Recent changes in the landscape of combination RAS blockade

The beneficial effects of blood pressure-lowering treatments on the risks of major cardiovascular events are well established [1]. Interruption of the renin–angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) has been shown to be an effective strategy for lowering blood pressure. Randomized trials have shown that ACEi can lower blood pressure by an average of 5/2 mmHg and reduce the risks of cardiovascular events and cardiovascular mortality by ∼20% (and total mortality by 10%) [2–6]. ARBs produce similar reductions in blood pressure and vascular events (although fewer patients have received them in randomized trials) [7–9]. Further, RAS blockade has been reliably shown to reduce the risk of kidney disease progression [10–15]. A meta-analysis of ACEi and ARB monotherapy in diabetic nephropathy demonstrated reductions in end-stage renal disease (ESRD) of around one-quarter for both treatments [16]. Similarly, an individual patient data meta-analysis of ACEi in non-diabetic kidney disease showed a relative risk reduction of 31% (95% CI 5–49%). The major trials of ACEi or ARB monotherapy in various patient populations are summarized in Table 1. As shown in Table 1, among patients at a low risk of renal progression ESRD occurs rarely, and only after many years or even decades. This probably explains the lack of renal benefit reported in large general population trials and meta-analyses of such trials [17–19]. Furthermore, there is some evidence that even the relative benefit might depend on baseline risk, making it even less likely that any true benefit could be detected in existing trials [10]. Whether the observed benefits of RAS blockade are only mediatedbytheirbloodpressure-loweringeffectorwhether other effects also play a role remains controversial; there is some evidence that interruption of the RAS provides more benefit than would simply be expected by the degree of blood pressure reduction alone [5,7,20]. It has been suggested that incomplete blockade of the RAS with ACEi or ARB monotherapy can cause a phenomenon called ‘aldosterone escape’, in which the lack of negative feedback from end-products of the RAS causes a reactive increase in renin and consequent increases in angiotensin I and II concentrations which overwhelm the pharmacological blockade [21]. Dual blockade would therefore be attractive as ACEi and ARB inhibit the RAS at different steps. However, there is continuing uncertainty about the balance of benefits and harms of dual RAS blockade, both in terms of cardiovascular risk and progression of kidney disease. This question will be discussed here in the context of recent evidence from randomized controlled trials.

Introduction: Angiotensin-converting enzyme (ACE) inhibitors have been shown to prevent cardiovascular events in high-risk patients in multiple studies. Among numerous trials, the use of ACE inhibitors was investigated for patients with left ventricular dysfunction [1], acute myocardial infarction (MI) [2], previous cardiovascular disease (CVD) or high-risk diabetes [3,4], and heart failure [5,6]. Additionally, the benefi t of angiotensin receptor blockers (ARBs) in high-risk patients with heart failure, MI, and left ventricular dysfunction was demonstrated in multiple studies [7–9]. However, ARB’s role in reducing the CVD events for high-risk patients without heart failure is not well defi ned. The renin-angiotensin system (RAS) plays an important role in hypertension, cardiovascular, and renal diseases. Because inhibition of RAS with ACE inhibitors or ARBs is usually incomplete due to various escape mechanisms [10,11], dual blockade of RAS with ACE inhibitors and ARBs appears to be an attractive medical treatment option. Combination therapy is supported by the recent meta-analysis in which combination therapy reduced proteinuria and blood pressure compared with monotherapy [12]; however, the fact that combination therapy leads to better clinical outcomes, such as reducing the CVD events, still remains controversial. Recent evidence from large trials and meta-analyses showed no additional clinical benefi t with combination therapy [13,14]. We reviewed the article on the recently published ONTARGET trial in which the effi cacy of telmisartan with or without ramipril in high-risk patients was investigated.

Objective: There is substantial evidence for a renoprotective effect of inhibitors of the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). However, it is unclear whether dual RAS blockade has additional benefits when compared to monotherapy in this population and whether any benefits outweigh the risks. Data sources: A systematic review and meta-analysis of English language articles was performed using MEDLINE, EMBASE, CINAHL, and the Cochrane database of systematic reviews. Study selection: All randomized, controlled trials comparing RAS blockade to monotherapy in patients with overt proteinuria were included. Data extraction: Articles were reviewed independently by two of the authors using a standardized data collection form including study quality indicators. Data synthesis: All pooled analyses were based on random-effects models. The primary efficacy outcome measure was the percent reduction in proteinuria with combination therapy versus monotherapy measured by difference in means. Secondary outcomes included changes in systolic blood pressure (SBP), glomerular filtration rate (GFR), and serum potassium, and incidence of hyperkalemia. The primary safety outcome was hyperkalemia. Results: Compared to monotherapy, combination therapy with an angiotensin converting enzyme inhibitor (ACEI) plus angiotensin receptor blocker (ARB) reduced proteinuria by an additional 25% (mean difference -25, 95% CI -33,- 17), whereas combination therapy with an aldosterone antagonist (ALDOA) plus ACEI or ARB reduced proteinurea by an additional 32% (mean difference -32, 95% CI -37,-27). SBP after treatment with combination therapy vs. monotherapy was significantly lower with both the ACEI/ARB and ALDOA combinations. Dual therapy was associated with an increase in serum potassium, in particular with the ALDOA combination. Limitations: Most studies were small and of short duration, and none included major patient outcome data such as kidney failure or death. Conclusion: Dual RAS blockade in patients with DKD reduces proteinuria and SBP but increases the risk of hyperkalemia.

No large cohort study has yet determined the incidence of acute kidney injury (AKI) in children with heart failure treated with renin-angiotensin system (RAS) inhibitors. We thus retrospectively analyzed the incidence and risk factors for severe AKI (stages 2-3 according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines) at our institutions from 2008 to 2011. Among 312 children (162 boys; median age, 7.3 months), 59 cases of AKI occurred in 45 children. The incidence of AKI was 14.3 cases per 100 person-years overall (follow-up 413.6 person-years), or 27.3, 16.8, and 4.5 cases per 100 person-years in children aged <1, 1-3, and ≥4 years, respectively. Among them, 23 (39.0 %) children had metabolic acidosis and 14 (23.7 %) had hyperkalemia. Younger age, myocardial disease, cyanotic congenital heart disease, use of spironolactone, and cardiac surgery were independent risk factors for AKI. Furthermore, 37.3 % of children suffered dehydration during AKI. AKI incidence is relatively high in children, particularly younger children, with heart failure treated using RAS inhibitors. Careful monitoring of renal function and serum electrolytes is essential. Proper management of fluid balance after infection and cardiac surgery may reduce the risk of AKI. Temporary discontinuation in RAS inhibitors should be considered during dehydration or surgery. • Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the two main classes of renin-angiotensin system (RAS) inhibitors used to treat hypertension, heart failure, and chronic kidney disease. Acute kidney injury (AKI) and hyperkalemia are potentially life-threatening complications associated with the use of ACEIs and ARBs. Some reports have suggested that dehydration and cardiac surgery are risk factors for AKI in children. However, no large-scale cohort studies have determined the incidence of AKI, its risk factors, and its outcomes in children with heart failure treated with ACEIs and/or ARBs. What is new: • In this retrospective cohort study, we determined the incidence, severity, and risk factors for severe AKI in children with heart failure treated with ACEIs and/or ARBs. The incidence of AKI in these children was relatively high (14.3 episodes per 100 person-years). In addition, younger age, myocardial disease, cyanotic congenital heart disease, concomitant use of spironolactone, and cardiac surgery were risk factors for AKI. Furthermore, 37.3 % of children had dehydration during AKI episodes. • Our results suggested that appropriate fluid balance after infection and cardiac surgery might reduce the risk of AKI and its complications. Temporary discontinuation or reductions in the levels of ACEIs and/or ARBs during dehydration or before surgery may also be warranted in these patients.

Aggressive blood pressure reduction and renin–angiotensin system blockade in chronic kidney disease: time for re-evaluation?

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2–3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

0273: Beneficial effect of sequential nephron blockade on central pressure and large artery remodeling in resistant hypertension

Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis

In this issue of the journal, Hines et al. [1] report incidence rates of ischemic colitis in treated hypertensive adults in the USA, with a focus on aliskiren, a direct renin inhibitor. While these investigators are to be commended for assessing such a large dataset (2,356,226 hypertensive patients), they provide no clear explanation for the focus on aliskiren. The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) trial, which concerned patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, was stopped prematurely because of a slight excess risk of cardiovascular events in patients receiving aliskiren plus an angiotensin receptor blocker (ARB) or angiotensinconverting enzyme inhibitor (ACEI) compared with those receiving placebo plus an ARB or ACEI. This study also demonstrated a significantly higher risk of renal impairment, hypotension, and hyperkalemia in the aliskiren group [2]. Consequently, the US FDA modified the labeling of aliskiren in April 2012 with a new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes, and a warning to avoid the use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment [3] The European Medicines Agency (EMA) contraindicated aliskiren in both situations [4]. One and a half years later, the FDA published a new warning and precaution about symptomatic hypotension that may occur after initiation of aliskiren in patients with marked volume depletion, those with salt depletion, or those receiving other agents acting on the renin–angiotensin–aldosterone system [5]. More recently, in light of two other clinical trials and a meta-analysis [6–8], the EMA recommended against the prescription of dual reninangiotensin system blockade through the combined use of ACEIs, ARBs, or aliskiren [9] because these combinations were associated with an increased risk of hyperkalemia, kidney damage, and hypotension. Furthermore, no significant benefits from dual blockade were seen in patients without heart failure. Benefits were thought to outweigh risks only in a selected group of patients with heart failure in whom other treatments were unsuitable. Hypotension is a risk factor of ischemic colitis, an uncommon, potentially severe, and sometimes fatal disease caused by a lack of blood flow. It is also a diagnosis of exclusion with no identified cause [10, 11]. The ageand sex-adjusted incidence rate was estimated to be 22.9 per 100,000 patient-years (PYs) (95 % confidence interval [CI] 18.6–27.3) for the period 2006–2009 among unselected subjects in a US county [12]. The incidence was twice as frequent for women and increased strongly with age, from 1.1 per 100,000 PYs before the age of 40 years to 107 per 100,000 PYs for subjects aged 80 years or older [10]. In this study, the main risk factor was a hypotensive episode in the previous month (odds ratio [OR] 33.0, 95 % CI 13.3–80.9) [11]. Other independent risk factors identified were collagen vascular disease (OR 8.0, 95 % CI 2.2–28.3), peripheral vascular disease (OR 7.9, 95 % CI 4.7–13.2), congestive heart failure (OR 4.1, 95 % CI 2.6–6.3), psychotropic medications used in the past This comment refers to the article available at doi:10.1007/s40256-014-0101-4.

BackgroundRAS inhibitors have been proved to antiproliferative effect on neointimal hyperplasia so as to prevent in-stent restenosis (ISR) in animal models. However whether RAS inhibitors could prevent ISR in human...

Type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular morbidity and end-stage renal disease. Renin-angiotensin-aldosterone system (RAAS) inhibitors, specifically angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are standard therapies for organ protection. However, uncertainty remains regarding their comparative efficacy and the safety of combination therapy. This systematic review and meta-analysis aimed to compare the efficacy of ACEIs versus ARBs in reducing cardiovascular and renal events in patients with T2DM and to assess the safety of dual blockade. PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) published up to 2025 comparing ACEIs, ARBs, or their combination against placebo or active controls in T2DM patients. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, and renal failure. Methodological quality was assessed using the Cochrane Risk of Bias 2 tool. Data were synthesized using frequentist pairwise and Bayesian network meta-analyses. Heterogeneity was explored via meta-regression, and trial sequential analysis (TSA) was used to assess the sufficiency of evidence. In total, 16 RCTs involving 47,406 participants were included. In pairwise analysis, both ACEIs (risk ratio (RR) = 0.87, 95% confidence interval (CI) = 0.81-0.94) and ARBs (RR = 0.90, 95% CI = 0.83-0.98) significantly reduced the risk of the primary composite endpoint compared to control. Network meta-analysis showed no statistically significant difference between ACEIs and ARBs (RR = 0.98, 95% CI = 0.88-1.09). Although ACEIs ranked slightly higher in probability for reducing all-cause mortality (surface under the cumulative ranking = 78% vs. 65%), this difference was not statistically significant. Dual blockade (ACEI + ARB) increased the risk of hyperkalemia (RR = 2.8) and acute kidney injury (RR = 1.7) without improving efficacy. Meta-regression identified baseline systolic blood pressure as a significant modifier of treatment benefit (p = 0.04). TSA indicated that the evidence for the RAAS blockade's benefit is conclusive. ACEIs and ARBs exhibit comparable efficacy in preventing cardiovascular and renal events in patients with T2DM, with a marginal mortality benefit favoring ACEIs. Dual blockade is associated with increased harm and is not recommended. Monotherapy with either agent remains the preferred strategy for organ protection.

This editorial refers to ‘Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial’[†][1], by K.K.Teo et al. , on page 1743 and ‘Renin–angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure’[‡][2], by E. Sorbets et al. , on page 1760. A series of randomized clinical trials demonstrated that when compared with placebo, angiotensin-converting enzyme (ACE) inhibitiors or angiotensin receptor blockers (ARBs) were drugs able to improve the prognosis of patients with heart failure accompanied by low ejection fraction, patients with a myocardial infarction (MI), and patients with chronic kidney disease (CKD; most notably demonstrated by ARBs in diabetic nephropathy), allowing the recognition by Guidelines that blockade of the renin–angiotensin system (RAS) must be used in all these situations. The use of ACE inhibitors and also of ARBs was later expanded to patients with an increased global cardiovascular (CV) risk, patients with stable coronary artery disease (CAD), diabetic patients independently of the presence of established CV or renal disease, and hypertensive patients if clustering of CV risk factors or target organ damage was present. Table 1 lists the different clinical situations where RAS blockade is indicated according to Guidelines that led to the wide use of ACE inhibitors and ARBs in clinical practice; as an example, either alone or in combination, these drugs are prescribed in > 30–40% of the hypertensive population.1 View this table: Table 1 Clinical situations where the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker has demonstrated positive effects Recently, the first orally active renin inhibitor was launched as an antihypertensive drug able theoretically to improve the degree … [1]: #fn-2 [2]: #fn-3

The outcome of patients with preoperative renin-angiotensin system (RAS) blockade, achieved either by angiotensin converting enzyme inhibitors or angiotensin receptor blocking agents, was assessed using 30-day mortality as a primary end point. An observational cohort study of 883 consecutive patients undergoing elective open abdominal aortic aneurysm repair (AAA) was undertaken and analyzed using a propensity score matched study. The data collected included medical history, anesthetic techniques, and postoperative outcomes. Logistic regression analysis identified predictors of RAS blockade: hypertension, stroke, congestive heart failure, diabetes, and heart disease. A propensity score for RAS blockade was calculated for each subject using several factors: age, sex, serum creatinine, hypertension, heart disease, congestive heart failure, stroke, diabetes, and exposure to cardiovascular medications. Subjects and controls were matched using the calculated propensity score. The overall 30-day mortality rate was 3.5% (31/883 patients). The crude mortality rate in RAS blocked patients was 5.8% (21/359) vs 1.9% (10/524) in unexposed patients (odds ratio 3.2, with 95% confidence intervals [CI(95)] 1.5-6.7; P < 0.001). Analysis of 261 propensity score matched pairs showed a 30-day mortality rate of 6.1% (16/261) in the RAS blocked group vs 1.5% (4/261) in unblocked patients (P = 0.008). The estimated odds ratio for 30-day mortality associated with RAS blockade was 5.0 (CI(95) 1.4-27). Examination of 883 cases of AAA repair showed increased mortality associated with preoperative RAS blockade. A better understanding of perioperative pharmacology and physiology of RAS blockade is needed as well as future studies to identify causality.

Chronic kidney disease (CKD) shares major risk factors with cardiovascular disease (CVD), including hypertension and diabetes mellitus. In patients with hypertensive kidney disease and diabetic nephropathy, inhibitors of the renin-angiotensin system (RAS) significantly reduce the risk of renal and cardiovascular endpoints. Whether the renoprotective effects of RAS inhibitors can be fully accounted for by blood pressure reductions or whether other mechanisms are involved has not been clearly established. Because RAS inhibitors reduce albuminuria and slow progression of kidney disease, they are recommended as first-line antihypertensive agents in patients with CKD, who often require aggressive treatment with ≥ 2 drugs to reach the goal blood pressure (< 130/80 mm Hg). Greater RAS inhibition with higher-than-usual doses of a single agent or dual RAS inhibition with an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker may be necessary for maximum renoprotective effects. Ongoing clinical trials assessing treatment and prevention of CKD may resolve unanswered questions about RAS inhibition in patients with hypertension and/or diabetes.