Role of preoperative intravenous iron therapy to correct anemia before major surgery: study protocol for systematic review and meta-analysis

Anemia is defined by the World Health Organization (WHO) as a hemoglobin concentration less than 13 g/dL in men and 12 g/dL in women [1]. Preoperative anemia is the most common hematological abnormality among the patients undergoing major elective surgery [2]. The prevalence of preoperative anemia ranges from 5% to 75%, depending on patient susceptibilities and the proposed surgical procedure [3]. Preoperative anemia is more common among older patients and those with chronic disease such as heart failure, diabetes mellitus, chronic kidney disease, primary hematologic diseases, other inflammatory diseases [4], and coronary artery disease [5,6]. Although diagnosis and treatment of anemia preoperatively is essential to optimize the patient’s condition [7], preoperative anemia treatment is not a priority for most surgeons [8].

Preoperative anemia has been associated with an increased risk for 30-day mortality [9,10]. Preoperative anemia has also been shown to be an independent risk factor for perioperative red blood cell (RBC) transfusion and for postoperative morbidity [11]. Major morbid outcomes include transfusion-related acute lung injury (TRALI) [12], nosocomial infections [13], increased graft occlusion after coronary artery bypass grafting (CABG) [14], myocardial events, neurological events, acute kidney injury [15], tumor recurrence [16], and suppressed immune function [17]. In a recent large study of 22,785 consecutive patients, investigators found that transfusing as little as 1 or 2 units of RBCs was associated with increased morbidity and mortality after cardiac surgery [18] supporting a previous systematic review of observational studies [19]. The findings from these studies would imply that strategies to reduce unnecessary RBC transfusions might be associated with improved postoperative outcomes.

RBC transfusions are also associated with significant cost related both to the product itself and the morbid events associated with unnecessary RBC transfusions which contribute to additional direct and indirect hospitalization costs [20]. In a recent RBC transfusion cost analysis study, the actual cost for each RBC unit was reported to range between US $522 and US $1,183 after calculating the direct and indirect costs, which include consumables, laboratory testing, nursing time, patient transport, treatment costs, and staff fees resulting in increased cumulative total costs [21]. This is substantially higher than previous estimates of the cost of each RBC unit at US $250 to $550 [22].

National USA data [23] showed a decline in blood transfusion usage estimate by 3% over each of the 2 years (2009 to 2010), and similar data [24] have been reported in the UK as well. Although many therapeutic modalities have been initiated to minimize the patients’ requirement for perioperative RBC transfusion, the rate of transfusion remains unacceptably high and variable across both cardiac (17 to 80%) [25,26] and non-cardiac major surgery [27]. These observations would imply that transfusion practices are variable across patient, provider, and health system factors. This may stem from the absence of high-quality evidence to guide the management of perioperative anemia and blood conservation.

A variety of contemporary perioperative pharmacologic and non-pharmacologic blood conservation strategies (Table 1) [28] have been proposed and variably adopted to minimize RBC transfusion. In a recent study, the outcomes of 322 Jehovah’s Witness (JW) patients undergoing cardiac surgery, who, for personal beliefs, refuse transfusion of all blood products including RBCs, were evaluated. In this study, JW patients had comparable long-term survival to those willing to receive RBC transfusion in a propensity-matched analysis; however, JW patients had fewer postoperative complications and shorter intensive care unit (ICU) lengths of stay [29]. These provocative findings would imply that many RBC transfusions might be unnecessary. In fact, these data suggest that blood conservation strategies, including preoperative treatment of anemia, may either reduce exposure to RBC transfusions or even act as a trigger for RBC transfusion. In addition, a more recent meta-analysis of randomized trials with 8,735 patients showed lower risk of health care-associated infection for a restrictive RBC transfusion strategy in comparison to a liberal transfusion strategy in hospitalized patients [30].

Preoperative pharmacologic treatment of anemia has been proposed to reduce perioperative RBC transfusion [31,32]. One potential strategy is the use of intravenous (IV) iron. Iron is fundamental in RBC formation and is the most common nutritional deficiency in both developed and developing countries [33]. A recent study [34] reported that usage of oral iron to treat iron deficiency anemia is limited by gastrointestinal absorption, particularly, in the patients with associated acute or chronic diseases [35]. IV iron has been reported to increase the hemoglobin (Hb) level and to replenish iron stores more rapidly than oral iron formulation in women with post-partum iron deficiency anemia in a variety of RCT studies in other areas of medicine such as post-partum hemorrhage [36], but in surgery, most have been observational in nature. Consequently, preoperative IV iron has been proposed as an efficacious strategy to increase serum hemoglobin and minimize exposure to perioperative RBC transfusions [37,38].

To date, there is no broad consensus or established clinical practice guideline to support the routine use of prophylactic IV iron to treat anemia before major elective surgery. Moreover, additional questions about the optimal timing of therapy, dose of iron, and whether anemic patients need additional nutritional supplementation have yet to be answered. However, there are a few guidelines recommending the use of IV for anemia in surgical cases, but all are lacking class 1A evidence-based medicine [39-41]. To date, there are relatively few studies, the majority of which have been small and non-definitive, that have evaluated the efficacy and safety of IV iron preparations in patients undergoing major elective surgery. A recent meta-analysis [42] showed that very low-quality evidence of IV iron results in modest increases in hemoglobin levels compared with oral iron or inactive control, but without clinical benefit. Unfortunately, this meta-analysis was less homogeneous than would be ideal, and they were not able to do subgroup analyses for different types of participants (blood loss, cancer, preoperative anemia, chronic heart failure, autoimmune disorders, and infectious disease). In addition, their literature search ended July 2013. Three other recent studies have been published as well. The first is a systematic review for RCTs with restricted language and search time frame [43], the second is a systematic review and meta-analysis for RCTs restricted to colorectal surgery [44], and the third is a systematic literature review of RCTs and observational studies restricted to cardiac surgery [45]. All three failed to find a sufficient evidence to support the use of IV iron to decrease RBC transfusion.

Accordingly, we propose to perform a systematic review and evidence synthesis on the efficacy and safety of IV iron therapy in the preoperative setting to treat anemia, reduce transfusions, and improve outcome. This review will capture recently published studies, will include a broad range of elective surgery, and will not be limited to English publications or RCTs.

We hypothesize preoperative IV iron therapy will improve preoperative hemoglobin concentrations in anemic patients undergoing major elective surgery, reduce the need for RBC transfusion, and reduce complications compared with placebo or standard of care. We will synthesize the available data on the efficacy and safety of IV iron therapy to increase hemoglobin levels, avoid transfusions, and improve outcomes for anemic patients undergoing major elective surgery.

Perform a systematic review and evidence synthesis of all randomized and quasi-randomized studies investigating (a) the efficacy of IV iron administration to improve preoperative hemoglobin concentration and reduce RBC transfusion rate, (b) the safety of IV iron formulations with respect to adverse effects, and (c) the effectiveness of IV iron administration to reduce perioperative major morbidity and health resource use.