BACKGROUND:In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)—prolonged ...P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA2DS2-VASc score would improve its ability to predict AF-related ischemic stroke.
METHODS:We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement.
RESULTS:Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33–2.55) independent of CHA2DS2-VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHA2DS2-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P2-CHA2DS2-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51–0.69) to 0.67 (0.60–0.75) in ARIC and 0.68 (0.52–0.84) to 0.75 (0.60–0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13–0.39) and 0.51 (0.18–0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96–1.44) and 0.82 (0.36–1.39), respectively.
CONCLUSIONS:Abnormal P-wave axis—an ECG correlate of left atrial abnormality— improves ischemic stroke prediction in AF. Compared with CHA2DS2-VASc, the P2-CHA2DS2-VASc is a better prediction tool for AF-related ischemic stroke.
The purpose of this study was to evaluate in-hospital outcomes among patients with a history of heart failure (HF) hospitalized with coronavirus disease-2019 (COVID-19).
Cardiometabolic comorbidities ...are common in patients with severe COVID-19. Patients with HF may be particularly susceptible to COVID-19 complications.
The Premier Healthcare Database was used to identify patients with at least 1 HF hospitalization or 2 HF outpatient visits between January 1, 2019, and March 31, 2020, who were subsequently hospitalized between April and September 2020. Baseline characteristics, health care resource utilization, and mortality rates were compared between those hospitalized with COVID-19 and those hospitalized with other causes. Predictors of in-hospital mortality were identified in HF patients hospitalized with COVID-19 by using multivariate logistic regression.
Among 1,212,153 patients with history of HF, 132,312 patients were hospitalized from April 1, 2020, to September 30, 2020. A total of 23,843 patients (18.0%) were hospitalized with acute HF, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 patients (75.6%) were hospitalized with alternative reasons. Hospitalization with COVID-19 was associated with greater odds of in-hospital mortality as compared with hospitalization with acute HF; 24.2% of patients hospitalized with COVID-19 died in-hospital compared to 2.6% of those hospitalized with acute HF. This association was strongest in April (adjusted odds ratio OR: 14.48; 95% confidence interval CI:12.25 to 17.12) than in subsequent months (adjusted OR: 10.11; 95% CI: 8.95 to 11.42; pinteraction <0.001). Among patients with HF hospitalized with COVID-19, male sex (adjusted OR: 1.26; 95% CI: 1.13 to 1.40) and morbid obesity (adjusted OR: 1.25; 95% CI: 1.07 to 1.46) were associated with greater odds of in-hospital mortality, along with age (adjusted OR: 1.35; 95% CI: 1.29 to 1.42 per 10 years) and admission earlier in the pandemic.
Patients with HF hospitalized with COVID-19 are at high risk for complications, with nearly 1 in 4 dying during hospitalization.
Display omitted
Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.
The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in ...patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.
The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.
Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.
Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure DELIVER; NCT03619213)
Display omitted
Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all ...individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known.
We used data from 2 SGLT2i trials (CANVAS Canagliflozin Cardiovascular Assessment and CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), 2 ns-MRA trials (FIDELIO-DKD Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease and FIGARO-DKD Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE.
Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained 95% CI, 2.1-4.3). There were also projected gains in survival free from hospitalized heart failure (3.2 years 95% CI, 2.4-4.0), chronic kidney disease progression (5.5 years 95% CI, 4.0-6.7), cardiovascular death (2.2 years 95% CI, 1.2-3.0), and all-cause death (2.4 years 95% CI, 1.4-3.4). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years 95% CI, 1.1-3.5), chronic kidney disease progression (4.5 years 95% CI, 2.8-5.9), and all-cause death (1.8 years 95% CI, 0.7-2.8).
In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.
Guidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.
This study sought to determine the optimal ...achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.
Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro−B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.
Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.
Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction PARAGON-HF; NCT01920711)
Display omitted
Aims
Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing ...of other elements of guideline‐directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β‐blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial.
Methods and results
Patients with full data on medication use were included. We examined β‐blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12‐month follow‐up. New initiations and discontinuations of β‐blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β‐blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of β‐blocker and MRA were similar between treatment groups at baseline and at 6‐month and 12‐month follow‐up. New initiations through 12‐month follow‐up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β‐blockers 37 (9.0%) vs. 42 (10.2%), P = 0.56 and MRA 127 (7.6%) vs. 143 (9.2%), P = 0.10. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months 125 (6.2%) vs. 187 (9.0%), P = 0.001. Discontinuations of β‐blockers were not significantly different between groups in follow‐up (2.2% vs. 2.6%, P = 0.26).
Conclusions
Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down‐titration of other key guideline‐directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow‐up.
Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of ...disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made.
To develop and validate a prognostic model for patients with HF.
Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018.
Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years.
Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8399), and 70.6% were New York Heart Association class II (n = 5919 of 8399). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, β-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual's risk (http://www.predict-hf.com).
Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.
This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on ...the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial.
Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown.
DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group.
A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan.
Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure DAPA-HF; NCT03036124).
PDF
