Disorders of iron metabolism (DIM) and accompanying anemia afflict many patients with advanced heart failure with reduced ejection fraction (HFrEF) who are candidates for continuous-flow left ventricular assist device (CF-LVAD) support.1 Hemolysis, bleeding, and inflammation contribute to DIM in the presence of CF-LVAD therapy, causing a milieu that is distinct from patients with advanced HFrEF without a CF-LVAD.1,2 Efficacy of intravenous (IV) must also be balanced against the increased risk of infection from the administration of the iron product in a immunocompromised CF-LVAD population.3,4 In this exploratory investigation, we sought to assess the effect of IV iron administration on iron and anemia indices in patients implanted with CF-LVADs and to compare their response with a similar cohort of advanced HFrEF patients without CF-LVADs.
Methods
This study was approved by the Mass General Brigham Institutional Review Board. Patients who underwent CF-LVAD implantation and received at least one dose of IV iron between January 2015 and August 2019 were included if they had available hemoglobin (Hgb), mean corpuscular volume (MCV), ferritin, or transferrin saturation (TSAT), measurements before and up to 90 days after IV iron treatment. Patients were excluded if they received a blood transfusion during the 90 days after initial IV iron administration or IV iron administration began within 30 days of CF-LVAD implant. A control cohort of HFrEF patients was selected if they had a left ventricular ejection fraction ≤30% with an estimated glomerular filtration rate of >45 ml/min per 1.73 m2, did not require CF-LVAD support, and had received IV iron therapy with no blood products administration during the same time period.
The principal end points were absolute change in Hgb and MCV from baseline up to 90 days after the last dose of IV iron. Change in serum ferritin and TSAT was also analyzed for both cohorts where follow-up values were available. Baseline characteristics, treatment regimen, and laboratory values were collected in all patients (values are represented as median [interquartile range]). Iron deficiency was defined as either ferritin <100 ng/ml or as ferritin between 100 and 300 ng/ml with TSAT <20%.5 Categorical variables were evaluated using χ2 test and nonparametric continuous variables were evaluated using either Mann–Whitney U or Wilcoxon signed-rank tests as appropriate.
Results
The study cohort included 12 CF-LVAD patients and 12 HFrEF patients. In the CF-LVAD cohort, the median age was 66[45–72] years, 10 (83%) were men, and nine (75%) were white persons. Six (50%) of the CF-LVAD patients were implanted with destination therapy intent, and seven (58%) underwent a HeartMate 3 pump (Abbott Labs, Illinois) implant. In the HFrEF cohort, the median age was 58 [51–68] years, 7 (58%) were men, and 5 (42%) were white persons. Iron deficiency based on ferritin <100 ng/ml was present in 9 (75%) of the CF-LVAD cohort and 11 (92%) of the HFrEF cohort. TSAT and Hgb were significantly lower in the CF-LVAD cohort than in the HFrEF cohort at baseline (Table 1). There was no difference between the two groups for median total elemental iron dose (CF-LVAD = 1000 [663–1020] mg; HFrEF = 450 [375–1000] mg; P = 0.38).
Table 1. -
Follow-Up Laboratory Values within 90 Days of Baseline
| Measurement |
LVAD n = 12 |
HFrEF n = 12 |
p-value |
| Ferritin (ng/mL) |
|  Baseline |
25 [19–52] (n = 12) |
51 [35–52] (n = 12) |
0.19 |
|  Follow-up |
53 [29–218] (n = 10) |
182 [95–185] (n = 5) |
0.50 |
|  Absolute change |
30 [9–134] (n = 10) |
77 [53–134] (n = 5) |
0.42 |
|  Percent change |
115 [23–252] (n = 10) |
263 [41–428] (n = 5) |
0.58 |
| TSAT (%) |
|  Baseline |
6 [5–8] (n = 12) |
10 [7–13] (n = 12) |
0.01
|
|  Follow-up |
15 [9–23] (n = 10) |
18 [15–23] (n = 5) |
0.50 |
|  Absolute change |
8 [4–16] (n = 10) |
5 [5–6] (n = 5) |
0.42 |
|  Percent change |
142 [75–241] (n = 10) |
43 [26–51] (n = 5) |
0.06 |
| Hemoglobin (g/dL) |
|  Baseline |
8.5 [8–9] (n = 12) |
9.8 [9–12] (n = 12) |
0.01
|
|  Follow-up |
10.7 [9–12] (n = 12) |
11.6 [11–13] (n = 10) |
0.25 |
|  Absolute change |
2.0 [1.3–2.9] (n = 12) |
0.8 [0.2–2.4] (n = 10) |
0.34 |
|  Percent change |
21 [12–34] (n = 12) |
7 [2–24] (n = 10) |
0.28 |
| HCT (%) |
|  Baseline |
28 [27–33] (n = 12) |
33 [30–38] (n = 12) |
<0.05
*
|
|  Follow-up |
35 [30–28] (n = 12) |
36 [34–41] (n = 10) |
0.49 |
|  Absolute change |
7 [4–8] (n = 12) |
3 [0–8] (n = 10) |
0.51 |
|  Percent change |
19 [13–30] (n = 12) |
11 [1–23] (n = 10) |
0.47 |
| MCV (fL) |
|  Baseline |
73 [70–85] (n = 12) |
84 [78–89] (n = 12) |
0.10 |
|  Follow-up |
79 [74–85] (n = 12) |
87 [85–93] (n = 10) |
0.20 |
|  Absolute change |
4 [0–7] (n = 12) |
4 [0–7] (n = 10) |
0.94 |
|  Percent change |
5 [0–10] (n = 12) |
5 [0–9] (n = 10) |
0.82 |
| Number of days between treatment and laboratory assessment |
46 [20–80] |
63 [43–81] |
0.38 |
HFrEF, heart failure with reduced ejection fraction; LVAD, left ventricular assist device.
*0.0466.
In the CF-LVAD cohort, ferritin increased by 30 [9–134] ng/ml, TSAT by 8 [4–16%] %, Hgb by 2.0 [1.2–2.9] g/dl, and MCV by 4 [0–7] fl. In the HFrEF cohort, ferritin increased by 105 [71–160] ng/ml, TSAT by 5 [5–6%] %, Hgb by 0.8 [0.2–2.4] g/dl, and MCV by 4 [0–7] fl. The increases in Hgb were statistically significant in the CF-LVAD and HFrEF cohorts. MCV was significantly increased in the CF-LVAD cohort (Figure 1). Serum ferritin (P = 0.02) and TSAT (P = 0.01) also significantly increased in the CF-LVAD cohort. There was no difference detected in changes in iron and anemia indices between the CF-LVAD and HFrEF groups (Table 1).
;)
Figure 1.: Absolute change in hemoglobin and mean corpuscular volume in LVAD and HFrEF cohorts. HFrEF, heart failure with reduced ejection fraction; LVAD, left ventricular assist device.
Discussion
In this retrospective study, biomarkers of iron storage and anemia improved significantly after a median administration of 1000 mg of IV elemental iron in CF-LVAD patients. These data suggest that CF-LVAD patients mount an appropriate hematologic response to IV iron repletion in a manner similar to HFrEF patients despite the distinct circulatory milieu.
CF-LVAD implantation increases inflammation and oxidative stress, two factors that influence iron storage, increase the risk of bleeding, and may blunt the therapeutic response.2 Hemolysis may also influence DIM; however, hemolysis is less of concern with newer generation devices.6 In a prospective analysis of 10 CF-LVAD patients receiving IV iron (median dose of 1,037 mg elemental iron) and 21 CF-LVAD patients receiving oral iron, serum ferritin, but not TSAT, increased significantly more in the IV iron group than in the oral iron group.7 This study and our investigation support a hematologic response to IV iron treatment in CF-LVAD patients.
Our study has strengths and limitations. The use of an HFrEF cohort provides a reference comparator for response to IV iron therapy. Additionally, exclusion of patients who received blood products provides the ability to assess the impact of IV iron independent of transfusion effect. Furthermore, exclusion of patients with advanced chronic kidney disease and renally mediated anemia allows for a less confounded study. Limitations include the single-center, retrospective design, and small sample size. It also remains unclear whether repeat dosing would further improve iron biomarkers. Finally, we cannot comment on the clinical and functional response or safety of IV iron therapy.
In conclusion, this study suggests that patients with CF-LVAD show an appropriate response to IV iron repletion despite the distinctly differing milieu when compared with advanced HFrEF patients without an implanted pump. Future studies should focus on the optimal IV iron regimen and the effect of iron repletion on functional, clinical, and safety outcomes in CF-LVAD patients.
References
1. Amione-Guerra J, Cruz-Solbes AS, Bhimaraj A, et al.:
Anemia after continuous-flow left ventricular assist device implantation: characteristics and implications. Int J Artif Organs 40: 481–488, 2017.
2. Mondal NK, Chen Z, Trivedi JR, et al.: Association of oxidative stress and platelet receptor glycoprotein GPIbα and GPVI shedding during nonsurgical bleeding in heart failure patients with continuous-flow left ventricular assist device support. ASAIO J 64: 462–471, 2018.
3. Shah AA, Donovan K, Seeley C, et al.: Risk of infection associated with administration of intravenous iron: a systematic review and meta-analysis. JAMA Netw Open 4: e2133935, 2021.
4. Patel CB, Blue L, Cagliostro B, et al.: Left ventricular assist systems and infection-related outcomes: a comprehensive analysis of the MOMENTUM 3 trial. J Heart Lung Transplant 39: 774–781, 2020.
5. Anker SD, Comin Colet J, Filippatos G, et al.; FAIR-HF Trial Investigators: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 361: 2436–2448, 2009.
6. Heilmann C, Geisen U, Benk C, et al.: Haemolysis in patients with ventricular assist devices: major differences between systems. Eur J Cardiothorac Surg 36: 580–584, 2009.
7. Bode LE, Wesner S, Katz JN, Chien CV, Hollis I: Intravenous versus oral iron replacement in patients with a continuous-flow left ventricular assist device. ASAIO J 65: e90–e91, 2019.
