England
England
High-dose intravenous iron reduces myocardial infarction in patients on haemodialysis
Having only won one World Cup in its history, this team is surely thirsty for success. Their singular victory is not for lack of trying. The Queen's team has participated in a total of fifteen (15) World Cup finals! Royalty was on their side in 1966 when they defeated then West Germany 4-2 in extra time. Of course, having the advantage of local soil (the 1966 World Cup championship was played in Wembley stadium in London) had a lot to do with the victory as well! Their unusual narrow attach formation earned them the moniker "Wingless Wonders". Today, this attack formation is known as the four-four-two (4-4-2) (Video 1).
Video 1: The 4-4-2 football attack explained
The 4-4-2 brings us to intravenous (IV) iron. Like the 4-4-2 attack formation, IV iron has a history of being an atypical therapy for dialysis-related anemia. Today, a growing body of evidence shows that both the 4-4-2 and IV iron have an established place in the football and CVRM worlds, respectively. England's bet that IV iron will lead to a 2022 NephroWorldCup victory may come as a surprise to those who haven't kept up with the recent and renewed interest in iron therapy.
In this pre-specified analysis of secondary end points of the PIVOTAL trial, the authors found a positive association between IV iron and the reduction of myocardial infarction (MI) in patients undergoing maintenance hemodialysis. To understand the ramifications of this finding, let's revisit the 2019 PIVOTAL trial (Figure 1).
Figure 1a (left): The years/decades of anemia trials leading up to the modern era of IV iron therapy | Presented at UK Kidney Week 2018 | Courtesy of Dr. Elaine Davies
Figure 1b (right): IV iron formulations (as of 2020) | Courtesy of Dr. Edgar Lerma
PIVOTAL analyzed 2141 adult patients who had started maintenance hemodialysis with a dialysis vintage of one (1) year and had a ferritin concentration < 400 micrograms/L and a TSAT (transferrin saturation) <30% (Carousel 1).
Carousel 1: Baseline characteristics | Presented at the 2018 Kidney Week meeting | Courtesy of Dr. Ernesto Lopez-Almaraz
Patients were randomized to receive either low-dose or high-dose IV iron. The administration of proactive high doses of IV iron reduced the composite outcome of non-fatal and fatal MI with a hazard ratio of 0.69 (95% CI 0.51-0.93, p = 0.01) compared to the reactive low-dose IV iron strategy (Carousel 2).
Carousel 2: ~30% reduction in MI with high-dose iron | Presented at the 2020 ERA meeting | Courtesy of Dr. Paddy Mark and Dr. Jennifer Lees
The current PIVOTAL trial takes a deeper dive into the protective effects of IV iron against myocardial infarctions (MI) (Carousel 3). Specifically, high-dose IV iron reduced all types of fatal and non-fatal MIs by 31% (HR 0.69, 95% CI 0.52 - 0.93; p = 0.01) compared to the low-dose arm.
The higher dose arm resulted in 3.5 events per 100 person-years compared to 4.9 events per 100 person-years in the low-dose arm (Video 2). And even though type 1 MIs are largely driven by atherosclerotic disease, using high-dose IV iron therapy reduced the time-to-first-event by 29% compared to the low-dose arm: 2.8 events per 100 patient-years versus 3.9 events per 100-patient years (HR 0.71, 95% CI 0.51-0.99)!
Video 2: IV iron and its effects on myocardial infarction subtypes in the 2021 PIVOTAL subgroup analysis | Courtesy of Dr. Enric Vilar
The results of PIVOTAL and its subsequent MI-focused subgroup analysis are sure to excite young and experienced nephrologists (Carousel 3). Until now very few (admittedly we're being generous) medications have demonstrated to reduce MI in patients on dialysis (specifically type 1 MIs). The PIVOTAL authors speculate that more IV iron is likely to result in better oxygen delivery, which in turn, may improve the oxygen supply demand mismatch seen in type 2 MIs (Carousel 3).
Carousel 3: Types of myocardial infarctions | Courtesy of the American College of Cardiology | Word cloud from the 2021 Kidney Week Meeting | Courtesy of Dr. Jason Misurac
Simple schematic of the effects of iron on oxygenation | Presented at the 2017 UK Kidney Week | Courtesy of Dr. Amanda Newnham
Are your coronaries bursting with joy? Does IV iron and the PIVOTAL trials deserve a win for the Queen's finest? History has not been kind to England and this team is poised to make a positive impact in the NephroWorldCup. Will you vote for them?