Harrington, Josephine

Abstract Aims Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. Methods and results HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (−0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. Conclusions Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037931.

Abstract Background Direct oral anticoagulation (DOACs) prevent stroke in patients with atrial fibrillation (AF) and have a superior safety profile compared with vitamin K antagonists (VKA). Yet, better definition of incidence and risk factors for major bleeding associated with DOACs in clinical practice may be important given emerging stroke prevention technologies, both pharmacologic and nonpharmacologic. Purpose To describe the incidence of and risk factors for major bleeding in individuals with AF on DOAC therapy. Methods We reviewed electronic health record data for two patient cohorts with AF prescribed DOACs: (1) Duke University Health System (DUHS) (2010–2018) and (2) Sites within the Patient-Centered Clinical Research Network (PCORnet) (2015–2019) which had ≥6 years assimilated data from both inpatient and outpatient encounters (7 sites). In each cohort, we assessed the 5-year incidence of major bleeding events defined as hospitalization for intracranial hemorrhage, or hospitalization for gastro-intestinal bleeding or procedure to control bleeding accompanied by transfusion within ±7 days or death within 30 days. Multivariable Fine-Gray proportional hazards modeling in each cohort was performed to evaluate independent risk factors for major bleeding on DOAC therapy. Results The cohorts included 10,625 patients (DUHS) and 58,321 patients (PCORnet) with AF. Major bleeding events occurred within 5 years of diagnosis in 639 (7.9%) of DUHS patients and 2568 (6.6%) of PCORnet patients (Table 1). The DUHS model predicted time to first major bleeding event with a C-index of 0.756 (95% CI 0.737, 0.775) and the PCORNet model had a c-index of 0.745 (0.736, 0.755) (Table 2). Independent factors associated with major bleeding consistent across both models (p<0.001 in PCORnet for all unless noted) were higher CHA2DS2-VASc scores, lower eGFR, anemia (HR per 1-point increase in hemoglobin up to 12 g/dL 0.79 [0.76, 0.82]), prior major bleeding (HR 2.70 [2.22, 3.30]), cancer (HR 1.23 [1.12, 1.36]), recent cardiac surgery (HR 0.70 [0.51, 0.97]; p=0.030), alcohol use (HR 1.56 [1.29, 1.88]), aspirin use (HR 1.44 [1.32, 1.57]), and selective serotonin reuptake inhibitor use (HR 1.30 [1.19, 1.42]). Conclusions Across a large and geographically diverse contemporary population, risk of bleeding on DOAC for stroke prevention in AF remains a frequent and important clinical problem. There is an unmet need for stroke prevention therapies with improved safety profiles. We identified risk factors for major bleeding events on DOAC therapy, some of which are not represented in traditional risk scores, which may inform shared decision making for stroke prevention. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer Pharmaceuticals