Purpose: Men with pulmonary arterial hypertension (PAH) have worse survival than women.While the reason remains unclear, proposed explanations have included worse hemodynamics, worse right ventricular (RV) function, greater comorbidity burden, and poorer responses to therapy.The purpose of this study was to examine sex differences in baseline hemodynamic, functional, and health related quality of life (HRQOL) variables in PHAR.Methods: We included all adults with PAH in the multicenter US-based PHAR.Baseline differences in hemodynamics and functional parameters were assessed by sex.HRQOL was assessed using the PAH-specific instrument, emPHasis-10; the generic-physical instrument, SF12-Physical; and the generic-mental instrument, SF12-Mental.Sensitivity analyses was performed including only idiopathic patients (n=715) or incident patients (diagnosed within 6 months of registry entry; n=847).Results: 1,619 PAH patients were included; the sex ratio was 3 to 1 (female to male).Compared to men, women had higher pulmonary vascular resistance, lower pulmonary artery compliance, and lower cardiac output, although these differences were not significant when correcting for body surface area.Women had lower right ventricular stroke work index (RVSWI) relative to men.There were no sex differences in the number of PAH therapies.Women were more likely to be classified as World Health Organization Functional Class III-IV and have higher REVEAL Lite 2 risk scores.Women also had worse HRQOL as measured by the emPHasis-10 and SF12-Mental.Sensitivity analyses showed similar findings.Conclusion: In a US-based cohort of patients new to PAH care, women unexpectedly had worse RVSWI, baseline functional impairments, and HRQOL compared to men.Further analysis will examine if sex differences in hospitalization, survival, and response to therapy exist in this large contemporary PAH cohort.

Purpose Recently, protein biomarkers such as N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) have been shown to predict risk for gastrointestinal bleeding (GIB) and stroke in atrial fibrillation. This study aims to assess the validity of these biomarkers in predicting the incidence of stroke or GIB in LVAD recipients. Methods Prospective LVAD patients were enrolled into the PREVENtion of Heartmate II Pump Thrombosis through Clinical Management (PREVENT) at 24 sites across the U.S along with patients from Inova Heart and Vascular Institute and Allegheny Health Network from 2014-2019. NT-proBNP and GDF-15 were measured before LVAD. Time to first stroke or GIB within 6-months was analyzed in relationship to the median biomarker concentration. Results A total of 470 patients were included in the analysis. Patients had the following characteristics: median patient age 60 years (IQR: 52-67), 80% male, 20% female, 75% White, 20% Black, 30% diabetes mellitus and 34% atrial fibrillation. Most patients had non-ischemic cardiomyopathy (46%) and were INTERMACS profile 2-3 (67%). At 6-months, 99 patients had a GIB (21%) and 32 had a stroke (7%). The median NT-proBNP was 2,551pg/ml (1,396-5,386) and GDF-15 was 5,000pg/ml (2,917-8,442). When patients were separated by the median biomarker concentrations, no difference in the incidence of stroke was noted (p=0.8). Similarly, the incidence of GIB with higher NT-proBNP concentrations was not significant (p=0.16, Figure A). Higher GDF-15 concentrations were associated with a higher incidence of GIB (p=0.02, Figure B). Patients with elevated GDF-15 levels had an incidence of GIB of 23% compared to 15% in patients with lower concentrations. Conclusion Elevated levels of GDF-15 predict risk of GIB following LVAD implant. These data highlight the ability of novel biomarkers to predict complications that could potentially guide the selection of antithrombotic therapy after LVAD placement. Recently, protein biomarkers such as N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) have been shown to predict risk for gastrointestinal bleeding (GIB) and stroke in atrial fibrillation. This study aims to assess the validity of these biomarkers in predicting the incidence of stroke or GIB in LVAD recipients. Prospective LVAD patients were enrolled into the PREVENtion of Heartmate II Pump Thrombosis through Clinical Management (PREVENT) at 24 sites across the U.S along with patients from Inova Heart and Vascular Institute and Allegheny Health Network from 2014-2019. NT-proBNP and GDF-15 were measured before LVAD. Time to first stroke or GIB within 6-months was analyzed in relationship to the median biomarker concentration. A total of 470 patients were included in the analysis. Patients had the following characteristics: median patient age 60 years (IQR: 52-67), 80% male, 20% female, 75% White, 20% Black, 30% diabetes mellitus and 34% atrial fibrillation. Most patients had non-ischemic cardiomyopathy (46%) and were INTERMACS profile 2-3 (67%). At 6-months, 99 patients had a GIB (21%) and 32 had a stroke (7%). The median NT-proBNP was 2,551pg/ml (1,396-5,386) and GDF-15 was 5,000pg/ml (2,917-8,442). When patients were separated by the median biomarker concentrations, no difference in the incidence of stroke was noted (p=0.8). Similarly, the incidence of GIB with higher NT-proBNP concentrations was not significant (p=0.16, Figure A). Higher GDF-15 concentrations were associated with a higher incidence of GIB (p=0.02, Figure B). Patients with elevated GDF-15 levels had an incidence of GIB of 23% compared to 15% in patients with lower concentrations. Elevated levels of GDF-15 predict risk of GIB following LVAD implant. These data highlight the ability of novel biomarkers to predict complications that could potentially guide the selection of antithrombotic therapy after LVAD placement.

In the first prospective, randomized double blind placebo-controlled study of an ASA free regimen in patients on durable LVAD support receiving warfarin, we did not observe increased rates of TE events. Our findings are only applicable to the HMII device and significantly limited by an early study stop. However, they provide supportive rationale for the study of antiplatelet free regimen in contemporary LVADs, specifically those with decreased device thrombosis.

Purpose The MAGENTUM 1 Trial targeted an INR of 1.50-1.90 in patients implanted with HeartMate 3 (HM3) pump. Anticoagulation was maintained in the low intensity range with high efficiency (INR 1.50-1.90, TTR, 75.2 ± 8.6% n=15 patients). None developed thromboembolic events. Factor X activity (FXa) has been suggested as a biologically relevant pharmacodynamic surrogate measure of anticoagulation intensity. We sought to correlate suppression of FXa in MAGENTUM 1 patients to demonstrate the effect of low intensity anticoagulation in HM3 patients. Methods Samples for chromogenic factor X (CFX) assays (Hyphen BioMed) were obtained simultaneously with INR values at routine intervals and stored for batch analysis and not made available to the investigators. Normal reference range for the CFX assay is 71-97%. INR was correlated with CFX; median values and interquartile ranges were determined for INR values >1.50, 1.50-1.90 and <1.90. Results The correlation of INR range with CFX is shown in Figure 1A. The median CFX value for INR range 1.50-1.90 was 40%. When the INRs were above 1.90 the median CFX value was 30%, when the INRs were below 1.50 the median CFX was 53%. Conclusion We demonstrate that a measured INR range of 1.50-1.90 pharmacodynamically corresponds to less suppression of FX activity than at an INR >1.90 but greater than with INR <1.50, indicating an effective range of modulation of the observed anticoagulation effect. We validate the range of low intensity anticoagulation in this analysis and suggest that decreased intensity warfarin monitoring is reliable and may lead to decreased bleeding complications without increasing the risk of thrombosis in patients with HM3 (NCT03078374).

Summary of Objectives The HeartMate 3 Left Ventricular Assist System has demonstrated absence of confirmed de-novo pump thrombosis and reduction in stroke. However, bleeding related adverse events persist under standard anticoagulation targeting a INR range of 2.0-3.0. In an initial experience we demonstrated safety of transition to low intensity anticoagulation (INR target 1.5-1.9, n=15, follow up of at least 6 months). Whether complete cessation of anticoagulation maintains "thromboresistance" in the HeartMate 3 pump remains unknown. Methods We previously reported on a strategy of low-intensity warfarin anticoagulation in patients implanted with HeartMate 3 (J Heart Lung Transplant. 2018;37(5):579-586). Following completion of this study phase, a staged trial was approved by the single site's ethics committee and registered as NCT03704220. All patients enrolled in the low intensity warfarin study (target INR of 1.5-1.9) were considered eligible for enrollment in the "anticoagulation withdrawal" study, if they were continuing on long-term support. All patients had to meet safe eligibility criteria including pump speed reduction to facilitate aortic valve opening (to avoid root thrombus), absence of thrombus in the pre-pump cardiac system, and absence of signs of poor unloading at reduced device speed. Careful surveillance for pump thrombosis was algorithmically mandated with biomarker and serial pump log file analyses. If enrolled, they were withdrawn from warfarin therapy and followed for survival free of pump thrombosis, disabling stroke or major bleeding for at least 3 months as the primary safety end point. Endpoints Enrollment and follow up in the low intensity anticoagulation study has been reported (n=15); 13 men, mean age 57 years (18-72), with intended goal of therapy of either BTT or DT, INTERMACS Profile mean 3 (2-5), Cardiac Index mean 1.62 l/min/m2. Of 10 patients followed beyond 1 year on reduced anticoagulation, 5 patients have qualified for complete withdrawal of anticoagulation and the safety endpoint analysis will be completed prior to the ISHLT meeting in March 2019. This pivotal study is the first indication-independent anticoagulation withdrawal study in the HeartMate 3 designed to establish thrombo-resistance for the device and form the rationale for a large scale multicenter trial.

Left ventricular assist devices (LVADs) are standard of care for end-stage heart failure patients. While overall outcomes have steadily improved, serious hemostatic disturbances remain. This study aims to characterize thrombin generation, fibrinolysis, contact system activation, and inflammation in LVAD recipients.

Bleeding is common among patients with left ventricular assist devices (LVADs). It has been recently shown in single center studies that angiopoietin-2 (Ang-2) and Tissue Necrosis Factor-α (TNF-α) are critically linked with bleeding in LVAD patients. The purpose of this study was to describe the changes in plasma levels of angiogenic and inflammatory biomarkers and correlate them with clinical outcome in patients enrolled in the PREVENT study.

Anemia remains a major risk factor for adverse events among patients with heart failure. The prognostic role of anemia with or without bleeding in patients with durable left ventricular assist devices is not well studied.

There is considerable practice variation in LVAD care and it is unknown how much this variation influences patient outcomes. The PREVENtion of HeartMate II pump Thrombosis through clinical management (PREVENT) study was a multicenter, prospective trial designed to evaluate rates of pump thrombosis (PT) following adoption of a uniform set of surgical and medical recommendations.

LVADs have become a mainstay therapy in advanced heart failure. However, thromboembolic (TE) events remain a leading cause of morbidity and mortality. The effect of pre-existing hypercoagulable (HC) conditions on post-LVAD outcomes is still not clear. This study aims to evaluate TE incidence in patients with pre-existing HC disorders undergoing HeartMate II implantation as part of a prospective, multi-center study.