Improvement of anemia with erythropoietin and intravenous iron reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive heart failure

doi:10.1016/j.ahj.2007.07.034

American Heart Journal

Volume 154, Issue 5, November 2007, Pages 870-876

https://doi.org/10.1016/j.ahj.2007.07.034 Get rights and content

Background

Central sleep apnea (CSA) (with or without Cheyne-Stokes breathing) or obstructive sleep apnea (OSA) are common in congestive heart failure (CHF). Correction of anemia may improve CHF. We hypothesized that correction of anemia might also improve sleep−related breathing disorders (SRBDs) in CHF.

Methods

Thirty-eight patients with CHF and anemia (hemoglobin level <12 g/dL) were treated with erythropoietin and intravenous iron to a target hemoglobin level of 13 g/dL. Home sleep recordings were done before and after 3 months of treatment.

Results

Thirty-seven patients had SRBD (Apnea Hypopnea Index [AHI] of ≥10). Hemoglobin level increased from 10.4 ± 0.8 to 12.3 ± 1.2 g/dL (P < .001). Total AHI values decreased from 35.9 ± 12.2 to 24.9 ± 12.2 (P < .001). The AHI of CSA, OSA and Cheyne-Stokes breathing decreased from 26.5 ± 14.6 to 18.6 ± 7.7, from 9.4 ± 10.9 to 6.9 ± 9.8, and from 13.1 ± 16.4 to 9.0 ± 12.2, respectively (all P < .05). Sleep minimal oxygen saturation (Sao₂) increased from 62% ± 12% to 71% ± 11%; Epworth Sleepiness Scale score improved from 9.4 ± 6.2 to 6.0 ± 5.0 and New York Heart Association class improved from 2.9 ± 0.4 to 1.7 ± 0.7, all P < .001. Hemoglogin level improvement correlated with improvement in OSA+CSA, CSA, minimal Sao₂, Epworth Sleepiness Scale score, and New York Heart Association class (all P < .001).

Conclusion

Improvement of anemia in CHF is associated with a reduction in SRBD and an improvement in daytime sleepiness.

Section snippets

Patients

Forty-nine consecutive CHF patients with anemia who were being jointly treated by cardiologists and nephrologists in 2 heart failure clinics and in 2 nephrology clinics and met the inclusion criteria were offered to participate in the study. The recruitment period began in June 2005 and ended in June 2006. Of these 49 patients, 5 refused to have the first sleep study because they considered it an inconvenience and another 5 patients refused to have the second polysomnography evaluation for the

Patients

A description of the main demographic and clinical data of the patients is seen in Table I. The main causes of CHF were ischemic heart disease in 30 (78.9%), idiopathic dilated cardiomyopathy in 7 (18.4%) and valvular heart disease in 1 (2.6%). The CHF medications the patients were receiving at the beginning and during the study are also shown. There was no change in the medication during the study.

Hematologic biochemical findings

Over the 3-month period of treatment, the mean Hb level increased from 10.4 ± 0.8 to 12.3 ± 1.2

Discussion

The main finding of this study is that the improvement of the anemia in CHF by treatment with a combination of subcutaneous EPO and IV iron was associated with significant reductions of SRBD. The most striking decrease was observed in CSA, whereas in OSA and Cheyne-Stokes breathing, although the changes were significant, they were less striking. The improvement in anemia also significantly ameliorated the severity of the hypoxia related to these apneic episodes and significantly improved

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Iron deficiency (ID) is associated with sleep disorders, but standardized assessment of iron status in the diagnostic work-up and iron supplementation as treatment have not been considered in clinical practice. We investigated associations of ID with type and severity of sleep disorders and whether iron supplementation improves sleep-related symptoms. In 2017, we conducted a scoping review for the period 1972-2016 using the terms “iron deficiency anemia” and “sleep” on biomedical database search engines, and in 2019, we updated our review with an ad-hoc search. Among the 93 articles meeting our inclusion criteria, 74/93 studies investigated restless legs syndrome (RLS), 8/93 periodic limb movements in sleep (PLMs), 3/93 sleep disordered breathing (SDB), 6/93 general sleep disturbances (GSD), and 2/93 attention-deficit/ hyperactivity disorder related sleep disorders (ADHD-SDs). A statistically supported positive association with ID was found in 22/42 RLS, 3/8 PLMs, 1/2 SDB, 3/4 GSD, and 1/2 ADHD-SDs association studies. The ad-hoc literature search revealed eight additional association studies with a statistically supported positive association in 2/5 RLS, 1/1 SDB, 1/1 ADHD-SDs, and 1/1 restless sleep disorder (RSD) studies. Iron supplementation was beneficial in 29/30 RLS (including five randomized controlled trials [RCTs]), 1/1 SDB, and 2/2 GSD treatment studies. Iron supplementation was also beneficial in 2/2 RLS (including two RCTs), 1/1 GSD (RCT), and 1/1 RSD studies identified in the ad-hoc search. In pediatric populations, 1/1 RLS, 1/1 SDB, 2/5 PLMs, 2/3 GSD and 1/2 ADHD-SDs studies found positive associations, and 6/6 RLS and 2/2 GSD studies demonstrated a benefit with iron supplementation. In conclusion, iron investigation and supplementation should be considered in patients presenting with sleep disorders. To investigate the role of ID in sleep in the future, a harmonization of study designs, including outcome measures and standardized iron and inflammation status is necessary.
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Preclinical data suggest that hypoxia stimulates fibroblast growth factor 23 (FGF23) transcription and cleavage in osteocytes, resulting in elevated circulating c-terminal (cFGF23) levels but normal intact FGF23 (iFGF23) levels. We conducted a case-control study within the Hispanic Community Health Study/Study of Latinos to investigate whether sleep disordered breathing, as a model of hypoxemia, is independently associated with elevated cFGF23 levels in the general population and with elevated cFGF23 and iFGF23 levels in patients with chronic kidney disease (CKD), in whom FGF23 cleavage may be impaired. Cases (n = 602) had severe sleep disordered breathing defined as an apnea/hypopnea index (AHI) of ≥30. Controls without severe sleep disordered breathing (n = 602) were matched for sex and CKD stage. The median AHI in the cases was 45.8 (IQR 35.5–62.5) compared to 2.6 (IQR 0.6–8.2) in the controls. Cases had higher cFGF23 levels than controls (66.2 RU/mL, IQR 52.8–98.4 vs. 61.2 RU/mL, IQR 49.5–80.1, p value <0.001). There were no differences in iFGF23 levels between cases and controls. In adjusted linear regression and multinomial regression analyses, body mass index attenuated the relationship between severe sleep disordered breathing and cFGF23 levels. No significant relationships were seen in analyses of severe sleep disordered breathing and iFGF23 levels or in analyses of iFGF23 and cFGF23 stratified by CKD status. Additional studies using other models of intermittent and chronic hypoxia are needed to confirm whether hypoxia stimulates FGF23 transcription in humans and to determine the impact on iFGF23 levels in CKD.
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All the patients had a polysomnographic evaluation at their home with a validated polysomnograph [12]. The details of the sleep study have been described elsewhere [11]. All patients were asked 4 questions (according to international criteria [13] three times: before anemia treatment, at 3 months at the clinic and at 12 months after treatment by telephone.
To assess the prevalence of Restless Legs Syndrome (RLS) in anemic patients with Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) and to evaluate the effect of anemia treatment on RLS.
38 anemic CHF–CRF patients were treated with subcutaneous Erythropoietin (EPO) and intravenous (IV) iron over 1 year. They were questioned initially and at 3 months post treatment about symptoms of RLS according to standard criteria. They were also contacted by telephone about RLS symptoms 12 months after onset of anemia treatment.
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RLS is common and often undiagnosed and untreated in anemic CHF–CRF patients. Unfortunately, successful treatment of anemia with EPO and IV iron did not improve this condition.
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View all citing articles on Scopus

: This study was part of the requirement for Maya Zilberman to obtain her PhD degree in the Brain Sciences Faculty of Bar Ilan University, Ramat Gan, Israel.

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Clinical InvestigationsCongestive Heart FailureImprovement of anemia with erythropoietin and intravenous iron reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive heart failure

Background

Methods

Results

Conclusion

Section snippets

Patients

Patients

Hematologic biochemical findings

Discussion

Int J Cardiol

Chest

J Amer Coll Cardiol

Chest

J Am Coll Cardiol

Semin Nephrol

Am Heart J

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Am J Kidney Dis

Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure

Am J Respir Crit Care Med

Treatment of sleep apnea in heart failure

Am J Respir Crit Care Med

Heart failure and sleep apnoea: to sleep perchance to dream

Eur J Heart Fail

Clinical Investigations
Congestive Heart Failure
Improvement of anemia with erythropoietin and intravenous iron reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive heart failure