human
***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 Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin‐based treatment of low‐density lipoprotein ( LDL ) cholesterol levels . The inhibition of cholesteryl ester transfer protein ( CETP ) by anacetrapib reduces LDL cholesterol levels and increases high‐density lipoprotein ( HDL ) cholesterol levels . However , trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes . METHODS We conducted a r and omized , double‐blind , placebo‐controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter ( 1.58 mmol per liter ) , a mean non‐HDL cholesterol level of 92 mg per deciliter ( 2.38 mmol per liter ) , and a mean HDL cholesterol level of 40 mg per deciliter ( 1.03 mmol per liter ) . The patients were assigned to receive either 100 mg of anacetrapib once daily ( 15,225 patients ) or matching placebo ( 15,224 patients ) . The primary outcome was the first major coronary event , a composite of coronary death , myocardial infa rct ion , or coronary revascularization . RESULTS During the median follow‐up period of 4.1 years , the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group ( 1640 of 15,225 patients [ 10.8 % ] vs. 1803 of 15,224 patients [ 11.8 % ] ; rate ratio , 0.91 ; 95 % confidence interval , 0.85 to 0.97 ; P=0.004 ) . The relative difference in risk was similar across multiple prespecified subgroups . At the trial midpoint , the mean level of HDL cholesterol was higher by 43 mg per deciliter ( 1.12 mmol per liter ) in the anacetrapib group than in the placebo group ( a relative difference of 104 % ) , and the mean level of non‐HDL cholesterol was lower by 17 mg per deciliter ( 0.44 mmol per liter ) , a relative difference of ‐18 % . There were no significant between‐group differences in the risk of death , cancer , or other serious adverse events . CONCLUSIONS Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy , the use of anacetrapib result ed in a lower incidence of major coronary events than the use of placebo . ( Funded by Merck and others ; Current Controlled Trials number , IS RCT N48678192 ; Clinical Trials.gov number , NCT01252953 ; and EudraCT number , 2010‐023467‐18 . 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 patients who had previously suffered from angina rather than infa rct ion . The cholesterol- and triglyceride-reducing properties of clofibrate were maintained throughout the period of the trial and side effects were very few . But the protective action of the drug against new infa rcts and death bore no apparent relation to these properties Objective : To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease . Design : Double blind placebo controlled r and omised trial . Setting : 85 general practice s and nine hospital vascular clinics . Participants : 1568 men , mean age 68.2 years ( range 35 to 92 ) at recruitment . Interventions : Bezafibrate 400 mg daily ( 783 men ) or placebo ( 785 men ) . Main outcome measures : Combination of coronary heart disease and of stroke . All coronary events , fatal and non-fatal coronary events separately , and strokes alone ( secondary end points ) . Results : Bezafibrate did not reduce the incidence of coronary heart disease and stroke . There were 150 and 160 events in the active and placebo groups respectively ( relative risk 0.96 , 95 % confidence interval 0.76 to 1.21 ) . There were 90 and 111 major coronary events in the active and placebo groups respectively ( 0.81 , 0.60 to 1.08 ) , of which 64 and 65 were fatal ( 0.95 , 0.66 to 1.37 ) and 26 and 46 non-fatal ( 0.60 , 0.36 to 0.99 ) . Beneficial effects on non-fatal events were greatest in men aged < 65 years at entry , in whom benefit was also seen for all coronary events ( 0.38 , 0.20 to 0.72 ) . There were no significant effects in older men . There were 60 strokes in those on active treatment and 49 in those on placebo ( 1.34 , 0.80 to 2.01 ) . There were 204 and 195 deaths from all causes in the two groups respectively ( 1.03 , 0.83 to 1.26 ) . Bezafibrate reduced the severity of intermittent claudication for up to three years . Conclusions : Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events , particularly in those aged < 65 years at entry , in whom all coronary events may also be reduced AIMS High-density lipoprotein cholesterol ( HDL-C ) is inversely associated with cardiovascular ( CV ) events and thus an attractive therapeutic target . However , in spite of marked elevations in HDL-C , the first cholesterol transport protein ( CETP ) inhibitor torcetrapib raised blood pressure ( BP ) , impaired endothelial function , and increased CV mortality and morbidity . Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib . As HDL stimulates nitric oxide ( NO ) , suppresses inflammation , and exerts protective CV effects , we investigated the effects of dalcetrapib on endothelial function , blood pressure , inflammatory markers , and lipids in patients with , or at risk of , coronary heart disease ( CHD ) in a double-blind r and omized placebo-controlled trial ( clinical trials.gov number NCT00655538 ) . METHODS AND RESULTS Patients with target low-density lipoprotein cholesterol ( LDL-C ) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of st and ard therapy ( including statins ) . The primary outcome measures were the change from baseline of flow-mediated dilatation ( % FMD ) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring ( ABPM ) at week 4 . Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks , changes in HDL-C , LDL-C , triglycerides , CETP activity , as well as st and ard safety parameters . Four hundred seventy-six patients were r and omized . Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4 % with placebo or dalcetrapib , respectively and did not change significantly from placebo after 12 and 36 weeks ( P = 0.1764 and 0.9515 , respectively ) . After 4 , 24 , and 36 weeks of treatment with dalcetrapib , CETP activity decreased by 51 , 53 , and 56 % ( placebo corrected , all P < 0.0001 ) , while at weeks 4 , 12 , and 36 HDL-C increased by 25 , 27 , and 31 % ( placebo corrected , all P < 0.0001 ) . Low-density lipoprotein cholesterol levels did not change . At baseline , ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group ( P = 0.3372 and 0.1248 , respectively , placebo-corrected change from baseline ) and did not change for up to 36 weeks . Biomarkers of inflammation , oxidative stress , and coagulation did not change during follow-up except for Lp-PLA(2 ) mass levels which increased by 17 % ( placebo corrected ) . Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event ( 11 events with dalcetrapib and 12 events with placebo ) . CONCL 
    Output:
    
agent
This significant effect was derived by the use of fibrates ( RR 0.80 , 95 % CI 0.73–0.87 , P < 0.001 , I2 = 22 % ) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol .
Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints .
Conclusion The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality , stroke or all-cause mortality .
The beneficial effect on myocardial infa rct ion was lost when drugs were used with statin therapy
***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 Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin‐based treatment of low‐density lipoprotein ( LDL ) cholesterol levels . The inhibition of cholesteryl ester transfer protein ( CETP ) by anacetrapib reduces LDL cholesterol levels and increases high‐density lipoprotein ( HDL ) cholesterol levels . However , trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes . METHODS We conducted a r and omized , double‐blind , placebo‐controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter ( 1.58 mmol per liter ) , a mean non‐HDL cholesterol level of 92 mg per deciliter ( 2.38 mmol per liter ) , and a mean HDL cholesterol level of 40 mg per deciliter ( 1.03 mmol per liter ) . The patients were assigned to receive either 100 mg of anacetrapib once daily ( 15,225 patients ) or matching placebo ( 15,224 patients ) . The primary outcome was the first major coronary event , a composite of coronary death , myocardial infa rct ion , or coronary revascularization . RESULTS During the median follow‐up period of 4.1 years , the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group ( 1640 of 15,225 patients [ 10.8 % ] vs. 1803 of 15,224 patients [ 11.8 % ] ; rate ratio , 0.91 ; 95 % confidence interval , 0.85 to 0.97 ; P=0.004 ) . The relative difference in risk was similar across multiple prespecified subgroups . At the trial midpoint , the mean level of HDL cholesterol was higher by 43 mg per deciliter ( 1.12 mmol per liter ) in the anacetrapib group than in the placebo group ( a relative difference of 104 % ) , and the mean level of non‐HDL cholesterol was lower by 17 mg per deciliter ( 0.44 mmol per liter ) , a relative difference of ‐18 % . There were no significant between‐group differences in the risk of death , cancer , or other serious adverse events . CONCLUSIONS Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy , the use of anacetrapib result ed in a lower incidence of major coronary events than the use of placebo . ( Funded by Merck and others ; Current Controlled Trials number , IS RCT N48678192 ; Clinical Trials.gov number , NCT01252953 ; and EudraCT number , 2010‐023467‐18 . 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 patients who had previously suffered from angina rather than infa rct ion . The cholesterol- and triglyceride-reducing properties of clofibrate were maintained throughout the period of the trial and side effects were very few . But the protective action of the drug against new infa rcts and death bore no apparent relation to these properties Objective : To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease . Design : Double blind placebo controlled r and omised trial . Setting : 85 general practice s and nine hospital vascular clinics . Participants : 1568 men , mean age 68.2 years ( range 35 to 92 ) at recruitment . Interventions : Bezafibrate 400 mg daily ( 783 men ) or placebo ( 785 men ) . Main outcome measures : Combination of coronary heart disease and of stroke . All coronary events , fatal and non-fatal coronary events separately , and strokes alone ( secondary end points ) . Results : Bezafibrate did not reduce the incidence of coronary heart disease and stroke . There were 150 and 160 events in the active and placebo groups respectively ( relative risk 0.96 , 95 % confidence interval 0.76 to 1.21 ) . There were 90 and 111 major coronary events in the active and placebo groups respectively ( 0.81 , 0.60 to 1.08 ) , of which 64 and 65 were fatal ( 0.95 , 0.66 to 1.37 ) and 26 and 46 non-fatal ( 0.60 , 0.36 to 0.99 ) . Beneficial effects on non-fatal events were greatest in men aged < 65 years at entry , in whom benefit was also seen for all coronary events ( 0.38 , 0.20 to 0.72 ) . There were no significant effects in older men . There were 60 strokes in those on active treatment and 49 in those on placebo ( 1.34 , 0.80 to 2.01 ) . There were 204 and 195 deaths from all causes in the two groups respectively ( 1.03 , 0.83 to 1.26 ) . Bezafibrate reduced the severity of intermittent claudication for up to three years . Conclusions : Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events , particularly in those aged < 65 years at entry , in whom all coronary events may also be reduced AIMS High-density lipoprotein cholesterol ( HDL-C ) is inversely associated with cardiovascular ( CV ) events and thus an attractive therapeutic target . However , in spite of marked elevations in HDL-C , the first cholesterol transport protein ( CETP ) inhibitor torcetrapib raised blood pressure ( BP ) , impaired endothelial function , and increased CV mortality and morbidity . Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib . As HDL stimulates nitric oxide ( NO ) , suppresses inflammation , and exerts protective CV effects , we investigated the effects of dalcetrapib on endothelial function , blood pressure , inflammatory markers , and lipids in patients with , or at risk of , coronary heart disease ( CHD ) in a double-blind r and omized placebo-controlled trial ( clinical trials.gov number NCT00655538 ) . METHODS AND RESULTS Patients with target low-density lipoprotein cholesterol ( LDL-C ) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of st and ard therapy ( including statins ) . The primary outcome measures were the change from baseline of flow-mediated dilatation ( % FMD ) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring ( ABPM ) at week 4 . Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks , changes in HDL-C , LDL-C , triglycerides , CETP activity , as well as st and ard safety parameters . Four hundred seventy-six patients were r and omized . Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4 % with placebo or dalcetrapib , respectively and did not change significantly from placebo after 12 and 36 weeks ( P = 0.1764 and 0.9515 , respectively ) . After 4 , 24 , and 36 weeks of treatment with dalcetrapib , CETP activity decreased by 51 , 53 , and 56 % ( placebo corrected , all P < 0.0001 ) , while at weeks 4 , 12 , and 36 HDL-C increased by 25 , 27 , and 31 % ( placebo corrected , all P < 0.0001 ) . Low-density lipoprotein cholesterol levels did not change . At baseline , ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group ( P = 0.3372 and 0.1248 , respectively , placebo-corrected change from baseline ) and did not change for up to 36 weeks . Biomarkers of inflammation , oxidative stress , and coagulation did not change during follow-up except for Lp-PLA(2 ) mass levels which increased by 17 % ( placebo corrected ) . Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event ( 11 events with dalcetrapib and 12 events with placebo ) . CONCL 
    Output:
    