Prevalence of prediabetes and undiagnosed diabetes in patients with HFpEF and HFrEF and associated clinical outcomes

Purpose: The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF). Methods: We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models. Results: HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c < 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c > 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups < 0.001. Dysglycemia was also associated with worse outcomes in HFrEF. Conclusions: These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF

Aliskiren, enalapril, or aliskiren and enalapril in heart failure

BACKGROUND Among patients with chronic heart failure, angiotensin-converting–enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. METHODS After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure. RESULTS After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001). CONCLUSIONS In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapri

Incidence of Atrial Fibrillation in Patients with either Heart Failure or Acute Myocardial Infarction and Left Ventricular Dysfunction: A Cohort Study

<p>Abstract</p> <p>Background</p> <p>We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months.</p> <p>Methods</p> <p>The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo.</p> <p>Results</p> <p>The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group.</p> <p>Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89).</p> <p>In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86).</p> <p>In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24).</p> <p>Conclusion</p> <p>In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).</p

Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure:pooled analysis of the DAPA-CKD and DAPA-HF trials

Background: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. Methods: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. Findings: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of −0·01% [95% CI −0·03 to 0·01], −0·1 mmol/mol [95% CI −0·3 to 0·1] at 12 months). Interpretation: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. Funding: AstraZeneca

Development and external validation of prognostic models to predict sudden and pump-failure death in patients with HFrEF from PARADIGM-HF and ATMOSPHERE

Background: Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF). Objective: Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies. Methods: We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial. Results: NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE. Conclusion: We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death. Trial registration number: PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658

Hereditary Hemochromatosis (HFE) genotypes in heart failure: Relation to etiology and prognosis

<p>Abstract</p> <p>Background</p> <p>It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the <it>HFE </it>gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of <it>HFE </it>genotypes.</p> <p>Methods</p> <p>We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known <it>HFE </it>variants C282Y, H63D and S65C.</p> <p>Results</p> <p>The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of <it>HFE </it>variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).</p> <p>Conclusion</p> <p><it>HFE </it>genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. <it>HFE </it>variants do not affect mortality in HF.</p

Effect of dapagliflozin on anaemia in DAPA-HF

Background: Anaemia is common in heart failure and associated with worse outcomes. We examined the effect of dapagliflozin on correction of anaemia in patients with heart failure and reduced ejection fraction (HFrEF) in DAPA‐HF. We also analyzed the effect of dapagliflozin on outcomes, according to anaemia status at baseline. Methods: Anaemia was defined at baseline as a haematocrit &lt;39% in men and &lt;36% in women. Resolution of anaemia was defined as two consecutive haematocrit measurements above these thresholds at any time during follow‐up. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.. Findings: Of the 4744 patients randomized in DAPA‐HF, 4691 had a haematocrit available at baseline, of which 1032 were anaemic (22.0%). The rate of the primary outcome was higher in patients with anaemia (16.1 per 100 person‐years) compared with those without (12.9 per 100 person‐years). Anaemia was corrected in 62.2% of patients in the dapagliflozin group, compared with 41.1% of patients in the placebo group. The effect of dapagliflozin on the primary outcome was consistent in anaemic compared with non‐anaemic patients (HR 0.68 [95%CI 0.52‐0.88] versus 0.76 [0.65‐0.89]; P‐interaction=0.44). Similar findings were observed for cardiovascular death, HF hospitalization, and all‐cause mortality. Patients with resolution of anaemia had better outcomes than those in which anaemia persisted. Conclusion: Patients with anaemia had worse outcomes in DAPA‐HF. Dapagliflozin corrected anaemia more often than placebo and improved outcomes, irrespective of anaemia status at baseline

Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction

Aims: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. Methods and results: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1–3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N‐terminal prohormone of B‐type natriuretic peptide (NT‐proBNP), and also examined using change from baseline heart rate to 1 year (≤ −10 bpm, ≥ +10 bpm, &lt; ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT‐proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35–1.66; P &lt; 0.001; per 10 bpm: 1.12, 95% CI 1.09–1.16; P &lt; 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09–1.26; P &lt; 0.001 vs. 1.07, 95% CI 1.02–1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. Conclusions: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT‐proBNP. There was no relationship between heart rate and outcomes in AF

Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144584/1/jah33160_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144584/2/jah33160-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144584/3/jah33160.pd