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Impact of Worsening Heart Failure on Long-Term Prognosis in Patients With Heart Failure With Reduced Ejection Fraction

Open AccessPublished:September 23, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.08.035
      Worsening heart failure (HF), defined as hospitalization for worsening signs and symptoms of HF or the need for urgent intravenous diuretics, is often considered a surrogate of poor prognosis in clinical trials. However, data on the prognostic implications of worsening HF in patients with HF and reduced ejection fraction is limited. Patients who had a first echocardiographic diagnosis of left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) ≤45%, were identified. Worsening HF was defined as hospitalization for HF or urgent need for intravenous diuretics. All-cause mortality was chosen as the study end point. A total of 1,801 patients (mean age 64 ± 12 years, 74% men) were analyzed. Worsening HF was observed in 275 patients (15%) during a median follow-up of 20 months, while, 435 patients (24%) died during a median follow-up of 60 months (Interquartile range 28 to 60 months). The 5-year survival rate was significantly lower in the worsening HF cohort compared with the non-worsening HF cohort (Log-rank p <0.0001), and it was significantly different between the worsening HF cohort and the nonworsening HF cohort for LVEF ≤25% (log-rank p <0.0001) and LVEF 26% to 34% (log-rank p = 0.038) but not for LVEF 35% to 45% (log-rank p = 0.14). After adjustment for important clinical and echocardiographic predictors, worsening HF was independently associated with a higher risk of all-cause mortality (hazard ratio 1.46, 95% confidence interval 1.09 to 1.96, p = 0.011). In conclusion, worsening HF, defined by HF hospitalization or the urgent need for intravenous diuretics, is independently associated with poor long-term prognosis in patients with HF and reduced ejection fraction.

      Introduction

      The prevalence of heart failure (HF) has been increasing over the past decades and causes a major economic and healthcare burden.
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      Although new treatments options, including guideline-directed medical therapy (GDMT), coronary revascularization, implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) have improved survival, HF with reduced ejection fraction (HFrEF) is still associated with a significantly increased risk for cardiovascular events and high mortality.
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      Hospitalization for worsening HF contributes to increased economic burden, reduced quality of life, and increased risk of death.
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      Predictors of mortality and morbidity in patients with chronic heart failure.
      Although different definitions of worsening HF have been used in clinical studies, rehospitalization because of worsening signs or symptoms of HF
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      or the need for intravenous diuretics
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      despite optimal GDMT is the most commonly accepted definition and is utilized in recent major HF trials.
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      VICTORIA Study Group
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      DAPA-HF Trial Committees and Investigators
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Worsening HF could occur at any stage of the HF disease process, regardless of baseline left ventricular (LV) systolic function. Integration of echocardiographic and clinical variables reflecting the severity of HF may further improve the risk stratification of patients with HF and reduced ejection fraction (HFrEF). A better understanding of the relation between worsening HF, baseline LV systolic function, and long-term outcomes is important and could have major implications for clinical care and postdischarge surveillance. In the present study, we investigated the association between worsening HF and all-cause mortality along with important echocardiographic parameters of LV systolic function using data from a large, real-life registry of patients with HFrEF who were treated with optimal GDMT.

      Methods

      From an ongoing registry of patients with HF and a first echocardiographic diagnosis of LV systolic dysfunction, defined as an LV ejection fraction (LVEF) ≤45% (Leiden University Medical Center, The Netherlands), patients ≥18 years who presented between November 1993 to June 2020 were identified. Patients diagnosed with active cancer at baseline or who died within the first 30 days of follow-up were excluded. Patients underwent complete clinical and echocardiographic evaluation at the time of the first diagnosis. Baseline clinical data were collected from the departmental information system (EPD-Vision, Leiden University Medical Centre, Leiden, The Netherlands) at the time of the first echocardiogram on which a LVEF ≤45% was documented. Baseline clinical data included demographic data, cardiovascular risk factors, co-morbidities, and laboratory results. Most patients received up-titration of GDMT within the first year after diagnosis of HF (LVEF ≤45%). Accordingly, maximum tolerated GDMT was defined at 1 year follow-up. Similarly, data on invasive procedures including percutaneous coronary intervention, coronary artery bypass graft surgery, ICD, and CRT were also considered 1 year after the index echocardiography. All data used in the present study were collected for routine clinical purposes and handled anonymously. Written informed consent was waived by the Institutional Review Board. The study was performed according to the principles outlined in the Declaration of Helsinki.
      • Rickham PP.
      Human experimentation. Code of ethics of the World Medical Association. Declaration of Helsinki.
      The index echocardiography was the first examination from which an LVEF ≤45% was diagnosed. All patients underwent transthoracic echocardiography in the left lateral decubitus position using a commercially available echocardiography system (Vivid 7, E9, and E95, GE Vingmed Ultrasound, Horten, Norway). M-mode and 2-dimensional images were obtained, saved in cine loop format, and digitally archived for offline analysis (EchoPac 202 and 203, GE Vingmed Ultrasound, Horten, Norway). The LV end-diastolic volume and LV end-systolic volume were measured and LVEF was calculated from the apical 4- and 2-chamber views using the Simpson's biplane method.
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      • Lancellotti P
      • Muraru D
      • Picard MH
      • Rietzschel ER
      • Rudski L
      • Spencer KT
      • Tsang W
      • Voigt JU.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      Left atrial (LA) volume was measured from the apical 4- and 2-chamber views using the biplane method of disks at LV end-systole
      • Lang RM
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      • Lancellotti P
      • Muraru D
      • Picard MH
      • Rietzschel ER
      • Rudski L
      • Spencer KT
      • Tsang W
      • Voigt JU.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      and indexed for body surface area (LA volume index). The severity of mitral regurgitation and tricuspid regurgitation was evaluated and graded according to current recommendations.
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      Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
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      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      The study end point was all-cause mortality. Worsening HF was defined as the first hospital admission for HF or a visit to the emergency department which required intensification of intravenous diuretic use after the index echocardiography. On the basis of the presence or absence of worsening HF, the study population was divided into 2 groups, “worsening HF” and “non-worsening HF.” Data on mortality were obtained from the departmental cardiology information system (EPD-Vision, Leiden University Medical Centre, Leiden, The Netherlands), which is linked to the governmental death registry database. Data on worsening HF were acquired by reviewing medical records archived in the departmental information system. Follow-up time was calculated from the date on which LVEF ≤45% was first documented on index echocardiography. All patients were followed up until the occurrence of the study end point, loss of follow-up, or 5-year follow-up.
      Normally distributed (assessed by the Shapiro-Wilk test and distribution histograms), continuous variables are presented as mean ± SD and not normally distributed variables as median and interquartile range. Categorical variables are presented as frequencies and percentages. Continuous variables were compared using independent samples t tests when normally distributed, whereas the Mann-Whitney U test was used to compare continuous variables that were not normally distributed. Categorical variables were compared using chi-square test. Survival curves were generated using the Kaplan–Meier method and differences between the worsening HF groups were compared with the log-rank test. Separate survival curves were generated according to different LVEF subgroups at baseline: LVEF ≤25%, LVEF 26% to 34%, and LVEF 35% to 45%. Univariable and multivariable Cox proportional hazard regression analyses were used to determine the relation between separate variables and all-cause mortality. The multivariable analysis included the variables which showed significant association with the univariable analysis. For both univariable and multivariable analyses, hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. The time-dependent effect of worsening HF was assessed using an additional landmark analysis defined as 24 months from the index echocardiography. Patients who died or were lost to follow-up before the prespecified landmark time were excluded from the landmark analysis.
      • Dafni U
      Landmark analysis at the 25-year landmark point.
      Finally, an unadjusted time-depending covariate analysis of all-cause mortality for worsening HF versus no worsening HF was modeled to correct the time dependency of worsening HF events. All statistical tests were two-sided, and a p <0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS for Windows version 25.0 (IBM Corporation, Armonk, New York) and R version 4.2.0 (survival package v3.1-12 and survminer 0.4.9 package, R Foundation for Statistical Computing, Vienna, Austria).

      Results

      A total of 1,801 patients were included (mean age 64 ± 12 years, 74% men). Baseline clinical and echocardiographic characteristics of the overall population and differences between patients who experienced and who did not experience worsening HF at follow-up are summarized in Table 1. Worsening HF was observed in 275 patients (15%) during a median follow-up of 20 months. Patients who experienced worsening HF at follow-up had a higher prevalence of family history of coronary artery disease (27% vs 18%, p = 0.004), myocardial infarction (49% vs 39%, p = 0.010), percutaneous coronary intervention (35% vs 27%, p = 0.010), ICD implantation (51% vs 31%, p <0.001) and CRT implantation (29% vs 17%, p <0.001). The use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (72% vs 63%, p = 0.010), diuretics (71% vs 55%, p <0.001), antiarrhythmic drugs (22% vs 14%, p = 0.003) and digoxin (16% vs 9%, p <0.001) were significantly higher in the patients who experienced worsening HF at follow-up compared with patients who did not. The differences in baseline echocardiographic parameters between patients who experienced worsening HF and those who did not are summarized in Table 2. LV end-diastolic volume (167 ± 84 ml vs 149 ± 72 ml, p <0.001), LV end-systolic volume (122 ± 71 ml vs 106 ± 57 ml, p <0.001), and LA volume index (43 ± 21 ml/m2 vs 40 ± 20 ml/m2, p = 0.041) were significantly larger, whereas LVEF (29 ± 9% vs 30 ± 9%, p = 0.010) was significantly lower in patients who experienced worsening HF compared with those who did not.
      Table 1Baseline characteristics
      VariableOverall population (n = 1801)Worsening HFp-Value
      Yes (n = 275)No (n = 1526)
      Age (years)64±1263±1264±130.168
      Men1334 (74%)214 (78%)1120 (73%)0.123
      BSA (m2)1.98±0.231.99±0.231.97±0.230.433
      Hemoglobin (mg/dl)148±24152±24147±240.009
      eGFR (ml/min/1.73m2)68±2666±2668±260.272
      Current smoker284 (16%)53 (19%)231 (15%)0.178
      Ex-smoker430 (24%)72 (26%)358 (24%)0.629
      DM363 (20%)61 (22%)302 (20%)0.610
      Arterial hypertension711 (40%)112 (41%)599 (39%)0.833
      Hyperlipidemia519 (29%)79 (29%)440 (29%)0.568
      Family history of CAD355 (20%)74 (27%)281 (18%)0.004
      CAD955 (53%)164 (60%)791 (52%)0.081
      MI724 (40%)134 (49%)590 (39%)0.008
      COPD193 (11%)36 (13%)157 (10%)0.270
      CKD461 (26%)79 (29%)382 (25%)0.484
      AF500 (28%)82 (30%)418 (27%)0.731
      PCI501 (28%)97 (35%)404 (27%)0.010
      CABG417 (23%)68 (25%)349 (23%)0.805
      ICD implantation611 (34%)141 (51%)470 (31%)<0.001
      CRT implantation343 (19%)79 (29%)264 (17%)<0.001
      Valvular intervention449 (25%)62 (23%)387 (25%)0.140
      Beta-blocker1110 (62%)187 (68%)923 (61%)0.058
      ACEi/ARB1154 (64%)198 (72%)956 (63%)0.010
      MRAs508 (28%)92 (34%)416 (27%)0.093
      Ca2+ channel antagonist206 (11%)42 (15%)164 (13%)0.057
      Diuretic1028 (57%)194 (71%)834 (55%)<0.001
      OACs840 (47%)147 (54%)693 (45%)0.052
      Anti-arrhythmic274 (15%)60 (22%)214 (14%)0.003
      Digoxin177 (10%)44 (16%)133 (9%)<0.001
      Statin1002 (56%)170 (62%)832 (55%)0.096
      LVEDV (ml)152±74167±84149±72<0.001
      LVESV (ml)108±60122±71106±57<0.001
      LVEF (%)30±8.629±9.030±8.50.010
      LAVi (ml/m2)41±2043±2140±200.041
      Moderate-to-severe MR653 (36%)113 (41%)540 (35%)0.064
      Moderate-to-severe TR438 (24%)78 (28%)360 (24%)0.074
      Values are mean±SD.
      ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      Table 2Univariable and multivariable Cox hazard regression analyses for all-cause mortality
      VariableUnivariable analysisMultivariable analysis
      HR95% CIp-ValueHR95% CIp-Value
      Age1.041.03-1.04<0.0011.031.01-1.04<0.001
      Male1.160.93-1.450.189
      BSA0.650.41-1.010.057
      Hemoglobin
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      0.910.87-0.95<0.0011.000.95-1.060.889
      eGFR
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      0.790.76-0.83<0.0010.870.79-0.960.005
      Current smoker0.910.70-1.190.498
      Ex-smoker0.860.69-1.090.213
      DM1.681.35-2.09<0.0011.391.06-1.810.016
      Arterial hypertension1.120.91-1.380.279
      Hyperlipidemia1.040.84-1.280.751
      Family history of CAD0.940.73-1.200.601
      CAD1.170.94-1.460.170
      MI1.030.84-1.270.763
      PCI0.890.71-1.120.322
      CABG1.140.91-1.430.266
      COPD1.851.43-2.40<0.0011.310.95-1.800.100
      CKD2.522.00-3.19<0.0011.050.68-1.620.845
      AF1.531.25-1.89<0.0011.020.76-1.380.895
      ICD implant0.920.74-1.140.433
      CRT implant1.070.84-1.360.589
      Valvular intervention1.090.87-1.360.474
      Beta-blocker0.730.58-0.920.0080.650.49-0.870.004
      ACEi/ARB0.650.51-0.83<0.0010.700.52-0.950.020
      MRA1.261.02-1.560.0341.140.87-1.500.341
      Ca2+ channel antagonist1.080.81-1.450.589
      Diuretics3.132.29-4.28<0.0012.051.37-3.06<0.001
      OACs1.401.12-1.740.0031.170.86-1.580.317
      Anti-arrhythmic1.451.14-1.860.0031.210.89-1.640.221
      Digoxin1.651.26-2.16<0.0011.250.89-1.760.199
      Statin1.040.83-1.300.759
      LVEDV
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      1.011.00-1.030.0351.130.98-1.300.091
      LVESV
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      1.021.01-1.040.0060.870.72-1.040.128
      LVEF0.980.97-0.99<0.0010.980.95-1.010.245
      LAVi1.011.01-1.01<0.0011.000.99-1.010.756
      Moderate-to-severe MR1.591.31-1.94<0.0011.010.77-1.330.945
      Moderate-to-severe TR1.671.36-2.05<0.0010.970.73-1.300.852
      Worsening HF1.711.37-2.13<0.0011.461.09-1.960.011
      low asterisk 10 unit increase.ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      During a median follow-up of 60 months (interquartile range 28 to 60 months), 435 patients (24%) died. The cumulative event rates for all-cause mortality at 5 years of follow-up were higher in the worsening HF group (37%, 95% CI 31% to 43%) compared with the nonworsening HF group (23%, 95% CI 21% to 25%) (log-rank p <0.0001) (Figure 1). A landmark analysis, which compared the survival rates between worsening HF and non-worsening HF groups from the landmark time of 24 months, demonstrated that the worsening HF group had significantly lower survival rates compared with the nonworsening HF group (log-rank p <0.0001) (Figure 1). The association between worsening HF and all-cause mortality was tested by constructing univariable and multivariable Cox regression models (Table 2). On multivariable analysis, worsening HF was significantly associated with a higher risk of all-cause mortality (HR 1.46, 95% CI 1.09 to 1.96, p = 0.011). In addition, worsening HF was significantly associated with all-cause mortality in the landmark analysis (HR 1.68, 95% CI 1.22 to 2.30, p = 0.001) (Table 3). Unadjusted time-dependent covariate analysis of worsening HF demonstrated that the effect of worsening HF on all-cause mortality was neutral in the first 24 months from diagnosis of HFrEF (HR 0.99, 95% CI 0.70 to 1.41, p = 0.964), but was associated with an increased risk of all-cause mortality after 24 months of follow-up (HR 2.84, 95% CI 2.11 to 3.82, p <0.001).
      Figure 1
      Figure 1Kaplan–Meier curves for all-cause mortality (A) and the landmark analysis for all-cause mortality (B).
      Table 3Univariable and multivariable Cox hazard regression landmark analyses for all-cause mortality
      VariableUnivariable analysisMultivariable analysis
      HR95% CIp-ValueHR95% CIp-Value
      Age1.031.02-1.03<0.0011.021.01-1.04<0.001
      Male1.271.03-1.550.0221.180.88-1.590.264
      BSA0.760.50-1.150.188
      Hemoglobin
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      0.960.92-1.000.058
      Egfr
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      0.850.82-0.89<0.0010.920.85-1.010.071
      Current smoker1.000.80-1.260.979
      Ex-smoker0.890.73-1.100.287
      DM1.451.18-1.77<0.0011.281.00-1.650.054
      Arterial hypertension1.090.91-1.310.348
      Hyperlipidemia1.110.92-1.340.274
      Family history of CAD1.060.86-1.300.587
      CAD1.110.92-1.350.275
      MI1.180.99-1.420.070
      PCI0.960.79-1.160.642
      CABG1.210.99-1.470.061
      COPD1.471.14-1.890.0031.170.85-1.610.337
      CKD2.061.64-2.58<0.0011.100.74-1.620.642
      AF1.321.10-1.590.0030.870.66-1.140.313
      ICD implant1.581.32-1.90<0.0011.511.11-2.040.008
      CRT implant1.541.27-1.87<0.0011.110.83-1.480.468
      Valvular intervention1.000.82-1.220.998
      Beta-blocker0.960.77-1.200.736
      ACEi/ARB1.090.84-1.400.523
      MRA1.211.00-1.470.0490.980.77-1.250.871
      Ca2+ channel antagonist1.291.01-1.650.0441.310.98-1.750.064
      Diuretics1.981.57-2.49<0.0011.431.04-1.960.028
      OACs1.601.32-1.96<0.0011.260.97-1.640.082
      Anti-arrhythmic1.601.29-1.99<0.0011.371.05-1.800.023
      Digoxin1.631.28-2.09<0.0011.451.06-1.980.021
      Statin1.241.00-1.530.0491.140.86-1.520.356
      LVEDV
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      1.031.01-1.04<0.0011.050.92-1.190.488
      LVESV
      10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      1.031.02-1.05<0.0010.950.81-1.130.578
      LVEF0.980.97-0.990.0011.000.97-1.030.930
      LAVi1.011.00-1.010.0021.001.00-1.010.380
      Moderate-to-severe MR1.281.07-1.540.0081.020.80-1.300.869
      Moderate-to-severe TR1.070.87-1.320.536
      Worsening HF1.821.41-2.33<0.0011.681.22-2.300.001
      low asterisk 10 unit increase.ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HF = heart failure; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.
      Patients who experienced worsening HF had higher 5-year cumulative mortality rates when compared with those who did not experience worsening HF according to baseline LVEF subgroups: LVEF ≤25% (50% [95% CI 40 to 60%] vs 26% [95% CI 22 to 30%]), LVEF 26% to 34% (35% [95% CI 25 to 45%] vs 26% [95% CI 22 to 30%]) and LVEF 35% to 45% (27% [95% CI 17 to 37%] vs 18% [95% CI 14 to 22%]). The 5-year survival rates of the worsening HF cohort and the non-worsening HF cohort were significantly different for LVEF ≤25% (log-rank p <0.0001) (Figure 2) and LVEF 26% to 34% (log-rank p = 0.038) (Figure 2) but not for LVEF 35% to 45% (log-rank p = 0.14) (Figure 2). Corresponding landmark analyses demonstrated that the survival rates, which were calculated from the landmark time of 24 months, were significantly lower in the worsening HF group for LVEF ≤25% (log-rank p <0.0001) (Figure 2) and LVEF 26% to 34% (log-rank p = 0.0092) (Figure 2), but not for LVEF 35% to 45% (log-rank p = 0.11) (Figure 2).
      Figure 2
      Figure 2Kaplan-Meier curves for all-cause mortality by LVEF subgroups: LVEF ≤25% (A), LVEF 26% to 34% (C), LVEF 35% to 45% (E), and the corresponding landmark analyses for all-cause mortality by LVEF subgroups (B, D, and F).
      Unadjusted time-dependent covariate analysis of worsening HF showed that the effect of worsening HF was attenuated in the first 24 months of follow-up for baseline LVEF subgroups: (HR 1.23, 95% CI 0.73 to 2.06, p = 0.446), (HR 0.83, 95% CI 0.46 to 1.48, p = 0.520) and (HR 0.80, 95% CI 0.34 to 1.86, p = 0.602) for LVEF ≤25%, LVEF 26% to 34% and LVEF 35% to 45%, respectively. However, the risk of mortality was significantly higher after 24 months of follow-up for the baseline LVEF subgroups: (HR 3.58, 95% CI 2.18 to 5.88, p <0.001), (HR 2.41, 95% CI 1.50 to 3.85, p <0.001) and (HR 2.38, 95% CI 1.25 to 4.52, p = 0.008) for LVEF ≤25%, LVEF 26% to 34% and LVEF 35% to 45%, respectively.

      Discussion

      The main findings of the present study, with data obtained from a large, ongoing registry including patients with a first diagnosis HFrEF, can be summarized as follows: (1) the incidence of worsening HF (defined as HF hospitalization or the urgent need for intensification of intravenous diuretics) was 15%; and (2) worsening HF was independently associated with poor outcomes, regardless of baseline LV systolic function.
      Different definitions of worsening HF have been used in clinical studies according to different criteria.
      • Butler J
      • Braunwald E
      • Gheorghiade M.
      Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
      Nonetheless, rehospitalization because of worsening signs and symptoms of HF or emergency intravenous diuretics despite optimal GDMT is the most commonly accepted definition of worsening HF
      • Butler J
      • Braunwald E
      • Gheorghiade M.
      Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
      ,
      • Greene SJ
      • Mentz RJ
      • Felker GM.
      Outpatient worsening heart failure as a target for therapy: a review.
      and was utilized in recent major HF trials.
      • Armstrong PW
      • Pieske B
      • Anstrom KJ
      • Ezekowitz J
      • Hernandez AF
      • Butler J
      • Lam CSP
      • Ponikowski P
      • Voors AA
      • Jia G
      • McNulty SE
      • Patel MJ
      • Roessig L
      • Koglin J
      • O'Connor CM
      VICTORIA Study Group
      Vericiguat in patients with heart failure and reduced ejection fraction.
      • McMurray JJ
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • Rouleau JL
      • Shi VC
      • Solomon SD
      • Swedberg K
      • Zile MR
      PARADIGM-HF Investigators and Committees
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • Ponikowski P
      • Sabatine MS
      • Anand IS
      • Bělohlávek J
      • Böhm M
      • Chiang CE
      • Chopra VK
      • de Boer RA
      • Desai AS
      • Diez M
      • Drozdz J
      • Dukát A
      • Ge J
      • Howlett JG
      • Katova T
      • Kitakaze M
      • Ljungman CEA
      • Merkely B
      • Nicolau JC
      • O'Meara E
      • Petrie MC
      • Vinh PN
      • Schou M
      • Tereshchenko S
      • Verma S
      • Held C
      • DeMets DL
      • Docherty KF
      • Jhund PS
      • Bengtsson O
      • Sjöstrand M
      • Langkilde AM
      DAPA-HF Trial Committees and Investigators
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      According to this definition, the prevalence of worsening HF was 15.6%, 13.4%, and 29.6% in the control arms of the Prospective Comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) with ACEI (Angiotensin-Converting–Enzyme Inhibitor) to PARADIGM-HF (Determine Impact on Global Mortality and Morbidity in Heart Failure) trial,
      • McMurray JJ
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • Rouleau JL
      • Shi VC
      • Solomon SD
      • Swedberg K
      • Zile MR
      PARADIGM-HF Investigators and Committees
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial,
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • Ponikowski P
      • Sabatine MS
      • Anand IS
      • Bělohlávek J
      • Böhm M
      • Chiang CE
      • Chopra VK
      • de Boer RA
      • Desai AS
      • Diez M
      • Drozdz J
      • Dukát A
      • Ge J
      • Howlett JG
      • Katova T
      • Kitakaze M
      • Ljungman CEA
      • Merkely B
      • Nicolau JC
      • O'Meara E
      • Petrie MC
      • Vinh PN
      • Schou M
      • Tereshchenko S
      • Verma S
      • Held C
      • DeMets DL
      • Docherty KF
      • Jhund PS
      • Bengtsson O
      • Sjöstrand M
      • Langkilde AM
      DAPA-HF Trial Committees and Investigators
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      and VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial,
      • Armstrong PW
      • Pieske B
      • Anstrom KJ
      • Ezekowitz J
      • Hernandez AF
      • Butler J
      • Lam CSP
      • Ponikowski P
      • Voors AA
      • Jia G
      • McNulty SE
      • Patel MJ
      • Roessig L
      • Koglin J
      • O'Connor CM
      VICTORIA Study Group
      Vericiguat in patients with heart failure and reduced ejection fraction.
      respectively. In the National Cardiovascular Data Registry PINNACLE, the prevalence of worsening HF was 17% during an average of 1.5 years after the initial diagnosis of HFrEF.
      • Butler J
      • Yang M
      • Manzi MA
      • Hess GP
      • Patel MJ
      • Rhodes T
      • Givertz MM.
      Clinical course of patients With worsening heart failure With reduced ejection fraction.
      In another study, which used data from Danish administrative registers, Madelaire et al
      • Madelaire C
      • Gustafsson F
      • Stevenson LW
      • Kristensen SL
      • Køber L
      • Andersen J
      • D'Souza M
      • Biering-Sørensen T
      • Andersson C
      • Torp-Pedersen C
      • Gislason G
      • Schou M
      One-year mortality After intensification of outpatient diuretic therapy.
      identified 7,677 worsening HF events (10.2%) of 74,990 patients with incident HF. In the present study, which was based on a large clinical registry of patients with HFrEF, the prevalence of worsening HF occurred in 15% of the study population after the initial diagnosis of HFrEF despite baseline GDMT.
      Worsening HF can be caused by various precipitating factors and may occur at any stage after an initial stable period of HF.
      • Butler J
      • Braunwald E
      • Gheorghiade M.
      Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
      Importantly, baseline LV systolic function (LVEF) may remain unchanged during an episode of worsening HF. In their study of worsening HF in ambulatory patients, Mallick et al
      • Mallick A
      • Gandhi PU
      • Gaggin HK
      • Ibrahim N
      • Januzzi JL.
      The importance of worsening heart failure in ambulatory patients: definition, characteristics, and effects of amino-terminal pro-B-type natriuretic peptide guided therapy.
      reported significantly higher values of baseline LVEF in patients who subsequently experienced worsening HF, compared with those who did not (31% vs 25%, p = 0.03). However, the size of the study population was relatively small (n = 151), limiting firm conclusions regarding the prognostic value of baseline LVEF for future worsening HF events. Although in the present study, baseline LVEF was significantly different between the worsening HF and non-worsening HF groups, this difference in baseline LVEF was not clinically relevant (only 1% difference) and was not associated with outcomes in the multivariable analysis.
      The prognostic impact of worsening HF has been previously evaluated in large, nationwide registries.
      • Butler J
      • Yang M
      • Manzi MA
      • Hess GP
      • Patel MJ
      • Rhodes T
      • Givertz MM.
      Clinical course of patients With worsening heart failure With reduced ejection fraction.
      ,
      • Solomon SD
      • Dobson J
      • Pocock S
      • Skali H
      • McMurray JJ
      • Granger CB
      • Yusuf S
      • Swedberg K
      • Young JB
      • Michelson EL
      • Pfeffer MA
      Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. IInfluence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure.
      ,
      • Madelaire C
      • Gustafsson F
      • Stevenson LW
      • Kristensen SL
      • Køber L
      • Andersen J
      • D'Souza M
      • Biering-Sørensen T
      • Andersson C
      • Torp-Pedersen C
      • Gislason G
      • Schou M
      One-year mortality After intensification of outpatient diuretic therapy.
      ,
      • Setoguchi S
      • Stevenson LW
      • Schneeweiss S.
      Repeated hospitalizations predict mortality in the community population with heart failure.
      Butler et al
      • Butler J
      • Yang M
      • Manzi MA
      • Hess GP
      • Patel MJ
      • Rhodes T
      • Givertz MM.
      Clinical course of patients With worsening heart failure With reduced ejection fraction.
      demonstrated that patients who developed worsening HF within 18 months after the initial diagnosis of HF, had a higher risk of recurrent HF hospitalization or mortality at 2 years of follow-up. In a study of 74,990 patients with a first diagnosis of HF, Madelaire et al
      • Madelaire C
      • Gustafsson F
      • Stevenson LW
      • Kristensen SL
      • Køber L
      • Andersen J
      • D'Souza M
      • Biering-Sørensen T
      • Andersson C
      • Torp-Pedersen C
      • Gislason G
      • Schou M
      One-year mortality After intensification of outpatient diuretic therapy.
      showed that 1-year mortality was 18% in patients who needed up-titration of diuretics and 22.6% in patients with subsequent HF hospitalization, with the prevalence in both groups being significantly higher compared with 10.4% in matched controls. Among these large registries, only Solomon et al
      • Solomon SD
      • Dobson J
      • Pocock S
      • Skali H
      • McMurray JJ
      • Granger CB
      • Yusuf S
      • Swedberg K
      • Young JB
      • Michelson EL
      • Pfeffer MA
      Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. IInfluence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure.
      took baseline LVEF into consideration when studying the influence of nonfatal HF hospitalization on subsequent mortality and reported that, after adjustment for baseline predictors of mortality (including LVEF), HF hospitalization remained significantly associated with all-cause mortality. The present study shows that, after adjusting for multiple, prognostically relevant risk factors, LVEF was not significantly associated with all-cause mortality. Moreover, in the present study, patients with worsening HF had significantly lower survival rates in the three subgroups of LVEF. These results indicate that worsening HF is an important determinant of long-term outcomes in patients with HFrEF, regardless of baseline LV systolic function.
      The in-hospital treatment of patients who are hospitalized for worsening HF despite baseline GDMT is mainly symptomatic,
      • Butler J
      • Braunwald E
      • Gheorghiade M.
      Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
      targeting congestion by intravenous diuretics, and correcting precipitating factors such as infections, dietary mistakes, sudden arrhythmias, and in rare instances, hypoperfusion.
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      • Gardner RS
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      • Chioncel O
      • Cleland JGF
      • Coats AJS
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      • Farmakis D
      • Gilard M
      • Heymans S
      • Hoes AW
      • Jaarsma T
      • Jankowska EA
      • Lainscak M
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      • Mebazaa A
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      ESC Scientific Document Group
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      Apart from a few studies,
      • Gheorghiade M
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      • Ambrosy AP
      • McCague K
      • Rocha R
      • Braunwald E
      PIONEER-HF Investigators
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      most of the randomized controlled trials
      • Armstrong PW
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      • Anstrom KJ
      • Ezekowitz J
      • Hernandez AF
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      • Lam CSP
      • Ponikowski P
      • Voors AA
      • Jia G
      • McNulty SE
      • Patel MJ
      • Roessig L
      • Koglin J
      • O'Connor CM
      VICTORIA Study Group
      Vericiguat in patients with heart failure and reduced ejection fraction.
      • McMurray JJ
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • Rouleau JL
      • Shi VC
      • Solomon SD
      • Swedberg K
      • Zile MR
      PARADIGM-HF Investigators and Committees
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • Ponikowski P
      • Sabatine MS
      • Anand IS
      • Bělohlávek J
      • Böhm M
      • Chiang CE
      • Chopra VK
      • de Boer RA
      • Desai AS
      • Diez M
      • Drozdz J
      • Dukát A
      • Ge J
      • Howlett JG
      • Katova T
      • Kitakaze M
      • Ljungman CEA
      • Merkely B
      • Nicolau JC
      • O'Meara E
      • Petrie MC
      • Vinh PN
      • Schou M
      • Tereshchenko S
      • Verma S
      • Held C
      • DeMets DL
      • Docherty KF
      • Jhund PS
      • Bengtsson O
      • Sjöstrand M
      • Langkilde AM
      DAPA-HF Trial Committees and Investigators
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      involving HF usually include stable HF patients in an outpatient setting, without including HF patients who have recently experienced worsening HF. As shown in the present study, however, worsening HF is associated with higher long-term mortality and therefore, it is reasonable to consider the early initiation of intensive HF treatment for this high-risk patient population. In the VICTORIA study, including 5,050 patients with worsening HF, the incidence of death from cardiovascular causes or hospitalization for HF was lower among those who received vericiguat than among those who received placebo.
      • Armstrong PW
      • Pieske B
      • Anstrom KJ
      • Ezekowitz J
      • Hernandez AF
      • Butler J
      • Lam CSP
      • Ponikowski P
      • Voors AA
      • Jia G
      • McNulty SE
      • Patel MJ
      • Roessig L
      • Koglin J
      • O'Connor CM
      VICTORIA Study Group
      Vericiguat in patients with heart failure and reduced ejection fraction.
      Recently, Bhatt et al
      • Bhatt DL
      • Szarek M
      • Steg PG
      • Cannon CP
      • Leiter LA
      • McGuire DK
      • Lewis JB
      • Riddle MC
      • Voors AA
      • Metra M
      • Lund LH
      • Komajda M
      • Testani JM
      • Wilcox CS
      • Ponikowski P
      • Lopes RD
      • Verma S
      • Lapuerta P
      • Pitt B
      SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure.
      studied the early initiation of sodium-glucose cotransporter 2 inhibitors in hospitalized patients with worsening HF in the SOLOIST-WHF (Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial. During a median follow-up of 9 months, the cumulative event rate (defined by the composite primary end point of cardiovascular death, hospitalizations, and worsening HF) was significantly lower in the sotagliflozin group than in the placebo group. These studies demonstrate that patients experiencing worsening HF may benefit from the initiation of newly introduced HF treatments during hospitalization.
      The present study has several limitations. The data used in the present study originate from a single center and were retrospectively analyzed. However, the study provides clinical data of patients as opposed to research-driven data derived from a large, ongoing registry of patients with HFrEF. Mortality data were only available for all-cause mortality, and information on the exact cause of death is missing.
      In conclusion, worsening HF, defined by HF hospitalization or urgent need for intravenous diuretics, in patients with HFrEF is independently associated with poor long-term prognosis. Patients who develop worsening HF during follow-up should be considered very high-risk patients, regardless of baseline LV systolic function. The timely institution of novel HF treatments should be considered after a first episode of worsening HF to improve prognosis.

      Disclosures

      Dr. Chimed reports a relation with European Society of Cardiology that includes funding grants. Dr. Chimed reports a relation with Turku PET Center that includes funding grants. Dr. Delgado reports a relation with Abbott Vascular that includes speaking and lecture fees. Dr. Delgado reports a relation with Edwards Lifesciences that includes speaking and lecture fees. Dr. Delgado reports a relation with GE Healthcare that includes speaking and lecture fees. Dr. Delgado reports a relation with Medtronic that includes speaking and lecture fees. Dr. Delgado reports a relation with Merck Sharp & Dohme that includes speaking and lecture fees. Dr. Delgado reports a relation with Novartis that includes speaking and lecture fees. Dr. Marsan reports a relation with Abbott Vascular that includes speaking and lecture fees. Dr. Marsan reports a relation with GE Healthcare that includes speaking and lecture fees. Dr. Bax reports a relation with Abbott Vascular that includes speaking and lecture fees. The remaining authors have no conflicts of interest to declare.

      Acknowledgment

      All individuals who contributed to this publication, have been included as authors.

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