***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The British Regional Heart Study ( BRHS ) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol ( HDLC ) and incidence of coronary heart disease was eliminated by covariance adjustment . Using the proportional hazards model and adjusting for age , blood pressure , smoking , body mass index , and low-density lipoprotein cholesterol , we analyzed this relation separately in the Framingham Heart Study ( FHS ) , Lipid Research Clinics Prevalence Mortality Follow-up Study ( LRCF ) and Coronary Primary Prevention Trial ( CPPT ) , and Multiple Risk Factor Intervention Trial ( MRFIT ) . In CPPT and MRFIT ( both r and omized trials in middle-age high-risk men ) , only the control groups were analyzed . A 1-mg/dl ( 0.026 mM ) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2 % in men ( FHS , CPPT , and MRFIT ) and 3 % in women ( FHS ) . In LRCF , where only fatal outcomes were documented , a 1-mg/dl increment in HDLC was associated with significant 3.7 % ( men ) and 4.7 % ( women ) decrements in cardiovascular disease mortality rates . The 95 % confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably , and all contained the range 1.9 - 2.9 % . HDLC levels were essentially unrelated to non-cardiovascular disease mortality . When differences in analytic methodology were eliminated , a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies BACKGROUND In observational analyses , higher levels of high-density lipoprotein ( HDL ) cholesterol have been associated with a lower risk of coronary heart disease events . However , whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain . Inhibition of cholesteryl ester transfer protein ( CETP ) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes . METHODS We r and omly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib  , at a dose of 600 mg daily , or placebo , in addition to the best available evidence -based care . The primary efficacy end point was a composite of death from coronary heart disease , nonfatal myocardial infa rct ion , ischemic stroke , unstable angina , or cardiac arrest with resuscitation . RESULTS At the time of r and omization , the mean HDL cholesterol level was 42 mg per deciliter ( 1.1 mmol per liter ) , and the mean low-density lipoprotein ( LDL ) cholesterol level was 76 mg per deciliter ( 2.0 mmol per liter ) . Over the course of the trial , HDL cholesterol levels increased from baseline by 4 to 11 % in the placebo group and by 31 to 40 % in the dalcetrapib group . Dalcetrapib had a minimal effect on LDL cholesterol levels . Patients were followed for a median of 31 months . At a prespecified interim analysis that included 1135 primary end-point events ( 71 % of the projected total number ) , the independent data and safety monitoring board recommended termination of the trial for futility . As compared with placebo , dalcetrapib did not alter the risk of the primary end point ( cumulative event rate , 8.0 % and 8.3 % , respectively ; hazard ratio with dalcetrapib , 1.04 ; 95 % confidence interval , 0.93 to 1.16 ; P=0.52 ) and did not have a significant effect on any component of the primary end point or total mortality . The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo ( P<0.001 for both comparisons ) . CONCLUSIONS In patients who had had a recent acute coronary syndrome , dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events . ( Funded by F. Hoffmann-La Roche ; dal- OUTCOMES Clinical Trials.gov number , NCT00658515 . ) Background — There is no r and omized , double-blind trial testing the prognostic effect of highly purified omega-3 fatty acids in addition to current guideline -adjusted treatment of acute myocardial infa rct ion . Methods and Results — OMEGA is a r and omized , placebo-controlled , double-blind , multicenter trial testing the effects of omega-3-acid ethyl esters-90 ( 1 g/d for 1 year ) on the rate of sudden cardiac death in survivors of acute myocardial infa rct ion , if given in addition to current guideline -adjusted treatment . Secondary end points were total mortality and nonfatal clinical events .  Patients ( n=3851 ; female , 25.6 % ; mean age , 64.0 years ) were r and omized in 104 German centers 3 to 14 days after acute myocardial infa rct ion from October 2003 until June 2007 .  Acute coronary angiography was performed in 93.8 % and acute percutaneous coronary intervention in 77.8 % of all patients . During a follow-up of 365 days , the event rates were ( omega and control groups ) as follows : sudden cardiac death , 1.5 % and 1.5 % ( P=0.84 ) ; total mortality , 4.6 % and 3.7 % ( P=0.18 ) ; major adverse cerebrovascular and cardiovascular events , 10.4 % and 8.8 % ( P=0.1 ) ; and revascularization in survivors , 27.6 % and 29.1 % ( P=0.34 ) . Conclusions — Guideline -adjusted treatment of acute myocardial infa rct ion results in a low rate of sudden cardiac death and other clinical events within 1 year of follow-up , which could not be shown to be further reduced by the application of omega-3 fatty acids . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00251134 BACKGROUND Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease . We aim ed to test the hypothesis that long-term use of eicosapentaenoic acid ( EPA ) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish . METHODS 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999 . Patients were r and omly assigned to receive either 1800 mg of EPA daily with statin ( EPA group ; n=9326 ) or statin only ( controls ; n=9319 ) with a 5-year follow-up . The primary endpoint was any major coronary event , including sudden cardiac death , fatal and non-fatal myocardial infa rct ion , and other non-fatal events including unstable angina pectoris , angioplasty , stenting , or coronary artery bypass grafting . Analysis was by intention-to-treat . The study was registered at Clinical Trials.gov , number NCT00231738 . FINDINGS At mean follow-up of 4.6 years , we detected the primary endpoint in 262 ( 2.8 % ) patients in the EPA group and 324 ( 3.5 % ) in controls-a 19 % relative reduction in major coronary events ( p=0.011 ) . Post-treatment LDL cholesterol concentrations decreased 25 % , from 4.7 mmol/L in both groups . Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events . Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group . Sudden cardiac death and coronary death did not differ between groups . In patients with a history of coronary artery disease who were given EPA treatment , major coronary events were reduced by 19 % ( secondary prevention subgroup : 158 [ 8.7 % ] in the EPA group vs 197 [ 10.7 % ] in the control group ; p=0.048 ) . In patients with no history of coronary artery disease , EPA treatment reduced major coronary events by 18 % , but this finding was not significant ( 104 [ 1.4 % ] in the EPA group vs 127 [ 1.7 % ] in the control group ; p=0.132 ) . INTERPRETATION EPA is a promising treatment for prevention of major coronary events , and especially non-fatal coronary events , in Japanese hypercholesterolaemic patients Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9 , which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol ( LDL-C ) levels in patients with hypercholesterolemia . In this 24-week , multicenter , double-blind , placebo-controlled , dose-ranging study ( NCT01592240 ) , subjects with LDL-C levels≥80 mg/dl on stable statin therapy were r and omized to Q14 days  subcutaneous placebo or bococizumab 50 , 100 , or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg . Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl . The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration . Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period . Of the 354 subjects r and omized , 351 received treatment  ( placebo [ n=100 ] or bococizumab [ n=251 ] ) . The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days . Compared with placebo , bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl ; this was despite dose reductions in 32.5 % and 34.2 % of subjects at week 10 or 8 , respectively . Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl , respectively . Adverse events were similar across placebo and bococizumab groups . Few subjects ( n=7 ; 2 % ) discontinued treatment because of treatment-related adverse events . In conclusion , bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects . Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction . The Q14 days regimen is being evaluated in phase 3 clinical trials A total of 96 patients with moderate elevations of low-density lipoprotein ( LDL ) cholesterol were r and omly assigned to 4 different double-blind treatment regimens : placebo ; colestipol 5 g and lovastatin 20 mg/day ( C5 + L20 ) ; colestipol 10 g and lovastatin 20 mg/day ( C10 + L20 ) ; and lovastatin 40 mg/day ( L40 ) . During 12 weeks of therapy , C10 + L20 achieved the greatest reduction in total cholesterol ( -32 % ) and LDL cholesterol ( -48 % ) levels from baseline . This combination also exhibited significantly greater reductions in LDL cholesterol levels than the C5 + L20 and L40 groups ( p < 0.01 ) . The differences in total and LDL cholesterol reduction between the C5 + L20 and L40 groups were not significant . Similar changes and differences between treatments were seen in apolipoprotein B levels . Whereas mean total apolipoprotein A-I levels increased with all treatments ( p < 0.05 ) , lipoprotein particles A-I were significantly increased in the C10 + L20 group ( p < 0.01 ) only . Results demonstrate that the combination of low-dose lovastatin ( 20 mg/day ) with low-dose colestipol ( 5 or 10 g/day ) produces LDL cholesterol reductions equal to or greater than higher doses of lovastatin ( 40 mg/day ) . In addition , low-dose combinations are > 25 % more cost-effective than high-dose monotherapy In a double-blind clinical trial of clofibrate versus identical quantity of corn oil 497 patients with ischaemic heart disease were observed over a period of five years . The death rate and the rate of non-fatal infa rcts were significantly less among the clofibrate group , and the difference was greatest in respect of sudden deaths and among 
    Output:
    
FINDINGS Niacin may reduce cardiovascular events as monotherapy ; however , recent trials in combination with statins have failed to show a benefit .
Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes .
Fibrates may improve cardiovascular outcomes as monotherapy ; however , trials in combination with statins have failed to show a benefit , except in those with elevated triglycerides ( > 200 mg/dL ) or low HDL-C ( < 40 mg/dL ) .
There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events .
IMPLICATION S Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline -directed statin therapy .
In certain clinical situations , such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy , those with persistent severe elevations in triglycerides , or patients with high cardiovascular risk , some nonstatin therapies may be useful in reducing cardiovascular events .