And/or Angiotensin II Receptor Blockers Research Articles

User of angiotensin-converting-enzyme inhibitor and/or angiotensin II receptor blocker might be associated with vascular calcification in predialysis chronic kidney disease patients: a retrospective single-center observational study

BackgroundVascular calcification is a prominent feature in chronic kidney disease (CKD) and diabetes mellitus. A recent report suggests that angiotensin II is protective to vascular calcification. Therefore, we investigated the relationship between vascular calcification and use of angiotensin-converting-enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) from a cross-sectional view.MethodsA total of 121 predialysis CKD patients (age 71 ± 12 y; male 72; estimated glomerular filtration rate (eGFR) 20.2 (11.8 - 40.3) mL/min/1.73 m2) who underwent thoracoabdominal plain computed tomography scan were included in this study. The total vascular calcification volume (Calc) was calculated with a three-dimensional imaging software and standardized by body surface area (BSA). The relevance between log [Calc/BSA] and ACEI/ARB use was investigated by multivariate linear regression analyses with or without a time-duration factor of ACEI/ARB use.ResultsThe Calc/BSA was 5.62 (2.01 - 12.7) mL/m2 in 121 patients. In multivariate analyses adjusted with age, sex, ACEI/ARB and log [eGFR], ACEI/ARB use is significantly and positively associated with log [Calc/BSA] (β = 0.2781, p = 0.0007). Even after the adjustment by age, sex, log [eGFR], phosphate, diabetes mellitus, systolic blood pressure, warfarin, hypertension, dyslipidemia, low-density lipoprotein cholesterol, diuretics and ACEI/ARB, ACEI/ARB use is significantly and positively associated with log [Calc/BSA] (β = 0.1677, p = 0.0487). When 90 patients whose time-duration of ACEI/ARB use was clear in medical records were studied, a multivariate analysis adjusted with age, sex, log [eGFR], and ACEI/ARB duration factors showed that the longer use of ACEI/ARB more than 2 years was significantly, independently and positively associated with log [Calc/BSA] (β = 0.2864, p = 0.0060).ConclusionsACEI/ARB user was associated with vascular calcification in predialysis patients with low eGFR. Prospective studies with larger numbers of patients or more in vitro studies are needed to confirm whether this phenomenon is due to the use of ACEI/ARB itself, the underlying disease condition or the prescription bias.

Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens.

This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). All adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n = 543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50-1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40-2.23), diabetes (AOR: 1.52; 1.05-2.18), CVD (AOR: 1.88; 1.32-2.70) and COPD (AOR: 1.88; 1.11-3.20). Only gender, age and diabetes also predicted very severe/lethal disease. No association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.

Neurohormonal Blockade During Left Ventricular Assist Device Support.

Neurohormonal blockade (NHB) is the mainstay of therapy for patients with systolic heart failure (HF). However, the efficacy in patients with left ventricular assist devices (LVADs) remains unknown. Of all, 114 LVAD patients (57 [48, 65] years old and 78% male) were enrolled and followed during the early period (6 months after index discharge), and 98 were followed during the late period (6-12 months following index discharge). Of them, 46% were on beta-blocker (BB), 49% on angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II receptor blocker (ARB), and 51% on aldosterone antagonist at baseline. Prevalence of BB and ACEi/ARB use increased during the study period. During the early period, similar event rates were found irrespective of the NHB uses. During the late period, BB was associated with reduced HF readmission, and ACEi/ARB was associated with reduced HF readmission and gastrointestinal bleeding (p < 0.05 for all). In conclusion, BB and ACEi/ARB use during the late period was associated with a reduction in HF recurrence in LVAD patients. Further prospective randomized control trials are warranted to clarify the utility of NHB therapy in LVAD patients.

Intervención farmacéutica para reducir el riesgo de iatrogenia asociada a la combinación triple whammy

ObjectiveTo analyze the effect of an intervention to reduce the iatrogenic risk associated with concomitant treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin-II receptor blockers (ARB) with diuretics and nonsteroidal anti-inflamatory drugs (NSAID), combination known as triple whammy (TW). DesignUncontrolled before-after intervention study. Location15 health centers from a health area (reference population of 292.746 habitants). Participants260 patients ≥18 years old with chronic and concomitant prescriptions of drugs from the therapeutic groups (ATC code): diuretics (C03), ACEi/ARBs (C09) and NSAID (M01) during the month of January 2015 InterventionsA double intervention was conducted during February and March 2015: an educational part, which consisted of an informative session, and an individualized part, in which recommendations to general practitioner were assessed after reviewing medical records. Main measurementsThe number of patients in whom at least one intervention was accepted and the number of patients who continued on TW combination in June 2015, were analyzed. Results were analyzed using descriptive statistics and the prevalence of TW was compared with the one in June 2015 using the Newcombe-Wilson's hybrid method. Results260 patients were included in the study. Recommendations were made in 165 patients (63.5%) and at least one was accepted in 97 (58.8%) patients. In June 2015, 184 patients continued with the TW combination. The TW prevalence decreased by 0.19/1,000 patients (IC 95%: 0.04/1,000 to 0.34/1,000; P=0.017) after the intervention. ConclusionsThe intervention improved the prescription and reduced the number of patients on TW combination.

Determinants of Left Ventricular Systolic Function Improvement Following Coronary Artery Revascularization in Heart Failure Patients With Reduced Ejection Fraction (HFrEF).

Revascularization therapy such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) should be considered for heart failure with reduced ejection fraction (HFrEF). However, revascularization therapy does not always improve left ventricular ejection fraction (LVEF). The purpose of this study was to investigate the determinants of LVEF improvement following revascularization in HFrEF patients. From 2,229 consecutive decompensated heart failure patients, a total of 47 HFrEF patients who underwent revascularization were included in the analysis. Improvement of LVEF was defined as [(LVEF during chronic phase) - (LVEF during acute phase)] ≥ 10%. Univariate and multivariate logistic regression analyses were applied to investigate the determinants of LVEF improvement. The prevalence of revascularization by PCIs including chronic total occlusion (CTO) was significantly greater in the improved EF group (45.0%) as compared to the non-improved EF group (11.1%) (P = 0.02). Multivariate logistic regression analysis revealed that revascularization by PCIs including CTO was the significant determinant of the LVEF improvement after adjusting for confounding factors (OR 5.43, 95% CI 1.06-27.74, P = 0.04). Optimal medical therapy (angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) and beta-blockers) was less frequently prescribed in patients with CABG (50.0% for ACE inhibitor and/or ARB and 41.7% for beta-blocker) than in patients without CABG (94.3% for both) (P < 0.01 and P < 0.001, respectively). In conclusion, revascularization by PCIs including CTO was the significant determinant of LVEF improvement in HFrEF patients. Our results underscore the importance of optimal medical therapy even if patients receive complete revascularization such as CABG.

Acceleration of Proteinuria without Significant Impact on Renal Function and Its Protection by Angiotensin II Receptor Blocker in Rats Treated with Axitinib.

Proteinuria is a dose-associated adverse event induced by anti-angiogenic agents; however, the mechanism mediating the induction of proteinuria by this type of agent remains largely unknown. The objective of this study was to assess the effects of treatment with axitinib and/or angiotensin II receptor blocker (ARB) on urinary protein excretion and renal function. Thirty-five rats were randomly selected for treatment with following agents for 4weeks: vehicle (group A), candesartan (group B), axitinib (group C), axitinib plus candesartan (group D), or axitinib and no treatment for subsequent 2weeks (group E). After completion of treatment schedule, urine protein-to-creatinine ratio (UPC) in group C was significantly higher than those in groups A and B, while the additional administration of candesartan resulted in the significant reduction of UPC in group D compared with group C. Following the no treatment interval for 2weeks, UPC in group E significantly decreased compared with that in group C. There were no significant differences in serum creatinine or blood urea nitrogen level among the five groups. Furthermore, semiquantitative evaluation of immunofluorescence findings showed that the expression levels of both nephrin and podocin in rat kidneys were inversely associated with the UPC value throughout these five groups. Despite the acceleration of proteinuria involving the downregulation of slit diaphragm-associated proteins, axitinib may not have an adverse impact on renal function, and axitinib-induced proteinuria can be partially prevented by additional treatment with ARB and reversibly recovered by its transient dose-interruption.

Management of renin-angiotensin system blockade in patients with chronic kidney disease under specialist care. Retrospective cross-sectional study.

Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. The aims were to check the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) in CKD patients. This was a retrospective, cross-sectional study analysing data from medical records of patients who received specialist care in 1996, 2001, 2006, 2011 in the Outpatient Unit. The numbers of CKD subjects included in the four independent surveys were as follows: 190, 490, 1799, 1696. The usage of RAAS blocking agents overall increased significantly in subsequent years as follows: 25, 49, 63, 74%. Patients with proteinuria and cardiovascular complications and/or diabetes were receiving RAAS blocking agents more commonly than others. The use of ACEI and/ or ARB in stage 4-5 CKD increased in subsequent years. In 2011 dual RAAS blockade was used in 10% CKD patients overall and 19% patients presented proteinuria. The use of RAAS blocking agents were increasing in CKD patients under specialist care between 1996-2011. The quality of the management was gradually improved.

Effect of spironolactone combined with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers on chronic glomerular disease

The aim of the present study was to observe the effects of spironolactone on urine protein level and kidney function in patients with chronic glomerular disease receiving angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs). A total of 221 patients with chronic glomerular disease were divided into spironolactone and control groups. The spironolactone group was treated with spironolactone at a dose of 20 mg/day, in addition to the original treatment regime and doses of ACEIs and/or ARBs. The control group continuously received the original doses of ACEIs and/or ARBs alone. Twenty-four-hour urine protein levels, serum creatinine and potassium, plasma aldosterone (ALD) and blood pressure were monitored at 0, 4, 8, 12 and 16 weeks. The estimated glomerular filtration rates (eGFRs) were calculated based on the obtained serum creatinine results. Following treatment, the urine protein level in the spironolactone group was notably decreased compared with that prior to the treatment, whereas the urine protein level in the control group did not show a significant difference. No significant differences were observed with regard to the renal function, eGFR, serum potassium, plasma ALD and blood pressure in either group prior to and following treatment. In conclusion, spironolactone administration, when co-administered with ACEIs and/or ARBs, markedly decreases the urine protein levels in patients with chronic glomerular disease. The protective effect of spironolactone on renal function remains to be demonstrated.

Choice of initial antihypertensive drugs and persistence of drug use—a 4-year follow-up of 78,453 incident users

To investigate patterns of initial drug therapy for the treatment of hypertension and to evaluate treatment persistence and change of treatment during a 4-year period in patients receiving thiazides (TZs) and/or angiotensin II-receptor blockers (ARBs) as first-line treatment. All initial users of antihypertensive drugs in 2005 and 2009 registered in the Norwegian Prescription Database were included. Treatment on five index dates at 1-year intervals was recorded. A patient was considered to be under treatment on an index date if a drug had been dispensed within the previous 180 days and to have maintained treatment persistence if he/she was on any antihypertensive treatment on the index date and all previous index dates. Among 78,453 new users of antihypertensives in 2005, women started more often with TZs than men (30 vs. 25 %) and less often with ARBs (22 vs. 25 %). In men, the hazard of non-persistence with antihypertensive treatment was significantly lower among initial ARB users than among TZ users (hazard ratio 0.87, 95 % confidence interval 0.81-0.94); in women no significant difference was found. After 4 years, 49 % of the men and 51 % of the women who had started with plain TZs were still using TZs, whereas 65 % of the male ARB users and 60 % of the female ARB users were still using ARBs. TZs and ARBs were the most widely used first-line antihypertensives. Among the men enrolled in the study, ARB users had a somewhat better persistence with antihypertensive treatment than TZ users. Among both genders, continuation on ARBs was more common than continuation on TZs.

Nonadherence to angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers among high-risk patients with diabetes in Medicare Part D programs

ObjectivesTo identify predictors of nonadherence to angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) and to assess the association between nonadherence to ACEIs/ARBs and potentially avoidable hospitalizations (PAHs) among elderly high-risk patients with diabetes. MethodsMedicare Part D enrollees from six states who had diabetes and coexisting hypertension and/or renal disease, were aged 65 years or older, and who had filled at least one prescription for ACEIs/ARBs in the first 6 months of 2006 were included in this retrospective cohort study. The primary outcomes of interests were patient nonadherence to ACEI/ARB therapy, which was defined as a proportion of days covered (PDC) less than 0.8 and PAH for diabetes during the patient follow-up period (July 1, 2006, to March 31, 2007). ResultsA total of 599,141 patients (mean [±SD] age 75.6± years, 66% women, 63% white, 15% black, and 9% Hispanic) were included. Among them, 46% were nonadherent to ACEI/ARB therapy and 6.3% had a PAH during the follow-up period. In multivariate logistic regressions, patients with diabetes and both hypertension and renal disease and patients with diabetes and renal disease only were 24% and 15% more likely, respectively, to be nonadherent to ACEI/ARB therapy compared with patients with diabetes and hypertension. Black and Hispanic patients were also more likely to be nonadherent to ACEI/ARB therapy. Nonadherence to ACEI/ARB therapy was associated with a 5% increase in the likelihood of PAH. ConclusionAdherence to ACEI/ARB therapy is suboptimal among elderly high-risk patients with diabetes enrolled in Medicare Part D programs from six states, and nonadherence to ACEIs/ARBs is associated with a slightly increased risk for PAH.

A computational framework to identify patients with poor adherence to blood pressure lowering medication

Background Blood pressure (BP) lowering medications have impressive efficacy in reducing cardiovascular and renal events; but low adherence threatens their effectiveness. Analysis of patterns in electronic prescribing from electronic medical records (EMRs) may have the potential to reveal cohorts of patients with significant adherence problems. Methods We developed a computational framework to identify patient cohorts with poor adherence to long-term medication through analysis of electronic prescribing patterns. A range of quality reporting criteria can be specified (as an XML document). We illustrate the framework by application to the EMRs of a New Zealand general practice with a focus on adherence to angiotensin-converting enzyme inhibitors (ACE-inhibitors) and/or angiotensin II receptor blockers (ARBs) in patients classified with hypertension and diabetes. We analyse medication supply based on Medication Possession Ratio (MPR) and duration of lapse in ACE-inhibitors/ARBs over a 12-month evaluation period. We describe graphical tools to assist visualisation of prescribing patterns and relationship of the analysis outputs to controlled blood pressure. Results Out of a cohort of 16,504 patient EMRs, 192 patients were found classified with both hypertension and diabetes and under active ACE-inhibitor and/or ARB management. Of these, 107 (56%) patients had an ACE-inhibitor/ARB MPR less than 80% together with a lapse in ACE-inhibitors/ARBs for greater than 30 days. We find non-adherent patients (i.e. MPR <80% or lapse >30 days) are three times more likely to have poor BP than adherent patients (odds ratio = 3.055; p = 0.012). Conclusions We have developed a generic computational framework that can be used to formulate and query criteria around issues of adherence to long-term medication based on practice EMRs. Within the context of the example we have used, the observed adherence levels indicate that a substantial proportion of patients classified with hypertension and diabetes have poor adherence, associated with poorer rates of blood pressure control, that can be detected through analysis of electronic prescribing. Further work is required to identify effective interventions using the reporting information to reduce non-adherence and improve patient outcomes.

Long Term Prognosis of Chronic Heart Failure Reduced vs Preserved Left Ventricular Ejection Fraction

Left ventricle diastolic dysfunction is attracting increasing attention of one of the etiologies of chronic heart failure (CHF). The study sample included 560 patients with CHF who were hospitalized during the 5-year period. They were classified into 2 groups according to the left ventricular ejection fraction (LVEF): reduced group (LVEF <50%, n=431); or preserved group (LVEF >or=50%, n=129). The degree of cardiac symptoms did not differ between the 2 groups; however, no difference was found between the 2 groups in the mortality rate (P=0.898), and readmission rates (P=0.674). The results of a multivariate analysis using a Cox proportional hazards model to identify predictors of the prognosis of heart failure revealed no difference in prognosis according to the presence/absence of decreased LVEF, whereas renal dysfunction and anemia were identified as significant prognostic determinants. Also, in the reduced group, the administration of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARB), beta-blockers reduced mortality. In the preserved group, ACE-I and/or ARB administration reduced mortality, whereas beta-blockers did not. In the present study, the likelihood of LVEF influencing prognosis was considered to be low, with the contribution of non-cardiac factors such as renal function and anemia concluded to be greater.

Impact of Previous Statin and Angiotensin II Receptor Blocker Use on Mortality in Patients Hospitalized with Sepsis

To examine the effect of previous outpatient use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and/or angiotensin II receptor blockers (ARBs) on 30-day mortality in patients hospitalized with sepsis. Retrospective national cohort study. Department of Veterans Affairs (VA) national patient care and pharmacy databases. A total of 3018 patients who were hospitalized with sepsis in fiscal year 2000, had at least 1 year of previous VA outpatient care, and had at least one active and filled VA prescription within 90 days of admission. The primary outcome was 30-day mortality. The primary analysis was a multilevel model with hospital as a random effect and control variables that included comorbid conditions, demographics, and other drugs. Among the 3018 patients hospitalized with sepsis, mean age was 74.4 years, 2975 (98.6%) were male, and 811 (26.9%) died within 30 days of admission. Regarding prescription drug use, 480 patients (15.9%) were taking statins and 107 (3.5%) were taking ARBs. After adjusting for potential confounders, statin use (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.36-0.64) and ARB use (OR 0.42, 95% CI 0.24-0.76) were significantly associated with decreased 30-day mortality. Use of statins and/or ARBs before admission was associated with decreased mortality in patients hospitalized with sepsis. Further research is needed to determine if these drugs might be started on admission for those with sepsis.

Aldosterone breakthrough during therapy with angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy

We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 +/- 0.3 g/day) outpatients (aged 41.5 +/- 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were treated with temocapril (1 mg; n = 14), losartan (12.5 mg; n = 16), or a combination therapy (n = 13) for 12 months. We prospectively evaluated blood pressure (BP), urinary protein excretion (UPE), biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment. Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months, they eventually increased in 23 (temocapril, seven patients; losartan, eight patients; combination, seven patients) of the 43 patients (53.4%; aldosterone breakthrough), and fell in the remainder (46.6%). Blood pressure and renal function did not differ among the three groups at 12 months. In contrast, UPE was significantly higher in patients with, than without aldosterone breakthrough during temocapril and losartan administration. However, combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough. A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy. This additive antiproteinuric effect is not dependent on aldosterone breakthrough. Additional larger, prospective, randomized studies will be needed for general acceptance of this strategy.

Impact of renin angiotensin system blockade on night to day blood pressure ratio in diabetic nephropathy

Sir, Elevated systemic blood pressure is a risk factor for progression of diabetic nephropathy. Ambulatory blood pressure measurements offer additional risk stratification compared to office blood pressure in patients with hypertension [1]. In addition, an abnormal diurnal blood pressure pattern characterized by an elevated night to day ratio is found more commonly in diabetic patients and, as reviewed by Miller et al. [2], is associated with poor renal outcome. The renin angiotensin system (RAS) is involved in both initiation and progression of diabetic nephropathy and blocking this system with ACE-inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) improves kidney survival and prognosis. Miller et al. [2] reported that treatment with enalapril (0.1 mg/kg BID) corrects the abnormally high night to day blood pressure ratio found in 10 uncomplicated adolescents, and this could contribute to the beneficial renoprotective effects of RAS blockade. In this letter, we further investigate whether RAS blockade corrects an abnormal 24 h blood pressure pattern by presenting data on the short-term effects of single and dual blockade of the RAS on a 24 h blood pressure profile and a night to day blood pressure ratio in type 1 diabetic patients with diabetic nephropathy. Our data are a post-hoc analysis of three earlier studies [3–5]. As described previously [3], we performed a randomized, double blind, cross-over trial, in which 18 patients received 8 weeks of placebo, benazepril 20 mg once daily, valsartan 80 mg once daily and a combination of benazepril 20 mg and valsartan 80 mg once daily in random order [3]. The main findings were: (1) mono-therapy with ACE-I or ARBs treatment was equally effective with regard to antialbuminuric and antihypertensive effects; (2) dual blockade of the RAS caused a further reduction in albuminuria of 43% and 7/6 mmHg in 24 h blood pressure compared with both mono-therapies; (3) night to day ratio of 24 h blood pressure on each treatment is shown in Table 1. A post-hoc power calculation estimated a power in each study of � 0.80 to detect a difference of 0.05 in night to day ratio with a significance level of 0.05. In agreement, when looking at the fraction of patients with night to day blood pressure ratio above the median on placebo treatment (>0.91), we found no changes in the night to day ratio on RAS blockade. Furthermore, in two other studies demonstrating that dual blockade of the RAS

The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion.

The optimal doses of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) for maximal reduction in urinary protein excretion are not known. Moreover, beneficial effects from ARBs, such as tissue protection owing to a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), may be independent of blood pressure-lowering by ARBs. In this investigation, we evaluated whether increasing the dose of candesartan cilexetil, in subjects already on the maximally-recommended FDA doses of 32 mg, would induce a further reduction in 24-hour urinary protein excretion in patients with heavy proteinuria (urinary protein excretion >1.5 g/day; mean 4.4±2 g/day). Ten patients were started on 16 or 32 mg of candesartan cilexetil daily. After 1-2 months of therapy, the dose was titrated upwards to 96 mg. In all subjects, there were further reductions in 24-hour urinary protein excretion when the dose was increased beyond the recommended 32 mg maximal dose. Increasing the dose of candesartan cilexetil to 96 mg was safe, as most subjects showed no changes in serum potassium and, as expected, only a slight increase (0.5-0.7 mg/dl) in serum creatinine. These data warrant further investigation, since some subjects may require higher doses of candesartan to achieve optimal regression of proteinuria.