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Aims: Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin-angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme-angiotensin II-angiotensin-1 receptor axis (Ang I-ACE-Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2-angiotensin-(1-7)-Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects., Methods: We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II-III) in a randomized placebo-controlled clinical trial 'Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)'. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication., Results: Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3-324.2) vs. 131.5 pmol/L (34.9-564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5-236.6) vs. 125.9 pmol/L (52.6-512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0-15.0) vs. 10.1 pmol/L (3.0-31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0-22.9) vs. 9.9 pmol/L (2.8-36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2-750.6) vs. 568.2 pmol/L (164.7-1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0-14.1) vs. 15.0 pmol/L (3.0-31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8-46.6) vs. 36.4 pmol/L (11.1-90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0-60.8) vs. 26.4 pmol/L (10.7-63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0-20.7) vs. 10.5 pmol/L (3.0-50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0-8.4) vs. 2.8 pmol/L (2.0-6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment)., Conclusions: Our data indicate that empagliflozin might lead to an activation of both the Ang I-ACE-Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I-ACE-Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In 28 790 patients recruited for the ONTARGET (Ongoing Treatment Alone and in Combination With Ramipril Global End Point Trials) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials, we investigated the prognostic value for cardiovascular events (primary outcome) of (1)on-treatment visit-to-visit systolic blood pressure (SBP) variability versus mean SBP and (2) the 2 measures together. SBP variability was measured by the coefficient of variation (CV) of mean SBP to which it was unrelated. Confounders such as variable time and number of visits from which to calculate SBP-CV were avoided by using the same number of visits at identical times in all patients. The covariate-adjusted risk of the primary outcome (Cox models) increased as SBP-CV or mean on-treatment quintile SBP increased, but only for mean on-treatment SBP, the relationship achieved statistical significance: global test for trend, P =0.12 versus P <0.0001. SBP-CV showed a relationship with fatal events, but it was unrelated to the risk of myocardial infarction and stroke, which were predicted by on-treatment mean SBP. Prediction of the primary outcome improved by the combined use of both measures: global test for trend, P <0.0001; hazard ratio for combined fifth versus first quintile, 1.42 (1.20-1.68) compared with 1.13 (1.01-1.27) for SBP-CV and 1.24 (1.11-1.40) for mean SBP. Thus, in the present study, on-treatment mean SBP provided an overall better prediction of cardiovascular risk than visit-to-visit SBP-CV. Prediction improved by their combined use, which may thus offer a more precise estimate of the protective effect of treatment., Clinical Trial Registration: URL: http//www.clinicaltrial.gov. Unique identifier: NCT00153101, (© 2017 American Heart Association, Inc.)

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The authors sought to retrospectively analyze the real-world evidence on aliskiren in diabetic patients with or without concomitant renin-angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non-RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS-blocking therapy alone., (©2016 Wiley Periodicals, Inc.)

Background: Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting., Methods: The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M., Results: A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73)., Conclusions: These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.

Background: Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not., Methods: Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-)., Results: Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5%) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1%; P<0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1%) than in the RCT+ AZL-M group (64.1%), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1%). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5%) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility., Conclusions: These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.

For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors., (© 2015 Wiley Periodicals, Inc.)

Background: Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited., Methods and Results: The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is NCT01454583. In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7 years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non-RAS; p<0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups., Conclusions: ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions., Methods/design: The "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013., Conclusions: The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice.

Hypertension is an important independent risk factor for renal disease. If hypertension and chronic renal disease co-exist, as is common in patients with diabetes mellitus, the risk of cardiovascular disease is heightened. The importance of rigorous blood pressure control is recognized in current guidelines, with a recommended target of office blood pressure of < 130/80 mmHg; although ambulatory blood pressure may be more appropriate in order to identify the 24-hour hypertensive burden. Even lower blood pressure may further reduce the progression of chronic kidney disease, but the incidence of cardiovascular events may increase. Albuminuria not only indicates renal damage, but is also a powerful predictor of cardiovascular morbidity and mortality at least in patients with high cardiovascular risk and potentially pre-existing vascular damage. Management of the multiple factors for renal and cardiovascular disease is mandatory in the diabetic patient. The renin-angiotensin system (RAS) plays a pivotal role in the progression of renal disease, as well as in hypertension and target-organ damage. The use of agents that target the RAS confer renoprotection in addition to antihypertensive activity. There is extensive evidence of the renoprotective effect of angiotensin II receptor blockers (ARBs), and specifically telmisartan. In addition to providing 24-hour blood pressure control, clinical studies in patients with diabetes show that telmisartan improves renal endothelial function, prevents progression from microalbuminuria to macroalbuminuria, slows the decline in glomerular filtration rate and reduces proteinuria in overt nephropathy. These effects cannot be solely attributed to blood pressure control. In contrast to other members of the ARB class, the renoprotective effect of telmisartan is not confined to the management of diabetic nephropathy; slowing the progression of albuminuria has been demonstrated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which included diabetic and non-diabetic patients at high risk of cardiovascular events.

Objectives: The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective., Background: Individual studies examining the effects of RAS inhibition on AF prevention have reported controversial results., Methods: All published randomized controlled trials reporting the effects of treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the primary or secondary prevention of AF were included., Results: A total of 23 randomized controlled trials with 87,048 patients were analyzed. In primary prevention, 6 trials in hypertension, 2 trials in myocardial infarction, and 3 trials in heart failure were included (some being post-hoc analyses of randomized controlled trials). In secondary prevention, 8 trials after cardioversion and 4 trials assessing the medical prevention of recurrence were included. Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001), but there was substantial heterogeneity among trials. In primary prevention, RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy but not in post-myocardial infarction patients overall. In secondary prevention, RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p < 0.00001)., Conclusions: This analysis supports the concept of RAS inhibition as an emerging treatment for the primary and secondary prevention of AF but acknowledges the fact that some of the primary prevention trials were post-hoc analyses. Further areas of uncertainty include potential differences among specific RAS inhibitors and possible interactions or synergistic effects with antiarrhythmic drugs., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showed that the angiotensin receptor blocker telmisartan 80 mg was not inferior to the angiotensin-converting enzyme inhibitor ramipril 10 mg, and the combination no more effective than ramipril alone, in decreasing morbidity and mortality in patients with cardiovascular disease or high-risk diabetes. Although therapy targeting angiotensin II is known to decrease left ventricular (LV) mass and volume, the relative influence of angiotensin-converting enzyme inhibitor inhibitors and angiotensin receptor blocker, and their combination, on the heart remains unclear in this population. Magnetic resonance imaging was performed in 287 patients enrolled in ONTARGET, across 8 centers in 6 countries, at randomization and after 2-year treatment (90, 100, and 97 patients in the ramipril, telmisartan, and combination therapy groups, respectively). Baseline patient characteristics showed higher frequencies of coronary artery disease, Asian ethnicity, and use of statins and beta blockers than the main ONTARGET trial. LV mass decreased in all groups (p <0.0001 for each), but there were no significant differences in change in LV mass or volume among groups, except that LV mass index decreased more on combination versus telmisartan (p = 0.04). Key determinants of LV mass decrease were a history of hypertension (p = 0.03), baseline mass (p <0.0001), and decrease in systolic blood pressure (p <0.0001). The best magnetic resonance imaging predictor of composite events was end-systolic volume (p <0.0001). In conclusion, telmisartan and ramipril had similar effects on LV mass and volume, and combination therapy was not more effective, in high-risk patients with cardiovascular disease. These results are consistent with the major outcome findings of the main ONTARGET study.

Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce left ventricular hypertrophy (LVH). The effect of these drugs on LVH in high-risk patients without heart failure is unknown., Methods and Results: In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of ACE inhibitors were randomly assigned to ramipril, telmisartan, or their combination (n=23 165). In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), patients intolerant of ACE inhibitors were randomized to telmisartan or placebo (n=5343). Prevalence of LVH at entry in TRANSCEND was 12.7%. It was reduced by telmisartan (10.5% and 9.9% after 2 and 5 years) compared with placebo (12.7% and 12.8% after 2 and 5 years) (overall odds ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.0017). New-onset LVH occurred less frequently with telmisartan compared with placebo (overall odds ratio, 0.63; 95% CI, 0.51 to 0.79; P=0.0001). LVH regression was similar in the 2 groups. In ONTARGET, prevalence of LVH at entry was 12.4%. At follow-up, it occurred slightly less frequently with telmisartan (odds ratio, 0.92; 95% CI, 0.83 to 1.01; P=0.07) and the combination (odds ratio, 0.93; 95% CI, 0.84 to 1.02; P=0.12) than with ramipril, but differences between the groups were not significant. New-onset LVH was associated with a higher risk of primary outcome during follow-up (hazard ratio, 1.77; 95% CI, 1.50 to 2.07)., Conclusions: In patients at high vascular risk, telmisartan is more effective than placebo in reducing LVH. New-onset LVH is reduced by 37%. The effect of combination of the 2 drugs on LVH is similar to that of ramipril alone.

Background: The ONTARGET and TRANSCEND clinical trials were designed to investigate the cardioprotective effects of telmisartan 80 mg and ramipril 10 mg, alone and in combination, in patients at high risk of cardiovascular disease. Cardiac MRI enables investigation of mechanistic effects of these agents on cardiac structural and functional variables. Here, we report the design, analysis protocol, reproducibility and relevant quality control procedures, and baseline patient characteristics of the ONTARGET/TRANSCEND cardiac MRI substudy. MRI was undertaken in 330 subjects enrolled in ONTARGET, and 38 subjects in TRANSCEND, across eight centers in six countries. Analyses were performed by two independent analysts using guide-point modeling. Cases with discrepancies in LV mass (LVM) of >5% were independently reanalyzed. Cases with discrepancies in end-diastolic volume (EDV) of >5%, or end-systolic volume (ESV) of >12%, were then reconciled by consensus., Results: Baseline characteristics were broadly similar to the main ONTARGET/TRANSCEND trials, except for a higher frequency of coronary artery disease and Asian ethnicity in the substudy. Reproducibility of MRI analyses (mean +/- SD) were 2.8 +/- 3.7 ml in EDV, -0.3 +/- 3.6 ml in ESV, 3.1 +/- 3.3 ml in SV, 1.1 +/- 1.8% in EF, and 0.4 +/- 4.5 g in LVM. Subgroup analyses revealed increased ESV and LVM, and reduced EF, in subjects with a history of either coronary artery disease or myocardial infarction., Conclusions: The ONTARGET/TRANSCEND cardiac MRI substudy protocol provides for a reliable assessment of the effects of telmisartan and ramipril, alone and in combination, on cardiac structural and functional parameters over a 2-year follow-up period.

Background: Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage., Methods: The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101., Findings: 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril., Interpretation: In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Background: The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment., Methods: A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring., Findings: One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%)., Interpretation: There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

Background: Hypertension is a common complication in autosomal dominant polycystic kidney disease (ADPKD). This prospective randomized double-blind study was performed to compare the renal and cardiac effects of the ACE inhibitor ramipril and the beta-blocker metoprolol as first line therapy in ADPKD patients with hypertension., Methods: Forty-six hypertensive ADPKD patients were randomized to either ramipril (n = 23) or metoprolol (n = 23). Twenty-four hour (24-h) ambulatory blood pressure (BP), glomerular filtration rate (GFR) as calculated by the Cockcroft and Gault formula, urinary albumin excretion (albumin/creatinine ratio), and left ventricular mass index (LVMI) were established at baseline and at yearly intervals. The total follow-up was 3 years. Baseline characteristics were similar in both groups., Results: Mean arterial pressure (MAP) decreased significantly in both the ramipril and the metoprolol group (-8 +/- 2 and -6 +/- 2 mmHg; both P < 0.01). There was a significant decline in renal function during follow-up which was similar in patients treated with ramipril or metoprolol (-2.5 +/- 0.7 vs -2.9 +/- 0.8 ml/min/year; P = NS). After the 3 years follow-up, no differences in GFR, LVMI and urinary albumin excretion were observed between the ramipril and the metoprolol group (80.7 +/- 10.7 vs 78.0 +/- 7.6 ml/min, 102.6 +/- 6.8 vs 100.3 +/- 5.4 g/m(2); and 42.6 +/- 12.3 vs 70.3 +/- 32.5 mg/g, respectively; all P = NS). A post-hoc analysis evaluating the effects of BP control, revealed that LVMI increased in patients with standard BP control while it remained stable in patients with rigorous BP control with a significant difference in LVMI between the groups after 3 years of follow-up (110.5 +/- 6.3 vs 90.9 +/- 4.7 g/m(2); P = 0.017). Also, by the end of the study albuminuria was lower in patients with rigorous vs standard BP control (23.5 +/- 6.7 vs 94.8 +/- 35.4 mg/g; P = 0.05)., Conclusions: In our study population of hypertensive ADPKD patients, no differences in renal function, urinary albumin excretion and LVMI were detected between those treated with ramipril or metoprolol, respectively, during a 3 years follow-up. Rigorous BP control prevented an increase in LVMI and reduced urinary albumin excretion, suggesting a crucial role of BP control for slowing progression of cardiac and renal organ damage in ADPKD.

Diabetic nephropathy and hypertension are the major causes of chronic kidney disease. The renin system plays a key role in the control of blood pressure (BP), as well as in the regulation of renal and adrenal function. Chronic activation of the renin system can lead to organ damage, particularly renal damage; increasing evidence indicates that suppression of the renin system can provide renal protection. Despite the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), the renin system is not completely suppressed. The direct renin inhibitors (DRIs) provide suppression of the entire renin system at the rate-limiting step. Studies in humans with early DRIs indicated potential renoprotective effects, but these agents failed in clinical development due to poor oral bioavailability. Aliskiren is a new orally active DRI with proven BP-lowering effects. Animal studies indicate that aliskiren may provide renal protection, and data from human studies are anticipated.

Objective: One of the earliest signs of vascular change is endothelial dysfunction, which is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial function., Research Design and Methods: In a multicenter, prospective, double-blind, forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate >80 ml/min, and normo- or microalbuminuria were treated once daily with 40/80 mg telmisartan or 5/10 mg ramipril for 9 weeks., Results: The mean +/- SE fall in renal plasma flow (RPF) in response to intravenous N(G)-monomethyl-L-arginine (L-NMMA), reflecting the magnitude of nitric oxide (NO) activity, increased with telmisartan from 71.9 +/- 9.0 ml/min before therapy to 105.2 +/- 9.7 ml/min at the end of treatment (P < 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 +/- 12.2 to 87.8 +/- 9.2 ml/min (P = 0.018). The adjusted difference between treatments was -17.1 +/- 13.7 ml/min (P = 0.214). In accordance, telmisartan increased RPF at rest (i.e., without L-NMMA) from 652.0 +/- 27.0 to 696.1 +/- 31.0 ml/min (P = 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater was the vasodilatory effect on renal vasculature (r = 0.47, P < 0.001)., Conclusions: In patients with type 2 diabetes, telmisartan and ramipril both increased NO activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function.

The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Basic research has revealed exciting new aspects, which could lead to novel or modified therapeutic approaches. Renin-angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system-ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of our strategies to reduce cardiovascular risk.

Background: Asymmetrical N(G), N(G)-dimethylarginine (ADMA) is associated with impaired endothelium-dependent vasodilation in humans., Methods: Twenty young, male, mildly hypertensive subjects were included in a randomized, double-blind, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or a combination of both drugs (10 and 300 mg/day, respectively) each over 1 week, followed by a 2-week wash-out phase. After each treatment phase, ADMA concentration was measured., Results: ADMA concentration was 1.69+/-0.59 micromol/L in the placebo phase, and was significantly lower in the enalapril, eprosartan, and combination phases (1.41+/-0.29, 1.42+/-0.43, and 1.38+/-0.30 micromol/L, respectively; all P < 0.05 v placebo). Changes in ADMA levels were independent of the drugs' action on blood pressure (BP)., Conclusions: Levels of ADMA were reduced with enalapril and eprosartan therapy. Our results suggest a specific action of these drugs on ADMA levels that is independent of BP.

Background: Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension., Methods: Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg)., Results: After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment., Conclusions: In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.

Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63+/-10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24+/-17 mm Hg and diastolic blood pressure by 12+/-11 mm Hg. An increase in serum creatinine (> 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P < .05). Serum creatinine decreased more frequently in patients with renal involvement than in those without (26%+/-4% v 12%+/-3.8%; P < .05). Overall renal function in patients with diabetic nephropathy (n = 318) improved (2.1+/-1.6 mg/dL v 1.7+/-1.4 mg/dL; P < .05). The frequency of proteinuria was lower after 1 year than at baseline (62%+/-9% v 82%+/-8%; P < .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P < .01). Scores for edema formation and exertional dyspnea improved as well (P < .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function.

In this paper we review the effect of medical treatment on renal function in patients with congestive heart failure. We have examined data from the large-scale heart failure studies with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-receptor blockers, an aldosterone antagonist, and a vasopeptidase inhibitor. Renal outcome was reported in almost all of the studies with angiotensin-converting enzyme inhibitors. Despite concern about renal adverse events with drugs in this class, they seem to be safe in patients with congestive heart failure. In contrast, we did not find any report about renal function in patients treated with beta-receptor blockers for congestive heart failure.

In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (Deltaglomerular filtration rate, 4.3+/-7.7 mL/min in normotensives without versus 5.6+/-8.4 mL/min in normotensives with a family history versus 10.1+/-5.7 mL/min in patients with mild essential hypertension; P:<0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (Deltaurinary sodium excretion, 0.12+/-0.17 mmol/min versus 0.10+/-0.14 mmol/min versus 0.05+/-0.14 mmol/min; P:<0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (Deltaurinary sodium excretion, 0.05+/-0.14 mmol/min with placebo versus 0.13+/-0.19 mmol/min with ACE inhibition; P:<0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II.

Objective: To examine the effects of angiotensin converting enzyme (ACE) inhibition on renal and systemic haemodynamics as well as on humoral regulators, under resting conditions and during mental stress in 20 normotensive and 20 mildly hypertensive subjects., Methods: All of the subjects received either 25 mg cilazapril or placebo once a day, in a randomized, double-blind, cross-over trial for 1 week, followed by a 2-week washout period before the alternative regimen was given. We measured renal blood flow with para-aminohippuran, glomerular filtration rate with inulin, cardiac output by impedance cardiography and blood pressure and heart rate by an oscillometric method. We also monitored effects on plasma renin activity, aldosterone, catecholamines and atrial natriuretic peptide. Mental stress consisted of a long-lasting, time-reaction device, thereby provoking activation of the sympathetic nervous system., Results: At rest ACE inhibition lowered mean arterial pressure (92 +/- 10 versus 98 +/- 9 mmHg), increased renal blood flow (803 +/- 109 versus 707 +/- 93 ml/min) and the renal fraction of cardiac output (25.9 +/- 2.5 versus 23.5 +/- 2.5%) and decreased the filtration fraction (17.9 +/- 2.5 versus 19.8 +/- 2.7%) in hypertensive but not in normotensive subjects. Sympathetic activation by mental stress leading to a transient increase in blood pressure did not alter significantly the effects of ACE inhibition on renal and systemic haemodynamics, in normotensive or in hypertensive subjects, although a tendency towards attenuation of the rise in glomerular filtration rate was noted in hypertensives (7.2 +/- 1.0 versus 5.1 +/- 0.8%). ACE inhibition led to increased plasma noradrenaline at rest but not during mental stress in hypertensive patients., Conclusion: ACE inhibition in patients with mild hypertension increased selectively renal perfusion, which is conserved during mental stress without persistent effects on the sympathetic nervous system. Thus, mental stress as a correlate of daily life stress appeared not to confound the selective renal vasodilatory effect of ACE inhibitors.

Cardiovascular responses to new antihypertensive agents have been studied extensively under resting and stress conditions. However, the effects of antihypertensive agents on renal hemodynamics have only been investigated at rest. To test whether antihypertensive therapy leads to disparate renal hemodynamic effects during exposure to mental stress as opposed to resting conditions, we performed a double-blind, placebo-controlled crossover study. In 17 normotensive healthy men, glomerular filtration rate (GFR; inulin clearance) and renal plasma flow (RPF; para-aminohippuric acid clearance) were measured at rest and after a standardized mental stress test, with or without one week's treatment with a new, long-acting ACE-inhibitor cilazapril 2.5 mg/day. ACE-inhibition did not change resting blood pressure, RPF, GFR, or derived parameters, such as filtration fraction, renal vascular resistance and renal fraction of cardiac output. Mental stress caused an acute increase in GFR (p < 0.001) and filtration fraction with both treatments (0.001). However, the increase in GFR and filtration with mental stress was greater (p < 0.05) with cilazapril treatment than with placebo. Thus, renal hemodynamic responses to mental stress were influenced by ACE inhibitors. We conclude that the impact of antihypertensive agents on renal hemodynamics during stress cannot a priori be delineated from measurements at rest.

To stop or reverse progression of congestive heart failure is so far an unreached therapeutic goal. Several prospective studies have now clearly shown that treatment with angiotensin-converting enzyme (ACE) inhibitors resulted in a clear reduction of cardiovascular and total mortality in patients with congestive heart failure. As a consequence, ACE-inhibitors are now standard therapy for congestive heart failure in addition to diuretics and glycosides. Of pathophysiologic importance is that ACE-inhibitors are potent vasodilators and counteract the neuroendocrine stimulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system which both contribute to the detrimental outcome in congestive heart failure. New results of the prevention trial of the SOLVD-Study showed that in patients with reduced ejection fraction the development of congestive heart failure could be attenuated or even stopped. The questions remain of what is the optimal dose, when should treatment with ACE-inhibitors be started, and how long should it be maintained. Thus, in patients with reduced ejection fraction after myocardial infarction ACE-inhibitors are today a cornerstone for preventing progressive congestive heart failure and improving cardiovascular prognosis. Whether beta-blockers offer additional benefit in subgroups of patients with congestive heart failure remains to be determined in future trials.

To determine the haemodynamic profile of angiotensin converting enzyme (ACE) inhibitors during stress, the cardiovascular response to various stress tests was examined in patients with essential hypertension before and after three months of therapy with lisinopril. Eighteen white patients were enrolled in the trial, of whom 12 completed the protocol. ACE inhibition with lisinopril effectively reduced systolic and diastolic pressure in the office (P less than 0.001), at rest (P less than 0.002), during mental stress (P less than 0.003), cold pressor test (P less than 0.003), and reaction time task (P less than 0.05). During physical exercise only diastolic pressure was significantly reduced (P less than 0.02). The fall in peak systolic pressure during cold pressor test and reaction time task was more pronounced than the fall in casual systolic pressure (P less than 0.05). At rest, cardiac output was unchanged, but total peripheral resistance was reduced after medication with lisinopril (P less than 0.05). During the cold pressor test, the increase in total peripheral resistance was attenuated by ACE inhibition (P less than 0.04). The haemodynamic response profile was not altered during the other tests. It is concluded that in middle-aged men ACE inhibitors reduce blood pressure during a variety of stressful events without altering the haemodynamic profile and even attenuating vasoconstriction during stress. This response pattern to ACE inhibition with lisinopril may reduce the impact of recurring stress-induced increases of blood pressure and of exaggerated vasoconstrictive stimuli on the cardiovascular system.

Systemic and renal hemodynamics were studied by invasive and noninvasive techniques in 30 patients with mild to moderate essential hypertension before and after antihypertensive therapy with captopril (12 patients), enalapril (8 patients), and lisinopril (10 patients). All three angiotensin-converting enzyme (ACE) inhibitors reduced arterial pressure to about the same extent: captopril by 14%, enalapril by 18%, and lisinopril by 13%. However, lisinopril produced a significant fall (14%, P less than 0.001) in cardiac output that was not seen with captopril or enalapril therapy. Moreover, lisinopril elicited an increase in renal blood flow (22%, P less than 0.05) that was more marked than that with enalapril (12%) or captopril (4%). Although left ventricular mass was reduced (P less than 0.05) with all three agents, enalapril induced a twofold greater reduction (29%) than captopril (14%) or lisinopril (12%). These findings suggest that systemic and renal hemodynamic effects may be drug specific and not uniform for all ACE inhibitors.

The immediate and short-term effects of lisinopril, a new converting enzyme inhibitor, on systemic and regional hemodynamics, cardiac structure and function and humoral indexes were evaluated in 10 patients with mild to moderate essential hypertension. A single oral dose of 5 mg lisinopril reduced mean arterial pressure from 118 to 104 mm Hg (p less than 0.01) and significantly increased (p less than 0.05) all load-dependent indexes of ventricular function (i.e., ejection fraction, velocity of circumferential fiber shortening and fractional fiber shortening rate). After 10 to 12 weeks of once-daily administration of lisinopril, mean arterial pressure remained reduced over a full 24-hour period (p less than 0.01), and was mediated through arteriolar dilation as expressed by the close correlation (r = 0.93, p less than 0.01) between changes in mean arterial pressure and changes in total peripheral resistance. Cardiac index decreased from 3.06 to 2.68 liters/min/m2 (p less than 0.01) without correlation to the decrease in arterial pressure (r = 0.06). Despite this reduction in cardiac index, renal blood flow increased from 861 to 1,053 ml/min (p less than 0.05) and renal vascular resistance decreased from 14 to 9 units (p less than 0.01). Left ventricular mass index decreased from 124 to 109 g/m2 (p less than 0.05), and left ventricular function remained unchanged. Thus, the decrease in arterial pressure produced by lisinopril was associated with improved renal hemodynamics and reduced left ventricular mass.