By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: Giving intravenous ferric carboxymaltose to stabilized post-acute heart failure patients with iron deficiency improved quality of life vs. placebo-treated patients within four weeks, which persisted during subsequent therapy for up to 24 weeks.
SOURCE: Jankowska EA, Kirwan BA, Kosiborod M, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: The results of the AFFIRM-AHF study. Eur Heart J 2021;42:3011-3020.
AFFIRM-AHF showed that for patients who were hospitalized with acute heart failure caused by reduced left ventricular ejection fraction (HFrEF) and iron deficiency (ID), treatment with intravenous (IV) ferric carboxymaltose (FCM) was safe and reduced the risk of HF rehospitalizations, but did not reduce cardiovascular death.1 One of the prespecified secondary outcomes was health quality of life (QOL), which is the subject of the Jankowska et al report.
ID was defined as a serum ferritin lower than 100 ng/mL, or 100 ng/mL to 299 ng/mL if the transferrin saturation was less than 20%. IV FCM was administered just before discharge from a hospitalization for acute HFrEF and at six weeks after discharge, then at 12 and 24 weeks (if necessary). Health QOL was assessed before randomization in the hospital and repeated at weeks 2, 4, 6, 12, 24, 36, and 52. Health QOL was determined by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), from which the overall summary score (OSS) and the clinical summary score (CSS) were derived for up to 52 weeks. The 1,108 patients included in the intention to treat analysis were a mean age of 71 years, recorded a mean EF of 33%, and 55% were men. Completion of the KCCQ-12 was 96% at week 2 and 73% at week 52. Most of this decline was because of mortality. KCCQ-12 scores ranged from 0-100, where 100 is the best QOL. The baseline OSS for the FCM group was 38 and 37 for the placebo group; the corresponding CSS were 41 and 40, respectively.
After week 4 post-discharge, FCM patients exhibited significantly greater improvements in OSS and CSS vs. placebo patients. The adjusted mean difference at week 4 was 2.9 (95% CI, 0.5-5.3; P = 0.018) for OSS and 2.8 (95% CI, 0.3-5.3; P = 0.029) for CSS. At 24 weeks, the mean difference was 3.0 for OSS (95% CI, 0.3-5.6; P = 0.028) and 2.9 for CSS (95% CI, 0.2-5.6; P = 0.035). At 52 weeks, the effect had attenuated but still favored FCM patients (OSS mean difference = 1.44; CSS = 0.63). Sensitivity analyses that incorporated mortality and the effect of COVID-19 on QOL showed similar results to the main analysis. The authors concluded that in patients hospitalized for acute HFrEF with ID and treated with IV FCM, clinically meaningful improvements in health QOL were observed as early as four weeks after discharge and lasted up to 24 weeks.
The AFFIRM-AHF study led to fewer hospitalizations, but showed no effect on mortality. Staying out of the hospital could mean one feels better, but a formal analysis of QOL is preferable. Thus, this analysis of the QOL data in AFFIRM-AHF is of interest. Jankowska et al showed treatment with IV FCM started in the hospital just before discharge and continued intermittently if ID persisted for 24 weeks improved QOL by about three points on the KCCQ-12 score vs. placebo. With a score range of 0-100, a three-point advantage over placebo seems modest at best. However, as the authors argued, this is a relevant change, which correlates with subjective well-being. This is like the changes observed for other pharmacological agents, such as the gliflozins and sacubitril/valsartan, and interventions, such as exercise training. To put this in perspective, the change in KCCQ-12 scores seen with cardiac resynchronization therapy is about 10 points in “good responders” to this device therapy where overall responses are heterogeneous. The KCCQ-12 focuses on symptom frequency, physical and social limitations, and QOL impairments. The KCCQ-23 features better psychometric properties but takes more time to complete, which reduces compliance. Also, the 12-question version correlates well with the 23-question version. The attenuation in effect after 24 weeks is not entirely surprising considering no further FCM was given after 24 weeks by protocol.
ID is associated with a poor prognosis in HFrEF, regardless of the presence of anemia. It is largely underdiagnosed and undertreated. One reason is the diagnosis of ID in HF is problematic. Ferritin levels are affected by inflammatory stress, renal dysfunction, malnutrition, and the catabolic state seen in severe HF. Also, volume shifts during the treatment of HF may increase or decrease ferritin levels. Interestingly, after the treatment of acute HF, ferritin levels tend to rise for six weeks without any therapy, perhaps because of lower plasma volume. Thus, to see changes in QOL at six weeks in the FCM group is remarkable.
Treating frank anemia in HF is known to improve outcomes, especially if the hemoglobin is < 8 g/dL. Why would iron therapy improve outcomes in the absence of frank anemia? Presumably because iron is a key component of muscle energetics. Based on the Jankowska et al study, after hemodynamic stabilization of acute HFrEF, if ID is identified, give FCM before discharge and reassess at six weeks and every three to four months after, with further administration of FCM as indicated.
- Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: A multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895-1904.