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Differential Effects of Combination of Renin-Angiotensin-Aldosterone System Inhibitors on Central Aortic Blood Pressure: A Cross-Sectional Observational Study in Hypertensive Outpatients.
Pradhan, A, Vishwakarma, P, Bhandari, M, Sethi, R, Narain, VS
Cardiovascular therapeutics. 2020;:4349612
Abstract
BACKGROUND Central aortic blood pressure (CABP) indices, central hemodynamics, and arterial stiffness are better predictors of cardiovascular events as compared with brachial cuff pressure measurements alone. The present study is aimed at assessing the effects of different antihypertensive drug combination regimens involving renin-angiotensin-aldosterone system (RAAS) inhibitors on CABP indices in Indian patients with hypertension. METHODS This was a cross-sectional, single-center study conducted in patients treated for hypertension for >6 weeks using different treatment regimens involving the combination of RAAS inhibitors with drugs from other classes. CABP indices, vascular age, arterial stiffness, and central hemodynamics were measured in patients using the noninvasive Agedio B900 device (IEM, Stolberg, Germany) and compared between different treatment regimens. RESULTS A total of 199 patients with a mean age of 54.22 ± 10.15 years were enrolled, where 68.8% had hypertension for over three years and 50.25% had their systolic blood pressure (SBP) < 140 mmHg. Combination treatment with angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) was given to 77.9% and to 20.1% patients, respectively. The mean vascular age was higher than the actual age (58.13 ± 12.43 vs. 54.22 ± 10.15, p = 0.001). The SBP and diastolic blood pressure (DBP) levels in patients treated with ACEI-based combinations were lower than those in patients treated with ARB-based combinations (p < 0.05). The mean central pulse pressure amplification, augmentation pressure, and augmentation index were lower in patients treated with ACEI-based combinations than those treated with other treatments (p = 0.001). In a subgroup analysis, patients given perindopril and calcium channel blockers (CCBs) or diuretics had significantly lower CABP and pulse wave velocity than those given other treatments (p < 0.05). A total of 6.5% patients experienced any side effects. CONCLUSION The majority of central hemodynamic parameters, including vascular age, were found to improve more effectively in patients treated with ACEIs than with ARBs. Our results indicate a gap between routine clinical practice and evidence-based guidelines in Indian settings and identify a need to reevaluate the current antihypertensive prescription strategy.
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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors.
Kloner, RA, Gross, C, Yuan, J, Conrad, A, Pergola, PE
Journal of cardiovascular pharmacology and therapeutics. 2018;(6):524-531
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INTRODUCTION Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
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Changes in Kidney Function in a Population With Essential Hypertension in Real Life Settings.
Ptinopoulou, AG, Pikilidou, MI, Tziolas, IM, Haidich, AB, Mark, PB, Zebekakis, PE, Lasaridis, AN
Iranian journal of kidney diseases. 2017;(3):192-200
Abstract
INTRODUCTION Hypertension has been identified as one of the commonest modifiable determinants for chronic kidney disease progression. A variety of antihypertensive drugs are available and their effect on kidney function has been investigated by a large number of randomized controlled trials. Observational studies, although scarcely been used, outpatient can reflect everyday practice, where drug exposures vary over time, and may provide an alternative for detecting longitudinal changes in kidney function. MATERIALS AND METHODS We applied mixed model repeated measures analysis to investigate the effect of antihypertensive drug categories and their combinations on kidney function change over time in a cohort of 779 patients with essential hypertension, using the data from a Greek hypertension outpatient clinic. Antihypertensive drugs were grouped in 5 categories. Their effect was evaluated and their combinations with and without renin-angiotensin-system inhibitors (RASI) to each other. In addition, the combination of RASI with calcium channel blockers (CCBs) was studied. RESULTS Diuretics, RASI, CCBs, and beta-blockers had a significant renoprotective and blood pressure lowering effect. Combinations with RASI had a smaller beneficial effect on kidney function compared to CCBs (0.75 mL/min/1.73 m2 per year of drug use versus 0.97 mL/min/1.73 m2). There was no additional effect when combining RASI with CCBs. However, the lowering effect on systolic blood pressure was greater (-0.83 mm Hg per year of drug use, P < .001). CONCLUSIONS RASI were found to have a smaller, although significant, renoprotective effect. There was no additional effect on kidney function when combining RASI with CCBs.
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ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men.
Kwok, T, Leung, J, Barrett-Connor, E, ,
Age and ageing. 2017;(1):57-64
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INTRODUCTION Angiotensin II, a major effector protein of the renin angiotensin system (RAS), induces bone loss under certain conditions. Drugs that block the RAS may therefore reduce bone loss and fracture incidence. The fracture incidence in older hypertensive men with long-term use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) were compared with the incidence in users of calcium channel blockers (CCBs) and non-users. METHODS A total of 5,994 US men aged 65 years or older who had bone mineral density measured at baseline in the Osteoporotic Fractures in Men Study (MrOS) were followed for fracture incidence for an average of 6.8 years. Men with follow-up dual-energy X-ray absorptiometry bone mineral density data and who reported hypertension at any visit, or use of antihypertensive medications at any visit among those with non-missing mediation data were included in the study (N = 2,573). RESULTS Six hundred and nineteen men had taken ACE inhibitors, while 182 took ARBs for at least 4 years. Using Cox regression for the incidence of non-vertebral fractures, we found that long-term users of ACE inhibitors and ARBs each had a significantly lower fracture incidence than non-users. The hazard ratio of non-vertebral fractures was three times lower in ARB users than ACE inhibitor users (Hazard ratio (95% confidence interval): 0.194 (0.079–0.474) versus 0.620 (0.453–0.850), P = 0.0168). There was a trend of greater fracture risk reduction with longer duration of ARB use, but not for ACE inhibitor use. CONCLUSIONS In older hypertensive men, ARBs use was associated with lower incidence of non-vertebral fracture than ACE inhibitors or CCBs.
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Renin-Angiotensin System Inhibitors vs Other Antihypertensives in Hypertensive Blacks: A Meta-Analysis.
Palla, M, Ando, T, Androulakis, E, Telila, T, Briasoulis, A
Journal of clinical hypertension (Greenwich, Conn.). 2017;(4):344-350
Abstract
The purpose of this study was to assess the effects of renin-angiotensin system (RAS) inhibitors vs other antihypertensive agents on cardiovascular outcomes in hypertensive black patients. The authors performed a systematic review and meta-analysis of studies that compared the effects of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with calcium channel blockers (CCBs), diuretics, and β-blockers in hypertensive black patients on cardiovascular outcomes. A total of 38,983 patients with a mean age of 60 years and mean follow-up of 4 years were included in our meta-analysis. No significant differences were found in all-cause mortality, myocardial infarction, heart failure, and cardiovascular mortality rates among patients treated with RAS inhibitors compared with CCBs, diuretics, and β-blockers. The incidence of stroke was significantly increased in patients treated with RAS inhibitors compared with CCBs (odds ratio, 1.56; 95% confidence interval, 1.31-1.87 [P<.00001]; I2 =0%) and diuretics (odds ratio, 1.59; 95% confidence interval, 1.16-2.17 [P=.004]; I2 =56%) but not β-blockers.
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The effect of aliskiren versus ramipril-based treatment on the Ambulatory Arterial Stiffness Index in hypertensive patients.
Andreadis, EA, Angelopoulos, ET, Kolyvas, GN, Agaliotis, GD, Mousoulis, CG, Mousoulis, GP
International angiology : a journal of the International Union of Angiology. 2014;(1):78-83
Abstract
AIM: Aim of the present study was to compare the effectiveness of two renin-angiotensin-aldosterone system inhibitors in arterial stiffness reduction in previously untreated hypertensive patients. METHODS In this open label study, 154 naïve, or not treated in the last six months hypertensive patients were randomly assigned to receive aliskiren 300 mg or ramipril 5 mg daily. Six weeks after the initiation of treatment, patients were evaluated for blood pressure (BP) control. Patients with SBP ≥140 and/or DBP ≥90 mmHg were assigned to an adjunct of 25 mg hydrochlorothiazide as combination treatment. A re-evaluation of BP control was done after another 6 weeks. Individuals with BP ≥140/90 mmHg were further administered amlodipine 5 mg. The final evaluation was performed six months after the start of the study. Twenty four-hour ambulatory blood pressure monitoring was carried out and the ambulatory arterial stiffness index (AASI) was calculated at baseline and after 6 months of treatment. RESULTS Aliskiren-based therapy, as compared with ramipril-based therapy reduced BP to a similar degree: 13±11 vs. 12±11 mmHg reduction in systolic (P=0.34) and 8±7 vs. 7±7 mmHg reduction in diastolic BP (P=0.44). AASI was reduced by 0.04±0.1 in the aliskiren group and by 0.02±0.2 in the ramipril group. AASI reduction did not differ significantly in the two groups (P=0.13). CONCLUSION In hypertensive patients, aliskiren-based treatment as well as ramipril-based treatment appears to have a beneficial effect on arterial stiffness. As arterial stiffness is an important modifiable risk factor, our findings highlight the value of aliskiren beyond BP lowering properties.
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Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy.
Van Buren, PN, Adams-Huet, B, Nguyen, M, Molina, C, Toto, RD
Clinical journal of the American Society of Nephrology : CJASN. 2014;(2):295-301
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BACKGROUND AND OBJECTIVES Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models. RESULTS Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study. CONCLUSION Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.
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Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers.
Azizi, M, Blanchard, A, Charbit, B, Wuerzner, G, Peyrard, S, Ezan, E, Funck-Brentano, C, Ménard, J
Hypertension (Dallas, Tex. : 1979). 2013;(6):1239-45
Abstract
Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.
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Pharmacokinetics, pharmacodynamics, and tolerability of ACT-077825, a new direct renin inhibitor after multiple-ascending doses in healthy subjects.
Nicolas, LB, Gutierrez, M, Binkert, C, Dingemanse, J
Journal of cardiovascular pharmacology. 2013;(1):42-50
Abstract
This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.
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25 (OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system.
Fernández-Juárez, G, Luño, J, Barrio, V, de Vinuesa, SG, Praga, M, Goicoechea, M, Lahera, V, Casas, L, Oliva, J, ,
Clinical journal of the American Society of Nephrology : CJASN. 2013;(11):1870-6
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BACKGROUND AND OBJECTIVES Experimental studies show that 25 (OH) vitamin D is a suppressor of renin biosynthesis and that vitamin D deficiency has been associated with CKD progression. Patients with type II diabetes and CKD have an exceptionally high rate of severe 25 (OH) vitamin D deficiency; however, it is not known whether this deficiency is a risk factor for progression of diabetic nephropathy. This study aimed to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 25 (OH) vitamin D levels were measured at baseline and 4 and 12 months in 103 patients included in a multicenter randomized controlled trial to compare the efficacy of combining an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker with the efficacy of each drug in monotherapy to slow progression of established diabetic nephropathy during 2006-2011. The primary composite endpoint was a >50% increase in baseline serum creatinine, ESRD, or death. All study participants were included in the analysis. RESULTS Fifty-three patients (51.5%) had 25 (OH) vitamin D deficiency (<15 ng/ml). After a median follow-up of 32 months, the endpoint was reached by 23 patients with deficiency (43.4%) and 8 patients without (16%). Multivariate Cox regression analysis adjusted for urinary protein/creatinine ratio, estimated GFR, and baseline aldosterone showed that 25 (OH) vitamin D deficiency was associated with the primary endpoint (hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67; P=0.04). CONCLUSIONS These results show that 25 (OH) vitamin D deficiency is independently associated with a higher risk of the composite outcome in patients with type II diabetic nephropathy.