Publications by authors named "Mandeep R Mehra"

386 Publications

Machine learning, artificial intelligence and mechanical circulatory support: A primer for clinicians.

J Heart Lung Transplant 2021 Feb 27. Epub 2021 Feb 27.

Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts. Electronic address:

Artificial intelligence (AI) refers to the ability of machines to perform intelligent tasks, and machine learning (ML) is a subset of AI describing the ability of machines to learn independently and make accurate predictions. The application of AI combined with "big data" from the electronic health records, is poised to impact how we take care of patients. In recent years, an expanding body of literature has been published using ML in cardiovascular health care, including mechanical circulatory support (MCS). This primer article provides an overview for clinicians on relevant concepts of ML and AI, reviews predictive modeling concepts in ML and provides contextual reference to how AI is being adapted in the field of MCS. Lastly, it explains how these methods could be incorporated in the practices of medicine to improve patient outcomes.
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http://dx.doi.org/10.1016/j.healun.2021.02.016DOI Listing
February 2021

Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.

J Heart Lung Transplant 2021 Feb 22. Epub 2021 Feb 22.

Division of Cardiology, Duke University School of Medicine, Durham, North Carolina.

Background: Several distinctly engineered left ventricular assist devices (LVADs) are in clinical use. However, contemporaneous real world comparisons have not been conducted, and clinical trials were not powered to evaluate differential survival outcomes across devices.

Objectives: Determine real world survival outcomes and healthcare expenditures for commercially available durable LVADs.

Methods: Using a retrospective observational cohort design, Medicare claims files were linked to manufacturer device registration data to identify de-novo, durable LVAD implants performed between January 2014 and December 2018, with follow-up through December 2019. Survival outcomes were compared using a Cox proportional hazards model stratified by LVAD type and validated using propensity score matching. Healthcare resource utilization was analyzed across device types by using nonparametric bootstrap analysis methodology. Primary outcome was survival at 1-year and total Part A Medicare payments.

Results: A total of 4,195 de-novo LVAD implants were identified in fee-for-service Medicare beneficiaries (821 HeartMate 3; 1,840 HeartMate II; and 1,534 Other-VADs). The adjusted hazard ratio for mortality at 1-year (confirmed in a propensity score matched analysis) for the HeartMate 3 vs HeartMate II was 0.64 (95% CI; 0.52-0.79, p< 0.001) and for the HeartMate 3 vs Other-VADs was 0.51 (95% CI; 0.42-0.63, p < 0.001). The HeartMate 3 cohort experienced fewer hospitalizations per patient-year vs Other-VADs (respectively, 2.8 vs 3.2 EPPY hospitalizations, p < 0.01) and 6.1 fewer hospital days on average (respectively, 25.2 vs 31.3 days, p < 0.01). The difference in Medicare expenditures, conditional on survival, for HeartMate 3 vs HeartMate II was -$10,722, p < 0.001 (17.4% reduction) and for HeartMate 3 vs Other-VADs was -$17,947, p < 0.001 (26.1% reduction).

Conclusions: In this analysis of a large, real world, United States. administrative dataset of durable LVADs, we observed that the HeartMate 3 had superior survival, reduced healthcare resource use, and lower healthcare expenditure compared to other contemporary commercially available LVADs.
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http://dx.doi.org/10.1016/j.healun.2021.02.010DOI Listing
February 2021

A principal components analysis of factors associated with successful implementation of an LVAD decision support tool.

BMC Med Inform Decis Mak 2021 Mar 20;21(1):106. Epub 2021 Mar 20.

Center for Medical Ethics and Health Policy, Baylor College of Medicine, One Baylor Plaza MC: 420, Houston, TX, 77030, USA.

Background: A central goal among researchers and policy makers seeking to implement clinical interventions is to identify key facilitators and barriers that contribute to implementation success. Despite calls from a number of scholars, empirical insights into the complex structural and cultural predictors of why decision aids (DAs) become routinely embedded in health care settings remains limited and highly variable across implementation contexts.

Methods: We examined associations between "reach", a widely used indicator (from the RE-AIM model) of implementation success, and multi-level site characteristics of nine LVAD clinics engaged over 18 months in implementation and dissemination of a decision aid for left ventricular assist device (LVAD) treatment. Based on data collected from nurse coordinators, we explored factors at the level of the organization (e.g. patient volume), patient population (e.g. health literacy; average sickness level), clinician characteristics (e.g. attitudes towards decision aid; readiness for change) and process (how the aid was administered). We generated descriptive statistics for each site and calculated zero-order correlations (Pearson's r) between all multi-level site variables including cumulative reach at 12 months and 18 months for all sites. We used principal components analysis (PCA) to examine any latent factors governing relationships between and among all site characteristics, including reach.

Results: We observed strongest inclines in reach of our decision aid across the first year, with uptake fluctuating over the second year. Average reach across sites was 63% (s.d. = 19.56) at 12 months and 66% (s.d. = 19.39) at 18 months. Our PCA revealed that site characteristics positively associated with reach on two distinct dimensions, including a first dimension reflecting greater organizational infrastructure and standardization (characteristic of larger, more established clinics) and a second dimension reflecting positive attitudinal orientations, specifically, openness and capacity to give and receive decision support among coordinators and patients.

Conclusions: Successful implementation plans should incorporate specific efforts to promote supportive and mutually informative interactions between clinical staff members and to institute systematic and standardized protocols to enhance the availability, convenience and salience of intervention tool in routine practice. Further research is needed to understand whether "core predictors" of success vary across different intervention types.
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http://dx.doi.org/10.1186/s12911-021-01468-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980808PMC
March 2021

Advanced cancer is also a heart failure syndrome: a hypothesis.

J Cachexia Sarcopenia Muscle 2021 Mar 18. Epub 2021 Mar 18.

Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (Campus CVK), Berlin, Germany.

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilatation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology.
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http://dx.doi.org/10.1002/jcsm.12694DOI Listing
March 2021

The management of secondary mitral regurgitation in patients with heart failure: a joint position statement from the Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), and European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Eur Heart J 2021 Mar 18. Epub 2021 Mar 18.

Department of Cardiology, St Thomas' Hospital, Westminster Bridge Road, London, UK.

Secondary (or functional) mitral regurgitation (SMR) occurs frequently in chronic heart failure (HF) with reduced left ventricular (LV) ejection fraction, resulting from LV remodelling that prevents coaptation of the valve leaflets. Secondary mitral regurgitation contributes to progression of the symptoms and signs of HF and confers worse prognosis. The management of HF patients with SMR is complex and requires timely referral to a multidisciplinary Heart Team. Optimization of pharmacological and device therapy according to guideline recommendations is crucial. Further management requires careful clinical and imaging assessment, addressing the anatomical and functional features of the mitral valve and left ventricle, overall HF status, and relevant comorbidities. Evidence concerning surgical correction of SMR is sparse and it is doubtful whether this approach improves prognosis. Transcatheter repair has emerged as a promising alternative, but the conflicting results of current randomized trials require careful interpretation. This collaborative position statement, developed by four key associations of the European Society of Cardiology-the Heart Failure Association (HFA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association of Cardiovascular Imaging (EACVI), and European Heart Rhythm Association (EHRA)-presents an updated practical approach to the evaluation and management of patients with HF and SMR based upon a Heart Team approach.
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http://dx.doi.org/10.1093/eurheartj/ehab086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014526PMC
March 2021

Heart failure re-hospitalizations and subsequent fatal events in coronary artery disease: insights from COMMANDER-HF, EPHESUS, and EXAMINE.

Clin Res Cardiol 2021 Mar 8. Epub 2021 Mar 8.

Centre d'investigations Cliniques Plurithématique, Inserm 1433, Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, CHRU Nancy-Hopitaux de Brabois, 4 rue du Morvan, 54500, Nancy, Vandoeuvre les Nancy, France.

Background: Patients with coronary artery disease (CAD) are at increased risk of developing and being hospitalised for heart failure (HFH). However, the risk of HFH versus ischemic events may vary among patients with CAD, depending on whether acute myocardial infarction (MI), left ventricular dysfunction or decompensated HF is present at baseline.

Aims: We aim to explore the risk of non-fatal events (HFH, MI, stroke) and subsequent death in 3 landmark trials, COMMANDER-HF, EPHESUS and EXAMINE that, together, included patients with CAD with and without reduced ejection fraction and acute MI.

Methods: Events, person-time metrics and time-updated Cox models.

Results: In COMMANDER-HF the event-rate for the composite of AMI, stroke or all-cause death was 13.5 (12.8-14.3) events/100 py. Rates for AMI and stroke were much lower (2.2 [2.0-2.6] and 1.3 [1.1-1.6] events/100 py, respectively) than the rate of HFH (16.9 [16.1-17.9] events/100 py). In EPHESUS, the rates of MI and stroke were also lower than the rate of HFH: 7.2 (6.7-7.8), 1.9 (1.7-2.3), and 10.6 (9.9-11.3) events/100 py, but this was not true for EXAMINE with 4.4 (4.0-4.9), 0.7 (0.6-0.9), and 2.4 (2.0-2.7) events/100 py, respectively. In all 3 trials, a non-fatal event (HFH, MI or stroke) during follow-up doubled the risk of subsequent mortality. This most commonly followed a HFH.

Conclusions: A first or recurrent HFH is common in patients with CAD and AMI or HFrEF and indicates a poor prognosis. Preventing the development of heart failure after AMI and control of congestion in patients with CAD and HFrEF are key unmet needs and therapeutic targets.

Registration: ClinicalTrials.gov Identifier: NCT01877915. URL: https://clinicaltrials.gov/ct2/show/NCT01877915 .
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http://dx.doi.org/10.1007/s00392-021-01830-1DOI Listing
March 2021

Hypokalemia in heart failure: A low or a high point?

Eur J Prev Cardiol 2020 Mar 22. Epub 2020 Mar 22.

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http://dx.doi.org/10.1177/2047487320914745DOI Listing
March 2020

Impact of Geographic Region on the COMMANDER-HF Trial.

JACC Heart Fail 2021 Mar 3;9(3):201-211. Epub 2021 Feb 3.

Centre d'Investigations Cliniques Plurithématique, Université de Lorraine, Inserm 1433, Nancy, France, Centre Hospitalier Régional Universitaire (CHRU) de Nancy, Inserm U1116, Nancy, France, French Clinical Research Infrastructure Network Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France.

Objectives: This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial.

Background: Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results.

Methods: Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America.

Results: Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interaction = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interaction = 0.017).

Conclusions: In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915).
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http://dx.doi.org/10.1016/j.jchf.2020.11.007DOI Listing
March 2021

Heart transplantation candidacy.

Curr Opin Organ Transplant 2021 Feb;26(1):69-76

Heart and Vascular Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1097/MOT.0000000000000828DOI Listing
February 2021

Expanded Access Programs, compassionate drug use, and Emergency Use Authorizations during the COVID-19 pandemic.

Drug Discov Today 2021 02 27;26(2):593-603. Epub 2020 Nov 27.

National Coalition on Health Care, Washington, DC, USA.

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.
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http://dx.doi.org/10.1016/j.drudis.2020.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694556PMC
February 2021

Advanced cancer is also a heart failure syndrome: a hypothesis.

Eur J Heart Fail 2021 Jan;23(1):140-144

Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (Campus CVK), Berlin, Germany.

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilatation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology.
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http://dx.doi.org/10.1002/ejhf.2071DOI Listing
January 2021

Citizenship Status and Cardiothoracic Organ Transplantation in the United States.

Circ Heart Fail 2020 12 9;13(12):e007788. Epub 2020 Nov 9.

Cardiovascular Division (M.R.M., M.V.), Brigham and Women's Hospital, Boston, MA.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007788DOI Listing
December 2020

Characteristics Associated With High-Performing Pediatric Heart Transplant Centers in the United States From 2006 to 2015.

JAMA Netw Open 2020 11 2;3(11):e2023515. Epub 2020 Nov 2.

Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.

Importance: Differences among pediatric transplant centers in long-term survival of pediatric recipients of heart transplants can be mostly explained by differences in 90-day mortality.

Objective: To understand characteristics associated with high-performing pediatric HT centers by comparing key outcomes among centers stratified by 90-day risk-adjusted mortality.

Design, Setting, And Participants: This retrospective cohort study included recipients of HT aged younger than 18 years in the US. Analyses included 44 US centers during 2006 to 2015 using the Organ Procurement and Transplant Network database. A risk model for 90-day mortality was developed using data from all recipients to estimate expected 90-day mortality and 90-day standardized mortality ratio (SMR; calculated as observed mortality divided by expected mortality) for each center. Centers were stratified into tertiles by SMR and compared for key outcomes. Data were analyzed from January to March 2020.

Exposures: High-, medium-, and low-performing centers (SMR tertile).

Main Outcomes And Measures: Posttransplant 90-day mortality across recipient risk spectrum and incidence of and mortality following early posttransplant complications.

Results: Of 3211 children analyzed, 1016 (31.6%) were infants younger than 1 year and 1459 (45.4%) were girls. The median (interquartile range) age was 4 (0-12) years. Centers were stratified by SMR tertile, and SMR was 0 to 0.71 among 15 high-performing centers, 0.79 to 1.12 among 14 medium-performing centers, and 1.19 to 3.33 among 15 low-performing centers. High-performing centers had 90-day mortality of 0.8% (95% CI, 0.3%-1.8%) in children with low risk and expected mortality of 2.0%, 2.3% (95% CI, 0.6%-5.7%) in children with intermediate risk and expected mortality of 6.5%, and 16.7% (95% CI, 7.9%-29.3%) in children with high risk and expected mortality of 30.8%. Incidence of acute rejection during transplant hospitalization was 10.3% at high-performing centers, 10.3% at medium-performing centers, and 9.7% at low-performing centers (P for trend = .68), and incidence of post-HT kidney failure requiring dialysis was 4.1% at high-performing centers, 5.2% at medium-performing centers, and 8.5% at low-performing centers (P for trend = .001). Ninety-day mortality was significantly lower at high-performing centers among children treated for rejection (high-performing: 2.0%; medium-performing: 6.9%; low-performing: 11.7%; P for trend = .006) and among recipients receiving dialysis for post-HT kidney failure (high-performing: 17.5%; medium-performing: 39.4%; low-performing: 47.6%; P for trend < .001).

Conclusions And Relevance: This cohort study found that high-performing pediatric HT centers had lower 90-day mortality across the recipient risk spectrum and lower mortality among recipients who develop rejection or post-HT kidney failure during transplant hospitalization. These findings suggest presence of superior processes and systems of care at high-performing pediatric HT centers.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.23515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607438PMC
November 2020

Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: a cross sectional analysis.

Am Heart J 2021 02 26;232:105-115. Epub 2020 Oct 26.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1016/j.ahj.2020.10.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586939PMC
February 2021

Hemocompatibility-Related Adverse Events and Survival on Venoarterial Extracorporeal Life Support: An ELSO Registry Analysis.

JACC Heart Fail 2020 11;8(11):892-902

Smith Center for Outcomes Research in Cardiology, Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address:

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 <0.001), but rates of medical bleeding and ischemic stroke remained stable. HRAEs had a cumulative association with mortality in adjusted analysis: 1 event, odds ratio (OR) of 1.43; 2 events, OR of 1.86; ≥3 events, OR of 3.27 (p < 0.001 for all). HRAEs most strongly associated with mortality were medical bleeding, including intracranial (OR: 7.71), pulmonary (OR: 3.08), and gastrointestinal (OR: 1.95) hemorrhage and ischemic stroke (OR: 2.31); p < 0.001 for all. Risk factors included the following: for bleeding: older age, lower pH, and female sex; for thrombosis: younger age, male sex, Asian race, and non-polymethylpentene oxygenator; and for both: time on ECLS, central cannulation, and renal failure.

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.
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http://dx.doi.org/10.1016/j.jchf.2020.09.004DOI Listing
November 2020

Transcatheter mitral valve intervention in advanced heart failure.

J Heart Lung Transplant 2020 12 17;39(12):1363-1365. Epub 2020 Sep 17.

Edward Hospital Center for Advanced Heart Failure, Advocate Heart Institute, Naperville, Illinois.

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http://dx.doi.org/10.1016/j.healun.2020.09.004DOI Listing
December 2020

Implications of obesity across the heart failure continuum.

Prog Cardiovasc Dis 2020 Sep - Oct;63(5):561-569. Epub 2020 Sep 28.

Department of Cardiovascular Diseases; John Ochsner Heart and Vascular Institute, Ochsner Clinical School-the University of Queensland School of Medicine, New Orleans, LA, United States of America.

The obesity paradox, which suggests a survival advantage for the obese in heart failure (HF) has sparked debate in the medical community. Studies demonstrate a survival advantage in obese patients with HF, including those with advanced HF requiring continuous inotropic support for palliation or disease modifying therapy with a left ventricular assist device (LVAD) or heart transplantation (HT). Importantly, the obesity paradox is affected by the level of cardiorespiratory fitness (CRF). It is now recommended that HF patients with body mass index ≥35 kg/m achieve at least 5-10% weight loss, in order to improve symptoms and cardiac function, though more robust data are urgently needed. CRF may be the single best predictor of overall health and small improvements in fitness levels may lead to improved outcomes in HF. In addition to implications of obesity in chronic HF, we also discuss management of obese patients with advanced HF and their implications for therapies such as LVAD implantation and HT.
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http://dx.doi.org/10.1016/j.pcad.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521376PMC
December 2020

Mechanical circulatory support devices in advanced heart failure: 2020 and beyond.

Prog Cardiovasc Dis 2020 Sep - Oct;63(5):630-639. Epub 2020 Sep 21.

Heart and Vascular Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pcad.2020.09.003DOI Listing
December 2020

Redefining Left Ventricular Assist Device Indications and Strategies-Reply.

JAMA Cardiol 2021 Jan;6(1):120-121

Montefiore Einstein Center for Heart and Vascular Care, New York, New York.

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http://dx.doi.org/10.1001/jamacardio.2020.4323DOI Listing
January 2021

Plasma D-dimer concentrations predicting stroke risk and rivaroxaban benefit in patients with heart failure and sinus rhythm: an analysis from the COMMANDER-HF trial.

Eur J Heart Fail 2020 Sep 21. Epub 2020 Sep 21.

Université de Lorraine, Centre d'Investigations Cliniques Plurithématique Inserm 1433, Nancy, France; CHRU de Nancy, Inserm U1116, Nancy, France; FCRIN INI-CRCT, Nancy, France.

Aims: D-dimer is a marker of fibrin degradation that reflects intravascular coagulation. Therefore, plasma concentrations of D-dimer might predict thromboembolic risk and rivaroxaban treatment effect. The aims of this study were to investigate the association between D-dimer levels and the risk of stroke and other thrombotic, bleeding and fatal events, and whether D-dimer concentrations could predict rivaroxaban 2.5 mg twice daily (vs. placebo) effect in patients enrolled in the COMMANDER-HF trial who were in sinus rhythm, had heart failure with reduced ejection fraction and coronary artery disease.

Methods And Results: Survival models with treatment-by-plasma D-dimer interaction. Baseline measurement of D-dimer was available in 4107 (82%) of 5022 patients enrolled. Median (percentile ) follow-up was 21 (12.9-32.8) months. The median (percentile ) plasma concentration of D-dimer was 360 (215-665) ng/mL. The D-dimer tertiles were: (i) ≤255 ng/mL; (ii) 256-515 ng/mL; and (iii) >515 ng/mL. Patients within the tertile 3 were older, and had lower body mass index, blood pressure, haemoglobin, estimated glomerular filtration rate, and left ventricular ejection fraction. Higher plasma D-dimer concentrations were independently associated with higher rates of death, stroke, and venous thromboembolism. For example, the all-cause death adjusted hazard ratio (HR) (95%CI) of tertile 3 vs. tertile 1 was 1.77 [95% confidence interval (CI) 1.48-2.11; P < 0.001]. The effect of rivaroxaban was similar in each tertile of D-dimer for all outcomes except stroke. Patients within the tertile 3 had the greatest absolute and relative stroke reduction (tertile 1: HR 1.16, 95% CI 0.49-2.74; tertile 2: HR 1.45, 95% CI 0.77-2.73; tertile 3: HR 0.36, 95% CI 0.18-0.70; P for interaction = 0.008). The number-needed-to-treat to prevent one stroke in tertile 3 was 36.

Conclusions: In COMMANDER-HF, rivaroxaban reduced the risk of stroke but the benefit may be confined to patients with D-dimer concentrations above 515 ng/mL. Prospective trials are warranted to confirm these findings.
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http://dx.doi.org/10.1002/ejhf.2003DOI Listing
September 2020

Cocaine use in organ donors and long-term outcome after heart transplantation: An International Society for Heart and Lung Transplantation registry analysis.

J Heart Lung Transplant 2020 12 2;39(12):1341-1350. Epub 2020 Sep 2.

Heart and Vascular Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: 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.

Methods: 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.

Results: 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; p < 0.001), 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.healun.2020.08.018DOI Listing
December 2020

Secular changes in organ donor profiles and impact on heart and lung transplantation.

J Heart Lung Transplant 2020 10 15;39(10):997-1002. Epub 2020 Aug 15.

Department of Medicine, Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.healun.2020.08.004DOI Listing
October 2020

Authors' Reply to Vrachatis et al. "Pharmaco-Immunomodulatory Therapy I COVID-19".

Drugs 2020 09;80(14):1501-1503

Division of Infectious Diseases, Department of Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA.

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http://dx.doi.org/10.1007/s40265-020-01396-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471515PMC
September 2020

Defining chronic rejection in vascularized composite allotransplantation-The American Society of Reconstructive Transplantation and International Society of Vascularized Composite Allotransplantation chronic rejection working group: 2018 American Society of Reconstructive Transplantation meeting report and white paper Research goals in defining chronic rejection in vascularized composite allotransplantation.

SAGE Open Med 2020 14;8:2050312120940421. Epub 2020 Jul 14.

Department of Transplantation, Nephrology and Clinical Immunology, Ed. Herriot Hospital, Lyon, France.

Objectives: This report summarizes a collaborative effort between the American Society of Reconstructive Transplantation and the International Society of Vascularized Composite Allotransplantation to establish what is known about chronic rejection in recipients of vascularized composite allografts, with an emphasis on upper extremity and face transplants. As a picture of chronic rejection in hand and face vascularized composite allografts emerges, the results will be applied to other types of vascularized composite allografts, such as uterine transplantation.

Methods: The overall goal is to develop a definition of chronic rejection in vascularized composite allografts so that we can establish longitudinal correlates of factors such as acute rejection, immunosuppressive therapy, de novo donor-specific antibody and trauma/infection and other external factors on the development of chronic rejection. As Dr Kanitakis eloquently stated at the 2017 International Society of Vascularized Composite Allotransplantation meeting in Salzburg, "Before we can correlate causative factors of chronic rejection, we have to define what chronic rejection in VCA is."

Results: The first meeting report was presented at the sixth Biennial meeting of the American Society of Reconstructive Transplantation in November 2018. Based on collaborative efforts and descriptions of clinical cases of chronic rejection in vascularized composite allograft recipients, a working definition of chronic rejection in vascularized composite allografts with respect to overt functional decline, subclinical functional decline, histologic evidence without functional decline, and normal allograft function in the absence of histologic evidence of chronic rejection is proposed.

Conclusions: It is the intent of this collaborative working group that these working definitions will help to focus ongoing research to define the incidence, risk factors and treatment regimens that will identify mechanisms of chronic rejection in vascularized composite allografts. As with all good research, our initial efforts have generated more questions than answers. We hope that this is the first of many updates.
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http://dx.doi.org/10.1177/2050312120940421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361482PMC
July 2020

Pharmaco-Immunomodulatory Therapy in COVID-19.

Drugs 2020 Sep;80(13):1267-1292

Division of Infectious Diseases, Department of Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA.

The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness is a syndrome of viral replication in concert with a host inflammatory response. The cytokine storm and viral evasion of cellular immune responses may play an equally important role in the pathogenesis, clinical manifestation, and outcomes of COVID-19. Systemic proinflammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Immune modulators have the potential to inhibit cytokines and treat the cytokine storm. A literature search using PubMed, Google Scholar, and ClinicalTrials.gov was conducted through 8 July 2020 using the search terms 'coronavirus', 'immunology', 'cytokine storm', 'immunomodulators', 'pharmacology', 'severe acute respiratory syndrome 2', 'SARS-CoV-2', and 'COVID-19'. Specific immune modulators include anti-cytokines such as interleukin (IL)-1 and IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab, siltuximab), Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib), anti-tumor necrosis factor-α (e.g. adalimumab, infliximab), granulocyte-macrophage colony-stimulating factors (e.g. gimsilumab, lenzilumab, namilumab), and convalescent plasma, with promising to negative trials and other data. Non-specific immune modulators include human immunoglobulin, corticosteroids such as dexamethasone, interferons, statins, angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin), hydroxychloroquine and chloroquine, colchicine, and prostaglandin D2 modulators such as ramatroban. Dexamethasone 6 mg once daily (either by mouth or by intravenous injection) for 10 days may result in a reduction in mortality in COVID-19 patients by one-third for patients on ventilators, and by one-fifth for those receiving oxygen. Research efforts should focus not only on the most relevant immunomodulatory strategies but also on the optimal timing of such interventions to maximize therapeutic outcomes. In this review, we discuss the potential role and safety of these agents in the management of severe COVID-19, and their impact on survival and clinical symptoms.
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http://dx.doi.org/10.1007/s40265-020-01367-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372203PMC
September 2020

Extrapulmonary manifestations of COVID-19.

Nat Med 2020 07 10;26(7):1017-1032. Epub 2020 Jul 10.

Division of Nephrology, Department of Medicine, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

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.
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http://dx.doi.org/10.1038/s41591-020-0968-3DOI Listing
July 2020

Myocardial edema in COVID-19 on cardiac MRI.

J Heart Lung Transplant 2020 07 28;39(7):730-732. Epub 2020 May 28.

Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.healun.2020.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834291PMC
July 2020

Obesity and Outcomes in COVID-19: When an Epidemic and Pandemic Collide.

Mayo Clin Proc 2020 07 19;95(7):1445-1453. Epub 2020 May 19.

Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.

Obesity has reached epidemic proportions in the United States and in much of the westernized world, contributing to considerable morbidity. Several of these obesity-related morbidities are associated with greater risk for death with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 penetrates human cells through direct binding with angiotensin-converting enzyme 2 receptors on the cell surface. Angiotensin-converting enzyme 2 expression in adipose tissue is higher than that in lung tissue, which means that adipose tissue may be vulnerable to COVID-19 infection. Obese patients also have worse outcomes with COVID-19 infection, including respiratory failure, need for mechanical ventilation, and higher mortality. Clinicians need to be more aggressive when treating obese, especially severely obese, patients with COVID-19 infection.
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http://dx.doi.org/10.1016/j.mayocp.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236707PMC
July 2020

A proposed strategy for management of immunosuppression in heart transplant patients with COVID-19.

Clin Transplant 2020 11 7;34(11):e14032. Epub 2020 Oct 7.

Center for Advanced Heart Disease, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

There is limited experience in management of orthotopic heart transplant (OHT) patients with COVID-19. In this study, we present our initial experience using a standardized management algorithm. Data collection was performed on OHT patients with COVID-19 after March 10, 2020 (declaration of state of emergency in Massachusetts). Among the 358 OHT patients currently followed at our program, 5 patients (1.4%) tested positive for COVID-19 (median age 50 years [IQR, 49-58], duration post-OHT 21 years [IQR, 6-25], and 4 of 5 [80%] were men). Among the 5 OHT patients, 2 of 5 (20%) had mild disease and had no change in baseline immunosuppression therapy. Two of 5 (20%) had moderate disease and received remdesivir as part of a clinical trial and reduced immunosuppression therapy. One patient (20%) died prior to presenting to the hospital, consistent with 20% case fatality rate. Four patients (80%) are doing well 4 weeks post-discharge. In this small cohort of OHT patients with COVID-19, we report a 1.4% COVID-19 infection rate and 20% case fatality rate. All OHT patients managed under our clinical management algorithm had good short-term outcomes. Further study to estimate the true risk profile of OHT patients and validate the proposed management strategy is warranted.
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http://dx.doi.org/10.1111/ctr.14032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361140PMC
November 2020