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Right heart failure (RHF) following implantation of a left ventricular assist device (LVAD) is a common and potentially serious condition with a wide spectrum of clinical presentations with an unfavourable effect on patient outcomes. Clinical scores that predict the occurrence of right ventricular (RV) failure have included multiple clinical, biochemical, imaging and haemodynamic parameters. However, unless the right ventricle is overtly dysfunctional with end-organ involvement, prediction of RHF post-LVAD implantation is, in most cases, difficult and inaccurate. For these reasons optimization of RV function in every patient is a reasonable practice aiming at preparing the right ventricle for a new and challenging haemodynamic environment after LVAD implantation. To this end, the institution of diuretics, inotropes and even temporary mechanical circulatory support may improve RV function, thereby preparing it for a better adaptation post-LVAD implantation. Furthermore, meticulous management of patients during the perioperative and immediate postoperative period should facilitate identification of RV failure refractory to medication. When RHF occurs late during chronic LVAD support, this is associated with worse long-term outcomes. Careful monitoring of RV function and characterization of the origination deficit should therefore continue throughout the patient's entire follow-up. Despite the useful information provided by the echocardiogram with respect to RV function, right heart catheterization frequently offers additional support for the assessment and optimization of RV function in LVAD-supported patients. In any patient candidate for LVAD therapy, evaluation and treatment of RV function and failure should be assessed in a multidimensional and multidisciplinary manner.

Background: The HeartMate 3 (HM 3; Abbott) left ventricular assist device (LVAD) has improved hemocompatibility-related adverse outcomes. In sporadic cases, external compression of the outflow graft causing obstruction (eOGO) can result from substance accumulation between the outflow graft and its bend relief. We sought to evaluate the prevalence, course, and clinical implications of eOGO in an international study. Methods: A multicenter retrospective analysis of HM 3 LVADs implanted between November 2014 and April 2021 (n = 2108) was conducted across 17 cardiac centers in 8 countries. We defined eOGO as obstruction >25% in the cross-sectional area in imaging (percutaneous angiography, computed tomography, or intravascular ultrasound). The prevalence and annual incidence were calculated. Serious adverse events and outcomes (death, transplantation, or device exchange) were analyzed for eOGO cases. Results: Of 2108 patients, 62 were diagnosed with eOGO at a median LVAD support duration of 953 (interquartile range, 600-1267) days. The prevalence of eOGO was 3.0% and the incidence at 1, 2, 3, 4, and 5 years of support was 0.6%, 2.8%, 4.0%, 5.2%, and 9.1%, respectively. Of 62 patients, 9 were observed, 27 underwent surgical revision, 15 underwent percutaneous stent implantation, 8 received a heart transplant, and 2 died before intervention. One patient underwent surgical revision and later stent implantation. The mortality with therapeutic intervention was 9/53 (17.0%). Conclusions: Although uncommon, HM 3 LVAD-supported patients might develop eOGO with an increasing incidence after 1 year of support. Although engineering efforts to reduce this complication are under way, clinicians must maintain a focus on early detection and remain vigilant.

[Abstract] This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

OBJECTIVES: COMMANDER-HF was a randomised trial comparing rivaroxaban 2.5 mg two times a day to placebo, in addition to antiplatelet therapy, in patients hospitalised for worsening heart failure with coronary artery disease and sinus rhythm. Patients with diabetes are at increased risk of cardiovascular events and therefore have more to gain. METHODS AND RESULTS: In this post-hoc analysis, we evaluated the efficacy and safety of rivaroxaban in patients with (n=2052) and without diabetes (n=2970). The primary outcome was the composite of cardiovascular death, myocardial infarction (MI) or ischaemic stroke. HRs and 95% CIs with interaction analyses were used to describe event-rates and treatment effects. Patients with diabetes had a higher prevalence of cardiovascular comorbidities (eg, hypertension, obesity) and increased incidence of cardiovascular events. Adjusted HRs for events in people with versus without diabetes were 1.34 (95% CI 1.19 to 1.50) for the primary outcome, 1.21 (95% CI 0.84 to 1.75) for stroke, 1.51 (95% CI 1.14 to 1.99) for MI, 1.17 (95% CI 1.05 to 1.31) for heart failure hospitalisation and 1.06 (95% CI 0.56 to 2.01) for major bleeding. Rivaroxaban had no significant effect on event-rates in patients with and without diabetes (all interaction p values >0.05). Low-dose rivaroxaban was associated with an overall reduction in ischaemic stroke (HR 0.66; 95% CI 0.47 to 0.95), with no apparent subgroup interaction according to diabetes status (p-int=0.93). CONCLUSIONS: In COMMANDER-HF a diagnosis of diabetes conferred higher rates of cardiovascular events that, with exception of ischaemic stroke, was not substantially reduced by rivaroxaban. Rivaroxaban was associated with reduced risk of ischaemic stroke for patients with and without diabetes. TRIAL REGISTRATION NUMBER: NCT01877915; Post-results.

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support)., This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

Silicone is utilized widely in medical devices for its compatibility with tissues and bodily fluids, making it a versatile material for implants and wearables. To effectively bond silicone devices to biological tissues, a reliable adhesive is required to create a strong and long‐lasting interface. This study introduces BioAdheSil, a silicone‐based bioadhesive designed to provide robust adhesion on both sides of the interface, facilitating bonding between dissimilar substrates, namely silicone devices and tissues. The adhesive's design focuses on two key aspects: wet tissue adhesion capability and tissue‐infiltration‐based long‐term integration. BioAdheSil is formulated by mixing soft silicone oligomers with siloxane coupling agents and absorbents for bonding the hydrophobic silicone device to hydrophilic biological tissues. Incorporation of biodegradable absorbents eliminates surface water and controls porosity, while silane crosslinkers provide interfacial strength. Over time, BioAdheSil transitions from non‐permeable to permeable through enzyme degradation, creating a porous structure that facilitates cell migration and tissue integration, potentially enabling long‐lasting adhesion. Experimental results demonstrate that BioAdheSil outperforms commercial adhesives and elicits no adverse response in rats. BioAdheSil offers practical utility for adhering silicone devices to wet tissues, including long‐term implants and transcutaneous devices. In this study, we demonstrate its functionality through applications such as tracheal stents and LVAD (Left Ventricular Assist Device) lines.

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support)., This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case-control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033-0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predic

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case-control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033-0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predic

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

[Abstract] Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

AimsStroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban.Methods and resultsIn this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years).ConclusionsPatients with HFrEF and CAD are at risk for st

AimsStroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban.Methods and resultsIn this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years).ConclusionsPatients with HFrEF and CAD are at risk for st

The US Food and Drug Administration (FDA) Expanded Access (EA) Program, which allows for compassionate uses of unapproved therapeutics and diagnostics outside of clinical trials, has gained significant traction during the Coronavirus 2019 (COVID-19) pandemic. While development of vaccines has been the major focus, uncertainties around new vaccine safety and effectiveness have spawned interest in other pharmacological options. Experimental drugs can also be approved under the FDA Emergency Use Authorization (EUA) program, designed to combat infectious disease and other threats. Here, we review the US experience in 2020 with pharmacological EA and EUA approvals during the pandemic. We also provide a description of, and clinical rationale for, each of the EA- or EUA-approved drugs (e.g. remdesivir, convalescent plasma, propofol 2%, hydroxychloroquine, ruxolitinib, bamlanivimab, baricitinib, casirivimab plus imdevimab) during the pandemic and concluding reflections on the EA program and its potential future uses.

The US Food and Drug Administration (FDA) Expanded Access (EA) Program, which allows for compassionate uses of unapproved therapeutics and diagnostics outside of clinical trials, has gained significant traction during the Coronavirus 2019 (COVID-19) pandemic. While development of vaccines has been the major focus, uncertainties around new vaccine safety and effectiveness have spawned interest in other pharmacological options. Experimental drugs can also be approved under the FDA Emergency Use Authorization (EUA) program, designed to combat infectious disease and other threats. Here, we review the US experience in 2020 with pharmacological EA and EUA approvals during the pandemic. We also provide a description of, and clinical rationale for, each of the EA- or EUA-approved drugs (e.g. remdesivir, convalescent plasma, propofol 2%, hydroxychloroquine, ruxolitinib, bamlanivimab, baricitinib, casirivimab plus imdevimab) during the pandemic and concluding reflections on the EA program and its potential future uses.

Aims: Over decades, left ventricular assist device (LVAD) technology has transitioned from less durable bulky pumps to smaller continuous-flow pumps which have substantially improved long-term outcomes and quality of life. Contemporary LVAD therapy is beleaguered by haemocompatibility-related adverse events including thrombosis, stroke and bleeding. A fully magnetically levitated pump, the HeartMate 3 (HM3, Abbott, USA) LVAD, has been shown to be superior to the older HeartMate II (HMII, Abbott, USA) pump by improving haemocompatibility. Experience with the HM3 LVAD suggests near elimination of de-novo pump thrombosis, a marked reduction in stroke rates, and only a modest decrease in bleeding complications. Since the advent of continuous-flow LVAD therapy, patients have been prescribed a combination of aspirin and anticoagulation therapy on the presumption that platelet activation and perturbations to the haemostatic axis determine their necessity. Observational studies in patients implanted with the HM3 LVAD who suffer bleeding have suggested a signal of reduced subsequent bleeding events with withdrawal of aspirin. The notion of whether antiplatelet therapy can be avoided in an effort to reduce bleeding complications has now been advanced. Methods: To evaluate this hypothesis and its clinical benefits, the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) has been introduced as the first-ever international prospective, randomized, double-blind and placebo-controlled, non-inferiority trial in a patient population implanted with a LVAD. Conclusion: This paper reviews the biological and clinical role of aspirin (100 mg) with LVADs and discusses the rationale and design of the ARIES HM3 trial.

Aims: Over decades, left ventricular assist device (LVAD) technology has transitioned from less durable bulky pumps to smaller continuous-flow pumps which have substantially improved long-term outcomes and quality of life. Contemporary LVAD therapy is beleaguered by haemocompatibility-related adverse events including thrombosis, stroke and bleeding. A fully magnetically levitated pump, the HeartMate 3 (HM3, Abbott, USA) LVAD, has been shown to be superior to the older HeartMate II (HMII, Abbott, USA) pump by improving haemocompatibility. Experience with the HM3 LVAD suggests near elimination of de-novo pump thrombosis, a marked reduction in stroke rates, and only a modest decrease in bleeding complications. Since the advent of continuous-flow LVAD therapy, patients have been prescribed a combination of aspirin and anticoagulation therapy on the presumption that platelet activation and perturbations to the haemostatic axis determine their necessity. Observational studies in patients implanted with the HM3 LVAD who suffer bleeding have suggested a signal of reduced subsequent bleeding events with withdrawal of aspirin. The notion of whether antiplatelet therapy can be avoided in an effort to reduce bleeding complications has now been advanced. Methods: To evaluate this hypothesis and its clinical benefits, the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) has been introduced as the first-ever international prospective, randomized, double-blind and placebo-controlled, non-inferiority trial in a patient population implanted with a LVAD. Conclusion: This paper reviews the biological and clinical role of aspirin (100 mg) with LVADs and discusses the rationale and design of the ARIES HM3 trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

BACKGROUND: Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.METHODS: In this double-blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, or stroke. The principal safety outcome was fatal bleeding or bleeding into a critical space with a potential for causing permanent disability.RESULTS: Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2507 patients assigned to rivaroxaban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P=0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P=0.48).CONCLUSIONS: Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation. (Funded by Janssen Research an

Objective: Extracorporeal life support (ECLS) is a life-saving procedure used in the treatment of severe cardiogenic shock. Within this retrospective single centre study, we examined our experience in this critically ill patient cohort to assess outcomes and clinical parameters by comparison of ECLS with or without selective left ventricular decompression. Methods: Between 2004 and 2014 we evaluated 48 adult patients with INTERMACS level 1 heart failure (age 49.7 ± 19.5 years), who received either central ECLS with (n = 20, 41.7%) or ECLS without (n = 28, 58.3%, including 10 peripheral ECLS) integrated left ventricular vent in our retrospective single centre trial. Results: Follow up was 100% with a mean of 0.83 ± 1.85 years. Bridge to ventricular assist device was feasible in 29.2% (n = 14), bridge to transplant in 10.4% (n = 5) and bridge to recovery in 8.3% (n = 4). Overall 30-day survival was 37.5%, 6-month survival 27.1% and 1-year survival 25.0%. ECLS support with left ventricular decompression showed favourable 30-day survival compared to ECLS without left ventricular decompression (p = 0.034). Thirty-day as well as long-term survival did not differ between the subgroups (central ECLS with vent, ECLS without vent and peripheral ECLS without vent). Multivariate logistic regression adjusted for age and gender revealed ECLS without vent as independent factor influencing 30-day survival. Conclusion: ECLS is an established therapy for patients in severe cardiogenic shock. Independent of the ECLS approach, 30-day mortality is still high but with superior 30-day survival for patients with ECLS and left ventricular venting. Moreover, by unloading the ventricle, left ventricular decompression may provide an important time window for recovery or further treatment, such as bridge to bridge or bridge to transplant.

AimsThrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease.MethodsThis is an international prospective, multicentre, randomized, double-blind, placebo-controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide ≥200 pg/mL or N-terminal pro-B-type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.ConclusionCOMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF-rEF patient population with coronary artery disease.

AimsThrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease.MethodsThis is an international prospective, multicentre, randomized, double-blind, placebo-controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide ≥200 pg/mL or N-terminal pro-B-type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.ConclusionCOMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF-rEF patient population with coronary artery disease.

BackgroundClinical trials have demonstrated benefit for cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure with reduced ejection fraction (HFrEF); yet, questions have been raised with regard to the benefit of device therapy for minorities.ObjectivesThe purpose of this study was to determine the clinical effectiveness of CRT and ICD therapies as a function of race/ethnicity in outpatients with HFrEF (ejection fraction ≤35%).MethodsData from IMPROVE HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) were analyzed by device status and race/ethnicity among guideline-eligible patients for mortality at 24 months. Multivariate Generalized Estimating Equations analyses were conducted, adjusting for patient and practice characteristics.ResultsThe ICD/cardiac resynchronization defibrillator (CRT-D)-eligible cohort (n = 7,748) included 3,391 (44%) non-Hispanic white, 719 (9%) non-Hispanic black, and 3,638 (47%) other racial/ethnic minorities or race-not-documented patients. The cardiac resynchronization pacemaker (CRT-P)/CRT-D-eligible cohort (n = 1,188) included 596 (50%) non-Hispanic white, 99 (8%) non-Hispanic black, and 493 (41%) other/not-documented patients. There was clinical benefit associated with ICD/CRT-D therapy (adjusted odds ratio: 0.64, 95% confidence interval: 0.52 to 0.79, p = 0.0002 for 24-month mortality), which was of similar proportion in white, black, and other minority/not-documented patients (device-race/ethnicity interaction p = 0.7861). For CRT-P/CRT-D therapy, there were also associated mortality benefits (adjusted odds ratio: 0.55, 95% confidence interval: 0.33 to 0.91, p = 0.0222), and the device-race/ethnicity interaction was not significant (p = 0.5413).ConclusionsThe use of guideline-directed CRT and ICD therapy was associated with reduced 24-month mortality without significant interaction by racial/ethnic group. Devic

BackgroundClinical trials have demonstrated benefit for cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure with reduced ejection fraction (HFrEF); yet, questions have been raised with regard to the benefit of device therapy for minorities.ObjectivesThe purpose of this study was to determine the clinical effectiveness of CRT and ICD therapies as a function of race/ethnicity in outpatients with HFrEF (ejection fraction ≤35%).MethodsData from IMPROVE HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) were analyzed by device status and race/ethnicity among guideline-eligible patients for mortality at 24 months. Multivariate Generalized Estimating Equations analyses were conducted, adjusting for patient and practice characteristics.ResultsThe ICD/cardiac resynchronization defibrillator (CRT-D)-eligible cohort (n = 7,748) included 3,391 (44%) non-Hispanic white, 719 (9%) non-Hispanic black, and 3,638 (47%) other racial/ethnic minorities or race-not-documented patients. The cardiac resynchronization pacemaker (CRT-P)/CRT-D-eligible cohort (n = 1,188) included 596 (50%) non-Hispanic white, 99 (8%) non-Hispanic black, and 493 (41%) other/not-documented patients. There was clinical benefit associated with ICD/CRT-D therapy (adjusted odds ratio: 0.64, 95% confidence interval: 0.52 to 0.79, p = 0.0002 for 24-month mortality), which was of similar proportion in white, black, and other minority/not-documented patients (device-race/ethnicity interaction p = 0.7861). For CRT-P/CRT-D therapy, there were also associated mortality benefits (adjusted odds ratio: 0.55, 95% confidence interval: 0.33 to 0.91, p = 0.0222), and the device-race/ethnicity interaction was not significant (p = 0.5413).ConclusionsThe use of guideline-directed CRT and ICD therapy was associated with reduced 24-month mortality without significant intera

Katelyn W Sylvester,1 Judy WM Cheng,1,3 Mandeep R Mehra2,41Department of Pharmacy, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 3Massachusetts College of Pharmacy and Health Sciences, Boston, MA, 4Harvard Medical School, Boston MA, USAAbstract: Low dose aspirin therapy plays a fundamental role in both the primary and secondary prevention of cardiovascular events. Although the evidence using low dose aspirin for secondary prevention is well-established, the decision to use aspirin for primary prevention is based on an evaluation of the patient’s risk of cardiovascular events compared to their risk of adverse events, such as bleeding. In addition to the risk of bleeding associated with long term aspirin administration, upper gastrointestinal side effects, such as dyspepsia often lead to discontinuation of therapy, which places patients at an increased risk for cardiovascular events. One option to mitigate adverse events and increase adherence is the addition of esomeprazole to the medication regimen. This review article provides an evaluation of the literature on the concomitant use of aspirin and esomeprazole available through February 2013. The efficacy, safety, tolerability, cost effectiveness, and patient quality of life of this regimen is discussed. A summary of the pharmacokinetic and pharmacodynamic interactions between aspirin and esomeprazole, as well as other commonly used cardiovascular medications are also reviewed. The addition of esomeprazole to low dose aspirin therapy in patients at high risk of developing gastric ulcers for the prevention of cardiovascular disease, significantly reduced their risk of ulcer development. Pharmacokinetic and pharmacodynamic studies suggested that esomeprazole did not affect the pharmacokinetic parameters or the antiplatelet effects of aspirin. Therefore, for those patients who are at a high risk of developing a gastrointestinal ulcer, the benefit of adding esomeprazole likel

ObjectivesWe sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation.BackgroundCardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome.MethodsFirst-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2).ResultsGroup 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004).ConclusionsThis multicenter study suggests that progression of intimal thickening >/=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

ObjectivesWe sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation.BackgroundCardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome.MethodsFirst-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2).ResultsGroup 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004).ConclusionsThis multicenter study suggests that progression of intimal thickening >/=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

Hypertension is the most significant risk factor for cardiovascular disease and mortality worldwide, affecting 1.3 billion adults. Global disparities in hypertension control are widening with low- and middle-income countries (LMIC) having the fastest growing rates of hypertension and low rates of control. Treatment for hypertension can be challenging, with multiple drug classes and dosing schedules. Combination antihypertensives have been suggested as a solution for their efficacy and potential to improve adherence. Global consumption of combination and non-combination antihypertensives across 75 countries and 2 regions from 2010 to 2021 was estimated using the IQVIA MIDAS database on pharmaceutical sales. Consumption rates were standardized using Standard Units (SUs) and analysed by high-income (HIC), upper-middle income (UMIC), and LMIC income classification. Global median consumption rate of all antihypertensives per 1000 inhabitants per day increased from 184.78 SUs in 2010 to 325.6 SUs in 2021, with HICs consistently having the highest rates. Median consumption rates of combination and non-combination antihypertensives increased across all country income groups but combination drugs were consumed at a lower rate and proportion. LMICs consumed a higher percentage of combination antihypertensives relative to non-combination (45.5%) than UMICs (24.3%) and HICs (24.4%) in 2021. While combination antihypertensives may be preferred for their potential for increased adherence and effectiveness, their global uptake is inconsistent. HICs consume less combination medication relative to non-combination, despite higher overall consumption rates of antihypertensives. LMICs show increasing use of combination medications, indicating a shift towards their use.

Background: The clinical and cost-effectiveness of left ventricular assist device (LVAD) therapy for patients with advanced heart failure (HF) who are ineligible for heart transplantation is debated in the UK. This study develops an indirect comparison between the fully magnetically levitated HeartMate 3 (HM 3) LVAD and medical therapy (MT) to evaluate expected clinical and cost-effectiveness in the UK National Health Service (NHS) context. Methods: We performed an economic analysis comparing the HM3 pump against the HeartMate II LVAD (MOMENTUM 3), and then another analysis comparing MT with the first- and second-generation HeartMate XVE pump LVAD and HeartMate II LVAD for the same patient population (REMATCH and ROADMAP, respectively). By bridging those 2 analyses, an indirect comparison between HM3 and MT in the form of a network meta-analysis was developed. A literature search was performed to select the most appropriate pair of studies for this purpose. Outcomes were adjusted to produce Kaplan-Meier curves for the cost-effectiveness evaluation by using a decision-analytic model. Data were extrapolated linearly over a 5-year time horizon. Uncertainty and additional scenarios were addressed by one-way and probabilistic sensitivity analysis. Local costs and health utility were used from England, thereby representing the UK context. Results: The incremental cost-effectiveness ratio (ICER) for LVAD vs MT in transplant ineligible patients with advanced HF was estimated to be £47,361 per quality-adjusted life year gained, with a 97.1% probability of being cost-effective at £50,000. In a subgroup of patients who are inotropic therapy dependent (INTERMACS 1-3 severity profile), the ICER was £45,616, while for a population with less-ill ambulatory HF (INTERMACS profile 4-7) the ICER changed to £64,051. Conclusions: This study provides evidence that HM3 LVAD therapy in advanced HF patients ineligible for heart transplantation may be cost-effective compared to MT in the NHS