The presented meta-analysis of four major RCT of IV iron vs. placebo or standard of care in HF with ID, stratified by baseline ferritin and TSAT subgroups, shows that baseline TSAT, notably the < 20% threshold, identifies a group of patients who experience the greatest benefit in terms of reduction of cardiovascular mortality or HF hospitalizations (Graphical abstract). The most commonly used threshold for baseline ferritin of 100 ng/mL, did not help deciding whom to treat, as treatment effect was similar regardless of baseline ferritin level.

The known association of ID with cardiovascular outcomes in patients with HF led to the conduction of multiple RCT to test whether IV iron would be effective in reducing cardiovascular outcomes in this high-risk population. The most recent HEART-FID trial, the largest RCT to date, failed to provide a significant reduction of the primary outcome: the hierarchical win ratio of cardiovascular death, hospitalizations for HF at 12 months or the change in 6-min walk test from baseline to 6-months. [6] One of the major criticisms involving the HEART-FID trial relates to whether it included a population with truly ID at baseline. In this trial, the mean (± standard deviation) TSAT was 23.9% (± 11.2), contrasting with the other trials where mean/median TSAT were lower than 20%.

The previous meta-analyses that provided subgroup analysis on TSAT and ferritin groups for the outcome of cardiovascular mortality and HF hospitalizations showed similar results. In both analyses, the TSAT < 20% subgroup consistently identified patients who benefited from IV iron therapy, whereas a ferritin level < 100 ng/mL did not [10, 12]. In a recent meta-analysis and meta-regression including more than 6000 patients with HF and ID further emphasized the impact of a lower baseline TSAT (< 20%) in the treatment response to IV iron, especially in HF-related events [16]. In this analysis, the higher heterogeneity in the effect of IV iron to impact HF-related events was mostly driven by the patients included in the HEART-FID, which, compared to previous trials, had the lowest proportion of patients with TSAT < 20%.

Moreover, in the individual trials and meta-analyses, the beneficial effect of IV iron versus placebo on the composite outcome of cardiovascular death or HFH was mostly driven by a reduction in HFH [10,11,12]. Although other factors, such as the short trial duration, could play a role in the low mortality rates seen during follow-up, the absence of a more relevant effect on cardiovascular death can also be related to the ID definition used for patient selection in these trials. In the most recent meta-analysis, the effect of IV iron versus placebo on cardiovascular mortality in the subgroup of patients with lower TSAT levels (TSAT < 20% or the lowest TSAT tertile [< 15%]) suggests that these patients could potentially derive mortality benefit from this intervention and further support the sole use of a lower TSAT threshold to guide IV iron treatment decisions [12].

Another evidence of the discriminative impact of TSAT arises from the IRONMAN trial. This trial was the only major RCT to date to use either a ferritin < 100 ng/mL or a TSAT < 20% regardless of ferritin levels as inclusion criteria. In IRONMAN, patients with a TSAT < 20% tended to show benefit from ferric derisomaltose (RR 0.80, 95%CI 0.63–1.03), whereas among those with a ferritin < 100 ng/mL and a TSAT ≥ 20% IV iron had a point estimate close to the unit (RR 0.96, 95%CI 0.6–1.52) [7].

It is also worth mentioning that, in most trials, patients with a TSAT < 20% had higher ferritin levels (as per inclusion criteria); still, the overall benefit was more pronounced in this subgroup, meaning that ferritin alone is not representative of true ID. In fact, our analysis showed that both ferritin subgroups benefited from IV iron treatment, suggesting that the most important driver of benefit is the TSAT level. It is important to highlight that in most trials patients with higher ferritin must have had a TSAT < 20% to be enrolled, whereas those with lower ferritin could have a TSAT < or ≥ 20%. Therefore, a low ferritin level per se is not representative of ID and may instead reflect a subset of patients with low inflammation and, therefore, with a low cardiovascular risk.

All this mounting evidence aligns for TSAT being a better and clinically relevant discriminator when selecting patients that will benefit from IV iron. Ferritin, on the other hand, should probably be seen as a marker of inflammation in HF, that ultimately plays an important role in promoting ID, but does not seem to be helpful in correctly identifying patients who benefit from treatment with IV iron. Future trials should consider using a TSAT < 20% as the main and potentially isolated inclusion criterion.

Furthermore, the currently used diagnostic criteria for ID in HF proposed by international guidelines is primarily centered on ferritin levels, with TSAT being considered only if ferritin is at less strict cut-offs [17, 18]. We think that this definition brings complexity and can potentially be a source of confusion for clinicians. The data presented in our meta-analysis suggest that a more simplified definition based on a TSAT < 20% should be adopted.

Our analysis has some limitations. First, our meta-analysis was not the result of individual patient data, as such analysis would provide more definite evidence not only on currently used cut-offs but also on continuous ferritin and TSAT values. Second, it focused primarily on a post hoc analysis of subgroups from individual trials; still, each group had a considerable number of patients and heterogeneity was not high between studies. Third, for the IRONMAN trial, data extracted for both ferritin groups was below the 100 ng/mL threshold. Forth, no detailed data was available for the proportion of patients within each studied subgroup (ferritin < 100 ng/mL vs ferritin ≥ 100 ng/mL; TSAT ≥ 20% vs TSAT < 20%) with lower TSAT or ferritin levels, respectively, limiting our analysis on the potential interaction of both baseline ferritin and TSAT levels on the effect of IV iron. Finally, as original trials included most patients based on a ferritin level < 100 ng/mL, ferritin subgroups were unbalanced.