Coronavirus disease 2019 in heart transplant recipients: Risk factors, immunosuppression, and outcomes.

BACKGROUND: COVID-19 continues to inflict significant morbidity and mortality, particularly on patients with preexisting health conditions. The clinical course, outcomes, and significance of immunosuppression regimen in heart transplant recipients with COVID-19 remains unclear. METHODS: We included the first 99 heart transplant recipients at participating centers with COVID-19 and followed patients until resolution. We collected baseline information, symptoms, laboratory studies, vital signs, and outcomes for included patients. The association of immunosuppression regimens at baseline with severe disease were compared using logistic regression, adjusting for age and time since transplant. RESULTS: The median age was 60 years, 25% were female, and 44% were white. The median time post-transplant to infection was 5.6 years. Overall, 15% died, 64% required hospital admission, and 7% remained asymptomatic. During the course of illness, only 57% of patients had a fever, and gastrointestinal symptoms were common. Tachypnea, oxygen requirement, elevated creatinine and inflammatory markers were predictive of severe course. Age ≥ 60 was associated with higher risk of death and the use of the combination of calcineurin inhibitor, antimetabolite, and prednisone was associated with more severe disease compared to the combination of calcineurin inhibitor and antimetabolite alone (adjusted OR = 7.3, 95% CI 1.8-36.2). Among hospitalized patients, 30% were treated for secondary infection, acute kidney injury was common and 17% required new renal replacement therapy. CONCLUSIONS: We present the largest study to date of heart transplant patients with COVID-19 showing common atypical presentations and a high case fatality rate of 24% among hospitalized patients and 16% among symptomatic patients.

Characteristics and Outcomes of COVID-19 in Patients on Left Ventricular Assist Device Support.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to afflict millions of people worldwide. Patients with end-stage heart failure and left ventricular assist devices (LVADs) may be at risk for severe COVID-19 given a high prevalence of complex comorbidities and functional impaired immunity. The objective of this study is to describe the clinical characteristics and outcomes of COVID-19 in patients with end-stage heart failure and durable LVADs. METHODS: The Trans-CoV-VAD registry is a multi-center registry of LVAD and cardiac transplant patients in the United States with confirmed COVID-19. Patient characteristics, exposure history, presentation, laboratory data, course, and clinical outcomes were collected by participating institutions and reviewed by a central data repository. This report represents the participation of the first 9 centers to report LVAD data into the registry. RESULTS: A total of 40 patients were included in this cohort. The median age was 56 years (interquartile range, 46-68), 14 (35%) were women, and 21 (52%) were Black. Among the most common presenting symptoms were cough (41%), fever, and fatigue (both 38%). A total of 18% were asymptomatic at diagnosis. Only 43% of the patients reported either subjective or measured fever during the entire course of illness. Over half (60%) required hospitalization, and 8 patients (20%) died, often after lengthy hospitalizations. CONCLUSIONS: We present the largest case series of LVAD patients with COVID-19 to date. Understanding these characteristics is essential in an effort to improve the outcome of this complex patient population.

Phase I trial of combretastatin a-4 phosphate with carboplatin.

PURPOSE: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. EXPERIMENTAL DESIGN: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion. RESULTS: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles. CONCLUSION: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.

Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow.

PURPOSE: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. PATIENTS AND METHODS: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. RESULTS: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. CONCLUSION: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.

Use of automated external defibrillators at NCAA Division I universities.

PURPOSE: The placement of automated external defibrillators (AED) at public sporting events is a growing national trend. The purpose of the present study was to investigate the prevalence, past use, and cost of implementing AED at university sporting venues. METHODS: Questionnaires were sent to the head athletic trainer at all Division I NCAA universities (N = 326) and responses collected between August and November 2003. RESULTS: Completed surveys were returned by 244 institutions (75% response rate). Ninety-one percent (221/244) had AED for an average of 3.3 yr (range 1-13) with a median of four AED per institution (range 1-30). There were 35 cases of AED use for sudden cardiac arrest with 77% (27/35) occurring in older nonstudents, 14% (5/35) in intercollegiate athletes, and 3% (1/35) in a student nonintercollegiate athlete (information unavailable in two cases). The immediate resuscitation rate was 54% (19/35). A shock was delivered in 21 cases with a resuscitation rate of 71% (15/21). None of the intercollegiate athletes were successfully resuscitated. The average cost per AED was 2460 US dollars. In a 10-yr model (expected useful life of an AED), the cost per life immediately resuscitated was 52,400 US dollars, and the estimated cost per life-year gained ranged 10,500 US dollars to 22,500 US dollars. CONCLUSIONS: Most Division I universities have AED available at selected sporting venues. Although no benefit was demonstrated for intercollegiate athletes, AED were successfully used in older nonstudents with cardiac arrest with a favorable long-term cost analysis.

A prospective study of continuous intravenous milrinone therapy for status IB patients awaiting heart transplant at home.

BACKGROUND: We performed a prospective study to determine the feasibility and safety of continuous intravenous milrinone therapy administered at home in patients listed as Status IB for heart transplant. METHODS: Patients who were Status IB could participate if they met specific criteria including an optimal dose of milrinone < or =0.5 microg/kg/min, presence of an implantable cardioverter-defibrillator (ICD), and no other serious comorbidity. The primary end-point of the study was survival to transplant. Hospitalizations, quality of life and cost comparisons were assessed. RESULTS: From May 1999 through October 2002, a total of 60 patients (51 men, 9 women), aged 55.5 +/- 8.4 years, entered the study. Before milrinone therapy, cardiac index was 1.98 +/- 0.66 liters/min/m2 and peak oxygen consumption was 11.4 +/- 2.6 ml/kg/min. Mean time in the study was 160.1 +/- 151.8 days. Fifty-three patients (88.3%) underwent heart transplant. There were only 2 deaths during the study. There were 89 hospital admissions in 46 patients over the 43-month follow-up period; 58 of these admissions were for heart failure. There were 6 episodes of ICD firing for ventricular tachycardia. Quality-of-life measures in a sub-group of patients significantly improved 1 month after discharge. Substantial estimated cost savings occurred. CONCLUSIONS: Continuous intravenous milrinone therapy can be safely administered at home in selected patients with advanced heart failure who are listed for transplant. This strategy may be an acceptable alternative to prolonged hospitalization for patients dependent on continuous inotropic support. Re-hospitalization is to be expected. An implantable cardioverter-defibrillator should be present due to the incidence of ventricular tachycardia.