title: Patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial. Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients with Hypertension The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren: A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. Direct Renin Inhibition With Aliskiren in Obese Patients With Arterial Hypertension Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients Reporting of harms data in RCTs: a systematic review of empirical assessments against the CONSORT harms extension Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Effectiveness of a diabetes education and self management programme (DESMOND) for people with newly diagnosed type 2 diabetes mellitus: three year follow-up of a cluster randomised controlled trial in primary care A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren Proceedings of the First International Conference on Stepped Wedge Trial Design Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria Aliskiren Effect on Plaque Progression in Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double-Blind Placebo-Controlled Trial Cardiorenal end points in a trial of aliskiren for type 2 diabetes. Evaluation of the dose--response relationship of aliskiren, a direct renin inhibitor, in an 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in adult patients with stage 1 or 2 essential hypertension. Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Left ventricular systolic and diastolic function, remodelling, and clinical outcomes among patients with diabetes following myocardial infarction and the influence of direct renin inhibition with aliskiren. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial. Efficacy and safety of aliskiren and amlodipine combination therapy in patients with hypertension: a randomized, double-blind, multifactorial study Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension Efficacy, safety, and tolerability of aliskiren monotherapy administered with a light meal in elderly hypertensive patients: a randomized, double-blind, placebo-controlled, dose-response evaluation study. Underreporting research is scientific misconduct. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial Effect of aliskiren on vascular remodelling in small retinal circulation [Facing the unreliability of clinical trials literature]. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial Differential effects of renin–angiotensin–aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension.
abstract: 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 atherosclerosis . DESIGN , SETTING , AND PARTICIPANTS A double-blind , r and omized , multicenter trial ( Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study ) comparing aliskiren with placebo in 613 participants with coronary artery disease , systolic blood pressure between 125 and 139 mm Hg ( prehypertension range ) , and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe , Australia , and North and South America ( enrollment from March 2009 to February 2011 ; end of follow-up : January 31 , 2013 ) . INTERVENTIONS Participants underwent coronary intravascular ultrasound ( IVUS ) imaging and were r and omized to receive 300 mg of aliskiren ( n = 305 ) or placebo ( n = 308 ) taken orally daily for 104 weeks . Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment . MAIN OUTCOMES AND MEASURES The primary efficacy parameter was the change in percent atheroma volume ( PAV ) from baseline to study completion . Secondary efficacy parameters included the change in normalized total atheroma volume ( TAV ) and the percentage of participants with atheroma regression . Safety and tolerability were also assessed . RESULTS Evaluable imaging data were available at baseline and follow-up for 458 participants ( 74.7 % ) . The primary IVUS efficacy parameter , PAV , did not differ between participants treated with aliskiren ( -0.33 % ; 95 % CI , -0.68 % to 0.02 % ) and placebo ( 0.11 % ; 95 % CI , -0.24 % to 0.45 % ) ( between-group difference , -0.43 % [ 95 % CI , -0.92 % to 0.05 % ] ; P = .08 ) . The secondary IVUS efficacy parameter , TAV , did not differ between participants treated with aliskiren ( -4.1 mm3 ; 95 % CI , -6.27 to -1.94 mm3 ) and placebo ( -2.1 mm3 ; 95 % CI , -4.21 to 0.07 mm3 ) ( between-group difference , -2.04 mm3 [ 95 % CI , -5.03 to 0.95 mm3 ] ; P = .18 ) . There were no significant differences in the proportion of participants who demonstrated regression of PAV ( 56.9 % vs 48.9 % ; P = .08 ) and TAV ( 64.4 % vs 57.5 % ; P = .13 ) in the aliskiren and placebo groups , respectively . CONCLUSIONS AND RELEVANCE Among participants with prehypertension and coronary artery disease , the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis . These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00853827 Current guidelines from the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients . The renin system is activated in obesity-associated arterial hypertension . Therefore , we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension ( body mass index ≥30 kg/m2 ; mean sitting diastolic blood pressure : 95 to 109 mm Hg ) who had not responded to 4 weeks of treatment with hydrochlorothiazide ( HCTZ ) 25 mg . After a 2- to 4-week washout , 560 patients received single-blind HCTZ ( 25 mg ) for 4 weeks ; 489 nonresponders were r and omly assigned to double-blind aliskiren ( 150 mg ) , irbesartan ( 150 mg ) , amlodipine ( 5 mg ) , or placebo for 4 weeks added to HCTZ ( 25 mg ) , followed by 8 weeks on double the initial doses of aliskiren , irbesartan , or amlodipine . After 8 weeks of double-blind treatment ( 4 weeks on the higher dose ) , aliskiren/HCTZ  lowered blood pressure by 15.8/11.9 mm Hg , significantly more ( P<0.0001 ) than placebo/HCTZ ( 8.6/7.9 mm Hg ) . Aliskiren/HCTZ  provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ ( 15.4/11.3 and 13.6/10.3 mm Hg , respectively ) , with similar tolerability to placebo/HCTZ . Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema ( 11.1 % versus 0.8 % to 1.6 % in other groups ) . In conclusion , combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment Background —Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection . This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator . Methods and Results —The study was a r and omized , multicenter , double-blind , placebo-controlled , active-comparator 8-week trial in patients with mild-to-moderate hypertension ( mean sitting diastolic blood pressure [ DBP ] ≥95 and < 110 mm Hg ) . After a 2-week , single-blind placebo run-in , 652 patients were r and omized to receive double-blind treatment with once-daily oral doses of aliskiren ( 150 , 300 , or 600 mg ) , irbesartan 150 mg , or placebo . Aliskiren 150 , 300 , and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure ( SBP ) ( P<0.001 versus placebo for both variables ) . The least-squares mean reductions in trough DBP were 9.3±0.8 , 11.8±0.8 , and 11.5±0.8 mm Hg , respectively , versus 6.3±0.8 mm Hg for placebo , and the least-squares mean reductions in trough SBP were 11.4±1.3 , 15.8±1.2 , and 15.7±1.2 mm Hg , respectively , versus 5.3±1.2 mm Hg for placebo . The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg ( 8.9±0.7 and 12.5±1.2 mm Hg , least-squares reduction in mean sitting DBP and SBP , respectively , for irbesartan ) . Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg ( P<0.05 ) . Aliskiren  showed safety and tolerability comparable to those of placebo and irbesartan ; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups . Conclusions —Once-daily oral treatment with aliskiren  lowers blood pressure effectively , with a safety and tolerability profile comparable to that of irbesartan and placebo , in patients with mild-to-moderate hypertension . Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure Objective To determine the st and ard of reporting of harms-related data , in r and omised controlled trials ( RCTs ) according to the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement extension for harms . Design Systematic review . Data sources The Cochrane library , Ovid MEDLINE , Scopus and ISI Web of Knowledge were search ed for relevant literature . Eligibility criteria for selecting studies We included publications of studies that used the CONSORT harms extension to assess the reporting of harms in RCTs . Results We identified 7 studies which included between 10 and 205 RCTs . The clinical areas of the 7 studies were : hypertension ( 1 ) , urology ( 1 ) , epilepsy ( 1 ) , complimentary medicine ( 2 ) and two not restricted to a clinical topic . Quality of the 7 studies was assessed by a risk of bias tool and was found to be variable . Adherence to the CONSORT harms criteria reported in the 7 studies was inadequate and variable across the items in the checklist . Adverse events are poorly defined , with 6 studies failing to exceed 50 % adherence to the items in the checklist . Conclusions Readers of RCT publications need to be able to balance the trade-offs between benefits and harms of interventions . This systematic review suggests that this is compromised due to poor reporting of harms which is evident across a range of clinical areas . Improvements in quality could be achieved by wider adoption of the CONSORT harms criteria by journals reporting RCTs AIMS Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system ( RAAS ) at the most proximal , specific , and rate-limiting step . We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following acute myocardial infa rct ion receiving stable , individually optimized therapy , including another inhibitor of the RAAS . METHODS AND RESULTS We r and omly assigned 820 patients between ∼2 and 8 weeks following acute myocardial infa rct ion , with the left ventricular ejection fraction ( LVEF ) ≤45 % , and regional wall motion abnormalities ( ≥20 % akinetic area ) , to  receive aliskiren ( n = 423 ) , titrated to 300 mg , or matched placebo ( n = 397 ) , added to the st and ard therapy . All patients were required to be on a stable dose of an ACE-inhibitor or ARB , and beta-blocker unless contraindicated or not tolerated . Echocardiograms were obtained at baseline , and following 26 - 36 weeks of treatment . The primary endpoint was change in left ventricular end-systolic volume from baseline to 36 weeks , and was evaluable in 329 patients in the placebo group and 343 patients in the aliskiren group . We observed no difference in the primary endpoint of end-systolic volume change between patients r and omized to aliskiren ( -4.4 ± 16.8 mL ) or placebo ( -3.5 ± 16.3 mL ) , or in secondary measures of end-diastolic volume , or LVEF . We also observed no differences in a composite endpoint of cardiovascular death , hospitalization for heart failure , or reduction in LVEF > 6 points . There were more investigator reported adverse events in the aliskiren group , including hypotension , increases in creatinine and hyperkalaemia . CONCLUSION Adding the direct renin inhibitor aliskiren to the st and ard therapy , including an inhibitor of the RAAS , in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling , and was associated with more adverse effects . These findings do not suggest that dual RAAS blockade with aliskiren would provide additional benefit in these high-risk post-MI patients Objective To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years . Design Three year follow-up of a multicentre cluster r and omised controlled trial in primary care , with r and omisation at practice level . Setting 207 general practice s in 13 primary care sites in the United Kingdom . Participants 731 of the 824 participants included in the original trial were eligible for follow-up . Biomedical data were collected on 604 ( 82.6 % ) and question naire data on 513 ( 70.1 % ) participants . Intervention A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care . Main outcome measures The primary outcome was glycated haemoglobin ( HbA1c ) levels . The secondary outcomes were blood pressure , weight , blood lipid levels , smoking status , physical activity , quality of life , beliefs about illness , depression , emotional impact of diabetes , and drug use at three years . Results HbA1c levels at three years had decreased in both groups . After adjusting for baseline and cluster the difference was not significant ( difference −0.02 , 95 % confidence interval −0.22 to 0.17 ) . The groups did not differ for the other biomedical and lifestyle outcomes and drug use . The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years ( P<0.01 ) . Depression scores and quality of life did not differ at three years . Conclusion A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs . Trial registration Current Controlled Trials IS RCT N17844016 Background Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents . TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel , thinner-strut , platinum-enriched metal alloy platform . The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents . The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials . Methods / Design The PERSEUS trials include two parallel studies of the TAXUS Element stent in single , de novo coronary atherosclerotic lesions . The PERSEUS Workhorse study is a prospect i ve , r and omized ( 3:1 ) , single-blind , non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express2 paclitaxel-eluting stent system . The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent . PERSEUS Small Vessel is a prospect i ve , single-arm , superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to < 2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control . Discussion The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent . PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010 . PERSEUS Workhorse and Small Vessel are registered at http://www . clinical trials.gov , identification numbers NCT00484315 and NCT00489541 Abstract —Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal . Aliskiren , the first known representative of a new class of completely nonpeptide , orally active , renin inhibitors , has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure ( BP ) in sodium-depleted marmosets . The aim of this r and omized , double-blind , active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren .  Two hundred twenty-six patients , 21 to 70 years of age , with mild to moderate hypertension , were r and omly assigned to receive 37.5 mg , 75 mg , 150 mg , or 300 mg aliskiren or 100 mg losartan daily for 4 weeks . Dose-dependent reductions in daytime ambulatory systolic pressure ( mean change , mm Hg [ SD of change ] ; −0.4 [ 11.7 ] , −5.3 [ 11.3 ] , −8.0 [ 11.0 ] , and −11.0 [ 11.0 ] , P = 0.0002 ) and in plasma renin activity ( median change % [ interquartile range ] ; −55 [ −64 , −11 ] , −60 [ −82 , −46 ] , −77 [ −86 , −72 ] , and −83 [ −92 , −71 ] , P = 0.0008 ) were observed with 37.5 , 75 , 150 , and 300 mg aliskiren . The change in daytime systolic pressure with 100 mg losartan ( −10.9 [ 13.8 ] ) was not significantly different from the changes seen with 75 , 150 , and 300 mg aliskiren . Aliskiren was well tolerated at all doses studied . This study demonstrates that aliskiren , through inhibition of renin , is an effective and safe orally active BP-lowering agent . Whether renin inhibition results in protection from heart attack , stroke , and nephropathy , similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade , needs to be research ed Table of contentsI1 Introduction Mona Kanaan , Noreen Dadirai Mdege , Ada KedingO1 The HiSTORIC trial : a hybrid before- and -after and stepped wedge design RA Parker , N Mills , A Shah , F Strachan , C Keerie , CJ WeirO2 Stepped wedge trials with non-uniform correlation structure And rew Forbes , Karla HemmingO3 Challenges and solutions for the operationalisation of the ENHANCE study : a pilot stepped wedge trial within a general practice setting Sarah A Lawton , Emma Healey , Martyn Lewis , Elaine Nicholls , Clare Jinks , Valerie Tan , And rew Finney , Christian D Mallen , on behalf of the ENHANCE Study TeamO4 Early lessons from the implementation of a stepped wedge trial design investigating the effectiveness of a training intervention in busy health care setting s : the Thistle study Erik Lenguerr and , Graeme MacLennan , John Norrie , Siladitya Bhattacharya , Tim Draycott , on behalf of the Thistle groupO5 Sample size calculation for longitudinal cluster r and omised trials : a unified framework for closed cohort and repeated cross-section design sRichard Hooper , Steven Teerenstra , Esther de Hoop , S and ra EldridgeO6 Restricted r and omisation schemes for stepped-wedge studies with a cluster-level covariateAlan Girling , Monica TaljaardO7 A flexible modelling of the time trend for the analysis of stepped wedge trials : results of a simulation study Gian Luca Di Tanna , Antonio GasparriniP1 Tackling acute kidney injury – a UK stepped wedge clinical trial of hospital-level quality improvement interventions Anna Casula , Fergus Caskey , Erik Lenguerr and , Shona Methven , Stephanie MacNeill , Margaret May , Nicholas SelbyP2 Sample size considerations for quantifying secondary bacterial transmission in a stepped wedge trial of influenza vaccineLeon Danon , Hannah Christensen , Adam Finn , Margaret MayP3 Sample size calculation for time-to-event data in stepped wedge cluster r and omised trialsFumihito Takanashi , Ada Keding , Simon Crouch , Mona KanaanP4 Sample size calculations for stepped-wedge cluster r and omised trials with unequal cluster sizesCaroline A. Kristunas , Karen L. Smith , Laura J. GrayP5 The design of stepped wedge trials with unequal cluster sizesJohn N.S. MatthewsP6 Promoting Recruitment using Information Management Efficiently ( PRIME ) : a stepped wedge SWAT ( study -within-a-trial)R Al-Shahi Salman , RA Parker , A Maxwell , M Dennis , A Rudd , CJ WeirP7 Implication s of misspecified mixed effect models in stepped wedge trial analysis : how wrong can it be?Jennifer A Thompson , Katherine L Fielding , Calum Davey , Alex and er M Aiken , James R Hargreaves , Richard J HayesS1 Stepped Wedge Design s with Multiple Interventions Vivian H Lyons , Lingyu Li , James Hughes , Ali Rowhani-RahbarS2 Analysis of the cross-sectional stepped wedge cluster r and omised trialKarla Hemming , Monica Taljaard , And rew OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination . RESEARCH DESIGN AND METHODS This was a double-blind , r and omized , crossover trial . After a 1-month washout period , 26 patients with type 2 diabetes , hypertension , and albuminuria ( > 100 mg/day ) were r and omly assigned to four 2-month treatment periods in r and om order with placebo , 300 mg aliskiren once daily , 300 mg irbesartan once daily , or the combination using identical doses . Patients received furosemide in a stable dose throughout the study . The primary end point was a change in albuminuria . Secondary measures included change in 24-h blood pressure and glomerular filtration rate ( GFR ) . RESULTS Placebo geometric mean albuminuria was 258 mg/day ( range 84–2,361 ) , mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg , and GFR was 89 ± 27 ml/min per 1.73 m2 . Aliskiren treatment reduced albuminuria by 48 % ( 95 % CI 27–62 ) compared with placebo ( P < 0.001 ) , not significantly different from the 58 % ( 42–79 ) reduction with irbesartan treatment ( P < 0.001 vs. placebo ) . Combination treatment reduced albuminuria by 71 % ( 59–79 ) , more than either monotherapy ( P < 0.001 and P = 0.028 ) . Fractional clearances of albumin were significantly reduced ( 46 , 56 , and 67 % reduction vs. placebo ) . Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren ( NS/P = 0.009 ) , 12/5 mmHg by irbesartan ( P < 0.001/P = 0.002 ) , and 10/6 mmHg by the combination ( P = 0.001/P < 0.001 ) . GFR was significantly reduced 4.6 ( 95 % CI 0.3–8.8 ) ml/min per 1.73 m2 by aliskiren , 8.0 ( 3.6–12.3 ) ml/min per 1.73 m2 by irbesartan , and 11.7 ( 7.4–15.9 ) ml/min per 1.73 m2 by the combination . CONCLUSIONS The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy Background The renin – angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis . The benefits of renin inhibition in atherosclerosis , especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers ( ACEIs/ARBs ) are currently not known . We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging ( MRI ) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease . Methods and Results This was a single-center , r and omized , double-blind , placebo-controlled trial in patients with established cardiovascular disease . After a 2-week single-blind placebo phase , patients were r and omized to receive either placebo ( n=37 , mean±SD age 64.5±8.9 years , 3 women )  or 150 mg of aliskiren ( n=34 , mean±SD age 63.9±11.5 years , 9 women ) . Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study . Patients underwent dark-blood , 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination ( up to 36 weeks of drug or matching placebo ) . Aliskiren use result ed in significant progression of aortic wall volume ( normalized total wall volume 5.31±6.57 vs 0.15±4.39 mm3 , P=0.03 , and percentage wall volume 3.37±2.96 % vs 0.97±2.02 % , P=0.04 ) compared with placebo . In a subgroup analysis of subjects receiving ACEI/ARB therapy , atherosclerosis progression was observed only in the aliskiren group , not in the placebo group . Conclusions MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease result ed in an unexpected increase in aortic atherosclerosis compared with placebo . Although preliminary , these results may have implication s for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease , especially in those receiving ACEI/ARB therapy . Clinical Trial Registration URL : http:// Clinical Trials.gov Unique identifier : NCT01417104 BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease , cardiovascular disease , or both . METHODS In a double-blind fashion , we r and omly assigned 8561 patients to aliskiren ( 300 mg daily ) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker . The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; nonfatal stroke ; unplanned hospitalization for heart failure ; end-stage renal disease , death attributable to kidney failure , or the need for renal-replacement therapy with no dialysis  or transplantation available or initiated ; or doubling of the baseline serum creatinine level . RESULTS The trial was stopped prematurely after the second interim efficacy analysis . After a median follow-up of 32.9 months , the primary end point had occurred in 783 patients ( 18.3 % ) assigned to aliskiren as compared with 732 ( 17.1 % ) assigned to placebo ( hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.98 to 1.20 ; P=0.12 ) . Effects on secondary renal end points were similar . Systolic and diastolic blood pressures were lower with aliskiren ( between-group differences , 1.3 and 0.6 mm Hg , respectively ) and the mean reduction in the urinary albumin-to-creatinine ratio was greater ( between-group difference , 14 percentage points ; 95 % CI , 11 to 17 ) . The proportion of patients with hyperkalemia ( serum potassium level , ≥6 mmol per liter ) was significantly higher in the aliskiren group than in the placebo group ( 11.2 % vs. 7.2 % ) , as was the proportion with reported hypotension ( 12.1 % vs. 8.3 % ) ( P<0.001 for both comparisons ) . CONCLUSIONS The addition of aliskiren to st and ard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful . ( Funded by Novartis ; ALTITUDE Clinical Trials.gov number , NCT00549757 . ) BACKGROUND Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission . It is generally well tolerated and provides 24-hour , dose-dependent blood pressure ( BP ) reduction ; however , the effect of the 75-mg dose has been inconsistent in previous trials . OBJECTIVES This study was design ed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren ( 75 , 150 , and 300 mg ) . METHODS In this 8-week , multicenter , r and omized , double-blind , parallel-group , placebo-controlled study , patients aged > or = 18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week , single-blind , placebo run-in period . Eligible patients were r and omized ( 1:1:1:1 ) to receive oral , once-daily doses of aliskiren 75 , 150 , or 300 mg or placebo . The primary efficacy variable was the change from baseline in mean sitting diastolic BP ( msDBP ) at the week-8 end point . Tolerability was assessed by monitoring and recording all adverse events ( AEs ) . RESULTS A total of 642 patients ( mean [ SD ] age , 52.0 [ 10.73 ] years ; 60.0 % male ; 80.8 % white ; mean body weight , 89.2 [ 18.4 ] kg [ range , 50 - 160 kg ] ) were included in the study . Overall , 576 patients ( 89.7 % ) completed the double-blind treatment period . The most frequent reasons for discontinuation were unsatisfactory therapeutic effect ( 27/642 r and omized patients [ 4.2 % ] ) and AEs ( 17/642 [ 2.6 % ] ) . At end point , aliskiren 150 and 300 mg significantly reduced msDBP ( both , P < 0.001 ) and mean sitting systolic CONCLUSIONS This study found a positive linear dose-response relationship in BP reduction with aliskiren 75 , 150 , and 300 mg dosed once daily , but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo . All 3 doses of aliskiren were generally well tolerated The antihypertensive efficacy and safety of the direct renin inhibitor aliskiren were assessed in a pooled analysis of data from seven r and omized , multicenter studies . Data were available for 7,045 patients ( mean age 52.5 to 59.8 years , 50.2 to 72.5 % men ) with mild-to-moderate hypertension ( mean sitting diastolic blood pressure [ msDBP ] 95 to 109 mm Hg ) over treatment duration s of 6 to 8 weeks . In placebo-controlled trials , aliskiren reduced mean sitting systolic blood pressure/msDBP from baseline by 8.6 to 12.1/7.2 to 10.3 mm Hg ( 75 mg ) , 8.7 to 13.0/7.8 to 10.3 mm Hg ( 150 mg ) , 14.1 to 15.8/10.3 to 12.3 mm Hg ( 300 mg ) , and 15.7 to 15.8/11.5 to 12.5 mm Hg ( 600 mg ) , compared with 2.9 to 10.0/3.3 to 8.6 mm Hg for placebo . Aliskiren demonstrated comparable efficacy in men and women , in patients aged < 65 years or > /=65 years , and lowered blood pressure ( BP ) effectively in all racial subgroups . Combination of aliskiren 150 mg or 300 mg with ramipril , amlodipine , or hydrochlorothiazide  provided significant additional BP reductions compared with the respective monotherapies . The overall incidence of adverse events with aliskiren monotherapy was similar to placebo ( 39.8 % vs. 40.2 % , respectively ) . The incidence of diarrhea with aliskiren was higher than placebo due to a significantly higher rate with aliskiren 600 mg ( P < .0001 vs. placebo ) . In conclusion , aliskiren 150 mg or 300 mg provides highly effective and consistent BP lowering with placebo-like tolerability in patients with mild-to-moderate hypertension AIMS We assessed the relationship between diabetes and cardiac structure and function following myocardial infa rct ion ( MI ) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular ( LV ) size . METHODS AND RESULTS The ASPIRE trial enrolled 820 patients 2 - 8 weeks after MI with ejection fraction ≤ 45 % and r and omized them to the direct renin inhibitor aliskiren ( n= 423 )  or placebo ( n = 397 ) added to st and ard medical therapy . Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies . Compared with non-diabetic patients , diabetic patients ( n = 214 ) were at higher risk for a composite of cardiovascular ( CV ) death , heart failure hospitalization , recurrent MI , stroke , or aborted sudden death ( 14 vs. 7 % ; adjusted hazard ratio 1.63 , 95 % confidence interval 1.01 - 2.64 , P= 0.045 ) , despite similar left ventricular ejection fraction ( 37.9 ± 5.3 vs. 37.6 ± 5.2 % , P= 0.48 ) and end-systolic volume ( ESV ) ( 84 ± 25 vs. 82 ± 28 mL , P= 0.46 ) . Diabetic patients demonstrated greater concentric remodelling ( relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07 , P= 0.0002 ) and evidence of higher LV filling pressure ( E/E ' 11.1 ± 5.3 vs. 9.1 ± 4.3 , P= 0.0011 ) . At 36 weeks , diabetic patients experienced similar per cent reduction in ESV overall ( -4.9 ± 17.9 vs. -5.5 ± 16.9 , P= 0.67 ) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren ( interaction P = 0.08 ) . CONCLUSIONS Compared with non-diabetic patients , diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function . Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure , suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients Objectives . To evaluate the efficacy , safety and tolerability of aliskiren in elderly patients ( ⩾65 years old ) with essential hypertension . Methods . In this double‐blind , multicenter study , 355 elderly patients with hypertension [ office mean sitting systolic blood pressure ( msSBP ) ⩾145–<180 mmHg and mean 24‐h ambulatory systolic BP ( ASBP ) ⩾135 mmHg ] were r and omized to once‐daily treatment for 8 weeks with aliskiren 75 mg ( n = 91 ) , 150 mg ( n = 84 ) , 300 mg ( n = 94 ) or the comparator lisinopril 10 mg ( n = 86 ) . The primary efficacy variable was change in mean 24‐h ASBP . Results . At endpoint , aliskiren 75 mg , 150 mg , 300 mg and lisinopril 10 mg lowered mean 24‐h ASBP ( least‐squares mean±SEM ) by 8.4±0.8 , 7.1±0.8 , 8.7±0.8 and 10.2±0.9 mmHg , and mean 24‐h ambulatory diastolic BP by 4.5±0.5 , 3.6±0.5 , 3.9±0.5 and 6.3±0.5 mmHg , respectively , with no significant difference between aliskiren doses . The trough‐to‐peak ratio for ASBP reduction with aliskiren 75 mg , 150 mg , 300 mg and lisinopril 10 mg was 0.77 , 0.64 , 0.79 and 0.87 , respectively . All treatments lowered office msSBP and mean sitting diastolic BP ( msDBP ) compared with baseline . A significantly greater proportion of patients receiving aliskiren 300 mg achieved BP control ( msSBP/msDBP < 140/90 mmHg ) compared with those receiving aliskiren 75 mg ( 36.2 % vs 24.2 % , p = 0.033 ) . There was no evidence of dose‐related increases in the rate of adverse events with aliskiren treatment . Conclusions . Aliskiren , a novel direct renin inhibitor , provides effective 24‐h BP lowering with no evidence of dose‐related increases in the incidence of adverse events in elderly patients with hypertension . Trial registration : Clinical Trials.gov identifier : NCT00219167 OBJECTIVES This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension . BACKGROUND Low blood pressure ( BP ) control rates among patients with hypertension indicate a need for improved treatment options . This study investigates aliskiren , the first in a new antihypertensive class called renin inhibitors . METHODS Patients with mean sitting diastolic BP 95 to 109 mm Hg were r and omized to aliskiren 150 , 300 , or 600 mg or placebo  once daily for 8 weeks . Patients completing this treatment phase entered a 2-week treatment-free withdrawal period . Office BP was recorded at baseline , weeks 2 , 4 , 6 , and 8 of treatment , and 4 days and 2 weeks after cessation of treatment . A subgroup of patients underwent ambulatory BP monitoring . RESULTS In total , 672 patients were r and omized to treatment . After 8 weeks , aliskiren 150 , 300 , and 600 mg significantly reduced mean sitting BP ( systolic/diastolic ) by 13.0/10.3 , 14.7/11.1 , and 15.8/12.5 mm Hg , respectively , versus 3.8/4.9 mm Hg with placebo ( all p < 0.0001 for systolic and diastolic BP ) . The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal . Aliskiren significantly reduced mean 24-h ambulatory BP ( p < 0.0001 vs. placebo with all doses ) exhibiting smooth , sustained effects and high trough-to-peak ratios .  Aliskiren was well tolerated ; overall adverse event rates were 40.1 % , 46.7 % , and 52.4 % with aliskiren 150 , 300 , and 600 mg , respectively , and 43.0 % with placebo . Few patients discontinued treatment due to adverse events . CONCLUSIONS Aliskiren provides significant antihypertensive efficacy in patients with hypertension , with no rebound effects on blood pressure after treatment withdrawal Patients with severe hypertension ( > 180/110 mm Hg ) require large blood pressure ( BP ) reductions to reach recommended treatment goals ( < 140/90 mm Hg ) and usually require combination therapy to do so . This 8-week , multicenter , r and omized , double-blind , parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension ( mean sitting diastolic blood pressure (msDBP)⩾105 mm Hg and < 120 mm Hg ) . In all , 183 patients were r and omized ( 2:1 ) to aliskiren 150 mg ( n=125 ) or lisinopril 20 mg ( n=58 ) with dose titration ( to aliskiren 300 mg or lisinopril 40 mg ) and subsequent addition of hydrochlorothiazide ( HCTZ ) if additional BP control was required . Aliskiren-based treatment ( ALI ) was similar to lisinopril-based treatment ( LIS ) with respect to the proportion of patients reporting an adverse event ( AE ; ALI 32.8 % ; LIS 29.3 % ) or discontinuing treatment due to AEs ( ALI 3.2 % ; LIS 3.4 % ) . The most frequently reported AEs in both groups were headache , nasopharyngitis and dizziness . At end point , ALI showed similar mean reductions from baseline to LIS in msDBP ( ALI −18.5 mm Hg vs LIS −20.1 mm Hg ; mean treatment difference 1.7 mm Hg ( 95 % confidence interval ( CI ) −1.0 , 4.4 ) ) and mean sitting systolic blood pressure ( ALI −20.0 mm Hg vs LIS −22.3 mm Hg ; mean treatment difference 2.8 mm Hg ( 95 % CI −1.7 , 7.4 ) ) . Responder rates ( msDBP<90 mm Hg and /or reduction from baseline⩾10 mm Hg ) were 81.5 % with ALI and 87.9 % with LIS . Approximately half of patients required the addition of  HCTZ  to achieve BP control ( ALI 53.6 % ; LIS 44.8 % ) . In conclusion , ALI alone , or in combination with HCTZ , exhibits similar tolerability and antihypertensive efficacy to LIS alone , or in combination with HCTZ , in patients with severe hypertension BACKGROUND Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension . METHODS In 569 patients with mild-to-moderate hypertension , blood pressure ( BP ) , plasma renin activity ( PRA ) and plasma renin concentration ( PRC ) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren ( 150 , 300 or 600 mg ) , irbesartan 150 mg or placebo . RESULTS Aliskiren 150 , 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP ( SBP ) from baseline ( p < 0.001 vs. placebo ) . Aliskiren 150 , 300 and 600 mg significantly reduced geometric mean PRA by 69 % , 71 % and 75 % from baseline respectively ( p < 0.05 vs. placebo ) . Irbesartan 150 mg significantly increased PRA by 109 % ( p < 0.05 vs. placebo ) . Aliskiren dose-dependently increased PRC from baseline by 157 % , 246 % and 497 % , at 150 , 300 and 600 mg respectively , compared with a 9 % decrease with placebo ( p < 0.05 ) . PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg ( 105 % ; p < 0.05 ) . Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups , but interestingly , the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were + 2.0 for placebo and -1.5 , -1.8 and -2.3 for aliskiren 150 , 300 and 600 mg respectively . The slope for irbesartan 150 mg ( -1.4 ) was similar to that for aliskiren 150 mg . CONCLUSIONS Aliskiren reduces SBP and PRA and increases PRC dose-dependently . In contrast , irbesartan reduces SBP but increases both PRC and PRA . As PRA is a measurement of angiotensin I-generating capacity , PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II , either directly ( renin inhibitors , beta-blockers , central alpha(2)-agonists ) or indirectly ( AT(1)-receptor blockers , ACE inhibitors ) BACKGROUND By blocking the renin-angiotensin-aldosterone system ( RAAS ) at its rate-limiting step , renin inhibition may provide improved RAAS suppression . We investigated the blood pressure (BP)-lowering effects of the oral direct renin inhibitor aliskiren , alone or in combination with the angiotensin receptor blocker valsartan . METHODS In this multicenter , r and omized , placebo-controlled , 8-week trial , 1123 patients with mild-to-moderate hypertension underwent a 3 to 4 week single-blind placebo run-in and were then r and omized in a modified factorial study design to receive once-daily , double-blind oral treatment with placebo , aliskiren monotherapy ( 75 , 150 , or 300 mg ) , valsartan monotherapy ( 80 , 160 , or 320 mg ) , aliskiren and valsartan in combination , or valsartan/hydrochlorothiazide ( 160/12.5 mg ) . The primary efficacy variable was the change from baseline in mean sitting diastolic BP ( DBP ) at endpoint . RESULTS Once-daily oral treatment with aliskiren 300 mg significantly ( P < .0001 ) lowered mean sitting DBP and systolic BP ( SBP ) compared with placebo ; aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo . Changes in DBP and SBP were fitted to a first-order dose-response surface ( lack-of-fit test , P = .65 ) , which showed that aliskiren and valsartan alone and in combination produced dose-related reductions in DBP and SBP . Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone , comparable in magnitude to the effect of valsartan/hydrochlorothiazide , with similar tolerability to the component monotherapies and to placebo . CONCLUSIONS Aliskiren monotherapy provides antihypertensive efficacy and placebo-like tolerability in patients with hypertension .  Aliskiren and valsartan in combination may provide additive BP-lowering effects with maintained tolerability Objectives Aliskiren is a novel , orally active renin inhibitor . Its antihypertensive efficacy and safety , alone and in combination with hydrochlorothiazide ( HCTZ ) , were investigated in an 8-week , double-blind , placebo-controlled trial in hypertensive patients . The effects of these treatments on plasma renin activity ( PRA ) were also assessed . Methods A total of 2776 patients aged ≥ 18 years with mean sitting diastolic blood pressure ( MSDBP ) 95–109 mmHg were r and omized to receive once-daily treatment with aliskiren ( 75 , 150 or 300 mg ) , HCTZ ( 6.25 , 12.5 or 25 mg ) , the combination of aliskiren and HCTZ , or placebo , in a factorial design . The primary endpoint was the change in MSDBP from baseline to week 8 . PRA was assessed at these timepoints at selected study centers . Results Aliskiren monotherapy was superior to placebo ( P < 0.001 ; overall Dunnett 's test ) in reducing MSDBP and mean sitting systolic blood pressure ( MSSBP ) . Combination treatment was superior to both component monotherapies in reducing BP ( maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg ) , and result ed in more responders ( patients with MSDBP < 90 mmHg and /or ≥ 10 mmHg reduction ) and better control rates ( patients achieving MSSBP/MSDBP < 140/90 mmHg ) than either monotherapy . Aliskiren monotherapy reduced PRA by up to 65 % from baseline . Although HCTZ monotherapy increased PRA by up to 72 % , PRA decreased in all of the combination therapy groups . All active treatments were well tolerated . Conclusions Aliskiren monotherapy demonstrated significant BP lowering , and its effect was considerably greater when combined with HCTZ . Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ AIMS We studied the unclear question whether blood pressure ( BP ) lowering reduces cardiovascular disease ( CVD ) in elderly individuals with systolic BP < 160 mm Hg . METHODS AND RESULTS We initiated a r and omized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure ( SBP ) between 130 and 159 mm Hg , for 5 years . Following 5-week active run-in , participants were r and omized to aliskiren ( 300 mg ) or placebo , and to an additional antihypertensive [ hydrochlorothiazide ( 25 mg ) or amlodipine ( 5 mg ) ] , or their respective placeboes . Study was terminated by sponsor after 1759 subjects ( age 72.1 ± 5.2 years , 88 % receiving at least one antihypertensive ) were r and omized and followed for 0.6 year . Study drugs were well tolerated with few serious adverse events during run-in and after r and omization , with no significant differences between treatment groups . By design , three levels of BP reductions were achieved , adjusted mean BP reductions of 3.5/1.7 mm Hg ( P < 0.001 ) by aliskiren , 6.8/3.3 mm Hg ( P < 0.001 ) by hydrochlorothiazide or amlodipine , and 10.3/5.0 mm Hg ( P < 0.001 ) by double therapy compared with placebo . Twenty-five major CVD events occurred . Non-significant trends towards fewer CVD events with greater BP reductions are evident : hazard ratios ( HR ) 0.82 [ 95 % confidence interval ( CI ) : 0.37 - 1.81 ] for 3.5 mm Hg SBP reduction ; HR 0.45 ( 95 % CI : 0.19 - 1.04 ) for 6.8 mm Hg ; and HR 0.25 ( 0.05 - 1.18 ) for 10.3 mm Hg reduction for primary composite of CV death , MI , stroke , or significant heart failure . CONCLUSIONS Sizeable reductions in BP , with potential for substantial CVD reduction , can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension . CLINICAL TRIAL REGISTRATION NCT01259297 Most patients with hypertension need more than one drug to achieve blood pressure ( BP ) control . This r and omized , double-blind , multifactorial study evaluated whether combinations of aliskiren and amlodipine provided superior BP reductions to component monotherapies in patients with hypertension ( mean sitting diastolic BP ( msDBP ) 95–<110 mm Hg ) . Overall , 1688 patients were r and omized to once-daily monotherapy with aliskiren 150 or 300 mg or amlodipine 5 or 10 mg , combination therapy with one of four corresponding aliskiren/amlodipine doses , or placebo for 8 weeks . At week 8 end point , aliskiren/amlodipine combinations provided significant msDBP reductions from baseline of 14.0–16.5 mm Hg , compared with reductions of 8.0 and 10.2 mm Hg for aliskiren 150 and 300 mg , respectively ( P<0.001 ) , and 11.0 and 13.8 mm Hg for amlodipine 5 and 10 mg , respectively ( P<0.05 ) . Aliskiren/amlodipine combinations provided reductions in mean sitting systolic BP 20.6–23.9 mm Hg , compared with decreases of 10.7 and 15.4 mm Hg for aliskiren 150 and 300 mg , respectively ( P<0.001 ) , and 15.8 and 21.0 mm Hg for amlodipine 5 ( P⩽0.001 ) and 10 mg ( P = NS ) , respectively . Aliskiren/amlodipine combination therapy provides greater BP lowering than either agent alone , hence offering an effective treatment option for patients with hypertension Objective . To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension . Methods . In this double-blind , multicentre trial , 837 patients with diabetes mellitus and hypertension ( mean sitting diastolic blood pressure [ BP ] > 95 and < 110 mmHg ) were r and omised to once-daily aliskiren ( 150 mg titrated to 300 mg after four weeks ; n=282 ) , ramipril ( 5 mg titrated to 10 mg ; n=278 ) or the combination ( n=277 ) for eight weeks . Efficacy variables were cuff mean sitting diastolic BP ( msDBP ) and mean sitting systolic BP ( msSBP ) ; 24-hour ambulatory BP , plasma renin activity ( PRA ) and plasma renin concentration ( PRC ) were also assessed . Results . At week 8 , aliskiren , ramipril and aliskiren/ramipril  lowered msDBP ( mean±SEM ) by 11.3±0.5 , 10.7±0.5 and 12.8±0.5 mmHg , and msSBP by 14.7±0.9 , 12.0±0.9 and 16.6±0.9 mmHg , respectively . Aliskiren/ramipril provided superior msDBP reductions to ramipril ( p=0.004 ) or aliskiren ( p=0043 ) monotherapy ; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg . Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction ( p=0.0002 ) and superior for msSBP reduction (p=0.021).All treatments significantly lowered mean 24-hour ambulatory BP . Aliskiren significantly reduced PRA from baseline as monotherapy ( by 66 % , p<0.0001 ) or in combination with ramipril ( by 48 % , p<0.0001 ) , despite large increases in PRC in all treatment groups . Aliskiren was well tolerated as monotherapy or in combination with ramipril . Conclusions . Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension This r and omized , double-blind , placebo-controlled study assessed the efficacy , safety , and tolerability of aliskiren 75 , 150 , and 300 mg to clarify the dose-response relationship and characterize the optimum aliskiren dose when given with a light meal to elderly hypertensive patients . After washout , 754 patients aged ≥65 years with hypertension ( mean sitting systolic blood pressure [ msSBP ] ≥150 and < 180 mm Hg ; mean sitting diastolic blood pressure [ msDBP ] < 110 mm Hg ) were r and omized to aliskiren 75 , 150 , or 300 mg or placebo for 8 weeks ; medication was taken each morning with a light meal . The primary efficacy variable was change in msSBP from baseline to week 8 end point . Change from baseline in msDBP and dose-response curves for aliskiren 75 , 150 , and 300 mg were also assessed . At week 8 end point , all 3 aliskiren doses provided significantly greater least squares mean reductions in msSBP/msDBP ( 75 mg , 13/5 mm Hg ; 150 mg , 15/6 mm Hg ; 300 mg , 14/7 mm Hg ) compared with placebo ( 8/4 mm Hg ; P < .05 ) . Aliskiren was generally well tolerated at all doses . There was a significant dose-response relationship for aliskiren , with an estimated minimum effective dose of 81.9 mg . In conclusion , aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal Substantial numbers of clinical trials are never reported in print , and among those that are , many are not reported in sufficient detail to enable judgments to be made about the validity of their results . Failure to publish an adequate account of a well- design ed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions . Investigators , research ethics committees , funding bodies , and scientific editors all have responsibilities to reduce underreporting of clinical trials . An extended use of prospect i ve registration of trials at inception , as well as benefiting clinical research in other ways , could help people to play their respective roles in reducing underreporting of clinical trials BACKGROUND The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan , compared with each drug alone in patients with hypertension . METHODS In this double-blind study , 1797 patients with hypertension ( mean sitting diastolic blood pressure 95 - 109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or = 90 mm Hg ) were r and omly assigned to receive once-daily aliskiren 150 mg ( n=437 ) , valsartan 160 mg ( 455 ) , a combination of aliskiren 150 mg and valsartan 160 mg ( 446 ) , or placebo ( 459 ) for 4 weeks , followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks . The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint . Analyses were done by intention to treat . This trial is registered at Clinical Trials.gov with the number NCT00219180 . FINDINGS 196 ( 11 % ) patients discontinued study treatment before the end of the trial ( 63 in the placebo group , 53 in the aliskiren group , 43 in the valsartan group , and 37 in the aliskiren/valsartan group ) , mainly due to lack of therapeutic effect . At week 8 endpoint , the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg , significantly more than either monotherapy ( aliskiren 300 mg 9.0 mm Hg decrease , p<0.0001 ; valsartan 320 mg , 9.7 mm Hg decrease , p<0.0001 ) , or with placebo ( 4.1 mm Hg decrease , p<0.0001 ) . Rates of adverse events and laboratory abnormalities were similar in all groups . INTERPRETATION The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension , with a tolerability profile similar to that with aliskiren and valsartan alone Background : In hypertension , changes in small arterial structure are characterized by an increased wall-to-lumen ratio ( WLR ) . These adaptive processes are modulated by the rennin – angiotensin system . It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensive patients . Methods : In this double-blind , r and omized , placebo-controlled study ( www . clinical trials.gov : NCT01318395 ) , 114 patients with primary hypertension were r and omized to additional therapy with either placebo or aliskiren 300 mg for 8 weeks after 4 weeks of st and ardized open-label treatment with valsartan 320 mg ( run-in phase ) . Parameter of arteriolar remodelling was WLR of retinal arterioles ( 80 – 140 & mgr;m ) assessed noninvasively and in vivo by scanning laser Doppler flowmetry ( Heidelberg Engineering , Germany ) . In addition , pulse wave analysis ( SphygmoCor , AtCor Medical , Australia ) and pulse pressure ( PP ) amplification were determined . Results : In the whole study population , no clear effect of additional therapy with aliskiren on vascular parameters was documented . When analyses were restricted to patients with vascular remodelling , defined by a median of WLR more than 0.3326 ( n = 57 ) , WLR was reduced after 8 weeks by the treatment with aliskiren compared with placebo ( –0.044 ± 0.07 versus 0.0043 ± 0.07 , P = 0.015 ) . Consistently , after 8 weeks of on-top treatment with aliskiren , there was an improvement of PP amplification compared with placebo ( 0.025 ± 0.07 versus -0.034 ± 0.08 , P = 0.013 ) , indicative of less stiff arteries in the peripheral circulation . Conclusion : Thus , our data indicate that treatment with aliskiren , given on top of valsartan therapy , improves altered vascular remodelling in hypertensive patients Journal publications of r and omized controlled trials ( " literature ") have so far formed the basis for evidence of the effects of pharmaceuticals and biologicals . In the last decade , progressively accumulating evidence has shown that literature is affected by reporting bias with evident implication s for the reliability of any decision based on literature or its derivatives such as research synthesis . Another important factor is the growing body of evidence of the fragility of editorial quality control mechanisms in biomedicine and e their easy exploitation for marketing purpose s in the symbiosis between publishing and the pharmaceutical industry . Regulatory documents are probably more reliable than currently accessible other sources but there are many severe limitations to the long-term use of regulatory documents for research synthesis and decision-making . Instead of trying to reform the fields of research , industry , government , regulation and publishing , I propose basing public health decisions and reimbursement of any important interventions on independent trials and studies following the model pioneered by the Mario Negri Institute of Pharmacological Research IMPORTANCE Hospitalizations for heart failure ( HHF ) represent a major health burden , with high rates of early postdischarge rehospitalization and mortality . OBJECTIVE To investigate whether aliskiren , a direct renin inhibitor , when added to st and ard therapy , would reduce the rate of cardiovascular ( CV ) death or HF rehospitalization among HHF patients . DESIGN , SETTING , AND PARTICIPANTS International , double-blind , placebo-controlled study that r and omized hemodynamically stable HHF patients a median 5 days after admission . Eligible patients were 18 years or older with left ventricular ejection fraction ( LVEF ) 40 % or less , elevated natriuretic peptides ( brain natriuretic peptide [ BNP ] ≥ 400 pg/mL or N -terminal pro-BNP [ NT-proBNP ] ≥ 1600 pg/mL ) , and signs and symptoms of fluid overload . Patients were recruited from 316 sites across North and South America , Europe , and Asia between May 2009 and December 2011 . The follow-up period ended in July 2012 . INTERVENTION All patients received 150 mg ( increased to 300 mg as tolerated ) of aliskiren or placebo daily , in addition to st and ard therapy . The study drug was continued after discharge for a median 11.3 months . MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months . RESULTS In total , 1639 patients were r and omized , with 1615 patients included in the final efficacy analysis cohort ( 808  aliskiren  , 807  placebo ) . Mean age was 65 years ; mean LVEF , 28 % ; 41 % of patients had diabetes mellitus , mean estimated glomerular filtration rate , 67 mL/min/1.73 m2 . At admission and r and omization , median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL , respectively . At r and omization , patients were receiving diuretics ( 95.9 % ) , β-blockers ( 82.5 % ) , angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers ( 84.2 % ) , and mineralocorticoid receptor antagonists ( 57.0 % ) . In total , 24.9 % of patients receiving aliskiren ( 77 CV deaths , 153 HF rehospitalizations ) and 26.5 % of patients receiving placebo ( 85 CV deaths , 166 HF rehospitalizations ) experienced the primary end point at 6 months ( hazard ratio [ HR ] , 0.92 ; 95 % CI , 0.76 - 1.12 ; P = .41 ) . At 12 months , the event rates were 35.0 % for the aliskiren group ( 126 CV deaths , 212 HF rehospitalizations ) and 37.3 % for the placebo group ( 137 CV deaths , 224 HF rehospitalizations ; HR , 0.93 ; 95 % CI , 0.79 - 1.09 ; P = .36 ) . The rates of hyperkalemia , hypotension , and renal impairment/renal failure were higher in the aliskiren group compared with placebo . CONCLUSION AND RELEVANCE Among patients hospitalized for HF with reduced LVEF , initiation of aliskiren in addition to st and ard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00894387 Objectives This double-blind study compared long-term efficacy , safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension . Methods After a 2–4-week placebo run-in , 842 patients [ mean sitting diastolic blood pressure ( msDBP ) 95–109 mmHg ] were r and omized to aliskiren 150 mg ( n = 420 ) or ramipril 5 mg ( n = 422 ) . Dose titration ( to aliskiren 300 mg/ramipril 10 mg ) and subsequent hydrochlorothiazide addition ( 12.5 mg , titrated to 25 mg if required ) were permitted at weeks 6 , 12 , 18 and 21 for inadequate blood pressure control . Patients completing the 26-week active-controlled treatment period were re-r and omized to their existing regimen or placebo for a 4-week double-blind withdrawal phase . Results Six hundred and eighty-seven patients ( 81.6 % ) completed the active treatment period . At week 26 , aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure ( 17.9 versus 15.2 mmHg , P = 0.0036 ) and msDBP ( 13.2 versus 12.0 mmHg , P = 0.025 ) , and higher rates of systolic blood pressure control ( < 140 mmHg ; 72.5 versus 64.1 % , P = 0.0075 ) compared with ramipril-based therapy . During withdrawal , blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy  ; median blood pressure reached 140/90 mmHg after 1 and 4 weeks , respectively . Blood pressure reductions were maintained with continued active treatment . Aliskiren therapy was well tolerated . Overall adverse event rates were similar with aliskiren ( 61.3 % ) and ramipril ( 60.4 % ) ; cough was more frequent with ramipril ( 9.5 % ) than aliskiren ( 4.1 % ) . Conclusions Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months , greater than those with ramipril-based therapy Objectives : The objective of this study is to determine the effects of renin -- angiotensin -- aldosterone system inhibition , sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension . Methods : A r and omized , four-way , double-blind , crossover study in 31 adults with previously untreated obesity-related hypertension , in which the effects of 8 weeks ’ inhibition of the renin -- angiotensin -- aldosterone system ( using aliskiren 300 mg ) , sympathoinhibition ( using moxonidine 0.4 mg ) , diuretic therapy ( using hydrochlorothiazide 25 mg ) or placebo on flow-mediated dilation and 24-h blood pressure were compared . Results : The median flow-mediated dilation during placebo was 4.0 % [ interquartile range ( IQR ) 2.9–5.5 % ] and was increased by aliskiren [ 0.81 % , 95 % confidence interval ( CI ) 0.02–1.79 ] , but not by moxonidine ( 0.20 % , 95 % CI −0.46 to 1.03 ) or hydrochlorothiazide ( 0.39 % , 95%CI −0.31%–1.26 % ) . Similarly , compared with placebo  , mean 24-h blood pressure was most reduced by aliskiren ( −9.8/−6.3 mmHg ) and to a lesser degree by hydrochlorothiazide ( −5.9/−2.6 mmHg ) . Moxonidine did not significantly affect blood pressure despite reduction of muscle sympathetic nerve activity . Insulin sensitivity deteriorated during hydrochlorothiazide treatment and was unaffected by aliskiren or moxonidine . Unlike aliskiren and moxonidine , hydrochlorothiazide  reduced urinary 8-iso-prostagl and in F2&agr;-VI , a marker of oxidative stress . Vascular stiffness , systemic inflammation , leptin , adiponectin and other oxidative stress markers ( plasma malondialdehyde , myeloperoxidase activity and urinary 8-hydroxydeoxyguanosine ) were unaffected by treatment . Conclusion : Renin inhibition , but not sympathoinhibition or diuretic therapy , improves endothelial function and results in larger reductions of 24-h , office , and central blood pressure in obesity-related hypertension . This adds weight to the hypothesis that inhibition of the renin -- angiotensin -- aldosterone system is an effective first step in the treatment of obesity-related hypertension While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers is well known , less is known about the new direct renin inhibitor aliskiren . The authors pooled data from 12 r and omized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events ( AEs ) and laboratory abnormalities . Studies were characterized as short-term ( ≤2 months ) placebo-controlled or long-term ( > 2 months ) active-controlled . Relative risks for AEs of particular interest for RAS blockers were calculated . In short-term studies , AEs occurred in similar proportions of aliskiren 150 mg and 300 mg ( 33.6 % and 31.6 % , respectively ) and placebo treatment groups ( 36.8 % ) . In long-term studies , a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs ( 33.7 % and 43.2 % , respectively ) than those treated with ACE inhibitors ( 60.1 % ) , angiotensin receptor blockers ( 53.9 % ) , and thiazide diuretics ( 48.9 % ) . Events of special interest , including angioedema , hyperkalemia , and diarrhea occurred in similar proportions of patients taking aliskiren , placebo , and comparator agents . In studies of up to 36 weeks , patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors . At the registered doses of 150 mg and 300 mg daily , aliskiren  has safety and tolerability profiles  similar to placebo , other RAS blockers , and diuretics . Cough rates are lower with aliskiren compared with ACE inhibitors
target: 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 .
background: BACKGROUND Hypertension is a chronic condition associated with an increased risk of mortality and morbidity .
  Renin is the enzyme responsible for converting angiotensinogen to angiotensin I , which is then converted to angiotensin II .
  Renin inhibitors are a new class of drugs that decrease blood pressure ( BP ) by preventing the formation of both angiotensin I and angiotensin II .
  OBJECTIVES To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension .
  To determine the change in BP variability , pulse pressure , and heart rate and to evaluate adverse events ( mortality , non-fatal serious adverse events , total adverse events , withdrawal due to adverse effects and specific adverse events such as dry cough , diarrhoea and angioedema ) .