The administration of intravenous iron (IVF) is indicated for the management of iron deficiency and ferropenic anemia in those cases where iron supplementing via the oral route is not possible or is ineffective.1,2 With the formulations available for clinical use in Spain, the benefits of IVF clearly outweigh the risks, provided adequate measures are taken to minimize possible allergic reactions.1,2 Both the DS201310 and the European guide for the management of severe surgical bleeding (ESA guide)11 recommend the use of IVF in surgical patients in order to improve anemia and replenish the iron deposits. Intravenous iron formulations that allow the rapid administration of high doses (e.g., iron isomaltose-1000 and iron carboxymaltose) facilitate the implementation of these recommendations.

However, two documents have been published on the risk or adverse effects of IVF: an alert referred to the risk of hypersensitivity, which led to revision of these drugs by the Committee for Medicinal Products for Human Use of the EMA,1,2 and a metaanalysis alerting to an increased risk of infection in patients treated with these products.6

Regarding the risk of hypersensitivity, the EMA and AEMPS consider that there is a clear association between the administration of IVF and hypersensitivity reactions. While the incidence of such reactions is very low, they can prove fatal.1,2 Nevertheless, the agencies underscore that the information supplied by the industry and the national pharmacovigilance centers affords very low quality evidence and is not valid for detecting safety differences among the different IVF formulations. They therefore recommend annual reviews of the reports on allergic reactions and prospective studies. The agencies have also drafted recommendations in relation to the administration and contraindications of IVF.1,2 A consensus document has recently been published on the management of hypersensitivity reactions.12

With regard to the increase in the risk of infection, a metaanalysis of 72 clinical trials (comprising about 10,000 patients) concluded that these formulations improve the hemoglobin (Hb) levels and reduce the allogeneic blood transfusion (ABT) rates, but increase the relative risk of infections (RR: 1.33; 95%CI: 1.10–1.64).6 Different experts have criticized this latter conclusion, however, since: (1) in most the included studies infection was not a predefined target variable; (2) there was great heterogeneity regarding the dose and duration of treatment, the types of iron, study populations, etc.; (3) no dose–effect relationship was observed between the administration of IVF and an increased incidence of infections or mortality, and (4) the studies that did include definition criteria for this variable recorded no increase in infection rate in the patients treated with IVF.13 Furthermore, a later metaanalysis involving a larger number of studies (n=103; over 19,000 patients) identified no increase in the risk of infection in the patients that received IVF.14

It should be remembered that the risk of infection is increased in situations of iron overload, but also in cases of ferropenia, and that the administration of IVF in non-ferropenic patients might increase the risk of infections.15 A correct diagnosis is therefore essential in order to guarantee the efficacy and safety of treatment with IVF.

The alerts regarding the adverse effects of erythropoiesis stimulators, such as an increased risk of thromboembolic events (TEEs) and mortality in different clinical contexts, are not new. However, they have led to changes in the indications of these stimulators and in the treatment schemes in renal and cancer patients.16,17

In the surgical context, recombinant human erythropoietin (epoetin-alpha, rHuEPO) is only indicated in patients undergoing elective orthopedic surgery with hemoglobin or for facilitating preoperative autogenous donation–though it has also been used in traumatologic, heart and cancer surgery.10 In relation to the approved indication, two studies in vertebral surgery have reported an increase in venous thrombosis in patients treated with rHuEPO and who had not received thromboprophylactic measures.7,8 In view of these data, the FDA required the Summary of Product Characteristics of these products to include a mention referring to “consideration of the use of deep venous thrombosis preventive measures during use of the product”. In Spain this recommendation was already included in the Summary of Product Characteristics of rHuEPO.

In the context of elective orthopedic surgery, a recent metaanalysis has confirmed the efficacy of rHuEPO in reducing ABT, without increasing the risk of TEE versus placebo–though the authors underscore that most of the patients received thromboprophylaxis and had a low cardiovascular and thromboembolic risk.18 Furthermore, it may be argued that this indication involves a series of factors that do not predispose to increased TEE risk: (1) treatment is relatively brief (3–4 weeks); (2) the rHuEPO dose tends to be adjusted to obtain a target hemoglobin concentration of 13–14g/dl (except in special patients such as Jehovah witnesses, or patients undergoing more bleeding-prone operations or revision surgery); (3) coadjuvant IVF is usually provided, which improves the erythropoietic effect and significantly lowers the platelet counts19,20; and (4) most patients are exposed to these hemoglobin levels for less than 15 days, since perisurgical bleeding causes them to quickly drop to 10g/dl or even lower.

Regarding the off-label use of human erythropoietin in other scenarios, the administration of rHuEPO in coronary or heart valve surgery with or without IVF has been shown to reduce ABT, lessen morbidity-mortality, and shorten hospital stay, without adverse effects in any of the published studies.10 In contrast, the available data reveal no benefit of administration in application to anemia and/or in reducing ABT in heart failure,21,22colorectal cancer surgery,23 or in critical patients–with no approved indication for this drug before admission to intensive care.24–26 Indeed, treatment may even increase the incidence of complications or mortality in some cases.21,22,25,26

Therefore, until further efficacy and safety information becomes available, rHuEPO should only be used in the context of its approved indications, and following the national and international recommendations and guidelines.10,11

Within this drug category, an analysis is made of the efficacy and safety of tranexamic acid (TXA), particularly in orthopedic surgery, and the reintroduction on the market of aprotinin (APT).

Total knee arthroplasty (TKA) or total hip arthroplasty (THA) is associated to significant perioperative blood loss and an ABT rate of 20–30%, with an average of two transfusion units per patient.27 The efficacy and very low cost of TXA (1000mg=1 €) have caused it to be increasingly used in TKA and THA, despite the fact that orthopedic surgery nominally is not included among the specific indications stated in the Summary of Product Characteristics of the drug.3 In addition to the above, the strong impact of the CRASH-2 study must be taken into account,28 as it has led many professionals to consider that the effects of TXA in patients with early coagulopathy and secondary hyperfibrinolysis, associated to bleeding trauma, are extrapolatable to patients undergoing elective orthopedic surgery–the clinical context of which is very different.29 Hence, the administration of TXA in orthopedic surgery patients generates uncertainties regarding safety.

Different large observational studies, randomized controlled trials and metaanalyses appear to confirm the efficacy of TXA in reducing perioperative or traumatic bleeding, as well as the need for ABT, in different clinical scenarios, with a high degree of recommendation by both the DS2013 and the ESA guide10,11–though there is some uncertainty regarding the increased risk of TEE, seizures and mortality in some of them.30–39

In orthopedic surgery, both documents only recommend the administration of TXA in TKA, THA and vertebral surgery for reducing perioperative bleeding and the need for ABT (grade 2A recommendation).10,11 The ESA guide moreover adds that TXA can contribute to a hypercoagulability state in some patients (with a history of TEE, hip fracture surgery, cancer, age<60 years, female sex). Therefore, an individualized risk/benefit analysis is advised instead of routine use of the drug in this clinical context (grade 2A recommendation). Furthermore, the guide points out that further studies are needed to clarify the neurological risk, the appropriate indications, and the dosing characteristics of TXA.11,37

Thus, the intravenous administration of TXA has demonstrated its efficacy in reducing blood losses and transfusion needs in orthopedic surgery, though with variable results.30 On the other hand, its impact upon perioperative TEE and mortality has not been adequately evaluated and remains unclear. This may be particularly relevant for the use of TXA in TKA and THA, where postoperative hypercoagulability has been demonstrated.38

A review of the published metaanalyses showed TXA to reduce perioperative blood loss and the proportion of patients requiring ABT, though with significant heterogeneity that points to the need for careful interpretation of the effect of the drug in this scenario.29 Since ABT is also a risk factor for hypercoagulability in patients subjected to TKA and THA, and considering that TXA significantly reduces the ABT rate, a lesser incidence of TEE should be expected. Since this decrease has not been confirmed,29 the alternative hypothesis is that the administration of TXA in TKA and THA would induce an increase in the risk of TEE, as has been evidenced in hip fracture surgery,39 and this could be compensated by the benefit derived from the lessened exposure to ABT. Thus, the existing evidence appears to advise caution rather than complacency when using TXA in TKA and THA.

In order to confirm the safety of TXA in this context, it would be necessary to design studies including an adequate number of transfused and non-transfused patients treated or not treated with the drug (approximately 5000 patients per arm), with a careful analysis of the incidence of TEE (deep venous thrombosis, pulmonary embolism, stroke and myocardial infarction) and mortality. In the meantime, we should abide with the specifications of Article 13 of Chapter III of Spanish Royal Decree (RD) 1015/2009, on “Requirements for access to medicines under conditions different from those authorized in Spain”. In this regard, although such drug use is not subject to case-by-case authorization by the AEMPS, the latter may issue recommendations that will have to be taken into account in developing treatment-care protocols in healthcare centers.40

In relation to heart surgery, a metaanalysis published in 2009 showed the use of aprotinin (APT) to be associated to an increase in mortality compared with TXA,41 though two recent metaanalyses have cast doubts on the purported greater toxicity of APT in comparison with the lysine analogs.42,43 Lastly, a fourth metaanalysis of randomized and observational studies found that in comparison with the lysine analogs, APT may be associated to increased mortality risk in low- and intermediate-risk heart surgery, but does not appear to have an impact upon mortality in high-risk heart surgery.44 On the basis of these data, the EMA recommends lifting suspension on the use of APT in the European Union, though restricting its administration to adult patients programmed for isolated myocardial revascularization with extracorporeal circulation and a high bleeding risk. The EMA moreover insists on maintaining adequate anticoagulation with heparin in these patients.4 We remain in wait of new data on the use of APT in relation to this revised indication.

The safety of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FBNC) used as ABTA for hemostatic control in surgical or traumatic bleeding is subject to controversy, since there are doubts regarding the reporting of TEE to the pharmacovigilance system (under-reporting problems).

The three PCC formulations marketed in Spain contain coagulation factors II, VII, IX and X (“four factors” PCC), with some differences in other components. Prothrombin complex concentrate is indicated in substitution of fresh frozen plasma (FFP) in patients receiving vitamin K antagonists and who suffer severe or critical bleeding (referred to amount or location–particularly in the intracranial hemorrhage [grade 1C]), or who need urgent or emergent surgery (grade 2A).10 However, its off-label utilization is increasingly common in bleeding patients not treated with vitamin K antagonists, as reflected in DS2013 (grade 2C),10 the ESA guide (grade B)11 and the European trauma guides (grade C).45

Fibrinogen levels are critical for effective hemostasis, and FBNC is indicated for the treatment of congenital fibrinogen deficiencies. Based on observational studies, the guides support the usefulness of the early administration of FBNC in patients with critical bleeding and hypofibrinogenemia (plasma fibrinogen<1.5g/l [Clauss method] and/or ROTEM-FIBTEM<7mm) (grade 1C),10,11,45 though the indication is not universally accepted.46

A review has been made of the TEE rates associated to the administration of PCC and/or FBNC, documented by a series of recent studies involving a large number of patients and in different clinical scenarios. The TEE rate associated to the use of PCC and/or FBNC varies between 1% and 4%, depending on the type of study, the clinical scenario and the drug administered, and in most cases no causal relationship has been established.

Furthermore, some studies have jointly administered PCC and FBNC, in addition to plasma, red cell concentrates and/or TXA, which further complicates evaluation of the safety of these products. There have been no reports of infectious disease transmission47–56 (Appendix A of the additional material available in the electronic version).

According to the Cochrane Library,56 the analysis of this information shows the quality of the existing evidence on the safety of these drugs to be low. We therefore need controlled studies specifically designed to assess efficacy and safety with respect to conventional therapy in the management of coagulopathy in patients with critical bleeding. Nevertheless, it is conceivable that early administration at adequate doses and in the context of an algorithm for the management of hemostasis, guided by point of care determinations (thromboelastography/thromboelastometry) instead of conventional laboratory tests, might improve the efficacy and safety of such products in this clinical setting.11

Lastly, it should be remembered that patients treated with these drugs are at a high risk of suffering TEE as a consequence of their background disease process and/or to concomitant treatments (red cells, plasma, platelets, TXA, etc.), and not necessarily due to the administration of clotting factor concentrates.