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Differential effects of renin-angiotensine-aldosteron system inhibition, sympathoinhibition and low sodium diet on blood pressure in women with a history of preeclampsia: A double-blind, placebo-controlled cross-over trial (the PALM study).
Zoet, GA, Paauw, ND, Veerbeek, JHW, Groenhof, TKJ, Spiering, W, Verhaar, MC, Franx, A, Titia Lely, A
Pregnancy hypertension. 2022;:173-175
Abstract
Current guidelines lack sufficient evidence to recommend a specific blood pressure lowering strategy to prevent cardiovascular disease after preeclampsia. We conducted a double-blind cross-over trial to identify the most potent antihypertensive strategy: renin-angiotensin-aldosterone system (RAAS) inhibition (losartan), sympathoinhibition (moxonidine), low sodium diet and placebo (n = 10). Due to low inclusion rate our study stopped prematurely. Initiatory analyses showed no significant effect of antihypertensive strategy on office blood pressure and 24-hour blood pressure. However, nocturnal dipping was significantly higher on RAAS inhibition and low sodium diet compared to placebo and sympathoinhibition. Optimal cardiovascular prevention after preeclampsia should be further explored.
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Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.
Van Driest, SL, Sleeper, LA, Gelb, BD, Morris, SA, Dietz, HC, Forbus, GA, Goldmuntz, E, Hoskoppal, A, James, J, Lee, TM, et al
The Journal of pediatrics. 2020;:213-220.e5
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Abstract
OBJECTIVE To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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On-treatment HDL cholesterol predicts incident atrial fibrillation in hypertensive patients with left ventricular hypertrophy.
Okin, PM, Hille, DA, Wachtell, K, Kjeldsen, SE, Julius, S, Devereux, RB
Blood pressure. 2020;(5):319-326
Abstract
Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined.Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels.Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90-1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16-2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78-1.31).Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF.Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1.
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Comparison of Blood Pressure Variability Between Losartan and Amlodipine in Essential Hypertension (COMPAS-BPV).
Lee, JW, Choi, E, Son, JW, Youn, YJ, Ahn, SG, Ahn, MS, Kim, JY, Lee, SH, Yoon, J, Ryu, DR, et al
American journal of hypertension. 2020;(8):748-755
Abstract
BACKGROUND Antihypertensive therapy using renin-angiotensin system blockers and calcium channel blockers to target blood pressure variability (BPV) has not yet been established. We aimed to compare the ability of losartan and amlodipine to lower BPV and systolic blood pressure (SBP) in essential hypertensive patients. METHODS Patients were randomly assigned either losartan 50 mg or amlodipine 5 mg. Medications were uptitrated and hydrochlorothiazide was added according to protocol for 6 months. The primary endpoint was the office visit-to-visit SD of SBP. The secondary endpoints included average real variability (ARV), office SBP, and home SBP. RESULTS The losartan group (n = 71) and amlodipine group (n = 73) finished the scheduled visits between April 2013 and May 2017. The office visit-to-visit SD of SBP was comparable between the losartan and amlodipine groups (11.0 ± 4.2 vs. 10.5 ± 3.8, P = 0.468). The office visit-to-visit ARV of SBP was significantly elevated in the losartan group (10.6 ± 4.3 vs. 9.1 ± 3.4, P = 0.02). The absolute SBP decrement from baseline to 6 months was similar between groups, although the office mean SBP at 6 months was higher in the losartan group (132.3 ± 12.9 vs. 127.5 ± 9.0 mm Hg, P = 0.011). In home blood pressure analysis, evening day-to-day BPV indexes (SD and ARV) were significantly higher in the losartan group at 6 months. CONCLUSIONS The lowering effect of the office visit-to-visit SD of SBP was similar between losartan and amlodipine. However, the losartan group showed a higher office visit-to-visit ARV of SBP and evening day-to-day home BPV indexes. Therefore, amlodipine may be better to lower BPV in essential hypertensive patients.
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Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome.
Handisides, JC, Hollenbeck-Pringle, D, Uzark, K, Trachtenberg, FL, Pemberton, VL, Atz, TW, Bradley, TJ, Cappella, E, De Nobele, S, Groh, GK, et al
The Journal of pediatrics. 2019;:250-255.e1
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Abstract
OBJECTIVE To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. STUDY DESIGN The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. RESULTS Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P < .001) domains; mean psychosocial scores for adults (19-25 years) were greater than healthy norms (P < .001). HRQOL across multiple domains correlated inversely with frequency of patient-reported symptoms (r = 0.30-0.38, P < .0001). Those <18 years of age with neurodevelopmental disorders (mainly learning disability, attention-deficit/hyperactivity disorder) had lower mean PedsQL scores (5.5-7.4 lower, P < .04). A multivariable model found age, sex, patient-reported symptoms, and neurodevelopmental disorder to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z score, number of skeletal features, or presence of ectopia lentis. CONCLUSIONS Children and adolescents with Marfan syndrome were at high risk for impaired HRQOL. Patient-reported symptoms and neurodevelopmental disorder, but not treatment arm or severity of Marfan syndrome-related physical findings, were associated with lower HRQOL.
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Effect of Losartan on the Acute Response of Human Elderly Skeletal Muscle to Exercise.
Heisterberg, MF, Andersen, JL, Schjerling, P, Bülow, J, Lauersen, JB, Roeber, HL, Kjaer, M, Mackey, AL
Medicine and science in sports and exercise. 2018;(2):225-235
Abstract
PURPOSE To investigate the effect of blocking the angiotensin II Type I receptor (AT1R) upon the response to acute heavy-resistance exercise in elderly human skeletal muscle. The hypothesis was that AT1R blocking would result in a superior myogenic response accompanied by down-regulation of transforming growth factor-beta and up-regulation of insulin-like growth factor-1 signaling. METHODS Twenty-eight healthy elderly men (+64 yr) were randomized into two groups, consuming either AT1R blocker (losartan, 100 mg·d) or placebo for 18 d before exercise. Participants performed one bout of heavy-unilateral-resistance exercise. Six muscle biopsies were obtained from the vastus lateralis muscles of each subject: two before exercise and four after exercise (4.5 h and 1, 4, and 7 d). Blood pressure and blood samples were collected at the same time points. Biopsies were sectioned for immunohistochemistry to determine the number of satellite cells associated with Type I and Type II fibers. Gene expression levels of Notch, connective tissue, and myogenic signaling pathways were determined by real-time reverse transcription polymerase chain reaction. RESULTS Changes over time were detected for circulating creatine kinase, the number of satellite cells per Type I fiber, and most of the gene targets, with no specific effect of losartan on these. However, when compared with placebo, losartan intake resulted in a greater suppression of myostatin messenger RNA. CONCLUSIONS In general, there does not seem to be any effect of AT1R blocking on satellite cell number or myogenic pathways in elderly men in the days after one bout of heavy-resistance exercise. However, the greater suppression of myostatin may prove to be beneficial over a long-term intervention designed to induce hypertrophy.
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Serum uric acid and progression of diabetic nephropathy in type 1 diabetes.
Pilemann-Lyberg, S, Lindhardt, M, Persson, F, Andersen, S, Rossing, P
Journal of diabetes and its complications. 2018;(5):470-473
Abstract
AIMS: Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS Baseline UA was 0.339 mmol/l (SD ±0.107), GFR 87 ml/min/1.73 m2 (±23), geometric mean UAER 1023 mg/24 h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). CONCLUSION Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.
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Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial.
Parvanova, A, Trillini, M, Podestà, MA, Iliev, IP, Ruggiero, B, Abbate, M, Perna, A, Peraro, F, Diadei, O, Rubis, N, et al
The lancet. Diabetes & endocrinology. 2018;(1):27-40
Abstract
BACKGROUND Macroalbuminuria predicts renal and cardiovascular events in patients with type 2 diabetes. We aimed to assess the albuminuria-lowering effects of salt restriction, paricalcitol therapy, or both, in this population. METHODS In this randomised, double-blind, placebo-controlled, crossover trial, we recruited adult patients with type 2 diabetes from six diabetology outpatient clinics in northern Italy, with 24 h albuminuria of more than 300 mg despite 100 mg per day losartan therapy, blood pressure of less than 140/90 mm Hg, serum creatinine concentration of less than 2 mg/dL, stable renal function on stable renin-angiotensin system inhibitor therapy with a fixed dose of losartan, parathyroid hormone concentration of 20 pg/mL to <110 pg/mL, serum calcium concentration of less than 9·5 mg/dL, and serum phosphate concentration of less than 5 mg/dL, who had been more than 80% compliant with placebo treatment during a 1 month placebo run-in. We allocated patients 1:1 with computer-generated randomisation to an open-label 3 month high-sodium (>200 mEq [4·8 g] per day) or low-sodium (<100 mEq [2·4 g] per day) diet and, within each diet group, to a 1 month double-blind treatment period of oral paricalcitol (2 μg per day) or placebo, followed by 1 month of placebo washout and then a further 1 month double-blind treatment period of paricalcitol or placebo in which patients crossed over to the opposite treatment period. The primary outcome was 24 h albuminuria (median of three consecutive measurements). Analyses were modified intention-to-treat (including all randomly allocated patients who took at least one dose of study drug and had an efficacy measurement after the first treatment period). Patients and investigators were masked to paricalcitol and placebo assignment. Those assessing outcomes were masked to both study drug and diet assignment. This study is registered with ClinicalTrials.gov, number NCT01393808, and the European Union Clinical Trials Register, number 2011-001713-14. FINDINGS Between Dec 13, 2011, and Feb 17, 2015, we randomly allocated 57 (50%) patients to a low-sodium diet (28 [49%] to paricalcitol then placebo and 29 [51%] to placebo then paricalcitol) and 58 (50%) to a high-sodium diet (29 [50%] to paricalcitol then placebo and 29 [50%] to placebo then paricalcitol). In the low-sodium group (30 mEq of daily sodium intake reduction, equivalent to approximately 1·7-1·8 g per day), 24 h albuminuria was reduced by 36·6% (95% CI 28·5-44·9) from 724 mg (441-1233) at baseline to 481 mg (289-837) at month 3 (p<0·0001), but no significant change occurred in the high-sodium group (from 730 mg [416-1227] to 801 mg [441-1365]; 2·9% [-16·8 to 16·4] increase; p=0·50). Changes between diet groups differed by 32·4% (17·2-48·8; p<0·0001) and correlated with changes in natriuresis (r=0·43; p<0·0001). On the high-sodium diet, paricalcitol reduced the salt-induced albuminuria increase by 17·8% (3·9-32·3) over the month of treatment compared with placebo (p=0·02), whereas on the low-sodium diet, paricalcitol did not have a significant effect versus placebo (increase of 4·1% [-9·3 to 21·6]; p=0·59). During placebo treatment, albuminuria decreased with the low-sodium diet (p=0·0002) and did not significantly change with the high-sodium diet, but changes were significantly different between diet groups (p=0·0004). Treatment was well tolerated and no patients withdrew from the study because of treatment-related effects. 67 adverse events occurred in 52 (45%) patients during paricalcitol treatment and 44 events occurred in 36 (31%) patients during placebo treatment. During paricalcitol therapy, 14 cases of hypercalciuria, six cases of hypercalcaemia, and five cases of hyperphosphataemia were reported in one patient each, all of which were possibly treatment related. One case of hypercalciuria was reported in one patient during the placebo treatment period. One stroke and one coronary event occurred during paricalcitol therapy. No patients died during the study. INTERPRETATION In patients with macroalbuminuria and type 2 diabetes, moderate salt restriction enhances the antialbuminuric effect of losartan, an effect that could be nephroprotective and cardioprotective in the long term. The finding that paricalcitol prevents a sodium-induced increase in albuminuria provides support for trials to test the long-term risk-benefit profile of paricalcitol add-on therapy in patients with type 2 diabetes and macroalbuminuria refractory to dietary salt restriction, including patients refractory to even moderate salt restriction. FUNDING AbbVie.
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A randomised controlled trial evaluating renal protective effects of selenium with vitamins A, C, E, verapamil, and losartan against extracorporeal shockwave lithotripsy-induced renal injury.
El-Nahas, AR, Elsaadany, MM, Taha, DE, Elshal, AM, El-Ghar, MA, Ismail, AM, Elsawy, EA, Saleh, HH, Wafa, EW, Awadalla, A, et al
BJU international. 2017;(1):142-147
Abstract
OBJECTIVE To evaluate the protective effects of selenium with vitamins A, C and E (selenium ACE, i.e. antioxidants), verapamil (calcium channel blocker), and losartan (angiotensin receptor blocker) against extracorporeal shockwave lithotripsy (ESWL)-induced renal injury. PATIENTS AND METHODS A randomised controlled trial was conducted between August 2012 and February 2015. Inclusion criteria were adult patients with a single renal stone (<2 cm) suitable for ESWL. Patients with diabetes, hypertension, congenital renal anomalies, moderate or marked hydronephrosis, or preoperative albuminuria (>300 mg/L) were excluded. ESWL was performed using the electromagnetic DoLiS lithotripter. Eligible patients were randomised into one of four groups using sealed closed envelopes: Group1, control; Group 2, selenium ACE; Group 3, losartan; and Group 4, verapamil. Albuminuria and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were estimated after 2-4 h and 1 week after ESWL. The primary outcome was differences between albuminuria and uNGAL. Dynamic contrast-enhanced magnetic resonance imaging was performed before ESWL, and at 2-4 h and 1 week after ESWL to compare changes in renal perfusion. RESULTS Of 329 patients assessed for eligibility, the final analysis comprised 160 patients (40 in each group). Losartan was the only medication that showed significantly lower levels of albuminuria after 1 week (P < 0.001). For perfusion changes, there was a statistically significant decrease in the renal perfusion in patients with obstructed kidneys in comparison to before ESWL (P = 0.003). These significant changes were present in the control or antioxidant group, whilst in the losartan and verapamil groups renal perfusion was not significantly decreased. CONCLUSIONS Losartan was found to protect the kidney against ESWL-induced renal injury by significantly decreasing post-ESWL albuminuria. Verapamil and losartan maintained renal perfusion in patients with post-ESWL renal obstruction.
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A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and the Tolerability of a Triple Combination of Amlodipine/Losartan/Rosuvastatin in Patients With Comorbid Essential Hypertension and Hyperlipidemia.
Lee, HY, Kim, SY, Choi, KJ, Yoo, BS, Cha, DH, Jung, HO, Ryu, DR, Choi, JH, Lee, KJ, Park, TH, et al
Clinical therapeutics. 2017;(12):2366-2379
Abstract
PURPOSE The objective of this study was to evaluate the efficacy and tolerability of a triple combination of amlodipine/losartan/rosuvastatin in patients with hypertension and hypercholesterolemia. METHODS A randomized, multicenter, double-blind, placebo-controlled study was conducted. Eligible patients with hypertension and a sitting diastolic blood pressure (SiDBP) of >90 mm Hg and LDL-C levels <250mg/dL were screened. After a 4-week run-in period with therapeutic lifestyle changes and losartan potassium 100mg once daily, patients who met both blood pressure criteria (80 mm Hg ≤ SiDBP < 110 mm Hg) and the LDL-C level criteria (defined in the National Cholesterol Education Program Adult Treatment Panel III cardiovascular risk categories) were randomized to 1 of 3 groups and treated once daily for 8 weeks: losartan potassium 100mg + rosuvastatin 20mg treatment (L/R 100/20) group, amlodipine camsylate 5mg + losartan potassium 100mg treatment (A/L 5/100) group, and amlodipine 5mg+ losartan potassium 100mg + rosuvastatin 20mg (A/L/R 5/100/20) group. The primary efficacy variables were the percent change in LDL-C in the A/L/R 5/100/20 and A/L 5/100 groups and the mean change of SiDBP in the A/L/R 5/100/20 and L/R 100/20 groups after 8 weeks of treatment, relative to baseline values. FINDINGS A total of 146 patients were enrolled and the demographic characteristics were similar among the 3 treatment groups. After 8 weeks of treatment, the mean (SD) percent change in LDL-C was significantly greater in the A/L/R group than in the A/L group (-48.40% [2.77%] vs -6.70% [3.00%]; P < 0.0001). Moreover, the mean change in SiDBP was significantly greater in the A/L/R group than in the L/R group (-9.75 [0.92] mm Hg vs -1.73 [1.03] mm Hg; P < 0.0001). SiDBP and LDL-C reductions in the A/L/R group were comparable to reductions in the A/L and L/R groups, respectively. Ten adverse events were reported in 7 patients (4.83%), and 1 patient from the A/L group (0.69%) experienced 2 adverse drug reactions (tachycardia and face edema), which were mild and resolved without specific treatment. There were no clinically significant tolerability issues during the treatment period. IMPLICATIONS Triple combination therapy with amlodipine/losartan/rosuvastatin can be an effective therapeutic strategy in patients with hypertension combined with dyslipidemia. These findings will form the foundation of the future development of a single-pill triple combination. ClinicalTrials.gov identifier: NCT02899455.