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Characterization and prediction of natriuretic peptide "nonresponse" during heart failure management: results from the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) and the NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) study

Gaggin, Hanna K; Truong, Quynh A; Rehman, Shafiq U; Mohammed, Asim A; Bhardwaj, Anju; Parks, Kimberly A; Sullivan, Dorothy A; Chen-Tournoux, Annabel; Moore, Stephanie A; Richards, A Mark; Troughton, Richard W; Lainchbury, John G; Weiner, Rory B; Baggish, Aaron L; Semigran, Marc J; Januzzi, James L
Many proven heart failure (HF) therapies decrease N-terminal pro B-type natriuretic peptide (NT-proBNP) values over time, yet some patients have an NT-proBNP >1000 pg/mL following treatment, which is associated with poor outcomes. A total of 151 patients with left ventricular systolic dysfunction were treated with aggressive HF therapy in the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study. Clinical characteristics and NT-proBNP were measured at each visit during 10 months. In this post hoc analysis, biomarker nonresponse was defined as an NT-proBNP >1000 pg/mL and its relationship with echocardiographic and clinical characteristics and outcomes were explored. A risk model predictive of nonresponse was derived and externally validated. A rising NT-proBNP over time was associated with increased cardiovascular event rates while a decreasing NT-proBNP was associated with better clinical outcomes (58.2% vs 27.6%, P=.001). A higher percentage of time in biomarker response was associated with lower event rates (P<.001). Importantly, responders showed improved left ventricular remodeling parameters (all P<.001), while nonresponders did not. A risk model for predicting nonresponse had a C statistic of 0.82 (P<.001) and predicted outcomes well. Using data from the NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) cohort, the risk score was validated for its ability to predict nonresponse (C statistic 0.73, P<.001). Serial changes in NT-proBNP inform risk for adverse outcome and are associated with prognostically meaningful metrics. Prediction of future NT-proBNP nonresponse to HF therapy is possible.
PMID: 23279139
ISSN: 1751-7133
CID: 4293502

Improvement in structural and functional echocardiographic parameters during chronic heart failure therapy guided by natriuretic peptides: mechanistic insights from the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study

Weiner, Rory B; Baggish, Aaron L; Chen-Tournoux, Annabel; Marshall, Jane E; Gaggin, Hanna K; Bhardwaj, Anju; Mohammed, Asim A; Rehman, Shafiq U; Barajas, Linda; Barajas, Justine; Gregory, Shawn A; Moore, Stephanie A; Semigran, Marc J; Januzzi, James L
AIMS/OBJECTIVE:We sought to determine if heart failure (HF) care with a goal to lower N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations, compared with standard of care (SOC) management, is associated with improvement in echocardiographic parameters of cardiac structure and function. METHODS AND RESULTS/RESULTS:Of 151 subjects with HF due to left ventricular systolic dysfunction (LVSD) prospectively randomized to NT-proBNP-guided vs. SOC HF care, 116 had serial echocardiographic data. Endpoints in this echocardiographic study included the relationship between change in NT-proBNP and LV reverse remodelling, as well as associations between biomarker-guided therapy and measures of diastolic function, right ventricular (RV) size and function, estimates of LV filling pressure and RV systolic pressure (RVSP), and the degree of mitral regurgitation (MR). After a mean of 10 months of study procedures, in adjusted analyses, final NT-proBNP concentrations predicted risk of remodelling [hazard ratio (HR) ↑LV end-diastolic volume index = 1.43, 95% confidence interval (CI) 1.10-1.86, P = 0.007; HR ↑LV end-systolic volume index = 1.54, 95% CI 1.10-1.91, P = 0.01; HR ↓LV ejection fraction (LVEF) = 1.53, 905% CI 1.12-1.89, P = 0.02]. In addition to greater improvement in LVEF and reductions in LV volume, compared with SOC, NT-proBNP-guided patients showed significant decreases in the ratio of early transmitral peak velocity to early diastolic peak annular velocity (E/E'), pulmonary vein peak S velocity, RV fractional area change, RVSP, and MR severity. CONCLUSION/CONCLUSIONS:NT-proBNP concentrations may serve as a non-invasive indicator of the state of cardiac structure and function in HF due to LVSD. Multiple, prognostically meaningful echocardiographic variables improved more significantly in patients treated with NT-proBNP-guided care vs. SOC.
PMID: 23132825
ISSN: 1879-0844
CID: 4293482

Quality of life and chronic heart failure therapy guided by natriuretic peptides: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study

Bhardwaj, Anju; Rehman, Shafiq U; Mohammed, Asim A; Gaggin, Hanna K; Barajas, Linda; Barajas, Justine; Moore, Stephanie A; Sullivan, Dorothy; Januzzi, James L
BACKGROUND:Heart failure (HF) treatment guided by amino-terminal pro-B type natriuretic peptide (NT-proBNP) may reduce cardiovascular event rates compared to standard-of-care (SOC) management. Comprehensive understanding regarding effect of NT-proBNP guided care on patient-reported quality of life (QOL) remains unknown. METHODS:One hundred fifty-one subjects with HF due to left ventricular systolic dysfunction were randomized to either SOC HF management or care with a goal to reduce NT-proBNP values ≤1000 pg/mL. Effects of HF on QOL were assessed using the Minnesota Living with HF Questionnaire (MLHFQ) quarterly, with change (Δ) in score assessed across study procedures and as a function of outcome. RESULTS:Overall, baseline MLHFQ score was 30. Across study visits, QOL improved in both arms, but was more improved and sustained in the NT-proBNP arm (repeated measures P = .01); NT-proBNP patients showing greater reduction in MLHFQ score (-10.0 vs -5.0; P = .05), particularly in the physical scale of the questionnaire. Baseline MLHFQ scores did not correlate with NT-proBNP; in contrast, ∆MLHFQ scores modestly correlated with ∆NT-proBNP values (ρ = .234; P = .006) as did relative ∆ in MLHFQ score and NT-proBNP (ρ = .253; P = .003). Considered in tertiles, less improvement in MLHFQ scores was associated with a higher rate of HF hospitalization, worsening HF, and cardiovascular death (P = .001). CONCLUSIONS:We describe novel associations between NT-proBNP concentrations and QOL scores among patients treated with biomarker guided care. Compared to SOC HF management, NT-proBNP guided care was associated with greater and more sustained improvement in QOL (Clinical Trial Registration: www.clinicaltrials.govNCT00351390).
PMID: 23137512
ISSN: 1097-6744
CID: 4293492

Heart failure outcomes and benefits of NT-proBNP-guided management in the elderly: results from the prospective, randomized ProBNP outpatient tailored chronic heart failure therapy (PROTECT) study

Gaggin, Hanna K; Mohammed, Asim A; Bhardwaj, Anju; Rehman, Shafiq U; Gregory, Shawn A; Weiner, Rory B; Baggish, Aaron L; Moore, Stephanie A; Semigran, Marc J; Januzzi, James L
BACKGROUND:Elderly patients with heart failure (HF) have a worse prognosis than younger patients. We wished to study whether elders benefit from natriuretic peptide-guided HF care in this single-center study. METHODS AND RESULTS/RESULTS:A total of 151 patients with HF resulting from left ventricular systolic dysfunction (LVSD) were treated with HF treatment by standard-of-care (SOC) management or guided by N-terminal pro-B type natriuretic peptide (NT-proBNP) values (with a goal to lower NT-proBNP ≤1000 pg/mL) over 10 months. The primary end point for this post-hoc analysis was total cardiovascular events in 2 age categories (<75 and ≥75 years). In those ≥75 years of age (n = 38), NT-proBNP values increased in the SOC arm (2570 to 3523 pg/mL, P = .01), but decreased in the NT-proBNP-guided arm (2664 to 1418 pg/mL, P = .001). Elderly patients treated with SOC management had the highest rate of cardiovascular events, whereas the elderly with NT-proBNP management had the lowest rate of cardiovascular events (1.76 events per patient versus 0.71 events per patient, P = .03); the adjusted logistic odds for cardiovascular events related to NT-proBNP-guided care for elders was 0.24 (P = .008), whereas in those <75 years (n = 113), the adjusted logistic odds for events following NT-proBNP-guided care was 0.61 (P = .10). CONCLUSIONS:Natriuretic peptide-guided HF care was well tolerated and resulted in substantial improvement in cardiovascular event rates in elders (ClinicalTrials.Gov #00351390).
PMID: 22858078
ISSN: 1532-8414
CID: 4293472

Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction

Januzzi, James L; Rehman, Shafiq U; Mohammed, Asim A; Bhardwaj, Anju; Barajas, Linda; Barajas, Justine; Kim, Han-Na; Baggish, Aaron L; Weiner, Rory B; Chen-Tournoux, Annabel; Marshall, Jane E; Moore, Stephanie A; Carlson, William D; Lewis, Gregory D; Shin, Jordan; Sullivan, Dorothy; Parks, Kimberly; Wang, Thomas J; Gregory, Shawn A; Uthamalingam, Shanmugam; Semigran, Marc J
OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate whether chronic heart failure (HF) therapy guided by concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is superior to standard of care (SOC) management. BACKGROUND:It is unclear whether standard HF treatment plus a goal of reducing NT-proBNP concentrations improves outcomes compared with standard management alone. METHODS:In a prospective single-center trial, 151 subjects with HF due to left ventricular (LV) systolic dysfunction were randomized to receive either standard HF care plus a goal to reduce NT-proBNP concentrations ≤1,000 pg/ml or SOC management. The primary endpoint was total cardiovascular events between groups compared using generalized estimating equations. Secondary endpoints included effects of NT-proBNP-guided care on patient quality of life as well as cardiac structure and function, assessed with echocardiography. RESULTS:Through a mean follow-up period of 10 ± 3 months, a significant reduction in the primary endpoint of total cardiovascular events was seen in the NT-proBNP arm compared with SOC (58 events vs. 100 events, p = 0.009; logistic odds for events 0.44, p = 0.02); Kaplan-Meier curves demonstrated significant differences in time to first event, favoring NT-proBNP-guided care (p = 0.03). No age interaction was found, with elderly patients benefitting similarly from NT-proBNP-guided care as younger subjects. Compared with SOC, NT-proBNP-guided patients had greater improvements in quality of life, demonstrated greater relative improvements in LV ejection fraction, and had more significant improvements in both LV end-systolic and -diastolic volume indexes. CONCLUSIONS:In patients with HF due to LV systolic dysfunction, NT-proBNP-guided therapy was superior to SOC, with reduced event rates, improved quality of life, and favorable effects on cardiac remodeling. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting; NCT00351390).
PMID: 22018299
ISSN: 1558-3597
CID: 4293462

The accuracy of the electrocardiogram during exercise stress test based on heart size

Siegler, Jason C; Rehman, Shafiq; Bhumireddy, Geetha P; Abdula, Raushan; Klem, Igor; Brener, Sorin J; Lee, Leonard; Dunbar, Christopher C; Saul, Barry; Sacchi, Terrence J; Heitner, John F
BACKGROUND:Multiple studies have shown that the exercise electrocardiogram (ECG) is less accurate for predicting ischemia, especially in women, and there is additional evidence to suggest that heart size may affect its diagnostic accuracy. HYPOTHESIS/OBJECTIVE:The purpose of this investigation was to assess the diagnostic accuracy of the exercise ECG based on heart size. METHODS:We evaluated 1,011 consecutive patients who were referred for an exercise nuclear stress test. Patients were divided into two groups: small heart size defined as left ventricular end diastolic volume (LVEDV) <65 mL (Group A) and normal heart size defined as LVEDV ≥65 mL (Group B) and associations between ECG outcome (false positive vs. no false positive) and heart size (small vs. normal) were analyzed using the Chi square test for independence, with a Yates continuity correction. LVEDV calculations were performed via a computer-processing algorithm. SPECT myocardial perfusion imaging was used as the gold standard for the presence of coronary artery disease (CAD). RESULTS:Small heart size was found in 142 patients, 123 female and 19 male patients. There was a significant association between ECG outcome and heart size (χ(2) = 4.7, p = 0.03), where smaller hearts were associated with a significantly greater number of false positives. CONCLUSIONS:This study suggests a possible explanation for the poor diagnostic accuracy of exercise stress testing, especially in women, as the overwhelming majority of patients with small heart size were women.
PMID: 21857990
ISSN: 1932-6203
CID: 4777432

Design and methods of the Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study

Bhardwaj, Anju; Rehman, Shafiq U; Mohammed, Asim; Baggish, Aaron L; Moore, Stephanie A; Januzzi, James L
BACKGROUND:Serial measurements of N-terminal pro-B type natriuretic peptide (NT-proBNP) provide prognostic information in patients with chronic heart failure (HF). Changes in NT-proBNP concentrations parallel prognosis; however, it remains unclear whether HF care with a goal to maximize medical therapy and also lower NT-proBNP concentrations is superior to standard HF care alone. AIMS/OBJECTIVE:The aim of the study was to evaluate the hypothesis that an HF strategy guided by NT-proBNP reduces cardiovascular events compared to standard of care HF management. METHODS:In a prospective randomized single-center trial, subjects with New York Heart Association class II to IV systolic HF (left ventricular ejection fraction < or =40%) will be enrolled. Both groups will receive standard HF management (with a goal for minimizing HF symptoms and achieving maximal dosages of therapies with proven mortality benefit in HF), whereas one group ("NT-proBNP") will also have treatment adjustments to reduce NT-proBNP concentrations < or =1,000 pg/mL. The primary end point of the trial is total cardiovascular events for a 1-year period; secondary end points will include effects of NT-proBNP-guided care on cardiac structure and function, quality of life, and total costs of care. RESULTS:Enrollment began in 2006; of the original 300 planned, thus far, 151 subjects have been randomized. Interim analysis in November 2009 indicated significant reduction of events in the NT-proBNP arm. Full results are expected in 2010. CONCLUSIONS:The Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study will test the hypothesis that therapy guided by NT-proBNP concentrations will be superior to standard of care HF management ( identifier NCT00351390).
PMID: 20362709
ISSN: 1097-6744
CID: 4293452

Relative value of amino-terminal pro-B-type natriuretic peptide testing and radiographic standards for the diagnostic evaluation of heart failure in acutely dyspneic subjects

Martinez-Rumayor, Abelardo A; Vazquez, Josue; Rehman, Shafiq U; Januzzi, James L
To define more clearly the relationship between the information provided by the chest radiograph (CXR) and the natriuretic peptide (NT-proBNP) test as part of the evaluation of dyspneic patients presenting to the emergency department with suspected acute heart failure (HF), we evaluated the PRIDE cohort of 599 patients with and without HF, focusing on blinded NT-proBNP and unblinded CXR information. Clinical characteristics and diagnostic performance for each test were compared. We found that NT-proBNP measurement is superior to routine CXR interpretation for diagnosis or exclusion of acute HF and that normal CXR results should not be used to exclude HF in this population.
PMID: 19911943
ISSN: 1366-5804
CID: 4293432

Natriuretic Peptide testing in primary care

Rehman, Shafiq U; Januzzi, James L
The incidence, as well as the morbidity and mortality associated with heart failure (HF) continue to rise despite advances in diagnostics and therapeutics. A recent advance in the diagnostic and therapeutic approach to HF is the use of natriuretic peptide (NP) testing, including both B-type natriuretic peptide (BNP) and its amino terminal cleavage equivalent (NT-proBNP). NPs may be elevated at an early stage among those with symptoms as well among those without. The optimal approach for applying NP testing in general populations is to select the target population and optimal cut off values carefully. Superior diagnostic performance is observed among those with higher baseline risk (such as hypertensives or diabetics). As well, unlike for acute HF, the cut off value for outpatient testing for BNP is 20-40 pg/mL and for NTproBNP it is 100-150 ng/L. In symptomatic primary care patients, both BNP and NT-proBNP serve as excellent tools for excluding HF based on their excellent negative predictive values and their use may be cost effective. Among those with established HF, it is logical to assume that titration of treatment to achieve lower NPs levels may be advantageous. There are several ongoing trials looking at that prospect.
PMID: 20066138
ISSN: 1875-6557
CID: 4293442

Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure

Rehman, Shafiq U; Mueller, Thomas; Januzzi, James L
OBJECTIVES/OBJECTIVE:The purpose of this study was to examine the patient-specific characteristics of the interleukin-1 receptor family member ST2 in patients with acute heart failure (HF). BACKGROUND:ST2 signaling is involved in the process of cardiac fibrosis and hypertrophy. METHODS:In all, 346 patients with acute HF had ST2 measured. Associations between ST2 and demographics, severity/type of HF, and other biomarkers were examined. Receiver-operator characteristic curves and multivariable Cox proportional hazards analyses evaluated the prognostic ability of ST2. RESULTS:The ST2 values correlated with the severity of HF (p < 0.001), left ventricular ejection fraction (r = -0.134; p = 0.014), creatinine clearance (r = -0.224; p < 0.001), B-type natriuretic peptide (r = 0.293; p < 0.001), amino terminal B-type natriuretic peptide (r = 0.413; p < 0.001), and C-reactive protein (r = 0.429; p < 0.001). ST2 was not associated with age, prior HF, or body mass index. The ST2 levels at presentation were higher among patients who died by 1 year. The area under the receiver-operator characteristic for death at 1 year was 0.71 (p < 0.001). In a multivariable Cox model containing established clinical and biochemical predictors (including natriuretic peptides), ST2 remained a predictor of mortality (hazard ratio: 2.04, 95% confidence interval: 1.30 to 3.24, p = 0.003), and was equally predictive in patients with HF and preserved or impaired systolic function. When both ST2 and natriuretic peptides were elevated, the highest rates of death were observed in cumulative hazard analysis (p < 0.001). In the presence of a low ST2 level, natriuretic peptides did not predict mortality. CONCLUSIONS:Consistent with its proposed role in a myocardial-specific response to stretch, ST2 has strong clinical and biochemical correlates in patients with acute HF. Prognostically, ST2 is powerful in acute HF and is synergistic with natriuretic peptides for this use.
PMID: 19017513
ISSN: 1558-3597
CID: 4293422