***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 Despite maximally tolerated statin therapy , many patients with high cardiovascular risk , with or without heterozygous familial hypercholesterolemia may require additional low-density lipoprotein cholesterol ( LDL-C ) reduction . We report pooled alirocumab ( ALI ) efficacy and safety data from eight Phase 3 trials in 4629 hypercholesterolemia patients , receiving background statin therapy .  MATERIAL AND METHODS Studies were pooled by ALI dose and control : ALI 75/150 mg every 2weeks ( Q2W ; dose increased to 150 mg Q2W at Week 12 based on Week 8 LDL-C ) versus ezetimibe ( EZE ; Pool 1 ) or placebo ( PBO ; Pool 2 ) , and ALI 150 mg Q2W versus PBO ( Pool 3 ) . RESULTS Mean baseline LDL-C was 109 vs. 105mg/dL ( Pool 1 ) , 129 vs. 130mg/dL ( Pool 2 ) and 126 vs. 125mg/dL ( Pool 3 ) . ALI 75/150 mg Q2W reduced LDL-C by 48.9 % ( vs. -19.3 % EZE ) and 48.6 % ( vs. + 4.2 % PBO ) from baseline to Week 24 , and ALI 150 mg Q2W reduced LDL-C by 60.4 % ( vs. + 0.5 % PBO ; all p<0.0001 ) . LDL-C reductions were sustained to Week 104 . Risk-based LDL-C goals ( < 70mg/dL or < 100mg/dL ) were achieved by 78.0 % , 75.2 % , and 79.0 % ( Pool 1 - 3 ) of ALI-treated patients ( vs. 52.4 % , 6.4 % , and 8.4 % , respectively , for controls ) at Week 24 . Consistent reductions were observed in apolipoprotein B , non-high-density lipoprotein cholesterol , and lipoprotein ( a ) ( p<0.0001 vs. control ) . Common adverse events in ALI-treated patients were nasopharyngitis , injection-site reactions , upper respiratory tract infections , and influenza . CONCLUSIONS Alirocumab treatment significantly reduced LDL-C in high cardiovascular risk patients , enabling most to achieve risk-based LDL-C goals Proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol ( LDL-C ) by upregulating LDL receptor availability . In early 2014 , the US Food and Drug Administration ( FDA ) directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials . Available trial evidence indicates that neurocognitive adverse events may occur more commonly in individuals receiving an antibody to PCSK9 , but these events are uncommon and have not been associated with on-treatment LDL-C levels . Moreover , it is unclear to what extent closer monitoring of trial participants allocated to PCSK9 inhibitors has led to an ascertainment bias . Regardless , further trial data are needed , and long-term outcomes trials are ongoing , with at least one including a neurocognitive sub study . Considering lessons learned from the statin experience , high- quality prospect i ve cohort studies and r and omized trials may not be enough to allay concerns or settle debate since the focus of effect in these studies is the group average . Therefore , we suggest that n-of-1 trials could be considered to bring the focus to the individual while retaining the benefits of blinding and r and omization in evidence generation . Ultimately , any neurocognitive adverse effects that might exist with PCSK9 inhibition and lipid lowering must be weighed against potential benefits of therapy , including avoidance of myocardial infa rct ion and stroke , and a reduced risk of dementia due to neurovascular benefits from long-term lipid lowering BACKGROUND The ODYSSEY COMBO I study ( http:// clinical trials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia . METHODS This multicenter , phase 3 , r and omized ( 2:1 alirocumab vs placebo ) , double-blind , 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia .  Alirocumab ( 75 mg every 2 weeks [ Q2W ] ) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen . The alirocumab dose was increased to 150 mg Q2W ( also 1 mL ) at week 12 if week 8 low-density lipoprotein cholesterol ( LDL-C ) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 ( intention-to-treat analysis ) . RESULTS At week 24 , estimated mean ( 95 % CI ) changes in LDL-C from baseline were -48.2 % ( -52.0 % to -44.4 % ) and -2.3 % ( -7.6 % to 3.1 % ) for alirocumab and placebo , respectively , an estimated mean ( 95 % CI ) difference of -45.9 % ( -52.5 % to -39.3 % ) ( P < .0001 ) . Low-density lipoprotein cholesterol < 70 mg/dL was achieved by 75 % alirocumab versus 9 % placebo patients at week 24 . At week 12 , 83.2 % of evaluable alirocumab-treated patients remained on 75-mg Q2W . Treatment-emergent adverse events were comparable between groups . CONCLUSIONS Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals , versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy . The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups The Sc and inavian Simvastatin Survival Study ( 4S ) and other r and omized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary atherosclerosis compared with placebo . The effect of therapy with statins beyond the typical 5 to 6 years ' duration of the trials , in particular regarding the risk of cancer , has not been investigated . This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease ( CHD ) . We performed an observational , government registry-based study of mortality in the groups originally r and omized to simvastatin or placebo in the 4S over an additional 2-year follow-up period , so that the median total follow-up period was 7.4 years ( range 6.9 to 8.3 in surviving patients ) . R and omization took place at outpatient clinics at 94 clinical centers in Denmark , Finl and , Icel and , Norway , and Sweden from 1988 to 1989 . Of 4,444 patients with CHD , 2,223 and 2,221 were r and omized to treatment with placebo or simvastatin therapy , respectively . Patients received treatment with simvastatin , starting at 20 mg/day , with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was > 5.2 mmol/L ( 200 mg/dl ) , or placebo . After the double-blind period , most patients in both treatment groups received simvastatin as open-label prescription . Of the 1,967 patients originally treated with placebo and surviving the double-blind period , 97 ( 4.9 % ) died during the following 2 years . In the group r and omized to simvastatin the corresponding number was 74 of the 2 , 039 survivors ( 3.6 % ) . Adding these deaths to those occurring during the original trial , the total was 353 ( 15.9 % ) and 256 ( 11.5 % ) deaths in the groups originally r and omized to placebo and simvastatin , respectively . The relative risk was 0.70 ( 95 % confidence interval 0 . 60 to 0.82 , p = 0.00002 ) . The total number of cancer deaths was 68 ( 3.1 % ) in the placebo group and 52 ( 2.3 % ) in the simvastatin group ( relative risk 0.73 , 95 % confidence interval 0.51 to 0.05 , p = 0 . 087 ) , and the numbers of noncardiovascular and other deaths were similar in both groups . We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit Aims To compare the efficacy [ low-density lipoprotein cholesterol ( LDL-C ) lowering ] and safety of alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9 , compared with ezetimibe , as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia . Methods and results COMBO II is a double-blind , double-dummy , active-controlled , parallel-group , 104-week study of alirocumab vs. ezetimibe .  Patients ( n = 720 ) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled ( August 2012–May 2013 ) . This pre-specified analysis was conducted after the last patient completed 52 weeks . Patients were r and omized to subcutaneous alirocumab 75 mg every 2 weeks ( plus oral placebo ) or oral ezetimibe 10 mg daily ( plus subcutaneous placebo ) on a background of statin therapy . At Week 24 , mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4 % for alirocumab vs. 20.7 ± 1.9 % for ezetimibe ( difference 29.8 ± 2.3 % ; P < 0.0001 ) ; 77.0 % of alirocumab and 45.6 % of ezetimibe patients achieved LDL-C < 1.8 mmol/L ( P < 0.0001 ) . Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe , and were maintained to Week 52 . Alirocumab was generally well tolerated , with no evidence of an excess of treatment-emergent adverse events . Conclusion In patients at high cardiovascular risk with inadequately controlled LDL-C , alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe , with a similar safety profile . Trial registration clinical trials.gov Identifier : NCT01644188 Aim To evaluate the effect of alirocumab on frequency of st and ard apheresis treatments [ weekly or every 2 weeks ( Q2W ) ] in heterozygous familial hypercholesterolaemia ( HeFH ) . Methods and results ODYSSEY ESCAPE ( NCT02326220 ) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis .  Patients were r and omly assigned ( 2:1 , respectively ) to receive alirocumab 150 mg ( n = 41 ) or placebo ( n = 21 ) Q2W subcutaneously for 18 weeks . From day 1 to week 6 , apheresis rate was fixed according to the patient ’s established schedule ; from weeks 7 to 18 , apheresis rate was adjusted based on the patient ’s low-density lipoprotein cholesterol ( LDL-C ) response in a blinded fashion . Apheresis was not performed when the LDL-C value was ≥30 % lower than the baseline ( pre-apheresis ) value . The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks ( weeks 7–18 ) , st and ardized to number of planned treatments . In the alirocumab group the least square ( LS ) mean ± SE ( 95 % confidence interval [ CI ] ) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7 ± 2.3 ( −58.2 to − 49.2 ) compared with 1.6 ± 3.1 ( –4.7 to 7.9 ) in the placebo group . The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab ( Hodges – Lehmann median estimate of treatment difference : 0.75 ; 
    Output:
    
Conclusions Anti‐PCSK9 antibodies  effectively lower LDL‐C levels in a broad patient population .
While awaiting comprehensive data from CV outcome trials , these agents should be considered in very high risk patients , such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs , have not achieved their LDL‐C goal and require substantial reductions in