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Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

ABSTRACT: : Iron deficiency is present in ?50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02188784.

SUBMITTER: Lewis GD

PROVIDER: S-EPMC6078413 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

Lewis Gregory D GD Semigran Marc J MJ Givertz Michael M MM Malhotra Rajeev R Anstrom Kevin J KJ Hernandez Adrian F AF Shah Monica R MR Braunwald Eugene E

Circulation. Heart failure 20160501 5

<h4>Unlabelled</h4>: Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with ...[more]

PMID: 27140203

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Project description:Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown.To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency.Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites.Oral iron polysaccharide (n?=?111) or placebo (n?=?114), 150 mg twice daily for 16 weeks.The primary end point was a change in peak oxygen uptake (V?o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life).Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V?o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V?o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P?=?.46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P?>?.05.Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF.clinicaltrials.gov Identifier: NCT02188784.

Project description:Aims: Evidence-based guidelines for heart failure management depend mainly on current left ventricular ejection fraction (LVEF). However, fewer studies have examined the impact of prior LVEF. Patients may enter the heart failure with midrange ejection fraction (HFmrEF) category when heart failure with preserved ejection fraction (HFpEF) deteriorates or heart failure with reduced ejection fraction (HFrEF) improves. In this study, we examined the association between change in LVEF and adverse outcomes. Methods: HFmrEF patients with at least two or more echocardiograms 3 months apart at the First Affiliated Hospital of Dalian Medical University between September 1, 2015 and November 30, 2019 were identified. According to the prior LVEF, the subjects were divided into improved group (prior LVEF < 40%), stable group (prior LVEF between 40 and 50%), and deteriorated group (prior LVEF ≥ 50%). The primary outcomes were cardiovascular death, all-cause mortality, hospitalization for worsening heart failure, and composite event of all-cause mortality or all-cause hospitalization. Results: A total of 1,168 HFmrEF patients (67.04% male, mean age 63.60 ± 12.18 years) were included. The percentages of improved, stable, and deteriorated group were 310 (26.54%), 334 (28.60%), and 524 (44.86%), respectively. After a period of follow-up, 208 patients (17.81%) died and 500 patients met the composite endpoint. The rates of all-cause mortality were 35 (11.29%), 55 (16.47%), and 118 (22.52%), and the composite outcome was 102 (32.90%), 145 (43.41%), and 253 (48.28%) for the improved, stable, and deteriorated groups, respectively. Cox regression analysis showed that the deterioration group had higher risk of cardiovascular death (HR: 1.707, 95% CI: 1.064-2.739, P = 0.027), all-cause death (HR 1.948, 95% CI 1.335-2.840, P = 0.001), and composite outcome (HR 1.379, 95% CI 1.096-1.736, P = 0.006) compared to the improvement group. The association still remained significant after fully adjusted for both all-cause mortality (HR = 1.899, 95% CI 1.247-2.893, P = 0.003) and composite outcome (HR: 1.324, 95% CI: 1.020-1.718, P = 0.035). Conclusion: HFmrEF patients are heterogeneous with three different subsets identified, each with different outcomes. Strategies for managing HFmrEF should include previously measured LVEF to allow stratification based on direction changes in LVEF to better optimize treatment.

Project description:AimsIn patients with heart failure and reduced ejection fraction (HFrEF), it remains unclear how exacerbated impairments in peak exercise oxygen uptake (V̇O2peak ) caused by coexistent obstructive or restrictive ventilatory defects affect mortality risk. We evaluated in patients with HFrEF, whether demonstrating either an obstructive or restrictive-patterned ventilatory defect on spirometry affects V̇O2peak to yield all-cause mortality risk predicted by V̇O2peak that is spirometry pattern specific.Methods and resultsWe retrospectively analysed resting spirometry and treadmill cardiopulmonary exercise testing data of patients with HFrEF (left ventricular ejection fraction ≤ 40%). The study sample (N = 329) was grouped by spirometry pattern: normal [Group 1: N = 101; forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) ≥ 0.70; FVC ≥ 80% predicted], restrictive without airflow obstruction (Group 2: N = 104; FEV1 /FVC ≥ 0.70; FVC < 80% predicted), or obstructive (Group 3: N = 124; FEV1 /FVC < 0.70). Patients were followed up to 1 year for the endpoint of all-cause mortality. V̇O2peak was higher in Group 1 versus Groups 2 and 3 (13.4 ± 4.0 vs. 12.1 ± 3.7 and 12.2 ± 3.3 mL/kg/min, respectively; P = 0.014). Over the 1 year follow-up, n = 9, n = 16, and n = 12 deaths occurred in Groups 1-3, respectively, with corresponding crude survival rates of 88%, 81%, and 92%, respectively (log-rank; P = 0.352). V̇O2peak was associated with all-cause mortality (crude hazard ratio = 0.77; P < 0.001). In multivariate analyses, a significant V̇O2peak -by-spirometry group interaction yielded 1.99 (95% confidence interval, 1.14-3.46) and 2.43 (95% confidence interval, 1.44-4.11) higher mortality risk associated with V̇O2peak in Group 2 versus Groups 1 and 3, respectively.ConclusionsDemonstrating a restrictive pattern on spirometry yields the severest mortality risk associated with V̇O2peak . Using spirometry to screen patients with HFrEF for ventilatory defects has a potential role in improving risk stratification based on V̇O2peak .

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.

Dataset Information

Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

Publications

Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

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