Sleep Outcomes From AWAKE-HF: A Randomized Clinical Trial of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Heart failure and sleep-disordered breathing have been increasingly recognized as co-occurring conditions. Their bidirectional relationship warrants investigation into whether heart failure therapy improves sleep and sleep-disordered breathing. We sought to explore the effect of treatment with sacubitril/valsartan on sleep-related endpoints from the AWAKE-HF study. METHODS AND RESULTS: AWAKE-HF was a randomized, double-blind study conducted in 23 centers in the United States. Study participants with heart failure with reduced rejection fraction and New York Heart Association class II or III symptoms were randomly assigned to receive treatment with either sacubitril/valsartan or enalapril. All endpoints were assessed at baseline and after 8 weeks of treatment. Portable sleep-monitoring equipment was used to measure the apnea-hypopnea index, including obstructive and central events. Total sleep time, wake after sleep onset and sleep efficiency were exploratory measures assessed using wrist actigraphy. THE RESULTS WERE AS FOLLOWS: 140 patients received treatment in the double-blind phase (sacubitril/valsartan, n = 70; enalapril, n = 70). At baseline, 39% and 40% of patients randomly assigned to receive sacubitril/valsartan or enalapril, respectively, presented with undiagnosed, untreated, moderate-to-severe sleep-disordered breathing (≥ 15 events/h), and nearly all had obstructive sleep apnea. After 8 weeks of treatment, the mean 4% apnea-hypopnea index changed minimally from 16.3/h to 15.2/h in the sacubitril/valsartan group and from 16.8/h to 17.6/h in the enalapril group. Mean total sleep time was long at baseline and decreased only slightly in both treatment groups at week 8 (-14 and -11 minutes for sacubitril/valsartan and enalapril, respectively), with small changes in wake after sleep onset and sleep efficiency in both groups. CONCLUSIONS: In a cohort of patients with heart failure with reduced rejection fraction who met prescribing guidelines for sacubitril/valsartan, one-third had undiagnosed moderate-to-severe obstructive sleep apnea. The addition of sacubitril/valsartan therapy did not significantly improve sleep-disordered breathing or sleep duration or efficiency. Patients who meet indications for treatment with sacubitril/valsartan should be evaluated for sleep-disordered breathing.

The efficacy of sonographic measurement of inferior vena cava diameter as an estimate of central venous pressure.

BACKGROUND: Central venous pressure (CVP) and right atrial pressure (RAP) are important parameters in the complete hemodynamic assessment of a patient. Sonographic measurement of the inferior vena cava (IVC) diameter is a non-invasive method of estimating these parameters, but there are limited data summarizing its diagnostic accuracy across multiple studies. We performed a comprehensive review of the existing literature to examine the diagnostic accuracy and clinical utility of sonographic measurement of IVC diameter as a method for assessing CVP and RAP. METHODS: We performed a systematic search using PubMed of clinical studies comparing sonographic evaluation of IVC diameter and collapsibility against gold standard measurements of CVP and RAP. We included clinical studies that were performed in adults, used current imaging techniques, and were published in English. RESULTS: Twenty one clinical studies were identified that compared sonographic assessment of IVC diameter with CVP and RAP and met all inclusion criteria. Despite substantial heterogeneity in measurement techniques and patient populations, most studies demonstrated moderate strength correlations between measurements of IVC diameter and collapsibility and CVP or RAP, but more favorable diagnostic accuracy using pre-specified cut points. Findings were inconsistent among mechanically ventilated patients, except in the absence of positive end-expiratory pressure. CONCLUSION: Sonographic measurement of IVC diameter and collapsibility is a valid method of estimating CVP and RAP. Given the ease, safety, and availability of this non-invasive technique, broader adoption and application of this method in clinical settings is warranted.

The AWAKE-HF Study: Sacubitril/Valsartan Impact on Daily Physical Activity and Sleep in Heart Failure.

BACKGROUND: AWAKE-HF evaluated the effect of the initiation of sacubitril/valsartan versus enalapril on activity and sleep using actigraphy in patients who have heart failure with reduced ejection fraction (HFrEF). METHODS: In this randomized, double-blind study, patients with HFrEF (n = 140) were randomly assigned to sacubitril/valsartan or enalapril for 8 weeks, followed by an 8-week open-label phase with sacubitril/valsartan. Primary endpoint was change from baseline in mean activity counts during the most active 30 min/day at week 8. The key secondary endpoint was change in mean nightly activity counts/minute from baseline to week 8. Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) was an exploratory endpoint. RESULTS: There were no detectable differences between groups in geometric mean ratio of activity counts during the most active 30 min/day at week 8 compared with baseline (0.9456 [sacubitril/valsartan:enalapril]; 95% confidence interval [CI] 0.8863-1.0088; P = 0.0895) or in mean change from baseline in activity during sleep (difference: 2.038 counts/min; 95% CI - 0.062 to 4.138; P = 0.0570). Change from baseline to week 8 in KCCQ-23 was 2.89 for sacubitril/valsartan and 4.19 for enalapril, both nonsignificant. CONCLUSIONS: In AWAKE-HF, no detectable differences in activity and sleep were observed when comparing sacubitril/valsartan with enalapril in patients with HFrEF using a wearable biosensor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02970669.

Feasibility of a voice-enabled automated platform for medical data collection: CardioCube.

AIM: A feasibility study was conducted to evaluate implementation of a voice-enabled automated platform for collection of medical data from patients with cardiovascular disease: CardioCube. METHODS: The study enrolled 22 individuals (10 males, 45.5%) including 9 patients with cardiovascular disease and 13 healthy participants. Utilizing (1) voice-enabled patient registration software implemented on the Amazon Echo and (2) web-based electronic health record (EHR) system, study participants verbally answered a set of clinical questions. Primary endpoint: accuracy of ​the ​CardioCube system. Secondary endpoints: acceptability, usability and technical performance. The study was performed at the Outpatient Cardiology Clinic, Cedars-Sinai Medical Center, Los Angeles, CA, USA. RESULTS: The CardioCube system collected 432 data points with a high agreement level between verbally provided data and corresponding EHR information (accuracy 97.51%). The CardioCube was able to automatically generate a summarized medical report, which was instantly available for a doctor in the web-based EHR system. Patients reported CardioCube was "easy to use". Applicability of the system was graded excellent by the medical staff. A single session utilized less than 0.002% of available computational resources. CONCLUSION: CardioCube can collect, index and document medical data using a voice interface. In this pilot study, CardioCube supported healthcare professionals by performing time-consuming paperwork during patient registration.

Activity Sensors to Evaluate the Effect of Sacubitril/Valsartan on Quality-of-Life in Heart Failure: rational and design of the AWAKE-HF study.

AIMS: Limited data are available regarding the ability of sacubitril/valsartan to provide clinically meaningful health-related quality of life (HRQoL) improvements among individuals with heart failure (HF). Objective measurement of physical activity and sleep using actigraphy can provide insight into daily functioning and HRQoL. METHODS AND RESULTS: We designed an 18 week, multicenter, randomized, double-blind, double-dummy, parallel-group study to objectively assess changes in function and HRQoL directly after initiating sacubitril/valsartan vs. enalapril in participants with HF in their home environments. A total of 136 outpatient, ambulatory participants with New York Heart Association Class II or III HF with reduced ejection fraction (HFrEF) will be included in the study. Patients will undergo a 2 week baseline observational phase (continuing current HF treatment); data from the second week of this phase will be the baseline value for comparison with those of subsequent periods. Patients will then enter an 8 week blinded-treatment phase (randomly assigned 1:1 to sacubitril/valsartan or enalapril), followed by an 8 week open-label extension phase (treatment with only sacubitril/valsartan). The primary efficacy endpoint is the change in mean activity counts during the most active 30 min of the participant's day between baseline and the final randomized treatment phase measurement. Secondary endpoints include the change in mean sleep activity during the randomized and open-label phases; questionnaires will also assess HRQoL measures. Rather than analysing pooled actigraphy data, the researchers are considering each participant to be acting as his or her own control. CONCLUSIONS: This will be the first study to assess the effects of sacubitril/valsartan on objective measures of sleep and activity in individuals with HFrEF within the context of their daily lives. Wearable accelerometer devices will be used to gain insight into how the medication affects physical activity and sleep.

Differential effects of carvedilol and metoprolol succinate on plasma norepinephrine release and peak exercise heart rate in subjects with chronic heart failure.

Dosing equivalency of carvedilol and metoprolol remains a debate. Degree of beta 1-blockade is best assessed by blunting of the exercise-induced heart rate. Accordingly, the authors have investigated dosing equivalency by examining baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. Thirty-seven subjects treated with carvedilol (32.9 +/- 3.5 mg; n = 23) or metoprolol succinate (XL) (96.4 +/- 15.9 mg; n = 14) referred for cardiopulmonary exercise testing were studied prospectively. Carvedilol versus metoprolol XL subjects did not differ with respect to baseline heart rate (73 +/- 2 vs 70 +/- 3 bpm), or baseline plasma norepinephrine levels (597.5 +/- 78.3 vs 602.1 +/- 69.6 pg/mL), P = NS. However, despite similar peak exercise norepinephrine levels (2735.8 +/- 320.1 vs 2403.1 +/- 371.6 pg/mL), heart rate at peak exercise was higher in subjects receiving carvedilol (135 +/- 4 bpm) than those receiving metoprolol XL (117 +/- 6 bpm), P = 0.02. Similar norepinephrine release and more complete beta 1-blockade is observed in well-matched subjects with chronic heart failure treated with a mean daily dose of metoprolol XL 96.4 mg compared with carvedilol 32.9 mg.

Implementation of a Home Monitoring System for Heart Failure Patients: A Feasibility Study.

BACKGROUND: Improving the management of patients with complex chronic disease is a substantial undertaking with the simultaneous goals of improving patient outcomes and controlling costs. Reducing avoidable hospitalization for such patients is a step toward both objectives. Some of the deterioration experienced in chronic disease patients occurs outside the view of their clinicians, and before the patient becomes overtly symptomatic. Home monitoring has been used for more than 20 years to detect deterioration earlier so that the patients could be treated before they became ill enough to require hospitalization. Patient participation is an important requirement for successful home monitoring. There has been some concern that patients would be unwilling or unable to engage in a program that collected multiple measurements. The Cedars-Sinai Cardiology Center provides a high-touch, intense management program for patients with congestive heart failure (CHF). A group of their patients were chosen to join a complex, multidevice home monitoring system to see whether such patients would find value in the additional effort. OBJECTIVE: The objective of our study was to determine whether patients already actively engaged in a high-touch intensive management program for CHF would take on the additional burden of a complex home monitoring effort. METHODS: A total of 20 patients from the Cedars-Sinai group were enrolled in a monitoring program utilizing 5 different devices. Anonymous surveys were collected from the patients to assess their satisfaction with the program. RESULTS: In total, 90% (18/20) completed the program, and 61% (11/20) submitted the survey. Among the 18 patients, overall compliance with the requested measurements was 70%. It was found that 73% (8/11) felt better about their health as a result of the program, whereas another 73% (8/11) believed that the care team now had a better picture of their health. CONCLUSIONS: Substantial patient compliance and satisfaction can be achieved in a sophisticated home monitoring program.

Usefulness of Serial Measurements of Inferior Vena Cava Diameter by VscanTM to Identify Patients With Heart Failure at High Risk of Hospitalization.

Estimation of volume status is integral to heart failure (HF) management. Measurement of inferior vena cava (IVC) diameter (IVCd) by ultrasound provides a noninvasive estimate of right atrial pressures. The GE Vscan is a handheld ultrasound (HHU) device that allows for point-of-care measurements to assess volume status. We hypothesize that IVCd measurements using HHU can predict the risk of HF admission. We retrospectively analyzed a cohort of patients with HF treated in an ambulatory care setting over 17 months. Serial measurements of IVCd were obtained using HHU in the supine position from the subcostal window. Log-binomial regression models were used to compare IVCd measurements between patients with and without HF admissions and to estimate the association between IVCd and risk of HF admission. Of the 355 patients with systolic (38%) and diastolic HF (62%) who were analyzed, 45% were women with a mean age of 73 years at the time of the first IVCd measurement. Overall, 3,488 measurements were obtained, and 32.4% of patients were hospitalized during follow-up. Patients with at least 1 hospital admission had a greater mean IVCd than those who were not admitted (2.0 vs 1.8 cm, p <0.01). In our analysis, every 0.5-cm increase in the mean IVCd was associated with a 38% increase in risk of HF admission (risk ratio [RR] 1.38, 95% CI 1.16 to 1.62, p <0.01). The risk of HF admission was also significantly increased in patients with IVCd 2.0 to 2.49 cm (RR 1.79, 95% CI 1.27 to 2.52, p <0.01) and ≥2.5 cm (RR 2.39, 95% CI 1.55 to 3.67, p <0.01), compared with patients with an IVCd < 2.0 cm. Increasing IVCd as measured by HHU at the point-of-care is associated with an increased risk of HF admission and may provide clinically useful information at the point-of-care to guide HF management.

Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial.

BACKGROUND: Digital wearable devices provide a "real-world" assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. OBJECTIVE: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. METHODS: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and coronary microvascular dysfunction (CMD) with no obstructive coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. RESULTS: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. CONCLUSIONS: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. TRIAL REGISTRATION: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO).