Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

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.

Antiplatelet therapy in percutaneous coronary intervention: recent advances in oral antiplatelet agents.

PURPOSE OF REVIEW: Dual antiplatelet therapy with aspirin and clopidogrel, in conjunction with heparin, is the most common antithrombotic strategy in percutaneous coronary intervention (PCI) used to reduce peri-procedural ischaemic complications. However, there remains significant inter-individual variability in post-treatment platelet inhibition with this current established therapy. This review focuses on recent developments in oral antiplatelet agents used in PCI, which promise to overcome, at least in part, current shortfalls. RECENT FINDINGS: Genetic polymorphisms and medication interactions involving CYP3A4 or CYP2C19, patient compliance and higher platelet reactivity in certain subgroups, such as those with diabetes, are important factors contributing to inter-individual variability in post-treatment platelet inhibition. Higher clopidogrel doses have been associated with improved clinical outcomes, especially in those presenting with acute coronary syndrome. Newer agents, namely prasugrel and ticagrelor, have been shown to have greater potency and superior clinical outcomes. However, this comes with a price of increased bleeding complications. SUMMARY: Whereas more potent antiplatelet therapies are associated with improved outcome, balancing the risk of bleeding and peri-procedural ischaemic complications remains a key aspect to consider when choosing among the ever-increasing number of agents available. The role of intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) needs to be re-examined in the current context of such potent oral antiplatelet agents. Further research will hopefully help to determine the preferred antithrombotic strategy in patients undergoing PCI.

Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation.

The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.