NT-proBNP Goal Achievement Is Associated With Significant Reverse Remodeling and Improved Clinical Outcomes in HFrEF

Daubert, Melissa A.; Adams, Kirkwood F.; Yow, Eric; Barnhart, Huiman X.; Douglas, Pamela S.; Rimmer, Susan; Norris, Casey; Cooper, Lawton S.; Leifer, Eric; Desvigne‐Nickens, Patrice; Anstrom, Kevin J.; Fiuzat, Mona; Ezekowitz, Justin A.; Mark, Daniel B.; O’Connor, Christopher M.; Januzzi, James L.; Felker, G. Michael

doi:10.1016/j.jchf.2018.10.014

Cited by 73 publications

(72 citation statements)

References 20 publications

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“…In patients with HFrEF, beneficial reverse LV remodeling initiated by pharmacological and device interventional therapies, as measured by LV volume changes, have been shown to have important prognostic significance. 77,93–95 These benefits have been reported for randomized clinical studies of ACE inhibitor, 2,96,97 ARBs, 2,98 β-adrenergic receptor blockers, 99,100 ivabradine, 3,101 and cardiac resynchronization therapy in which reverse remodeling predicts improved clinical outcomes and reduction in arrhythmic events. 102,103 Importantly, LVESV and LVESV index have been shown to be powerful predictors of subsequent cardiovascular-related morbidity and mortality in patients with HFrEF who are treated with an array of drug, biologic, or device therapies.…”

Section: Mpcs In Advanced Chronic Hfref Patients: Is There Biologic Pmentioning

confidence: 79%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

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Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell–based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF...

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Section: Mpcs In Advanced Chronic Hfref Patients: Is There Biologic Pmentioning

confidence: 79%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

View full text Add to dashboard Cite

show abstract

“…Taken together, the results of this study suggest that patients with NT-proBNP reduction following ARNI initiation are likely to experience reverse cardiac remodeling. As studies have suggested that a lack of NT-proBNP reduction after therapy for HFrEF is associated with worse LV size and function, 7,20 studies evaluating meaning of NT-proBNP nonresponse in this study are planned. Because of the design of the PARADIGM-HF trial, which required all patients to receive stable ACEI or ARB therapy, to have elevated natriuretic peptide concentrations, and to achieve target doses of enalapril and sacubitril-valsartan during the run-in period to remain in the trial, there was ambiguity about the effects of ARNI in patients not meeting these criteria.…”

Section: Discussionmentioning

confidence: 99%

Association of Change in N-Terminal Pro–B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction

Januzzi

Prescott

Butler

et al. 2019

JAMA

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488

423

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IMPORTANCE In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES The primary outcome was the correlation between changes in log 2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) at 12 months. RESULTS Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log 2-NT-proBNP concentration was correlated with changes in LVEF

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“…Many studies have shown that elevated BNP is an independent predictor of mortality and other cardiac outcomes in patients with heart diseases ( Balion et al, 2006 ; Di Angelantonio et al, 2009 ). BNP is used as a diagnostic, management, and prognostic tool for HF ( Thygesen et al, 2012 ; Daubert et al, 2019 ). An unconfirmed report by Liang et al (2003) described a thyroid response element (TRE) on the BNP gene and T3 induced expression of BNP in neonatal cultured myocytes.…”

Section: Discussionmentioning

confidence: 99%

BNP as a New Biomarker of Cardiac Thyroid Hormone Function

et al. 2020

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Background: Cardiac re-expression of fetal genes in patients with heart failure (HF) suggests the presence of low cardiac tissue thyroid hormone (TH) function. However, serum concentrations of T3 and T4 are often normal or subclinically low, necessitating an alternative serum biomarker for low cardiac TH function to guide treatment of these patients. The clinical literature suggests that serum Brain Natriuretic Peptide (BNP) levels are inversely associated with serum triiodo-L-thyronine (T3) levels. The objective of this study was to investigate BNP as a potential serum biomarker for TH function in the heart. Methods: Two animal models of thyroid hormone deficiency: (1) 8-weeks of propyl thiouracil-induced hypothyroidism (Hypo) in adult female rats were subsequently treated with oral T3 (10 µg/kg/d) for 3, 6, or 14 days; (2) HF induced by coronary artery ligation (myocardial infarction, MI) in adult female rats was treated daily with low dose oral T3 (5 µg/kg/d) for 8 or 16 wks. Results: Six days of T3 treatment of Hypo rats normalized most cardiac functional parameters. Serum levels of BNP increased 5-fold in Hypo rats, while T3 treatment normalized BNP by day 14, showing a significant inverse relationship between serum BNP and free or total T3 concentrations. Myocardial BNP mRNA was increased 2.5fold in Hypo rats and its expression was decreased to normal values by 14 days of T3 treatment. Measurements of hemodynamic function showed significant dysfunction in MI rats after 16 weeks, with serum BNP increased by 4.5-fold and serum free and total T3 decreased significantly. Treatment with T3 decreased serum BNP while increasing total T3 indicating an inverse correlation between these two biologic factors (r 2 = 0.676, p < 0.001). Myocardial BNP mRNA was increased 5-fold in MI rats which was significantly decreased by T3 over 8 to 16 week treatment periods. Conclusions: Results from the two models of TH dysfunction confirmed an inverse relationship between tissue and serum T3 and BNP, such that the reduction in serum BNP could potentially be utilized to monitor efficacy and dosing of T3 treatment. Thus, serum BNP may serve as a reliable biomarker for cardiac TH function.

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NT-proBNP Goal Achievement Is Associated With Significant Reverse Remodeling and Improved Clinical Outcomes in HFrEF

Cited by 73 publications

References 20 publications

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Association of Change in N-Terminal Pro–B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction

BNP as a New Biomarker of Cardiac Thyroid Hormone Function

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