Author + information
- Received July 27, 2018
- Revision received October 5, 2018
- Accepted October 12, 2018
- Published online January 28, 2019.
- Melissa A. Daubert, MDa,b,∗ (, )
- Kirkwood Adams, MDc,
- Eric Yow, MSb,
- Huiman X. Barnhart, PhDa,b,
- Pamela S. Douglas, MDa,b,
- Susan Rimmer, RDCSb,
- Casey Norris, MSb,
- Lawton Cooper, MD, MPHd,
- Eric Leifer, PhDd,
- Patrice Desvigne-Nickens, MDd,
- Kevin Anstrom, PhDa,b,
- Mona Fiuzat, PharmDa,
- Justin Ezekowitz, MBBCh, MSce,
- Daniel B. Mark, MD, MPHa,b,
- Christopher M. O’Connor, MDa,f,
- James Januzzi, MDg and
- G. Michael Felker, MDa,b
- aDuke University Medical Center, Durham, North Carolina
- bDuke Clinical Research Institute, Durham, North Carolina
- cUniversity of North Carolina, Chapel Hill, North Carolina
- dNational Heart, Lung, and Blood Institute, Bethesda, Maryland
- eUniversity of Alberta, Edmonton, Alberta, Canada
- fInova Heart and Vascular Institute, Falls Church, Virginia
- gMassachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Melissa A. Daubert, Duke University and Duke Clinical Research Institute, 2400 Pratt St, Room 0311 Terrace Level, Durham, North Carolina 27705.
Objectives This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.
Background In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.
Methods The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) Echo Substudy was a multicenter study that randomized 268 patients with HFrEF (EF ≤40%) to either pro-B-type natriuretic peptide (NT-proBNP)-guided treatment or usual care. Echocardiograms were performed at baseline and 12 months in 124 patients. Remodeling indices and clinical outcomes were compared between treatment arms and by achievement of the NT-proBNP goal of <1,000 pg/ml at 12 months.
Results At 12 months, the changes in EF and LV volumes were similar between the biomarker-guided and usual care arms with no difference in clinical outcomes; however, lowering NT-proBNP to <1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF compared with those not reaching goal (9.9 ± 8.8% vs. 2.9 ± 7.9%; p < 0.001) and lower LV volumes. The extent of reverse remodeling correlated with the change in NT-proBNP: a decrease of 1,000 pg/ml was associated with an increase in EF of 6.7% and a reduction in systolic and diastolic volumes of 17.3 ml/m2 and 15.7 ml/m2, respectively. Adverse events were significantly lower among patients achieving the NT-proBNP goal (p < 0.001).
Conclusions Among patients with HFrEF, lowering NT-proBNP to <1,000 pg/ml by 12 months was associated with significant reverse remodeling and improved outcomes. A greater reduction in NT-proBNP was associated with more extensive reverse remodeling. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)
The prevalence of heart failure (HF) is increasing with the aging population and constitutes an alarming public health problem (1). Although evidence-based HF therapy has improved the prognosis among patients with HF with reduced ejection fraction (HFrEF), the rate of adverse events remains high. The natriuretic peptides, specifically B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide (NT-proBNP), are released from the myocardium in response to hemodynamic stress and are objective biomarkers that provide important prognostic information in patients with HFrEF. Elevated concentrations of these biomarkers are powerfully predictive of adverse events (2–5). Conversely, a decrease in natriuretic peptide concentration over time in patients with HFrEF has been associated with improved clinical outcomes (6–8). Despite these associations, it is unclear if changes in natriuretic peptides reflect structural and functional changes in the heart.
A potential link between lowering NT-proBNP and reverse left ventricular (LV) remodeling was first demonstrated in the PROTECT (Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy) study (2,9). In PROTECT, patients with HFrEF randomized to receive biomarker-guided HF care had significantly lower NT-proBNP concentrations, a greater increase in EF, and smaller LV volumes compared with usual HF care (2,9). This single-center experience with a relatively short duration of follow-up was insufficient, however, to delineate the complex relationship between change in natriuretic peptide concentration, cardiac remodeling, and clinical events; therefore, the large, multicenter GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial and Echocardiographic Substudy were designed to prospectively study the interrelationship of these 3 key elements. We hypothesized that patients with HFrEF treated with biomarker-guided therapy would demonstrate more reverse remodeling and have fewer adverse events than patients treated with usual care. The GUIDE-IT Echocardiographic Substudy provided a unique opportunity to evaluate the effect of biomarker-guided therapy on cardiac structure and function and assess the association between NT-proBNP reduction, reverse remodeling, and clinical outcomes.
The study design for the main GUIDE-IT trial has been previously published (10). Briefly, GUIDE-IT was a multicenter trial that randomized patients with HFrEF (EF ≤40%) to either NT-proBNP–guided HF treatment strategy or usual guideline-directed HF care. The objective was to compare a strategy of medical therapy titration aimed at achieving and maintaining an NT-proBNP target of <1,000 pg/ml to usual care in patients with HFrEF. The study was discontinued early after 894 patients were enrolled (81% of planned) because biomarker-guided treatment strategy was not more effective than usual care in improving outcomes (11).
The GUIDE-IT Echo Substudy was a prespecified substudy designed to understand the influence of biomarker-guided therapy on cardiac structure and function compared with usual care among chronic patients with HFrEF with at least moderate systolic dysfunction (EF ≤40%) and an NT-proBNP concentration >2,000 pg/ml within 30 days before randomization. The Echo Substudy was conducted in 18 sites in the United States and Canada. Patients were eligible if they met the same inclusion and exclusion criteria as the main GUIDE-IT trial and agreed to echocardiography at baseline and 12 months (10). All participants provided written informed consent for participation in the Echo Substudy, which was obtained concurrently with the main trial informed consent. All patients were consented and enrolled before main trial randomization to preserve the randomization schema in the Echo Substudy. Patients were followed for up to 24 months after randomization. The Echo Substudy was approved by the institutional review board at each study site. The GUIDE-IT study was funded by the National Heart, Lung, and Blood Institute (NCT01685840); the Echo Substudy was funded by Roche Diagnostics Inc. (Rotkreutz, Switzerland).
The primary endpoint of the GUIDE-IT Echo Substudy was change in LV end-systolic volume index (ESVi) from baseline to 12 months among patients receiving NT-proBNP–guided treatment compared with patients treated with usual care. Secondary endpoints were change in: end-diastolic volume index (EDVi), EF, diastolic parameters, right heart function, and valvular regurgitation. Additionally, remodeling indices were assessed among patients achieving NT-proBNP goal of <1,000 pg/ml at 12 months compared with those not achieving the NT-proBNP goal (≥1,000 pg/ml), regardless of treatment strategy. NT-proBNP concentration was assessed using Roche Elecsys assay. Patients with missing or unmeasurable baseline or 12-month echocardiograms were excluded from quantitative analyses. The composite outcome of death or HF hospitalization after 12 months was compared between treatment groups and by achievement of NT-proBNP goal.
The GUIDE-IT Echo Substudy protocol required 2-dimensional echocardiographic imaging with spectral and color Doppler acquisitions from standard parasternal and apical views. The echocardiographic parameters analyzed were: EF, LV volumes, LV mass, left atrial volume, ratio of early transmitral peak velocity to early diastolic peak annular velocity (E/e′), valve regurgitation, right ventricular systolic function as assessed by tricuspid annular plane systolic excursion, right ventricular systolic pressure, stroke volume, cardiac output, and global longitudinal strain. Measurements were indexed for body surface area when appropriate. Cardiac volumes and EF were quantified by the biplane Simpson’s method using Digisonics Digiview software (version 3.8.4, Houston, Texas). LV longitudinal strain was obtained in the apical views and averaged to determine a global longitudinal value. Strain calculations were performed using TOMTEC software version 4.6.2 (Unterschleissheim, Germany).
Echocardiographic analysis was performed in an independent core laboratory at Duke Clinical Research Institute (Durham, North Carolina). All echocardiographic interpretations were performed by blinded readers in accordance with best practices and current guidelines (12–15). There was high inter-reader reproducibility across readers (intraclass correlation coefficient: 0.95 for EDV, 0.98 for ESV, and 0.99 for EF).
The sample size of the Echo Substudy was selected to detect a clinically meaningful change in ESVi of 10 ml/m2 between the treatment groups at 12 months. With 64 patients in each treatment arm with quantitative echocardiography at baseline and 12 months, there would be at least 80% power at the 0.05 level of statistical significance to detect a difference of 10 ml/m2 between treatment groups assuming a SD of 20 ml/m2. Accounting for a 20% loss to follow-up and an unmeasurable rate for LV volumes of 45%, a total of 290 patients (145 per treatment strategy) was planned.
Continuous and categorical variables were compared between groups using Wilcoxon rank sum test and Fisher exact test, respectively. Continuous variables are presented as mean ± SD or median (interquartile range [IQR]), as appropriate; categorical variables are shown as counts and percentages. Treatment group analyses were made on the principle of intention-to-treat. Univariable and multivariable logistic regression modeling were used to determine factors independently associated with attainment of NT-proBNP goal. The multivariable model included the following variables: age, sex, coronary artery disease, ischemic cardiomyopathy, natural log of baseline NT-proBNP, and EF at baseline. The association between the degree of LV remodeling and NT-proBNP change was initially evaluated with locally estimated scatterplot smoothing plots. Visual inspection of this exploratory analysis suggested the use of a 2-piece linear spline model. Transformation analysis was performed to determine the optimal NT-proBNP cutpoint for EF, ESVi, and EDVi, defined as the 12-month NT-proBNP concentration below which there was a significant increase in EF and decrease in LV volumes, respectively. Clinical outcomes after 12 months were evaluated with a landmark analysis that included time to death or HF hospitalization from 12 months to study end. For the time-to-event analysis, Kaplan-Meier (KM) cumulative risk curves were used to estimate the event rate; log-rank statistics were used for comparisons between groups. The threshold for statistical significance was 2-sided with a type I error rate of 0.05. There was no adjustment performed for multiple comparisons. Analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
Of the 894 patients in the main GUIDE-IT trial, 268 (92% of planned) were enrolled in the Echo Substudy between August 2013 and July 2016. Of these, 135 patients completed the study before early trial cessation. Mean follow-up was 18.7 months. Echocardiographic image quality was excellent; as a result, the unmeasurable rate for quantitative LV volumes and EF was only 12%, which was markedly lower than projected for this chronic HF population.
Treatment group analysis
Among the 268 patients in the Echo Substudy, 141 were randomized into the NT-proBNP-guided arm and 127 into the usual care arm. After excluding patients who died before 12 months, were lost to follow-up, or lacked a 12-month echocardiogram because of early study termination (Online Table 1), there were 67 patients in the biomarker-guided arm and 57 patients in the usual care arm that had paired baseline and 12-month echocardiograms with quantitative measurements (Figure 1A). Baseline clinical characteristics were not significantly different among patients with HFrEF in either of the treatment groups, except for a greater proportion of patients with prior myocardial infarction in the usual care arm (Table 1). The NT-proBNP values were similar at baseline. The treatment groups were also well balanced with respect to the baseline echocardiography results (Table 2), which demonstrated markedly dilated LV volumes and severely reduced systolic function: EF = 29.0 ± 9.7% in the NT-proBNP–guided arm and 27.7 ± 10.7% in the usual care arm (p = 0.37).
At 12 months, median NT-proBNP concentrations in the biomarker-guided arm were not significantly different from the usual care arm: 1,072 (IQR: 440 to 3,067) pg/ml versus 1,286 (IQR: 504 to 2,923) pg/ml; p = 0.73. The primary outcome of ESVi decreased by 15.2 ± 20.4 ml/m2 in the biomarker-guided arm compared with a decrease of 17.4 ± 28.4 ml/m2 in the usual care arm (p = 0.82). The decreases in EDVi were similar (Table 2). Improvement in EF was not significantly different between the treatment groups: +6.0 ± 8.0% in the NT-proBNP–guided arm versus +6.6 ± 10.5% in the usual care arm (p = 0.75).
NT-proBNP goal analysis
In the NT-proBNP goal analysis, we pooled the 2 treatment groups, considering them as a function of achieved NT-proBNP concentration at 12 months. There were 116 patients with paired echocardiograms and a 12-month NT-proBNP value. Of these, 52 patients achieved the NT-proBNP goal of <1,000 pg/ml at 12 months, whereas 64 had an NT-proBNP value of ≥1,000 pg/ml at 12 months (Figure 1B). Age, sex, race, and baseline NT-proBNP values were not significantly different between groups (Table 3); however, patients not achieving NT-proBNP goal at 12 months were significantly more likely to have ischemic heart disease. After multivariable adjustment, patients with ischemic cardiomyopathy remained significantly more likely to have an NT-proBNP ≥1,000 pg/ml at 12 months (odds ratio: 4.2; 95% confidence interval [CI]: 1.1 to 16.0; p = 0.04). A higher baseline NT-proBNP was also independently associated with the inability to achieve the NT-proBNP goal at 12 months (odds ratio: 2.5; 95% CI: 1.4 to 4.3; p = 0.002). There was no significant difference in baseline EF or LV volumes between achieved NT-proBNP groups (Table 4).
At 12 months, the median NT-proBNP in the goal-achieving group was 6-fold lower than the nongoal group: 424 (IQR: 180 to 650) pg/ml versus 2,669 (IQR: 1503 to 5184) pg/ml. Compared with those not achieving goal, patients achieving the NT-proBNP goal of <1,000 pg/ml at 12 months had significantly greater reverse LV remodeling (Figure 2). LV ESVi and EDVi were significantly more reduced among patients achieving the NT-proBNP goal than those who did not (Table 4). Correspondingly, patients achieving the NT-proBNP goal had an absolute increase in EF of 9.9 ± 8.8% compared with 2.9 ± 7.9% among those not reaching goal (p < 0.001). Global longitudinal strain was also significantly improved among patients achieving goal (−2.8 ± 3.3) compared with those who did not (−0.6 ± 3.0) (p = 0.003). There was significantly less moderate or severe mitral regurgitation among patients achieving NT-proBNP goal at 12 months: 5.8% versus 18.8%; p = 0.04. There was also a trend toward improved LV diastolic function and right heart function in patients achieving goal compared to those who did not.
NT-proBNP and reverse LV remodeling
At 12 months, NT-proBNP concentrations correlated with LV volumes and EF (Figure 3). Notably, locally estimated scatterplot smoothing curves showed a distinct inflection point at approximately 1,000 pg/ml at which the decreases in LV volumes and the increase in EF were greater below this threshold than above it (Online Figure 1). Transformation analyses determined that the optimal 12-month cutpoint for NT-proBNP was 1,028 pg/ml for EF, 941 pg/ml for ESVi, and 1,286 pg/ml for EDVi, thus approximating the prespecified NT-proBNP target goal of 1,000 pg/ml. These results were confirmed with 2-piece linear spline analyses that revealed significantly steeper slopes below the NT-proBNP cutpoints for LV volumes and EF than above (Figure 3).
Of importance, the extent of reverse LV remodeling correlated with changes in NT-proBNP. Linear spline regression modeling demonstrated that the greater the reduction in NT-proBNP, the more extensive the reverse LV remodeling. Specifically, an NT-proBNP decrease of 1,000 pg/ml corresponded to an absolute increase in EF of 6.7% and a reduction in ESVi and EDVi of 17.3 and 15.7 ml/m2, respectively (Figure 4).
The composite outcome of death or HF hospitalization after 12 months was not significantly different between treatment arms and occurred in 9 patients (13%) in the biomarker-guided group and 7 patients (12%) in the usual care group with KM rates of 20% (95% CI: 0.10 to 0.37) and 18% (95% CI: 0.09 to 0.36), respectively (p = 0.77). In contrast, patients achieving an NT-proBNP goal of <1,000 pg/ml at 12 months had substantially better clinical outcomes after 12 months. The composite endpoint of death or HF hospitalization after 12 months was significantly lower among patients achieving NT-proBNP goal (KM rate of 0%) compared with patients who did not achieve goal at 12 months (KM rate of 30%, 95% CI: 0.19 to 0.46); p < 0.001 (Table 5). Furthermore, median NT-proBNP concentrations after 12 months continued to decrease in the goal-achieving group compared to an increase in NT-proBNP among those patients who did not achieve goal: 310 (IQR: 134 to 654) pg/ml versus 3,038 (IQR: 1,382 to 4,711) pg/ml, respectively.
The GUIDE-IT Echo Substudy evaluated the impact of biomarker-guided therapy on cardiac structure and function compared with usual care among HFrEF patients. Reduction in LV volumes and improvement in EF were not significantly different between treatment strategies and, like the main GUIDE-IT trial, there was no difference in clinical outcomes between study arms. When evaluated by achievement of NT-proBNP goal <1,000 pg/ml at 12 months, however, irrespective of treatment strategy, those patients who attained the NT-proBNP goal had significantly greater reverse remodeling and better clinical outcomes than those not achieving goal. This study also demonstrated an important link between lowering NT-proBNP and improvements in cardiac structure and function such that a greater reduction in NT-proBNP over time was associated with more extensive reverse remodeling.
Previous studies have shown that biomarker-guided HF treatment is associated with better outcomes than usual care (2,16,17). In particular, the previously mentioned PROTECT study randomized 151 patients to receive NT-proBNP–guided therapy or usual HF care and found that, after a mean follow-up of 10 months, biomarker-guided therapy resulted in significantly lower NT-proBNP concentrations and reduced adverse events compared with usual care (2). Similarly, a meta-analysis of 11 trials showed a reduction in all-cause mortality with natriuretic peptide-guided therapy compared with usual care (hazard ratio: 0.62 [95% CI: 0.45 to 0.86]; p = 0.004) (17). One the basis of this foundational work, the GUIDE-IT trial was designed to be the largest study to compare biomarker-guided HF management with usual guideline-directed HF care in patients with HFrEF; however, unlike prior studies, the GUIDE-IT trial showed no difference in clinical outcomes between these treatment strategies (11).
The GUIDE-IT Echo Substudy may provide unique insight into the lack of treatment effect in the main GUIDE-IT trial and help explain the discrepant results when compared with prior studies. First, a similar degree of reverse LV remodeling, or more specifically, a similar reduction in LV volumes and increase in EF, was seen in the biomarker-guided and usual care arms. The extent to which clinical outcomes are influenced by LV recovery would be expectedly equivalent in both groups. Second, both treatment arms were on guideline-directed HF care, had frequent follow-up visits, and nearly equivalent reductions in NT-proBNP levels at 12 months; thus, it is not surprising that both treatment groups showed improvement in cardiac structure and function at 12 months. This could explain why clinical outcomes were also similar in the Echo Substudy and the main GUIDE-IT trial. Finally, the findings from the Echo Substudy suggest that perhaps it is not the treatment strategy, but the response to treatment as assessed by change in NT-proBNP that is important.
Patients with greater reductions in NT-proBNP at 12 months had more extensive improvement in LV structure and function and significantly fewer adverse outcomes regardless of treatment strategy. A similar association between lowering NT-proBNP and indices of reverse remodeling was demonstrated in the echocardiographic subgroup analysis of the PROTECT study (9). The GUIDE-IT Echo Substudy confirms these findings and is the first study to have sufficient power to quantitate the magnitude of change in NT-proBNP and correlate this with indices of reverse remodeling (i.e., for every decrease of 1,000 pg/ml in NT-proBNP there was an incremental increase in EF and corresponding reduction in indexed LV volumes). These results suggest that changes in NT-proBNP not only reflect the response to HF therapy, but can also serve as a noninvasive indicator of the dynamic state of cardiac structure and function in patients with HFrEF. Such knowledge may be leveraged to decide on the timing of echocardiography in patients with chronic HFrEF (18). It has been suggested that reassessment of LV size and function might not be necessary in the context of a low and stable NT-proBNP (4,9,19). The GUIDE-IT Echo Substudy supports such an approach, which is likely to be cost-effective and safe compared with routine monitoring.
In the GUIDE-IT Echo Substudy, patients with a nonischemic HF etiology were significantly more likely to achieve the NT-proBNP goal at 12 months and patients who achieved this goal had a greater propensity for reverse LV remodeling. In contrast, patients who failed to achieve the NT-proBNP goal were more likely to have coronary artery disease, atrial fibrillation, and renal dysfunction, and therefore constituted a sicker population. The failure to attain the NT-proBNP goal may be an epiphenomenon in which the primary issue is actually the greater burden of myocardial scarring and comorbidities that are limiting the extent of reverse remodeling and resulting in more adverse events. Further study is needed to assess the mechanisms underlying this differential response to therapy.
This study also provided mechanistic insight on the complex interplay among NT-proBNP change, reverse remodeling, and clinical outcomes. In the GUIDE-IT Echo Substudy, there was a mean decrease of 42 and 48 ml for EDV and ESV, respectively, among patients achieving the NT-proBNP goal compared with a mean decrease in EDV of 16 ml and ESV of 18 ml in those patients not achieving goal at 12 months. In a meta-analysis of drug- or device-related changes in LV volumes among patients with HFrEF (20), therapies that decreased EDV or ESV by a mean of 11 ml were associated with a 65% to 75% likelihood of favorable effects on mortality, with greater decreases portending better outcomes, as was seen in this study. Furthermore, achieving the NT-proBNP goal in the GUIDE-IT Echo Substudy was associated with a lack of adverse events in the follow-up period. Such a salubrious response was also reported in the PRIDE (NT-proBNP Investigation of Dyspnea in the Emergency Department) study, which also had a 0% death rate among patients with a NT-proBNP concentration <986 pg/ml, and thus was 1 of the original studies establishing 1,000 pg/ml as the NT-proBNP target (21). The GUIDE-IT Echo Substudy extends this work and supports the hypothesis that patients with HFrEF on optimized therapy who achieve the NT-proBNP goal of <1,000 pg/ml, can reverse the maladaptive remodeling associated with HF progression and reduce the incidence of adverse clinical events.
To our knowledge, the GUIDE-IT Echo Substudy is the largest study to definitively show that a reduction in NT-proBNP is associated with salutary changes in cardiac structure and function in patients with HFrEF. Specifically, these results suggest that the NT-proBNP concentration of 1,000 pg/ml is an optimal target for HF therapy because attainment of this goal is associated with significant reverse remodeling and improved clinical outcomes. Additionally, this is the first study to demonstrate the proportionality between NT-proBNP and reverse remodeling, such that a greater reduction in NT-proBNP corresponds to more extensive reverse remodeling.
This was a pre-specified, subgroup analyses of the GUIDE-IT Echo Substudy. The relatively small number of patients was a result of the GUIDE-IT trial early termination and the requirement for paired echocardiograms to assess for cardiac remodeling over time. For these reasons, quantitative analysis at baseline and 12 months was only available in approximately one-half of the substudy patients, yet nearly 80% power was maintained because of the low rate of unmeasurable echocardiograms in this study. The duration of NT-proBNP <1,000 pg/ml was not assessed in this study; however, the evaluation of whether reverse LV remodeling and improved outcomes is associated with duration below goal, specific pharmacologic therapies, and/or dose titrations is ongoing. Further study is needed to evaluate the exact mechanisms underlying both a decrease in NT-proBNP and reverse remodeling. It is speculated that a common mechanism may be decreased intracardiac pressures, decreased wall stress, and more efficient energy expenditure; however, additional studies with invasive monitoring and a pathologic correlate would be needed for confirmation, which may not be possible in this high-risk HFrEF population. Finally, there was only a small number of adverse events, likely because of the truncated trial duration; however, the profound difference in outcomes between patients achieving the NT-proBNP goal and those who did not supports that therapy aimed at attaining this target may significantly improve clinical outcomes among patients with HFrEF.
Whether patients with HFrEF in the GUIDE-IT Echo Substudy were treated with biomarker-guided HF therapy or usual care, changes in cardiac structure and function were similar and there was no significant difference in clinical outcomes. Lowering NT-proBNP to a goal <1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF, more extensive reductions in LV volumes, and markedly reduced adverse events compared with those not achieving goal at 12 months. The improved outcomes associated with achieving the NT-proBNP goal may be explained, in part, by reverse LV remodeling.
COMPETENCY IN MEDICAL KNOWLEDGE: The greater the reduction in NT-proBNP with HF treatment, the more extensive the improvement in LV structure and function in patients with HFrEF. Among patients with HFrEF, HF treatment that results in lowering NT-proBNP to <1,000 pg/ml at 1 year is associated with reverse remodeling and improved clinical outcomes.
TRANSLATIONAL OUTLOOK: Patients with a nonischemic cardiomyopathy are more likely to achieve a NT-proBNP goal <1,000 pg/ml at 1 year than patients with an ischemic cardiomyopathy. Further study is needed to assess the mechanisms underlying this differential response to therapy.
Duke Clinical Research Institute was the recipient of research grants from Roche Diagnostics. The GUIDE-IT Trial was funded by the National Heart, Lung, and Blood Institute. The GUIDE-IT Echo Substudy was funded by Roche Diagnostics. Dr. Daubert has received grant support from Roche Diagnostics. Dr. Douglas has received grant support from the National Institutes of Health. Drs. Cooper, Leifer, and Desvigne-Nickens are faculty of the National Heart, Lung, and Blood Institute; and were members of the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment Steering Committee. Drs. Adams, Anstrom, Fiuzat, O’Connor, Mark, Januzzi, and Felker have received grant support from the National Institutes of Health and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Barry Greenberg, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- confidence interval
- end-diastolic volume index
- end-systolic volume index
- heart failure
- heart failure with reduced ejection fraction
- interquartile range
- left ventricle
- amino-terminal pro-B-type natriuretic peptide
- Received July 27, 2018.
- Revision received October 5, 2018.
- Accepted October 12, 2018.
- 2019 American College of Cardiology Foundation
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- Januzzi J.L. Jr..,
- Rehman S.U.,
- Mohammed A.A.,
- et al.
- Fonarow G.C.,
- Peacock W.F.,
- Phillips C.O.,
- et al.
- Cleland J.G.,
- McMurray J.J.,
- Kjekshus J.,
- et al.
- Anand I.S.,
- Fisher L.D.,
- Chiang Y.T.,
- et al.
- Bettencourt P.,
- Azevedo A.,
- Pimenta J.,
- Frioes F.,
- Ferreira S.,
- Ferreira A.
- Masson S.,
- Latini R.,
- Anand I.S.,
- et al.
- Weiner R.B.,
- Baggish A.L.,
- Chen-Tournoux A.,
- et al.
- Felker G.M.,
- Ahmad T.,
- Anstrom K.J.,
- et al.
- Felker G.M.,
- Anstrom K.J.,
- Adams K.F.,
- et al.
- Nagueh S.F.,
- Smiseth O.A.,
- Appleton C.P.,
- et al.
- Berger R.,
- Moertl D.,
- Peter S.,
- et al.
- Yancy C.W.,
- Januzzi J.L. Jr..,
- Allen L.A.,
- et al.
- Kramer D.G.,
- Trikalinos T.A.,
- Kent D.M.,
- Antonopoulos G.V.,
- Konstam M.A.,
- Udelson J.E.