted their benefits in people with CVD .
The case for primary prevention was uncertain when the last version of this review was published ( 2011 ) and in light of new data an up date of this review is required .
OBJECTIVES To assess the effects , both harms and benefits , of statins in people with no history of CVD .