|First Author (Year; Trial Name) (Ref. #)||Surrogate Marker Change||Outcome||Comments/Agreement Between Test and Outcomes|
|McKelvie et al. (1999; RESOLVD pilot study) (77)||Candesartan + enalapril reduced delta log BNP compared with candesartan and enalapril alone||Lower increment in EDV and ESV with candesartan + enalapril as compared with candesartan and enalapril alone||DB-RCT.|
|Conraads et al. (2004) (78)||Combined endurance/resistance training reduced mean NT-proBNP levels at 4 months||Reduction in mean NT-proBNP was the primary outcome||Nonrandomized parallel-group study with 27 patients.|
The primary outcome was NT-proBNP
|Hartmann et al. (2004; data from the COPERNICUS trial) (13,14)||Median NT-proBNP values between carvedilol and placebo groups were not significantly different at baseline, 1 month, 4 months, and study end. However, compared with placebo, carvedilol induced a steeper decrease in NT-proBNP levels (in % of change relative to baseline) at 4 and 7 months: –17% vs. –5% and –28% vs. –5%, respectively||Carvedilol reduced mortality compared with placebo (HR: 0.65; 95% CI: 0.52–0.81)||Data derived from DB-RCT.|
The association of NT-proBNP changes and outcome were not tested.
The steeper decrease in % NT-proBNP relative to baseline in the carvedilol group (but no difference in median values) may be explained by a greater reduction of extremely high values by carvedilol treatment, but these data are not shown.
Agreement: yes (for absolute delta changes)
|Krum et al. (2007) (79)||Rosuvastatin did not reduce mean or % change in BNP levels at 6 months compared to placebo||Rosuvastatin did not affect the primary endpoint of change in LVEF or any of the other pre-specified endpoints||DB-RCT.|
|Toblli et al. (2007) (50)||Iron therapy reduced mean NT-proBNP levels compared with placebo at 6 months||Iron therapy improved functional capacity, symptoms, and QoL||DB-RCT.|
|Fruhwald et al. (2007; from CARE-HF data) (17)||Patients in CRT arm had significantly lower median NT-proBNP at 3 and 18 months (but not at baseline)|
At baseline, the median plasma concentration of NT-proBNP was similar in patients assigned to CRT or medical therapy, 1,920 (IQR: 744–4,288) pg/ml vs. 1,809 (IQR: 719–3,949) pg/ml.
The differences in medians between the CRT and medical therapy groups were highly significant at both 3 months (537 pg/ml; p < 0.001) and 18 months of follow-up (567 pg/ml; p < 0.001)
|CRT is associated with lower death rates (HR: 0.64; 95% CI: 0.48 to 0.85; p < 0.002)||DB-RCT. CRT exerts an early and sustained reduction in NT-proBNP, reflecting improvements in ventricular function.|
|Masson et al. (2008; from Val-HeFT data) (3)||Steady levels or reduction (in % quartiles) in NT-proBNP from baseline to 4 months were associated with lower mortality rates as compared with the highest quartile (>33% NT-proBNP increase)||Death rates of 9.2% in quartile 1 (reduction|
>31% at 4-month NT-proBNP relative to baseline) to 21.5% in quartile 4 (increase >33%)
|Data derived from DB-RCT.|
Absolute changes in NT-proBNP were not consistently associated, possibly because patients with highest baseline NT-proBNP (associated with dismal outcomes) had also great reductions.
Observational studies limitations.
|Pascual-Figal et al. (2008) (80)||≥26% (median) reduction at 2 weeks after decompensation was associated with ∼23% lower 1-year event rates. In multivariable Cox models, each 10% NT-proBNP reduction was associated with ∼17% fewer event rates at 1 year||Lower event rates at 1 year in patients with NT-proBNP reduction||Observational study in 71 patients. Any absence of decline associated with worse outcomes.|
|Boccanelli et al. (2009; AREA IN-CHF trial) (18)||Canrenone produced a steeper decrease in delta BNP levels at 6 months (–37% in the canrenone arm vs. –8% in the placebo arm)||The composite endpoint of cardiac death and hospitalization was significantly lower in the canrenone arm at 12 months (7.9% in canrenone arm vs. 15.1% in placebo arm; p = 0.02)||DB-RCT.|
|Bielecka-Dabrowa et al. (2009) (81)||Atorvastatin therapy reduced mean NT-proBNP levels at 2 months, whereas NT-proBNP levels increased in the control group||Atorvastatin reduced hospitalizations due to HF||Randomized open-label in 68 patients with DCM.|
|Solomon et al. (2012; PARAMOUNT trial) (25)||LCZ696 significantly reduced NT-proBNP at 12 weeks as compared with valsartan (LCZ696 baseline = 783 [IQR: 670–914] pg/ml, LCZ696 12 weeks = 605 [IQR: 512–714] pg/ml; valsartan baseline = 862 [IQR: 733–1,012] pg/ml, valsartan 12 weeks = 835 [IQR: 710–981] pg/ml; ratio LCZ696/valsartan = 0.77 [95% CI: 0.64–0.92], p = 0.005)||Phase II trial. No CV outcomes measured.||DB-RCT.|
|Gheorghiade et al. (2013; ASTRONAUT trial) (20)||Aliskiren was associated with a statistically significant decrease in the adjusted geometric mean NT-proBNP level compared with placebo at each time point tested (months 1, 6, and 12).|
Randomization: 2,838 (IQR: 1,516–5,235) pg/ml in aliskiren vs. 2,674 (IQR: 1,552–5,234) pg/ml in placebo
1 month: median NT-proBNP = 2,433 (IQR: 1,275–4,387) pg/ml in aliskiren vs. 2,522 (IQR: 1,455–4,625) pg/ml in placebo
Adjusted geometric mean NT-proBNP = 0.86 (0.81–0.91) in aliskiren vs. 0.95 (0.90–1.00) in placebo
Ratio aliskiren/placebo = 0.90 (0.84–0.97); p = 0.01
6 months: median NT-proBNP = 1,754 (IQR: 864–3,641) pg/ml in aliskiren vs. 1,897 (IQR: 1,015–3,781) pg/ml in placebo
Adjusted geometric mean NT-proBNP = 0.64 (0.59–0.70) in aliskiren vs. 0.76 (0.70–0.82) in placebo
Ratio aliskiren/placebo = 0.85 (0.76–0.95); p < 0.01
12 months: median NT-proBNP = 1,576 (IQR: 681–3,156) pg/ml in aliskiren vs. 1,792 (IQR: 887–3,518) pg/ml in placebo
Adjusted geometric mean NT-proBNP = 0.62 (0.57–0.69) in aliskiren vs. 0.74 (0.67–0.82) in placebo
Ratio aliskiren/placebo = 0.84 (0.73–0.96); p < 0.01
|Aliskiren did not reduce CV death or HF rehospitalization at 6 months (HR: 0.92; 95% CI: 0.76–1.12; p = 0.41) or 12 months after discharge (HR: 0.93; 95% CI: 0.79–1.09; p = 0.36)||DB-RCT.|
|Zannad et al. (2014; NECTAR-HF trial) (82)||No significant differences at 6 months in median NT-proBNP between therapy vs. controls||VNS failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodeling and functional capacity in symptomatic HF patients||DB-RCT.|
|Packer et al. (2015; from PARADIGM-HF data) (19)||NT-proBNP was similar between LCZ969 and enalapril groups at baseline, ∼1,300 pg/ml. Patients in the LCZ696 group had lower median NT-proBNP at 4 weeks ∼800 (IQR: 600–1,500) pg/ml vs. 1,250 (750–2,100) pg/ml in the enalapril group, p < 0.001 and at 8 months ∼800 (IQR: 400–1,600) pg/ml in the LCZ969 group vs. 1,250 (IQR: 700–2,100) pg/ml in the enalapril group, p < 0.001||The trial was stopped at 27 months due to LCZ696 superiority (HR: 0.80; 95% CI: 0.73–0.87; p < 0.001) for the primary outcome of hospitalization for HF or CV death||DB-RCT. LCZ696 exerts an early and sustained reduction in NT-proBNP.|
|Ordu et al. (2015) (83)||Patients in the ivabradine group had lower mean NT-proBNP at 6 months compared with the control group.|
NT-proBNP at baseline = 1,353 ± 1,453 pg/ml in the ivabradine group vs. 1,383 ± 1,064 pg/ml in the control group
NT-proBNP at 6 months = 717 ± 834 pg/ml in the ivabradine group vs. 1,323 ± 979 pg/ml in the control group
|In the SHIFT trial, after a median follow-up of ∼23 months, ivabradine reduced the primary outcome of hospitalization for HF or CV death (HR: 0.82; 95% CI: 0.75–0.90; p < 0.001)||Open-label parallel-group study with 98 patients.|
|Gheorghiade et al. (2015; SOCRATES-REDUCED trial) (84)||Pooled vericiguat doses showed no significant difference in 12-week log-transformed NT-proBNP levels. However, patients in the highest vericiguat dose groups (2.5 to 10 mg) had significant reductions in the ratios of geometric mean changes from baseline to week 12.|
Pooled vericiguat group
Log-transformed: baseline = 7.969; 12 weeks = 7.567; difference = −0.402; Geometric means: baseline = 2,890 pg/ml; 12 weeks = 1,932 pg/ml
Log-transformed: baseline = 8.283;
12 weeks = 8.002; difference = −0.280; Geometric means: baseline = 3,955 pg/ml; 12 weeks = 2,988 pg/ml
Difference of means = −0.122 (−0.32 to 0.07)
Ratio of geometric means, 0.885 (0.73–1.08); p = 0.15
|Change from baseline to week 12 in log-transformed NT-proBNP level was the primary endpoint. Phase 3 trial underway||DB-RCT.|
|Mebazaa et al. (2007; from the SURVIVE trial) (28)||Levosimendan group had greater decreases in BNP level as compared with dopamine:|
Mean change of around –631 pg/ml in the levosimendan group vs. –397 pg/ml in the dobutamine group; p < 0.001. Overlapping changes persisted through 5 days compared with the dobutamine group (p < 0.001 for all time points)
|No statistical differences were observed between treatment groups for the primary outcome of all-cause mortality at 180 days (HR: 0.91; 95% CI: 0.74–1.13; p = 0.40) or any other secondary endpoints (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 h, and CV mortality at 180 days)||DB-RCT.|
|Metra et al. (2013; from RELAX-AHF trial) (31)||Serelaxin group had significant decrease in NT-proBNP levels from baseline to day 2|
Baseline geometric mean = 5,003.50 in placebo vs. 5,125.46 in serelaxin
Day 2 geometric mean = 3,037.50 in placebo vs. 2,544.23 in serelaxin
Geometric mean change = 0.607 in placebo vs. 0.492 in serelaxin; p < 0.001
30% decrease from baseline to day 2 = 58.0% in placebo vs. 69.0% in serelaxin; p < 0.001
|Serelaxin improved the VAS AUC primary dyspnea endpoint compared with placebo, but had no significant effect on the other primary endpoint Likert scale.|
No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for HF or renal failure until day 180 (HR = 1.02; 95% CI: 0.74–1.41; p = 0.89) or days alive out of the hospital up to day 60.
Fewer deaths at day 180 were observed in the serelaxin group (HR 0.63; 95% CI: 0.42–0.93; p = 0.019)
Agreement: not for the coprimary nor secondary endpoints.
|Guyatt et al. (1985) (36)||6MWT was reproducible, and correlated with the conventional measures of functional status and exercise capacity.||Validation study.||Observational study.|
|Lipkin et al. (1986) (85)||Patients with HF-REF on NYHA functional class III walked less than those on NYHA functional class II (402 m vs. 558 m; p < 0.01)||Group comparison.||Observational study.|
Distance walked varied little in patients with a high maximal oxygen consumption.
No delta differences are provided.
|Roul et al. (1998) (46)||Patients who walked ≤300 m had a worse prognosis compared with those walking farther||Group comparison||Observational study.|
No delta differences are provided.
|McKelvie et al. (1999; RESOLVD pilot study) (77)||During the 43 weeks of the study, there were no significant differences in 6MWT between groups (candesartan + enalapril vs. candesartan alone vs. enalapril alone)||Lower increment in EDV and ESV with candesartan + enalapril compared with candesartan and enalapril alone||DB-RCT.|
|Cazeau et al. (2001) (42)||The mean distance in the 6MWT was ∼22% greater after 3 months with active pacing (399 ± 100 m vs. 326 ± 134 m, p < 0.01)||QoL and peak oxygen consumption also improved and hospitalizations were reduced||Single-blind, crossover, RCT.|
|Abraham et al. (2002) (43)||Patients assigned to CRT experienced an improvement of ∼26% in the 6MWT (+39 m vs. +10 m, p < 0.01)||QoL, time on the treadmill, and LVEF also improved||Single-blind RCT.|
|Auricchio et al. (2003) (49)||CRT in patients with QRS interval >150 ms improved 6MWT in ∼10% (407 ± 61 to 447 ± 72 m), whereas patients with thin QRS intervals did not||CRT significantly improved the maximal and submaximal exercise capacity, QoL, and functional status of HF patients, especially those with QRS intervals >150 ms||Single-blind, crossover, RCT.|
|Higgins et al. (2003) (39)||CRT improved 6MWT from baseline to 6 months compared with the no CRT group (35 ± 7 m vs. 15 ± 7 m, p < 0.05)||CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay||Single-blind, crossover, RCT.|
|Young et al. (2003; MIRACLE ICD trial) (41)||Patients assigned to CRT presented no differences in the change of 6MWT compared to control (55 m vs. 53 m; p = 0.36)||CRT improved QoL, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias||DB-RCT.|
|Abraham et al. (2004; from MIRACLE ICD II trial) (38)||CRT did not improve 6MWT as compared to ICD in NYHA functional class II patients with a QRS interval >130 ms||CRT improved cardiac structure and function, and composite clinical response over 6 months||DB-RCT.|
|Toblli et al. (2007) (50)||Iron therapy improved mean 6MWT from baseline to 6 months between iron therapy and placebo groups (184.5 ± 58.5 m vs. 240.1 ± 51.2 m; p < 0.05)||Iron therapy improved symptoms, QoL and reduced NT-proBNP||DB-RCT.|
Delta improvement in meters was not calculated, although differences were statistically significant.
|Guazzi et al. (2009) (86)||No significant differences were observed in 6MWT distance between patients who remained alive vs. those who died at 4 years.||6MWT was not significantly associated with the outcome of death||Observational study.|
No delta comparisons where provided.
CPET-derived variables were associated with the outcome.
|Täger et al. (2014) (87)||Submaximal exercise capacity as represented by the 6MWT varies little in stable HF-REF patients for up to 1-year intervals.|
The MID for changes in 6MWT values over a period of 6 to 12 months is ∼36 m.
|Group comparison and validation study||Observational study.|
One SE of measurement was used as a proxy for MID in 6MWT.
|Ingle et al. (2014) (88)||Distance in 6MWT is an independent predictor of mortality in patients with HF-REF both at baseline and at 1 year||All-cause death: ∼3% mortality reduction at 8 years for each meter increment in 6MWT, both at baseline and at 1 year||Observational study.|
Delta values were not provided.
|Gold et al. (2016; from INOVATE-HF trial) (44)||VNS improved 6MWT distance (+28.2 m in the VNS group vs. –4.6 m in the control group; p < 0.01)||VNS did not improve the primary efficacy outcome of death or HF hospitalization (HR: 1.14; 95% CI: 0.86–1.53; p = 0.37)||Open RCT|
|McKelvie et al. (1999; RESOLVD pilot study) (77)||Candesartan + enalapril did not improve QoL scores as compared to candesartan and enalapril alone||Lower increment in EDV and ESV with candesartan + enalapril as compared with candesartan and enalapril alone||DB-RCT.|
|Cazeau et al. (2001) (42)||Active pacing improved QoL by ∼32%, as assessed by the MLHFQ||6MWT and peak oxygen consumption also improved and hospitalizations were reduced||Single-blind, crossover, RCT.|
|Abraham et al. (2002) (43)||Patients assigned to CRT experienced improvement in QoL (–18 points vs. –9 points, p < 0.01), as assessed by the MLHFQ||6MWT, time in the treadmill, and LVEF also improved||Single-blind RCT|
|Auricchio et al. (2003) (49)||CRT in patients with QRS interval >150 ms improved QoL, as assessed by the MLHFQ (17 ± 13 points vs. 25 ± 15 points, p < 0.01)||CRT significantly improved the maximal and submaximal exercise capacity, 6MWT, and functional status of HF patients, especially in patients with QRS intervals >150 ms||Single-blind, crossover, RCT|
|Higgins et al. (2003) (39)||CRT improved QoL from baseline to 6 months compared with the no CRT group, as assessed by the MLHFQ (–17.5 vs. –11.0, p = 0.02)||CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay||Single-blind, crossover, RCT|
|Abraham et al. (2004; from MIRACLE ICD II trial) (38)||CRT did not improve QoL scores as compared with ICD in NYHA functional class II patients with a QRS interval >130 ms||CRT improved cardiac structure and function and composite clinical response over 6 months||DB-RCT|
|Tate et al. (2007; from BEST trial) (51)||QoL questionnaires were strongly associated with mortality. At 12 months, bucindolol-treated patients had improvement according to some QoL questionnaires, but not according to others.||Beta-blocker therapy is mainstay treatment in HF-REF||DB-RCT|
|Toblli et al. (2007) (50)||Iron therapy improved QoL compared with placebo at 6 months, as assessed by the MLHFQ (59 ± 8 points vs. 41 ± 7 points; p < 0.05)||Iron therapy improved functional capacity, symptoms, and NT-proBNP||DB-RCT|
|Zannad et al. (2014; NECTAR-HF trial) (82)||VNS improved QoL, as assessed by the MLHFQ, at 6 months compared with controls (35.8 ± 20.8 points vs. 41.8 ± 24.3 points; p < 0.05)||VNS failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodeling and functional capacity in symptomatic HF patients||DB-RCT|
|O’Connor et al. (53), and Flynn et al. (52) (2009; ACTION-HF)||Sustained improvements in KCCQ in exercise arm||Primary endpoint of all-cause mortality or hospitalization was negative in primary protocol-specified analysis||RCT|
|Anker et al. (2009; FAIR-HF) (54)||Improvements in QoL KCCQ at 4, 12, and 24 weeks||Patient-reported global assessment and NYHA functional class both improved at 24 weeks||RCT|
|Costanzo et al. (2012; PEERLESS-HF) (56)||Improvement in KCCQ in the device arm||Study stopped after enrollment of 122 patients for futility on the primary endpoint of VO2||RCT|
|Moss et al. (2009) (57) and Veazie et al. (2012) (58) (MADIT-CRT)||Improvements in KCCQ in LBBB group only||Primary endpoint of all-cause death and HF events showed significant reduction in the CRT arm||RCT|
Overall positive study, but QoL analysis positive only in LBBB in subgroup
|Ponikowski et al. (2015; CONFIRM-HF) (55)||Significant improvement in KCCQ at 24 weeks||Significant improvement with the primary outcome of 6MWT at 24 weeks||RCT|
|Pitt et al. (2014) (59) and Lewis et al. (2016) (60) (TOPCAT)||Spironolactone improved KCCQ at 4, 12, and 36 months||Composite of death from CV causes, aborted cardiac arrest, or hospitalization for the management of HF not improved||DB-RCT|
|Gold et al. (2016; from INOVATE-HF trial) (44)||VNS improved QoL, as assessed by the KCCQ score (+11.2 points in the VNS group vs. +6.9 points in the control group; p < 0.01).||VNS did not improve the primary efficacy outcome of death or HF hospitalization (HR: 1.14; 95% CI: 0.86–1.53; p = 0.37)||Open RCT|
6MWT = 6-min walking test; ACTION-HF = Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure; AREA IN-CHF = Anti-remodelling effect of canrenone in patients with mild chronic heart failure trial; ASTRONAUT = Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure; BEST = Beta-Blocker Bucindolol in Patients with Advanced Chronic Heart Failure; BNP = B-type natriuretic peptide; CARE-HF = The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure trial; CI = confidence interval; CONFIRM-HF = Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency; COPERNICUS = Carvedilol prospective randomized cumulative survival trial; CRT = cardiac resynchronization therapy; CV = cardiovascular; DB-RCT = double-blind randomized controlled trial; DCM = dilated cardiomyopathy; EDV = end-diastolic volume; ESV = end-systolic volume; HF = heart failure; HF-REF = heart failure with reduced ejection fraction; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; INOVATE-HF = Vagus Nerve Stimulation for the Treatment of Heart Failure; IQR = interquartile range; KCCQ = Kansas City Cardiomyopathy Questionnaire; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; MID = minimal important difference; MIRACLE ICD = Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NECTAR-HF = NEural Cardiac TherApy foR Heart Failure; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; PARADIGM-HF = Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure; PARAMOUNT = Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion; PEERLESS-HF = Prospective evaluation of elastic restraint to lessen the effects of heart failure; QoL = quality of life; RCT = randomized controlled trial; RELAX-AHF = Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure; RESOLVD Pilot Study = Randomized Evaluation of Strategies for Left Ventricular Dysfunction; SOCRATES-REDUCED =Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES); SURVIVE = Levosimendan vs dobutamine for patients with acute decompensated heart failure; TOPCAT = Spironolactone for Heart Failure with Preserved Ejection Fraction; Val-HeFT = Valsartan Heart Failure Trial; VNS = vagal nerve stimulation; VO2 = ventilatory oxygen uptake.