- Email: [email protected]
Intravenous ferric carboxymaltose-associated hypophosphatemia in patients with iron deficiency anemia. A common side effect
Med Clin (Barc). 2016;145(3):108–111
www.elsevier.es/medicinaclinica
Brief report
Intravenous ferric carboxymaltose-associated hypophosphatemia in patients with iron deficiency anemia. A common side effect夽 Rebeca Sánchez González a,1 , Hugo Guillermo Ternavasio-de la Vega a,∗,1 , Leticia Moralejo Alonso b , Sandra Inés Revuelta b , Aurelio Fuertes Martín b a b
Servicio de Medicina Interna, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain Unidad y Consulta de Atención Inmediata (UCAI), Servicio de Medicina Interna, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
a r t i c l e
i n f o
Article history: Received 22 May 2014 Accepted 2 October 2014 Available online 1 February 2016 Keywords: Iron deficiency anemia Ferric carboxymaltose Hypophosphatemia
a b s t r a c t Objectives: To determine the frequency, severity, time of onset and factors associated with the development of hypophosphatemia (HF) in patients with iron deficiency anemia treated with intravenous ferric carboxymatose (ivFCM). Material and methods: Retrospective cohort study in patients iron deficiency anemia who received ivFCM and had an a prior and subsequent determination of serum phosphate. We carried out a comparative analysis between baseline and post-ivFCM levels of serum phosphate. In order to identify variables independently associated with HF a logistic regression analysis was also performed. Results: One hundred twenty-five patients were included. HF frequency was 58%. The median time to onset of HF was 18 days. Age, baseline ferritin levels and baseline phosphate levels were independently associated with the development of HF. The risk of HF in patients with baseline phosphate levels ≤3.1 mg/dl was 67% higher than patients with ≥3.7 mg/dl. Conclusions: ivFCM-associated HF is a frequent, early and, sometimes, prolonged effect in patients with iron deficiency anemia. Serum phosphate levels should be monitored after ivFCM administration, especially in older patients and in those with lower baseline phosphate or ferritin levels. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Hipofosfatemia asociada a la administración intravenosa de hierro carboximaltosa en pacientes con anemia ferropénica. Un efecto secundario frecuente r e s u m e n Palabras clave: Anemia ferropénica Hierro carboximaltosa Hipofosfatemia
Objetivos: Determinar la frecuencia, gravedad, momento de aparición y variables asociadas al desarrollo de hipofosfatemia (HF) en pacientes con anemia ferropénica tratados con hierro carboximaltosa por vía intravenosa (HCMiv). Material y método: Estudio de cohortes retrospectivo en pacientes que contaran con determinaciones de fosfato previa (normal) y posterior a la administración de HCMiv. Se compara la concentración de fosfato basal y posterior a la administración de HCMiv, y mediante regresión logística binaria se determinan las variables asociadas con la HF. Resultados: Se incluyeron 125 pacientes. La frecuencia de HF fue del 58%. El tiempo medio hasta la aparición de HF fue de 18 d. La edad, las concentraciones basales de ferritina y de fosfato se relacionaron con el desarrollo de HF. El riesgo de HF de los pacientes con fosfato basal ≤3,1 mg/dl fue un 67% mayor que en pacientes con fosfato basal ≥3,7 mg/dl.
夽 Please cite this article as: Sánchez González R, Ternavasio-de la Vega HG, Moralejo Alonso L, Revuelta SI, Fuertes Martín A. Hipofosfatemia asociada a la administración intravenosa de hierro carboximaltosa en pacientes con anemia ferropénica. Un efecto secundario frecuente. Med Clin (Barc). 2015;145:108–111. ∗ Corresponding author. E-mail address: [email protected] (H.G. Ternavasio-de la Vega). 1 Rebeca Sánchez González and Hugo Guillermo Ternavasio-de la Vega have contributed equally to this work. ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
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Conclusiones: La HF asociada a HCMiv en pacientes con anemia ferropénica es un efecto frecuente, precoz y en ocasiones prolongado. En pacientes mayores, con fosfato y ferritina más bajas, se debe vigilar el fosfato tras la administración de HCMiv. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Introduction Ferric carboxymaltose by the intravenous route (IV FCM) supplies high doses of elemental iron in a single administration, in a short space of time, with demonstrated efficacy and safety.1 The side effects related to IV FCM administration that have been reported include a decrease in serum phosphate levels, which, while it is not an effect exclusive to IV FCM, is exceptional among iron formulations for intravenous administration.2–4 The information available to date on onset and severity of hypophosphataemia (HP) and time to normalisation of phosphate levels is limited.2,4–6 The objectives of this study were to report the frequency,
severity and time to HP onset and to assess which variables are associated with HP onset in patients with iron deficiency anemia (IDA) treated with IV FCM. Materials and methods A retrospective study of patients with a diagnosis of IDA, followed up in our unit between 2008 and 2012, who had a normal baseline phosphate (BP) determination (in the previous 15 days) and a phosphate determination subsequent to an episode of IV FCM infusion (up to 180 days). Epidemiological, clinical, IDA-related and IV FCM administration-related variables were recorded.
Table 1 Characteristics at baseline and in accordance with hypophosphataemia onset following administration of ferric carboxymaltose by the intravenous route in the patients enrolled in the study. All (No. = 125)
Hypophosphataemia
p
No (No. = 52)
Yes (No. = 73)
Age (years) Male
76 (15) 51 (40.8)
74 (17) 15 (28.8)
77 (13) 36 (49.3)
0.09 0.02
Prior history Anemia of any type Iron-deficiency anemia Diabetes mellitus Chronic kidney failure Heart failure Chronic lung disease Gastrointestinal disease Active neoplasm Cognitive decline/dementia Osteoporosis/osteopenia Hyperparathyroidism
20 (16) 30 (24) 39 (31.2) 17 (13.6) 22 (17.6) 14 (11.2) 16 (12.8) 18 (14.4) 10 (8) 7 (5.6) 1 (0.8)
8 (15.4) 8 (15.4) 12 (23.1) 10 (19.2) 9 (17.3) 6 (11.5) 5 (9.6) 9 (17.3) 6 (11.5) 4 (7.7) 1 (1.9)
12 (16.4) 22 (30.1) 27 (37) 7 (9.6) 13 (17.8) 8 (11) 11 (15.1) 9 (12.3) 4 (5.5) 3 (4.1) 0 (0)
0.87 0.06 0.10 0.12 0.94 0.92 0.37 0.44 0.32 0.45 0.42
Previous treatment Oral iron Transfusion (15 days) Oral anticoagulants Anti-platelet agents Bisphosphonates
44 (35.2) 55 (44) 36 (28.8) 34 (27.2) 5 (4)
17 (32.7) 26 (50) 13 (25) 10 (19.2) 4 (7.7)
27 (37) 29 (39.7) 23 (31.5) 24 (32.9) 1 (1.4)
0.62 0.25 0.43 0.09 0.16
104 (83.2) 10 (8) 2 (1.6) 4 (3.2) 8 (6.4)
41 (78.8) 5 (9.6) 2 (3.8) 1 (1.9) 3 (5.8)
63 (86.3) 5 (6.8) 0 (0) 3 (4.2) 5 (6.8)
0.27 0.74 0.17 > 0.99 > 0.99
45 (36) 42 (33.6) 13 (10.4) 2 (1.6) 1 (0.8) 31 (24.8) 9.1 (1.8) 12.2 (22.5) 3.3 (0.6)
20 (38.5) 14 (26.9) 7 (13.5) 2 (3.8) 1 (1.9) 11 (21.2) 9.1 (1.7) 18.6 (49.3) 3.5 (0.7) 1000 (100)
25 (34.2) 28 (38.4) 6 (8.2) 0 (0) 0 (0) 20 (27.4) 9.1 (1.8) 10.5 (16.2) 3.2 (0.6) 1000 (400)
0.63 0.18 0.34 0.17 0.42 0.43 0.76 0.02 0.02 0.18
Mechanism of anemia onseta Gastrointestinal bleeding Gynaecological bleeding Malabsorption Other Unknown or not studied Indication for IV FCMa Need for rapid replacement Lack of response to oral iron Social cause Malabsorption Intolerance to oral iron Unknown or not recorded Haemoglobin (g/dl) Ferritin (ng/ml) Baseline serum phosphate (mg/dl) Total dose of iron received during the risk period assessed (1–35 days)b
The data indicate frequency (percentage) for the categorical variables and median (interquartile range) for the quantitative variables. Pearson’s chi-squared test or Fisher’s exact test was used to compare variables between groups for categorical variables, and Student’s t test was used to compare means for quantitative variables. IV FCM: ferric carboxymaltose by the intravenous route. a Each patient could be included in more than one category of the variable. b In the group with hypophosphataemia, the dose of iron received until hypophosphataemia was assessed. In the group without hypophosphataemia, total dose up to 35 days was assessed.
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R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
IDA was considered to be present when haemoglobin was <12 g/dl in females and <13 g/dl in males, accompanied by a ferritin level <30 ng/ml and/or a soluble transferrin receptor level >4.73 mg/l. An episode of IV FCM administration included all doses of IV FCM administered in the period of time elapsed from the first dose to day +35. Beyond that period of time, if the patient required another IV FCM administration, the case could be included as a new episode. With the aim of standardising comparisons with respect to BP, phosphate levels following IV FCM infusion were divided into 4 periods: i) 7–14 days (P7–14); ii) 15–21 days (P15–21); iii) 22–35 days (P22–35); and iv) 60–180 days since IV FCM infusion (P60–180). In those cases in which iron had been administered by the intravenous route again between 35 and 60 days since the first IV FCM infusion, the data for P60–180 were discarded. For purposes of analysis, only the cases with information for the periods studied were assessed. Any serum phosphate level <2.5 mg/dl was considered HP, and any serum phosphate level <1 mg/dl or with symptoms attributed to HP by the physician responsible for the case was considered serious HP. Statistical analysis Quantitative variables are reported in terms of median and interquartile range. Categorical variables are reported in terms of absolute frequency and percentage. The t test for repeated measures was used to compare BP with phosphate levels for each of the sub-periods analysed. To determine the variables related to HP onset, a multi-variable analysis was performed by means of logistic
regression using HP onset in the period between 7 and 35 days as an independent variable. Variables with a p < 0.20 in the univariate analysis were selected as co-variables. For the statistical analysis, the SPSS v. 19 program was used, and a p value <0.05 was considered statistically significant. Results During the study period, 622 doses of IV FCM were administered to 262 patients. Of these, 125 cases that met the inclusion criteria in our study received 179 infusions of IV FCM (mean of 1.43 infusions per patient), with a mean of 1204 mg of total iron administered to each one. Table 1 shows the characteristics of the patients enrolled and the groups depending on HP development. During follow-up, 73 patients had HP (58%), with a single episode of asymptomatic serious HP. HP appeared with a mean of 18 days following administration of IV FCM (considering the first HP datum available) and a mean of 78 days was necessary to reach normalisation of serum phosphate (considering the first normalisation datum available). For the periods P7–14, P15–21, P22–35 and P60–180, the numbers of patients with data available were 40, 62, 41 and 63, and HP frequencies were 26 (65%), 31 (50%), 24 (59%) and 8 (13%), respectively. Mean serum phosphate levels in each period were significantly lower compared to BP (Fig. 1, panels A–D). In the binary logistic regression analysis, the variables related to HP onset were: age (odds ratio [OR] 1.032; 95% confidence interval [95% CI] 1.001–1.064; p = 0.04), baseline ferritin level (OR 0.983; 95% CI 0.967–0.999; p = 0.0001) and BP level (OR 0.319; 95% CI
Fig. 1. Comparison of phosphate levels in each period studied versus baseline levels. The box diagrams show the distribution of serum phosphate levels only for patients who provide information for the 2 periods compared: 40 patients in panel A, 62 in panel B, 41 in panel C and 63 in panel D. The p value was obtained by means of the t test for repeated measures.
R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
0.112–0.908; p = 0.03). Finally, in patients with BP ≤3.1 mg/dl, the risk of HP onset was multiplied by 1.67 (95% CI 1.03–2.70) compared to patients with BP ≥3.7 mg/dl. Discussion The most noteworthy result of this study was the high frequency of HP associated with IV FCM administration in patients with IDA. This result supports the findings of some authors who have reported this complication in up to 74% of patients,7 but differs from others, who have placed its frequency under 13%.2,3 This variability could be explained by the different profile of patients enrolled in clinical trials or in the design of studies. Our study, with limitations inherent to its observational and retrospective design, had the advantages of enrolling a high number of patients screened from clinical practice. In our series, HP was an early and, in some cases, lasting effect. The time to onset (18 d) and time to correction (78 d) of HP found were limited by the heterogeneity of the time of phosphate determination, so they should be confirmed in a prospective study. Even so, it is noteworthy that up to 65% of patients in whom phosphate levels were determined in the P7–14 period had HP. In the few published studies that have mentioned the start of the drop in phosphate levels, this drop appeared between the first and second week, and the nadir was reached between the second and third week following IV FCM infusion.3,6 HP duration in this study had greater uncertainty owing to a lack of data in some patients. However, assuming a lack of HP in patients in whom serum phosphate was not determined, the real incidence of HP would have been at least 20% for P22–35 and 6% for P60–180. Prats et al.7 found that patients who developed HP sustained levels below baseline at 12 weeks from IV FCM infusion. As far as we know, this was the first time that the relationship between age and HP onset in patients with IDA who receive IV FCM was reported, but this should be confirmed in prospective studies. Patients who showed a greater risk of developing HP were those who had BP ≤3.1 mg/dl, for which they would be likely to be followed up more closely. Although the exact mechanism is unknown, some studies have proposed that phosphatonins are involved in the development of HP associated with IV FCM administration. Thus, the inverse association found between baseline ferritin and risk of HP could be explained by the existing relationship between ferritin and the phosphatonin fibroblast growth factor-23 previously mentioned by Wolf et al.8
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These results support the hypothesis that the short-term seriousness of HP associated with isolated infusion of IV FCM is limited. This state of affairs has been mentioned in the majority of published studies,2,6 although there have been sporadic reports of cases of serious HP associated with this iron formula for intravenous administration.5 The 24 weeks of follow-up in this study limited observation of the incidence of other complications, such as the hypophosphataemic osteomalacia that is associated with IV FCM and that has been mentioned in other studies.9 In conclusion, the HP associated with IV FCM administration in patients with IDA is a common and early effect that may persist for months. In patients of advanced age and/or with lower baseline phosphate and ferritin levels, phosphate levels must be monitored in the first 2 weeks and regularly until normalisation. Conflicts of interest The authors declare that they have no conflicts of interest. References 1. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48. 2. Barish CF, Koch T, Butcher A, Morris D, Bregman DB. Safety and efficacy of intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency anemia: two randomized, controlled trials. Anemia. 2012;2012:1–9. 3. Hussain I, Bhoyroo J, Butcher A, Koch TA, He A, Bregman DB. Direct comparison of the safety and efficacy of ferric carboxymaltose versus iron dextran in patients with iron deficiency anemia. Anemia. 2013;2013:1–10. 4. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94:2332–7. 5. Barea Mendoza JA, Gredilla Zubiria I, González Olmedo J, Mateo Alvarez S. Hipofosfatemia, una reacción adversa poco conocida del hierro intravenoso. Med Clin (Barc). 2014;143:284–5. 6. Seid MH, Derman RJ, Baker JB, Banach W, Goldberg C, Rogers R. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial. Am J Obstet Gynecol. 2008;199:435 e1–7e. 7. Prats M, Font R, Garcia C, Cabre C, Jariod M, Vea AM. Effect of ferric carboxymaltose on serum phosphate and C-terminal FGF23 levels in non-dialysis chronic kidney disease patients: post-hoc analysis of a prospective study. BMC Nephrol. 2013;14:167–74. 8. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28:1793–803. 9. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009;46:167–9.
www.elsevier.es/medicinaclinica
Brief report
Intravenous ferric carboxymaltose-associated hypophosphatemia in patients with iron deficiency anemia. A common side effect夽 Rebeca Sánchez González a,1 , Hugo Guillermo Ternavasio-de la Vega a,∗,1 , Leticia Moralejo Alonso b , Sandra Inés Revuelta b , Aurelio Fuertes Martín b a b
Servicio de Medicina Interna, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain Unidad y Consulta de Atención Inmediata (UCAI), Servicio de Medicina Interna, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
a r t i c l e
i n f o
Article history: Received 22 May 2014 Accepted 2 October 2014 Available online 1 February 2016 Keywords: Iron deficiency anemia Ferric carboxymaltose Hypophosphatemia
a b s t r a c t Objectives: To determine the frequency, severity, time of onset and factors associated with the development of hypophosphatemia (HF) in patients with iron deficiency anemia treated with intravenous ferric carboxymatose (ivFCM). Material and methods: Retrospective cohort study in patients iron deficiency anemia who received ivFCM and had an a prior and subsequent determination of serum phosphate. We carried out a comparative analysis between baseline and post-ivFCM levels of serum phosphate. In order to identify variables independently associated with HF a logistic regression analysis was also performed. Results: One hundred twenty-five patients were included. HF frequency was 58%. The median time to onset of HF was 18 days. Age, baseline ferritin levels and baseline phosphate levels were independently associated with the development of HF. The risk of HF in patients with baseline phosphate levels ≤3.1 mg/dl was 67% higher than patients with ≥3.7 mg/dl. Conclusions: ivFCM-associated HF is a frequent, early and, sometimes, prolonged effect in patients with iron deficiency anemia. Serum phosphate levels should be monitored after ivFCM administration, especially in older patients and in those with lower baseline phosphate or ferritin levels. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Hipofosfatemia asociada a la administración intravenosa de hierro carboximaltosa en pacientes con anemia ferropénica. Un efecto secundario frecuente r e s u m e n Palabras clave: Anemia ferropénica Hierro carboximaltosa Hipofosfatemia
Objetivos: Determinar la frecuencia, gravedad, momento de aparición y variables asociadas al desarrollo de hipofosfatemia (HF) en pacientes con anemia ferropénica tratados con hierro carboximaltosa por vía intravenosa (HCMiv). Material y método: Estudio de cohortes retrospectivo en pacientes que contaran con determinaciones de fosfato previa (normal) y posterior a la administración de HCMiv. Se compara la concentración de fosfato basal y posterior a la administración de HCMiv, y mediante regresión logística binaria se determinan las variables asociadas con la HF. Resultados: Se incluyeron 125 pacientes. La frecuencia de HF fue del 58%. El tiempo medio hasta la aparición de HF fue de 18 d. La edad, las concentraciones basales de ferritina y de fosfato se relacionaron con el desarrollo de HF. El riesgo de HF de los pacientes con fosfato basal ≤3,1 mg/dl fue un 67% mayor que en pacientes con fosfato basal ≥3,7 mg/dl.
夽 Please cite this article as: Sánchez González R, Ternavasio-de la Vega HG, Moralejo Alonso L, Revuelta SI, Fuertes Martín A. Hipofosfatemia asociada a la administración intravenosa de hierro carboximaltosa en pacientes con anemia ferropénica. Un efecto secundario frecuente. Med Clin (Barc). 2015;145:108–111. ∗ Corresponding author. E-mail address: [email protected] (H.G. Ternavasio-de la Vega). 1 Rebeca Sánchez González and Hugo Guillermo Ternavasio-de la Vega have contributed equally to this work. ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
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Conclusiones: La HF asociada a HCMiv en pacientes con anemia ferropénica es un efecto frecuente, precoz y en ocasiones prolongado. En pacientes mayores, con fosfato y ferritina más bajas, se debe vigilar el fosfato tras la administración de HCMiv. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Introduction Ferric carboxymaltose by the intravenous route (IV FCM) supplies high doses of elemental iron in a single administration, in a short space of time, with demonstrated efficacy and safety.1 The side effects related to IV FCM administration that have been reported include a decrease in serum phosphate levels, which, while it is not an effect exclusive to IV FCM, is exceptional among iron formulations for intravenous administration.2–4 The information available to date on onset and severity of hypophosphataemia (HP) and time to normalisation of phosphate levels is limited.2,4–6 The objectives of this study were to report the frequency,
severity and time to HP onset and to assess which variables are associated with HP onset in patients with iron deficiency anemia (IDA) treated with IV FCM. Materials and methods A retrospective study of patients with a diagnosis of IDA, followed up in our unit between 2008 and 2012, who had a normal baseline phosphate (BP) determination (in the previous 15 days) and a phosphate determination subsequent to an episode of IV FCM infusion (up to 180 days). Epidemiological, clinical, IDA-related and IV FCM administration-related variables were recorded.
Table 1 Characteristics at baseline and in accordance with hypophosphataemia onset following administration of ferric carboxymaltose by the intravenous route in the patients enrolled in the study. All (No. = 125)
Hypophosphataemia
p
No (No. = 52)
Yes (No. = 73)
Age (years) Male
76 (15) 51 (40.8)
74 (17) 15 (28.8)
77 (13) 36 (49.3)
0.09 0.02
Prior history Anemia of any type Iron-deficiency anemia Diabetes mellitus Chronic kidney failure Heart failure Chronic lung disease Gastrointestinal disease Active neoplasm Cognitive decline/dementia Osteoporosis/osteopenia Hyperparathyroidism
20 (16) 30 (24) 39 (31.2) 17 (13.6) 22 (17.6) 14 (11.2) 16 (12.8) 18 (14.4) 10 (8) 7 (5.6) 1 (0.8)
8 (15.4) 8 (15.4) 12 (23.1) 10 (19.2) 9 (17.3) 6 (11.5) 5 (9.6) 9 (17.3) 6 (11.5) 4 (7.7) 1 (1.9)
12 (16.4) 22 (30.1) 27 (37) 7 (9.6) 13 (17.8) 8 (11) 11 (15.1) 9 (12.3) 4 (5.5) 3 (4.1) 0 (0)
0.87 0.06 0.10 0.12 0.94 0.92 0.37 0.44 0.32 0.45 0.42
Previous treatment Oral iron Transfusion (15 days) Oral anticoagulants Anti-platelet agents Bisphosphonates
44 (35.2) 55 (44) 36 (28.8) 34 (27.2) 5 (4)
17 (32.7) 26 (50) 13 (25) 10 (19.2) 4 (7.7)
27 (37) 29 (39.7) 23 (31.5) 24 (32.9) 1 (1.4)
0.62 0.25 0.43 0.09 0.16
104 (83.2) 10 (8) 2 (1.6) 4 (3.2) 8 (6.4)
41 (78.8) 5 (9.6) 2 (3.8) 1 (1.9) 3 (5.8)
63 (86.3) 5 (6.8) 0 (0) 3 (4.2) 5 (6.8)
0.27 0.74 0.17 > 0.99 > 0.99
45 (36) 42 (33.6) 13 (10.4) 2 (1.6) 1 (0.8) 31 (24.8) 9.1 (1.8) 12.2 (22.5) 3.3 (0.6)
20 (38.5) 14 (26.9) 7 (13.5) 2 (3.8) 1 (1.9) 11 (21.2) 9.1 (1.7) 18.6 (49.3) 3.5 (0.7) 1000 (100)
25 (34.2) 28 (38.4) 6 (8.2) 0 (0) 0 (0) 20 (27.4) 9.1 (1.8) 10.5 (16.2) 3.2 (0.6) 1000 (400)
0.63 0.18 0.34 0.17 0.42 0.43 0.76 0.02 0.02 0.18
Mechanism of anemia onseta Gastrointestinal bleeding Gynaecological bleeding Malabsorption Other Unknown or not studied Indication for IV FCMa Need for rapid replacement Lack of response to oral iron Social cause Malabsorption Intolerance to oral iron Unknown or not recorded Haemoglobin (g/dl) Ferritin (ng/ml) Baseline serum phosphate (mg/dl) Total dose of iron received during the risk period assessed (1–35 days)b
The data indicate frequency (percentage) for the categorical variables and median (interquartile range) for the quantitative variables. Pearson’s chi-squared test or Fisher’s exact test was used to compare variables between groups for categorical variables, and Student’s t test was used to compare means for quantitative variables. IV FCM: ferric carboxymaltose by the intravenous route. a Each patient could be included in more than one category of the variable. b In the group with hypophosphataemia, the dose of iron received until hypophosphataemia was assessed. In the group without hypophosphataemia, total dose up to 35 days was assessed.
110
R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
IDA was considered to be present when haemoglobin was <12 g/dl in females and <13 g/dl in males, accompanied by a ferritin level <30 ng/ml and/or a soluble transferrin receptor level >4.73 mg/l. An episode of IV FCM administration included all doses of IV FCM administered in the period of time elapsed from the first dose to day +35. Beyond that period of time, if the patient required another IV FCM administration, the case could be included as a new episode. With the aim of standardising comparisons with respect to BP, phosphate levels following IV FCM infusion were divided into 4 periods: i) 7–14 days (P7–14); ii) 15–21 days (P15–21); iii) 22–35 days (P22–35); and iv) 60–180 days since IV FCM infusion (P60–180). In those cases in which iron had been administered by the intravenous route again between 35 and 60 days since the first IV FCM infusion, the data for P60–180 were discarded. For purposes of analysis, only the cases with information for the periods studied were assessed. Any serum phosphate level <2.5 mg/dl was considered HP, and any serum phosphate level <1 mg/dl or with symptoms attributed to HP by the physician responsible for the case was considered serious HP. Statistical analysis Quantitative variables are reported in terms of median and interquartile range. Categorical variables are reported in terms of absolute frequency and percentage. The t test for repeated measures was used to compare BP with phosphate levels for each of the sub-periods analysed. To determine the variables related to HP onset, a multi-variable analysis was performed by means of logistic
regression using HP onset in the period between 7 and 35 days as an independent variable. Variables with a p < 0.20 in the univariate analysis were selected as co-variables. For the statistical analysis, the SPSS v. 19 program was used, and a p value <0.05 was considered statistically significant. Results During the study period, 622 doses of IV FCM were administered to 262 patients. Of these, 125 cases that met the inclusion criteria in our study received 179 infusions of IV FCM (mean of 1.43 infusions per patient), with a mean of 1204 mg of total iron administered to each one. Table 1 shows the characteristics of the patients enrolled and the groups depending on HP development. During follow-up, 73 patients had HP (58%), with a single episode of asymptomatic serious HP. HP appeared with a mean of 18 days following administration of IV FCM (considering the first HP datum available) and a mean of 78 days was necessary to reach normalisation of serum phosphate (considering the first normalisation datum available). For the periods P7–14, P15–21, P22–35 and P60–180, the numbers of patients with data available were 40, 62, 41 and 63, and HP frequencies were 26 (65%), 31 (50%), 24 (59%) and 8 (13%), respectively. Mean serum phosphate levels in each period were significantly lower compared to BP (Fig. 1, panels A–D). In the binary logistic regression analysis, the variables related to HP onset were: age (odds ratio [OR] 1.032; 95% confidence interval [95% CI] 1.001–1.064; p = 0.04), baseline ferritin level (OR 0.983; 95% CI 0.967–0.999; p = 0.0001) and BP level (OR 0.319; 95% CI
Fig. 1. Comparison of phosphate levels in each period studied versus baseline levels. The box diagrams show the distribution of serum phosphate levels only for patients who provide information for the 2 periods compared: 40 patients in panel A, 62 in panel B, 41 in panel C and 63 in panel D. The p value was obtained by means of the t test for repeated measures.
R. Sánchez González et al. / Med Clin (Barc). 2016;145(3):108–111
0.112–0.908; p = 0.03). Finally, in patients with BP ≤3.1 mg/dl, the risk of HP onset was multiplied by 1.67 (95% CI 1.03–2.70) compared to patients with BP ≥3.7 mg/dl. Discussion The most noteworthy result of this study was the high frequency of HP associated with IV FCM administration in patients with IDA. This result supports the findings of some authors who have reported this complication in up to 74% of patients,7 but differs from others, who have placed its frequency under 13%.2,3 This variability could be explained by the different profile of patients enrolled in clinical trials or in the design of studies. Our study, with limitations inherent to its observational and retrospective design, had the advantages of enrolling a high number of patients screened from clinical practice. In our series, HP was an early and, in some cases, lasting effect. The time to onset (18 d) and time to correction (78 d) of HP found were limited by the heterogeneity of the time of phosphate determination, so they should be confirmed in a prospective study. Even so, it is noteworthy that up to 65% of patients in whom phosphate levels were determined in the P7–14 period had HP. In the few published studies that have mentioned the start of the drop in phosphate levels, this drop appeared between the first and second week, and the nadir was reached between the second and third week following IV FCM infusion.3,6 HP duration in this study had greater uncertainty owing to a lack of data in some patients. However, assuming a lack of HP in patients in whom serum phosphate was not determined, the real incidence of HP would have been at least 20% for P22–35 and 6% for P60–180. Prats et al.7 found that patients who developed HP sustained levels below baseline at 12 weeks from IV FCM infusion. As far as we know, this was the first time that the relationship between age and HP onset in patients with IDA who receive IV FCM was reported, but this should be confirmed in prospective studies. Patients who showed a greater risk of developing HP were those who had BP ≤3.1 mg/dl, for which they would be likely to be followed up more closely. Although the exact mechanism is unknown, some studies have proposed that phosphatonins are involved in the development of HP associated with IV FCM administration. Thus, the inverse association found between baseline ferritin and risk of HP could be explained by the existing relationship between ferritin and the phosphatonin fibroblast growth factor-23 previously mentioned by Wolf et al.8
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These results support the hypothesis that the short-term seriousness of HP associated with isolated infusion of IV FCM is limited. This state of affairs has been mentioned in the majority of published studies,2,6 although there have been sporadic reports of cases of serious HP associated with this iron formula for intravenous administration.5 The 24 weeks of follow-up in this study limited observation of the incidence of other complications, such as the hypophosphataemic osteomalacia that is associated with IV FCM and that has been mentioned in other studies.9 In conclusion, the HP associated with IV FCM administration in patients with IDA is a common and early effect that may persist for months. In patients of advanced age and/or with lower baseline phosphate and ferritin levels, phosphate levels must be monitored in the first 2 weeks and regularly until normalisation. Conflicts of interest The authors declare that they have no conflicts of interest. References 1. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48. 2. Barish CF, Koch T, Butcher A, Morris D, Bregman DB. Safety and efficacy of intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency anemia: two randomized, controlled trials. Anemia. 2012;2012:1–9. 3. Hussain I, Bhoyroo J, Butcher A, Koch TA, He A, Bregman DB. Direct comparison of the safety and efficacy of ferric carboxymaltose versus iron dextran in patients with iron deficiency anemia. Anemia. 2013;2013:1–10. 4. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94:2332–7. 5. Barea Mendoza JA, Gredilla Zubiria I, González Olmedo J, Mateo Alvarez S. Hipofosfatemia, una reacción adversa poco conocida del hierro intravenoso. Med Clin (Barc). 2014;143:284–5. 6. Seid MH, Derman RJ, Baker JB, Banach W, Goldberg C, Rogers R. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial. Am J Obstet Gynecol. 2008;199:435 e1–7e. 7. Prats M, Font R, Garcia C, Cabre C, Jariod M, Vea AM. Effect of ferric carboxymaltose on serum phosphate and C-terminal FGF23 levels in non-dialysis chronic kidney disease patients: post-hoc analysis of a prospective study. BMC Nephrol. 2013;14:167–74. 8. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28:1793–803. 9. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009;46:167–9.