***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: OBJECTIVES The purpose of this study was to characterize the determinants of plaque progression despite achieving very low levels of low-density lipoprotein cholesterol ( LDL-C ) . BACKGROUND Despite achieving very low levels of LDL-C , many patients continue to demonstrate disease progression and have clinical events . METHODS A total of 3,437 patients with coronary artery disease underwent serial intravascular ultrasound examination in 7 clinical trials . Patients who achieved an on-treatment LDL-C level of < or=70 mg/dl ( n = 951 ) were stratified as progressors ( n = 200 ) and nonprogressors ( n = 751 ) and compared . RESULTS Despite achieving LDL-C < or=70 mg/dl , > 20 % of patients continued to progress . There were no demographic differences between groups . Progressors demonstrated higher baseline levels of glucose ( 117.1 + /- 42.5 mg/dl vs. 112.1 + /- 40.0 mg/dl , p = 0.02 ) , triglycerides ( 157.5 mg/dl vs. 133.0 mg/dl , p = 0.004 ) , and a smaller decrease of apolipoprotein B ( -25.1 + /- 3.4 mg/dl vs. -27.4 + /- 3.35 mg/dl , p = 0.01 ) at follow-up . Multivariable analysis revealed that independently associated risk factors of progression in patients with LDL-C < or=70 mg/dl included baseline percent atheroma volume ( p = 0.001 ) , presence of diabetes mellitus ( p = 0.02 ) , increase in systolic blood pressure ( p = 0.001 ) , less increase in high-density lipoprotein cholesterol ( p = 0.01 ) , and a smaller decrease in apolipoprotein B levels ( p = 0.001 ) , but not changes in C-reactive protein ( p = 0.78 ) or LDL-C ( p = 0.84 ) . CONCLUSIONS Residual risk factors are associated with the likelihood of disease progression in patients who achieve very low LDL-C levels . In addition , the association between apolipoprotein B and atheroma progression highlights the potential importance of LDL particle concentration in patients with optimal LDL-C control . This finding highlights the need for intensive modification of global risk in patients with coronary artery disease CONTEXT Prior intravascular ultrasound ( IVUS ) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume ( PAV ) , the most rigorous IVUS measure of disease progression and regression . OBJECTIVE To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging . DESIGN AND SETTING Prospect i ve , open-label blinded end-points trial ( A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ ASTEROID ] ) was performed at 53 community and tertiary care centers in the United States , Canada , Europe , and Australia . A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment . Each pair of baseline and follow-up IVUS assessment s was analyzed in a blinded fashion . PATIENTS Between November 2002 and October 2003 , 507 patients had a baseline IVUS examination and received at least 1 dose of study drug . After 24 months , 349 patients had evaluable serial IVUS examinations . INTERVENTION All patients received intensive statin therapy with rosuvastatin , 40 mg/d . MAIN OUTCOME MEASURES Two primary efficacy parameters were prespecified : the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline . A secondary efficacy variable , change in normalized total atheroma volume for the entire artery , was also prespecified . RESULTS The mean ( SD ) baseline low-density lipoprotein cholesterol ( LDL-C ) level of 130.4 ( 34.3 ) mg/dL declined to 60.8 ( 20.0 ) mg/dL , a mean reduction of 53.2 % ( P<.001 ) . Mean ( SD ) high-density lipoprotein cholesterol ( HDL-C ) level at baseline was 43.1 ( 11.1 ) mg/dL , increasing to 49.0 ( 12.6 ) mg/dL , an increase of 14.7 % ( P<.001 ) . The mean ( SD ) change in PAV for the entire vessel was -0.98 % ( 3.15 % ) , with a median of -0.79 % ( 97.5 % CI , -1.21 % to -0.53 % ) ( P<.001 vs baseline ) . The mean ( SD ) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 ( 10.1 ) mm3 , with a median of -5.6 mm3 ( 97.5 % CI , -6.8 to -4.0 mm3 ) ( P<.001 vs baseline ) . Change in total atheroma volume showed a 6.8 % median reduction ; with a mean ( SD ) reduction of -14.7 ( 25.7 ) mm3 , with a median of -12.5 mm3 ( 95 % CI , -15.1 to -10.5 mm3 ) ( P<.001 vs baseline ) . Adverse events were infrequent and similar to other statin trials . CONCLUSIONS Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7 % , result ing in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden . Treatment to LDL-C levels below currently accepted guidelines , when accompanied by significant HDL-C increases , can regress atherosclerosis in coronary disease patients . Further studies are needed to determine the effect of the observed changes on clinical outcome . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00240318 BACKGROUND Alirocumab , a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) , has been shown to reduce low-density lipoprotein ( LDL ) cholesterol levels in patients who are receiving statin therapy .  Larger and longer-term studies are needed to establish safety and efficacy . METHODS We conducted a r and omized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter ( 1.8 mmol per liter ) or more and were receiving treatment with statins at the maximum tolerated dose ( the highest dose associated with an acceptable side-effect profile ) , with or without other lipid-lowering therapy .  Patients were r and omly assigned in a 2:1 ratio to receive alirocumab ( 150 mg ) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks . The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24 . RESULTS At week 24 , the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points ( P<0.001 ) ; the treatment effect remained consistent over a period of 78 weeks . The alirocumab group , as compared with the placebo group , had higher rates of injection-site reactions ( 5.9 % vs. 4.2 % ) , myalgia ( 5.4 % vs. 2.9 % ) , neurocognitive events ( 1.2 % vs. 0.5 % ) , and ophthalmologic events ( 2.9 % vs. 1.9 % ) . In a post hoc analysis , the rate of major adverse cardiovascular events ( death from coronary heart disease , nonfatal myocardial infa rct ion , fatal or nonfatal ischemic stroke , or unstable angina requiring hospitalization ) was lower with alirocumab than with placebo ( 1.7 % vs. 3.3 % ; hazard ratio , 0.52 ; 95 % confidence interval , 0.31 to 0.90 ; nominal P=0.02 ) . CONCLUSIONS Over a period of 78 weeks , alirocumab , when added to statin therapy at the maximum tolerated dose , significantly reduced LDL cholesterol levels . In a post hoc analysis , there was evidence of a reduction in the rate of cardiovascular events with alirocumab . ( Funded by Sanofi and Regeneron Pharmaceuticals ; ODYSSEY LONG TERM Clinical Trials.gov number , NCT01507831 . ) BACKGROUND Evolocumab , a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) , significantly reduced low-density lipoprotein ( LDL ) cholesterol levels in short-term studies . We conducted two extension studies to obtain longer-term data . METHODS In two open-label , r and omized trials , we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ( " parent trials " ) of evolocumab .  Regardless of study -group assignments in the parent trials , eligible patients were r and omly assigned in a 2:1 ratio to receive either evolocumab ( 140 mg every 2 weeks or 420 mg monthly ) plus st and ard therapy or st and ard therapy alone . Patients were followed for a median of 11.1 months with assessment of lipid levels , safety , and ( as a prespecified exploratory analysis ) adjudicated cardiovascular events including death , myocardial infa rct ion , unstable angina , coronary revascularization , stroke , transient ischemic attack , and heart failure . Data from the two trials were combined . RESULTS As compared with st and ard therapy alone , evolocumab reduced the level of LDL cholesterol by 61 % , from a median of 120 mg per deciliter to 48 mg per deciliter ( P<0.001 ) . Most adverse events occurred with similar frequency in the two groups , although neurocognitive events were reported more frequently in the evolocumab group . The risk of adverse events , including neurocognitive events , did not vary significantly according to the achieved level of LDL cholesterol . The rate of cardiovascular events at 1 year was reduced from 2.18 % in the st and ard-therapy group to 0.95 % in the evolocumab group ( hazard ratio in the evolocumab group , 0.47 ; 95 % confidence interval , 0.28 to 0.78 ; P=0.003 ) . CONCLUSIONS During approximately 1 year of therapy , the use of evolocumab plus st and ard therapy , as compared with st and ard therapy alone , significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis . ( Funded by Amgen ; OSLER-1 and OSLER-2 Clinical Trials.gov numbers , NCT01439880 and NCT01854918 . ) BACKGROUND Statin-mediated low-density lipoprotein cholesterol ( LDL-C ) lowering fails to prevent more than half of cardiovascular events in clinical trials . Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering , with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels < 70 mg/dL. Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitors permit LDL-C-lowering by a further 54 % to 75 % in statin-treated patients . The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated . AIMS To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor , evolocumab , will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy . METHODS A phase 3 , multicenter , double-blind , r and omized , placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinical ly indicated coronary angiogram with angiographic evidence of coronary atheroma , and after 78 weeks of treatment . Subjects ( n = 968 ) were r and omized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections . CONCLUSIONS The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy . GLAGOV will provide important mechanistic , safety , and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis ( 
    Output:
    
Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes .