High-dose Angiotensin-converting Enzyme Inhibitor Research Articles

Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitor in Combination with Angiotensin-Receptor Blocker in Chronic Kidney Disease Based on Dose: A Systematic Review and Meta-Analysis.

Background: The purpose of this meta-analysis was to evaluate the controversy of angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) in the treatment of chronic kidney disease (CKD) based on dose. Methods: PubMed, EMBASE, and Cochrane Library were searched to identify randomized controlled trials (RCTs) from inception to March 2020. The random effects model was used to calculate the effect sizes. Potential sources of heterogeneity were detected using sensitivity analysis and meta-regression. Results: This meta-analysis of 53 RCTs with 6,375 patients demonstrated that in patients with CKD, ACEI in combination with ARB was superior to low-dose ACEI or ARB in reducing urine albumin excretion (SMD, −0.43; 95% CI, −0.67 to −0.19; p = 0.001), urine protein excretion (SMD, −0.22; 95% CI, −0.33 to −0.11; p < 0.001), and blood pressure (BP), including systolic BP (WMD, −2.89; 95% CI, −3.88 to −1.89; p < 0.001) and diastolic BP (WMD, −3.02; 95% CI, −4.46 to −1.58; p < 0.001). However, it was associated with decreased glomerular filtration rate (GFR) (SMD, −0.13; 95% CI, −0.24 to −0.02; p = 0.02) and increased rates of hyperkalemia (RR, 2.07; 95% CI, 1.55 to 2.76; p < 0.001) and hypotension (RR, 2.19; 95% CI, 1.35 to 3.54; p = 0.001). ACEI in combination with ARB was more effective than high-dose ACEI or ARB in reducing urine albumin excretion (SMD, −0.84; 95% CI, −1.26 to −0.43; p < 0.001) and urine protein excretion (SMD, −0.24; 95% CI, −0.39 to −0.09; p = 0.002), without decrease in GFR (SMD, 0.02; 95% CI, −0.12 to 0.15; p = 0.78) and increase in rate of hyperkalemia (RR, 0.94; 95% CI, 0.65 to 1.37; p = 0.76). Nonetheless, the combination did not decrease the BP and increased the rate of hypotension (RR, 3.95; 95% CI, 1.13 to 13.84; p = 0.03) compared with high-dose ACEI or ARB. Conclusion: ACEI in combination with ARB is superior in reducing urine albumin excretion and urine protein excretion. The combination is more effective than high-dose ACEI or ARB without decreasing GFR and increasing the incidence of hyperkalemia. Despite the risk of hypotension, ACEI in combination with ARB is a better choice for CKD patients who need to increase the dose of ACEI or ARB (PROSPERO CRD42020179398).

Risks of ACE Inhibitor and ARB Usage in COVID-19: Evaluating the Evidence.

Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID‐19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a literature review of studies (n = 12) in experimental animals and human subjects (n = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID‐19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Might Be Associated with Lung Adenocarcinoma Risk: A Nationwide Population-Based Nested Case–Control Study

Objectives: To analyze the association of the use of different doses of angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) independently with lung cancer risk and to evaluate the lung cancer type that may be related to ARB or ACEI use. Patients and Methods: A nationwide population-based nested case–control study was conducted using Taiwan National Health Insurance Research Database linked to the Taiwan Cancer Registry database between January 1, 2000, and December 31, 2016. The cumulative defined daily dose (DDD) was estimated. We divided all users of ACEI or ARB into three categories based on the DDD of ACEI or ARB: low dose, middle dose, and high dose. Results: We identified 16,091 patients with newly diagnosed lung cancer, and 80,455 controls with hypertension were selected. Univariate and multivariate conditional logistic regressions showed that the independent risk factor for lung cancer was high-dose (≥1095 DDD) ARB use (adjusted odds ratio [OR]: 1.069, 95% confidence interval [CI]: 1.02–1.12, P = 0.003). An increase in lung adenocarcinoma (ADC) risk was associated with middle-dose (adjusted OR: 1.073, 95% CI: 1.01–1.14, P = 0.025) to high-dose (adjusted OR: 1.106, 95% CI: 1.05–1.17, P < 0.001) ARB use and high-dose ACEI use (adjusted OR: 1.095, 95% CI: 1.01–1.19, P = 0.033). No association was observed between different ARB or ACEI dose levels and the risk of lung squamous cell carcinoma and small-cell lung carcinoma. Conclusions: Our results suggest that the use of both ACEI and ARB at a high cumulative dose is associated with the risk of lung ADC. Funding Statement: Taipei Medical University and Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital (Funding Number 10908 & 10909). Declaration of Interests: The authors have no potential conflicts of interest to declare. Ethics Approval Statement: Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. 201712019).

DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs.

Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR).

Higher versus lower doses of ACE inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction: Systematic review and meta-analysis.

BackgroundCurrent heart failure (HF) guidelines recommend titrating angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and beta-blockers (BBs) to target doses used in pivotal placebo-controlled randomized controlled trials (RCTs). Despite a number of RCTs comparing different doses (i.e. higher versus lower doses) of ACEIs, ARBs and BBs, the effects of higher versus lower doses on efficacy and safety remains unclear. For this reason, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of higher versus lower doses of ACEIs, ARBs and BBs in patients with HFrEF.MethodsWe searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) via Ovid from inception to April 25th, 2018 and opentrials.net and clinicaltrials.gov for relevant trials that compared different doses of medications in heart failure. We analyzed trials by drug class (ACEIs, ARBs, and BBs) for efficacy outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalizations, HF hospitalizations, HF worsening). For safety outcomes, we pooled trials within and across drug classes.ResultsOur meta-analysis consisted of 14 RCTs. Using GRADE criteria, the quality of evidence for ACEIs and ARBs was assessed as generally moderate for efficacy and high for adverse effects, whereas overall quality for BBs was very low to low. Over ~2–4 years higher versus lower doses of ACEIs, ARBs or BBs did not significantly reduce all-cause mortality [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.87–1.02)], ARBs RR 0.96 (0.87–1.04), BBs RR 0.25 (0.06–1.01)] or all cause hospitalizations [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.86–1.02)], ARBs RR 0.98 (0.93–1.04), BBs RR 0.93 (0.39–2.24)]. However, all point estimates favoured higher doses. Higher doses of ARBs significantly reduced hospitalization for HF [RR 0.89 (0.80–0.99)– 2.8% ARR], and higher doses of ACEIs and ARBs significantly reduced HF worsening [RR 0.85 (0.79–0.92)– 5.1% ARR and 0.91 (0.84–0.99)– 3.2% ARR, respectively] compared to lower doses. None of the differences between higher versus lower doses of BBs were significant; however, precision was low. Higher doses of these medications compared to lower doses increased the risk of discontinuation due to adverse events, hypotension, dizziness, and for ACEIs and ARBs, increased hyperkalemia and elevations in serum creatinine. Absolute increase in harms for adverse effects ranged from ~ 3 to 14%.ConclusionsHigher doses of ACEIs and ARBs reduce the risk of HF worsening compared to lower doses, and higher doses of ARBs also reduce the risk of HF hospitalization but the evidence is sparse and imprecise. Higher doses increase the chance of adverse effects compared to lower doses. Evidence for BBs is inconclusive. These results support initially always starting at low doses of ACEIs/ARBs and only titrating the dose up if the patient tolerates dose increases.

Dose of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Outcomes in Heart Failure: A Meta-Analysis.

The association between angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) doses on outcomes in patients with heart failure (HF) with reduced ejection fraction is uncertain. The objective of this study was to investigate the effect of dose of ACEI and ARBs on outcomes and drug discontinuation in patients with HF with reduced ejection fraction. MEDLINE, Ovid SP, and Embase were searched from the inception of these databases till August 2016. Randomized controlled trials that compared high doses of ACEI or ARB against low doses among patients with HF with reduced ejection fraction were included. Pooled analysis was done using a random-effects model, and quality of the studies was assessed by JADAD scale. The main outcomes were all-cause mortality and drug discontinuation. A total of 6 studies (4841 patients in low-dose and 4330 patients in high-dose groups) were included. Compared with low dose, high-dose ACEI or ARBs decreased all-cause mortality modestly (relative risk, 0.94; 95% confidence interval (CI), 0.89-1.00; P=0.05; I2=0%) and composite of HF hospitalizations and all-cause mortality (relative risk, 0.93; 95% CI, 0.87-1.00; P=0.04; I2=39.8%). No significant difference was found between the 2 groups in HF hospitalizations (relative risk, 0.94; 95% CI, 0.70-1.26; P=0.68; I2=52.8%) and all-cause hospitalizations (relative risk, 0.97; 95% CI, 0.85-1.11; P=0.67; I2=31.7%) risk. Discontinuation rates were also not significantly different in both groups (odds ratio, 1.13; 95% CI, 0.92-1.39; P=0.25; I2=32.6%). In patients with HF with reduced ejection fraction, compared with lower doses, higher doses of ACEI and ARB significantly though modestly improved the composite end point of all-cause mortality or HF hospitalization without significantly increasing the chances of discontinuation.

Change in Cardiac Geometry and Function in CKD Children During Strict BP Control

Left ventricular hypertrophy (LVH) and abnormal systolic function are present in a high proportion of children with CKD. This study evaluated changes in left ventricular (LV) geometry and systolic function in children with mild to moderate CKD as an ancillary project of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of Chronic Renal Failure in Pediatric Patients trial. Echocardiograms and ambulatory BP monitoring were performed at baseline and at 1- or 2-year follow-up in 84 patients with CKD and 24-hour mean BP above the 50th percentile and/or receiving fixed high-dose angiotensin converting enzyme inhibition and randomized to conventional or intensified BP control. LVH prevalence decreased from 38% to 25% (P<0.05). Changes in LV mass index (LVMI) were restricted to patients with LVH at baseline (-7.9 g/m(2.7); P<0.02). Changes in LVMI were independent of randomization, reduction in BP, hemoglobin, and estimated GFR. A significant increase in midwall fractional shortening was observed in the total cohort (P<0.05), and was greater in the intensified group compared with the conventional BP control group (12%±1.9% versus 8%±1.5%; P=0.05). In multivariate analysis, improvement in myocardial function was associated with reduction in BP (r=-0.4; P<0.05), independently of LVMI reduction. In children with CKD, angiotensin converting enzyme inhibition with improved BP control, LVH regression, and improved systolic function was observed within 12 months. Lowering BP to the low-normal range led to a slightly more marked improvement in myocardial function but not in LVMI.

Prognosis of scleroderma renal crisis: a long-term observational study

Despite the efficacy of angiotensin-converting enzyme (ACE) inhibitors, the prognosis of patients with Scleroderma renal crisis (SRC) is characterized by a high rate of mortality and progression into end-stage renal disease (ESRD). Our aim was to evaluate the prognosis of SRC in our cohort of scleroderma patients. We reviewed clinical charts of all our patients who developed SRC from 1980 to 2005. Outcome measures were ESRD, patients' survival and SRC-related mortality. ESRD was defined as the need for chronic dialysis; survival was calculated from the time of SRC occurrence by Kaplan-Meier method. All patients were treated with ACE inhibitors and 10 patients were also treated with plasma exchange (PEx). Indications to PEx were concomitant micro-angiopathic haemolytic anaemia or intolerance to high doses of ACE inhibitors. SPSS package was used for calculation. Of 606 patients, affected with systemic sclerosis, who came at our observation during the aforementioned interval, 20 (3.3%) developed SRC. One year after SRC onset, 55% of patients developed ESRD. The survival rate was 70% at 1 year and 50% at 5 years; the mortality rate related to SRC was 35%. Notably, in the subgroup of patients treated with PEx, 20% developed ESRD; the survival rate was 90% at 1 year and 70% at 5 years; the mortality rate related to SRC was 10%. Short-term prognosis of SRC has improved, but long-term prognosis remains disappointing. PEx in addition to ACE inhibitors seems to be a therapeutic option in patients with SRC who develop micro-angiopathy or are intolerant to high doses of ACE inhibitors.

Combined renin angiotensin blockade in childhood steroid‐resistant nephrotic syndrome

Reduced proteinuria results in delayed deterioration of renal function and remission of proteinuria predicts a good long-term prognosis in steroid-resistant nephrotic syndrome (SRNS). The aim of this study was to analyze the effects of the combined angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker in reducing proteinuria in SRNS. A prospective study of eight patients with SRNS was conducted at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University from September 2003 to December 2007. Enalapril was given at 0.1 mg/kg/day and was increased by 0.1 mg/kg/day every 4 weeks up to 0.6 mg/kg/day (maximum 40 mg/day) and 1 mg/kg/day of losartan was added for 4 weeks and stepped up to 2 mg/kg/day (maximum 100 mg/day) for another 4 weeks. There were five boys (62.5%) and three girls (37.5%). The mean age at diagnosis was 8.3 ± 4.1 years (range 2.05-13 years) and age at enrollment was 11.7 ± 3.8 years (range 6-16 years). Renal histology revealed seven focal segmental glomerulosclerosis and one immunoglobulin M nephropathy. The results showed significant reduction on mean spot urine protein : creatinine ratio from 9.6 ± 2.3 to 3.6 ± 1.6 (P < 0.05) and 24-h urine protein from 182.8 ± 59.6 to 28.7 ± 8.2 mg/m(2) /h (P < 0.05). Urine protein reduction ratio at the end of the study was 50% (P= 0.08). Serum cholesterol, albumin, potassium, blood pressure and renal function had no significant change. No clinical and laboratory side-effects were reported. Combined high-dose angiotensin II receptor blocker to high-dose angiotensin-converting enzyme inhibitor therapy is safe and effective in reducing proteinuria in childhood SRNS. However a large-scale study should be conducted to validate this result.

The Cardiologist’s Role in the Management of Type 2 Diabetes—A Review

Evidence-based medicine is key to the cardiologist’s role in the management of type 2 diabetes. Proven therapies that reduce cardiovascular (cV) events with few off-target effects are imperative. evidence from epidemiology studies supports the concept that increased blood sugar is correlated with increased cV events. unfortunately, the lowering of glucose with current agents shows limited benefit in reducing cV events. Metformin in the obese individual reduced cV events and is currently first-line therapy in most clinical practice guidelines. recently, a meta-analysis reported that current hypoglycemic agents did not improve cV outcomes and were possibly harmful. Possible exceptions come from the Prospective pioglitazone clinical trial in macrovascular events (Proactive), a secondary prevention trial in patients with prior myocardial infarction in which pioglitazone was found to reduce cV events. glucagon-like peptide-1 (gLP-1) agonists appear to be the most exciting new cV agents, but a dipeptidyl peptidase-4 (DPP4) inhibitor (sitagliptin) combined with a high-dose angiotensin-converting enzyme inhibitor (Acei) (enalapril) may increase blood pressure and heart rate. Lifestyle modification and proven global risk reduction are still the number one ways to reduce cV events in type 2 diabetes.

The renin–angiotensin system in the breast and breast cancer

Much evidence now suggests that angiotensin II has roles in normal functions of the breast that may be altered or attenuated in cancer. Both angiotensin type 1 (AT1) and type 2 (AT2) receptors are present particularly in the secretory epithelium. Additionally, all the elements of a tissue renin-angiotensin system, angiotensinogen, prorenin and angiotensin-converting enzyme (ACE), are also present and distributed in different cell types in a manner suggesting a close relationship with sites of angiotensin II activity. These findings are consistent with the concept that stromal elements and myoepithelium are instrumental in maintaining normal epithelial structure and function. In disease, this system becomes disrupted, particularly in invasive carcinoma. Both AT1 and AT2 receptors are present in tumours and may be up-regulated in some. Experimentally, angiotensin II, acting via the AT1 receptor, increases tumour cell proliferation and angiogenesis, both these are inhibited by blocking its production or function. Epidemiological evidence on the effect of expression levels of ACE or the distribution of ACE or AT1 receptor variants in many types of cancer gives indirect support to these concepts. It is possible that there is a case for the therapeutic use of high doses of ACE inhibitors and AT1 receptor blockers in breast cancer, as there may be for AT2 receptor agonists, though this awaits full investigation. Attention is drawn to the possibility of blocking specific AT1-mediated intracellular signalling pathways, for example by AT1-directed antibodies, which exploit the possibility that the extracellular N-terminus of the AT1 receptor may have previously unsuspected signalling roles.

Antihypertensive effects exerted by enalapril in mild to moderate hypertension are not associated with changes in the circulating levels of nitric oxide-related markers

The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients. Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n=10) or 20 mg/day (n=8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively. Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril. Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi.

Glomerular scarring: can we delay or even reverse glomerulosclerosis by RAAS inhibition?

Summary In a recent publication, Macconi et al. show that reversal of focal and segmental glomerulosclerosis (FSGS) lesions in aged Munich Wistar Fromter (MWF) rats treated with high-dose angiotensin-converting enzyme inhibitors (ACE) inhibitors is associated with a reconstitution of the number of podocytes [1]. Aged MWF rats spontaneously develop hypertension, proteinuria, and focal and segmental glomerulosclerosis due to an unknown genetic defect. In 2006, the Remuzzi group has shown that treatment of aged MWF rats with very high doses of the ACE inhibitor lisinopril (∼10 mg/ kg/day) could revert proteinuria, and additional loss of renal function could be prevented effectively [2]. A detailed histological analysis showed that glomerular scarring was effectively reduced by this treatment suggesting that regression of glomerular scars could be achieved in these animals. In a recent paper, Macconi et al. followed up on this important finding and investigated changes in resident glomerular cells. They showed that the absolute podocyte number was decreased from 159 to 109 podocytes per glomerulus in aged MWF rats and that lisinopril treatment could restore the podocyte number to 144 (P < 0.01). As a mechanism for this cell renewal, the authors show that ∼10% of podocytes co-expressed the proliferation marker Ki-67 in the treated rats suggesting that podocytes could undergo cell divisions in situ or that these cells could be regenerated from parietal cells. To support the latter notion, the authors show that a significantly higher proportion of parietal podocytes were present in the treated animals. This raises the interesting possibility for the existence of a glomerular regenerative mechanism.

“Pulse” Treatment With High-Dose Angiotensin Blocker Reverses Renal Arteriolar Hypertrophy and Regresses Hypertension

One ultimate goal of hypertension therapy is to cause permanent reversal ("regression") of already established hypertension. Our aim was to examine whether high-dose "pulse" treatment with a renin-angiotensin system inhibitor could cause regression of established hypertension and to link this action to reversal of arteriolar hypertrophy and changes in vascular matrix metalloproteinase activities. First, 16-week-old male spontaneously hypertensive rats (n=60) were pulse treated for 2 weeks with high-dose angiotensin-converting enzyme inhibitor (enalapril), angiotensin receptor blocker (candesartan), calcium channel blocker (nifedipine), or vasodilator (hydralazine) with or without salt restriction, and the long-term effects on blood pressure were examined. Second, spontaneously hypertensive rats were treated with angiotensin receptor blocker or calcium channel blocker, and the effects on renal gene expressions, arteriolar structure, and vascular matrix metalloproteinase were compared. Treatment of spontaneously hypertensive rats with different antihypertensive agents caused apparently similar reductions in blood pressure during the course of the pulse treatment, within the limitations of the tail-cuff method. After cessation of medications, blood pressure in the rats treated with renin-angiotensin system inhibitor remained reduced by >30 to 40 mm Hg for 4 months. No such effect was seen with calcium channel blocker or vasodilator. The 2-week angiotensin receptor blocker treatment induced a marked reversal of the arteriolar hypertrophy specifically in the small (30 to 100 microm) renal arterioles, together with increased expression and activity of matrix metalloproteinase-13. In conclusion, transient high-dose pulse treatment with angiotensin receptor blocker caused changes in vascular matrix metalloproteinase activity, specific reversal of renal arteriolar hypertrophy, and regression of hypertension in spontaneously hypertensive rats.

High-dose angiotensin-converting enzyme inhibitor attenuates oxidative stress in patients with chronic kidney disease

High-dose angiotensin-converting enzyme inhibitor attenuates oxidative stress in patients with chronic kidney disease

Pulse Pressure Lowering Effect of Dual Blockade With Candesartan and Lisinopril vs. High-dose ACE Inhibition in Hypertensive Type 2 Diabetic Subjects: A CALM II Study Post-hoc Analysis

Elevated pulse pressure (PP) is strongly associated with micro- and macrovascular complications in type 2 diabetic patients. We examined the effect of 12 months of dual blockade with candesartan and lisinopril vs. high-dose lisinopril monotherapy on ambulatory PP in hypertensive type 2 diabetic patients from the CALM (Candesartan and Lisinopril Microalbuminuria Trial) II study. The CALM II study was a 12-month prospective, randomized, parallel-group, double-masked study that included 75 type 1 and type 2 diabetic subjects with hypertension. Participants were randomized for treatment with either high-dose lisinopril (40 mg once daily (o.d.)) or for dual blockade treatment with candesartan (16 mg o.d.) and lisinopril (20 mg o.d.). In this article, we present data from the post-hoc subgroup of 51 type 2 diabetic subjects who completed the full 12-month study period with successful ambulatory blood pressure (BP) measurements at both baseline and follow-up visits. Baseline 24-h BP values were similar in the two groups (24-h systolic BP (SBP) 130 +/- 12 vs. 127 +/- 9, 24-h diastolic BP (DBP) 77 +/- 8 vs. 74 +/- 7, and 24-h PP 53 +/- 8 vs. 53 +/- 7 mm Hg, for the lisinopril and dual blockade groups, respectively, P > 0.2 for all). Compared with lisinopril monotherapy, dual blockade treatment caused a highly significant reduction in 24-h PP levels (-5 +/- 5 mm Hg, P = 0.003), albeit the difference in the BP lowering effect between the treatment groups did not differ significantly for 24-h systolic (P = 0.21) or diastolic (P = 0.49) BP. Dual blockade treatment significantly lowered 24-h SBP (-5 +/- 11 mm Hg, P = 0.03), but not 24-h DBP (-2 +/- 7 mm Hg, P = 0.29), whereas in the lisinopril group, the opposite effect was observed (24-h SBP -1 +/- 9 mm Hg, P = 0.45, 24-h SBP -3 +/- 7 mm Hg, P = 0.03). Twelve months of dual blockade with candesartan and lisinopril significantly reduced PP when compared with high-dose monotherapy with lisinopril. Larger studies are needed to confirm this observation, and to evaluate whether this effect translates into a greater degree of end-organ protection from dual blockade treatment than from conventional angiotensin-converting enzyme (ACE) inhibition.

Dual blockade of the renin–angiotensin–aldosterone system with high-dose angiotensin-converting enzyme inhibitor for nephroprotection: An open, controlled, randomized study

Despite the proven effectiveness of combination therapy with an angiotensin I-converting enzyme inhibitor (ACEI) and angiotensin II-receptor blockers (ARBs) for the prevention and treatment of kidney disease, it has not proved possible to inhibit the progress of chronic nephropathies completely. To improve renal outcome one may consider using increased dosages of ACEI above those usually recommended for hypertension. A randomized, open, controlled study was conducted to evaluate the influence of two combination therapies on proteinuria, markers of tubular injury and renal fibrosis. A total of 18 patients with a creatinine level of 109+/-36 micromol/l and proteinuria of 0.97+/-0.76 g/24 h were enrolled in the study. In the 8-week run-in period, an ACEI (cilazapril 5 mg once-daily) and an ARB (telmisartan 80 mg once-daily) were administered to achieve the target blood pressure of < or = 130/80 mmHg. Next, the patients were randomly assigned to either an increased dose of cilazapril (10 mg) or the previous dose (5 mg) in two active-treatment periods, each lasting 8 weeks. A significant increase in renin activity was observed after administration of cilazapril 10 mg (6.46+/-1.12 vs 4.67+/-0.7 ng/ml/h; p=0.028). Proteinuria, urine excretion of N-acetyl-beta-D-glucosaminidase, and alpha1-microglobulin and amino-terminal propeptide of type III procollagen were unchanged. An increased dosage of cilazapril (twice the maximum recommended dose) in addition to combination therapy with telmisartan was associated with increased blockade of the renin-angiotensin-aldosterone system, with no additional effect on proteinuria, markers of tubular injury or renal fibrosis.

ASSOCIATION BETWEEN PSYCHOTROPIC DRUG USE AND HEART FAILURE THERAPY IN ELDERLY LONG‐TERM CARE RESIDENTS

ASSOCIATION BETWEEN PSYCHOTROPIC DRUG USE AND HEART FAILURE THERAPY IN ELDERLY LONG‐TERM CARE RESIDENTS

What is the Optimal Angiotensin‐Converting Enzyme Inhibitor Dose in Heart Failure?

Doses of angiotensin-converting enzyme (ACE) inhibitors used in the landmark heart failure trials that demonstrated survival benefit are rarely reached in routine practice. The authors review the current literature regarding optimal dosing of ACE inhibitors in heart failure with specific focus on neurohormonal, functional capacity, and clinical outcomes. Neurohormonal studies have shown that lower ACE inhibitor dosing may provide inadequate suppression of the renin-angiotensin-aldosterone system. Higher doses of ACE inhibitors have resulted in greater increments in exercise and functional capacity. Clinically, patients on high-dose ACE inhibitor therapy had significant reductions in all-cause mortality or hospitalization, cardiovascular hospitalizations, and heart failure-specific hospitalizations. There is, however, conflicting evidence, and so continued uncertainty exists regarding optimal dosing. Despite underutilization of ACE inhibitors, there is insufficient evidence to support lower doses. Likewise, limited data exist for doses higher than those used in the landmark trials. Clinicians should therefore attempt to reach target doses in heart failure whenever possible.

Effects of angiotensin converting enzyme inhibitor with different doses on plasma brain natriuretic peptide and norepinephrine in patients with chronic heart failure

To investigate the effects of angiotensin converting enzyme inhibitor (ACEI) with different doses on the plasma brain natriuretic peptide and norepinephrine (NE) of patients with chronic heart failure and the feasibility and safety of high dose ACEI treatment. Sixty-six patients with chronic heart failure were randomly divided into 2 groups: low-dose group, treated by perindopril with the dosage of 2 mg/d initially and gradually increased up to 2-4 mg/d, and high-dose group, treated by perindopril with the dosage of 2 mg/d initially and gradually increased up to 8 approximately 10 mg/d. Treatment lasted for 12 weeks. Before and after the treatment peripheral blood was collected to test the plasma NE and brain natriuretic peptide levels, and the left ventricular ejection fraction (LVEF), left ventricular end diameter (LVED), blood pressure, and heart rate were examined. The differences of these indexes between the two groups and within the same group before and after the 12-week treatment were analyzed. Thirty healthy subjects were used as control group. The levels of plasma brain natriuretic peptide and NE of the chronic heart failure patients were significantly higher than those of the normal controls, and the higher the NYHA class of heart failure the higher the plasma levels of NE and brain natriuretic peptide. The plasma brain natriuretic peptide level was negatively correlated with LVEF (r = -0.327, P = 0.012) and positively correlated with plasma NE level (r = 0.402, P = 0.002) and LVED (r = 0.42, P = 0.015). The plasma brain natriuretic peptide and NE levels in the high-dose group were 6 microg/L +/- 4 microg/L and 250 ng/L +/- 63 ng/L respectively, both significantly lower than those of the low-dose group (8 microg/L +/- 4 microg/L and 387 ng/L +/- 211 ng/L respectively, both P < 0.05). Most of the patients in these 2 groups tolerated well. Plasma brain natriuretic peptide level is negatively correlated with the severity of heart failure and positively correlated with plasma NE. Treatment of CHF by perindopril with gradually increasing dose obviously decreases the plasma brain natriuretic peptide and NE levels and is tolerable for the patients.