Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and nvprt early reocclusion

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Lack of elevation of platelet factor IV in plasma from patients with myocardial infarction

Platelet factor IV and beta-thromboglobulin are protein constituents of platelet granules. Elevated levels of these proteins in plasma have been used as sensitive indicators of platelet degranulation. Clearance of platelet factor IV is much faster than that of beta-thromboglobulin after release of the proteins in vivo. Although increases of platelet factor IV have been observed in patients with infarction, the implication that they reflect pathogenetic phenomena such as coronary thrombosis has not been assessed explicitly. Accordingly, plasma samples obtained serially from 52 patients with acute myocardial infarction under rigorous conditions verified to minimize platelet degranulation in vitro were evaluated prospectively. Correlative studies were performed to detect left ventricular mural thrombus, and coronary thrombosis was assessed independently in selected patients with indium-Ill platelet scintigraphy.Platelet factor IV was normal at the time of admission in patients with infarction, averaging 6.3 ± 3.3 ng/ml, similar to values in 44 other patients with chest pain without subsequent infarction (5.7 ± 2.7 ng/ml) and in 25 normal subjects (4.3 ± 1.6 ng/ml). Platelet factor IV generally did not increase during hospitalization in patients with infarction despite recurrent chest pain, development of left ventricular thrombus or documented recurrent infarction. However, platelet factor IV increased consistently after invasive procedures, accounting for 104 of the total of 110 increases due to platelet activation in vivo as reflected by persistence of elevated levels of beta-thromboglobulin. Thus, platelet factor IV values generally remain normal despite acute myocardial infarction. Rare increases that occur reflect platelet degranulation in vitro due to sampling artifact or perturbations of platelets in vivo due to invasive procedures. They do not provide a definitive criterion of coronary thrombosis