Intravenous Ferric Carboxymaltose for Heart Failure with Iron Deficiency (2017)

This article refers to ‘Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis’ by S.D. Anker et al., published in this issue on pages 125–133. The most recent heart failure (HF) guidelines of the Heart Failure Association of the European Society of Cardiology, published in mid-2016, include a significantly expanded section on HF with comorbidities.1 The reason for this is that HF is affecting ever-older patients and hence occurs with increasing numbers of comorbidities and greater complexity in their interactions with HF, in terms of both inter-disease interaction and the potential for drug–drug and drug–disease interactions. In addition, as we struggle to find new treatments to reduce mortality in treated HF, we turn our attention to treating quality of life and exercise intolerance and preventing hospitalization. Such strategies quite frequently involve managing comorbidities that have been shown to be frequent causes of emergency hospitalization in patients with established chronic HF.2-4 The comorbidities section of the guidelines1 includes two ‘new’ entries in which expanded advice is given, namely, sleep apnoea5, 6 and iron deficiency.7, 8 For iron deficiency, the new recommendations concern the screening for, diagnosis of and treatment of iron deficiency. It is recommended that ferritin and transferrin saturation (TSAT) be measured in all newly presenting cases of HF. If this advice is followed, this particular comorbidity will be detected in significantly greater numbers than we ever have seen before and therefore we must gear up our facilities and knowledge to incorporate this into routine practice. Of course, in some cases of chronic HF, iron deficiency will develop later during the disease process and hence screening may need to be repeated during follow-up. Iron deficiency may also be associated with the development of other comorbidities, such as skeletal muscle wasting and cachexia, which raises further potential opportunities to detect and intervene.9 Not all iron deficiency is associated with anaemia, just as not all anaemia is associated with iron deficiency, and therefore the practitioner must be alert to the possibility even in non-anaemic patients. Anaemia and iron deficiency are interrelated, but are also to a substantial extent semi-independent comorbidities in HF. A Class IIaA recommendation (‘should be considered’ with a strong level of evidence) is given for one particular form of iron therapy, namely, i.v. ferric carboxymaltose (FCM) for the purpose of alleviating HF symptoms, improving exercise capacity and quality of life in symptomatic HF with reduced ejection fraction (HFrEF) patients with iron deficiency (as defined by a serum ferritin level of <100 μg/L, or a ferritin level of 100–299 μg/L with a TSAT value of <20%).1 These recommendations were based on two trials, FAIR-HF10 and CONFIRM-HF.11 The text1 also includes a discussion of the possible benefits in hospitalization rates in meta-analyses of i.v. iron trials in iron-deficient HF patients.12, 13 The findings summarized in this discussion1 were not, however, sufficiently robust to support a strong recommendation because the trials so summarized were heterogeneous in terms of the patients they recruited and the methods they used for iron repletion. They also referred to mean data summary meta-analyses rather than to the preferred individual patient data meta-analysis. The best meta-analysis, at least in my opinion, is one that is comprehensive [i.e. includes all randomized controlled trials (RCTs) of a particular therapy performed in a defined patient population], is precise (in that it looks at treatments that are identical or substantially the same) and in which access is obtained to all source patient data, which allows for the conducting of time-to-event analyses and the evaluation of subgroups of interest. It is of advantage in contexts in which there is only one manufacturer of a product or therapy because such contexts allow a better chance of ensuring access to all the available data for patients recruited into an RCT. Accordingly, the present individual patient data meta-analysis published in the journal represents a significant advance.14 What does it show? There is a significant reduction in the prespecified primary endpoint of this analysis – the composite of recurrent cardiovascular (CV) hospitalization and CV death – with a rate ratio of 0.59 (95% confidence interval 0.40–0.88; P = 0.009). Subsequent outcomes were listed as the composites of HF hospitalization and CV death, CV hospitalization and all-cause death, and HF hospitalization and all-cause death, in addition to the individual composite components.14 All of the composite end-points were significantly improved by i.v. FCM, but the numbers of both CV deaths and all deaths were identical across the two groups,14 which shows that this was driven entirely by a reduction in hospitalization rates. Although the abstract concludes that i.v. FCM was associated with a significant reduction in recurrent CV hospitalization, a statement creeps into the concluding section of the main text to the effect that i.v. FCM may decrease CV hospitalizations and CV mortality rates.14 Clearly, there is no evidence as yet for any effect on mortality. As with all subgroup analyses, we must be cautious, but where a significant consistent and logical effect is seen, we should take notice. The lack of benefit in the highest tertile of TSAT values (i.e. ≥20.1%) suggests we should focus only on eligible patients with TSAT values of <20%. Whether this is true regardless of ferritin level remains to be seen. These findings suggest that i.v. iron therapy with FCM could potentially be a beneficial addition to the standard medical management of HF. An adequately powered RCT is needed to confirm these findings. These results support the guidelines' recommendations1 and raise a real prospect that this therapy may also improve major outcomes. It does appear highly likely that i.v. FCM in appropriately selected patients with HFrEF and iron deficiency may also protect against emergency CV hospitalization. Only the larger-scale mortality and morbidity trials proposed will be able to prove or disprove this suggestion. Conflict of interest: A.J.S.C. received consulting and lecture fees from Resmed, Respicardia, Lone Star Heart, Servier, Vifor and Verona Pharmaceuticals.