# Influence of iron deficiency definition on the efficacy of intravenous iron in heart failure: a meta-analysis of randomized trials

Pedro Marques, Francisco Vasques-Nóvoa, Paula Matias, Joana T Vieira, Thomas A Mavrakanas, Abhinav Sharma, Fernando Friões, João Pedro Ferreira

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Pedro Marques, Francisco Vasques-Nóvoa, Paula Matias, Joana T Vieira, Thomas A Mavrakanas, et al. Influence of iron deficiency definition on the efficacy of intravenous iron in heart failure: a meta-analysis of randomized trials. Clinical Research in Cardiology, 2024, 10.1007/s00392-024-02557-5. [https://doi.org/10.1007/s00392-024-02557-5](https://doi.org/10.1007/s00392-024-02557-5).

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# Influence of iron deficiency definition on the efficacy of intravenous iron in heart failure: a meta-analysis of randomized trials

Pedro Marques¹,²,³,⁴ ID · Francisco Vasques-Nóvoa¹,² · Paula Matias¹ · Joana T. Vieira¹ · Thomas A. Mavrakanas³ · Abhinav Sharma⁴ · Fernando Friões¹,⁵ · João Pedro Ferreira²,⁶

Received: 4 March 2024 / Accepted: 5 October 2024

© The Author(s) 2024

## Abstract

**Background** Intravenous iron improves symptoms in heart failure (HF) with iron deficiency (ID) but failed to consistently show a benefit in cardiovascular outcomes. The ID definition used may influence the response to intravenous iron. The aim of this meta-analysis is to assess the influence of ID definition on the intravenous iron effect in HF.

**Methods/Results** We performed a random-effects meta-analysis of randomized controlled trials (RCT) on intravenous iron (vs. placebo or standard of care) in patients with HF and ID that provided data on transferrin saturation (TSAT) and ferritin subgroups on the composite outcome of cardiovascular death (CVD) or HF hospitalizations (HFH). The risk ratio (RR) and 95% confidence intervals (95% CI) were extracted on the TSAT (< 20% and ≥ 20%) and ferritin (< 100 ng/mL and ≥ 100 ng/ mL) subgroups. Data from four major RCT was collected including a total of more than 5500 patients. In patients with a TSAT < 20%, intravenous iron reduced the composite outcome of CVD or HFH: RR 0.81, 95%CI 0.69–0.94, while in patients with a TSAT ≥ 20% the effect was neutral: RR 0.98, 95%CI 0.79–1.21, interaction, *P* = 0.05. On the other hand, ferritin levels did not modify the effect of IV iron: ferritin ≥ 100 ng/mL RR 0.84, 95%CI 0.65–1.09, and ferritin < 100 ng/mL RR 0.85, 95%CI 0.74–0.97; interaction, *P* = 0.96.

**Conclusions** Our meta-analysis suggests that the benefit of intravenous iron may be restricted to patients with TSAT < 20% regardless of ferritin levels and supports the single use of TSAT < 20% to identify patients with ID who may benefit from intravenous iron therapy.

## Graphical abstract

In this meta-analysis of > 5500 patients, intravenous iron reduced the composite outcome of CVD or HFH in those with a transferrin saturation (TSAT) < 20%, while for TSAT ≥ 20%, treatment effect was neutral. Ferritin, however, had no impact on intravenous iron response. This analysis suggests that the benefit from intravenous iron may be limited to patients with TSAT < 20%, irrespective of ferritin levels. Utilizing a TSAT < 20% to identify patients with ID who may benefit from intravenous iron therapy should be considered.
<figure><img src="image_2.png" /></figure>

**Keywords** Heart failure · Iron deficiency · IV iron · Ferritin · Transferrin saturation

**Background**

Iron deficiency (ID), either absolute or functional, is prevalent in patients with heart failure (HF) and associated with an increased risk of hospitalizations and mortality [1, 2].

Multiple randomized control trials (RCT) have tested the effect of intravenous (IV) iron on cardiovascular outcomes in patients with either acute or chronic HF with ejection fraction < 45–50% and ID, defined as a ferritin level of < 100 ng/mL or a ferritin 100–300 ng/mL with a transferrin saturation (TSAT) < 20% [3–7].

The pathophysiology of ID in HF is complex and multifactorial, with chronic inflammation, congestion and chronic kidney disease playing important roles [1]. These factors also lead to an upregulation of inflammatory pathways, leading to overexpression of hepcidin and ferritin. Therefore, low ferritin may be representative of low inflammatory activity and not of ID [8]. In fact, it has been shown that HF patients with a ferritin level < 100 ng/ mL and a TSAT > 20% do not have evidence of ID on bone marrow examination and experience a lower risk of hospitalizations compared to patients with higher ferritin levels [9].

In pivotal trials, ferric carboxymaltose or ferric desomaltose led to improvements in symptoms, functional capacity and quality of life but failed to show consistent reductions in the composite endpoint of cardiovascular

death or HF hospitalizations. We hypothesize that this lack of consistency of IV iron to improve “hard” outcomes is linked to the way ID has been defined. If a low ferritin represents low inflammation rather than ID, then ferritin would be a poor discriminator of ID and of little utility to decide whom to treat with IV iron.

Previous meta-analyses showed that IV iron (vs. placebo or standard of care) reduced the rate of cardiovascular hospitalizations and the composite of cardiovascular death or HF hospitalizations, with no effect on mortality. However, these meta-analyses were not designed specifically to study whether TSAT is a better discriminator than ferritin for IV iron treatment benefit and did not include all recently published studies [10, 11].

The aim of this study is to assess the influence of baseline TSAT and ferritin on the effect of IV iron in HF.

**Methods**

The systematic review of the literature was performed using the PubMed/Medline and Cochrane databases from inception to October 2023. The search strategy is detailed in Supplemental Table 1. Recent meta-analysis on the topic were also reviewed to help retrieving relevant studies [10, 12]. In this meta-analysis, we included data from randomized controlled trials which tested the use of IV iron
<table><caption>**Table 1** Main baseline characteristics and overall/subgroup data on the composite outcome of cardiovascular death or heart failure hospitalizations from included trials</caption><thead><tr><th>Study</th><th>CONFIRM-HF</th><th>AFFIRM-AHF</th><th>IRONMAN</th><th>HEART-FID</th></tr></thead><tbody><tr><td>Randomization</td><td>1:1 (FCM:Placebo)</td><td>1:1 (FCM:Placebo)</td><td>1:1 (FDM: SoC)</td><td>1:1 (FCM:Placebo)</td></tr><tr><td>Patients</td><td>301</td><td>1108</td><td>1137</td><td>3065</td></tr><tr><td>Setting</td><td>CHF</td><td>AHF</td><td>AHF (14%); CHF (86%)</td><td>CHF</td></tr><tr><td>Ejection fraction</td><td>≤45%</td><td>&lt;50%</td><td>≤45%</td><td>&lt;40%</td></tr><tr><td>Follow-up (years), median (IQR)*</td><td>1.0</td><td>1.0</td><td>2.7 (1.8–3.6)</td><td>1.9 (1.3–3.0)</td></tr><tr><td>Laboratory parameters</td><td></td><td></td><td></td><td></td></tr><tr><td>Ferritin (ng/mL)</td><td>57 ± 48</td><td>84 ± 62</td><td>70 ± 64</td><td>FCM: 56 ± 47<br>Placebo: 57 ± 51</td></tr><tr><td>Ferritin &lt; 100 ng/mL, n(%)</td><td>269 (89)</td><td>788 (71)</td><td>Not reported</td><td>2715 (89)</td></tr><tr><td>TSAT (%)</td><td>20 ± 18</td><td>15 ± 8</td><td>16 ± 8</td><td>24 ± 11</td></tr><tr><td>TSAT &lt; 20%, n(%)</td><td>190 (63)</td><td>926 (84)</td><td>841 (74)</td><td>1207 (40)</td></tr><tr><td>CVD or HHF (IV iron vs Placebo)—Rate ratio (95%CI)</td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>0.54 (0.28–1.07)</td><td>0.85 (0.64–1.12)</td><td>0.82 (0.66–1.02)</td><td>0.92 (0.76–1.10)</td></tr><tr><td>Subgroups</td><td></td><td></td><td></td><td></td></tr><tr><td>Ferritin &lt; 100 ng/mL<sup>#</sup></td><td>0.52 (0.25–1.08)</td><td>0.79 (0.58–1.07)</td><td>0.80 (0.52–1.23)</td><td>0.93 (0.75–1.15)</td></tr><tr><td>Ferritin ≥ 100 ng/mL<sup>#</sup></td><td>1.95 (0.27–14.00)</td><td>1.00 (0.62–1.61)</td><td>0.73 (0.51–1.05)</td><td>0.88 (0.48–1.61)</td></tr><tr><td>TSAT &lt; 20%</td><td>0.50 (0.25–1.01)</td><td>0.82 (0.62–1.09)</td><td>0.80 (0.63–1.02)</td><td>0.88 (0.66–1.18)</td></tr><tr><td>TSAT ≥ 20%</td><td>1.42 (0.28–7.18)</td><td>0.95 (0.51–1.77)</td><td>0.96 (0.60–1.53)</td><td>0.98 (0.75–1.28)</td></tr><tr><td>Quality of evidence</td><td>High</td><td>High</td><td>High</td><td>High</td></tr></tbody></table>

(vs. placebo or standard of care) in patients with HF and ID. In those trials, we specifically looked at trials presenting subgroup analysis on the effect of IV iron vs. placebo according to baseline ferritin and TSAT on the combined outcome of cardiovascular death or HF hospitalizations. The framework of our meta-analysis regarding the PICOS design was as follows: P—patients with heart failure and iron deficiency; I—intravenous iron; C—Placebo or standard of care; O—combined outcome of cardiovascular death or heart failure hospitalizations and S—randomized clinical trials [13]. Trial eligibility and data extraction, including trial information, relevant baseline characteristics and data on the combined outcome of cardiovascular death or HF hospitalizations, was performed using a standardized digital form by two independent researchers (P.M. and J.P.F.). In addition, quality assessment was independently performed by P.M. and J.P.F. using the Cochrane risk of bias in randomized trials, the RoB 2, tool [14]. We have also cross-checked the RCTs selected to the present analysis with other recently published meta-analyses and the agreement was perfect [10, 12]. We have completed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.

We included four trials that provided subgroup analysis by categories of TSAT and ferritin on the composite outcome of cardiovascular death or HF hospitalizations. Beyond the recent Ferric Carboxymaltose in Heart Failure With Iron Deficiency (HEART-FID; NCT03037931) trial, we included previously reported subgroup analysis of the Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency (IRONMAN; NCT02642562) trial, the Ferric Carboxymaltose evaluation on performance in patients with Iron deficiency in combination with chronic Heart Failure (CONFIRM-HF; NCT01453608) trial, and the A Randomised, Double-blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure (AFFIRM-AHF; NCT02937454).

With the exception of IRONMAN trial which tested the effect of ferric derisomaltose vs. standard of care, all other trials included in this meta-analysis tested the effect of ferric carboxymaltose vs. placebo. A detailed description of each individual trial is provided in the respective main reports and both studied outcomes were independently adjudicated in the respective trials [3–7].

<footnote>*Maximal follow-up available for the CONFIRM-HF and AFFIRM-AHF trials was 12 months</footnote>

<footnote>#For the IRONMAN trial the upper tertile of ferritin was used as above median and the lower tertile as below media</footnote>

<footnote>AHF Acute heart failure, CHF Chronic heart failure, CI Confidence interval, CVD Cardiovascular death, IQR Interquartile range, FCM Ferric carboxymaltose, FDM Ferric derisomaltose, HHF Heart failure hospitalizations, IV Intravenous, SOC Standard of Care, TSAT Transferrin saturation</footnote>
Definition of ferritin and TSAT groups was based on a ferritin level < 100 ng/mL or ≥ 100 ng/mL and a TSAT < 20% or ≥ 20%. For the analysis of TSAT subgroups, data collected from the IRONMAN trial was originally provided for the TSAT < 20% subgroup and TSAT ≥ 20% with ferritin < 100 ng/mL. For the analysis of ferritin subgroups, the IRONMAN trial provided ferritin data in tertiles, and the upper (ferritin > 70 ng/mL) and lower (ferritin < 35 ng/mL) tertiles were used to define high and low ferritin, respectively.

A random-effect meta-analysis approach was used with heterogeneity assessed using the Thompson *I*². Heterogeneity was considered low, moderate, or high if *I*² was < 25%, 25–75% or > 75%, respectively. This statistical test was chosen given its robustness, the fact that it is not affected by the small number of studies included in our meta-analysis and is easy to interpret. Data on the rate ratio (RR) and respective lower and upper limit of the confidence interval (CI) for the composite outcome of cardiovascular mortality or HF hospitalizations was collected. Estimates from each study were combined by use of inverse variance-weighted averages of logarithmic RR in random-effects analysis. We used the GRADE approach to rate the confidence in effect estimates in the selected trials [15]. We assessed publication bias by visual inspection of funnel plots, with the ascertainment for potential asymmetry of published results by Egger's regression test and Duval and Tweedie's trim-and-fill method. The statistical analyses were performed using Stata® (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC.).

The study protocol was registered prior to data extraction and analysis in PROSPERO (registration number: CRD 42023467441).

## Results

From the data collected on the five major trials, a total of 2592 patients were included in the subgroup of TSAT < 20%, and 2519 patients in the TSAT ≥ 20% subgroup. Percentage of patients with TSAT < 20% differed between trials, ranging from 40% in HEART-FID and 84% in the AFFIRM-AHF trial. For the ferritin subgroups, 4114 patients were included in the ferritin < 100 ng/mL and 1065 in the ferritin ≥ 100 ng/mL subgroup. Main baseline characteristics and data on the composite outcome of cardiovascular death or HF hospitalizations from individual trials is detailed in Table 1. The included studies differed in their duration, from a median 1.9 and 2.7 years for the HEART-FID and IRONMAN trials, respectively, to a maximal 1-year follow-up for the AFFIRM-AHF and CONFIRM-HF trials.

IV iron (vs. placebo or standard of care) reduced the composite outcome of cardiovascular death or HF hospitalizations in the subgroup of patients with TSAT < 20%: RR 0.81, 95%CI 0.69–0.94. However, the effect was neutral in the subgroup of patients with TSAT ≥ 20%: RR 0.98, 95%CI 0.79–1.21; interaction *P* = 0.05 (Fig. 1).

In contrast with TSAT, ferritin levels did not influence the effect of IV iron on the composite outcome of cardiovascular death or HF hospitalizations, as both groups showed similar estimates of benefit: ferritin ≥ 100 ng/mL RR 0.84, 95%CI 0.65–1.09, and ferritin < 100 ng/mL RR 0.85, 95%CI 0.74–0.97; interaction *P* = 0.96 (Fig. 2).

The absence of publication bias was assessed by funnel plots, Egger's regression test and trim-and-fill method (Supplementary Fig. 1 and 2) and further supported by the RoB 2 tool (Supplementary Fig. 3).

## Discussion

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
<figure><img src="image_3.png" /><figcaption>**Fig. 1** Intravenous iron treatment effect (vs. placebo or standard of care) on the composite outcome of cardiovascular death or heart failure hospitalizations according to transferrin saturation subgroups (<20% and ≥20%). Results presented by TSAT subgroups (<20% and ≥20%). For the TSAT ≥20% subgroup, the overall risk rate was</figcaption></figure>

0.98 (95%CI 0.79–1.21) with a subgroup *P*-value=0.84. For the TSAT <20% subgroup, overall risk rate was 0.81 (95%CI 0.69–0.94) with a subgroup *P*-value=0.01.No overall data is presented given a significant treatment-by-TSAT subgroup interaction *P* value=0.05. CI Confidence interval, TSAT Transferrin saturation

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 [10–12]. 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
<figure><img src="image_4.png" /><figcaption>**Fig. 2** Intravenous iron treatment effect (vs. placebo or standard of care) on the composite outcome of cardiovascular death or heart failure hospitalizations according to ferritin subgroups (<100 ng/mL and ≥ 100 ng/mL). Results presented by ferritin subgroups (<100 ng/mL and ≥ 100 ng/mL). For the ferritin ≥ 100 ng/mL subgroup, the overall risk rate was 0.84 (95%CI 0.65–1.09) with a subgroup *P* value=0.07. For the ferritin < 100 ng/mL subgroup, overall risk rate</figcaption></figure>

was 0.85 (95%CI 0.72–0.99) with a subgroup *P*-value=0.04. Overall data is presented (green diamond) with a risk rate of 0.85 (95%CI 0.74–0.97), overall *P*-value=0.02. No significant interaction was seen between subgroups with an interaction *P* value=0.96. For the IRONMAN trial, the upper tertile of TSAT was used as above median and the lower tertile as below median. *CI* confidence interval

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.

## Conclusions

Our meta-analysis shows that a TSAT < 20% identified HF patients who may benefit from IV iron in terms of reduction in cardiovascular mortality or HF hospitalization. On the other hand, ferritin levels did not help identifying treatment responders. Our findings suggest that a TSAT < 20% should probably be used for the identification of ID and to decide whom to treat with IV iron therapy.

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1007/s00392-024-02557-5.

**Acknowledgements** The graphical abstract was elaborated using the BioRender® application.

**Funding** Open access funding provided by FCTIFCCN (b-on). None.

**Data availability** The data that support the findings of this study are available upon reasonable request.

## Declarations

**Conflict of interest** PM received salary support from an educational grant by Janssen. AS has received support from the Fonds de Recherche Santé Quebec (FRSQ Junior 1 clinician scholars' program, Canadian Institute of Health Research (Grant #175095), Roche Diagnostics, Boehringer-Ingelheim, Novartis, Janssen, Novo-Nordisk, Servier, AstraZeneca, and Takeda. TAM received speaker honoraria from Daiichi Sankyo, BMS Canada, Janssen, Astra Zeneca, and Pfizer and has served on advisory boards for Böhringer Ingelheim, Bayer, GSK, and Servier outside the submitted work. He has also received an unrestricted research grant from Astra Zeneca and operational grants from the Kidney Foundation of Canada, the Heart & Stroke foundation of Canada and the Canadian Institute of Health Research. He is receiving salary support from the Fonds de Recherche Quebec Santé (Junior 1 Clinician Scholar Award # 298742) and is supported by a KRESCENT New Investigator Award. JPF has received research support from Boehringer-Ingelheim, AstraZeneca and Novartis, through his institution, the University of Porto. The reminder authors report not having relevant conflicts of interest regarding the content of this manuscript.

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## Authors and Affiliations

Pedro Marques<sup>1,2,3,4</sup> · Francisco Vasques-Nóvoa<sup>1,2</sup> · Paula Matias<sup>1</sup> · Joana T. Vieira<sup>1</sup> · Thomas A. Mavrakanas<sup>3</sup> · Abhinav Sharma<sup>4</sup> · Fernando Friões<sup>1,5</sup> · João Pedro Ferreira<sup>2,6</sup>

<figure><img src="image_5.png" /></figure>

Pedro Marques
pedro.marques@mail.mcgill.ca

<figure><img src="image_6.png" /></figure>

João Pedro Ferreira
jpferreira@med.up.pt

1. Department of Internal Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal

2. Department of Surgery and Physiology, Cardiovascular Research and Development Center (UnIC@RISE), Faculty of Medicine of the University of Porto, Porto, Portugal

3. Division of Nephrology, McGill University Health Centre, Montreal, QC, Canada

4. Division of Cardiology, DREAM-CV Lab, McGill University Health Centre, Montreal, QC, Canada

5. Department of Medicine, Faculty of Medicine of the University of Porto, Porto, Portugal

6. Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France

<figure><img src="image_7.png" /></figure>