Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis.

Objective: Angiotensin receptor blockers (ARB) are among the recommended first-line treatment options in patients with hypertension and chronic kidney disease (CKD). This meta-analysis evaluated the effect of ARB on blood pressure (BP) and renal function in patients with concomitant hypertension and CKD with or without diabetes.Methods: Literature search was performed in PubMed/MEDLINE, EMBASE and BIOSIS to identify parallel-group, randomized controlled trials (≥8 weeks) reporting the effects of ARB on office systolic/diastolic BP (SBP/DBP), estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria in adults with hypertension and CKD. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to report an outcome.Results: Among the 24 studies identified, 19 evaluated ARB as monotherapy, 4 evaluated ARB as combination therapy and one evaluated ARB both as monotherapy and combination therapy. Median (range) duration of the studies was 12 (1.84-54.0) months. ARB monotherapy significantly (p < 0.01) reduced BP (treatment ≥1 year: SBP [MD: -14.84 mmHg; 95% CI: -17.82 to -11.85]/DBP [-10.27 mmHg; -12.26 to -8.27]) and proteinuria (≥1 year [-0.90 g/L; -1.22 to -0.59]). Results were consistent for combination therapy. In these studies, non-significant changes were observed for eGFR, CrCl and SCr. The impact of SBP changes on eGFR was not significant; however, studies were of a relatively short duration.Conclusion: ARB had a favorable impact on BP and renal parameters such as proteinuria with monotherapy as well as with combination therapy, highlighting their potential benefits in patients with hypertension and CKD. During the short follow-up of these studies, no significant change in eGFR was observed.

N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts the cardio-renal response to aliskiren in patients with type 2 diabetes at high renal and cardiovascular risk.

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.

Mortality following a cardiovascular or renal event in patients with type 2 diabetes in the ALTITUDE trial.

AIMS: Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular (CV) and renal disease. We examined the burden of, and risk of death following, CV and renal events in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), a randomized trial of alikiren vs. placebo. METHODS AND RESULTS: We followed 8561 patients with T2DM and evidence of chronic kidney disease, CV disease, or both in ALTITUDE until the first non-fatal CV or renal event of myocardial infarction (MI), stroke, heart failure (HF), and end-stage renal disease (ESRD; initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL) and then to death or censoring. Time-updated multivariable Cox models were used to estimate the relative risk of death following each event. In total 1008 patients (12%) experienced at least one first non-fatal CV or renal event (4.1% HF, 2.8% MI, 2.8% stroke, and 2.2% ESRD). Death occurred subsequently in 26.4% of those experiencing a first HF event, 29.7% of those experiencing an MI event, 23.7% of those experiencing a stroke, and 14.7% of those experiencing ESRD, and in 6.5% (488) of the 7553 patients (88%) who did not experience a non-fatal CV or renal event. Compared with patients who did not experience a non-fatal event, the adjusted hazard ratio for death was 5.9 (95% confidence interval 4.6-7.6) after HF, 9.7 (7.5-12.6) after MI, 7.1 (5.3-9.5) after stroke, and 5.8 (3.7-9.0) after ESRD. CONCLUSION: The majority of deaths occurred in patients who did not experience a non-fatal CV or renal event, although the risk of death was higher following an event. Our findings illustrate continuing opportunities to reduce morbidity and mortality in patients with type 2 diabetes.

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

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 randomly 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 infarction; 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 standard 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 ClinicalTrials.gov number, NCT00549757.).

Inhibition of the renin-angiotensin system reduces the rise in serum aldosterone in acute coronary syndrome patients with preserved left ventricular function: observations from the AVANT GARDE-TIMI 43 trial.

BACKGROUND: Acute coronary syndrome (ACS) activates neurohormonal pathways, including elevations in circulating aldosterone, with deleterious cardiovascular effects. We aimed to determine if early, more complete renin-angiotensin-aldosterone system inhibition (RAASI) in post-ACS patients without ventricular dysfunction or heart failure would result in a graded reduction in aldosterone concentrations. METHODS: We performed serial measurement of serum aldosterone within the Aliskiren and Valsartan to Reduce NT-proBNP via Renin-Angiotensin-Aldosterone-System Blockade (AVANT GARDE)-Thrombolysis in Myocardial Infarction (TIMI) 43 trial, a randomized double-blind, placebo controlled trial of RAASI by valsartan, aliskiren, or both in post-ACS patients with preserved ventricular function but increased natriuretic peptides. Aldosterone was measured at randomization and week 8. RESULTS: Median aldosterone concentrations were comparable across treatment arms at baseline (9.26 ng/dL; interquartile range 7.12-12.76; n = 1073). In the placebo group, there was a significant increase in aldosterone over 8 weeks (19.7% rise, 2.20 (0.36) ng/dL, P < 0.0001) that was significantly reduced across active RAASI therapies (1.36 (0.39) ng/dL with aliskiren; 1.02 (0.37) ng/dL with valsartan; and 0.85 (0.37) ng/dL with combination therapy, P trend = 0.008). Compared to placebo, RAASI monotherapy resulted in a pooled relative absolute aldosterone change of -1.01 (0.45) ng/dL (P = 0.026 vs placebo), and combination therapy resulted in a relative absolute aldosterone change of -1.35 (0.52) ng/dL (P = 0.01 vs placebo). No significant difference in aldosterone concentrations was achieved between dual vs single RAASI (P = 0.47). CONCLUSIONS: In ACS patients with preserved ventricular function but increased natriuretic peptides, serum aldosterone rises over time and is blunted by more complete RAASI. The clinical implications and role for RAASI in this population warrant further investigation.

Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial.

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, randomized, 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 randomized 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: clinicaltrials.gov Identifier: NCT00853827.

Flow cytometer based on triggered supercontinuum laser illumination.

Multiple wavelength operation in a flow cytometer is an exciting way for cell analysis based on both fluorescence and optical scattering processing. For example, this multiparametric technique is currently used to differentiate blood cells subpopulations. The choice of excitation wavelengths matching fluorochrome spectra (it is currently the opposite) and the use of a broader range of fluorochromes can be made by taking advantage of a filtered supercontinuum white light source. In this study, we first wished to validate the use of a specific triggered supercontinuum laser in a flow cytometer based on white light scattering and electric sizing on human blood cells. Subsequently, to show the various advantages of this attractive system, using scattering effect, electrical detections, and fluorescence analysis, we realized cells sorting based on DNA/RNA stained by thiazole orange. Discrimination of white blood cells is efficiently demonstrated by using a triggered supercontinuum-based flow cytometer operating in a "one cell-one shot" configuration. The discriminated leukocyte populations are monocytes, lymphocytes, granulocytes, immature granulocytes, and cells having a high RNA content (monoblasts, lymphoblasts, and plasma cells). To the best of our knowledge, these results constitute the first practical demonstration of flow cytometry based on triggered supercontinuum illumination. This study is the starting point of a series of new experiments fully exploiting the spectral features of such a laser source. For example, the large flexibility in the choice of the excitation wavelength allows to use a larger number of fluorochromes and to excite them more efficiently. Moreover, this work opens up new research directions in the biophotonics field, such as the combination of coherent Raman spectroscopy and flow cytometry techniques.

Wavelength encoding technique for particle analyses in hematology analyzer.

The aim of this study is to combine multiple excitation wavelengths in order to improve accuracy of fluorescence characterization of labeled cells. The experimental demonstration is realized with a hematology analyzer based on flow cytometry and a CW laser source emitting two visible wavelengths. A given optical encoding associated to each wavelength allows fluorescence identification coming from specific fluorochromes and avoiding the use of noisy compensation method.

Impact of a multi-faceted training intervention on the improvement of hand hygiene and gloving practices in four healthcare settings including nursing homes, acute-care geriatric wards and physical rehabilitation units.

AIMS: To assess the impact of a multi-faceted training program on the compliance with hand hygiene and gloving practices. BACKGROUND: Hand hygiene is considered as the cornerstone of the prevention of hospital-acquired infections. Several studies have enhanced the poor effectiveness of training programs in improving hand hygiene compliance. DESIGN: A before-after evaluation study. METHODS: The study was conducted in four healthcare settings before and after an intervention program which included the performance feedback of the first evaluation phase, three six-h training sessions, the assessment of hand hygiene performance with teaching boxes and the organisation of one full-day session devoted to institutional communication around hand hygiene in each setting. Hand hygiene compliance and quality of hand rubbing were evaluated. Hand hygiene opportunities were differentiated into extra-series opportunities (before or after a single contact and before the first contact or after the last contact of a series of consecutive contacts) and intra-series opportunities (from the opportunity following the first contact to the opportunity preceding the last in the same series). RESULTS: Overall, 969 contacts corresponding to 1,470 hand hygiene opportunities (760 during the first phase and 710 during the second) were observed. A significant improvement of observed practices was recorded for the hand hygiene compliance in intra-series opportunities (39·0% vs. 19·0%; p < 10(-5) ), the proportion of gloves worn if indicated (71·4% vs. 52·0%; p < 0·001) and the quality of hand rubbing (85·0% vs. 71·9%; p < 10(-5) ). CONCLUSIONS: Some of the performances measured for both hand hygiene and gloving practices were improved. We plan to extend this investigation by performing a qualitative study with experts in behavioural sciences to try improving practices for which adherence was still weak after the training program such as hand hygiene in intra-series opportunities. RELEVANCE TO CLINICAL PRACTICE: This study underscored the usefulness of implementing contextualised training programs, while more traditional courses have shown little impact.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies.

OBJECTIVE: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg). METHODS: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60-90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8-12 of treatment were compared. RESULTS: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (-23.1/-13.8 vs. -17.9/-9.1 mmHg) but the difference was non-significant for msPP (-8.6 vs. -9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence. CONCLUSION: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.

Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.

Renal outcomes with aliskiren in patients with type 2 diabetes: a prespecified secondary analysis of the ALTITUDE randomised controlled trial.

BACKGROUND: The primary results of the ALTITUDE trial showed no benefit of aliskiren on renal outcomes (doubling of serum creatinine and end-stage renal disease) when used as an adjunct to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease. We did a prespecified analysis of the ALTITUDE trial to analyse the effects of aliskiren on surrogate renal outcomes in all patients and on primary renal outcomes in subgroups of patients. METHODS: In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to-creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757. FINDINGS: Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups. INTERPRETATION: Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study. FUNDING: Novartis.

Nateglinide improves early insulin secretion and controls postprandial glucose excursions in a prediabetic population.

OBJECTIVE: The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement < or =3.3 mmol/l (plasma glucose < or =3.7 mmol/l). RESULTS: Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo. CONCLUSIONS: Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes.

Effects of exercise on central aortic pressure before and after treatment with renin-angiotensin system blockade in patients with hypertension.

INTRODUCTION: Brachial blood pressure increases with exercise and an excessive rise predicts increased cardiovascular risk. Measurement of brachial blood pressure alone may exaggerate the true blood pressure elevation due to exercise-induced change to pressure amplification. Whether blood pressure-lowering treatment modulates pressure amplification during exercise is unknown. METHODS: Thirty-two participants with stage 1-2 hypertension (mean age 59.2 years) received eight weeks' blood pressure lowering with either aliskiren (300mg, n=16) or valsartan (320mg, n=16). Brachial and central aortic pressure (CASP) were measured non-invasively during treadmill exercise (Bruce protocol) at baseline, after eight weeks' treatment and 48 hours following treatment withdrawal. RESULTS: The rise in brachial blood pressure with exercise exceeded the rise in CASP, indicative of enhanced pressure amplification. Eight weeks' treatment elicited similar reductions in brachial blood pressure and CASP which did not differ between rest and peak exercise (p>0.05). The exercise-induced increase in systolic pressure amplification did not differ between baseline and following eight weeks' treatment (p>0.05). These effects remained unchanged following treatment withdrawal. CONCLUSION: Blood pressure lowering does not directly influence the relationship between aortic and brachial pressure either at rest or during exercise in patients with hypertension, other than through proportionate lowering of both pressures. These effects remained unchanged 48 hours after a simulated missed medication dose.

Effects of treatment withdrawal on brachial and central aortic pressure after direct renin inhibition or angiotensin receptor blockade.

INTRODUCTION: Whilst sustained lowering of brachial systolic blood pressure (Br-SBP) and central aortic systolic pressure (CASP) have been demonstrated in patients with hypertension, effects of treatment withdrawal on these parameters have not been investigated. The ASSERTIVE study previously reported more sustained control of Br-SBP with aliskiren versus telmisartan in patients with hypertension, following 7-days treatment withdrawal. In this ASSERTIVE sub-study, we hypothesised that aliskiren would similarly exert more sustained control of CASP than telmisartan during treatment withdrawal. METHODS: We investigated the effects of treatment withdrawal on both Br-SBP and CASP following 12-weeks treatment with either aliskiren (300 mg) or telmisartan (80 mg). Br-SBP and CASP were measured at the end of treatment, and at days 2 and 7 following treatment withdrawal in 303 patients (CASP randomised set). RESULTS: Of the CASP randomised set, 94 patients completed CASP measurements at all time points (CASP completer set). After 7 days of treatment withdrawal, aliskiren demonstrated lesser increases in both Br-SBP and CASP than telmisartan; Br-SBP change: -2.0±1.6 vs. +5.6±1.7 mmHg, p = 0.001; CASP change: -0.4±1.6 vs. +4.6±1.7 mmHg, p = 0.041, n = 94. Similar findings were obtained for the CASP randomised set. CONCLUSIONS: Following treatment withdrawal, aliskiren demonstrated more sustained control of both brachial and central SBP than telmisartan.

Effects of aliskiren in diabetic and non-diabetic patients with coronary artery disease: Insights from AQUARIUS.

BACKGROUND: Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM). METHODS: AQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation. RESULTS: In multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057). CONCLUSIONS: Aliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro-atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren.

Insulin sensitivity in type 2 diabetes: univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified intravenous glucose tolerance test (FSIGT).

The use of univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified FSIGT were investigated in 12 Type 2 diabetic subjects aged (mean+/-S.D.) 59+/-9.5 years and BMI 28.1+/-2.2 kg m(-2), who underwent both a FSIGT and an isoglycemic hyperinsulinemic clamp. Reproducibility of the FSIGT was tested in four patients on three separate occasions. FSIGT data were assessed by both univariate and multivariate techniques. The sensitivity index for the FSIGT ranged from 0.162 to 3.292 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the univariate approach and from 0.163 to 2.727 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the multivariate method. Mean S(Iclamp) was 44.41 x 10(-4) x l(-2) min(-1) x mU(-1) (range 22.0-77.92). The correlation of the insulin sensitivity indices between the clamp and the FSIGT was 0.51 (P=0.056) for the univariate and 0.67 (P=0.017) for the multivariate analyses. Repeated FSIGTs showed a lower variability for the multivariate than for the standard approach.

Effects of aliskiren- and ramipril-based treatment on central aortic blood pressure in elderly with systolic hypertension: a substudy of AGELESS.

BACKGROUND: Systolic hypertension is the most common form of hypertension in elderly patients. There is increasing evidence that measurement of central aortic pressure (CAP) better accounts for cardiovascular risk than brachial blood pressure (BP). The Aliskiren for GEriatric LowEring of SyStolic hypertension (AGELESS) study in elderly patients with systolic hypertension showed that aliskiren-based therapy provided greater reductions in peripheral BP than ramipril-based therapy over 12 and 36 weeks of treatment. Here, we present CAP results in a substudy of elderly patients from the AGELESS study. METHODS: This was a post hoc analysis of a 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study in patients ≥65 years of age with systolic BP ≥140 mmHg. Changes in both central and peripheral BP and pulse pressure (PP) and changes in systolic and PP amplification ratios from baseline to the week 36 end point with aliskiren-based versus ramipril-based therapy were analyzed. RESULTS: Of the 901 patients randomized in the overall study, 154 patients (aliskiren, n=78; ramipril, n=76) had CAP data. Numerically comparable reductions were seen for central aortic systolic pressure (CASP) in aliskiren-based therapy (baseline: 143.7±15.0; week 36: -20.3±16.2) compared with ramipril-based therapy (baseline: 147.9±11.9; week 36: -20.7±14.6). However, for the change in central aortic diastolic pressure, the least squares mean between-treatment difference (-3.6 mmHg [95% confidence interval, -6.76, -0.43; P=0.0263]) was in favor of aliskiren, while the other changes were comparable between the two groups with a trend in favor of aliskiren for CASP as well (-2.6 mmHg [95% confidence interval, -7.38, 2.19; P=0.2855)]. Correlation coefficients for change from baseline between CASP and systolic BP and between central aortic pulse pressure and PP (r=0.8, P<0.0001) were highly significant. CONCLUSION: Aliskiren-based therapy provides comparable reductions in CASP to ramipril-based therapy. Although the results did not reach statistical significance, these findings, when coupled with those of the main study, suggest that aliskiren may offer effective control of central BP in elderly patients with systolic hypertension and may be a good alternative to ramipril.

Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study.

INTRODUCTION: Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. METHODS AND ANALYSIS: In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12-24 weeks, if the BP target has not been attained (msSBP <140 and ms diastolic BP <90 mm Hg), amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. ETHICS AND DISSEMINATION: The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. CLINICAL TRIALS IDENTIFIER: EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.

Exercise testing in hypertensive patients for assessing the cardiovascular protective potential of antihypertensive drugs.

Exercise testing is an established noninvasive tool in cardiology used to diagnose and guide treatment in individuals with suspected or confirmed coronary artery disease. Owing to the wealth of information it provides, exercise testing is also being utilized to evaluate prehypertensive stages, characterize hypertension, assess tolerance to exercise and the efficacy of antihypertensive therapies, and predict target organ damage and cardiovascular risk. The literature on exercise tolerance tests is relatively limited since these studies are difficult to conduct although they represent a valuable test for evaluating the benefits of antihypertensive therapies beyond their blood-pressure-lowering efficacy at rest or during exercise. Such a setting can be immensely useful for the evaluation and for the differentiation of treatments, especially in patients with evident rises in systolic blood pressure and with concomitant diseases, who are at higher risk of stroke. Exercise-induced increase in systolic blood pressure from rest to peak exercise should therefore be used as the primary efficacy variable. There is growing evidence that central pressure is a better predictor for cardiovascular risk than peripheral blood pressure, since this variable takes into account the overall effect of vascular aging and increased arterial stiffness that age and other concomitant diseases may induce. It is also important to include central aortic blood pressure and biomarkers of hypertension and cardiac disease in the overall assessment.