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1.
Comparisons of Three Main Treatments on Renoprotective Effects in Diabetes Mellitus.
Huang, Q, Li, K, Li, M, Xu, G
Iranian journal of kidney diseases. 2019;(1):36-47
Abstract
INTRODUCTION Antihypertension, intensive glucose control (IGC), and lipid lowering were the main therapeutic strategies in diabetes mellitus. However, the comparative effects of them on renoprotection remain unclear. MATERIALS AND METHODS We searched the PubMed, EMBase, and Cochrane Library up to May 18, 2017, for studies with comparative interventions on regression, end-stage renal disease and all-cause death in diabetes mellitus. Statistical analysis was done using the Bayesian network meta-analysis (NMA). The surface under the cumulative ranking area and median rank were calculated to rank the interventions. RESULTS A total of 73 randomized controlled trials with 13 3703 participants were included for the comparisons of 14 interventions. Angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker (ACEI-ARB) ranked first in regression (odds ratio, 62; 95% confidence interval, 5.2 to > 999); ACEI-ARB also ranked first in end-stage renal disease decline (odds ratio, 0.58, 95% confidence interval, 0.39 - 0.85), followed by IGC hemoglobin A1c less than 6.5% (odds ratio, 0.58, 95% confidence interval, 0.36 - 0.90). The ACEI plus calcium channel blocker reduced all-cause death leaving other interventions insignificant (odds ratio, < 0.001; 95% confidence interval, < 0.001 to 0.30). ). The surface under the cumulative ranking area analyses also matched the result ranks. CONCLUSIONS Compared with antihypertension interventions, IGC including IGC hemoglobin A1c less than 6.5% and lipid lowering, ACEI-ARB showed the best renoprotective effects.
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2.
Implications of renin-angiotensin-system blocker discontinuation in acute decompensated heart failure with systolic dysfunction.
Darden, D, Drazner, MH, Mullens, W, Dupont, M, Tang, WHW, Grodin, JL
Clinical cardiology. 2019;(10):1010-1018
Abstract
BACKGROUND Renin-angiotensin-system blockers (RASB) improve clinical outcomes in patients with chronic heart failure with reduced fraction; however, there remains ambiguity whether RASB therapy should be continued during the treatment of acute decompensated heart failure (ADHF). HYPOTHESIS In comparison to patients with RASB use, RASB discontinuation in ADHF will be associated with worsening renal function, hypotension, and adverse long-term clinical outcomes. METHODS Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were separated into four groups based on RASB use at baseline and discharge: continuation (n = 316), discontinuation (n = 21), initiation (n = 42), and nonuse (n = 23). Post-discharge outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253). RESULTS RASB discontinuation and nonuse were associated with higher serial creatinine and blood urea nitrogen levels than RASB continuation or initiation (P < .001 for both), but not with serial potassium and systolic blood pressure measurements. No other clinical parameter changes were significant. In comparison to RASB continuation, RASB discontinuation and nonuse was associated with ~75% increased risk of a 180-day composite of death, transplant, or rehospitalization (HR 1.87, 95% CI 1.09-3.20, P = 0.02 and HR 1.72, CI 1.04-2.82, P = .03, respectively). Post-discharge outcomes were similar in the validation cohort. CONCLUSION Compared to RASB continuation, RASB discontinuation and nonuse were associated with higher baseline and serial creatinine levels during treatment for ADHF, but not with changes in SBP and potassium levels. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes.
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Medical Management of Heart Failure With Reduced Ejection Fraction in Patients With Advanced Renal Disease.
Hein, AM, Scialla, JJ, Edmonston, D, Cooper, LB, DeVore, AD, Mentz, RJ
JACC. Heart failure. 2019;(5):371-382
Abstract
Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT). This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research directions.
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4.
Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial.
Morrow, DA, Velazquez, EJ, DeVore, AD, Prescott, MF, Duffy, CI, Gurmu, Y, McCague, K, Rocha, R, Braunwald, E
European heart journal. 2019;(40):3345-3352
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Abstract
AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION NCT02554890 clinical.trials.gov.
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Real-World Associations of Renin-Angiotensin-Aldosterone System Inhibitor Dose, Hyperkalemia, and Adverse Clinical Outcomes in a Cohort of Patients With New-Onset Chronic Kidney Disease or Heart Failure in the United Kingdom.
Linde, C, Bakhai, A, Furuland, H, Evans, M, McEwan, P, Ayoubkhani, D, Qin, L
Journal of the American Heart Association. 2019;(22):e012655
Abstract
Background Dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real-world associations of RAASi dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAASi-prescribed patients with new-onset chronic kidney disease (n=100 572) or heart failure (n=13 113) first recorded between January 2006 and December 2015 in Clinical Practice Research Datalink and linked Hospital Episode Statistics databases. Odds ratios associating hyperkalemia and RAASi dose modification were estimated using logistic generalized estimating equations with normal (<5.0 mmol/L) serum potassium level as the reference category. Patients with serum potassium ≥5.0 mmol/L had higher risk of RAASi down-titration (adjusted odds ratios, chronic kidney disease: 1.79 [95% CI, 1.64-1.96]; heart failure: 1.33 [95% CI, 1.08-1.62]). Poisson models were used to estimate adjusted incident rate ratios of adverse outcomes based on total RAASi exposure (<50% and ≥50% of the guideline-recommended RAASi dose). Incidence of major adverse cardiac events and mortality was consistently higher in the lower dose group (adjusted incident rate ratios: chronic kidney disease: 5.60 [95% CI, 5.29-5.93] for mortality and 1.60 [95% CI, 1.55-1.66] for nonfatal major adverse cardiac events; heart failure: 7.34 [95% CI, 6.35-8.48] for mortality and 1.85 [95% CI, 1.71-1.99] for major adverse cardiac events). Conclusions The results of this real-world analysis highlight the potential negative impact of suboptimal RAASi dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation.
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Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis.
Wang, Y, Zhou, R, Lu, C, Chen, Q, Xu, T, Li, D
Journal of the American Heart Association. 2019;(13):e012272
Abstract
Background The angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin-converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM-HF (Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established. Methods and Results We conducted a meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD -0.79, 95% CI -0.86, -0.71) and 6-minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD -3.25 g/m2, 95% CI -3.78, -2.72) and left atrial volume (MD -7.20 mL, 95% CI -14.11, -0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow-up to 12 months. The regression equation for the relationship between left ventricular EF and end-diastolic dimension was y=0.041+0.071x+0.045x2+0.006x3. Conclusions ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short-term follow-up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.
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B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial.
Myhre, PL, Vaduganathan, M, Claggett, B, Packer, M, Desai, AS, Rouleau, JL, Zile, MR, Swedberg, K, Lefkowitz, M, Shi, V, et al
Journal of the American College of Cardiology. 2019;(11):1264-1272
Abstract
BACKGROUND Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. OBJECTIVES The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. METHODS BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. RESULTS Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). CONCLUSIONS Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).
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Recent advances in the treatment of chronic heart failure.
Buckley, LF, Shah, AM
F1000Research. 2019
Abstract
After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy.
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Activity Sensors to Evaluate the Effect of Sacubitril/Valsartan on Quality-of-Life in Heart Failure: rational and design of the AWAKE-HF study.
Khandwalla, RM, Birkeland, K, Heywood, JT, Steinhubl, S, McCague, K, Fombu, E, Grant, D, Riebman, JB, Owens, RL
ESC heart failure. 2019;(6):1313-1321
Abstract
AIMS: Limited data are available regarding the ability of sacubitril/valsartan to provide clinically meaningful health-related quality of life (HRQoL) improvements among individuals with heart failure (HF). Objective measurement of physical activity and sleep using actigraphy can provide insight into daily functioning and HRQoL. METHODS AND RESULTS We designed an 18 week, multicenter, randomized, double-blind, double-dummy, parallel-group study to objectively assess changes in function and HRQoL directly after initiating sacubitril/valsartan vs. enalapril in participants with HF in their home environments. A total of 136 outpatient, ambulatory participants with New York Heart Association Class II or III HF with reduced ejection fraction (HFrEF) will be included in the study. Patients will undergo a 2 week baseline observational phase (continuing current HF treatment); data from the second week of this phase will be the baseline value for comparison with those of subsequent periods. Patients will then enter an 8 week blinded-treatment phase (randomly assigned 1:1 to sacubitril/valsartan or enalapril), followed by an 8 week open-label extension phase (treatment with only sacubitril/valsartan). The primary efficacy endpoint is the change in mean activity counts during the most active 30 min of the participant's day between baseline and the final randomized treatment phase measurement. Secondary endpoints include the change in mean sleep activity during the randomized and open-label phases; questionnaires will also assess HRQoL measures. Rather than analysing pooled actigraphy data, the researchers are considering each participant to be acting as his or her own control. CONCLUSIONS This will be the first study to assess the effects of sacubitril/valsartan on objective measures of sleep and activity in individuals with HFrEF within the context of their daily lives. Wearable accelerometer devices will be used to gain insight into how the medication affects physical activity and sleep.
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Hyperkalemia and renin-angiotensin aldosterone system inhibitor therapy in chronic kidney disease: A general practice-based, observational study.
Jun, M, Jardine, MJ, Perkovic, V, Pilard, Q, Billot, L, Rodgers, A, Rogers, K, Gallagher, M
PloS one. 2019;(3):e0213192
Abstract
Data on hyperkalemia frequency among chronic kidney disease (CKD) patients receiving renin-angiotensin aldosterone system inhibitors (RAASis) and its impact on subsequent RAASi treatment are limited. This population-based cohort study sought to assess the incidence of clinically significant hyperkalemia among adult CKD patients who were prescribed a RAASi and the proportion of patients with RAASi medication change after experiencing incident hyperkalemia. We conducted a retrospective, population-based cohort study (1 January 2013-30 June 2017) using Australian national general practice data from the NPS MedicineWise's MedicineInsight program. The study included adults aged ≥18 years who received ≥1 RAASi prescription during the study period and had CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2). Study outcomes included incident clinically significant hyperkalemia (serum potassium >6 mmol/L or a record of hyperkalemia diagnosis) and among patients who experienced incident hyperkalemia, the proportion who had RAASi medication changes (cessation or dose reduction during the 210-day period after the incident hyperkalemia event). Among 20,184 CKD patients with a median follow-up of 3.9 years, 1,992 (9.9%) patients experienced an episode of hyperkalemia. The overall incidence rate was 3.1 (95% CI: 2.9-3.2) per 100 person-years. Rates progressively increased with worsening eGFR (e.g. 3.5-fold increase in patients with eGFR <15 vs. 45-59 ml/min/1.73m2). Among patients who experienced incident hyperkalemia, 46.6% had changes made to their RAASi treatment regimen following the first occurrence of hyperkalemia (discontinuation: 36.6% and dose reduction: 10.0%). In this analysis of adult RAASi users with CKD, hyperkalemia and subsequent RAASi treatment changes were common. Further assessment of strategies for hyperkalemia management and optimal RAASi use among people with CKD are warranted.