Anita Szady

Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary Left Ventricular Assist Devices

Background— Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results— In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions— In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.

Phase II Clinical Research Design in Cardiology Learning the Right Lessons Too Well: Observations and Recommendations From the Cardiovascular Cell Therapy Research Network (CCTRN)

Clinical trials demonstrate the best of medical expertise and epidemiological elegance. From the simple building blocks of contemporaneous control groups, randomization, and blinding, they assemble a clear picture of the nature of the treatment-effect relationship. This accomplishment has earned them the star ascendant position in cardiovascular research. Their advantage was demonstrated with Bradford Hill’s work on streptomycin, and as knowledge of the pathogenesis of atherosclerotic disease produced possibilities for new treatments, cardiovascular researchers applied this new research tool to identify effective therapies in a sequential approach (Figure 1). Figure 1. The traditional phases of clinical trials. *The study takes place before Food and Drug Administration approval. This work accelerated with clinical trials demonstrating treatment benefits for chronic diseases such as hypertension,1,2 lipid abnormalities,3,4 and heart failure,5,6 cementing their role in identifying new therapies to prevent the sequela of cardiovascular disease in vulnerable populations. However, the limitations of early clinical trial interpretation also appeared. The findings of the Multiple Risk Factor Intervention Trial (MRFIT),7 the International Verapamil SR/Trandolapril Study (INVEST),8,9 the Early Versus Late Intervention Trial With Estradiol (ELITE),7,10 the Cardiac Arrhythmia Suppression Trial (CAST),11,12 and the US Carvedilol program controversy13–19 together served to undermine the confidence of cardiologists in the interpretation of clinical trial results. Thought leaders in the field identified the interpretation problem (ie, the hyperreliance on P values to reflect positive results for any analysis in a clinical trial) and called for a fundamental change in the design and analysis of clinical trials. Subsequent work produced the following clinical trials principles: (1)There should be clear and prospective declaration in the written protocol about all important aspects of the clinical trial with particular emphasis on the end points …

Cardiovascular Events in a Physical Activity Intervention Compared With a Successful Aging Intervention: The LIFE Study Randomized Trial

IMPORTANCE Whether sustained physical activity prevents cardiovascular disease (CVD) events in older adults is uncertain. OBJECTIVE To test the hypothesis that cardiovascular morbidity and mortality would be reduced in participants in a long-term physical activity program. DESIGN, SETTING, AND PARTICIPANTS The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial. Participants were recruited at 8 centers in the United States. We randomized 1635 sedentary men and women aged 70 to 89 years with a Short Physical Performance Battery (SPPB) score of 9 or less but able to walk 400 m. INTERVENTIONS The physcial activity (PA) intervention was a structured moderate-intensity program, predominantly walking 2 times per week on site for 2.6 years on average. The successful aging intervention consisted of weekly health education sessions for 6 months, then monthly. MAIN OUTCOMES AND MEASURES Total CVD events, including fatal and nonfatal myocardial infarction, angina, stroke, transient ischemic attack, and peripheral artery disease, were adjudicated by committee, and silent myocardial infarction was assessed by serial electrocardiograms. A limited outcome of myocardial infarction, stroke, and CVD death was also studied. Outcome assessors and adjudicators were blinded to intervention assignment. RESULTS The 1635 LIFE study participants were predominantly women (67%), with a mean (SD) age of 78.7 (5.2) years; 20% were African-American, 6% were Hispanic or other race or ethnic group, and 74% were non-Latino white. New CVD events occurred in 121 of 818 PA participants (14.8%) and 113 of 817 successful aging participants (13.8%) (HR, 1.10; 95% CI, 0.85-1.42). For the more focused combined outcome of myocardial infarction, stroke, or cardiovascular death, rates were 4.6% in PA and 4.5% in the successful aging group (HR, 1.05; 95% CI, 0.67-1.66). Among frailer participants with an SPPB score less than 8, total CVD rates were 14.2% in PA vs 17.7% in successful aging (HR, 0.76; 95% CI, 0.52-1.10), compared with 15.3% vs 10.5% among those with an SPPB score of 8 or 9 (HR, 1.59; 95% CI, 1.09-2.30) (P for interaction = .006). With the limited end point, the interaction was not significant (P = .59), with an HR of 0.94 (95% CI, 0.50-1.75) for an SPPB score less than 8 and an HR of 1.20 (95% CI, 0.62-2.34) for an SBBP score of 8 or 9. CONCLUSIONS AND RELEVANCE Among participants in the LIFE Study, an aerobically based, moderately intensive PA program was not associated with reduced cardiovascular events in spite of the interventions previously documented ability to prevent mobility disability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116194.

Diuretics in Heart Failure: A Critical Appraisal of Efficacy and Tolerability

Heart failure is a significant cause of morbidity and mortality worldwide. While the aetiology varies and there are a wide variety of treatment options, a large amount of the morbidity related to heart failure is due to fluid retention and the symptoms of volume overload. Multiple neurohormonal pathways are activated in heart failure, and contribute to the symptoms of fluid retention and volume overload. Although not ideal, diuretic therapy is one of the mainstays of treatment of fluid overload in patients with heart failure. This review focuses on the pathophysiology of heart failure leading to volume overload, the different classes of diuretics used in alleviating the symptoms of fluid retention, their mechanisms of action within the kidney, and strategies for using them in ways that minimize their deleterious effects in patients with heart failure.

Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary LVADs

Background— Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results— In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions— In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.

A training program in cardiovascular cell-based therapy: from the NHLBI Cardiovascular Cell Therapy Research Network

Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician-scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs.

GLOBAL LONGITUDINAL STRAIN IN PATIENTS WITH NEW LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AFTER ANTICANCER TARGETED THERAPIES

Background: Reductions in global longitudinal strain (GLS) may be observed prior to the onset of systolic dysfunction in patients receiving trastuzumab and anthracycline agents and has been targeted as a method of early detection of cardiotoxicity. Data on cardiotoxicity in the setting of non-

Abstract 987: Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors

INTRODUCTION: Unanticipated cardiotoxicity is now identified as a significant clinical problem associated with new anti-cancer targeted agents. Risk factors and natural history are still poorly understood. We aim to determine potential clinical risk factors for cardiotoxicity among patients with hematologic malignancies (HM) who were treated with targeted therapies over a 10-year period. METHODS: We used 114 diagnosis codes for HM and 17 codes for cardiac diseases in order to identify patients in our electronic medical records (EPIC) and identify patients with HM who met above criteria. Cardiotoxicity was defined mainly by left ventricular ejection fraction (LVEF) of RESULTS: Of 820 patients with both HM and cardiac diagnosis, 29 patients developed cardiotoxicity after initiation of targeted therapies. We selected 70 matched controls based on type of targeted therapy. In the study group, the median time from exposure to cardiac event was 120 days (range, 1-1176). Significantly higher number of patients had prior exposure to anthracyclines in study versus control group (65.5% vs 42.8%, P=0.04), however, this was not significant in multivariable analysis. Multiple other variables, including traditional risk factors for heart disease, were analyzed and did not differ significantly between the two groups. Only two variables remained significant in the multivariable analysis, including prior history of DVT/PE (OR 4.88, 95% CI: 1.44-16.54, P=0.011), and Karnofsky score of ≥80% (OR 3.99, 95% CI: 1.51-10.6, P= 0.005). With median follow-up of 27 months (range, 1-120), 17 patients in the study group died, but only 2 of cardiac causes. Repeat echocardiograms showed worsening of LVEF in 4 patients while stable/improved in 23 patients, and 21 patients were able to receive further chemotherapy. There was a trend towards worse overall survival in the study group (P= 0.071). CONCLUSIONS: About 3.5% of patients with HM experience unanticipated cardiotoxicity due to targeted anti-cancer agents with related mortality of 6.8 %. Most patients do well with stable compensated cardiac function and 35% have an objective improvement in LVEF. Risk of cardiotoxicity was significantly higher in patients with known history of DVT/PE. Future studies of possible underlying genetic predisposition will be of great importance. Citation Format: Chintan Shah, Yan Gong, Anita Szady, Qian Sun, carl J. Pepine, Taimour Langaee, Alexandra R. Lucas, Jan S. Moreb. Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2017-987

Abstract 1431: Incidence and natural history of cardiovascular toxicity associated with biologic and targeted therapies used in hematologic malignancies

INTRODUCTION: Unanticipated cardiac toxicity has been reported with anti cancer targeted and biological treatments. In this retrospective study, we aim at identifying the number of cardiac toxicity cases among patients with hematologic malignancies (HM) who were treated with targeted therapies over 10-year period with emphasis on natural history and outcomes. METHODS: With the help of the Faculty Practice Decision Support (FPDS) team, we used 114 diagnosis codes for HM and 17 codes for cardiac diseases in order to mine our electronic medical records (EPIC) and identify patients with HM and specific cardiac problems, then sorted them according to whether they received known biologic agents such as thymidine kinase inhibitors (TKIs), proteasome inhibitors, monoclonal antibodies, hypomethylating agents, and immunomodulatory drugs. RESULTS: FPDS team provided us with a file that contained medical records of 820 patients that had both HM and cardiac abnormalities. We pulled out 53 patients who received the drugs of interest. We were able to confirm cardiac toxicity defined mainly by left ventricular ejection fraction (LVEF) of CONCLUSIONS: About 4.1% of patients with HM experience unanticipated cardiac toxicity with related mortality of 17.6%. Most patients do well with stable compensated cardiac function with objective improvement in LVEF. Whether Rituximab can cause cardiac toxicity is controversial and we will present specific arguments. Citation Format: Jan S. Moreb, Haneen Mohammad, Lindsay McCullough, Anita Szady, Leslie Pettiford, Alexandra Lucas. Incidence and natural history of cardiovascular toxicity associated with biologic and targeted therapies used in hematologic malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1431.

Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary Left Ventricular Assist DevicesCLINICAL PERSPECTIVE

Background— Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results— In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions— In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.