Progression to Stage D Heart Failure

Study Questions:

What is the the rate of progression to Stage D heart failure (HF) among outpatients with Stage C HF, and what are risk factors for progression?


The study cohort was comprised of 964 consecutive adult (age ≥18 years) outpatients with Stage C HF with reduced ejection fraction (HFrEF) (EF ≤40%) who received care between January 1, 2012 and March 31, 2012 in a single health care system in the United States. The inception time frame was selected to allow for ≥3 years of follow-up. The study authors estimated 3-year progression to clinically determined Stage D HF and competing mortality. The primary endpoint was progression to Stage D HF in a time-to-event analysis accounting for the competing risk of death. The secondary endpoints were: 1) the combined endpoint of either death or progression to Stage D HF (time to event), and 2) competing mortality. They selected the composite endpoint to reflect progression rates from stable Stage C HF to unstable status. They powered this study to demonstrate progression rates to Stage D HF within prespecified confidence limits. Based on an interim analysis, they estimated that 3-year rate of progression to Stage D HF was 13.0%. Therefore, the authors targeted a final sample size of 930 patients with 10% margin for loss to follow-up. This sample size would provide 80% power at the 2-sided α = 0.05 to reject the hypothesis that the lower 95% confidence interval (CI) of 3-year progression to Stage D HF crosses the 10% boundary. To identify risk factors for progression to Stage D HF (primary endpoint) taking into account competing mortality, they used Fine and Gray competing-risks proportional hazards models, which are appropriate here because of the high rate of the competing event.


The mean age of the study cohort was 62 ± 15 years; 47% were white and 46% black; 35% were women; median (25th-75th percentile) left ventricular EF was 28% (20%-35%); 47% had ischemic heart disease; and 49% were in New York Heart Association (NYHA) class I-II versus 51% in NYHA class III-IV. Beta-blockers were used in 90%, angiotensin-modulating agents in 72%, and aldosterone antagonists in 28% of patients; 48% had an implantable cardioverter-defibrillator and 20% were on cardiac resynchronization therapy. The median follow-up period was 3.0 years (1.7-3.2). Over 90% of patients had at least 1 year of follow-up. During this period, 112 patients progressed to Stage D and 116 died before progressing to Stage D HF. The 3-year incidence of progression to Stage D HF (primary endpoint) after accounting for competing mortality was 12.2% (95% CI, 10.2%-14.6%) with an annualized rate of 4.5% (95% CI, 3.8%-5.5%) and 116 died before progression (3-year competing mortality: 12.9%; annualized: 4.7%; 95% CI, 3.9%-5.6%). By 3 years, 25.1% of patients (95% CI, 22.2%-28.1%) had either progressed to Stage D or died (annualized: 9.2%; 95% CI, 8.1%-10.5%). Annualized progression rates were higher in black versus white (6.3% vs. 2.7%; p < 0.001), nonischemic versus ischemic (6.1% vs. 2.9%; p < 0.001), and NYHA class III-IV versus I-II patients (7.5% vs. 1.9%; p < 0.001), but similar for men and women (4.7% vs. 4.2%; p = 0.53). Additional predictors of progression included lower EF and blood pressure, renal and hepatic dysfunction, and chronic lung disease. Predictors of competing mortality were different from those of disease progression—older age, worse NYHA class, history of hypertension, presence of atrial fibrillation, serum sodium, and creatinine were independent predictors of competing mortality; use of angiotensin-modulating agents and beta-blockers was associated with lower mortality. Gender, race, and ischemic etiology did not independently predict competing mortality. One out of eight outpatients with Stage C HFrEF receiving care in cardiology (including HF) clinics progressed to Stage D within 3 years, and another one out of eight died within the same period; in all, one out of four patients either died or progressed to Stage D within 3 years. Half of the patients died before progressing to Stage D.


The study authors concluded that among patients with Stage C HFrEF receiving care in a referral center, 4.5% progressed to Stage D HF each year, with earlier progression among black and nonischemic patients. Based on these data, conservative estimates suggest that over 100,000 patients with HFrEF would progress to Stage D HF in the United States annually.


Although this is a single-center study, the findings are important because they suggest that risk factors for progression of HF are different from that for mortality. Therefore, the management of HF should target risk reduction of both disease progression and mortality. Estimates from the study suggest that palliative care will play an important role in the management of HF. Multicenter data are needed to improve outcomes, particularly in a minority population, and also for resource planning such as development of palliative care services.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Interventions and Coronary Artery Disease, Hypertension

Keywords: Adrenergic beta-Antagonists, Atrial Fibrillation, Blood Pressure, Cardiac Resynchronization Therapy, Cardiac Surgical Procedures, Coronary Artery Disease, Creatinine, Defibrillators, Implantable, Disease Progression, Geriatrics, Heart Failure, Hypertension, Lung Diseases, Mineralocorticoid Receptor Antagonists, Palliative Care, Risk Factors, Stroke Volume

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