Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial.

BACKGROUND: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain. METHODS: In this prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we assessed the association between various nonfatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite end point of cardiovascular death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification. RESULTS: In DELIVER, 4532 (72%) patients experienced no worsening HF event, whereas 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had an HF hospitalization, and 271 (4%) died of cardiovascular causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 [8-12] per 100 patient-years) than those without a worsening HF event (4 [3-4] per 100 patient-years) but similar to rates of subsequent death after an urgent HF visit (10 [6-18] per 100 patient-years). Patients with an HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 [31-40] per 100 patient-years). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary end point (cardiovascular death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1122 to 1731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (hazard ratio, 0.72 [95% CI, 0.64-0.82]) and when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84]). CONCLUSIONS: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Missense Genetic Variation of ICAM1 and Incident Heart Failure.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF. METHODS AND RESULTS: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25-4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 - 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant. CONCLUSIONS: A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific.

Validation of the Calgary Postoperative Pain after Spine Surgery Score for Poor Postoperative Pain Control after Spine Surgery.

OBJECTIVE: The Calgary Postoperative Pain after Spine Surgery (CAPPS) score was developed to identify patients at risk of experiencing poorly controlled pain after spine surgery. The goal of this study was to independently validate the CAPPS score on a prospectively collected patient sample. METHODS: Poor postoperative pain control was defined as a mean numeric rating scale (NRS) for pain >4 at rest in the first 24 hours after surgery. Baseline characteristics in this study (validation cohort) were compared to those of the development cohort used to create the CAPPS score. Predictive performance of the CAPPS score was assessed by the area under the curve (AUC) and percentage misclassification for discrimination. A graphical comparison between predicted probability vs. observed incidence of poorly controlled pain was performed for calibration. RESULTS: Fifty-two percent of 201 patients experienced poorly controlled pain. The validation cohort exhibited lower depression scores and a higher proportion using daily opioid medications compared to the development cohort. The AUC was 0.74 [95%CI = 0.68-0.81] in the validation cohort compared to 0.73 [95%CI = 0.69-0.76] in the development cohort for the eight-tier CAPPS score. When stratified between the low- vs. extreme-risk and low- vs. high-risk groups, the percentage misclassification was 21.2% and 30.7% in the validation cohort, compared to 29.9% and 38.0% in the development cohort, respectively. The predicted probability closely mirrored the observed incidence of poor pain control across all scores. CONCLUSIONS: The CAPPS score, based on seven easily obtained and reliable prognostic variables, was validated using a prospectively collected, independent sample of patients.

Apolipoprotein E Polymorphism, Cardiac Remodeling, and Heart Failure in the ARIC Study.

BACKGROUND: ß-Amyloid has recently been discovered in the myocardium of patients with Alzheimer's disease (AD). Whether genetic variation in apolipoprotein E (APOE) ɛ4, a common variant associated with Alzheimer's disease, is associated with incident heart failure (HF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac structure and function is unknown. METHODS AND RESULTS: We studied 15,064 White and Black participants in the Atherosclerosis Risk in Communities, relating genotype status at visit 1 (1987-1989) to incident HF hospitalization using Cox regression. At visits 2, 4, and 5, we assessed NT-proBNP levels by genotype. At visits 3 and 5, we related Aß peptides to incident HF. At visit 5 (2011-2013, n = 6251), we assessed the relationship of genotype with prevalent HF and echocardiographic parameters. The mean participant age was 54.7 ± 5.8 years, 45% were men, and 73% were White. At visit 5, there was no difference in prevalent HF by genotype. The APOE ε4 carriers did not have increased risk for HF hospitalization. The APOE ε4 genotype was not associated with cardiac structure and function or NT-proBNP levels. The Aß peptides were not associated with incident HF after multivariable adjustment. CONCLUSIONS: A genetic predisposition to Alzheimer's disease through APOE ε4 is not associated with an increased prevalence of HF, HF hospitalization, myocardial remodeling, or biochemical evidence of HF.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials.

BACKGROUND: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. METHODS: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. RESULTS: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. CONCLUSIONS: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

Excess mortality in solid organ transplant recipients hospitalized with COVID-19: A large-scale comparison of SOT recipients hospitalized with or without COVID-19.

BACKGROUND: Solid-organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) have higher risk of adverse outcomes compared to the general population. Whether hospitalized SOT recipients with COVID-19 are at higher risk of mortality than SOT recipients hospitalized for other causes, including non-COVID-19 pneumonia, remains unclear. METHODS: We used logistic regression to compare outcomes of SOT recipients hospitalized with COVID-19 to non-COVID-19 related admissions and with non-COVID-19 pneumonia. RESULTS: Of 17,012 hospitalized SOT recipients, 1682 had COVID-19. Those with COVID-19 had higher odds of ICU admission (adjusted odds ratio [aOR] 2.12 [95%CI: 1.88-2.39]) and mechanical ventilation (aOR 3.75 [95%CI: 3.24-4.33]). COVID-19 was associated with higher odds of in-hospital death, which was more pronounced earlier in the pandemic (aOR 9.74 [95%CI: 7.08-13.39] for April/May vs. aOR 7.08 [95%CI: 5.62-8.93] for June through November 2020; P-interaction = .03). Compared to SOT recipients hospitalized with non-COVID-19 pneumonia, odds of in-hospital death were higher in SOT recipients with COVID-19 (aOR 2.44 [95% CI: 1.90-3.13]), regardless of time of hospitalization (P-interaction > .40). CONCLUSIONS: In this large cohort of SOT recipients, hospitalization with COVID-19 was associated with higher odds of complications and in-hospital mortality than non-COVID-19 related admissions, and 2.5-fold higher odds of in-hospital mortality, compared to SOT recipients with non-COVID-19 pneumonia.

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.

BACKGROUND: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and ß blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. METHODS: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, ß blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and ß blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and ß blocker). FINDINGS: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. INTERPRETATION: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, ß blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard. FUNDING: None.

Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation.

Peak oxygen consumption (pVO2) measured by cardiopulmonary exercise test (CPET) predicts mortality in adults with a Fontan circulation. The purpose of this study was to assess the additive prognostic value of change in pVO2 over time. METHODS: We analyzed a cohort of adults (≥18 years old) with a Fontan circulation who underwent at least 2 maximal CPETs separated by 6-30 months at Boston Children's Hospital between 2000 and 2015. Survival analysis was performed to determine whether changes in CPET variables, including pVO2 between consecutive tests, were associated with subsequent clinical events. The primary outcome was transplant-free survival. RESULTS: The study included 130 patients with 287 CPET test pairs. Average age was 26.6±9.5 years. Baseline pVO2 averaged 22.0±5.7 mL/kg/min or 60.9%±13.7% predicted. In the cohort overall, there was no change in mean pVO2 between sequential CPETs. Eleven patients died and 2 underwent transplant. On average, pVO2 declined for patients who subsequently died or underwent transplant but remained stable among those who did not (-9.8%±14.6% vs 0.0±13.0%, P<.01). Those with a decline in pVO2 between CPETs were at greater risk of death or transplantation (per 10% decrease in pVO2: HR=2.0, 95% CI 1.2-3.1, P=.004). Change in pVO2 remained a significant predictor of death or transplant after adjusting for pVO2 at first CPET (per 10% decline in pVO2: HR=2.5, 95% CI 1.5-4.2, P<.001). CONCLUSIONS: A decline in pVO2 between consecutive CPETs predicts increased risk for death or transplant in adults with a Fontan circulation independent of baseline pVO2. These results support the additive clinical value of serial CPET in this population.

Natural Language Processing for Adjudication of Heart Failure in a Multicenter Clinical Trial: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The gold standard for outcome adjudication in clinical trials is medical record review by a physician clinical events committee (CEC), which requires substantial time and expertise. Automated adjudication of medical records by natural language processing (NLP) may offer a more resource-efficient alternative but this approach has not been validated in a multicenter setting. Objective: To externally validate the Community Care Cohort Project (C3PO) NLP model for heart failure (HF) hospitalization adjudication, which was previously developed and tested within one health care system, compared to gold-standard CEC adjudication in a multicenter clinical trial. Design, Setting, and Participants: This was a retrospective analysis of the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared 2 influenza vaccines in 5260 participants with cardiovascular disease at 157 sites in the US and Canada between September 2016 and January 2019. Analysis was performed from November 2022 to October 2023. Exposures: Individual sites submitted medical records for each hospitalization. The central INVESTED CEC and the C3PO NLP model independently adjudicated whether the cause of hospitalization was HF using the prepared hospitalization dossier. The C3PO NLP model was fine-tuned (C3PO + INVESTED) and a de novo NLP model was trained using half the INVESTED hospitalizations. Main Outcomes and Measures: Concordance between the C3PO NLP model HF adjudication and the gold-standard INVESTED CEC adjudication was measured by raw agreement, κ, sensitivity, and specificity. The fine-tuned and de novo INVESTED NLP models were evaluated in an internal validation cohort not used for training. Results: Among 4060 hospitalizations in 1973 patients (mean [SD] age, 66.4 [13.2] years; 514 [27.4%] female and 1432 [72.6%] male]), 1074 hospitalizations (26%) were adjudicated as HF by the CEC. There was good agreement between the C3PO NLP and CEC HF adjudications (raw agreement, 87% [95% CI, 86-88]; κ, 0.69 [95% CI, 0.66-0.72]). C3PO NLP model sensitivity was 94% (95% CI, 92-95) and specificity was 84% (95% CI, 83-85). The fine-tuned C3PO and de novo NLP models demonstrated agreement of 93% (95% CI, 92-94) and κ of 0.82 (95% CI, 0.77-0.86) and 0.83 (95% CI, 0.79-0.87), respectively, vs the CEC. CEC reviewer interrater reproducibility was 94% (95% CI, 93-95; κ, 0.85 [95% CI, 0.80-0.89]). Conclusions and Relevance: The C3PO NLP model developed within 1 health care system identified HF events with good agreement relative to the gold-standard CEC in an external multicenter clinical trial. Fine-tuning the model improved agreement and approximated human reproducibility. Further study is needed to determine whether NLP will improve the efficiency of future multicenter clinical trials by identifying clinical events at scale.

Finerenone in Patients With a Recent Worsening Heart Failure Event: The FINEARTS-HF Trial.

BACKGROUND: Patients with heart failure (HF) and a recent worsening heart failure (WHF) event are known to be at high risk of recurrent hospitalization and death, regardless of ejection fraction. OBJECTIVES: This study examined the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in relation to the recency of a WHF event. METHODS: FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. In this prespecified analysis, we assessed the risk of cardiovascular (CV) events and response to finerenone vs placebo in relation to the time from WHF to randomization (during or within 7 days, 7 days to 3 months, >3 months, or no prior WHF). The primary outcome was a composite of total (first and recurrent) WHF events and CV death, analyzed using a proportional rates method. RESULTS: Of 6,001 patients validly randomized to finerenone or placebo, 1,219 (20.3%) were enrolled during (749 [12.5%]) or within 7 days (470 [7.8%]), 2,028 (33.8%) between 7 days and 3 months, and 937 (15.6%) >3 months from a WHF event; 1,817 (30.3%) had no prior history of WHF. Rates of the primary composite outcome varied inversely with time since WHF, with >2-fold higher risk in those enrolled during or within 7 days of WHF compared with those enrolled >3 months from WHF or without prior WHF (risk ratio [RR]: 2.13; 95% CI: 1.82-2.55). Compared to placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7 days of WHF (RR: 0.74; 95% CI: 0.57-0.95) or between 7 days and 3 months of WHF (RR: 0.79; 95% CI: 0.64-0.97) than in those >3 months from WHF or without prior WHF (RR: 0.99; 95% CI: 0.81-1.21); however, no definitive treatment-by-time interaction could be confirmed (P = 0.07). Greater absolute risk reductions with finerenone were accordingly seen in those with recent WHF (Ptrend = 0.011). The risk of adverse events including hyperkalemia and worsening renal function among patients assigned to finerenone was not increased in those with recent WHF. CONCLUSIONS: Compared with those without recent WHF, patients with HF and mildly reduced or preserved ejection fraction who have experienced a recent WHF event are at higher risk for recurrent HF events and CV death; a possible signal of enhanced absolute treatment benefit with finerenone in this population requires further confirmation in future studies. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; A study to gather information on the influence of study drug finerenone on the number of deaths and hospitalizations in participants with heart failure EudraCT 2020-000306-29).

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Impact of preoperative insomnia on poor postoperative pain control after elective spine surgery and the modified Calgary postoperative pain after spine surgery (MCAPPS) score.

Background: Approximately 30% to 64% of patients experience inadequate pain control following spine surgery. The Calgary postoperative pain after spine surgery (CAPPS) score was developed to identify this subset of patients. The impact of preoperative insomnia on postoperative pain control is unknown. This study aimed to investigate the relationship between preoperative insomnia and poor pain control after spine surgery, as well as improve the predictive accuracy of the CAPPS score. Methods: A prospective cohort study was conducted in patients undergoing elective spine surgery. Poor pain control was defined as a mean numeric rating scale pain score >4 at rest within the first 24-hours after surgery. Patients were evaluated using the CAPPS score, which included 7 prognostic factors. A multivariable logistic regression model was used to examine the association between preoperative insomnia severity index (ISI) and poor pain control, adjusting for the CAPPS score. The Modified CAPPS score was derived from this model. Results: Of 219 patients, 49.7% experienced poorly controlled pain. Prevalence of clinical insomnia (ISI≥15) was 26.9%. Preoperative ISI was independently associated with poor pain control (odds ratio [OR] 1.09, [95%CI=1.03-1.16], p=.004), after adjusting for the CAPPS score (OR 1.61, [95%CI=1.38-1.89], p<.001). The model exhibited good discrimination (c-statistics 0.80, [95%CI=0.74-0.86]) and calibration (Hosmer-Lemeshow chi-square=8.95, p=.35). The Modified CAPPS score also demonstrated good discrimination (c-statistic 0.78, [95%CI=0.72-0.84]) and calibration (Hosmer-Lemeshow chi-square=2.92, p=.57). Low-, high-, and extreme-risk groups stratified by the Modified CAPPS score had 17.3%, 49.1%, and 80.7% predicted probability of experiencing inadequate pain control compared to 32.0%, 64.0%, and 85.1% in the CAPPS score. Conclusions: Preoperative insomnia is prevalent and is a modifiable risk factor for poor pain control following spine surgery. Early identification and management of preoperative insomnia may lead to improved postoperative pain outcomes. Future external validation is needed to confirm the accuracy of the Modified CAPPS score.

Incremental prognostic value of biomarkers in PARADIGM-HF.

AIMS: It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure. METHODS AND RESULTS: Aldosterone, cystatin C, high-sensitivity troponin T (hs-TnT), galectin-3, growth differentiation factor-15 (GDF-15), kidney injury molecule-1, matrix metalloproteinase-2 and -9, soluble suppression of tumourigenicity-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM-HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT-HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all-cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow-up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs-TnT, GDF-15, cystatin C and TIMP-1. When all biomarkers were added simultaneously to the PREDICT-HF models, only hs-TnT remained an independent predictor of all three endpoints. GDF-15 also remained predictive of the primary endpoint; TIMP-1 was the only other predictor of both cardiovascular and all-cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification. CONCLUSIONS: None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables.

Natural Language Processing for Adjudication of Heart Failure Hospitalizations in a Multi-Center Clinical Trial.

Background: The gold standard for outcome adjudication in clinical trials is chart review by a physician clinical events committee (CEC), which requires substantial time and expertise. Automated adjudication by natural language processing (NLP) may offer a more resource-efficient alternative. We previously showed that the Community Care Cohort Project (C3PO) NLP model adjudicates heart failure (HF) hospitalizations accurately within one healthcare system. Methods: This study externally validated the C3PO NLP model against CEC adjudication in the INVESTED trial. INVESTED compared influenza vaccination formulations in 5260 patients with cardiovascular disease at 157 North American sites. A central CEC adjudicated the cause of hospitalizations from medical records. We applied the C3PO NLP model to medical records from 4060 INVESTED hospitalizations and evaluated agreement between the NLP and final consensus CEC HF adjudications. We then fine-tuned the C3PO NLP model (C3PO+INVESTED) and trained a de novo model using half the INVESTED hospitalizations, and evaluated these models in the other half. NLP performance was benchmarked to CEC reviewer inter-rater reproducibility. Results: 1074 hospitalizations (26%) were adjudicated as HF by the CEC. There was high agreement between the C3PO NLP and CEC HF adjudications (agreement 87%, kappa statistic 0.69). C3PO NLP model sensitivity was 94% and specificity was 84%. The fine-tuned C3PO and de novo NLP models demonstrated agreement of 93% and kappa of 0.82 and 0.83, respectively. CEC reviewer inter-rater reproducibility was 94% (kappa 0.85). Conclusion: Our NLP model developed within a single healthcare system accurately identified HF events relative to the gold-standard CEC in an external multi-center clinical trial. Fine-tuning the model improved agreement and approximated human reproducibility. NLP may improve the efficiency of future multi-center clinical trials by accurately identifying clinical events at scale.

Machine Learning to Understand Genetic and Clinical Factors Associated With the Pulse Waveform Dicrotic Notch.

BACKGROUND: Absence of a dicrotic notch on finger photoplethysmography is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease. However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident cardiovascular disease. METHODS: In 169 787 participants in the UK Biobank, we identified absent dicrotic notch on photoplethysmography and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait. RESULTS: Heritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome-wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10-26), IGFBP3 (P=4.8×10-18), and PHACTR1 (P=1.4×10-13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident cardiovascular disease and all-cause death in UK Biobank participants without available photoplethysmography data. CONCLUSIONS: We found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on photoplethysmography was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident cardiovascular disease. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

Genetics of myocardial interstitial fibrosis in the human heart and association with disease.

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor ß1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.