Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.

IMPORTANCE: Prevention strategies for heart failure are needed. OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years). INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service. MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002). CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960.

B-type natriuretic peptide measurement in primary care; magnitude of associations with cardiovascular risk factors and their therapies. Observations from the STOP-HF (St. Vincent's Screening TO Prevent Heart Failure) study.

BACKGROUND: An effective prevention strategy for heart failure in primary care requires a reliable screening tool for asymptomatic ventricular dysfunction. Preliminary data indicate that B-type natriuretic peptide (BNP) may be suitable for this task. However, for the most effective use of this peptide, the interrelationships between associated risk factors and their therapies on BNP, and in particular their magnitude of effect, needs to be established in a large primary care population. Therefore, the objective of the study was to establish the extent of the association between BNP, cardiovascular risk factors and their therapies. METHODS: BNP measurement and clinical review was preformed on 1122 primary care patients with cardiovascular risk factors. Multivariate analyses identified significant associates of BNP concentrations which were further explored to establish the magnitude of their association. RESULTS: Associates of BNP were age (1.36-fold increase in BNP/decade), female (1.28), ß-blockers (1.90), myocardial infarction (1.36), arrhythmia (1.98), diastolic blood pressure; all p<0.01. A novel method was devised that plotted median BNP per sliding decade of age for the various combinations of these principal associates. CONCLUSIONS: The data presented underline the importance of considering several clinical and therapeutic factors when interpreting BNP concentrations. Most of these variables were associated with increased concentrations, which may in part explain the observed false-positive rates for detecting ventricular dysfunction using this peptide. Furthermore, the design of studies or protocols using BNP as an endpoint or a clinical tool should take particular account of these associations. This analysis provides the foundation for age, risk factor and therapy adjusted reference ranges for BNP in this setting.

Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover.

AIMS: Heart failure with preserved ejection fraction (HF-PEF) can be difficult to diagnose in clinical practice. Myocardial fibrosis is a major determinant of diastolic dysfunction (DD), potentially contributing to the progression of HF-PEF. The aim of this study was to analyse whether serological markers of collagen turnover may predict HF-PEF and DD. METHODS AND RESULTS: We included 85 Caucasian treated hypertensive patients (DD n=65; both DD and HF-PEF n=32). Serum carboxy (PICP), amino (PINP), and carboxytelo (CITP) peptides of procollagen type I, amino (PIIINP) peptide of procollagen type III, matrix metalloproteinases (MMP-1, MMP-2, and MMP-9), and tissue inhibitor of MMP levels were assayed. Using receiver operating characteristic curve analysis, MMP-2 (AUC=0.91; 95% CI: 0.84, 0.98), CITP (0.83; 0.72, 0.92), PICP (0.82; 0.72, 0.92), B-type natriuretic peptide (BNP) (0.82; 0.73, 0.91), MMP-9 (0.79; 0.68, 0.89), and PIIINP (0.78; 0.66, 0.89) levels were significant predictors of HF-PEF (P<0.01 for all). Carboxytelo peptides of procollagen type I (AUC=0.74; 95% CI: 0.62, 0.86), MMP-2 (0.73; 0.62, 0.84), PIIINP (0.73; 0.60, 0.85), BNP (0.69; 0.55, 0.83) and PICP (0.66; 0.54, 0.78) levels were significant predictors of DD (P<0.05 for all). A cutoff of 1585 ng/mL for MMP-2 provided 91% sensitivity and 76% specificity for predicting HF-PEF and combinations of biomarkers could be used to adjust either sensitivity or specificity. CONCLUSION: Markers of collagen turnover identify patients with HF-PEF and DD. Matrix metalloproteinase 2 may be more useful than BNP in the identification of HF-PEF. This suggests that these new biochemical tools may assist in identifying patients with these diagnostically challenging conditions.

Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction.

BACKGROUND: The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, which compromises filling. The present study investigates collagen metabolism in hypertensive patients in different phases of diastolic function with and without proven DHF. METHODS AND RESULTS: We studied 86 hypertensive patients divided into groups according to the presence of DHF (32 with, 54 without) and phase of diastolic function (20 with normal function, 38 with impaired relaxation, 10 with pseudonormalization, and 16 with restrictive-like filling). Serum carboxy-terminal, amino-terminal, and carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, matrix metalloproteinases (MMPs; total MMP-1, active MMP-2, and MMP-9), and tissue inhibitor of MMPs levels were assayed by radioimmunoassay and ELISA. Doppler-echocardiographic assessment of diastolic filling was made with measurements of E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Serum carboxy-terminal telopeptide of procollagen type I, carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 levels (P<0.001 for all, controlled for age and gender) were greater in patients with DHF than in those without. When we controlled for age and gender, levels of serum carboxy-terminal telopeptide of procollagen type I, tissue inhibitor of MMP-1, amino-terminal propeptide of procollagen type III (all P<0.001), carboxy-terminal telopeptide of procollagen type I (P=0.008), and MMP-2 (P=0.03) were greater in more severe phases of diastolic dysfunction. Within phases of diastolic dysfunction, serum carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 were elevated in those with DHF compared with those without DHF (all P<0.001). CONCLUSIONS: These data demonstrate serological evidence of an active fibrotic process in DHF, which is more marked in more severe diastolic dysfunction. This observation may help explain the pathophysiology of DHF and may suggest new avenues for diagnostic and therapeutic intervention.

Multiple neurohumoral modulating agents in systolic dysfunction heart failure: are we lowering blood pressure too much?

BACKGROUND: Disease-modifying drug treatment in heart failure (HF) reduces blood pressure. Titration of these agents is guided by clinic blood pressure readings; however, the impact of such treatment on blood pressure is unknown because diurnal blood pressure patterns remain poorly described. The aim of this study was to examine the impact of additional neurohumoral modulating agents on ambulatory blood pressure monitoring (ABPM) control in patients with systolic HF and examine the relationship between the burden of hypotension and clinical outcomes. METHODS AND RESULTS: In a prospective analysis on 45 patients undergoing initiation and optimization of additional medications (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or beta-blockers), mean daytime systolic (P = .035) and mean daytime and nocturnal diastolic hypotensive episodes (both P < .001) increased significantly posttitration. There was no change in clinic blood pressure before and after titration. In a cross-sectional analysis on 144 patients, those with the most diastolic hypotensive episodes had higher rates of HF readmissions (P = .01) and the composite end point of all-cause mortality and all-cause readmissions (P = .03). CONCLUSIONS: Additional neurohumoral modulating agents could produce significant increases in 24-hour hypotension burden despite reassuring clinic blood pressure readings. The burden of diastolic hypotension is independently predictive of HF readmissions and the composite end point of all-cause mortality and emergency readmissions.

Need and evolution of need for device therapy in a community heart failure population.

BACKGROUND: New guidelines for implantable cardiac defibrillators (ICD) and cardiac resynchronisation therapy (CRT) have expanded the potential use for device therapy. The implications of this on a community heart failure (HF) population are unknown. AIM: To assess the need for device therapy and the change in need over time. METHODS: We reviewed device need in a community HF population using ESC guidelines. Change in need was assessed by comparing data between an annual visit called TP2 and an earlier visit called TP1. Patients' need and change in need between TP1 and TP2 was determined. RESULTS: 210 patients were included; mean age 70+/-12 years, 67% male and 54% ischaemic. At TP1, 34% of patients were suitable for ICD and 3% for CRT. At TP2, 22% and 1% were suitable respectively. Of those suitable for ICD at TP1, 19% lost the need at TP2; in addition 9% of patients unsuitable for ICD at TP1 had acquired the need by TP2. Fifty five percent of patients were unsuitable for ICD at either time point, and 16% were suitable at both time points. CRT need was negligible but also noted to change. CONCLUSION: ICD need is substantial in a community HF population, but CRT need is limited. ICD need changes significantly. Identifying those likely to change their need may optimise ICD use.

Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability.

BACKGROUND: To examine the clinical effect of fluid restriction in patients admitted to the hospital with class IV heart failure (HF). METHODS AND RESULTS: This is a single-blind randomized controlled study. Time to clinical stability was compared between the fluid restricted (FR: n = 34) and free fluid (FF: n = 33) groups respectively showing no significant difference (8.3 +/- 6.3 days versus 7.0 +/- 6.0 days, P = .17). There was no significant difference between groups in time to discontinuation of intravenous diuretic therapy (FR: 2.7 +/- 4.5 days, FF: 3.2 +/- 5.6 days, P = .70). Changes from baseline to achievement of clinical stability in serum urea (P = .23), serum creatinine (P = .14), BNP (P = .42), and sodium (P = .14) did not differ between the FF and FR groups. Baseline serum sodium levels did not predict the time to clinical stability (beta = -0.11, 95% CI: -0.60, 0.23). CONCLUSIONS: Fluid restriction is not an evidence-based therapy although it is occasionally applied in the management of HF. These results suggest that FR is not of any clinical benefit in patients with acute decompensated HF and this hypothesis should be tested in a larger randomized controlled study.

The biologic variability of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in stable heart failure patients.

BACKGROUND: There are conflicting data on the usefulness of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in the optimization of therapy for heart failure (HF). Discordant results may be explained by the intra-individual variability of these peptides. This study evaluates the intraindividual variability of BNP and NT-proBNP and the impact of the covariates of age, sex, and renal function. METHODS AND RESULTS: Stable HF patients attending our unit were included. Blood samples were drawn 1 hour apart on 2 occasions 1 week apart. Forty-five patients were enrolled (69.6 +/- 12.1 years, 64% male, 84% systolic HF). Within-hour and within-week intraindividual variability were: 6.9% and 21.1% for NT-proBNP; 14.6% and 28.4% for BNP (P < .01 for within-hour comparison of BNP and NT-proBNP). Reference change values over 1 week for NT-proBNP and BNP were 49.2% and 66.2%, respectively. There were no significant relationships identified between variability and age, gender, or glomerular filtration rate. CONCLUSION: There is considerable intraindividual variability in these peptides in stable HF patients. Changes of approximately 50% and 66% for NT-proBNP and BNP from week to week are needed to indicate an altered clinical status and caution should be exercised in interpreting serial changes in these peptide levels when monitoring patient responses to treatment or clinical status.

Disease management programs for heart failure: not just for the 'sick' heart failure population.

The development of disease management programs has been a major advance in heart failure care, bringing about significant improvements for the heart failure population, with reduction in readmission, better use of guideline therapy and improved survival. However, at present, the majority of such programs focus their attention only on the sicker segment of this population, with little application of this important service to the broader heart failure population, where potentially benefits may be even more impressive. This has led to an imbalance in the care of patients with heart failure, where aspects of management such as regular structured review and education are preferentially given to the group at the later stages of the natural history of the syndrome. This paper argues for a far wider application of the disease management program concept in heart failure care so as to bring the benefits of specialist care, patient education and follow-up to patients at an earlier stage in the natural history of heart failure.

Progression of left atrial volume index in a population at risk for heart failure: a substudy of the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) trial.

AIMS: Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre-heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation. METHODS AND RESULTS: This was a prospective substudy within the framework of the STOP-HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow-up time between assessments was 15 ± 6 months. 'Progressors' (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m(2) (and baseline LAVI between 20 and 34 mL/m(2)). This cut-off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta-blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 'Progressors' matched to 30 'Non-progressors'. For 'Progressors', relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05). CONCLUSION: Accelerated LAVI increase was found to occur in up to 14% of all pre-HF patients undergoing serial echocardiograms over a relatively short follow-up period. In a randomly selected subcohort of 'Progressors', changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at-risk group.

Quality of life predicts outcome in a heart failure disease management program.

BACKGROUND: Chronic heart failure (HF) is associated with a poor Health Related Quality of Life (HRQoL). HRQoL has been shown to be a predictor of HF outcomes however, variability in the study designs make it difficult to apply these findings to a clinical setting. The aim of this study was to establish if HRQoL is a predictor of long-term mortality and morbidity in HF patients followed-up in a disease management program (DMP) and if a HRQoL instrument could be applied to aid in identifying high-risk patients within a clinical context. METHODS: This is a retrospective analysis of HF patients attending a DMP with 18+/-9 months follow-up. Clinical and biochemical parameters were recorded on discharge from index HF admission and HRQoL measures were recorded at 2 weeks post index admission. RESULTS: 225 patients were enrolled into the study (mean age=69+/-12 years, male=61%, and 78%=systolic HF). In multivariable analysis, all dimensions of HRQoL (measured by the Minnesota Living with HF Questionnaire) were independent predictors of both mortality and readmissions particularly in patients <80 years. A significant interaction between HRQoL and age (Total((HRQoL))age: p<0.001) indicated that the association of HRQoL with outcomes diminished as age increased. CONCLUSIONS: These data demonstrate that HRQoL is a predictor of outcome in HF patients managed in a DMP. Younger patients (<65 years) with a Total HRQoL score of > or =50 are at high risk of an adverse outcome. In older patients > or =80 years HRQoL is not useful in predicting outcome.

Causes and consequences of nonpersistence with heart failure medication.

Persistence with therapy may be more easily and objectively identified in the clinical setting than compliance and recent work has shown it to be linked to mortality in heart failure (HF). The aim of this study was to determine the extent, causes, and clinical impact of nonpersistence with disease-modifying therapy in a retrospective cohort study of 183 patients with systolic HF participating in a disease management program. The main outcome measurements were reasons/determinants of nonpersistence and its impact on hospitalizations. Fifty-three patients (29%) had 74 separate occurrences of nonpersistence with disease-modifying therapy. There was no medical reason for discontinuing medications in 50% of occurrences, whereas medication was discontinued for an adverse reaction in 30% and for a justified medical reason in 15% of occurrences. Nonpersistence was a significant predictor of all-cause readmission (hazard ratio 3.20, 95% confidence interval 1.74 to 11.37) and cardiovascular readmission (hazard ratio 4.45, 95% confidence interval 1.74 to 11.37). In the adjusted model, there was no significantly increased risk of HF readmission (hazard ratio 2.41, 95% confidence interval 0.88 to 6.62). In conclusion, nonpersistence with HF therapy is common, is often not medically justified, and is associated with an increased risk of hospitalization.