Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure ...hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI Angiotensin Receptor-Neprilysin Inhibitor With ACEI Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only.
Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29;
=0.008) and KCCQ overall summary score (+1.13 versus -0.14;
<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%;
=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months.
Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
This study compares a deep learning interpretation of 23 echocardiographic parameters-including cardiac volumes, ejection fraction, and Doppler measurements-with three repeated measurements by core ...lab sonographers. The primary outcome metric, the individual equivalence coefficient (IEC), compares the disagreement between deep learning and human readers relative to the disagreement among human readers. The pre-determined non-inferiority criterion is 0.25 for the upper bound of the 95% confidence interval. Among 602 anonymised echocardiographic studies from 600 people (421 with heart failure, 179 controls, 69% women), the point estimates of IEC are all <0 and the upper bound of the 95% confidence intervals below 0.25, indicating that the disagreement between the deep learning and human measures is lower than the disagreement among three core lab readers. These results highlight the potential of deep learning algorithms to improve efficiency and reduce the costs of echocardiography.
Data were analyzed from 40,195 patients with heart failure with reduced ejection fraction enrolled in 12 clinical trials in the 1995–2014 period. Sudden-death rates declined substantially over time, ...a finding consistent with a cumulative effect of evidence-based medical therapy.
Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that ...circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.
This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).
N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.
At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval CI: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.
Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction PARAGON-HF; NCT01920711)
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Abstract
Aims
The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin–angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) ...with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF).
Methods and results
We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 95% confidence interval (CI) 0.45–0.65 for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35–58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7–46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64–0.82), first HF hospitalization (RR 0.67, 95% CI 0.58–0.78), cardiovascular death (RR 0.76, 95% CI 0.64–0.89), and all-cause death (RR 0.83, 95% CI 0.71–0.96); all P < 0.02.
Conclusion
This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.
Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. ...We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure).
Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death.
Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7;
<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (
=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1;
=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class.
In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty.
URL: https://www.
gov; Unique identifier: NCT03619213.
Background and Aims Current guidelines advise that upper endoscopy be performed within 24 hours of presentation in patients with acute nonvariceal upper GI bleeding (UGIB). However, the role of ...urgent endoscopy (<12 hours) is controversial. Our aim was to assess whether patients admitted with acute nonvariceal UGIB with lower-risk versus high-risk bleeding have different outcomes with urgent compared with nonurgent endoscopy. Methods A retrospective cohort study was conducted of patients admitted to an academic hospital with nonvariceal UGIB. The primary outcome was a composite of inpatient death from any cause, inpatient rebleeding, need for surgical or interventional radiologic intervention, or endoscopic reintervention. The Glasgow-Blatchford score (GBS) was calculated; lower risk was defined as a GBS < 12, and high risk was defined as a GBS ≥ 12. Results Of 361 patients, 37 patients (10%) experienced the primary outcome. Patients who underwent urgent endoscopy had a greater than 5-fold increased risk of reaching the composite outcome (unadjusted odds ratio OR, 5.6; 95% confidence interval CI, 2.8-11.4; P < .001). Lower-risk patients who were taken urgently to endoscopy were more likely to reach the composite outcome (adjusted OR, 0.71 per 6 hours; 95% CI, 0.55-0.91; P = .008). However, in the high-risk patients, time to endoscopy was not a significant predictor of the primary outcome (adjusted OR, 0.93 per 6 hours; 95% CI, 0.77-1.13; P = .47; adjusted P for interaction = .039). Conclusion Urgent endoscopy is a predictor of worse outcomes in select patients with acute nonvariceal UGIB.
The purpose of this study was to compare the win ratio (WR) with the corresponding hazard ratios (HRs) and 1/HR.
The primary outcome in many cardiovascular trials is a composite that includes ...nonfatal and fatal events. The time-to-first event analysis gives equal statistical weighting to each component event. The WR, which takes into account the clinical importance and timing of the outcomes, has been suggested as an alternative approach.
Cox proportional hazards models and WR.
In the these trials (n = 16) the WR and HR differed only slightly. For example, in the PARADIGM-HF (sacubitril/valsartan vs. enalapril), the primary outcome of time to first heart failure hospitalization (HFH) or cardiovascular death (CVD) and use of the Cox model gave a 1/HR of 1.25 (95% confidence interval CI: 1.12 to 1. 41; z-score = 4.8). Using WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.27 (95% CI: 1.15 to 1.39; z-score = 4.7), reflecting an effect similar to that of sacubitril/valsartan therapy on CVD and HFH. In the DIG (digoxin vs. placebo) trial, the outcome of time-to-first HFH or CVD using Cox gave a 1/HR of 1.18 (95% CI: 1.10 to 1.27; z-score = 4.5). Using the WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.14 (95% CI: 1.05 to 1.20; z-score = 3.1), reflecting a larger effect of digoxin on HFH than on CVD. Several other trials and endpoints including patient-reported measurements were studied.
In 16 large cardiovascular outcome trials, HR and WR provided similar estimates of treatment effects. The WR allows prioritization of fatal outcomes and the hierarchical testing of broader composite endpoints including patient-reported outcomes. In this way, the WR allows for the incorporation of patient-centered and other outcomes, while prioritizing the competing risk of death and hospital admission.
This study sought to describe characteristics and risk of adverse outcomes associated with the H2FPEF and HFA-PEFF scores among participants in the community with unexplained dyspnea.
Diagnosing ...heart failure with preserved ejection fraction (HFpEF) can be challenging. The H2FPEF and HFA-PEFF scores have recently been developed to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea.
The study included 4,892 ARIC (Atherosclerosis Risk In Communities) study participants 67 to 90 years of age at visit 5 (2011 to 2013) without other common cardiopulmonary causes of dyspnea. Participants were categorized as asymptomatic (76.6%), having known HFpEF (10.3%), and having tertiles of each score among those with ≥moderate, self-reported dyspnea (13.1%). The primary outcome was heart failure (HF) hospitalization or death.
Mean age was 75 ± 5 years, 58% were women, and 22% were black. After a mean follow-up of 5.3 ± 1.2 years, rates of HF hospitalization or death per 1,000 person-years for asymptomatic and known HFpEF were 20.7 (95% confidence interval CI: 18.9 to 22.7) and 71.6 (95% CI: 61.6 to 83.3), respectively. Among 641 participants with unexplained dyspnea, rates were 27.7 (95% CI: 18.2 to 42.1), 44.9 (95% CI: 34.9 to 57.7), and 47.3 (95% CI: 36.5 to 61.3) (tertiles of H2FPEF score) and 31.8 (95% CI: 20.3 to 49.9), 32.4 (95% CI: 23.4 to 44.9), and 54.3 (95% CI: 43.8 to 67.3) (tertiles of HFA-PEFF score). Participants with unexplained dyspnea and scores above the diagnostic threshold suggested for each algorithm, H2FPEF score ≥6 and HFA-PEFF score ≥5, had equivalent risk of HF hospitalization or death compared with known HFpEF. Among those with unexplained dyspnea, 28% had “discordant” findings (only high risk by 1 algorithm), while 4% were high risk by both.
Participants with unexplained dyspnea and higher H2FPEF or HFA-PEFF scores face substantial risks of HF hospitalization or death. A significant fraction of patients are classified discordantly by using both algorithms.
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