Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p = 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p = 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF.
Iron deficiency has been identified as a common co-morbidity in patients with heart failure (HF). The prevalence of iron deficiency has been suggested to increase with disease severity and is associated with poor outcomes in patients with HF. The utility of oral iron supplementation may be limited in patients with HF due to impaired absorption, food and medication interactions, gastrointestinal adverse reactions, and the substantial medication burden associated with correction of deficiency. Because of these concerns with oral iron therapy, the use of intravenous (IV) iron therapy in patients with HF has been explored. Studies conducted in patients with chronic HF have demonstrated improvements in hematologic, functional capacity, and quality of life parameters with the administration of IV iron, with the most robust data available in the ambulatory HF population. To date, only one study has examined the use of IV iron in patients hospitalized with HF. This study found significant improvement in hematologic parameters with IV iron administration but was limited by a small sample size, lack of control group, and short duration of follow-up. Overall, there remains a paucity of data regarding the correction of iron deficiency in patients with acute HF and the clinical outcomes that result from treatment, in particular, that of rehospitalization. Furthermore, the use of total dose infusions of IV iron has not previously been described in an HF population. The purpose of this study was to determine the safety and efficacy of total dose infusion IV iron administration in patients with acute HF.
Methods
This study was conducted as a retrospective cohort analysis of patients admitted to the University of Michigan Health System (UMHS) from January 2010 to August 2014 with a primary diagnosis of acute HF, anemia, and low-iron studies during admission. Patients were grouped into cohorts on the basis of receipt of IV iron therapy or no IV iron during the index admission and the study was approved by the University of Michigan Institutional Review Board.
The study included patients who were aged 18 years or older with HF as a primary discharge diagnosis, a hemoglobin <13 g/dl, and a transferrin saturation (TSAT) <20% during admission. Patients were excluded from the study based on the receipt of an erythropoietin-stimulating agent or blood transfusion, significant hepatic impairment (aspartate transaminase or alanine transaminase >3 times the upper limit of normal), significant renal impairment (serum creatinine >3 mg/dl or receiving renal replacement therapy), documented folate or vitamin B12 deficiency, or death during admission.
The primary outcome was change in hemoglobin over time within 30 days of therapy. Secondary efficacy outcomes included the rate of 30-day all-cause rehospitalization, defined as any readmission to UMHS within 30 days of the date of discharge. The primary safety outcome assessed in this study was the rate of documented adverse events associated with IV iron therapy. Further details of the methods are described in the Supplementary Appendix .
IV iron dextran and iron sucrose were preparations used during the study period. Doses were commonly calculated based on iron dextran labeling using a target hemoglobin of 12 g/dl. After the tolerance of a test dose, IV iron was primarily administered as a total dose infusion, with the entire calculated iron dose given in a single infusion over 4 to 6 hours.
The primary outcome was assessed using repeated measures mixed-modeling controlling for baseline hemoglobin. The chi-square testing was used to assess categorical variables, and the Student t testing was used for continuous variables. Cox proportional hazard models were used to assess time to readmission outcomes. A p value of <0.05 was considered to be significant. Descriptive statistics were used for analysis of adverse events experienced with therapy. All analyses were performed using SAS, version 9.4 (SAS Institute, Cary, North Carolina).
Results
Forty-four patients who received IV iron and 128 control patients were identified for study inclusion. Baseline characteristics for patients included in the study are summarized in Table 1 . Age, gender, race, and co-morbidities on admission were similar between the 2 groups. Diabetes and coronary artery disease were common co-morbidities in study patients, with similar proportions of patients with each at baseline. Patients in the IV iron group had a greater incidence of chronic obstructive pulmonary disease at baseline. Vital signs at admission and mean left ventricular ejection fraction were not significantly different between the 2 groups. However, the length of hospital stay during the index admission was significantly longer in the IV iron group and hemoglobin, ferritin, and TSAT were significantly lower in patients who received IV iron.
| Variable | IV Iron (n = 44) | Control (n = 128) | P value |
|---|---|---|---|
| Age (years) | 61 ± 14 | 66 ± 14 | 0.07 |
| Women | 23 (52%) | 48 (38%) | 0.086 |
| Black | 9 (21%) | 28 (22%) | 0.2136 |
| White | 29 (66%) | 93 (73%) | |
| Other race | 6 (12%) | 7 (5%) | |
| Comorbidities upon admission | |||
| Diabetes mellitus | 25 (57%) | 61 (48%) | 0.2944 |
| Coronary artery disease | 21 (48%) | 64 (50%) | 0.7948 |
| Prior percutaneous coronary intervention | 8 (18%) | 24 (19%) | 0.9334 |
| Aortic stenosis | 3 (7%) | 7 (5%) | 0.7414 |
| Prior stroke or transient ischemic attack | 7 (16%) | 21 (16%) | 0.9386 |
| Chronic obstructive pulmonary disease | 4 (9%) | 29 (23%) | 0.487 |
| Dementia | 2 (5%) | 4 (3%) | 0.6578 |
| Length of stay (days) | 17 ± 16 | 10 ± 7 | <0.0001 |
| Systolic blood pressure (mm Hg) ∗ | 114 ± 21 | 122 ± 25 | 0.05 |
| Heart rate (beats/minute) ∗ | 84 ± 14 | 82 ± 17 | 0.44 |
| Respiratory rate (respirations/minute) ∗ | 19 ± 2 | 20 ± 4 | 0.19 |
| Left ventricular ejection fraction (%) | 33 ± 22 | 37 ± 21 | 0.31 |
| Hemoglobin (g/dL) † | 9.4 ± 1.4 | 10.0 ± 1.4 | 0.008 |
| Transferrin saturation (%) † | 6.7 ± 2.5 | 13.2 ± 4.9 | <0.0001 |
| Ferritin (mg/dL) | 77.5 ± 97.6 | 226.0 ± 254.5 | 0.0005 |
IV iron dosing is described in Table 2 . Patients in the IV iron group received a mean dose of 1,057 (±336) mg of iron during their admission, and doses ranged from 25 mg to 1,925 mg. Most patients in the cohort received therapy with iron dextran alone, with the remaining receiving a combination of iron dextran and iron sucrose. Doses administered were commonly rounded from calculated dosing requirements to an easily measureable dose and varied from predicted requirements by an average of 97 mg.
| Variable | Intravenous Iron (n = 44) |
|---|---|
| Total dose of intravenous iron in milligrams, median (minimum, maximum) | 1025 (25, 1925) |
| Intravenous iron product received | |
| Dextran alone | 41 (93%) |
| Sucrose alone | 0 |
| Dextran and sucrose | 3 (7%) |
| Number of non-test doses | |
| 0 | 1 (2%) |
| 1 | 36 (82%) |
| 2 | 4 (9%) |
| 3 | 3 (7%) |
Figure 1 depicts the change in hemoglobin over the first 30 days in study patients. In the model, patients receiving IV iron had significantly greater improvements in hemoglobin over time after therapy (p = 0.0001). The mean baseline hemoglobin was 9.4 (±0.23) g/dl and 10.1 (±0.13) g/dl in the IV iron and control patients, respectively. The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at 28 days, respectively. The improvement associated with IV iron therapy remained significant when the model was adjusted for additional baseline differences in TSAT and hospital length of stay in addition to predictors of hemoglobin over time within the data set, including ferritin, albumin, and the co-morbidity of diabetes, as shown in Figure 1 (p = 0.001).
