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Figure 1.
Flow of Patients Through the Trial
Flow of Patients Through the Trial

NT-proBNP indicates N-terminal pro-B-type natriuretic peptide; BNP, B-type natriuretic peptide; BP, blood pressure; LVEF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate.

aOne patient in the 2.5-mg vericiguat group was too old according to local regulation (initial age limit <75 y, later suspended).

bMajor reasons for exclusion. Each patient may have >1 reason for exclusion.

Figure 2.
Change From Baseline in NT-proBNP Level for Vericiguat Dose Groups Compared With Placebo (Per-Protocol Set)
Change From Baseline in NT-proBNP Level for Vericiguat Dose Groups Compared With Placebo (Per-Protocol Set)

Data are expressed as ratio of geometric means for the change from baseline to week 12 in the dosing group compared with change from baseline to week 12 in the placebo group. A value of 1.0 on the y-axis represents no difference. Number of patients included for the placebo group, 69; 1.25-mg vericiguat group, 69; 2.5-mg group, 73; 2.5- to 5-mg group, 67; 2.5- to 10-mg group, 73; and pooled 2.5/5/10-mg group, 213. Error bars indicate 90% CI; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

aExploratory analysis of decreasing slope among vericiguat dose groups.

bExploratory pairwise comparison of 10-mg target dose group with placebo, 1-sided test.

Figure 3.
Time to Composite of Cardiovascular Death or Heart Failure Hospitalization
Time to Composite of Cardiovascular Death or Heart Failure Hospitalization

CV indicates cardiovascular; HF, heart failure. Hazard ratios for vericiguat/placebo for each group were as follows:

1.25-mg vericiguat group, 0.97 (95% CI, 0.50-1.88)

2.5-mg group, 1.01 (95% CI, 0.52-1.94)

2.5- to 5-mg group, 0.63 (95% CI, 0.30-1.34)

2.5- to 10-mg group, 0.53 (95% CI, 0.25-1.16)

pooled 2.5-/5-/10-mg group, 0.72 (95% CI, 0.41-1.26)

Figure 4.
Longitudinal Changes in Blood Pressure and Heart Rate
Longitudinal Changes in Blood Pressure and Heart Rate

Data displayed as mean (SD) comparing the 10-mg vericiguat group with the placebo group.

Table 1.  
Baseline Characteristics (Full Analysis Set)
Baseline Characteristics (Full Analysis Set)
Table 2.  
Primary and Secondary Analyses of the Primary End Point (Change From Baseline to 12 Weeks in Log-Transformed NT-proBNP Level) (Per-Protocol Set)
Primary and Secondary Analyses of the Primary End Point (Change From Baseline to 12 Weeks in Log-Transformed NT-proBNP Level) (Per-Protocol Set)
Table 3.  
Select Clinical Exploratory End Points (Full Analysis Set)
Select Clinical Exploratory End Points (Full Analysis Set)
Table 4.  
Select Echocardiographic and Vital Sign Exploratory End Points
Select Echocardiographic and Vital Sign Exploratory End Points
Table 5.  
Adverse Events (Safety Analysis Set)
Adverse Events (Safety Analysis Set)
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Marti  CN, Gheorghiade  M, Kalogeropoulos  AP, Georgiopoulou  VV, Quyyumi  AA, Butler  J.  Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012;60(16):1455-1469.
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McKie  PM, Schirger  JA, Costello-Boerrigter  LC,  et al.  Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction. J Am Coll Cardiol. 2011;58(20):2095-2103.
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Bonderman  D, Ghio  S, Felix  SB,  et al; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group.  Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128(5):502-511.
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Taylor  AL, Ziesche  S, Yancy  C,  et al; African-American Heart Failure Trial Investigators.  Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057.
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McMurray  JJ, Packer  M, Desai  AS,  et al; PARADIGM-HF Investigators and Committees.  Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.
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Gupta  D, Georgiopoulou  VV, Kalogeropoulos  AP,  et al.  Nitrate therapy for heart failure: benefits and strategies to overcome tolerance. JACC Heart Fail. 2013;1(3):183-191.
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Sharkovska  Y, Kalk  P, Lawrenz  B,  et al.  Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens. 2010;28(8):1666-1675.
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Masuyama  H, Tsuruda  T, Kato  J,  et al.  Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats. Hypertension. 2006;48(5):972-978.
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Vaduganathan  M, Butler  J, Pitt  B, Gheorghiade  M.  Contemporary drug development in heart failure: call for hemodynamically neutral therapies. Circ Heart Fail. 2015;8(4):826-831.
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Patel  PA, Heizer  G, O’Connor  CM,  et al.  Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF. Circ Heart Fail. 2014;7(6):918-925.
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Original Investigation
December 1, 2015

Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection FractionThe SOCRATES-REDUCED Randomized Trial

Author Affiliations
  • 1Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Division of Cardiology, Duke University Medical Center, Durham, North Carolina
  • 3Division of Cardiology, Stony Brook University, Stony Brook, New York
  • 4Heart Failure Unit, Department of Cardiology, Athens University Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
  • 5Department of Cardiology, National Heart Centre Singapore and Duke, National University of Singapore, Singapore
  • 6Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy
  • 7Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland
  • 8Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 9Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 10Department of Internal Medicine and Cardiology, Charité University Medicine Berlin–Campus Virchow Klinikum, Berlin, Germany
  • 11Bayer, São Paulo, Brazil
  • 12Bayer Pharma, Wuppertal, Germany
  • 13Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany
JAMA. 2015;314(21):2251-2262. doi:10.1001/jama.2015.15734
Abstract

Importance  Worsening chronic heart failure (HF) is a major public health problem.

Objective  To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).

Design, Setting, and Participants  Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.

Interventions  Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.

Main Outcomes and Measures  The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.

Results  Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, −0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, −0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, −0.122; 90% CI, −0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.

Conclusions and Relevance  Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.

Trial Registration  clinicaltrials.gov Identifier: NCT01951625

Introduction

More than 1 million hospitalizations for heart failure (HF) occur annually in the United States alone, and more than 80% of these hospitalized patients have worsening chronic HF.1,2 Despite an often rapid and substantial in-hospital improvement in HF signs and symptoms with standard therapy, approximately 25% of patients are rehospitalized within 30 days and 30% of patients may die within 1 year.3,4 Patients with worsening chronic HF who are not hospitalized, but require outpatient intravenous diuretic administration, may carry a similarly poor prognosis.5

Preclinical and clinical evidence supports augmentation of the nitric oxide–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway as a potential therapeutic target for worsening chronic HF. Under physiologic conditions, the cGMP pathway is a critical regulator of myocardial energetics, cardiac performance, and endothelial function.69 In HF, increased inflammation and vascular dysfunction results in reduced nitric oxide bioavailability, with resultant decrease in downstream cGMP synthesis.9 This cGMP deficiency causes systemic, coronary, and renal microcirculatory dysfunction, which may lead to progressive myocardial damage and further inflammation.6,7,10 Derangements in cGMP signaling have been correlated with worse clinical outcomes among patients with reduced left ventricular ejection fraction (LVEF).6

Soluble guanylate cyclase stimulators offer a novel approach for addressing the relative cGMP deficit in worsening chronic HF. These agents modulate sGC in a nitric oxide–independent manner, mimicking nitric oxide and restoring downstream cGMP signaling. The recent availability of oral formulations of sGC stimulators affords the opportunity to test the hypothesis that enhancement of the cGMP pathway using an sGC stimulator will favorably influence the clinical course of worsening chronic HF. The Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study (SOCRATES-REDUCED) was designed to evaluate the effect on natriuretic peptide trajectory and tolerability of 12 weeks of treatment with 4 doses of oral vericiguat (BAY1021189), a novel once-daily sGC stimulator, in clinically stable patients with worsening chronic HF and reduced LVEF.

Methods

SOCRATES-REDUCED was a multicenter, randomized, double-blind, placebo-controlled, dose-finding trial that enrolled patients with worsening chronic HF after clinical stabilization. The study design has been previously described, and the protocol and statistical analysis plan are online (see the trial protocol in Supplement 1 and statistical analysis plan in Supplement 2).11 Institutional review board or ethics committee approval was obtained at each study site. All patients provided written informed consent.

Study Patients

The full inclusion and exclusion criteria of the SOCRATES-REDUCED study can be found in the trial protocol in Supplement 1.11 Briefly, eligible patients had LVEF less than 45% and a recent episode of worsening chronic HF defined by 3 components: (1) worsening HF symptoms requiring either hospitalization or outpatient administration of intravenous diuretics; (2) signs of congestion (clinical or chest radiograph findings); and (3) elevated natriuretic peptide level (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥1000 pg/mL or B-type natriuretic peptide [BNP] ≥300 pg/mL if in sinus rhythm, or NT-proBNP ≥1600 pg/mL or BNP ≥500 pg/mL if in atrial fibrillation [BNP inclusion level criteria were different in Japan; see the eAppendix in Supplement 3]). All patients had a history of chronic HF, defined as New York Heart Association class II through IV symptoms and treatment with guideline-directed medical HF therapy for 30 days or longer before hospitalization or intravenous diuretic administration without hospitalization. Prior to randomization, patients were required to be clinically stable, defined as not having received intravenous vasodilator therapy for at least 24 hours and not having received intravenous diuretic therapy for at least 12 hours, and having systolic blood pressure 110 mm Hg or greater and less than 160 mm Hg, and heart rate 50/min or greater and less than 100/min.

Exclusion criteria included intravenous inotropes at any time between hospitalization and randomization; concurrent use of nitrates, phosphodiesterase type 5 inhibitors, or alternative sGC stimulators; acute coronary syndrome within 60 days prior to randomization; listing for cardiac transplant or anticipated placement of ventricular assist device; glomerular filtration rate less than 30 mL/min; and several specific HF etiologies, including hypertrophic cardiomyopathy, pericardial disease, infiltrative/inflammatory myocardial disease, and severe valvular disease.

Study Design

Patients who met selection criteria were randomized 1:1:1:1:1 to 1 of 5 equally sized study groups (4 vericiguat groups, 1 placebo group) (Figure 1). Patients were randomized in blocks with a block size of 10. If patient screening began during hospitalization, randomization occurred within 4 weeks of clinical stabilization, either before or after discharge. If screening began after hospital discharge, the randomization period extended up to 4 weeks after the index discharge. When screening began after outpatient intravenous diuretic therapy, randomization was permitted for 4 weeks from time of diuretic administration. Patient race/ethnicity was recorded and determined at the discretion of the investigator.

The 4 vericiguat treatment groups targeted a maximal dose of 1.25 mg, 2.5 mg, 5 mg, and 10 mg, administered orally once daily. All active treatment groups except the 1.25-mg once-daily group started with 2.5 mg once daily of vericiguat at randomization (visit 1). Study protocol specified up-titration (ie, dose doubling) or sham titration of dose at week 2 (visit 2) and week 4 (visit 3) after randomization. Dose titration in all groups was predicated on safety assessments and systolic blood pressure criteria. Planned total treatment duration was 12 weeks (visit 5), followed by a safety follow-up at 16 weeks after randomization.

Study End Points

The primary end point of the study was change from baseline to week 12 in log-transformed NT-proBNP level. All additional end points were exploratory or related to safety. Echocardiographic end points included changes in LVEF, left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) from baseline to week 12. Additional end points included clinical events, blood pressure and heart rate, and changes in multiple biomarker levels. For the primary end point and the other biomarker end points, only blood samples analyzed by the central laboratory were considered (Covance Central Laboratory Services, Geneva, Switzerland). Echocardiograms at randomization and week 12 were read centrally by the blinded echocardiography core laboratory (Charité University Medicine, Berlin, Germany). Clinical events were adjudicated by a blinded clinical event committee. All patients, researchers, and clinicians were blinded to study treatment randomization. An independent data and safety monitoring board was charged to monitor patient safety during the trial.

Statistical Analysis

A sample size of 325 patients (65 patients per study group) was estimated to provide 80% power for the primary analysis with 1-sided α = 5%. Assuming a 20% dropout rate, 410 was the target sample size for randomization. This calculation was based on an earlier study of an sGC stimulator in patients with reduced LVEF and pulmonary hypertension and derived from an assumed difference in treatment effect of −0.187 log (pg/mL) between the placebo and pooled treatment groups with a standard deviation of 0.52 log (pg/mL).11,12 The full analysis set for the present study included all patients randomized to treatment and was used to display baseline characteristics and exploratory efficacy assessments. The safety analysis set included the full analysis set of all patients who received at least 1 dose of the study drug and was used to display safety data. The per-protocol set included all patients randomized to treatment who were alive with valid measurement of NT-proBNP at baseline and week 12 and had no major protocol deviations. The per-protocol set was used for primary efficacy analysis, with the rationale being that intention-to-treat analysis would require inclusion of patients without postbaseline NT-proBNP values and thus be less appropriate for a dose-finding study. Nonetheless, several sensitivity analyses were performed including imputation by last observation carried forward, an analysis of observed cases that included patients with visit 5 NT-proBNP values and patients who dropped out due to adverse event or death, and multiple imputation analysis.

For the primary analysis of the primary end point, the 3 highest-dose vericiguat groups (2.5 mg, 5 mg, and 10 mg) were prespecified to be pooled and compared with placebo with a 2-sample t test at the 1-sided significance level α = 5%. The 1.25-mg dose group was assumed to have no or minimal effect and hence was not included in the pool of presumed effective dose groups. Secondary analyses of the primary end point were prespecified to investigate a dose-response relationship by linear regression model. In addition, if the null hypothesis of the primary analysis was rejected, pairwise comparisons of the individual vericiguat groups with placebo were planned in a hierarchical manner with a 2-sample t test at the 1-sided significance level α = 5%. If the primary analysis showed no statistical significance, comparisons of individual dose groups with placebo were to be deemed descriptive only. Only the primary and secondary analyses of NT-proBNP change from baseline to 12 weeks were prespecified in the hierarchical testing procedure and thus were α-adjusted (secondary analyses only α-adjusted if primary analysis statistically significant). All other analyses and end points were only exploratory, and hence P values are only descriptive and do not reflect statistical significance. SAS version 9.2 was used for all analyses.

Results

Of the 632 patients screened, 456 patients were randomized (Figure 1). The mean (SD) time from clinical stabilization to randomization was 14.4 (9.8) days. Patients were randomized from 144 sites across Europe, North America, and Asia between November 2013 and January 2015. The follow-up period ended in June 2015. Overall, 351 patients (77.0%) completed treatment with study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were included in the per-protocol set for evaluation of the primary end point. There were 6 patients (1.3%) with unknown vital status at completion of safety follow-up.

The treatment groups were generally well balanced with respect to baseline characteristics, with exception of higher median baseline NT-proBNP level among those randomized to receive placebo and 1.25-mg vericiguat (Table 1). Overall, 77.9% of patients fulfilled worsening chronic HF criteria by being hospitalized, and 22.1% met criteria by requiring outpatient intravenous diuretic use. Mean age of the cohort was 68 years, and the majority of patients were men and white. Mean LVEF was 29.6%, and mean blood pressure was 126/75 mm Hg. Median baseline NT-proBNP level was 3076 pg/mL, and mean estimated glomerular filtration rate was 58 mL/min/1.73 m2. At randomization, patients were receiving diuretics (94%), angiotensin-converting enzyme (ACE) inhibitors (61%), angiotensin II receptor blockers (23%), β-blockers (90%), and mineralocorticoid receptor antagonists (62%). The actual study medication dosing achieved per the protocol dose titration schedules is displayed in eTable 1 in Supplement 3. Of those patients randomized to receive the highest vericiguat dose and receiving study treatment on and after 8 weeks of follow-up, 71.8% reached the 10-mg daily target dose.

Primary End Point

Analyses of the primary end point are displayed in Figure 2 and Table 2. The primary end point, change in log-transformed NT-proBNP level from baseline to 12 weeks, was not significantly different in the pooled vericiguat treatment group (log-transformed values: baseline, 7.969; 12 weeks, 7.567; difference, −0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) compared with the placebo group (log-transformed values: baseline, 8.283; 12 weeks, 8.002; difference, −0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, −0.122; 90% CI, −0.32 to 0.07; ratio of geometric means on original scale, 0.885; 90% CI, 0.73-1.08; P = .15). Exploratory secondary analyses of the primary end point using linear regression modeling suggested a dose-response relationship (P < .02), with higher vericiguat doses associated with greater reduction in NT-proBNP levels. Several sensitivity analyses, including imputation by last observation carried forward, an analysis of observed cases that included patients with visit 5 NT-proBNP values and patients dropping out due to adverse event or death, and multiple imputation analysis, did not meaningfully alter results. Results of sensitivity analyses for the primary and secondary analyses of the primary end point are displayed in eTable 3, eTable 4, and eTable 5 in Supplement 3.

Exploratory End Points

Pairwise exploratory analyses of individual vericiguat groups found differences in the primary end point between the 10-mg vericiguat group (log-transformed values: baseline, 8.131; 12 weeks, 7.602; difference, −0.529; geometric means: baseline, 3400 pg/mL; 12 weeks, 2001 pg/mL) and placebo, with greater reductions in NT-proBNP level with vericiguat (difference of means, −0.250; 90% CI, −0.50 to 0.00; ratio of geometric means on original scale, 0.779; 90% CI, 0.61-1.00; P = .048). Comparison of the primary end point between other individual vericiguat groups and placebo all yielded P > .05 in these descriptive analyses.

Additional select exploratory clinical and echocardiographic end points are displayed in Table 3 and Table 4. All-cause death as 12 weeks occurred at a rate of 3.3% among patients taking placebo and 2.2% to 4.4% among patients randomized to receive vericiguat. The rate of HF hospitalization at 12 weeks was 9.9% in the 10-mg and 5-mg vericiguat groups, 17.6% in the 2.5-mg and 1.25-mg groups, and 17.4% in the placebo group. The rate of the composite of cardiovascular death or HF hospitalization was 11% in the 10-mg vericiguat group, 12.1% in the 5-mg group, 19.8% in the 2.5-mg group, 18.7% in the 1.25-mg group, and 19.6% in the placebo group (Figure 3).

Patients in the 10-mg vericiguat group experienced an increase in LVEF at 12 weeks compared with placebo (+3.7% vs +1.5%; P = .02; descriptive analysis) (Table 4). There were no significant differences in change in LVEDV or LVESV between placebo and any vericiguat group. Changes in mean systolic and diastolic blood pressure and mean heart rate from baseline to 12 weeks were similar between the placebo and 10-mg vericiguat groups (all P ≥ .57) (Table 4 and Figure 4). Data regarding changes in exploratory biomarkers are displayed in eTable 2 in Supplement 3.

Safety Outcomes

Safety outcomes were evaluated in all patients who received at least 1 dose of the study drug (455 patients, safety analysis set). Data for adverse events (AEs), serious AEs (SAEs), and study discontinuations secondary to AEs are displayed in Table 5. Rates of any AE were similar across study groups: 77.2% among patients taking placebo and as high as 78.9% among the vericiguat groups (2.5-mg group). Rates of SAE were highest among placebo patients at 39.1%. Rates of treatment-emergent acute kidney injury (placebo: 3.3%; vericiguat groups: 1.1%-5.5%) and study drug discontinuation due to SAEs (placebo: 5.4%; vericiguat groups: 2.2%-7.7%) were similar between treatment groups.

Treatment-emergent syncope was most frequent in the 10-mg vericiguat group (4 patients, 4.4%; in 3/4 patients, events occurred during the first 2 weeks after randomization, ie, when taking the 2.5-mg dose). Treatment-emergent hypotension was most common in the 10-mg vericiguat group (14 patients, 15.4%) and was next most frequent in the 2.5-mg vericiguat group (6 patients, 6.7%). Among the 14 patients with treatment-emergent hypotension in the 10-mg vericiguat group, 8 patients experienced hypotension between weeks 0 and 2, when the maximal vericiguat dose per the study titration schedule was 2.5 mg once daily. Two patients experienced hypotension between weeks 2 and 4, when the maximal vericiguat dose was 5 mg once daily. The cumulative proportion of patients with treatment-emergent hypotension during the first 2 weeks in the three 2.5-mg starting-dose groups was 4.4%, compared with 3.3% in the placebo group. Two patients in the trial discontinued the study drug due to hypotension (1 in the placebo group; 1 in the 5-mg vericiguat group).

Discussion

The SOCRATES-REDUCED trial was designed to evaluate the tolerability and optimal dose of 4 regimens of vericiguat in stabilized patients with worsening chronic HF and reduced LVEF. The primary analysis of the primary end point was not met, as pooled analysis of the 3 higher-dose vericiguat groups found no significant difference in 12-week NT-proBNP reduction compared with placebo. Prespecified secondary analyses demonstrated a dose-response relationship between increasing vericiguat dose and NT-proBNP reduction. Overall, vericiguat appeared well tolerated without an excess in AEs or SAEs compared with placebo. Further prospective testing in a phase 3 trial is needed to definitively determine the effect of vericiguat on clinical outcomes in this patient population.

The nitric oxide–sGC–cGMP pathway represents a long-established therapeutic target in HF with reduced LVEF, most notably with use of combination isosorbide dinitrate and hydralazine therapy in African American patients.13 More recently, targeting the particulate guanylate cyclase–cGMP pathway via neprilysin inhibition and augmentation of the natriuretic peptide system demonstrated clinical benefits.14 However, additional attempts at cGMP enhancement in HF with reduced LVEF have been challenging, as treatment with exogenous organic nitrates is limited by tolerance and impaired bioactivation.15 Moreover, oxidative stress decreases the sensitivity of sGC to nitric oxide, which may impair downstream cGMP production even if nitric oxide levels are sufficient.6 Direct sGC modulators have the advantage of stimulating sGC in a nitric oxide–independent manner, circumventing problems with reduced upstream nitric oxide bioavailability and diminished endogenous activity of sGC.

Although the primary analysis of the primary end point of this trial was not met, there are several notable findings. The first is that all doses of vericiguat appeared well tolerated compared with placebo. Patients receiving placebo and those in the 2.5-mg vericiguat group had higher rates of any SAE and any AE compared with other vericiguat groups. While this study was not powered for clinical events, rates of mortality and HF hospitalization were generally numerically lower among patients receiving vericiguat, particularly among those randomized to the 2 highest-dose vericiguat groups. Specifically, the rate of HF hospitalization in these 2 highest-dose vericiguat groups was 9.9% compared with 17.4% to 17.6% in the placebo and lower-dose vericiguat groups. Although investigator-reported episodes of treatment-emergent hypotension and syncope were more frequent among patients in the highest-dose vericiguat group, these events did not prompt excess study drug discontinuation, and there were no significant differences in 12-week follow-up blood pressure and heart rate measurements among patients randomized to receive 10-mg vericiguat or placebo. Moreover, excess hypotensive events in the 10-mg vericiguat group were mostly early events (ie, ≤2 weeks after randomization) when patients were still receiving low-dose vericiguat identical to other study groups, thus suggesting the possibility of a chance finding.

The dose-response relationship of vericiguat with NT-proBNP level reduction in the prespecified exploratory secondary analyses warrants comment. The 10-mg vericiguat group yielded concurrent improvements in NT-proBNP level and LVEF at 12 weeks, and the observed similarities in blood pressure and heart rate between the 10-mg vericiguat and placebo groups over this period suggest that these improvements were most likely not related to reduction in diastolic blood pressure. In the setting of stable hemodynamics, these findings may signal intrinsic reverse remodeling of the heart with corresponding decreases in ventricular filling pressures and improvement in myocardial function. This conclusion would be consistent with preclinical data for sGC modulators in HF, for which these agents have been associated with reductions in cardiac fibrosis and left ventricular mass, improvement in endothelial dysfunction, and preservation of renal function, in a blood pressure–independent manner.1618 In the current trial, although only exploratory in nature, the collective signal toward potential benefit in natriuretic peptide trajectory, clinical events, and LVEF at 12 weeks of treatment with the higher vericiguat dosing schedule, while maintaining safety, suggests that titration to the 5-mg or 10-mg once daily dose may be reasonable for further testing in a phase 3 study.

The contemporary treatment approach for HF with reduced LVEF centers on systemic blockade of the sympathetic and renin-angiotensin-aldosterone systems with hemodynamically active agents that decrease cardiac workload by reducing heart rate, preload, or afterload.19 These medications may lower blood pressure as an intended or unintended consequence. Continued stepwise addition of investigational agents with pronounced blood pressure–lowering effects to target doses of existing guideline-directed medications raises safety and tolerability concerns.19,20 The present study generates the hypothesis that a once-daily sGC stimulator may exert favorable cardiac effects without sizeable changes in blood pressure and heart rate and thus may be safely tolerated for a broad HF population in combination with contemporary therapies. Although the present study required systolic blood pressure 110 mm Hg or greater for enrollment, the observation that vericiguat, as titrated in SOCRATES-REDUCED, did not meaningfully influence mean blood pressure at 12 weeks’ follow-up suggests this agent could be favorable for patients with worsening chronic HF who have even lower baseline blood pressure, a subpopulation at heightened risk of adverse outcomes yet less likely to tolerate available therapies proven to reduce morbidity and mortality.21 Independent of hemodynamic considerations, effective therapies for worsening chronic HF and reduced LVEF are needed, and SOCRATES-REDUCED is among the first studies to test a medication for this indication.

Limitations of the current study should be acknowledged. Consistent with the dose-finding objective of this exploratory phase 2 trial, the findings from this study should be considered nonconfirmatory and descriptive, including the observed dose-response relationship in the primary end point and reduction in NT-proBNP level in the 10-mg vericiguat target dose group compared with placebo. By nature of its phase 2 design, SOCRATES-REDUCED was not intended to make definitive claims on the clinical efficacy of vericiguat in this study population. Although change in natriuretic peptide level is a commonly used surrogate end point in HF studies due to associations with outcomes and response to proven guideline-therapies, discordance between natriuretic peptide improvement and clinical events may be seen with trials of investigational therapies.22,23 Moreover, although natriuretic peptide inclusion criteria differed in SOCRATES-REDUCED by presence or absence of atrial fibrillation, the effect of vericiguat on subsequent change in NT-proBNP level may have been influenced by the prevalence of atrial fibrillation in the population.23

Conclusions

Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.

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Article Information

Corresponding Author: Mihai Gheorghiade, MD, Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 E Huron St, Galter 3-150, Chicago, IL 60611 (mgheorgh@nm.org).

Published Online: November 8, 2015. doi:10.1001/jama.2015.15734.

Author Contributions: Drs Gheorghiade and Pieske had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Gheorghiade, Butler, Filippatos, Lam, Maggioni, Ponikowski, Shah, Solomon, Samano, Müller, Roessig, Pieske.

Acquisition, analysis, or interpretation of data: Gheorghiade, Greene, Butler, Filippatos, Lam, Maggioni, Ponikowski, Shah, Kraigher-Krainer, Samano, Müller, Roessig, Pieske.

Drafting of the manuscript: Gheorghiade, Greene, Butler, Roessig, Pieske.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Müller.

Administrative, technical, or material support: Gheorghiade, Greene, Shah, Samano.

Study supervision: Gheorghiade, Greene, Butler, Maggioni, Ponikowski, Roessig, Pieske.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Gheorghiade reported relationships with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma, Cardiocell, Cardiorentis, Corthera, Cytokinetics, CytoPherx, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis Pharma, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor Therapeutics, Protein Design Laboratories, sanofi-aventis, SC Pharma, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Stealth BioTherapeutics, Takeda Pharmaceuticals, and Trevena Therapeutics. Dr Butler reported receiving research support from the National Institutes of Health and European Union and serving as a consultant to Amgen, Bayer, Cardiocell, Novartis, Boehringer Ingelheim, Merck, Stealth Peptides, Trevena, Relypsa, Z Pharma, Pharmain, and Zensun. Dr Filippatos reported receiving a research grant from the European Union and serving as a consultant for Bayer, Novartis, and Cardiorentis. Dr Lam reported receiving support via clinician Scientist Award from the National Medical Research Council of Singapore and research support from Boston Scientific, Medtronic, and Vifor Pharma and consulting for Bayer, Novartis, Takeda, Merck, Astra Zeneca, and Janssen Research & Development. Dr Maggioni reported serving on committees of clinical studies sponsored by Amgen, Bayer, Abbott Vascular, Cardiorentis, Johnson & Johnson, and Novartis Pharma. Dr Ponikowski reported being on the speakers’ bureau and an advisory board for Bayer and receiving other support from Vifor Pharma, Amgen, Servier, Novartis, Johnson & Johnson, Pfizer, Abbott Vascular, Boehringer Ingelheim, Respicardia, Coridea, Celladon, Cardiorentis, Singulex, and DC Devices. Dr Shah reported service as an advisory board member for Bayer, Novartis, DC Devices, and the Pulmonary Hypertension Association. Dr Solomon reported consulting for Bayer and Ironwood and receiving grants from Novartis. Dr Kraigher-Krainer reported consulting for Bayer and CVRx. Dr Pieske reported speakers’ bureau and/or advisory/steering committee honoraria from Daiichi-Sankyo, Bayer Healthcare, Novartis Pharma, Stealth Peptides, Servier, Abbott Vascular, and Astra-Zeneca. Dr Samano, Ms Müller, and Dr Roessig reported being employees of Bayer. No other disclosures were reported.

Funding/Support: The SOCRATES-REDUCED study was funded by affiliates of Bayer and Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey.

Role of the Funder/Sponsor: The sponsor participated in the design, conduct, and management of the study; the collection and analysis of the data; and the preparation, review, and approval of this manuscript. The sponsor had no role in the interpretation of the data. The sponsor did not have the right to prevent submission or publication of the data.

SOCRATES-REDUCED Trial Investigators:Austria: Lukas Ameri, Charlotte Buchheim, Apollonia Daburger, Christian Ebner, Veronika Eder, David Gregor, Petra Carmen Gunacker, Uta Hoppe, Charlotte Anna Huber, Gustav Huber, Dirk von Lewinski, Regina Mascherbauer-Steringer, Deddo Mörtl, Michael Nemec, Claudia Pfnib, Burkert Pieske, Rita Riedlbauer, Thomas Stefenelli, Thomas Sturmberger, Nicolas Verheyen, Maximilian Winhard; Australia: Andrew Black, Nathan Dwyer, Christopher Hayward, David Kaye, Anne Keogh, Eugene Kotlyar, Peter MacDonald, Phil Roberts-Thompson, David Russell, Michael Stokes; Belgium: Wim Anne, An-Kristin Ascoop, Philip Baetsle, Aydin Basoglu, Oana Bodea, Christophe Borin, Pierre Cambier, Patrick Coussement, Philippe Debonnaire, Michel De Ceuninck, Marc Delforge, Daniel Dëndooven, Khaled Draoui, Karl Dujardin, Mattias Duytschaever, Michèle Kamga Dzukou, Frauke Gorre, Pierre Hausman, Kurt Hermans, Jean-Marc Joris, Ruud Koevoets, Jean Leroy, Rachid Maamar, Christian Marchal, Patrick Marechal, Luc Missault, Luc Muyldermans, Jan Nimmegeers, Anne-Catherine Pouleur, Max Romagnoli, Chris Scheurwegs, Francis Stammen, Harry Striekwold, Rene Tavernier, Christophe Tombeux, Louise Tsessue, Katarina Van Beeumen, Laurent Vande Kerckhove, Hans Vandekerckhove, Yves Vandekerckhove, Olivier Vanderdonckt, Hugues Verloove, Geert Vervoort; Bulgaria: Katia Aleksieva, Nikolay Dimitrov, Neli Georgieva, Zhozafina Georgieva, Mladen Grigorov, Asen Gudev, Ivan Kamburov, Elena Kinova, Emil Kolev, Ivanka Kulevska, Tonka Kurteva, Bojidar Krastev, Veselina Mateeva, Milen Minchev, Velentina Mincheva, Petar Petrov, Tatyana Petrusheva, Nikolay Poroiliev, Chavdar Shalganov, Desislava Smoleva, Natalia Spasova, Vasil Stoyanovski, Veska Tsanova, Toni Velikov, Katerina Vitlianova; Canada: Benoit Coutu, Sebastien Bergeron, Serge Lepage, Mark Liszkowski, Gordon Moe, Daniel Savard; Czech Republic: Jan Belohlavek, Josef Bis, Ondrej Cermak, Pavel Cervinka, Gabriela Dostalova, Jaroslav Dusek, Lumir Francek, Marketa Hegarova, Tomas Hnatek, Jiri Knot, Tomas Kolouch, Ales Kral, Eva Krcova, Petr Kuchynka, Jan Macha, Vojtech Melenovsky, Ivana Marusincova, Pavla Nadenickova, Adrian Reichenbach, Jana Rudolecka, Radovan Stancik, Jiri Teply, Pavel Trestik, Renata Valentikova, Zdenek Vavera, Jan Vojacek, Jevgenija Vymetalova; Denmark: Niels Bruun, Lars Fog, Gunnar Gislason, Søren Mellemkjær, Bent Roni Nielsen, Eric Nielsen, Kirsten Nielsen, Jens Refsgaard, Peter Søgaard, Susanne Sørensen, Hanne Sortsøe; France: Fabrice Bauer, Bastien Glinel, Pascal De Groote, Albert-Alain Hagege, Nathan Mewton, Yannick Neuder, François Picard; Germany: Johann Bauersachs, Daniel Beug, Michael Böhm, Stephan Felix, Cornelia Finger, Jürgen Kilian, Ingrid Kindermann, Harald Lapp, Niels Menck, Kai Müllerleile, Alexander Riad, Stephan Rosenkranz, Andreas Schäfer, Heribert Schunkert, Carolin Sonne, Reinhard Stöhring, Joerg Stypmann, Thomas Viethen, Johannes Waltenberger, Dirk Westermann, Bernhard R. Winkelmann; Greece: Sophia Arapi, Despoina Balta, Stylianos Fotakis, Apostolos Karavidas, Anastasia Perpinia, Sotirios Patsilinakos, George Tsitsinakis, Eleftherios Vidalakis; Hungary: Robert Kirschner, Valery Meledin, Ebrahim Noori, Imre Varju; Israel: Mouin Aboud, Offer Amir, Lev Bloch, Olga Broudner, Natalie Bogomolny, Adi Butnaru, Shemy Carasso, Ehud Chorin, Dmitry Dratva, Tatiana Drogenikov, Irina Fugenfirov, Tuvia Ben Gal, Diab Ghanim, Sorel Goland, Jihad Hamuda, Tal Hasin, Ofer Havakuk, Evgeny Hazanov, Mohamed Jabaren, Rami B. Jubeh, Eran Kalmanovich, Amos Katz, Moayad Khatib, Marc W. Klutstein, Fabio Kusniec, Jacek Linde, Israel Mats, Simcha R. Meisel, Gil Moravsky, Mady Moriel, Daniel Murninkas, Menachem Nahir, Ali Nassar, Elena Neiman, Roman Nevzorov, Tsafrir Or, Jana Yehezkel Paskin, Michal Laufer Perl, Tatiana Plaev, Dahud Qarawani, Youri Rabkin, Michael Rahkovich, May-Tal Rofe, Nabeeh Salman, Michael Shochat, Avraham Shotan, Hillel A. Steiner, Ivetta Sukholutsky, Yoav Turgeman, Dan Tzivoni, Lubov Vassilenko, Alicia Vazan, Zvi Vered, Tanya Weitsman, Giora Wiesz, Inna Yofik, Liaz Zilberman; Italy: PierGiuseppe Agostoni, Alessandro Barbarossa, Ivano Bonadei, Giovanna Branzi, Ambra Bulgarelli, Carlo Campana, Alessandro Capucci, Valentina Carubelli, Maria Grazia Castelli, Anna Isotta Castrini, Gaia Cattadori, Laura Cattaneo, Claudia Cefalù, Francesca Ciambellotti, Franco Cosmi, Nicolò Dasseni, Giuseppe De Angelis, Luigi Delfino, Vincenzo Duino, Giovanni Forni, Alessia Mafalda Giglio, Valentina Giuli, Alessandra Gualco, Paola Guarise, Federico Guerra, Rosanna Jemoli, Valentina Lazzarini, Carlo Mario Lombardi, Laura Lupi, Gabriella Malfatto, Maria Vittoria Matassini, Marco Metra, Chiara Mollica, Giorgio Morando, Cristina Opasich, Gianfranco Parati, Claudia Pavesi, Filippo Quinzani, Claudia Raineri, Valentina Regazzoni, Laura Scelsi, Michele Senni, Franco Tettamanti, Eleftheria Trichaki, Monica Tinto, Annalisa Turco, Clara Villa, Enrico Vizzardi; Japan: Isao Aburatani, Toru Aizawa, Madoka Akashi, Kentaro Amenomori, Takahiko Aoyama, Tomohiro Asahi, Kenji Ayata, Mai Azuma, Akio Chikata, Hiroyuki Doi, Nobuyuki Enzan, Kazuki Fukui, Shinya Fujii, Kanichi Fujimori, Hiroyuki Fujinaga, Kensuke Fujioka, Susumu Fujino, Hirofumi Fukagawa, Ko Fukuda, Yukihiro Fukuda, Masaya Fukuda, Shinnosuke Furudono, Shoichiro Furukawa, Yoshitaka Furuyashiki, Jun Fuse, Chiaki Goten, Daiki Gyotoku, Kenji Harada, Tomoya Harada, Tomoko Henmi, Yoshikazu Hiasa, Namio Higa, Norioki Hirano, Hidekazu Hirao, Motoaki Hirasawa, Shunichiro Hondo, Yasunari Hoshiba, Shinobu Hosokawa, Naoki Iinuma, Kohei Iguchi, Takeshi Ikeda, Yukinori Ikegami, Yoshihiro Ikeuchi, Tsutomu Ima, Kohei Inagawa, Keita Inanaga, Harukazu Iseki, Daiki Ito, Yoshihiro Imamura, Takamasa Iwasawa, Tomoko Izumi, Shuhei Kaibara, Norihito Kageyama, Izaya Kamei, Naomi Kanamori, Naoko Katagiri, Chieko Kato, Shingo Kato, Yuko Kato, Hiroya Kawai, Yota Kawamura, Masaki Kinoshita, Hidekuni Kirigaya, Koichi Kishi, Katsunori Kitano, Kunihiko Kiuchi, Hiroshi Kobayashi, Seichi Kobayashi, Masashi Koga, Masaya Kurobe, Shigeru Kuroki, Yuka Kusakawa, Tomohito Mabuchi, Mamoru Manita, Michiro Maruyama, Tami Mashidori, Takuya Mayumi, Yuko Miki, Kazutoshi Minami, Naoya Mitsuba, Takashi Miwa, Hitoshi Miyajima, Junichi Miyamoto, Yuji Miyazaki, Yutaka Mizumasa, Yukihiko Momiyama, Ayako Monji, Kyoko Mori, Yasuhiro Morikami, Susumu Morosawa, Takahiro Muroya, Hideo Nagai, Yoshiki Nagata, Tatsuya Nakachi, Yoichiro Nakagawa, Ryuichi Nakaike, Masatsugu Nakano, Hiroshi Nakashima, Mayui Nakazawa, Marohito Nakata, Hisato Nako, Kazuhiro Nitta, Satoru Niwa, Shinpei Nogi, Yasumasa Nouno, Yuichi Numata, Tatsuya Nunohiro, Yoshihiro Noji, Riyo Ogura, Shogo Oishi, Ayumi Okada, Katsunori Okajima, Fumio Okamoto, Mitsunori Okamoto, Sho Okamura, Takanobu Okumura, Wataru Omi, Haruhiko Onaka, Tetsuari Onishi, Jun Osada, Yuki Oshida, Ryuji Otani, Koji Otsuka, Takahiro Saeki, Satoru Sakagami, Munehisa Sakamoto, Shinichiro Sakota, Takuo Sakura, Koji Sato, Takahiro Sawada, Tomokazu Sawada, Akira Shimane, Kuniyuki Shirasawa, Kazuyoshi Suenari, Tatsuya Sugihara, Toru Sugiura, Shinichiro Sunamura, Kazuhiko Tabata, Takefumi Takahashi, Midori Takakura, Satoshi Takeshita, Kazuki Tanaka, Toshie Tanaka, Yasuyo Taniguchi, Kojiro Tanimoto, Naho Terada, Jin Teranishi, Takayoshi Toba, Yohei Tobetto, Tomoyuki Tobushi, Hideki Tokuhisa, Tetsuya Tomariguchi, Hideko Tomimoto, Takumi Tozawa, Yasue Tsukishiro, Takaki Tsutsumi, Tatsuro Uchida, Mio Uchida, Yuzo Uchida, Tomoki Uchikawa, Hironori Ueda, Tokuhisa Uejima, Yoji Urabe, Kazuo Usuda, Tomohiko Watanabe, Yuichiro Watari, Masahiro Yagi, Akira Yamada, Nao Yamada, Shinichiro Yamada, Takahiro Yamada, Masahiro Yamagami, Masato Yamaguchi, Fumi Yamamoto, Hirofumi Yamamoto, Ryo Yamazato, Yoshinori Yasaka, Bun Yashiro, Tatsuo Yasuoka, Kiminobu Yokoi, Yasuhiro Yokoyama, Kohei Yoneda, Kenichiro Yuba; Netherlands: Eric A. Badings, R. W. Breedveld, C. de Nooijer, W. E. M. Kok, D. J. A. Lok, Fabrice Martens, Remco Nijmeijer, G. Tjeerdsma, Patrick Perik, Luc Theunissen, Marieke Torn, Ype Tuininga, Ruben Uijlings, Aize van der Sluis, Jan van Wijngaarden; Poland: Maciej Banasiak, Slawomir Bobon, Tomasz Ciurus, Monika Chudzicka, Urszula Czubek, Jaroslaw Drozdz, Barbara Engel, Andrzej Gackowski, Robert Gil, Karolina Golinska-Grzybala, Stefan Grajek, Piotr Jakubowski, Marcin Kasprzyk, Miroslaw Kastelik, Lukasz Kicinski, Aneta Klotzka, Jan Krekora, Waldemar Krysiak, Malgorzata Lange-Szczesiak, Magdalena Misztal-Teodorczyk, Beata Moczulska, Renata Mroziak, Wlodzimierz Musial, Jadwiga Nessler, Alicja Nowak, Zofia Oko-Sarnowska, Agnieszka Pawlak, Grzegorz Piotrowski, Anna Przybylska, Pawel Rehan, Piotr Rola, Edyta Skorek, Marta Stepien, Ewa Straburzynska-Migaj, Krzysztof Szymczak, Beata Tomaszewska, Agnieszka Tycinska, Marta Wegrzynowska, Tadeusz Zechowicz; Republic of Korea: Jae-Joong Kim, MinSeok Kim; Singapore: Hean Yee Ong, David Sim, Raymond Wong, Daniel Yeo; Spain: Miguel Cainzos Achiriga, Sergio García Blas, Luís Almenar Bonet, Manuel Gómez Bueno, Sonia Ruíz Bustillo, Amparo Carrasco, Fernando Cereto Castro, Josep Comín Colet, Jordi Bruguera Cortada, Luís Martínez Dolz, Ignasi Durán, José González, Cristina Enjuanes Grau, Ignacio Sánchez Lázaro, Núria Farré López, Clara Bonanad Lozano, David Couto Mallón, Nicolás Manito, Marta Cobo Marcos, Joel Salazar Mendiguchía, Herminio Morillas, Julio Núñez, Enrique Santas Olmeda, Diego Plaza, Marcelo Rizzo, Josep Roca, Iris Rodríguez, Ruperto Carlos Olivero Soldevilla, Ernesto Valero, José Antonio Vázquez de Prada, Francisco González Vílchez; Sweden: Per Ahlström, Urban Alehagen, Monthir Alfetlawi, Karin Arinell, Stella Cizinsky, Rolanda Daher-Knutsen, Ulf Dahlström, Maja Eriksson-Östman, Edit Floderer, Ole Hansen, Ola Hallén, Anders Hedman, Laila Hübbert, Dimitrios Kostakiotis, Johan Lugnegård, Dora Norring, Jens Olson, Emil Pantev, Martin Stagmo, Barna Szabo, Gordana Tasevska-Dinevska, Fredrik Utter, Peter Wodlin; Switzerland: Monya Bondio, Carmela Crljenica, Frank Enseleit, Werner Estlinbaum, Andreas Flammer, Michelle Frank, Marc Gutmann, Stephanie Kniencke, Stefan Kreuzer, Gregor Leibundgut, Sandrine Meyer-Monard, Tiziano Moccetti, Cristina Montipanzeri, Peter Rickenbacher, Mariagrazia Rossi, Frank Ruschitzka, Isabella Sudano; Taiwan: Wan-Khey Chan, Yi-Yao Chang, Chern-En Chiang, Fu-tien Chiang, Yu-Wei Chiu, Wen-Po Chuang, Jung-Cheng Hsu, Shan-Hui Huang, Juey-Jen Hwang, Jyn-Ming Juang, Shin-Rong Ke, Wen-Ter Lai, Pen-Chih Liao, Chun-Chung Lin, Heng Hsu Lin, Jiunn-Lee Lin, Lian-Yu Lin, Lung-Chun Lin, Shing-Jong Lin, Yen-Hung Lin, Cheng-Wei Liu, Yuan-Hung Liu, Tse-Min Lu, Ju-Pin Pan, Shih-hsien Sung, Chia-Ti Tsai, Chung-Ming Tu, Kang-Ling Wang, Tzung-Dau Wang, Cho-Kai Wu, Yen-Wen Wu, Wen-Chung Yu; United Kingdom: Justin Cooke, Mohamed Farag, Diana Gorog, Clare Hawley, Osita Okafor; United States: Anthony Alfieri, Douglas Chapman, Veronica Franco, Robert Gianfagna, Jalal Ghali, Steven Goldsmith, Garrie Haas, David Lanfear, Joshua Larned, Daniel Lenihan, Robert Long, David Markham, Frank McGrew, Vinay Mehta, David Pham, Sajan Rao, Frank Smart, James Talano, Cristina Tita, Lynne Wagoner, Michael Zile, Dianne Zwicke.

Steering Committee: Mihai Gheorghiade (co-chair), Burkert Pieske (co-chair), Javed Butler, Gerasimos Filippatos, Piotr Ponikowski, Carolyn Lam, Aldo P. Maggioni, Sanjiv J. Shah, Scott D. Solomon. Data and Safety Monitoring Committee: John J. V. McMurray (chair, replaced Paul W. Armstrong during the trial), Christopher Granger, Wilhelm Haverkamp. Clinical Event Committee: Gerasimos Filippatos (chair), Aldo P. Maggioni, Piotr Ponikowski.

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