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Clinical characteristics, treatment patterns and outcomes in real-world HFrEF patients with worsening HF
Literature - Butler J, Yang M, Manzi MA et al. - JACC 2019;73(8): 935-44

Introduction and methods

Heart failure (HF) is an inherently progressive clinical condition. Worsening HF, characterized by development of progressively escalating symptoms and signs of HF that require intravenous diuretic therapy in the outpatient, emergency department or hospitalized setting, is suggested to be linked with markedly worse prognosis [1-4].

Because of high risk of adverse outcomes, there is growing interest in clinical trials with new interventions conducted in both acute and chronic stetting in subjects with worsening HF [5]. However, data on HF patients with reduced ejection fraction (HFrEF) and worsening HF has largely been derived from either clinical trial databases or registries limited to the patient’s hospital course, providing a limited understanding of this important, growing, and costly problem. This cohort analysis of linked registry- and claims-based data therefore examined the epidemiology, demographic and clinical characteristics, treatment patterns, and outcomes in patients with HFrEF who developed worsening HF.

This analysis (n=1.851) included data on patients aged ≥18 years with incident HFrEF (LVEF ≤45%; diagnosed between Jan 2011-Dec 2014) from the National Cardiovascular Data Registry (NCDR) PINNACLE who were followed (through June 2016) to assess worsening HF events. These data were linked to data from the Symphony Health (SH) claims databases. Patients with worsening HF were defined as those who: had ≥30 days of initial HF therapy after HFrEF diagnosis, were free from HF-related emergency care, hospitalizations, and outpatient intravenous diuretic administrations for ≥90 days from HFrEF diagnosis, and subsequently required ≥1 intravenous diuretic treatment in any health care setting or an HF-related hospitalization. Medication use was assessed 3 months before, at the time of, and 6 months after the worsening chronic HF event. All-cause mortality and hospitalization for HF, and numbers of recurrent hospitalization for HF were examined over 2 years of follow-up after the worsening chronic HF event.

Among 11.064 eligible HFrEF patients, 16.7% developed worsening of HF during the study period (mean 1.5 years) from the initial diagnosis of HF.

Main results


  • At least one comorbidity was seen in 94% of all patients and in 100% of those with worsening HF.
  • Patients who developed worsening HF were more likely to have hypertension (78.6% vs. 68.2%), CAD (63.5% vs. 52.8%), dyslipidemia (58.1% vs. 53.6%), AF/flutter (47.9% vs. 36.4%), diabetes mellitus (45.9% vs. 36.1%), MI (33.2% vs. 23.8%), COPD (28.9% vs. 16.6%), CKD (19.9% vs. 9.1%), PAD (19.3% vs. 12.5%), and anemia (24.0% vs. 15.1%) (all P<0.001), compared to those without worsening HF.

Treatment patterns

  • Across all 3 time points, beta-blocker use was higher than ACEi/ARB or MRA use in patients with worsening HF, regardless of regimen.
  • Reduced use of both beta-blockers (89.9% to 69.1%) and ACEi/ARB (54.6% to 46.0%) was seen at 6 months after the worsening HF event. MRA use remained consistently low across all 3 time points (21.2 to 24.7%).
  • Prior to worsening HF onset, dual therapy was used by 34.1% of patients and triple therapy by 13.7%. Among those taking monotherapy (33.7%), most patients (24.6%) took beta-blockers. Overall, 18.6% of patients did not take any of the 3 assessed therapies, 3 months prior to the index worsening event.
  • At time of worsening event, similar treatment patterns were observed. No appreciable change was seen in therapy patterns 6 months post-worsening event, with 13.4% of patients not taking any of the 3 assessed drug classes, and a smaller proportion (26.0%) receiving monotherapy.
  • At all time points, one-half of the participants took <50% maximum dose of beta-blockers and ACEi/ARBs.


  • 2-Year mortality rate was 22.5% and the mean survival time using Kaplan-Meier estimate was 19.7 (SD: 0.2) months in patients with worsening HF.
  • At all 3 time points, recurrent HF-related hospitalization was observed in 56%-70% of patients with worsening HF, and the numbers of recurrent hospitalization for HF increased with time from 0.7 (SD: 0.7) at 30 days post-worsening event to 2.0 (SD: 2.6) at 24 months post-worsening event.
Clinical characteristics, treatment patterns and outcomes in real-world HFrEF patients with worsening HF


In real-world setting, worsening HF in HFrEF patients is linked with high comorbidity burden and poor outcomes. HFrEF patients with worsening HF may have low medication use and suboptimal treatment regimens before and after the development of HF worsening events. These data indicate a need for both improved pharmacotherapy to prevent or delay the development of worsening HF and for new treatments in HFrEF patients, especially for those who are intolerant to available HF therapies.

Editorial comment

Bress and King [6] explain that HF is a complicated and progressive clinical syndrome. Although HFrEF pharmacotherapy can prevent disease progression, optimizing pharmacotherapy is challenging, particularly since it links to achieving target dosing. HFrEF patients who achieve <50% of target doses have an increased risk of mortality and hospitalization for HF.

The question therefore is: “why are medications not being initiated or up titrated?” despite guideline-directed medical therapy for HFrEF. The authors explain that the answer is elusive and likely includes multifactorial factors: health system (e.g. transitions of care between inpatient and outpatient clinical encounters), providers (e.g. poor documentation or clinical inertia), and patient (e.g. physiological limitations, acceptance, insurance, and cost status). These factors are interrelated and can stem from fragmented care across different providers and health systems. At the same time, it is hard to distinguish between appropriate inaction and inappropriate inaction (e.g. physiological limitations vs. lack of knowledge on importance of reaching target doses). It is therefore unclear to what degree low drug use represents an opportunity for improvement in the population vs. reality of physiological tolerability.

Another important question is: “With or without worsening HF, how do we improve medication initiation and titration in patients with HFrEF?”. The authors explain that although this answer is not simple, it has been shown that team-based care approaches, similar to those in hypertension, can effectively improve initiation and titration of HFrEF medications. Team-based care with a pharmacist has been shown to reduce hospitalization for HF compared with usual care, and to increase both the proportion of patients prescribed ACEis or ARBs and beta-blockers and the proportion at target or maximum tolerated doses. The ongoing PHARM-CHF trial will provide more information on medication adherence with team-based care.


1. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33.

2. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF). Circulation 2016; 133:2254–62.

3. Skali H, Dwyer EM, Goldstein R, et al. Prognosis and response to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail 2014;16: 560–5.

4. Rame JE, Sheffield MA, Dries DL, et al. Outcomes after emergency department discharge with a primary diagnosis of heart failure. Am Heart J 2001;142:714–9.

5. Butler J, Braunwald E, Gheorghiade M. Recognizing worsening chronic heart failure as an entity and an end point in clinical trials. JAMA 2014;312:789–90.

6. Bress AP and King JB. Optimizing Medical Therapy in Chronic Worsening HFrEF. A Long Way to Go. JACC 2019;73(8): 945-7

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