Chronotropic Incompetence after Heart Transplantation Is Associated with Increased Mortality and Decreased Functional Capacity.

INTRODUCTION: The contribution of chronotropic incompetence to reduced exercise tolerance after a heart transplant is well known, but its role as a prognostic marker of post-transplant mortality is unclear. The aim of this study is to examine the relationship between post-transplant heart rate response (HRR) and survival. METHODS: We performed a retrospective analysis of all adult heart transplant recipients at the University of Pennsylvania between the years 2000 and 2011 who underwent a cardiopulmonary exercise test (CPET) within a year of transplant. Follow-up time and survival status were observed through October 2019, using data merged from the Penn Transplant Institute. HRR was calculated by subtracting the resting HR from the peak exercise HR. The association between HRR and mortality was analyzed using Cox proportional hazard models and Kaplan-Meier analysis. The optimal cut-off point for HRR was generated by Harrell's C statistic. Patients with submaximal exercise tests were excluded, defined by a respiratory exchange ratio (RER) cut-off of 1.05. RESULTS: Of 277 patients with CPETs performed within a year post-transplant, 67 were excluded for submaximal exercise. In the 210 included patients, the mean follow-up time was 10.9 years (Interquartile range (IQR) 7.8-14). Resting HR and peak HR did not significantly impact mortality after adjusting for covariates. In a multivariable linear regression analysis, each 10-beat increase in heart rate response was associated with a 1.3 mL/kg/min increase in peak VO2 and a 48 s increase in the total exercise time. Each beat/min increase in HRR was associated with a 3% reduction in the hazard of mortality (HR 0.97; 95% CI 0.96-0.99, p = 0.002). Using the optimal cut-off point generated by Harrell's C statistic, survival was significantly higher in patients with an HRR > 35 beats/min compared to those with an HRR < 35 beats/min (log rank p = 0.0012). CONCLUSION: In heart transplant patients, a low HRR is associated with increased all-cause mortality and decreased exercise capacity. Additional studies are needed to validate whether targeting HRR in cardiac rehabilitation may improve outcomes.

Early Cardiopulmonary Fitness after Heart Transplantation as a Determinant of Post-Transplant Survival.

BACKGROUND: Decreased peak oxygen consumption during exercise (peak Vo2) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established. METHODS AND RESULTS: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively. CONCLUSIONS: Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity.

The Anemia Stress Index-Anemia, Transfusions, and Mortality in Patients with Continuous Flow Ventricular Assist Devices.

We aimed to identify a simple metric accounting for peri-procedural hemoglobin changes, independent of blood product transfusion strategies, and assess its correlation with outcomes in patients undergoing left ventricular assist device (LVAD) implantation We included consecutive patients undergoing LVAD implantation at a single center between 10/1/2008 and 6/1/2014. The anemia stress index (ASI), defined as the sum of number of packed red blood cells transfused and the hemoglobin changes after LVAD implantation, was calculated for each patient at 24 h, discharge, and 3 months after LVAD implantation. Our cohort included 166 patients (80.1% males, mean age 56.3 ± 15.6 years) followed up for a median of 12.3 months. Increases in ASI per unit were associated with a higher hazard for all-cause mortality and early RV failure. The associations between the ASI and all-cause mortality persisted after multivariable adjustment, irrespective of when it was calculated (adjusted HR of 1.11, 95% CI 1.03-1.20 per unit increase in ASI). Similarly, ASI at 24 h after implant was associated with early RV failure despite multivariable adjustment (OR 1.09, 95% CI 1.05-1.14). We present a novel metric, the ASI, that is correlated with an increased risk for all-cause mortality and early RV failure in LVAD recipients.

Safety and Effectiveness of Intravenous Iron Therapy in Patients Supported by Durable Left Ventricular Assist Devices.

AIMS: While it is common practice to use intravenous (IV) iron in patients with left ventricular assist devices (LVADs) and iron deficiency, there is insufficient evidence regarding outcomes in this patient population. We evaluated the safety and effectiveness of IV iron therapy in patients supported by LVADs with iron deficiency. METHODS: We performed a retrospective analysis of iron deficient patients on continuous LVAD support at a large academic center between 2008 and 2019. Patients were divided into two cohorts based on IV iron sucrose treatment. The primary endpoint was hemoglobin at 12 weeks. Secondary endpoints were mean corpuscular volume (MCV) and New York Heart Association (NYHA) class at 12 weeks. Safety endpoints included hospitalization, infection, pump thrombosis, arrhythmia, and gastrointestinal bleed. Models were weighted by the inverse probability of receiving IV iron using a propensity score, and endpoints were adjusted for their corresponding baseline values. RESULTS: Among 213 patients, 70 patients received IV iron and 143 patients did not. Hemoglobin at 12 weeks was significantly greater among those treated (intergroup difference: 0.6 g/dL; 95% CI, 0.1 to 1.1; p = 0.01), while MCV was similar in both groups (intergroup difference: 0.7 µm3; 95% CI, -1.3 to 2.7; p = 0.50). NYHA class distribution at 12 weeks was significantly different (odds ratio for improvement: 2.84; 95% CI, 1.42 to 4.68; p = 0.003). The hazards of adverse events in each group were similar. CONCLUSIONS: In patients with LVADs and iron deficiency, treatment with IV iron sucrose was safe and associated with improvements in functional status and hemoglobin.

Remote Monitoring and Behavioral Economics in Managing Heart Failure in Patients Discharged From the Hospital: A Randomized Clinical Trial.

Importance: Close remote monitoring of patients following discharge for heart failure (HF) may reduce readmissions or death. Objective: To determine whether remote monitoring of diuretic adherence and weight changes with financial incentives reduces hospital readmissions or death following discharge with HF. Design, Setting, and Participants: The Electronic Monitoring of Patients Offers Ways to Enhance Recovery (EMPOWER) study, a 3-hospital pragmatic trial, randomized 552 adults recently discharged with HF to usual care (n = 280) or a compound intervention (n = 272) designed to inform clinicians of diuretic adherence and changes in patient weight. Patients were recruited from May 25, 2016, to April 8, 2019, and followed up for 12 months. Investigators were blinded to assignment but patients were not. Analysis was by intent to treat. Interventions: Participants randomized to the intervention arm received digital scales, electronic pill bottles for diuretic medication, and regret lottery incentives conditional on the previous day's adherence to both medication and weight measurement, with $1.40 expected daily value. Participants' physicians were alerted if participants' weights increased 1.4 kg in 24 hours or 2.3 kg in 72 hours or if diuretic medications were missed for 5 days. Alerts and weights were integrated into the electronic health record. Participants randomized to the control arm received usual care and no further study contact. Main Outcomes and Measures: Time to death or readmission for any cause within 12 months. Results: Of the 552 participants, 290 were men (52.5%); 291 patients (52.7%) were Black, 231 were White (41.8%), and 16 were Hispanic (2.9%); mean (SD) age was 64.5 (11.8) years. The mean (SD) ejection fraction was 43% (18.1%). Each month, approximately 75% of participants were 80% adherent to both medication and weight measurement. There were 423 readmissions and 26 deaths in the control group and 377 readmissions and 23 deaths in the intervention group. There was no significant difference between the 2 groups for the combined outcome of all-cause inpatient readmission or death (unadjusted hazard ratio, 0.91; 95% CI, 0.74-1.13; P = .40) and no significant differences in all-cause inpatient readmission or observation stay or death, all-cause cardiovascular readmission or death, time to first event, and total all-cause deaths. Participants in the intervention group were slightly more likely to spend fewer days in the hospital. Conclusions and Relevance: In this randomized clinical trial, there was no reduction in the combined outcome of readmission or mortality in a year-long intensive remote monitoring program with incentives for patients previously hospitalized for HF. Trial Registration: ClinicalTrials.gov Identifier: NCT02708654.

The Electronic Health Record as the Primary Data Source in a Pragmatic Trial: A Case Study.

HIGHLIGHTS: Electronic health records are not a single system but a series of overlapping and legacy systems that require time and expertise to use efficiently.Commonly measured patient characteristics such as weight and body mass index are relatively easy to locate for most trial enrollees but less common characteristics, like ejection fraction, are not.Acquiring essential supplementary data-in this trial, state data on hospital admission-can be a lengthy and difficult process.

Left Ventricular Assist Device as a Bridge to Recovery: Single Center Experience of Successful Device Explantation.

Continuous-flow left ventricular assist devices (CF-LVAD) have been shown to enhance reverse remodeling and myocardial recovery in certain patients allowing for device removal. We sought to analyze the characteristics and describe outcomes of patients who underwent CF-LVAD explantation at a large academic center. We retrospectively identified all patients who underwent CF-LVAD explants due to recovery from 2006 to 2019. Patient baseline characteristics and data on pre- and postexplant evaluation were collected and analyzed. Of 421 patients who underwent CF-LVAD implantation, 13 underwent explantation (3.1%). Twelve HeartMate II and one HeartWare LVAD were explanted. All patients had nonischemic cardiomyopathy. Median time from heart failure diagnosis to LVAD implant was 12 months (interquartile range [IQR], 2-44) and the median time supported on LVAD was 22 months (IQR, 11-28). Two patients died within 30 days of explant. Three additional patients died during the follow-up period and all were noted to be nonadherent to medical therapy. After a mean follow-up duration of 5 years, overall survival was 52%. Mean pre-explant ejection fraction was 49%, which decreased at most recent follow-up to 32%. Mean pre-explant left ventricular internal diameter in diastole (LVIDD) was 4.37 cm and increased to 5.52 cm at most recent follow-up. Continuous-flow left ventricular assist device explantation is feasible and safe in select patients.

The pleiotropic cardiovascular effects of sodium-glucose cotransporter-2 inhibitors.

PURPOSE OF REVIEW: Throughout the history of medicine, scientists and clinicians have observed unanticipated drug effects leading at times to an entirely new use for a drug class, and other times eliminating them from practice. The sodium-glucose cotransporter-2 (SGLT2) inhibitors are one such class of drugs. These agents were initially studied as diabetic agents and their unanticipated and significant cardiovascular benefit has now created a new class of drugs for an entirely new population. Here we review the pleiotropic cardiovascular effects of SGLT2 inhibitors, the potential mechanisms of action, side effect profile and future directions. RECENT FINDINGS: Large clinical trials have evaluated the cardiovascular outcomes of SGLT2 inhibitors including myocardial infarction and strokes as well as new onset and worsening systolic heart failure. SUMMARY: SGLT2 inhibitors are being incorporated into the guidelines for the treatment of heart failure with the goal of preventing heart failure hospitalizations and promoting positive ventricular remodeling in patients with or without diabetes. The reduction in cardiovascular events including cardiovascular death, myocardial infarction, and other atherosclerotic effects appears to be driven by baseline risk with those who have known atherosclerosis seeing a reduction in events but those without disease seeing less benefit.

Using Clinical Trial Data to Estimate the Costs of Behavioral Interventions for Potential Adopters: A Guide for Trialists.

Behavioral interventions involving electronic devices, financial incentives, gamification, and specially trained staff to encourage healthy behaviors are becoming increasingly prevalent and important in health innovation and improvement efforts. Although considerations of cost are key to their wider adoption, cost information is lacking because the resources required cannot be costed using standard administrative billing data. Pragmatic clinical trials that test behavioral interventions are potentially the best and often only source of cost information but rarely incorporate costing studies. This article provides a guide for researchers to help them collect and analyze, during the trial and with little additional effort, the information needed to inform potential adopters of the costs of adopting a behavioral intervention. A key challenge in using trial data is the separation of implementation costs, the costs an adopter would incur, from research costs. Based on experience with 3 randomized clinical trials of behavioral interventions, this article explains how to frame the costing problem, including how to think about costs associated with the control group, and describes methods for collecting data on individual costs: specifications for costing a technology platform that supports the specialized functions required, how to set up a time log to collect data on the time staff spend on implementation, and issues in getting data on device, overhead, and financial incentive costs.

Right ventricular outflow tract velocity time integral-to-pulmonary artery systolic pressure ratio: a non-invasive metric of pulmonary arterial compliance differs across the spectrum of pulmonary hypertension.

Pulmonary arterial compliance (PAC), invasively assessed by the ratio of stroke volume to pulmonary arterial (PA) pulse pressure, is a sensitive marker of right ventricular (RV)-PA coupling that differs across the spectrum of pulmonary hypertension (PH) and is predictive of outcomes. We assessed whether the echocardiographically derived ratio of RV outflow tract velocity time integral to PA systolic pressure (RVOT-VTI/PASP) (a) correlates with invasive PAC, (b) discriminates heart failure with preserved ejection-associated PH (HFpEF-PH) from pulmonary arterial hypertension (PAH), and (c) is associated with functional capacity. We performed a retrospective cohort study of patients with PAH (n = 70) and HFpEF-PH (n = 86), which was further dichotomized by diastolic pressure gradient (DPG) into isolated post-capillary PH (DPG < 7 mmHg; Ipc-PH, n = 54), and combined post- and pre-capillary PH (DPG ≥ 7 mm Hg; Cpc-PH, n = 32). Of the 156 patients, 146 had measurable RVOT-VTI or PASP and were included in further analysis. RVOT-VTI/PASP correlated with invasive PAC overall (ρ = 0.61, P < 0.001) and for the PAH (ρ = 0.38, P = 0.002) and HFpEF-PH (ρ = 0.63, P < 0.001) groups individually. RVOT-VTI/PASP differed significantly across the PH spectrum (PAH: 0.13 [0.010-0.25] vs. Cpc-PH: 0.20 [0.12-0.25] vs. Ipc-PH: 0.35 [0.22-0.44]; P < 0.001), distinguished HFpEF-PH from PAH (AUC = 0.72, 95% CI = 0.63-0.81) and Cpc-PH from Ipc-PH (AUC = 0.78, 95% CI = 0.68-0.88), and remained independently predictive of 6-min walk distance after multivariate analysis (standardized ß-coefficient = 27.7, 95% CI = 9.2-46.3; P = 0.004). Echocardiographic RVOT-VTI/PASP is a novel non-invasive metric of PAC that differs across the spectrum of PH. It distinguishes the degree of pre-capillary disease within HFpEF-PH and is predictive of functional capacity.