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BACKGROUND: Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation. OBJECTIVES: The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. METHODS: The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated. RESULTS: Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next. CONCLUSIONS: A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).

We assessed the incidence, predictors and clinical correlates of de-novo aortic regurgitation (AR), which physiologically reduces left ventricular assist device (LVAD) effectiveness due to recirculation syndrome, in the MOMENTUM 3 trial portfolio of the fully magnetically levitated HeartMate 3 (HM3) pump using the randomized pivotal trial (PT) and post-trial continued access protocol (CAP).De-novo aortic regurgitation incidence at 2 years was analysed in the randomized PT and validated in the first 1000 implanted patients of the CAP. Patients with concomitant/prior aortic valve surgery or without baseline or post-implant echocardiograms were excluded from this analysis. AR severity was assessed qualitatively by site-adjudicated echocardiograms (significant AR was defined as moderate or severe grade on echocardiogram). Of 1028 patients enrolled in the PT, 918 were eligible for inclusion in this analysis (HM3, n = 465; HMII, n = 453). At 2 years of LVAD support, freedom from significant AR was greater in the HM3 (92%) than HMII (82%) (hazard ratio 0.45, 95% confidence interval 0.27-0.75, p 0.01). Of 907 HM3 patients analysed from the first 1000 implanted CAP patients, the rate of freedom from significant AR was 90%, consistent with the PT (p = 0.3). In the combined HM3 group (n = 1372), multivariable Cox modelling identified increasing age and female sex as significant predictors. Survival free of urgent transplant or AR corrective procedure was similar between HM3 patients with and without significant de-novo AR.The development of moderate or severe grade de-novo AR is reduced with the fully magnetically levitated HM3 LVAD compared to the axial-flow HMII pump. The occurrence of significant de-novo AR with the HM3 pump is not associated with a worse outcome at 2 years of follow-up.

Background: Body wasting in patients with cancer can affect the heart. Objectives: The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. Methods: This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction

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).

Aims The minute ventilation–carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. Methods and results In this single‐centre retrospective observational study of 1347 patients with HF referred for cardiopulmonary exercise testing, patients with HF were categorized into HF with reduced (HFrEF, LVEF

Summary Background Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II–IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. Methods The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II–IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov , NCT03387813 . Findings Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74–1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66–1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80–1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70–1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61–0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. Interpretation Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. Funding Abbott.

Increased left ventricular dilation and reduced systolic function are consistently associated with a poor prognosis and worse clinical outcomes. In this review, we discuss the pathophysiological me...

A previously healthy 39-year-old man presented in cardiogenic shock with evidence of multisystem inflammatory syndrome of adults 2 months after a mild case of coronavirus disease 2019. He was treated with intravenous immunoglobulin and pulse-dose corticosteroids with rapid resolution of his symptoms and normalization of biventricular function. (Level of Difficulty: Intermediate.), Central Illustration

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., This figure incorporates the rationale for ARIES HM3 (Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump), the principal study hypothesis and a summary of its design. LVAD, left ventricular assist device.

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.

Background Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. Methods ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. Results A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). Conclusions A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

Purpose of review Timely referral of eligible candidates for consideration of advanced therapies, such as a heart transplantation or mechanical circulatory support is essential. The characteristics of heart transplantation candidates have changed significantly over the years, leading to a more complex evaluation process. The present review summarizes recent advances in the evaluation process for heart transplantation eligibility. Recent findings The heart transplantation allocation policy was recently reviewed in the USA in an effort to reduce waitlist mortality and to ensure fair geographic allocation of organs to the sickest patients. Moreover, patients with chronic infectious diseases, as well as malignancies, are being currently considered acceptable candidates for transplantation. Listing practices for heart transplantation vary between programmes, with a greater willingness to consider high-risk candidates at higher-volume centres. Summary The ultimate decision to place high-risk candidates on the heart transplantation waitlist should be based on a combination of quantitative and qualitative data analysis informed by clinical judgement, and the chronic shortage of organ donors makes this process an important ethical concern for any society. Future guidelines should discuss approaches to achieve fair organ allocation while preserving improved outcomes after transplantation.

Cardiac allografts from donors with a history of cocaine use (DHCU) are often discarded owing to concerns regarding organ quality. We investigated long-term outcomes of de novo adult heart transplantation (HTx) using DHCU.Using the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry, we identified 24,430 adult recipients of primary, deceased donor, heart-alone transplants between January 1, 2000, and June 30, 2013. Transplants were categorized on the basis of DHCU. Survival rates were compared using Kaplan-Meier curves and log-rank tests.A total of 3,246 (13.3%) HTx were performed using DHCU during the study period. Of these, 1,477 (45.5%) were classified as current users. Organs from DHCU were transplanted at a later sequence number (data from a sub-group of patients transplanted in the United States) than those from the non-cocaine use group (mean sequence number 16.1 ± 55.6 vs 11.5 ± 38.2; p0.001), suggesting higher decline rates by centers. Kaplan-Meier estimates of survival were not different between groups (p = 0.16), with post-transplant survival rates at 1, 5, and 10 years of 88.1%, 75.8%, and 58.5%, respectively, in the non-cocaine use group and 90.0%, 76.7%, and 59.7%, respectively, in the DHCU group. On multivariate analysis, DHCU were not associated with mortality (hazard ratio [HR]: 0.94; 95% CI: 0.88-1.00; p = 0.050), cardiac allograft vasculopathy (HR: 1.02; 95% CI: 0.94-1.11; p = 0.56), or allograft rejection (HR: 0.98; 95% CI: 0.92-1.05; p = 0.61).Our findings demonstrate that adult HTx performed using DHCU is not associated with an adverse impact on long-term clinical outcomes. These findings should spur efforts to reduce discard rates of organs from DHCU.

The increased need for heart transplantation in patients with advanced heart failure has introduced demand for a greater supply of donor hearts. Progress in cross-species experimental models has led to promise for ushering in the clinical use of xenotransplantation (XTx) as a potential solution to the organ shortage worldwide. In this review, the authors first highlight the historical advances that led to the first pig-to-human heart transplantation, a landmark moment in the field of advanced heart failure. The authors discuss immunologic, infectious, and physiological challenges for implementation of XTx, as well as innovations in the science of genetic manipulation that allowed clinical translation of this therapy. The authors consider ongoing barriers that affect ongoing translation of this technology into clinical care in the current era. Finally, the authors propose a framework for advancing clinical application of XTx.

A growing proportion of transplant donors and recipients have a history of COVID-19 infection. This study sought to characterize clinical practice after recipient or donor COVID-19 infection.An online survey was distributed to heart transplant clinicians through a professional society message board and social media. Responses were collected between September 29 and November 5, 2021.There were 222 health care professionals (68% transplant cardiologists, 22% transplant surgeons, 10% other) across diverse geographic regions who completed the survey. While there was significant variation in donor acceptance, as it relates to past and current COVID-19 infection, the respondents were fairly cautious: 28% would not typically accept a donor with a history of COVID-19 regardless of the infection course and 80% would not accept donors who had evidence of myocardial dysfunction during past COVID-19 infection, or who died of COVID-19 or its complications. The timing of candidate reactivation on the waiting list after COVID-19 infection also varied and often diverged from scenarios addressed by social guidelines. Eighty-one percent of the respondents felt COVID-19 vaccine should be mandatory before transplant, but this rate varied by geographic region.Our results reflect evolving experience of the heart transplant field at a time of lack of high-quality evidence. In the absence of longer-term outcome data for donors and transplant candidates with history of COVID-19 infection, clinicians remain cautious; however, this approach will likely need to be refined as an increasing proportion of the population will continue to be infected with COVID-19.

As left ventricular assist device (LVAD) survival rates continue to improve, evaluating site-specific variability in outcomes can facilitate identifying targets for quality-improvement initiative opportunities in the field.Deidentified center-specific outcomes were analyzed for HeartMate 3 (HM3) patients enrolled in the MOMENTUM 3 pivotal and continued access protocol trials. Centers25th percentile for HM3 volumes were excluded. Variability in risk-adjusted center mortality was assessed at 90 days and 2 years (conditional upon 90-day survival). Adverse event (AE) rates were compared across centers.In the 48 included centers (1958 patients), study-implant volumes ranged between 17 and 106 HM3s. Despite similar trial-inclusion criteria, patient demographics varied across sites, including age quartile ((Q)1-Q3:57-62 years), sex (73%-85% male), destination therapy intent (60%-84%), and INTERMACS profile 1-2 (16%-48%). Center mortality was highly variable, nadiring at ≤ 3.6% (≤ 25th percentile) and peaking at ≥ 10.4% (≥ 75th percentile) at 90 days and ≤ 10.2% and ≥ 18.7%, respectively, at 2 years. Centers with low mortality rates tended to have lower 2-year AE rates, but no center was a top performer for all AEs studied.Mortality and AEs were highly variable across MOMENTUM 3 centers. Studies are needed to improve our understanding of the drivers of outcome variability and to ascertain best practices associated with high-performing centers across the continuum of intraoperative to chronic stages of LVAD support.

Correction of valvular disease is often undertaken during left ventricular assist device (LVAD) implantation with uncertain benefit. We analyzed clinical outcomes with HeartMate 3 (HM3; Abbott) LVAD implantation in those with various concurrent valve procedures (HM3+VP) with those with an isolated LVAD implant (HM3 alone).The study included 2200 patients with HM3 implanted within the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial portfolio who underwent 820 concurrent procedures among which 466 (21.8%) were HM3+VP. VPs included 101 aortic, 61 mitral, 163 tricuspid; 85 patients had multiple VPs. Perioperative complications, major adverse events, and survival were analyzed.Patients who underwent HM3+VP had higher-acuity Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles (1-2: 41% vs 31%) compared with no VPs (P .05). The cardiopulmonary bypass time (124 vs 76 minutes; P.0001) and hospital length of stay (20 vs 18 days; P.0001) were longer in HM3+VP. A higher incidence of stroke (4.9% vs 2.4%), bleeding (33.9% vs 23.8%), and right heart failure (41.5% vs 29.6%) was noted in HM3+VP at 0 to 30 days (P .01), with no difference in 30-day mortality (3.9% vs 3.3%) or 2-year survival (81.7% vs 80.8%). Analysis of individual VP showed no differences in survival compared to HM3 alone. No differences were noted among patients with either significant mitral (moderate or worse) or tricuspid (moderate or worse) regurgitation with or without corrective surgery.Concurrent VPs, commonly performed during LVAD implantation, are associated with increased morbidity during the index hospitalization, with no effect on short- and long-term survival. There is sufficient equipoise to consider a randomized trial on the benefit of commonly performed VPs (such as mitral or tricuspid regurgitation correction), during LVAD implantation.

Objectives This study sought to determine the frequency, incidence rates over time, association with mortality, and potential risk factors for hemocompatibility-related adverse events (HRAEs) occurring during venoarterial-extracorporeal life support (VA-ECLS). Background HRAEs are common complications of VA-ECLS. Studies examining relevant clinical predictors and the association of HRAEs with survival are limited by small sample size and single-center setting. Methods We queried adult patients supported with VA-ECLS from 2010 to 2017 in the Extracorporeal Life Support Organization database to assess the impact of HRAEs on in-hospital mortality. Results Among 11,984 adults meeting study inclusion, 8,457 HRAEs occurred; 62.1% were bleeding events. The HRAE rate decreased significantly over the study period (p trend Conclusions Although decreasing, HRAEs remain common during VA-ECLS and have a cumulative association with survival. Bleeding events are twice as common as thrombotic events, with a hierarchy of HRAEs influencing survival. Differential risk factors for bleeding and thrombotic complications exist and raise the possibility of a tailored approach to ECLS management.

Substantial progress in the field of mechanical circulatory support (MCS) has expanded the treatment options for patients with advanced-stage heart failure (HF). Currently available MCS devices can be implanted percutaneously or surgically. They can also be configured to support the left, right, or both ventricles, offering varying levels of circulatory support. Short-term temporary MCS devices are primarily used in high-risk percutaneous coronary intervention, cardiogenic shock, and post-cardiac arrest, while durable left ventricular assist systems (LVAS) are increasingly utilized either as a bridge-to-transplant, bridge to decision, or as a destination therapy. The evolution from older pulsatile devices to continuous-flow LVAS and the incorporation of smaller pumps, with no valves, fewer moving parts, and improved hemocompatibility has translated into improved clinical outcomes, greater durability, fewer adverse events, and reduced overall cost of care. However, despite marked advances in device design and clinical management, determining MCS candidacy is often difficult and requires the integration of clinical, biomarker, imaging, exercise, and hemodynamic data. This review aims to provide a summary of the current use of short-term and durable MCS devices in the treatment of advanced-stage HF, highlighting several aspects of LVAS support and the challenges that remain.

To understand the challenges for thoracic transplantation and mechanical circulatory support during the current coronavirus disease 2019 pandemic, we propose separating the effects of the pandemic into 5 distinct stages from a healthcare system perspective. We discuss how the classical ethical principles of utility, justice, and efficiency may need to be adapted, and we give specific recommendations for thoracic transplantation and mechanical circulatory support centers to balance their clinical decisions and strategies for advanced heart and lung disease during the current pandemic.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Author(s): Anker, Stefan D; Butler, Javed; Khan, Muhammad Shahzeb; Abraham, William T; Bauersachs, Johann; Bocchi, Edimar; Bozkurt, Biykem; Braunwald, Eugene; Chopra, Vijay K; Cleland, John G; Ezekowitz, Justin; Filippatos, Gerasimos; Friede, Tim; Hernandez, Adrian F; Lam, Carolyn SP; Lindenfeld, JoAnn; McMurray, John JV; Mehra, Mandeep; Metra, Marco; Packer, Milton; Pieske, Burkert; Pocock, Stuart J; Ponikowski, Piotr; Rosano, Giuseppe MC; Teerlink, John R; Tsutsui, Hiroyuki; Van Veldhuisen, Dirk J; Verma, Subodh; Voors, Adriaan A; Wittes, Janet; Zannad, Faiez; Zhang, Jian; Seferovic, Petar; Coats, Andrew JS | Abstract: 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.