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Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction.

ABSTRACT: RATIONALE & OBJECTIVE:Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes. STUDY DESIGN:Post hoc analysis of trial data. SETTINGS & PARTICIPANTS:Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD). EXPOSURE:Enalapril versus placebo. OUTCOMES:Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by?0.3mg/dL, (2)>30% eGFR decline, (3)>40% eGFR decline, and (4) incident eGFR<30mL/min/1.73m2. ANALYTICAL APPROACH:Shared parameter models, multivariable Cox regression models. RESULTS:Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5±19.8 (SD) versus 76.2±18.6mL/min/1.73m2. Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (-0.84 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.08) or Prevention Trial (-1.27 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by?0.3mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline> 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline> 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR<30mL/min/1.73m2), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period. LIMITATIONS:Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level. CONCLUSION:Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group.

SUBMITTER: McCallum W

PROVIDER: S-EPMC7460181 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction.

McCallum Wendy W Tighiouart Hocine H Ku Elaine E Salem Deeb D Sarnak Mark J MJ

American journal of kidney diseases : the official journal of the National Kidney Foundation 20190711 1

<h4>Rationale & objective</h4>Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes.<h4>Study design</h4>Post hoc analysis of trial data.<h4>Settings & participants</h4>Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of ...[more]

PMID: 31303349

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Project description:IntroductionA worsening heart failure event (WHFE) is defined as progressively escalating heart failure signs/symptoms requiring intravenous diuretic treatment or hospitalization. No studies have compared the burden of chronic heart failure with reduced ejection fraction (HFrEF) following a WHFE versus stable disease to inform healthcare decision makers.MethodsA retrospective study using the IBM® MarketScan® Commercial Database included patients younger than 65 years of age with HFrEF (one inpatient or two outpatient claims of systolic HF or one outpatient claim of systolic HF plus one outpatient claim of any HF). The first claim for HFrEF during 2016 was the index date. Patients were followed for the first 12 months after the index date (the worsening assessment period) to identify a WHFE, and for an additional 12 months or until the end of continuous enrollment (the post-worsening assessment period). Mean per patient per month (PPPM) health care resource use (HCRU) and costs were compared between patients following a WHFE and stable patients during the two periods using generalized linear models adjusting for patient characteristics.ResultsOf 16,646 patients with chronic HFrEF, 26.8% developed a WHFE. Adjusted all-cause hospitalizations (0.16 vs. 0.02 PPPM, P < 0.0001), outpatient visits (3.54 vs. 2.73 PPPM, P < 0.0001), and emergency department visits (0.25 vs. 0.06 PPPM, P < 0.0001) were higher in patients following a WHFE than stable patients during the worsening assessment period. Similar differences in HCRU were observed between the two cohorts during the post-worsening assessment period. Mean total adjusted cost of care PPPM was $8657 in patients with HFrEF following a WHFE versus $2195 in stable patients during the worsening assessment period, and $6809 versus $2849, respectively, during the post-worsening assessment period.ConclusionHCRU and costs were significantly greater in patients with chronic HFrEF following a WHFE compared to those who remained stable, suggesting an unmet need to improve clinical and economic outcomes among these patients.

Project description:BackgroundLifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.MethodsParticipant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.ResultsWe included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.ConclusionsLifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Project description:BackgroundMicrovascular dysfunction plays an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link between systemic microvasculature and congestion, a central feature of the syndrome, has yet been investigated.ObjectivesThis study aimed to investigate capillary-interstitium fluid exchange in HFpEF, including lymphatic drainage and the potential osmotic forces exerted by any hypertonic tissue Na+ excess.MethodsPatients with HFpEF and healthy control subjects of similar age and sex distributions (n = 16 per group) underwent: 1) a skin biopsy for vascular immunohistochemistry, gene expression, and chemical (water, Na+, and K+) analyses; and 2) venous occlusion plethysmography to assess peripheral microvascular filtration coefficient (measuring capillary fluid extravasation) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation).ResultsSkin biopsies in patients with HFpEF showed rarefaction of small blood and lymphatic vessels (p = 0.003 and p = 0.012, respectively); residual skin lymphatics showed a larger diameter (p = 0.007) and lower expression of lymphatic differentiation and function markers (LYVE-1 [lymphatic vessel endothelial hyaluronan receptor 1]: p < 0.05; PROX-1 [prospero homeobox protein 1]: p < 0.001) compared with control subjects. In patients with HFpEF, microvascular filtration coefficient was lower (calf: 3.30 [interquartile range (IQR): 2.33 to 3.88] l × 100 ml of tissue-1 × min-1 × mm Hg-1 vs. 4.66 [IQR: 3.70 to 6.15] μl × 100 ml of tissue-1 × min-1 × mm Hg-1; p < 0.01; forearm: 5.16 [IQR: 3.86 to 5.43] l × 100 ml of tissue-1 × min-1 × mm Hg-1 vs. 5.66 [IQR: 4.69 to 8.38] μl × 100 ml of tissue-1 × min-1 × mm Hg-1; p > 0.05), in keeping with blood vascular rarefaction and the lack of any observed hypertonic skin Na+ excess, but the lymphatic drainage was impaired (isovolumetric pressure in patients with HFpEF vs. control subjects: calf 16 ± 4 mm Hg vs. 22 ± 4 mm Hg; p < 0.005; forearm 17 ± 4 mm Hg vs. 25 ± 5 mm Hg; p < 0.001).ConclusionsPeripheral lymphatic vessels in patients with HFpEF exhibit structural and molecular alterations and cannot effectively compensate for fluid extravasation and interstitial accumulation by commensurate drainage. Reduced lymphatic reserve may represent a novel therapeutic target.

Dataset Information

Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction.

Publications

Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction.

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