Iron deficiency in heart failure patients should not be ignored! Recently at the American Heart Association (AHA) 2022 Annual Meeting held in Chicago, a study on intravenous iron supplementation improves mortality and rehospitalization rates in patients with heart failure (IRONMAN study) results were released, and the article was published [1] in the top international medical journal Lancet on the same day, which brought new iron supplementation therapy for patients with chronic heart failure basis. After the release of the research results, it aroused widespread attention from experts from various countries at the conference site! The principal investigator, Professor Paul R Kalra, said in an interview, “IRONMAN study showed for the first time the long-term benefits and safety of intravenous iron in the treatment of heart failure, providing stronger evidence for intravenous iron in the treatment of heart failure. We should now recommend , for patients with heart failure, regular iron status assessment, and timely treatment if iron deficiency is found. Now is an appropriate time to update the national clinical guidelines.”
A survey based on medical insurance data for urban workers in China found that among people aged 25 and over in China, the standardized prevalence rate of heart failure (heart failure) was 1.1%. The rate is 275/100 000 person-years, based on which it is estimated that there are 12.05 million heart failure patients and 2.97 million new heart failure patients every year[2]. The annual per capita hospitalization cost of heart failure patients was 29,746 yuan. These data suggest that heart failure has brought a huge public health burden to our country, and it is urgent to take effective preventive and therapeutic measures to reduce heart failure readmission[2], improve the quality of life and even mortality of heart failure patients .
Iron deficiency is common in patients with chronic heart failure (CHF). In recent years, studies have found that iron deficiency not only affects chronic contraction Symptoms in patients with chronic heart failure are also associated with increased risk of hospitalization and death [3]. Iron is an essential raw material for the synthesis of hemoglobin, and is also an essential element for the oxidation and energy metabolism of cells such as myoglobin and cytochrome oxidase. Iron deficiency can not only cause anemia and affect the oxygen-carrying capacity of the blood, but also affect the utilization of oxygen by cells by affecting cytochrome oxidase, etc. As early as 2012, the European guidelines for the diagnosis and treatment of acute and chronic heart failure [ 4] has recommended ferritin/total ferritin binding capacity (TIBC) testing for all CHF patients to evaluate whether the patient has iron deficiency. The Chinese Expert Consensus 2022 on Comprehensive Management of Patients with Exacerbated Chronic Heart Failure in China also pointed out that iron deficiency is a common complication of CHF and is strongly related to the prognosis of heart failure, and intravenous iron supplementation is recommended to improve symptoms.
Currently, iron has different dosage forms such as oral and intravenous injection, and clinical studies have shown that oral iron does not improve CHF patients Symptoms and prognosis of [5, 6]. Multiple studies of intravenous iron have shown that it can improve symptoms and exercise capacity of patients, but there is still insufficient evidence on whether it can improve hard endpoints such as rehospitalization rate and mortality, which makes clinicians still have doubts about the use of intravenous iron. The publication of the results of the IRONMAN study provides a strong basis for intravenous iron in the treatment of CHF!
The IRONMAN study was an investigator-initiated study designed by members of the TSC (ClinicalTrials.gov identifier: NCT02642562), British Heart Foundation (grant award CS/15/1/31175) Funded, overseen by an independent committee. The product involved in the study, the manufacturer of iron isomaltose, Pharmacosmos A/S, provided free medicine and research funding.
IRONMAN was initiated by the investigators, a prospective, randomized, open-label, Endpoint-blinded, endpoint-event-driven study conducted at 70 hospitals in the UK.
Study included symptomatic heart failure patients aged ≥18 years with left ventricular ejection within the past 24 months Score ≤45%, combined with iron deficiency (serum ferritin <100 μg/L, or transferrin saturation <20%). The primary study endpoint was "all hospital admissions for heart failure and cardiovascular death, analyzed by recurrent events".
The patients in the iron isomaltose anhydride group were given the corresponding dose of iron isomaltose anhydride intravenous infusion according to the product instructions, and reexamined after 4 weeks. Follow-up every 4 months thereafter until the end of the study. During the follow-up, if the serum ferritin is found to be <100 μg/L, or the serum ferritin is <400 μg/L and the transferrin saturation is <25%, the drug will be given again.
From August 2016 to October 2021, a total of 1137 patients were enrolled in the study for 5 years, and were randomly assigned to the iron isomaltose anhydride treatment group (569 cases) and the conventional treatment group (568 cases) ), and the average follow-up time was 2.7 years. The incidence of the primary endpoint (heart failure hospitalization or cardiovascular death) was 336 cases in the iron isomaltose anhydride group, 22.4/100 patient-years, and 411 cases in the conventional treatment group, 27.5/100 patient-years. The RR between the two groups was 0.82, P=0.070 . The primary safety endpoint of “hospitalization and death due to infection” was not different between the two groups, demonstrating that repeated treatment with iron isomaltose did not increase infection. At the same time, the incidence of severe cardiovascular adverse events in the iron isomaltose anhydride group was significantly lower than that in the conventional treatment group (36% vs 43%, P=0.016).
During the study period, the new crown epidemic broke out. During the silent period, some patients could not return to the hospital to recheck their iron indicators and receive intravenous iron infusions, and hospitalizations also decreased significantly. To mitigate the impact of COVID-19, a prespecified COVID-19 sensitivity analysis was performed that included 91% of patients randomized before March 2020 (start of quiescence in the UK) (527 iron isomaltose group, 536 cases of conventional treatment group), followed up until September 2020. The results showed that the incidence of the primary end point in the iron isomaltose anhydride group was 210 cases, 22.3/100 patient-years, which was significantly lower than the 280 cases in the conventional treatment group, 29.3/100 patient-years. The risk decreased by 24% (RR 0.76, P=0.047). In the further post-hoc analysis for this population, the follow-up time was set at 1 year to make it consistent with the previous AFFIRM-AHF study for comparability. The risk reduction was 34% (RR 0.66, P=0.011).
Intravenous iron isomaltose is associated with a lower risk of hospitalization for heart failure and risk of cardiovascular death in patients with heart failure with extensive reduced left ventricular ejection fraction and iron deficiency, further supporting Benefits of iron supplementation in this population.
References
1. Paul R Kalra, John G F Cleland et al. Published Online November 5, 2022. https://doi.org/10.1016/S0140-6736(22)02083-9.
2. Wang H, Chai K, Du M , et al. Prevalence and incidence of heart failure among urban patients in China: a national population-based analysis[J]. Circ Heart Fail, 2021, 14(10): e008406. DOI: 10. 1161/CIRCHEARTFAILURE. 121. 008406 .
3. Okonko DO, Mandal AK, Missouris CG, et al. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival[J]. J Am Coll Cardiol, 2011, 58(12):1241-1251.
4. Van Craenenbroeck EM, Pelle AJ, Beckers PJ, et al. Red cell distribution width as a marker of impaired exercise tolerance in patients with chronic heart failure[J]. Eur J Heart Fail, 2012, 14(1):54-60.
5. Silverberg DS, Iaina A, Schwartz D, et al. Intravenous iron in heart Failure: beyond targeting anemia[J]. Curr Heart Fail Rep, 2011, 8(1):14-21.
6. Bailie GR. Efficacy and safety of ferric carboxymaltose in correcting iron-deficiency anemia: a review of randomized controlled trials across different indications[J]. Arzneimittelforschung, 2010, 60(6a):386-398.