Abstract

Aims

Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial.

Methods and results

RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 μg/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (≥50%) and reduced (<50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 [mean change, 461 (−195, 1117) vs. 397 (10, 783) mm h, P = 0.87], but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h [odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030]. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups.

Conclusions

In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.

See page 1017 for the editorial comment on this article (doi:10.1093/eurheartj/eht567)

Introduction

Acute heart failure (AHF) is characterized by high morbidity and mortality.1 Several recent trials have evaluated novel vasoactive agents in this syndrome, but failed to provide any evidence on outcome improvement.2–5 Hence, the management of AHF patients is still based primarily on drugs that improve symptoms but have a neutral or even negative effect on patients' prognosis.6

Heart failure with preserved ejection fraction (HFpEF) represents up to 50% of AHF patients, depending on the definition, and this proportion seems to be increasing because of aging of the general population.7 Despite the therapeutic advances in the medical therapy for the patients with chronic heart failure and reduced left ventricular ejection fraction (HFrEF), evidence on an effective therapy in HFpEF is still missing. Previous randomized trials in chronic HF failed to show efficacy, and no agent has been specifically evaluated in AHF patients with HFpEF.8–12

Serelaxin, a recombinant form of human relaxin-2, administered to AHF patients, caused in improvement of symptoms and prevention of organ damage with a reduction in 180-day mortality, compared with placebo.13,14 A substantial proportion of patients in RELAX-AHF had a preserved left ventricular ejection fraction (LVEF). In the present study, we assessed the efficacy and safety of serelaxin in patients with HFpEF, compared with those with HFrEF.

Patients and methods

The methods of the RELAX-AHF trial (NCT00520806) are described in detail elsewhere.13–15 Briefly, the study randomized 1161 AHF patients to 48-h intravenous infusion of serelaxin (30 μg/kg/day, n = 581) or placebo (n = 580) within 16 h from presentation. We compared the effects of serelaxin vs. placebo on the pre-specified efficacy endpoints, safety endpoints, and biomarkers indicative of organ damage, in patients with preserved in comparison to those with reduced LVEF, defined as ≥50 and <50%, respectively, according to the recently published guidelines.6 According to the study protocol, the recorded LVEF was the most recently available, including the one during the index hospitalization. The primary efficacy endpoints were dyspnoea improvement, defined as dyspnoea change from baseline in the visual analogue scale-area under the curve (VAS-AUC) through Day 5 and proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale at 6, 12, and 24 h. The secondary efficacy endpoints included cardiovascular death or rehospitalization for heart or renal failure and days alive and out of hospital through Day 60. Cardiovascular death through Day 180 was pre-specified as an additional efficacy endpoint, and all-cause death through Day 180 was a pre-specified safety endpoint. Biomarkers indicative of congestion and/or organ damage, including high-sensitivity troponin T (hs-TnT), N-terminal β-type natriuretic pro-peptide (NT-proBNP), cystatin-C, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were assessed serially using a central core lab.14

Statistical analysis

Baseline characteristics were compared between HFrEF and HFpEF patients using two-sample t-tests for continuous variables and χ2 tests for categorical variables. An evaluation of the possible interaction between the effect of serelaxin on the two primary and key secondary efficacy endpoints and LVEF <40 vs. ≥40% was pre-specified. The cut-off of 50% to classify patients with HFrEF vs. those with HFpEF was selected post hoc to be consistent with the guidelines.5,6 Estimates of the serelaxin treatment effect (odds ratio, mean difference, or hazard ratio) for patients with HFrEF and HFpEF and an interaction test were obtained from a separate regression model (logistic, analysis of covariance, or Cox) for each outcome that included the effects of serelaxin, LVEF (<50 vs. ≥50%), and the serelaxin-by-ejection fraction interaction.

Analyses were conducted on an intent-to-treat basis. All P-values were two-sided, and values <0.05 were considered nominally statistically significant. SAS© release 9.2 (SAS Institute, Cary, NC, USA) was used for analysis.

Results

An LVEF measurement was available for 1091 of the 1161 patients randomized; 281 of them (26%) had HFpEF. A comparison of baseline features between HFrEF and HFpEF patients is shown in Table 1. Patients with HFpEF were older and more often female compared with those with HFrEF. They were less likely to have a history of ischaemic heart disease or of a prior AHF hospitalization in the year before randomization and were more likely to have arterial hypertension and atrial fibrillation. Regarding medication, HFpEF patients had similar use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers but lower use of beta-blockers and mineralocorticosteroid receptor antagonists compared with patients with HFrEF. As expected, the use of device therapy was low in HFpEF. Upon presentation, the two groups did not differ in clinical signs and symptoms of congestion. However, HFpEF patients had higher systolic blood pressure and lower concentrations of NT-proBNP, troponin T and serum creatinine.

Table 1

Comparison of baseline characteristics between patients with reduced (<50%) and preserved (≥50%) left ventricular ejection fraction

 LVEF < 50 (n = 810) LVEF ≥ 50 (n = 281) P-value 
Demographics 
 Age, years 70.5 (11.4) 75.4 (9.9) <0.0001 
 Male 571 (70.5%) 117 (41.6%) <0.0001 
Geographic region (%)   0.74 
 Eastern EU 412 (50.9) 132 (47.0  
 Western EU 140 (17.3) 47 (6.7)  
 South America 38 (4.7) 14 (5.0)  
 North America 81 (10.0) 32 (11.4)  
 Israel 139 (17.2) 56 (19.9)  
Heart failure characteristics 
 LVEF 31.7 (9.0) 58.7 (7.2) <0.0001 
 Ischaemic heart disease 461 (56.9%) 120 (42.7%) <0.0001 
NYHA class 30 days before admission (%)   0.13 
 I 14 (2.3) 9 (4.5)  
 II 212 (34.8) 80 (39.8)  
 III 293 (48.1) 81 (40.3)  
 IV 90 (14.8) 31 (15.4)  
Time from presentation to randomization, h 7.7 (4.6) 8.5 (4.7) 0.011 
HF hospitalization past year 298 (36.8%) 83 (29.5%) 0.028 
Number of HF hospitalizations past year 1.7 (1.4) 1.4 (0.8) 0.032 
Clinical signs 
 Body mass index, kg/m2 29.2 (5.5) 29.7 (6.4) 0.24 
 Systolic blood pressure, mmHg 140.8 (16.2) 145.7 (16.7) <0.0001 
 Diastolic blood pressure, mmHg 82.6 (13.6) 79.6 (13.9) 0.0015 
 Heart rate, bpm 79.8 (14.5) 78.0 (16.0) 0.081 
 Respiratory rate, breaths per minute 21.9 (4.6) 21.8 (4.7) 0.58 
Congestion at baseline (%) 
 Oedema 634 (78.7) 221 (79.5) 0.77 
 Orthopnoea 768 (95.4) 269 (96.4) 0.47 
 JVP, mm Hg (<6 vs. ≥6) 601 (76.5) 200 (73.3) 0.29 
 DOE 795 (99.7) 274 (100) 1.00 
 Dyspnoea by VAS 43.9 (19.8) 43.2 (19.7) 0.64 
Comorbidities (%) 
 Hypertension 684 (84.4) 262 (93.2) 0.0002 
 Diabetes mellitus 394 (48.6) 130 (46.3) 0.49 
 Stroke or other cerebrovascular event 110 (13.6) 39 (13.9) 0.90 
 Asthma, bronchitis, or COPD 130 (16.0) 44 (15.7 0.88 
 Atrial fibrillation at screening 307 (38.0) 137 (48.8) 0.0016 
 History of atrial fibrillation or flutter 391 (48.3) 172 (61.2) 0.0002 
Devices (%) 
 Pacemaker 82 (10.1) 31 (11.0) 0.67 
 Implantable cardiac defibrillator 145 (17.9) 4 (1.4) <0.0001 
 Biventricular pacing 101 (12.5) 7 (2.5) <0.0001 
Medication (Day 0, except nitrates) (%) 
 ACE inhibitor 455 (56.2) 148 (52.7) 0.31 
 Angiotensin-receptor blocker 131 (16.2) 46 (16.4) 0.94 
 Beta-blocker 586 (72.3) 174 (61.9) 0.0011 
 Aldosterone antagonist 289 (35.7 63 (22.4) <0.0001 
 Intravenous loop diuretics 808 (99.8) 280 (99.6) 1.0000 
 Digoxin 172 (21.2) 45 (16.0) 0.059 
 Nitrates at randomization 46 (5.7) 26 (9.3) 0.038 
Baseline labs 
 Sodium, mmol/L 140.7 (3.6) 141.3 (3.7) 0.026 
 Haemoglobin, g/dL 13.03 (1.84) 12.14 (1.76) <0.0001 
 Haematocrit ratio 0.4213 (0.0565) 0.3929 (0.0539) <0.0001 
 White blood cell count, ×109/L 8.140 (2.710) 8.215 (3.134) 0.71 
 Lymphocyte, (%) 18.30 (7.75) 18.18 (7.95) 0.84 
 Potassium, mmol/L 4.31 (0.64) 4.21 (0.65) 0.031 
 Creatinine, µmol/L 118.7 (34.2) 112.1 (30.5) 0.0050 
 Uric acid, µmol/L 483.4 (142.2) 462.2 (121.4) 0.028 
 Troponin T, µg/L 0.037 (0.035, 0.039) 0.030 (0.028, 0.034) 0.0013 
 BUN, mmol/L 9.85 (4.02) 9.78 (4.23) 0.82 
 Cystatin-C, mg/L 1.44 (1.41, 1.47) 1.52 (1.47, 1.57) 0.0055 
 Alanine aminotransferase, U/L 30.6 (35.0) 26.2 (20.4) 0.051 
 Aspartate aminotransferase, U/L 32.1 (31.9) 27.5 (13.9) 0.025 
 NT-proBNP, ng/L 5535 (5194, 5897) 3992 (3632, 4388) <0.0001 
 LVEF < 50 (n = 810) LVEF ≥ 50 (n = 281) P-value 
Demographics 
 Age, years 70.5 (11.4) 75.4 (9.9) <0.0001 
 Male 571 (70.5%) 117 (41.6%) <0.0001 
Geographic region (%)   0.74 
 Eastern EU 412 (50.9) 132 (47.0  
 Western EU 140 (17.3) 47 (6.7)  
 South America 38 (4.7) 14 (5.0)  
 North America 81 (10.0) 32 (11.4)  
 Israel 139 (17.2) 56 (19.9)  
Heart failure characteristics 
 LVEF 31.7 (9.0) 58.7 (7.2) <0.0001 
 Ischaemic heart disease 461 (56.9%) 120 (42.7%) <0.0001 
NYHA class 30 days before admission (%)   0.13 
 I 14 (2.3) 9 (4.5)  
 II 212 (34.8) 80 (39.8)  
 III 293 (48.1) 81 (40.3)  
 IV 90 (14.8) 31 (15.4)  
Time from presentation to randomization, h 7.7 (4.6) 8.5 (4.7) 0.011 
HF hospitalization past year 298 (36.8%) 83 (29.5%) 0.028 
Number of HF hospitalizations past year 1.7 (1.4) 1.4 (0.8) 0.032 
Clinical signs 
 Body mass index, kg/m2 29.2 (5.5) 29.7 (6.4) 0.24 
 Systolic blood pressure, mmHg 140.8 (16.2) 145.7 (16.7) <0.0001 
 Diastolic blood pressure, mmHg 82.6 (13.6) 79.6 (13.9) 0.0015 
 Heart rate, bpm 79.8 (14.5) 78.0 (16.0) 0.081 
 Respiratory rate, breaths per minute 21.9 (4.6) 21.8 (4.7) 0.58 
Congestion at baseline (%) 
 Oedema 634 (78.7) 221 (79.5) 0.77 
 Orthopnoea 768 (95.4) 269 (96.4) 0.47 
 JVP, mm Hg (<6 vs. ≥6) 601 (76.5) 200 (73.3) 0.29 
 DOE 795 (99.7) 274 (100) 1.00 
 Dyspnoea by VAS 43.9 (19.8) 43.2 (19.7) 0.64 
Comorbidities (%) 
 Hypertension 684 (84.4) 262 (93.2) 0.0002 
 Diabetes mellitus 394 (48.6) 130 (46.3) 0.49 
 Stroke or other cerebrovascular event 110 (13.6) 39 (13.9) 0.90 
 Asthma, bronchitis, or COPD 130 (16.0) 44 (15.7 0.88 
 Atrial fibrillation at screening 307 (38.0) 137 (48.8) 0.0016 
 History of atrial fibrillation or flutter 391 (48.3) 172 (61.2) 0.0002 
Devices (%) 
 Pacemaker 82 (10.1) 31 (11.0) 0.67 
 Implantable cardiac defibrillator 145 (17.9) 4 (1.4) <0.0001 
 Biventricular pacing 101 (12.5) 7 (2.5) <0.0001 
Medication (Day 0, except nitrates) (%) 
 ACE inhibitor 455 (56.2) 148 (52.7) 0.31 
 Angiotensin-receptor blocker 131 (16.2) 46 (16.4) 0.94 
 Beta-blocker 586 (72.3) 174 (61.9) 0.0011 
 Aldosterone antagonist 289 (35.7 63 (22.4) <0.0001 
 Intravenous loop diuretics 808 (99.8) 280 (99.6) 1.0000 
 Digoxin 172 (21.2) 45 (16.0) 0.059 
 Nitrates at randomization 46 (5.7) 26 (9.3) 0.038 
Baseline labs 
 Sodium, mmol/L 140.7 (3.6) 141.3 (3.7) 0.026 
 Haemoglobin, g/dL 13.03 (1.84) 12.14 (1.76) <0.0001 
 Haematocrit ratio 0.4213 (0.0565) 0.3929 (0.0539) <0.0001 
 White blood cell count, ×109/L 8.140 (2.710) 8.215 (3.134) 0.71 
 Lymphocyte, (%) 18.30 (7.75) 18.18 (7.95) 0.84 
 Potassium, mmol/L 4.31 (0.64) 4.21 (0.65) 0.031 
 Creatinine, µmol/L 118.7 (34.2) 112.1 (30.5) 0.0050 
 Uric acid, µmol/L 483.4 (142.2) 462.2 (121.4) 0.028 
 Troponin T, µg/L 0.037 (0.035, 0.039) 0.030 (0.028, 0.034) 0.0013 
 BUN, mmol/L 9.85 (4.02) 9.78 (4.23) 0.82 
 Cystatin-C, mg/L 1.44 (1.41, 1.47) 1.52 (1.47, 1.57) 0.0055 
 Alanine aminotransferase, U/L 30.6 (35.0) 26.2 (20.4) 0.051 
 Aspartate aminotransferase, U/L 32.1 (31.9) 27.5 (13.9) 0.025 
 NT-proBNP, ng/L 5535 (5194, 5897) 3992 (3632, 4388) <0.0001 

Continuous variables are expressed as mean (SD) or geometric mean (95% CI) and categorical variables as n (%). EU, Europe; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; HF, heart failure; JVP, jugular venous pressure; DOE, dyspnoea on exertion; VAS, visual analogue scale; COPD, chronic obstructive pulmonary disease; ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; NT-proBNP, N-terminal prohormone of brain natriuretic peptide.

Efficacy

The effect of treatment (serelaxin vs. placebo) on several efficacy endpoints in HFrEF and HFpEF patients is presented in Table 2. Serelaxin induced a similar dyspnoea relief in HFpEF and HFrEF patients through Day 5 according to VAS-AUC (mean AUC change, 461 vs. 397 mm × h, respectively, P for interaction = 0.8683; Figure 1A). A nominally statistically significant interaction was found for the proportion of patients with moderately or markedly improved dyspnoea at 6, 12, and 24 h on Likert scale (odds ratio 1.70 vs. 0.85, P for interaction = 0.030), which was not reflected at each individual time point (Figure 1B). Regarding short- and long-term outcome, serelaxin had a similar effect in HFpEF and HFrEF patients on cardiovascular death or hospitalization for heart or renal failure through Day 60 (hazard ratio, 1.08 vs. 1.10, P for interaction = 0.97, Figure 2), days alive and out of hospital through Day 60 (−1.28 vs. 0.86, P for interaction = 0.19), cardiovascular death through Day 180 (0.59 vs. 0.64, P for interaction = 0.87, Figure 3). While serelaxin appeared to reduce the risk of cardiovascular mortality by roughly the same extent in both HFpEF and HFrEF (Figure 3), the rate of rehospitalization for HF/RF was higher in the serelaxin group in both EF groups, particularly in patients with HFrEF, reflected in an apparently greater detrimental serelaxin effect on the composite outcome in the HFrEF group (Figure 2); however, given the smaller size of the HFpEF group, the role of chance in these findings cannot be ruled out. There was no difference between HFpEF and HFrEF patients in the effects of serelaxin on all additional endpoints such as total dose of intravenous loop diuretics to Day 5, change in weight through Day 5, and length of hospital stay or days in ICU/CCU (Table 2). An analysis reclassifying nine HFpEF patients with biventricular pacing and/or implantable cardiac defibrillator as HFrEF showed nearly identical results.

Table 2

Treatment effect (serelaxin vs. placebo) on various outcomes in patients with reduced (<50%) and preserved (≥50%) left ventricular ejection fraction

Outcome LVEF < 50 (n = 810)
 
LVEF ≥ 50 (n = 281)
 
P-value for interaction 
Placebo (n = 397) Serelaxin (n = 413) Treatment effect (95% CI) Placebo (n = 142) Serelaxin (n = 139) Treatment effect (95% CI) 
Dyspnoea improvement by VAS-AUC to Day 5 2312.3 (3034.5) 2708.9 (2484.3) 396.67 (10.3, 783.0) 2366.4 (2963.3) 2827.5 (2827.9) 461.02 (−194.8, 1116.9) 0.87 
Dyspnoea improvement by Likert scale at 6, 12, and 24 h 113 (28.5%) 104 (25.2%) 0.85 (0.62, 1.15) 28 (19.7%) 41 (29.5%) 1.70 (0.98, 2.95) 0.030 
Total dose of IV loop diuretics before Day 5, mg 229.5 (399.2) 161.5 (268.8) −68.0 (−112.6,−23.4) 176.3 (242.2) 167.9 (275.4) −8.4 (−84.0, 67.3) 0.18 
Change in bodyweight to Day 5, kg −3.0 (3.4) −2.8 (3.4) 0.2 (−0.3, 0.7) −3.0 (3.4) −2.4 (3.3) 0.6 (−0.2, 1.4) 0.38 
Length of initial hospital stay, days 10.4 (9.3) 9.4 (8.6) −1.0 (−2.3, 0.3) 10.7 (10.4) 10.6 (10.9) −0.04 (−2.3, 2.2) 0.47 
Days in ICU/CCU 3.7 (6.4) 3.4 (6.6) −0.4 (−1.4, 0.6) 4.2 (8.1) 4.0 (8.9) −0.1 (−1.8, 1.5) 0.82 
Days alive out of hospital through Day 60 47.7 (11.8) 48.6 (11.3) 0.86 (−0.77, 2.49) 47.9 (12.3) 46.6 (13.3) −1.28 (−4.05, 1.50) 0.19 
Cardiovascular death or HF/RF hospitalization through Day 60 50 (12.64%) 56 (13.68%) 1.10 (0.75, 1.61) 18 (12.75%) 19 (13.85%) 1.08 (0.57, 2.06) 0.97 
All-cause death through Day 180 44 (11.14%) 29 (7.08%) 0.63 (0.39, 1.00) 16 (11.32%) 11 (8.08%) 0.70 (0.32, 1.50) 0.82 
Cardiovascular death through Day 180 37 (9.43%) 25 (6.12%) 0.64 (0.39, 1.07) 12 (8.53%) 7 (5.13%) 0.59 (0.23, 1.50) 0.87 
Outcome LVEF < 50 (n = 810)
 
LVEF ≥ 50 (n = 281)
 
P-value for interaction 
Placebo (n = 397) Serelaxin (n = 413) Treatment effect (95% CI) Placebo (n = 142) Serelaxin (n = 139) Treatment effect (95% CI) 
Dyspnoea improvement by VAS-AUC to Day 5 2312.3 (3034.5) 2708.9 (2484.3) 396.67 (10.3, 783.0) 2366.4 (2963.3) 2827.5 (2827.9) 461.02 (−194.8, 1116.9) 0.87 
Dyspnoea improvement by Likert scale at 6, 12, and 24 h 113 (28.5%) 104 (25.2%) 0.85 (0.62, 1.15) 28 (19.7%) 41 (29.5%) 1.70 (0.98, 2.95) 0.030 
Total dose of IV loop diuretics before Day 5, mg 229.5 (399.2) 161.5 (268.8) −68.0 (−112.6,−23.4) 176.3 (242.2) 167.9 (275.4) −8.4 (−84.0, 67.3) 0.18 
Change in bodyweight to Day 5, kg −3.0 (3.4) −2.8 (3.4) 0.2 (−0.3, 0.7) −3.0 (3.4) −2.4 (3.3) 0.6 (−0.2, 1.4) 0.38 
Length of initial hospital stay, days 10.4 (9.3) 9.4 (8.6) −1.0 (−2.3, 0.3) 10.7 (10.4) 10.6 (10.9) −0.04 (−2.3, 2.2) 0.47 
Days in ICU/CCU 3.7 (6.4) 3.4 (6.6) −0.4 (−1.4, 0.6) 4.2 (8.1) 4.0 (8.9) −0.1 (−1.8, 1.5) 0.82 
Days alive out of hospital through Day 60 47.7 (11.8) 48.6 (11.3) 0.86 (−0.77, 2.49) 47.9 (12.3) 46.6 (13.3) −1.28 (−4.05, 1.50) 0.19 
Cardiovascular death or HF/RF hospitalization through Day 60 50 (12.64%) 56 (13.68%) 1.10 (0.75, 1.61) 18 (12.75%) 19 (13.85%) 1.08 (0.57, 2.06) 0.97 
All-cause death through Day 180 44 (11.14%) 29 (7.08%) 0.63 (0.39, 1.00) 16 (11.32%) 11 (8.08%) 0.70 (0.32, 1.50) 0.82 
Cardiovascular death through Day 180 37 (9.43%) 25 (6.12%) 0.64 (0.39, 1.07) 12 (8.53%) 7 (5.13%) 0.59 (0.23, 1.50) 0.87 

Continuous variables are expressed as mean (SD) or geometric mean (95% CI), categorical variables as n (%), and time-to-event variables as n (K-M%). Treatment effect represents mean difference for continuous variables, odds ratio for dichotomous variables, and hazard ratio for time-to-event variables, estimated from ANCOVA, logistic regression, and Cox regression models, respectively. VAS, visual analogue scale; AUC, area under the curve; ICU/CCU, intensive care unit/coronary care unit; HF, heart failure; RF, renal failure.

Figure 1

Patient-reported dyspnoea change (serelaxin vs. placebo) by category of left ventricular ejection fraction (LVEF), (<50% vs. ≥50%), according to visual analogue scale from baseline to Day 5 (A; increasing values represent improvement) and Likert scale during the first 24 h (B; interaction P values are for the proportions of patients with markedly or moderately improved dyspnoea).

Figure 1

Patient-reported dyspnoea change (serelaxin vs. placebo) by category of left ventricular ejection fraction (LVEF), (<50% vs. ≥50%), according to visual analogue scale from baseline to Day 5 (A; increasing values represent improvement) and Likert scale during the first 24 h (B; interaction P values are for the proportions of patients with markedly or moderately improved dyspnoea).

Figure 2

Kaplan–Meier curves for cardiovascular death or hospitalization for heart/renal failure through Day 60 according to LVEF. HR, hazard ratio.

Figure 2

Kaplan–Meier curves for cardiovascular death or hospitalization for heart/renal failure through Day 60 according to LVEF. HR, hazard ratio.

Figure 3

Kaplan–Meier curves for cardiovascular death through Day 180 (A, upper panel) and all-cause death through Day 180 (B, lower panel) according to LVEF. HR, hazard ratio.

Figure 3

Kaplan–Meier curves for cardiovascular death through Day 180 (A, upper panel) and all-cause death through Day 180 (B, lower panel) according to LVEF. HR, hazard ratio.

Using an LVEF cut-off of 40% to differentiate between HFpEF and HFrEF, 46% of patients were classified as HFpEF. In this case, the results regarding primary and secondary endpoints were similar, except for the difference in dyspnoea relief by Likert scale that was significant between HFpEF and HFrEF only with the 50% threshold.

Safety

The effect of treatment (serelaxin vs. placebo) on safety endpoints in HFrEF and HFpEF patients is presented in Table 3. Serelaxin had a similar effect in HFpEF and HFrEF patients on all-cause death through Day 180 (0.70 vs. 0.63, P for interaction = 0.82, Figure 3). There was no difference in the occurrence of confirmed blood pressure decrease or confirmed blood pressure decrease that led to dose reduction or to drug discontinuation following serelaxin between HFrEF and HFpEF patients (P for interaction, 0.17, 0.06 and 0.77, respectively). Furthermore, no differences between the two groups were observed in the occurrence of additional safety endpoints (Table 3).

Table 3

Treatment effect (serelaxin vs. placebo) on safety endpoints in patients with reduced (<50%) and preserved (≥50%) left ventricular ejection fraction

Outcome LVEF < 50 (n = 793)
 
LVEF ≥ 50 (n = 275)
 
P-value for interaction 
Placebo (n = 388) (%) Serelaxin (n = 405) (%) Placebo (n = 141) (%) Serelaxin (n = 134) (%) 
Patients with any SAE through Day 14 12.1 14.1 17.7 17.2 0.58 
Patients with SAE with an outcome of death through Day 14 1.5 1.5 4.3 3.0 0.71 
Total % of patients with AE indicative of hypotension through Day 14a 4.9 4.7 4.3 5.2 0.69 
Total % of patients with AE indicative of renal impairment through Day 14b 7.5 4.0 11.3 9.0 0.42 
Total % of patients with AE indicative of hepatic impairment through Day 14c 2.6 1.0 4.3 0.7 0.52 
Outcome LVEF < 50 (n = 793)
 
LVEF ≥ 50 (n = 275)
 
P-value for interaction 
Placebo (n = 388) (%) Serelaxin (n = 405) (%) Placebo (n = 141) (%) Serelaxin (n = 134) (%) 
Patients with any SAE through Day 14 12.1 14.1 17.7 17.2 0.58 
Patients with SAE with an outcome of death through Day 14 1.5 1.5 4.3 3.0 0.71 
Total % of patients with AE indicative of hypotension through Day 14a 4.9 4.7 4.3 5.2 0.69 
Total % of patients with AE indicative of renal impairment through Day 14b 7.5 4.0 11.3 9.0 0.42 
Total % of patients with AE indicative of hepatic impairment through Day 14c 2.6 1.0 4.3 0.7 0.52 

SAE, serious adverse events; AE, adverse events.

aBlood pressure decreased, dizziness, loss of consciousness, hypotension, orthostatic hypotension, presyncope, somnolence, or syncope.

bAzotemia, blood creatinine increased, oliguria, proteinuria, renal failure, renal failure acute, or renal impairment.

cBlood bilirubin increased, cholestasis, hepatic congestion, hepatic cyst, hepatic steatosis, hyperbilirubinaemia, hypoalbuminaemia, INR increased, or liver disorder.

Biomarkers of organ damage

The effect of treatment (serelaxin vs. placebo) on biomarkers indicative of organ damage in HFrEF and HFpEF patients is presented in Table 4. Serelaxin reduced plasma levels of NT-proBNP, cardiac troponin T, cystatin-C, serum creatinine and BUN and transaminases, compared with placebo, and there appeared to be no difference based on ejection fraction status (HFrEF vs. HFpEF) regarding the effects of serelaxin on any of these biomarkers measured from baseline to 48 h (all P for interaction > 0.05).

Table 4

Treatment effect (serelaxin vs. placebo) on biomarkers of organ damage in patients with reduced (<50%) and preserved (≥50%) left ventricular ejection fraction

Outcome LVEF < 50% (n = 810)
 
LVEF ≥ 50% (n = 281)
 
P for interaction 
Placebo (n = 397) Serelaxin (n = 413) Treatment effect (95% CI) Placebo (n = 142) Serelaxin (n = 139) Treatment effect (95% CI) 
Ratio (95% CI) of change from baseline to 48 h 
 Cystatin-C 1.07 (1.05, 1.09) 1.02 (1.00, 1.04) 0.95 (0.93, 0.97) 1.09 (1.06, 1.12) 1.03 (1.00, 1.07) 0.95 (0.91, 0.99) 0.96 
 cTNT 1.045 (0.997, 1.095) 0.955 (0.911, 1.002) 0.91 (0.86, 0.98) 1.002 (0.927, 1.083) 0.946 (0.888, 1.008) 0.94 (0.85, 1.05) 0.62 
 NT-proBNP 0.626 (0.583, 0.672) 0.498 (0.469, 0.529) 0.80 (0.72, 0.87) 0.555 (0.500, 0.615) 0.469 (0.409, 0.536) 0.84 (0.72, 0.99) 0.53 
Mean (SD) change from baseline to 48 h 
 AST, U/L −0.7 (38.8) −8.4 (28.4) −7.69 (−12.07, −3.30) −3.7 (8.1) −5.3 (8.8) −1.58 (−9.02, 5.87) 0.17 
 ALT, U/L −1.0 (27.0) −6.4 (19.3) −5.44 (−8.41, −2.47) −4.8 (9.1) −5.9 (9.4) −1.07 (−6.16, 4.02) 0.15 
Outcome LVEF < 50% (n = 810)
 
LVEF ≥ 50% (n = 281)
 
P for interaction 
Placebo (n = 397) Serelaxin (n = 413) Treatment effect (95% CI) Placebo (n = 142) Serelaxin (n = 139) Treatment effect (95% CI) 
Ratio (95% CI) of change from baseline to 48 h 
 Cystatin-C 1.07 (1.05, 1.09) 1.02 (1.00, 1.04) 0.95 (0.93, 0.97) 1.09 (1.06, 1.12) 1.03 (1.00, 1.07) 0.95 (0.91, 0.99) 0.96 
 cTNT 1.045 (0.997, 1.095) 0.955 (0.911, 1.002) 0.91 (0.86, 0.98) 1.002 (0.927, 1.083) 0.946 (0.888, 1.008) 0.94 (0.85, 1.05) 0.62 
 NT-proBNP 0.626 (0.583, 0.672) 0.498 (0.469, 0.529) 0.80 (0.72, 0.87) 0.555 (0.500, 0.615) 0.469 (0.409, 0.536) 0.84 (0.72, 0.99) 0.53 
Mean (SD) change from baseline to 48 h 
 AST, U/L −0.7 (38.8) −8.4 (28.4) −7.69 (−12.07, −3.30) −3.7 (8.1) −5.3 (8.8) −1.58 (−9.02, 5.87) 0.17 
 ALT, U/L −1.0 (27.0) −6.4 (19.3) −5.44 (−8.41, −2.47) −4.8 (9.1) −5.9 (9.4) −1.07 (−6.16, 4.02) 0.15 

Treatment effect represents ratio of relative changes or mean difference.

cTNT, cardiac troponin-T; NT-proBNP, N-terminal B-type natriuretic pro-peptide; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

The results concerning efficacy and safety endpoints were similar when analyses were performed using an LVEF cut-off of 40%.

Discussion

In the RELAX-AHF study, a 48-h infusion of serelaxin in AHF patients improved dyspnoea and other symptoms and signs of congestion and reduced early AHF worsening and hospitalization length.13 The drug failed to improve post-discharge readmission rate, but provided a significant 37% reduction in 180-day cardiovascular and all-cause mortality and was well tolerated.13 In addition, serelaxin induced a short-term favourable effect on biomarkers of myocardial, renal, and hepatic injury, an effect that may be associated with increased survival.14 In the present trial, we showed that the aforementioned effects of serelaxin on symptoms, outcome, and organ protection were similar in patients with HFrEF and HFpEF. Although the treatment groups differed with respect to in-hospital IV loop diuretic use, the difference was similar in patients with preserved and reduced EF. Decreases in body weight, incidence of adverse events related to hypotension or renal failure, and changes in biomarkers were similar in the treatment groups and between subgroups. Further data with respect to post-randomization management of patients who may have affected outcomes and they may have differed in HFpEF patients, such HbA1c levels or conversion to sinus rhythm, are not available. Serelaxin was well tolerated in both subgroups. Serelaxin was even more effective in improving dyspnoea at 6, 12, and 24 h on Likert scale in patients with HFpEF compared with those with HFrEF, although this was not reflected at each individual time point or by VAS-AUC through Day 5 and therefore it may not represent a real effect.

Patients with HFpEF represent a population with particular demographic and clinical features. The HFpEF patients enrolled in RELAX-AHF are representative of the HFpEF population. In accordance with earlier registries such as the Acute Decompensated Heart Failure National Registry (ADHERE)16 or the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF)17 and the most recent Meta-analysis of Global Group in Chronic Heart Failure (MAGGIC) that concerned nearly 42 000 cases from 31 trials,18 the HFpEF patients are older and more often female and have a higher prevalence of arterial hypertension and atrial fibrillation and a lower prevalence of ischaemic aetiology, compared with the patients with HFrEF. Older age, female gender, and atrial fibrillation were among the strong risk factors for new-onset HFpEF according to recently released data from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study.19

Given the lack of evidence-based therapies, the recently published findings of the Cardiovascular Research Network show that HFpEF patients are significantly less likely to be treated with multiple cardioactive drugs or multiple heart failure-related drug therapies.20 Accordingly, the present HFpEF population was treated less frequently with beta-blockers, mineralocorticosteroid receptor antagonists, or device therapies compared with the HFrEF subgroup. Upon presentation, the two subgroups had similar clinical signs of congestion, but HFpEF patients had higher systolic blood pressure and lower NT-proBNP. The presence of lower natriuretic peptide levels in acutely decompensated HFpEF in association with similar AHF severity compared with HFrEF has also been previously reported by a sub-analysis of the Diuretic Optimization Strategies Evaluation (DOSE) trial.21

RELAX-AHF was the first trial to provide an intermediate-term mortality reduction in AHF and these results were obtained in a patient population including a meaningful proportion of patients with HFpEF. This is rather unique as several drug classes that represent established therapies of HFrEF failed to provide similar benefits in HFpEF. Hence, none of the three earlier randomized studies on renin–angiotensin–aldosterone system inhibitors (perindopril, candesartan, and irbesartan) in chronic HFpEF patients met their primary endpoints and the same applied to the two recently released trials testing the mineralocorticosteroid receptor antagonist spironolactone and the phosphodiesterase-5 inhibitor sildenafil, while no drug has been previously studied specifically in AHF with preserved LVEF.8–12 A number of reasons have been postulated for these neutral effects. The lack of a universally accepted definition of HFpEF and the heterogeneity of HFpEF population22 and the presence of mild haemodynamic, neurohormonal, or other pathogenetic changes in many of the patients enrolled in those trials have been postulated as potential explanations for the observed lack of clinical benefit. In addition, it may be that HFpEF becomes symptomatic mainly as AHF with the characteristics of an episodic disease.23 Thus, AHF might be a more appropriate setting to study the efficacy of treatment in these patients. In RELAX-AHF, all HFpEF patients were acutely decompensated and were required to have objective evidence of congestion and increased levels of natriuretic peptide, hence allowing more space for clinical improvement.

A main drawback of drugs used in AHF such as inotropes and diuretics is the induction of organ function deterioration and/or damage.24,25 Myocardial, renal, and hepatic injury, as depicted by corresponding biomarkers, has been associated with an adverse outcome in AHF.26–28 This may be the key to the neutral or negative effects of previous trials in AHF. On the other hand, it has been hypothesized that the prevention of these detrimental effects may improve patients' prognosis and survival.13,27 The RELAX-AHF trial showed that serelaxin was followed by a reduction of biomarkers indicative of myocardial (troponin T), renal (cystatin-C), and hepatic (aminotransferases) injury.14 We showed herein that this effect was observed both in patients with HFrEF and in those with HFpEF. This favourable action may account at least in part for the observed beneficial outcome associated with serelaxin. Moreover, serelaxin was able to manage congestion effectively, as shown not only by the significant relief of dyspnoea and other symptoms and signs of congestion and the decreased heart failure worsening rate but also by the reduction of natriuretic peptide levels. The response of natriuretic peptides to AHF treatment has been associated with adverse prognosis in AHF.29,30 Additional pathogenetic mechanisms of AHF worsening that may theoretically be addressed by serelaxin and therefore may contribute to the observed benefit from the drug include increased LV afterload, inflammation, and oxidative stress.31

The present study bears the expected limitations of a post hoc subgroup analysis. Moreover, the main RELAX-AHF study was not primarily designed and powered to assess mortality.13,15 Given these limitations, the effects of serelaxin on HFpEF patients should be confirmed by subsequent trials.

In conclusion, serelaxin was well tolerated and effective in early dyspnoea relief and in improving multiple outcomes including 180-day mortality irrespectively of LVEF. Future studies with larger sample sizes will be needed to confirm these findings.

Funding

The RELAX-AHF trial was supported by Corthera Inc., a member of the Novartis group of companies. Steve Winter of Novartis Pharma AG, Basel, Switzerland and Graham Allcock of CircleScience (Tytherington, UK) helped in the preparation of the figures, which was funded by Novartis Pharma AG, Basel, Switzerland. Funding to pay the Open Access publication charges for this article was provided by Novartis Pharma AG.

Conflict of interest: G.F. is an executive committee member and consultant to Corthera (a Novartis company), Bayer, Cardiorentis, and has received research grants from Amgen, Nanosphere, European Committee. J.R.T. has received research grants or consulting fees from Amgen, Bayer, Corthera, Cardio3 BioSciences, Cytokinetics, Merck, Novartis, Takeda, Teva, and Trevena. G.C. and B.A.D. are employees of Momentum Research, which has provided consulting services to NovaCardia, Merck, Corthera, Novartis, Singulex, ChanRx, Sorbent Therapeutics, Cardio3 BioSciences, Trevena, Amgen, and Anexon. G.M.F. reports consulting income from Novartis, Medpace, Amgen, Otsuka, Trevena, Roche Diagnostics, Merck, BG Medicine, Medtronic, and St Judes and grant funding from Amgen, Otsuka, Roche Diagnostics, and NHLBI. B.H.G. served as a consultant for Corthera and Novartis. P.P. was a consultant for Astellas, Bayer, EKR Therapeutics, J&J, the Medicines Company, Medtronic, Novartis, Otsuka, Palatin Technologies, PDL BioPharma, Pericor Therapeutics, SigmaTau, Solvay Pharmaceuticals, and Trevena; has received honoraria from Alere, Beckman-Coulter, BiogenIdec, Corthera, Ikaria, Nile Therapeutics, Momentum Research, and Overcome; has received research support from Abbott, Merck, and PDL BioPharma; and has received travel support from MyLife and equipment support from Sonosite. T.H. and T.S. are employed by the sponsor Novartis. E.U. is a former employee of Corthera, Inc., a member of the Novartis group of companies. A.A.V. has received consultancy fees and/or research grants from Alere, Bayer, Cardio3 BioSciences, Celladon, Ceva, European Committee, Dutch Heart Foundation, Novartis, Servier, Torrent, and Vifor. M.M. has received consulting income from Abbott Vascular, Bayer, Corthera, and Novartis, as well as travel support and honoraria from Servier and Novartis.

References

1
Roger
VL
Go
AS
Lloyd-Jones
DM
Benjamin
EJ
Berry
JD
Borden
WB
Bravata
DM
Dai
S
Ford
ES
Fox
CS
Fullerton
HJ
Gillespie
C
Hailpern
SM
Heit
JA
Howard
VJ
Kissela
BM
Kittner
SJ
Lackland
DT
Lichtman
JH
Lisabeth
LD
Makuc
DM
Marcus
GM
Marelli
A
Matchar
DB
Moy
CS
Mozaffarian
D
Mussolino
ME
Nichol
G
Paynter
NP
Soliman
EZ
Sorlie
PD
Sotoodehnia
N
Turan
TN
Virani
SS
Wong
ND
Woo
D
Turner
MB
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Heart disease and stroke statistics—2012 update: a report from the American Heart Association
Circulation
 , 
2012
, vol. 
125
 (pg. 
e2
-
220
)
2
Gheorghiade
M
Konstam
MA
Burnett
JC
Jr
Grinfeld
L
Maggioni
AP
Swedberg
K
Udelson
JE
Zannad
F
Cook
T
Ouyang
J
Zimmer
C
Orlandi
C
Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials
JAMA
 , 
2007
, vol. 
297
 (pg. 
1332
-
1343
)
3
Mebazaa
A
Nieminen
MS
Packer
M
Cohen-Solal
A
Kleber
FX
Pocock
SJ
Thakkar
R
Padley
RJ
Põder
P
Kivikko
M
SURVIVE Investigators
Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized Trial
JAMA
 , 
2007
, vol. 
297
 (pg. 
1883
-
1891
)
4
Massie
BM
O'Connor
CM
Metra
M
Ponikowski
P
Teerlink
JR
Cotter
G
Weatherley
BD
Cleland
JG
Givertz
MM
Voors
A
DeLucca
P
Mansoor
GA
Salerno
CM
Bloomfield
DM
Dittrich
HC
PROTECT Investigators and Committees
Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
1419
-
1428
)
5
O'Connor
CM
Starling
RC
Hernandez
AF
Armstrong
PW
Dickstein
K
Hasselblad
V
Heizer
GM
Komajda
M
Massie
BM
McMurray
JJ
Nieminen
MS
Reist
CJ
Rouleau
JL
Swedberg
K
Adams
KF
Jr
Anker
SD
Atar
D
Battler
A
Botero
R
Bohidar
NR
Butler
J
Clausell
N
Corbalán
R
Costanzo
MR
Dahlstrom
U
Deckelbaum
LI
Diaz
R
Dunlap
ME
Ezekowitz
JA
Feldman
D
Felker
GM
Fonarow
GC
Gennevois
D
Gottlieb
SS
Hill
JA
Hollander
JE
Howlett
JG
Hudson
MP
Kociol
RD
Krum
H
Laucevicius
A
Levy
WC
Méndez
GF
Metra
M
Mittal
S
Oh
BH
Pereira
NL
Ponikowski
P
Tang
WH
Tanomsup
S
Teerlink
JR
Triposkiadis
F
Troughton
RW
Voors
AA
Whellan
DJ
Zannad
F
Califf
RM
Effect of nesiritide in patients with acute decompensated heart failure
N Engl J Med
 , 
2011
, vol. 
365
 (pg. 
32
-
43
)
6
McMurray
JJ
Adamopoulos
S
Anker
SD
Auricchio
A
Böhm
M
Dickstein
K
Falk
V
Filippatos
G
Fonseca
C
Gomez-Sanchez
MA
Jaarsma
T
Køber
L
Lip
GY
Maggioni
AP
Parkhomenko
A
Pieske
BM
Popescu
BA
Rønnevik
PK
Rutten
FH
Schwitter
J
Seferovic
P
Stepinska
J
Trindade
PT
Voors
AA
Zannad
F
Zeiher
A
ESC Committee for Practice Guidelines
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
1787
-
1847
)
7
Alla
F
Zannad
F
Filippatos
G
Epidemiology of acute heart failure syndromes
Heart Fail Rev
 , 
2007
, vol. 
12
 (pg. 
91
-
95
)
8
Yusuf
S
Pfeffer
MA
Swedberg
K
Granger
CB
Held
P
McMurray
JJ
Michelson
EL
Olofsson
B
Ostergren
J
CHARM Investigators and Committees
Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial
Lancet
 , 
2003
, vol. 
362
 (pg. 
777
-
781
)
9
Cleland
JG
Tendera
M
Adamus
J
Freemantle
N
Polonski
L
Taylor
J
PEP-CHF Investigators
The perindopril in elderly people with chronic heart failure (PEP-CHF) study
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
2338
-
2345
)
10
Massie
BM
Carson
PE
McMurray
JJ
Komajda
M
McKelvie
R
Zile
MR
Anderson
S
Donovan
M
Iverson
E
Staiger
C
Ptaszynska
A
I-PRESERVE Investigators
Irbesartan in patients with heart failure and preserved ejection fraction
N Engl J Med
 , 
2008
, vol. 
359
 (pg. 
2456
-
2467
)
11
Edelmann
F
Wachter
R
Schmidt
AG
Kraigher-Krainer
E
Colantonio
C
Kamke
W
Duvinage
A
Stahrenberg
R
Durstewitz
K
Löffler
M
Düngen
HD
Tschöpe
C
Herrmann-Lingen
C
Halle
M
Hasenfuss
G
Gelbrich
G
Pieske
B
Aldo-DHF Investigators
Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial
JAMA
 , 
2013
, vol. 
309
 (pg. 
781
-
791
)
12
Redfield
MM
Chen
HH
Borlaug
BA
Semigran
MJ
Lee
KL
Lewis
G
LeWinter
MM
Rouleau
JL
Bull
DA
Mann
DL
Deswal
A
Stevenson
LW
Givertz
MM
Ofili
EO
O'Connor
CM
Felker
GM
Goldsmith
SR
Bart
BA
McNulty
SE
Ibarra
JC
Lin
G
Oh
JK
Patel
MR
Kim
RJ
Tracy
RP
Velazquez
EJ
Anstrom
KJ
Hernandez
AF
Mascette
AM
Braunwald
E
RELAX Trial
Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial
JAMA
 , 
2013
, vol. 
309
 (pg. 
1268
-
1277
)
13
Teerlink
JR
Cotter
G
Davison
BA
Felker
GM
Filippatos
G
Greenberg
BH
Ponikowski
P
Unemori
E
Voors
AA
Adams
KF
Jr
Dorobantu
MI
Grinfeld
LR
Jondeau
G
Marmor
A
Masip
J
Pang
PS
Werdan
K
Teichman
SL
Trapani
A
Bush
CA
Saini
R
Schumacher
C
Severin
TM
Metra
M
RELAXin in Acute Heart Failure (RELAX-AHF) Investigators
Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomized, placebo-controlled trial
Lancet
 , 
2013
, vol. 
381
 (pg. 
29
-
39
)
14
Metra
M
Cotter
G
Davison
BA
Felker
GM
Filippatos
G
Greenberg
BH
Ponikowski
P
Unemori
E
Voors
AA
Adams
KF
Jr
Dorobantu
MI
Grinfeld
L
Jondeau
G
Marmor
A
Masip
J
Pang
PS
Werdan
K
Prescott
MF
Edwards
C
Teichman
SL
Trapani
A
Bush
CA
Saini
R
Schumacher
C
Severin
T
Teerlink
JR
RELAX-AHF Investigators
Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes
J Am CollCardiol
 , 
2013
, vol. 
61
 (pg. 
196
-
206
)
15
Ponikowski
P
Metra
M
Teerlink
JR
Unemori
E
Felker
GM
Voors
AA
Filippatos
G
Greenberg
B
Teichman
SL
Severin
T
Mueller-Velten
G
Cotter
G
Davison
BA
Design of the RELAXin in acute heart failure study
Am Heart J
 , 
2012
, vol. 
163
 (pg. 
149
-
155
)
16
Yancy
CW
Lopatin
M
Stevenson
LW
De Marco
T
Fonarow
GC
ADHERE Scientific Advisory Committee and Investigators
Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database
J Am Coll Cardiol
 , 
2006
, vol. 
47
 (pg. 
76
-
84
)
17
Fonarow
GC
Stough
WG
Abraham
WT
Albert
NM
Gheorghiade
M
Greenberg
BH
O'Connor
CM
Sun
JL
Yancy
CW
Young
JB
OPTIMIZE-HF Investigators and Hospitals
Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
768
-
777
)
18
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC)
The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
1750
-
1757
)
19
Brouwers
FP
de Boer
RA
van der Harst
P
Voors
AA
Gansevoort
RT
Bakker
SJ
Hillege
HL
van Veldhuisen
DJ
van Gilst
WH
Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND
Eur Heart J
 , 
2013
, vol. 
34
 (pg. 
1424
-
1431
)
20
Goldberg
RJ
Gurwitz
JH
Saczynski
JS
Hsu
G
McManus
DD
Magid
DJ
Smith
DH
Go
AS
CVRN PRESERVE HF Investigators
Comparison of medication practices in patients with heart failure and preserved versus those with reduced ejection fraction (from the Cardiovascular Research Network [CVRN])
Am J Cardiol
 , 
2013
, vol. 
111
 (pg. 
1324
-
1329
)
21
Bishu
K
Deswal
A
Chen
HH
LeWinter
MM
Lewis
GD
Semigran
MJ
Borlaug
BA
McNulty
S
Hernandez
AF
Braunwald
E
Redfield
MM
Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction
Am Heart J
 , 
2012
, vol. 
164
 (pg. 
763
-
770
)
22
Cleland
JG
Pellicori
P
Defining diastolic heart failure and identifying effective therapies
JAMA
 , 
2013
, vol. 
309
 (pg. 
825
-
826
)
23
Banerjee
P
Clark
AL
Nikitin
N
Cleland
JG
Diastolic heart failure. Paroxysmal or chronic?
Eur J Heart Fail
 , 
2004
, vol. 
6
 (pg. 
427
-
431
)
24
Januzzi
JL
Jr
Filippatos
G
Nieminen
M
Gheorghiade
M
Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
2265
-
2271
)
25
Parissis
JT
Farmakis
D
Nieminen
M
Classical inotropes and new cardiac enhancers
Heart Fail Rev
 , 
2007
, vol. 
12
 (pg. 
149
-
156
)
26
Kociol
RD
Pang
PS
Gheorghiade
M
Fonarow
GC
O'Connor
CM
Felker
GM
Troponin elevation in heart failure prevalence, mechanisms, and clinical implications
J Am Coll Cardiol
 , 
2010
, vol. 
56
 (pg. 
1071
-
1078
)
27
Metra
M
Cotter
G
Gheorghiade
M
Dei Cas
L
Voors
AA
The role of the kidney in heart failure
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
2135
-
2142
)
28
Ambrosy
AP
Vaduganathan
M
Huffman
MD
Khan
S
Kwasny
MJ
Fought
AJ
Maggioni
AP
Swedberg
K
Konstam
MA
Zannad
F
Gheorghiade
M
EVEREST trial investigators
Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial
Eur J Heart Fail
 , 
2012
, vol. 
14
 (pg. 
302
-
311
)
29
Farmakis
D
Parissis
JT
Bistola
V
Paraskevaidis
IA
Iliodromitis
EK
Filippatos
G
Kremastinos
DT
Plasma B-type natriuretic peptide reduction predicts long-term response to levosimendan therapy in acutely decompensated chronic heart failure
Int J Cardiol
 , 
2010
, vol. 
139
 (pg. 
75
-
79
)
30
Maisel
A
Mueller
C
Adams
K
Jr
Anker
SD
Aspromonte
N
Cleland
JG
Cohen-Solal
A
Dahlstrom
U
DeMaria
A
Di Somma
S
Filippatos
GS
Fonarow
GC
Jourdain
P
Komajda
M
Liu
PP
McDonagh
T
McDonald
K
Mebazaa
A
Nieminen
MS
Peacock
WF
Tubaro
M
Valle
R
Vanderhyden
M
Yancy
CW
Zannad
F
Braunwald
E
State of the art: using natriuretic peptide levels in clinical practice
Eur J Heart Fail
 , 
2008
, vol. 
10
 (pg. 
824
-
839
)
31
Teichman
SL
Unemori
E
Teerlink
JR
Cotter
G
Metra
M
Relaxin: review of biology and potential role in treating heart failure
Curr Heart Fail Rep
 , 
2010
, vol. 
7
 (pg. 
75
-
82
)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Supplementary data

Comments

0 Comments