Key Points

• This was the first randomized trial to evaluate the safety and efficacy of everolimus and low-dose tacrolimus in pediatric heart transplant recipients.
• The open-label trial demonstrated that this combination is safe compared to standard dose tacrolimus and mycophenolate mofetil but was not associated with a lower burden of coronary allograft vasculopathy, rejection, and chronic kidney disease.
• TEAMMATE was limited by lower event rates than expected and challenges related to protocol adherence due to the COVID19 pandemic.

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Key Points:

• Prior data suggest that heart failure with reduced ejection fraction (HFrEF) patients with iron deficiency receiving IV iron supplementation had improvement in exercise capacity and HF hospitalizations, but the long-term safety and efficacy of the treatment is unknown.
• The HEART-FID trial was a double-blind, placebo-controlled event-driven randomized trial assessing whether there would be improvement in the incidence of death and hospitalization for heart failure or 6-minute walk distance with ferric carboxymaltose therapy compared with placebo in patients with heart failure with a reduced ejection fraction and iron deficiency.
• Patients receiving IV ferric carboxymaltose (FCM) had slightly fewer all-cause mortality events, HF hospitalizations and modestly longer 6-minute walk duration. However,there was no apparent difference in the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.
• Overall FCM supplementation is safe and shows potential clinical benefits; further context can be obtained via pooled analysis with other IV FCM trials.

Iron deficiency has a prevalence of nearly 50% among patients with heart failure with reduced ejection fraction (HFrEF) and leads to impaired health-related quality of life, worsening heart failure (HF) symptoms, and adverse outcomes. The mechanism for iron deficiency in HF is not fully understood though thought to be related to reduction in iron intake as well as absorption and mobilization with increased loss as well. Treatment with intravenous (IV) ferric carboxymaltose (FCM) has previously been shown to improve HF patients’ symptoms and functional capacity. Notably, evidence regarding the utility of IV FCM for improving clinical outcomes such as morbidity and mortality is more limited. Information regarding the long-term efficacy and safety of IV iron infusions is also limited. Furthermore, the majority of available data on the subject was obtained in Europe and excluded other geographic HF populations.

The HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency) (NCT03037931) was a multicenter, randomized, double-blind, placebo-controlled trial that sought to assess the efficacy and safety of IV FCM in the treatment of symptomatic patients in HFrEF with iron deficiency over a period of at least 12 months. Over three thousand patients were randomized at 281 study locations in various geographic regions that included North America, Australia, New Zealand, and Europe. Heart failure patients had ejection fraction (EF) ≤40% within 24 months or ≤30% within 36 months of screening and NYHA Class II-IV symptoms on maximally tolerated background therapy for ≥2 weeks before randomization. They had to have documented HF hospitalization within 12 months of enrollment or elevated N-terminal-pro-brain natriuretic peptide within 90 days of randomization. Criteria for iron deficiency were ferritin <100 ng/mL or 100 to 300 ng/mL with a transferrin saturation <20% with hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL (males). Importantly, the trial included those patients with and without anemia. Active bleeding or recent blood transfusion was prohibitive for enrollment.

Eligible patients were given an initial 28-day screening period and then randomized in a 1:1 ratio to receive FCM or placebo. They were then given the study drug on day 0 and 7 and followed up with additional study visits at 3 month intervals. Patients were eligible for additional dosing of the drug every 6 months as needed. HEART-FID trial clinical endpoints included a hierarchical composite of death and HF hospitalizations in the first 12 months, and change in 6 minute walk test (6-MWT) distance at 6 months. Notably a significance level of 0.01 was pre-specified for regulatory purposes by the US Food and Drug Administration (FDA).

Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group, and a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12. The mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon–Mann–Whitney P=0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients.

Presented at the 2023 European Society of Cardiology Congress on August 26^th by Dr. Robert Mentz (Duke Clinical Research Institute, Durham, NC) the HEART-FID trial data showed that administration of FCM resulted in modest improvement for the primary hierarchical endpoint which narrowly missed statistical significance (P=0.019).. When reporting the win ratio in order to translate the endpoint into clinical significance, there were 20% more wins with FCM than placebo for all-cause mortality. When assessing heart failure hospitalizations in those without a death event, there were similar wins in both groups. Change in 6MWT slightly benefited the FCM group. There was a similar percentage of treatment emergent adverse events in each group.

Overall Dr. Mentz states that there was “modest improvement” in the FCM group compared to placebo but importantly IV iron supplementation showed “numerical improvements in mortality.” He goes on to say, “FCM is safe and we build on the prior data showing benefit in quality of life and exercise capacity [with FCM]. Each component of the primary endpoint favors FCM.” He believes that the importance of this study is in providing “another tool in our toolkit in addition to quadruple therapy specifically for HFrEF patients with iron deficiency.” He stated that one significant advantage of FCM is that it does not involve another daily medication and can be administered in clinic in a straightforward way to produce net benefit. Overall, FCM can be used clinically for patients with HFrEF and iron deficiency to help them feel and function better with evidence of a clinical outcome benefit as well. The trial results were simultaneously published in The New England Journal of Medicine.

A recent study by Dr. Kilic, published in the American Heart Association Journal, showed similar adverse outcomes in the 1-year survival, rejection rates, and complications of patients who received a heart transplant using hepatitis C-positive (HCV+) donors whereas those using hepatitis C-negative donors.

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In an observational case series of 80 patients who underwent heart transplant using hearts from hepatitis C (HCV)–positive donors, it has been shown that short-term (30-day) and long-term survival (1-year) of recipients testing positive for HCV exceeds 90% and is not significantly different to that of patients receiving heart transplants from HCV negative donors.

Results of the study titled “Expanding Heart Transplant in the Era of Direct-Acting Antiviral Therapy for Hepatitis C” were published in JAMA Cardiology. Dr. Kelly H. Schlendorf, MD (Vanderbilt University Medical Center, Nashville, Tennessee) and colleagues analyzed data from 80 patients (median age, 54.5 years; 71% men; 69% white) who underwent heart transplants with HCV-positive donors between September 2016 and April 2019. The authors found that the median active wait-list time from the time patients consented to accept HCV-positive donor hearts was 4 days (interquartile range [IQR], 1-18) versus 28 days (IQR, 6-168) for patients before providing consent. This was significantly lower than the national reported median wait times between 70 and 535 days.

The investigators categorized HCV positive donors into two groups: viremia positive and viremia negative (as determined by nucleic acid amplification test [NAAT]). Those with presence of viremia, a total of 70 donors had 95.7% transmission rate of HCV to their recipients, while none of the 10 recipients of hearts from NAT-negative donors developed infection (transmission rate, 0%). In patients testing positive with donor-derived HCV (ddHCV) 30-day and 1-year patient survival rates were 92.5% and 90.4%, respectively. A total of 6 (8.5%) patients with ddHCV died (5 due to primary allograft rejection and 1 due to development of pulmonary embolism). In addition, in the ddHCV cohort, 10 (14.9%) had acute cellular rejection and 1 patient (1.5%) had a single antibody-mediated graft rejection. Length of hospital stay and readmissions of ddHCV recipients were not significantly different from those who received heart transplants from HCV negative donors (median length of stay 15 days vs. 17 days, respectively; P = .79 for difference). Similarly, rates of coronary allograft vasculopathy in recepients also did not reveal any difference regardless of HCV positivity in donors. However, the authors noted that the recipients of transplants from HCV-positive donors exhibited significantly higher rates of severe primary graft dysfunction than recipients of transplants from HCV-negative donors (13.7% vs 3.1%; P = .002). Recipients suffering from ddHCV received direct anti-virals combinations using either Ledipasvir-sofosbuvir (90 mg-400 mg), Sofosbuvir-velpatasvir (400 mg-100 mg) or Glecaprevir-pibrentasvir (100 mg-40 mg) for 12 weeks. It was found that sustained virologic response at 12 weeks was 100% for ddHCV positive recepients.

Extended periods of wait-times for patients requiring heart transplants leads to significant morbidity and mortality. It has been shown that atleast 10% of patients requiring heart transplants die due to long wait-list times and the numbers get worse as wait times increase further. Results from the current study indicate that in the current era of direct acting anti-virals for HepC treatment, heart transplants from HepC positive donors is a viable option for expansion of donor pools and reduce wait list times for those awaiting transplants. Nevertheless, results from this study need to be interpreted with caution due to its limitations. The study was done at a single-center with surrounding municipalities that were affected by opioid crisis with an increased load of HepC donors, which may fail to account for geographical differences that exist in other areas.