Analysis of Worsening Heart Failure Events in an Integrated Health Care System.

BACKGROUND: There is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. OBJECTIVES: The purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. METHODS: We studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. RESULTS: We identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. CONCLUSIONS: ED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

A Natural Language Processing-Based Approach for Identifying Hospitalizations for Worsening Heart Failure Within an Integrated Health Care Delivery System.

Importance: The current understanding of epidemiological mechanisms and temporal trends in hospitalizations for worsening heart failure (WHF) is based on claims and national reporting databases. However, these data sources are inherently limited by the accuracy and completeness of diagnostic coding and/or voluntary reporting. Objective: To assess the overall burden of and temporal trends in the rate of hospitalizations for WHF. Design, Setting, and Participants: This cohort study, performed from January 1, 2010, to December 31, 2019, used electronic health record (EHR) data from a large integrated health care delivery system. Exposures: Calendar year trends. Main Outcomes and Measures: Hospitalizations for WHF (ie, excluding observation stays) were defined as 1 symptom or more, 2 objective findings or more including 1 sign or more, and 2 doses or more of intravenous loop diuretics and/or new hemodialysis or continuous kidney replacement therapy. Symptoms and signs were identified using natural language processing (NLP) algorithms applied to EHR data. Results: The study population was composed of 118 002 eligible patients experiencing 287 992 unique hospitalizations (mean [SD] age, 75.6 [13.1] years; 147 203 [51.1%] male; 1655 [0.6%] American Indian or Alaska Native, 28 451 [9.9%] Asian or Pacific Islander, 34 903 [12.1%] Black, 23 452 [8.1%] multiracial, 175 840 [61.1%] White, and 23 691 [8.2%] unknown), including 65 357 with a principal discharge diagnosis and 222 635 with a secondary discharge diagnosis of HF. The study population included 59 868 patients (20.8%) with HF with a reduced ejection fraction (HFrEF) (<40%), 33 361 (11.6%) with HF with a midrange EF (HFmrEF) (40%-49%), 142 347 (49.4%) with HF with a preserved EF (HFpEF) (≥50%), and 52 416 (18.2%) with unknown EF. A total of 58 042 admissions (88.8%) with a primary discharge diagnosis of HF and 62 764 admissions (28.2%) with a secondary discharge diagnosis of HF met the prespecified diagnostic criteria for WHF. Overall, hospitalizations for WHF identified on NLP-based algorithms increased from 5.2 to 7.6 per 100 hospitalizations per year during the study period. Subgroup analyses found an increase in hospitalizations for WHF based on NLP from 1.5 to 1.9 per 100 hospitalizations for HFrEF, from 0.6 to 1.0 per 100 hospitalizations for HFmrEF, and from 2.6 to 3.9 per 100 hospitalizations for HFpEF. Conclusions and Relevance: The findings of this cohort study suggest that the burden of hospitalizations for WHF may be more than double that previously estimated using only principal discharge diagnosis. There has been a gradual increase in the rate of hospitalizations for WHF with a more noticeable increase observed for HFpEF.

Rationale and design of the pragmatic randomized trial of icosapent ethyl for high cardiovascular risk adults (MITIGATE).

OBJECTIVE: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). BACKGROUND: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. METHODS: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. CONCLUSION: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.

Detecting Suspected Pump Thrombosis in Left Ventricular Assist Devices via Acoustic Analysis.

OBJECTIVE: Left ventricular assist devices (LVADs) fail in up to 10% of patients due to the development of pump thrombosis. Remote monitoring of patients with LVADs can enable early detection and, subsequently, treatment and prevention of pump thrombosis. We assessed whether acoustical signals measured on the chest of patients with LVADs, combined with machine learning algorithms, can be used for detecting pump thrombosis. METHODS: 13 centrifugal pump (HVAD) recipients were enrolled in the study. When hospitalized for suspected pump thrombosis, clinical data and acoustical recordings were obtained at admission, prior to and after administration of thrombolytic therapy, and every 24 hours until laboratory and pump parameters normalized. First, we selected the most important features among our feature set using LDH-based correlation analysis. Then using these features, we trained a logistic regression model and determined our decision threshold to differentiate between thrombosis and non-thrombosis episodes. RESULTS: Accuracy, sensitivity and precision were calculated to be 88.9%, 90.9% and 83.3%, respectively. When tested on the post-thrombolysis data, our algorithm suggested possible pump abnormalities that were not identified by the reference pump power or biomarker abnormalities. SIGNIFICANCE: We showed that the acoustical signatures of LVADs can be an index of mechanical deterioration and, when combined with machine learning algorithms, provide clinical decision support regarding the presence of pump thrombosis.

Heart-lung transplantation: A viable option for connective tissue diseases.

BACKGROUND: While lung transplantation (LTx) has been effective for connective tissue disease (CTD) patients with pulmonary involvement, outcomes for heart-lung transplantation (HLTx) are less defined. The aim of this study is to evaluate HLTx in CTD patients utilizing the UNOS database. METHODS: HLTx patients with CTD (HLTx-CTD) were compared to both LTx patients with CTD (LTx-CTD) and HLTx patients with all other indications (HLTx-OI) from 1999 to 2018. Primary outcome was 1- and 5-year graft survival. Secondary outcomes included freedom from first-year rejection and outcomes prior to transplant discharge. RESULTS: 1143/29 323 adults received first-time HLTx or LTx for CTD. Seventeen were HLTx-CTD (3.3% of total HLTx) and 1126 were LTx-CTD (3.9% of total LTx). There were 492 HLTx-OI. Transplant hemodynamic values including cardiac output, pulmonary capillary wedge pressure, and calculated pulmonary vascular resistance were significantly worse for HLTx-CTD vs LTx-CTD (4.2 vs 5.4 L/min, P = .005; 14 vs 10 mm Hg, P = .009; 439 vs 267 dynes, P = .007, respectively). Cardiac status 1 was more common for HLTx-CTD vs HLTx-OI (94% vs 56%, P < .001). HLTx-CTD 1 and 5-year graft survival was similar compared to LTx-CTD and HLTx-OI. CONCLUSION: HLTx-CTD is a valid option for carefully selected patients with CTD cardiac and pulmonary involvement with similar morbidity and mortality compared to LTx-CTD and HLTx-OI.

Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.

Background Long-term corticosteroid therapy is the standard of care for treatment of cardiac sarcoidosis (CS). The efficacy of long-term corticosteroid-sparing immunosuppression in CS is unknown. The goal of this study was to assess the efficacy of methotrexate with or without adalimumab for long-term disease suppression in CS, and to assess recurrence and adverse event rates after immunosuppression discontinuation. Methods and Results Retrospective chart review identified treatment-naive CS patients at a single academic medical center who received corticosteroid-sparing maintenance therapy. Demographics, cardiac uptake of 18-fluorodeoxyglucose, and adverse cardiac events were compared before and during treatment and between those with persistent or interrupted immunosuppression. Twenty-eight CS patients were followed for a mean 4.1 (SD 1.5) years. Twenty-five patients received 4 to 8 weeks of high-dose prednisone (>30 mg/day), followed by taper and maintenance therapy with methotrexate±low-dose prednisone (low-dose prednisone, <10 mg/day). Adalimumab was added in 19 patients with persistently active CS or in those with intolerance to methotrexate. Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake, and patients receiving adalimumab-containing regimens experienced improved (84%) or resolved (63%) 18-fluorodeoxyglucose uptake. Radiologic relapse occurred in 8 of 9 patients after immunosuppression cessation, 4 patients on methotrexate-containing regimens, and in no patients on adalimumab-containing regimens. Conclusions Corticosteroid-sparing regimens containing methotrexate with or without adalimumab is an effective maintenance therapy in patients after an initial response is confirmed. Disease recurrence in patients on and off immunosuppression support need for ongoing radiologic surveillance regardless of immunosuppression regimen.

Patient Commitment to Health (PACT-Health) in the Heart Failure Population: A Focus Group Study of an Active Communication Framework for Patient-Centered Health Behavior Change.

BACKGROUND: Over 6 million Americans have heart failure, and 1 in 8 deaths included heart failure as a contributing cause in 2016. Lifestyle changes and adherence to diet and exercise regimens are important in limiting disease progression. Health coaching and public commitment are two interactive communication strategies that may improve self-management of heart failure. OBJECTIVE: This study aimed to conduct patient focus groups to gain insight into how best to implement health coaching and public commitment strategies within the heart failure population. METHODS: Focus groups were conducted in two locations. We studied 2 patients in Oakland, California, and 5 patients in Los Angeles, California. Patients were referred by local cardiologists and had to have a diagnosis of chronic heart failure. We used a semistructured interview tool to explore several patient-centered themes including medication adherence, exercise habits, dietary habits, goals, accountability, and rewards. We coded focus group data using the a priori coding criteria for these domains. RESULTS: Medication adherence barriers included regimen complexity, forgetfulness, and difficulty coping with side effects. Participants reported that they receive little instruction from care providers on appropriate exercise and dietary habits. They also reported personal and social obstacles to achieving these objectives. Participants were in favor of structured goal setting, use of online social networks, and financial rewards as a means of promoting health lifestyles. Peers were viewed as better motivating agents than family members. CONCLUSIONS: An active communication framework involving dissemination of diet- and exercise-related health information, structured goal setting, peer accountability, and financial rewards appears promising in the management of heart failure.

Noninvasive estimation of pulmonary vascular resistance improves portopulmonary hypertension screening in liver transplant candidates.

Despite limitations in sensitivity and specificity, estimation of the pulmonary artery systolic pressure (ePASP) on echocardiography is used for portopulmonary hypertension (PoPH) screening in liver transplant (LT) candidates. We proposed that alternative echocardiographic models, such as estimated pulmonary vascular resistance (ePVR), may provide improved testing characteristics in PoPH screening. In a retrospective analysis of 100 LT candidates, we found that the formula ePVR = ePASP/VTIRVOT  + 3 if MSN (VTIRVOT  = right ventricular outflow tract time velocity integral; MSN = mid-systolic notching of the VTIRVOT Doppler signal) significantly improves accuracy of PoPH screening compared to ePASP. We determined the optimal ePVR cutoff for PoPH screening to be 2.76 Wood units, as this cutoff provided 100% sensitivity and 73% specificity in screening for clinically significant PoPH. Comparatively, ePASP at a cutoff of 40 mm Hg provided 91% sensitivity and 48% specificity. We devised a new screening algorithm based on the use of ePVR at intermediate ePASP values (35-54 mm Hg), and we confirmed the testing characteristics of this algorithm in a separate validation cohort of 50 LT candidates. In screening LT candidates for PoPH, the ePASP lacks accuracy, leading to unnecessary RHCs and undiagnosed cases of PoPH. A screening algorithm which incorporates the ePVR may be more reliable.

Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation. OBJECTIVES: This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure. METHODS: ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot). RESULTS: AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10-12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects. CONCLUSIONS: AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130).

The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease.

OBJECTIVES: This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD). BACKGROUND: Patients with combined post- and pre-capillary PH-LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed. METHODS: A retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses. RESULTS: DPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg. CONCLUSIONS: In this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival.

What's new in the treatment of acute heart failure?

Acute heart failure is associated with substantial morbidity and mortality. Goals of treatment are decongestion, correction of hemodynamic abnormalities, symptom relief, and reducing long-term morbidity and mortality. Loop diuretics are a first-line agent for treatment of volume overload, with ultrafiltration reserved for those who do not respond to pharmacologic therapy. In patients with normal or elevated blood pressure, vasodilators are used to correct hemodynamics and reverse central volume redistribution, although no currently available agent has been shown to improve outcomes. Intravenous inotropes and inodilators are associated with frequent adverse effects and are reserved for patients with hypotension and evidence of inadequate perfusion. Novel drugs designed to maximize hemodynamic benefits while minimizing adverse effects are under investigation, with several agents showing promise in clinical studies.

Doppler echocardiography does not accurately estimate pulmonary artery systolic pressure in HIV-infected patients.

Doppler echocardiography is used to screen for HIV-related pulmonary arterial hypertension (HRPAH). We studied patients with HIV infection to determine the accuracy of Doppler echocardiography-estimated pulmonary artery systolic pressure (PASP) compared with PASP measured during right heart catheterization. Doppler echocardiography-estimated PASP was inaccurate in 19.7% of cases. Using Doppler echocardiography-estimated PASP, one in three patients with HRPAH was missed. Doppler echocardiography estimates of PASP are not accurate in patients with HIV.

The association of CD4+ T-cell counts and cardiovascular risk in treated HIV disease.

OBJECTIVE: HIV-infected individuals are at high risk of developing cardiovascular disease. Whether earlier initiation of HIV therapy at higher CD4 cell counts has any effect on cardiovascular risk as assessed by endothelial function is unknown. DESIGN: Cross-sectional study of 74 antiretroviral-treated men with undetectable plasma HIV RNA levels. METHODS: Participants underwent noninvasive assessment of endothelial function using brachial artery flow-mediated dilation (FMD). The association of nadir and current CD4 T-cell count with FMD was assessed using multivariable linear regression. RESULTS: The median age was 47 years [interquartile range (IQR) 42-55], median current CD4 T-cell count was 659 cells/µl (IQR 542-845), and nadir CD4 cell count was 314 cells/µl (IQR 150-490). Twenty-eight percent had hypertension, and 32% hyperlipidemia. Nadir CD4 T-cell count less than 350 cells/µl was associated with lower FMD in age-adjusted and race-adjusted analyses and remained an independent predictor of FMD after adjustment for cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidemia) and HIV-related characteristics (HIV duration, HAART duration). After multivariable adjustment, individuals with nadir CD4 T-cell count less than 350 cells/µl had a 1.22% lower FMD compared with those with higher T-cell counts [95% confidence interval (CI) -2.20 to -0.19, P=0.02]. Proximal CD4 T-cell count showed little association with FMD. CONCLUSION: Among treated HIV-infected individuals, nadir CD4 T-cell count less than 350 cells/µl is independently associated with lower FMD, suggesting that delayed therapy results in sustained harm to endothelial function. Our data support future prospective studies evaluating cardiovascular effects of HAART initiation at higher CD4 cell counts.

Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium.

Subjects infected with human immunodeficiency virus (HIV) have increased risk for atherosclerosis. Carotid artery intima-media thickness (IMT) assessed using ultrasound and coronary artery calcium (CAC) detected using computed tomography predict cardiovascular risk in the general population; however, their usefulness and comparability in patients with HIV are less well defined. The purpose of this study was to compare IMT and CAC in the detection of atherosclerosis in subjects with HIV. CAC and IMT were measured in 253 HIV-infected and 58 uninfected adults. Associations among HIV-related factors, traditional risk factors, and CAC and IMT were evaluated. The distribution of IMT among subjects with and without CAC was compared. Among the patients with HIV, 37% had detectable CAC compared to 28% of controls (p = 0.19); 16% of the patients with HIV had CAC >100 compared to 5% of controls (p = 0.03). With either detectable or undetectable CAC, HIV-infected subjects had higher IMT compared to controls (1.02 ± 0.34 vs 0.78 ± 0.12 mm, p <0.0001), even after adjustment for traditional risk factors. Among those with undetectable CAC, 34% of patients with HIV had markedly increased IMT (≥1 mm) compared to no controls (p <0.0001). HIV-related factors were associated with IMT but not with CAC. In conclusion, patients with HIV and controls had similar rates of detectable CAC, while absolute CAC scores were modestly higher in the HIV group. Conversely, carotid IMT detected advanced subclinical atherosclerosis in patients with HIV even in the absence of CAC. Thus, with HIV, IMT is associated with disease-related factors and may be a more sensitive indicator of subclinical atherosclerosis than CAC.

Cardiac arrest in patients who smoke crack cocaine.

The aim of the study is to determine the clinical features and outcomes of cocaine users admitted to the hospital after cardiac arrest and compare them with nonusers. Cocaine is associated with cardiovascular complications, including ventricular arrhythmias; however, resuscitated cardiac arrest in relation to cocaine use is not a well-defined clinical entity. We reviewed available hospital charts at San Francisco General Hospital with the International Classification of Diseases, Ninth Revision diagnosis of cardiac arrest and cocaine use from 1994 to 2006. Clinical features and outcomes of cocaine users were compared with those of randomly selected control patients and age-matched controls with resuscitated cardiac arrest without cocaine use. We identified 22 patients with resuscitated cardiac arrest in the setting of cocaine use. Their average age was 42 +/- 10 years, >20 years younger than nonusers (68 +/- 16 years, p <0.01). After cardiac arrest, 12 of 22 patients (55%) who used cocaine had complete neurologic recovery in contrast to only 3 of 20 unmatched controls (15%, p <0.01) and 7 of 41 age-matched controls (17%, p <0.01). Only 10 of 22 cocaine users (46%) died compared with 15 of 20 unmatched controls (75%, p = 0.05) and 32 of 41 age-matched controls (78%, p <0.01). In a combined analysis of all patients, cocaine use was the only significant predictor of neurologic recovery (p <0.01) and survival (p <0.01). In conclusion, cocaine use is associated with cardiac arrest. In patients with cardiac arrest, cocaine users are younger than nonusers and more likely to survive with neurologic recovery, even compared with age-matched controls with cardiac arrest.