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: AIMS Elevated natriuretic peptides ( NPs ) are associated with an increased cardiovascular risk following acute coronary syndromes ( ACSs ) . However , the therapeutic implication s are still undefined . We hypothesized that early inhibition of renin-angiotensin-aldosterone system ( RAAS ) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo . METHODS AND RESULTS AVANT GARDE-TIMI 43 trial , a multinational , double-blind trial , r and omized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function < or=40 % but with an increased level of NP 3 - 10 days after admission to aliskiren , valsartan , their combination , and placebo .  The primary endpoint was the change in NT-proBNP from baseline to Week 8 . NT-proBNP declined significantly in each treatment arm , including placebo , by Week 8 , though there were no differences in the reduction between treatment strategies ( 42 % in placebo , 44 % in aliskiren , 39 % in valsartan , and 36 % in combination arm ) . Although several subgroups had higher baseline levels of NP and greater reductions over the study period , there were no differences among treatment groups in any subgroup . There were no differences in clinical outcomes but there were more adverse events , including serious events and adverse events leading to early study drug discontinuation , in patients treated with active therapy . CONCLUSION In this study of a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS , there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan , aliskiren , or their combination compared with placebo with respect to a reduction in NP over 8 weeks of therapy . Moreover , adverse events were reported more frequently in patients assigned to active therapy Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension . This study evaluated the antihypertensive efficacy , safety and tolerability of aliskiren in Japanese patients with hypertension . Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95–110 mmHg were r and omized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75 , 150 or 300 mg or placebo . Aliskiren produced significant , dose-dependent reductions in mean sitting diastolic blood pressure ( p<0.0005 vs. placebo for each dose ) and mean sitting systolic blood pressure ( p<0.001 vs. placebo for each dose ) . The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0 , 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75 , 150 and 300 mg groups , respectively . After 8 weeks ' treatment , 27.8 % , 47.8 % , 48.2 % and 63.7 % of patients in the placebo and aliskiren 75 , 150 and 300 mg groups , respectively , achieved a successful treatment response ( diastolic blood pressure < 90 mmHg and /or reduced by ≥10 mmHg from baseline ; p<0.005 vs. placebo for each dose ) . Aliskiren treatment was well tolerated , with the incidence of adverse events reported in the active treatment groups ( 53–55 % ) being similar to that in the placebo group ( 50 % ) . This study , which is the first to assess the antihypertensive efficacy and safety  of aliskiren in Japanese patients with hypertension , demonstrates that the once-daily oral renin inhibitor aliskiren provides significant , dose-dependent reductions in blood pressure with placebo-like tolerability Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension Thiazide diuretics , angiotensin-converting enzyme inhibitors , and angiotensin receptor blockers all cause reactive rises in plasma renin activity . We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering . In 3 open-label studies in which blood pressure was assessed with ambulatory measurement , aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide ( n=23 ) , ramipril  ( n=21 ) , or irbesartan  ( n=23 ) . In the diuretic combination study , the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure , compared with aliskiren monotherapy ( systolic/diastolic mean change from baseline [ SEM ] : daytime : −18.4 [2.1]/ −10.6 [ 1.7 ] versus −10.4 [1.8]/−5.8 [ 1.4 ] ; nighttime : −15.6 [2.7]/−8.1 [ 1.8 ] versus −8.8 [2.9]/−5.0 [ 2.2 ] ) . In the angiotensin-converting enzyme inhibitor combination study , the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy ( daytime : −10.5 [2.9]/−8.1 [ 2.1 ] and −14 [3.7]/−8.7 [ 2.3 ] versus −6.1 [2.4]/−5.9 [ 1.5 ] ; nighttime : −8.1 [2.6]/−5.3 [ 2.4 ] and −9.6 [3.4]/−5.3 [ 2.4 ] versus −2 [2.3]/−0.7 [ 2.2 ] ) . In the angiotensin receptor blocker combination study , the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone , for 3 weeks , result ed in significantly lower nighttime pressures compared with irbesartan monotherapy ( daytime : −14.8 [2]/−8.2 [ 1.3 ] and −13.3 [1.6]/−6.8 [ 0.9 ] versus −11.4 [1.6]/−6.5 [ 1.1 ] ; nighttime : −16.1 [2.4]/−8.6 [ 1.7 ] and −13.2 [2.7]/−7.2 [ 1.9 ] versus −9.0 [2.5]/−4.7 [ 1.9 ] ) . Aliskiren ( 150 mg ) alone significantly inhibited plasma renin activity by 65 % ( P<0.0001 ) . Ramipril and irbesartan monotherapy caused 90 % and 175 % increases in plasma renin activity , respectively . By contrast , when aliskiren was coadministered with hydrochlorothiazide , ramipril , or irbesartan  , plasma renin activity did not increase but remained similar to baseline levels or was decreased ( combination therapy versus untreated ; median [ interquartile range ] ; aliskiren and hydrochlorothiazide : 0.4 [ 0.2 to 1.1 ] versus 0.7 [ 0.5 to 1.3 ] ; ramipril and aliskiren : 0.5 [ 0.3 to 0.9 ] versus 0.6 [ 0.5 to 0.8 ] ; irbesartan and aliskiren : 0.4 [ 0.2 to 0.9 ] versus 0.6 [ 0.4 to 0.9 ] ) . These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression , improves 24-hour blood pressure control , and may ultimately provide better end-organ protection in patients with hypertension IMPORTANCE Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis . The effect of renin inhibition on coronary disease progression has not been investigated . OBJECTIVE To determine the effects of renin inhibition with aliskiren on progression of coronary 
    Output:
    
agent
There was a dose-dependent decrease in blood pressure for aliskiren 75 mg , 150 mg and 300 mg .
Aliskiren had no effect on blood pressure variability .
Due to very limited information available regarding change in heart rate and pulse pressure , it was not possible to meta-analyze these outcomes .Mortality and non-fatal serious adverse events were not increased .
AUTHORS ' CONCLUSIONS Compared to placebo , aliskiren lowered BP and this effect is dose-dependent .
This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) .
There is no difference in mortality , nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy .
***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: AIMS Elevated natriuretic peptides ( NPs ) are associated with an increased cardiovascular risk following acute coronary syndromes ( ACSs ) . However , the therapeutic implication s are still undefined . We hypothesized that early inhibition of renin-angiotensin-aldosterone system ( RAAS ) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo . METHODS AND RESULTS AVANT GARDE-TIMI 43 trial , a multinational , double-blind trial , r and omized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function < or=40 % but with an increased level of NP 3 - 10 days after admission to aliskiren , valsartan , their combination , and placebo .  The primary endpoint was the change in NT-proBNP from baseline to Week 8 . NT-proBNP declined significantly in each treatment arm , including placebo , by Week 8 , though there were no differences in the reduction between treatment strategies ( 42 % in placebo , 44 % in aliskiren , 39 % in valsartan , and 36 % in combination arm ) . Although several subgroups had higher baseline levels of NP and greater reductions over the study period , there were no differences among treatment groups in any subgroup . There were no differences in clinical outcomes but there were more adverse events , including serious events and adverse events leading to early study drug discontinuation , in patients treated with active therapy . CONCLUSION In this study of a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS , there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan , aliskiren , or their combination compared with placebo with respect to a reduction in NP over 8 weeks of therapy . Moreover , adverse events were reported more frequently in patients assigned to active therapy Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension . This study evaluated the antihypertensive efficacy , safety and tolerability of aliskiren in Japanese patients with hypertension . Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95–110 mmHg were r and omized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75 , 150 or 300 mg or placebo . Aliskiren produced significant , dose-dependent reductions in mean sitting diastolic blood pressure ( p<0.0005 vs. placebo for each dose ) and mean sitting systolic blood pressure ( p<0.001 vs. placebo for each dose ) . The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0 , 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75 , 150 and 300 mg groups , respectively . After 8 weeks ' treatment , 27.8 % , 47.8 % , 48.2 % and 63.7 % of patients in the placebo and aliskiren 75 , 150 and 300 mg groups , respectively , achieved a successful treatment response ( diastolic blood pressure < 90 mmHg and /or reduced by ≥10 mmHg from baseline ; p<0.005 vs. placebo for each dose ) . Aliskiren treatment was well tolerated , with the incidence of adverse events reported in the active treatment groups ( 53–55 % ) being similar to that in the placebo group ( 50 % ) . This study , which is the first to assess the antihypertensive efficacy and safety  of aliskiren in Japanese patients with hypertension , demonstrates that the once-daily oral renin inhibitor aliskiren provides significant , dose-dependent reductions in blood pressure with placebo-like tolerability Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension Thiazide diuretics , angiotensin-converting enzyme inhibitors , and angiotensin receptor blockers all cause reactive rises in plasma renin activity . We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering . In 3 open-label studies in which blood pressure was assessed with ambulatory measurement , aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide ( n=23 ) , ramipril  ( n=21 ) , or irbesartan  ( n=23 ) . In the diuretic combination study , the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure , compared with aliskiren monotherapy ( systolic/diastolic mean change from baseline [ SEM ] : daytime : −18.4 [2.1]/ −10.6 [ 1.7 ] versus −10.4 [1.8]/−5.8 [ 1.4 ] ; nighttime : −15.6 [2.7]/−8.1 [ 1.8 ] versus −8.8 [2.9]/−5.0 [ 2.2 ] ) . In the angiotensin-converting enzyme inhibitor combination study , the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy ( daytime : −10.5 [2.9]/−8.1 [ 2.1 ] and −14 [3.7]/−8.7 [ 2.3 ] versus −6.1 [2.4]/−5.9 [ 1.5 ] ; nighttime : −8.1 [2.6]/−5.3 [ 2.4 ] and −9.6 [3.4]/−5.3 [ 2.4 ] versus −2 [2.3]/−0.7 [ 2.2 ] ) . In the angiotensin receptor blocker combination study , the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone , for 3 weeks , result ed in significantly lower nighttime pressures compared with irbesartan monotherapy ( daytime : −14.8 [2]/−8.2 [ 1.3 ] and −13.3 [1.6]/−6.8 [ 0.9 ] versus −11.4 [1.6]/−6.5 [ 1.1 ] ; nighttime : −16.1 [2.4]/−8.6 [ 1.7 ] and −13.2 [2.7]/−7.2 [ 1.9 ] versus −9.0 [2.5]/−4.7 [ 1.9 ] ) . Aliskiren ( 150 mg ) alone significantly inhibited plasma renin activity by 65 % ( P<0.0001 ) . Ramipril and irbesartan monotherapy caused 90 % and 175 % increases in plasma renin activity , respectively . By contrast , when aliskiren was coadministered with hydrochlorothiazide , ramipril , or irbesartan  , plasma renin activity did not increase but remained similar to baseline levels or was decreased ( combination therapy versus untreated ; median [ interquartile range ] ; aliskiren and hydrochlorothiazide : 0.4 [ 0.2 to 1.1 ] versus 0.7 [ 0.5 to 1.3 ] ; ramipril and aliskiren : 0.5 [ 0.3 to 0.9 ] versus 0.6 [ 0.5 to 0.8 ] ; irbesartan and aliskiren : 0.4 [ 0.2 to 0.9 ] versus 0.6 [ 0.4 to 0.9 ] ) . These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression , improves 24-hour blood pressure control , and may ultimately provide better end-organ protection in patients with hypertension IMPORTANCE Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis . The effect of renin inhibition on coronary disease progression has not been investigated . OBJECTIVE To determine the effects of renin inhibition with aliskiren on progression of coronary 
    Output:
    